



THE ONLY PPI WITH A 2ND RELEASE FOR MAINTAINED RELIEF2,3
• the MOST POWERFUL inhibitory effect on the proton pump of ALL available PPIs.4
• TRUE once-daily dosing.5
References: 1. South African Medicine Price Registry. Database of Medicine Prices, 01 November 2023 [online]. [cited November 2023]; Available from URL: http://www.mpr.gov.za/. 2. Monthly Index of Medical Specialities. September 2023;63(No. 8):185-191. 3. Metz DC, Howden CW, Perez MC, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther. 2009;29(7):742-54. doi: 10.1111/j.1365-2036.2009.03954.x. 4. Gąsiorowska A. The role of pH in symptomatic relief and effective treatment of gastroesophageal reflux disease. Prz Gastroenterol. 2017;12(4):244249. doi: 10.5114/pg.2017.72097. 5. Frye JW, Peura DA. Managing gastroesophageal reflux disease - comparative efficacy and outcomes of dexlansoprazole MR. Ther Clin Risk Manag 2015;11:1649-56. doi: 10.2147/TCRM.S66680. 6. Dexilant Professional Information. Takeda (Pty) Ltd, South Africa; August 2021. 7. Sharma P, Shaheen NJ, Perez MC, et al Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation--results from two randomized controlled studies. Aliment Pharmacol Ther 2009;29(7):731-41. doi: 10.1111/j.1365-2036.2009.03933.x. 8. Fass R, Chey WD, Zakko SF, et al. Clinical trial: the effects of the proton pump inhibitor dexlansoprazole MR on daytime and nighttime heartburn in patients with non-erosive reflux disease. Aliment Pharmacol Ther. 2009;29(12):1261-72. doi: 10.1111/j.1365-2036.2009.04013.x.
domino effect of hypertension
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Corralling the ‘pink eye’ pandemonium in kids 55 Tiny ears, big drama 59 Bouncing off the walls: ADHD in kids and teens
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Welcome to 2025! As we step into a new year, we are excited to reconnect with you and continue providing valuable insights that enrich your professional journey. This year, we are committed to bringing you more cutting-edge, evidence-based content to help you excel in your practice and better serve your patients.
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Additionally, we highlight breakthroughs in the treatment of HIV that are transforming the landscape of care for individuals living with the condition.
Conjunctivitis is covered with a comprehensive look at diagnostic and treatment updates for this common ocular condition in paediatric patients. Otitis media in paediatric
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Losartan potassium 50/100 mg
Bisoprolol fumarate 2.5/5/10 mg
Losartan potassium/hydrochlorothiazide 50/12.5 mg, 100/25 mg
Perindopril tert-butylamine 4/8 mg
Metformin hydrochloride 500/850/1000 mg
Amlodipine besilate 5/10 mg
Ezetimibe 10 mg
Torasemide 5/10 mg
SAHPRA approved ANNIN professional information. Date of publication: 18 September 2021. S3 ANNIN 50 mg (tablet). Reg. No.: 43/7.1.3/0494. S3 ANNIN 100 mg (tablet). Reg. No.: 43/7.1.3/0495. Each film-coated tablet contains 50 mg or 100 mg losartan potassium respectively. Contains sugar: 40 mg or 80 mg lactose respectively. SAHPRA approved ANNIN CO professional information. Date of publication: 24 February 2023. S3 ANNIN CO 50/12,5 mg (film-coated tablet). Reg. No.: 45/7.1.3/1054. S3 ANNIN CO 100/25 mg (film-coated tablet). Reg. No.: 45/7.1.3/1055. Each film-coated tablet contains 50 mg losartan potassium/12,5 mg hydrochlorothiazide or 100 mg losartan potassium/25 mg hydrochlorothiazide respectively. Contains sugar: 111 mg or 222 mg lactose respectively. SAHPRA approved APRATE professional information. Date of publication: 30 December 2023. S3 APRATE 5 mg (tablet). Reg. No.: 41/7.1/00754. S3 APRATE 10 mg (tablet). Reg. No.: 41/7.1/0755. Each tablet contains 5 mg or 10 mg amlodipine besilate respectively. Sugar free. SAHPRA approved BISBETA professional information. Date of publication: 11 February 2022. S3 BISBETA 2,5 mg (tablet). Reg. No.: 45/5.2/0789. S3 BISBETA 5 mg (tablet). Reg. No.: 45/5.2/0790. S3 BISBETA 10 mg (tablet). Reg. No.: 45/5.2/0791. Each film-coated tablet contains (2:1) 2,5 mg, 5 mg or 10 mg bisoprolol fumarate respectively. Sugar free. SAHPRA approved EZOTAK professional information. Date of publication: 17 August 2021. S3 EZOTAK (tablets). Reg. No.: 52/7.5/0279. Each tablet contains 10 mg ezetimibe. Contains sugar: 62 mg lactose. Sugar free. SAHPRA approved REPREX professional information. Date of publication: 18 September 2021. S3 REPREX 4 mg (tablet). Reg. No.: 43/7.1.3/1033. S3 REPREX 8 mg (tablet). Reg. No.: 43/7.1.3/1034. Each uncoated tablet contains 4 mg or 8 mg perindopril tert-butylamine respectively. Contains sugar: 59,33 mg or 118,66 mg lactose respectively. SAHPRA approved RISAT professional information. Date of publication: 13 December 2022. S3 RISAT 5 mg (tablet). Reg. No.: 43/18.1/1042. S3 RISAT 10 mg (tablet). Reg. No.: 43/18.1/1043. Each uncoated tablet contains 5 mg or 10 mg torasemide anhydrous respectively. Contains sugar: 79 mg or 158 mg lactose respectively. SAHPRA approved ROMIDAB TABLETS professional information. Date of Publication: 7 October 2021. S3 ROMIDAB 500 mg (tablet). Reg. No.: 45/21.2/0207. Each film-coated tablet contains 500 mg metformin hydrochloride. Sugar free. S3 ROMIDAB 850 mg (tablet). Reg. No.: 45/21.2/0208. Each film-coated tablet contains 500 mg metformin hydrochloride. Sugar free. S3 ROMIDAB 1000 mg (tablet). Reg. No.: 45/21.2/0209. Each film-coated tablet contains 500 mg metformin hydrochloride. Sugar free. SAHPRA approved URODOXA professional information. Date of publication: 20 December 2023. S3 URODOXA 4 mg (tablet). Reg. No.: 45/7.1/0152. Each uncoated tablet contains doxazosin mesilate equivalent to doxazosin 4 mg. Contains sugar: 48 mg lactose. For full prescribing information refer to the professional information approved by the medicines regulatory authority.
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An estimated 1.28 billion adults between 30- and 79-years are living with hypertension globally.
More than 60% live in low- and middle-income countries. In South Africa >30% of adults are currently living with the condition, which are responsible for ~50% of strokes and ~40% of MIs. 3,4
Often referred to as a ‘silent killer’, hypertension typically manifests without noticeable symptoms or visible warnings, leaving >50% of affected individuals unaware of their condition. 4
While symptoms like headaches, visual disruptions, nosebleeds, nausea, vomiting, facial flushing, and sleepiness may arise in cases of exceptionally high blood pressure (BP), the absence of overt signs highlights the urgent need for proactive monitoring and awareness of this potentially lifethreatening condition.
Men have a higher risk of hypertension (34%) compared to women (32%).
Furthermore, only ~20% of adults living with hypertension have it under control. 2,3,4
May is designated as High Blood Pressure Awareness Month, with the culmination being World Hypertension Day on May 17. The American Heart Association describes hypertension as a domino effect, which can lead to an increased risk of stroke, coronary artery disease (CAD), heart failure (HF), myocardial infarction (MI), vision impairment, chronic kidney disease, dyslipidaemia, impaired glucose tolerance, type 2 diabetes, and sexual dysfunction.1,2
According to the 2023 European Society of Hypertension (ESH) guidelines, hypertension is defined as: Repeated office systolic BP (SBP) values of 140mmHg and/or diastolic BP (DBP) 90mmHg. The society cautions that life-threatening cardiovascular (CV) and renal events can also occur at low BP levels (eg 115mmHg/75mmHg). 2
Hypertension is classified into:2,5
Responsible for the majority of cases.
Caused by an interplay between genetic and environmental factors, as well as the ageing process. Genetic and environmental factors induce changes in CV regulatory systems, leading to increased systemic vascular resistance – a key haemodynamic abnormality in hypertension. Studies show that alterations in major CV control systems, including the renin-angiotensinaldosterone system (RAAS), autonomic
cardiac and vascular regulation, the endothelin system, nitric oxide, natriuretic peptides, and gut microbial dysbiosis, contribute to chronic BP elevation. 2
The immune system, particularly inflammation, has also been implicated in the pathophysiology of hypertension. Inflammation is thought to influence BP regulation and has been implicated in the onset of, and progression to hypertensive target organ damage (HMOD). 2
Secondary hypertension
Accounts for 5%-10% of cases. More common (prevalence ~30%) in younger individuals (18- to 40-years). Arises from specific causes such as:2,5
_ Renovascular hypertension: Defined as systemic hypertension that manifests secondary to the compromised blood supply to the kidneys, usually due to an occlusive lesion in the main renal artery
_ Renal disease
_ Aldosteronism: A disorder caused by autonomous production of aldosterone
by the adrenal cortex due to hyperplasia, adenoma, or carcinoma _ Obstructive sleep apnoea.
Secondary hypertension can also be caused by mutations in specific genes, mostly coding for proteins involved in sodium tubular reabsorption or steroid metabolism. 2,5
A diagnosis of secondary hypertension should be considered when a young individual presents with symptoms such as either severe hypertension (>180mmHg/120mmHg), resistant hypertension (defined as BP that remains >140/90mmHg despite optimal use of three antihypertensive medications of different classes, including a diuretic), or malignant/accelerated hypertension (defined as a recent significant increase over baseline BP that is associated with target organ damage).2,5
Management of hypertension:
Antihypertensive treatment
Antihypertensive treatment is crucial to reduce CV events, mortality, and organ damage associated with hypertension. The main objective of antihypertensive treatment should be to lower BP to <140/90mmHg in all patients. 2
If treatment is well tolerated, treated BP values should be targeted to ≤130/80mmHg, with the caveat that in some clinical conditions (eg chronic kidney disease), the evidence for this lower BP target is uncertain. It is also recommended that treatment should never target BP values to <120/70mmHg because of the lack of consistent evidence.2
The benefits of antihypertensive treatment are well-supported by numerous outcomebased randomised controlled trials (RCTs). While lifestyle changes (see below) can improve BP and overall CV risk, the majority of patients will require pharmacotherapy.2
Meta-analyses have consistently shown that a 7mmHg average reduction in SBP lowers the risk of major CV events such as stroke, CAD and HF, as well as all-cause mortality.2
Antihypertensive treatment has also demonstrated a protective effect against asymptomatic CV and kidney damage. Furthermore, increasing evidence suggests that antihypertensives resulting in lowered BP levels can prevent cognitive decline and dementia, irrespective of baseline BP, CV risk, comorbidities, age, sex, or ethnicity.2
Recent meta-analyses indicate that the advantages of antihypertensive treatment remain consistent, even with the concomitant use of other pharmacotherapies such as lipid-lowering, antidiabetic, and antiplatelet agents. 2
Furthermore, comprehensive costeffectiveness analyses support the use of pharmacological treatment for hypertension. The prevention of fatal and non-fatal events, which can lead to hospitalisation and morbidity, result in a substantial reduction in healthcare-related costs. The cost-effectiveness is attributed to the use of inexpensive drug classes, often available as generics. 2
According to the ESH, the decision to initiate treatment should be based on office BP levels rather than CV risk alone. Grade 2 or 3 hypertension typically requires drug treatment (see Table 1). Together with pharmacotherapy, lifestyle changes (see below) is recommended for the treatment for grade 1 hypertension in patients at high risk of CVD. 2
Regarding treatment initiation in patients with BP <140/90mmHg, the guidelines discourage antihypertensive treatment in patients who have a low-to-moderate risk of CVD with high-normal BP. Lifestyle changes are recommended for these patients. In patients with BP >140/90mmHg, but at high risk of CVD, treatment initiation is warranted.2
For patients aged 60- to 79-years, the
guidelines recommend initiating treatment when SBP is ≥140mmHg, regardless of DBP levels. This recommendation includes patients with isolated systolic hypertension even if DBP is <90mmHg or <80mmHg. 2
Recent trials have shown significant CV benefits with BP-lowering treatment in this age group. In patients aged ≥80-years. However, the Hypertension in the Very Elderly Trial (HYVET) demonstrated benefits in patients with SBP ≥160mmHg. 2 The recommended SBP threshold for pharmacotherapy in this age group is 150mmHg based on extrapolation from HYVET data. A critical recommendation is to continue antihypertensive treatment in patients who tolerate treatment. Discontinuation is associated with a rebound increase in adverse outcomes. 2
Exceptions can be considered for very old patients with low SBP values (≤120mmHg) or severe orthostatic hypotension, especially those who use polypharmacy and have high frailty levels. 2
Key drug classes include:
_ Angiotensin-converting enzyme inhibitors (ACEis)
_ Angiotensin II receptor blockers (ARBs) _ Beta-blockers (BBs)
_ Calcium channel blockers (CCBs) _ Thiazide/thiazide-like diuretics. These agents along with their combinations, are recommended as first-line therapy in the management of hypertension. Initiation of therapy with a two-drug combination is recommended for the majority of patients living with hypertension. 2
Single- or multi-pill combinations are preferred. Recommended combinations are an ARB with a CCB or a thiazide/ thiazide-like diuretic. BBs should be used at therapy initiation or any treatment step – particularly in conditions like HF with reduced ejection fraction, antiischaemic therapy in chronic coronary syndromes, and heart rate control in atrial fibrillation. However, caution is advised, when considering BBs appropriate patient selection is crucial. 2
and 80-84 High-normal
and/or 85-89
Grade 1 hypertension 140-159 and/or 90-99
Grade 2 hypertension 160-179 and/or 100-109
Grade 3 hypertension
Isolated systolic hypertension
Isolated diastolic hypertension (Isolated systolic or diastolic hypertension is graded 1, 2 or 3 according to SBP and DBP values in the ranges indicated. The same classification is used for adolescents ≥16 years old)
≥180 and/or ≥110
≥140 and <90
<140 and ≥90
Furthermore, combinations that provide 24-hour BP control and once-daily drug administration are preferred. Extendedrelease formulations and bedtime administration may be considered, with evidence suggesting no harm in taking antihypertensive drugs at bedtime. 2
In certain cases, initiation with monotherapy may be considered for patients with grade 1 hypertension and low risk, highnormal BP with very high CV risk, or those exhibiting frailty and advanced age.2
If BP control is not achieved with the initial two-drug combination, escalation to a three-drug combination is recommended, typically comprising a RAAS blocker, CCB, and thiazide/thiazide-like diuretic. The combination of two RAAS blockers is discouraged due to an increased risk of adverse events, particularly acute kidney injury (AKI). In cases where BP remains uncontrolled with a three-drug combination, treatment for true resistant hypertension is recommended. 2
Several arguments support the use of two antihypertensives at the onset of treatment. Firstly, evidence suggests that initial combination therapy is consistently more effective in lowering BP than monotherapy. Even low-dose combination therapy tends to surpass the efficacy of maximal dose monotherapy. 2
This approach not only reduces the heterogeneity of BP response but also provides a steeper dose-response effect compared to escalating doses of monotherapy. Moreover, it is considered safe and well-tolerated, with minimal increase in the risk of hypotensive episodes, even in patients with grade 1 hypertension. 2
Secondly, the use of a two-drug combination leads to a faster reduction in BP compared to monotherapy. Observational evidence indicates that the time taken to achieve BP control is a critical determinant of clinical outcomes, particularly in high-risk patients, with shorter time to control associated with lower risk. 2
Thirdly, studies show that patients starting treatment with a two-drug combination are more likely to achieve frequent BP control
after one year. This is attributed to the prevention of therapeutic inertia, better long-term adherence, and persistence to the prescribed treatment regimen. 2
For patients whose BP is not adequately controlled with two-drug combination therapy, options include:2
_ Using a different two-drug combination
_ Increasing the dose of the current combination components
_ Transitioning to three-drug combination therapy, usually involving a RAAS inhibitor, a CCB, and a thiazide/thiazide-like diuretic.
What about fixed-dose combination therapy?
Although single-pill combinations are preferred, Verma et al found that fixed-dose combination (FDC) therapy improves patient adherence to treatment. The team conducted a retrospective cohort study comparing clinical outcomes and medication adherence in a real-world setting between FDC therapy and single-pill combination therapy.5
The study included 13 350 participants who were newly prescribed either an ACEi or ARB in combination with a thiazide diuretic, with a
follow-up period of up to five years.5
To minimise selection bias, the researchers employed high-dimensional propensity score matching to compare outcomes between those receiving FDC and single-pill therapy.5 The primary outcome was a composite of death or hospitalisation for acute MI, HF, or stroke. Two analyses were performed to assess the association between medication adherence and patient outcomes.5
In the on-treatment analysis, where patients were censored upon discontinuation of treatment, no significant difference in the primary outcome was observed between the two groups. 5
However, in the intention-to-treat analysis, which allowed for breaks in treatment, FDC recipients showed a significantly higher proportion of total follow-up days covered with medications (70%) compared to the single-pill combination group (42%). The primary outcome was less frequent in the FDC group (3.4 versus 3.9 events per 100 person-years). 5
Lifestyle changes in preventing and managing hypertension is extremely important. These interventions not only contribute to lowering BP but also have broader CV benefits.2
Individuals following a healthy lifestyle have 4mmHg-5mmHg lower BP, regardless of underlying genetic risks. Lifestyle changes not only lower BP but also improves the effectiveness of pharmacological interventions, potentially reducing the need for multiple therapies.2
Various lifestyle interventions have demonstrated heart-healthy benefits beyond BP reduction, with the most established approaches being weight loss, the Dietary Approaches to Stop Hypertension (DASH) diet, salt reduction, increased potassium intake, regular physical activity, and moderation of alcohol consumption. These interventions are pivotal in reducing premature CV morbidity and mortality.2
Weight reduction: Being overweight or obese is directly associated with hypertension. Weight-loss interventions, particularly through a low-caloric diet and exercise, have shown significant reductions in both systolic and diastolic BP. Modest weight loss is recommended and should be tailored to individual needs.2
Restriction of sodium intake: High sodium consumption is strongly associated with increased BP. Lifestyle interventions restricting sodium intake to <5.844 grams per day have been shown to result in an average 5/2mmHg reduction in BP. However, the debate over optimal sodium
Table 2: Similarities and differences between ACC/AHA and ESH hypertension guidelines 6
Guideline similarities
Accurate BP measurement
2017 American College of Cardiology/American Heart Association
Guideline differences
Hypertension definitions
2023 ESH
Office-based BP measurements and use of validated cuffed devices and home/ambulatory BP monitoring are recommended prior to diagnosis of hypertension
Pooled cohort equation and SCORE2/SCORE2-OP provide estimates of 10-year risk of fatal and non-fatal CV event and should be used to guide treatment decisions
Initial therapeutic choices include ACEi, ARBs, thiazide/thiazide-like diuretics and CCBs
Single-pill combination therapy is a first-line strategy for most patients
2017 American College of Cardiology/American Heart Association
≥130/80mmHg
Normal BP ranges Normal: <120/80mmHg
Optimal: <120/80mmHg
Elevated: 120-129mmHg
Hypertensive ranges
BP targets for treatment
18- to 64-years
65-79-years
≥80-years
Pharmacotherapy
Hypertension stage 1: 120-139mmHg/80-89mmHg
Hypertension stage 2: ≥140/90mmHg
<130/80mmHg
<130/80mmHg
<130/80mmHg
Initial therapy with BBs reserved for specific conditions including ischaemic heart disease or HF
restriction levels and potential adverse effects requires further research. 2
Augmentation of dietary potassium intake: Dietary potassium is associated with BP regulation, with evidence supporting both the effectiveness of potassium supplementation and potassium-rich diets in lowering BP. The recommended population goal for potassium intake is ~3.5 grams.2
Increase in physical activity: Habitual physical activity has an inverse relation with the incidence of hypertension. Structured exercise, especially dynamic aerobic exercise, has demonstrated BP-lowering effects, contributing to ~2-4mmHg and 5mmHg-8mmHg reductions in systolic BP for normotensive and hypertensive adults, respectively.2
Moderation of alcohol intake: Observational studies highlight a positive linear association between alcohol consumption and BP. Reduction in alcohol intake, especially close to abstinence, has been associated with a 3.3mmHg/2mmHg reduction in systolic and diastolic BP. The
2023 ESH
≥140/90mmHg
Normal:
120-129mmHg/80-84mmHg
High normal:
130-139mmHg/85-89mmHg
See Table 1
<130/80mmHg
<140/80mmHg
<140-150/80mmHg
BBs included as first-line therapy. Patients selection is critical.
hypertensiogenic effect of binge drinking should be avoided. 2
Smoking cessation: Tobacco smoking is a significant contributor to hypertension and cardiovascular risk. Smoking cessation is crucial, and health professionals should counsel and support individuals in quitting. Water pipe and e-cigarette smoking, once considered alternatives, have been associated with increased BP and CV risks.2
Other dietary interventions: Diets, such as the DASH and Mediterranean diets, have synergistic effects on BP reduction beyond individual foods or nutrients. These diets promote the consumption of fruits, vegetables, low-fat dairy, and whole grains. Coffee consumption, within moderation, appears not to adversely affect BP.2
Stress management: Stress and anxiety are linked to an increased risk of hypertension. Mind-body stress-reducing interventions, such as meditation and yoga, have shown promise in reducing both stress levels and BP.2
Exposure to noise and air pollution:
Environmental noise and air pollution contribute to increased BP and CV risks. Reduction in exposure to traffic noise and air pollution, both on a policy level and individual efforts, can contribute to better BP control and overall CV health.2
Hypertension is a global healthcare challenge, affecting >1.28 billion adults, with a significant burden in low- and middleincome countries. Often asymptomatic, it earns its ‘silent killer’ moniker, leading to severe consequences, including strokes and myocardial infarctions.
The interplay of genetic, environmental, and immunological factors underscores the complexity of hypertension. Management, primarily through antihypertensive treatment is essential, supported by robust evidence of reduced CV events and mortality. Lifestyle changes complement pharmacotherapy.
1. American Heart Association. Consequences of High Blood Pressure. 2022. [Internet]. Available at: https://www.heart.org/-/media/files/health-topics/ high-blood-pressure/consequences-of-highblood-pressure-infographic.pdf.
2. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension. Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). Journal of Hypertension, 2023.
3. World Health Organization. Hypertension. Updated 2023. [Internet]. Available at: https:// www.who.int/news-room/fact-sheets/detail/ hypertension.
4. The Heart and Stroke Foundation South Africa. Blood Pressure. [Internet]. Available at: https://heartfoundation.co.za/bloodpressure/#:~:text=In%20South%20Africa%20 more%20than,that%20blood%20pressure%20 is%20high
5. Verma AA, Khuu W, Tadrous M, et al. Fixeddose combination antihypertensive medications, adherence, and clinical outcomes: A populationbased retrospective cohort study. PLoS Med, 2018.
6. Vemu PL, Yang E, Ebinger J. 2023 ESH
Hypertension Guideline Update: Bringing Us Closer Together Across the Pond. JACC, 2024. SF Click for
SOUTH AFRICA’S
BRAND*1
Effective reduction in blood pressure with significant reduction in CV mortality, myocardial infarction, stroke and LVH in at-risk hypertensive patients2,3
Significant renal-protective benefits in type 2 diabetic patients with nephropathy4
Affordable, making its antihypertensive, cardiovascular and renoprotective benefits accessible to more South Africans3,4,5
Reimbursed by medical aids on all plans#6
Plus is South Africa’s
Email: medinfo@accordhealth.co.za. Tel. No.: 011 234 5701/2. LOP/001/AUG24/AD. Abbreviations: CV: cardiovascular; LVH: left ventricular hypertrophy
References: 1. IMS MAT, June 2024. 2. Williams B, Mancia G, Spiering W, et al. ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104. doi: 10.1093/eurheartj/ehy339. 3. Lindholm LH, Ibsen H, Dahlöf B, et al. LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002 Mar 23;359(9311):1004-10. doi: 10.1016/S0140-6736(02)08090-X. 4. Brenner BM, Cooper ME, de Zeeuw D, et al. RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-9. doi: 10.1056/NEJMoa011161. 5. Database of Medicine Prices [30 August 2024]. Available from URL: https://www.health.gov.za/nhi-pee/. 6. Accord Data on File.
This article was independently sourced by Specialist Forum.
In 2019, 1.3 billion people were living with hypertension, defined by systolic blood pressure (SBP) ≥140 mmHg and diastolic blood pressure (DBP) ≥90 mmHg. SBP is often referred to as a ‘silent killer’ and causes >10 million deaths annually, making it the leading global health risk.1
Globally, about 33% of adults between 30- and 79-years have hypertension, but only 54% are diagnosed, 42% receive treatment, and just 21% have it under control. In Africa, hypertension affects 36% of adults, with 43% diagnosed, 27% receiving treatment, and only 12% having it under control. If countries can achieve a 50% hypertension control rate by 2050, the World Health Organization (WHO) estimates that 76 million cardiovascular
(CV) deaths and 450 million disabilityadjusted life years could be prevented.1
Three common triggers for hypertension are high sodium intake, alcohol consumption, and tobacco use. In Africa, sodium intake averages 2687mg/day, exceeding the recommended <2000mg/ day. Alcohol, while temporarily lowering BP, often leads to a rebound increase and chronic hypertension, making its reduction
crucial for mitigating hypertension-related health issues. Tobacco use was responsible for 8.7 million deaths globally in 2019, with acute effects on BP due to sympathetic nervous system stimulation, although the long-term impact on chronic hypertension is less clear.1
Effective interventions
Pharmacological treatment for hypertension has been around since the 1950s, contributing to ~20% of the decline in
CV mortality in high-income countries over the past four decades.1
The WHO sets treatment goals of BP <140mmHg/90mmHg for patients without comorbidities, while for those with CV disease (CVD) or high CV risk, including diabetes or chronic kidney disease (CKD), the target is SBP <130mmHg.1
The 2024 European Society of Hypertension (ESH) guidelines support these targets, recommending a target SBP of <130mmHg and DBP <80mmHg for most patients up to 79-years. Lifestyle interventions have also proven effective in reducing blood pressure, including adopting a healthy diet, regular physical activity, weight reduction, sodium restriction to <5g/ day, increasing potassium intake, limiting alcohol intake, quitting smoking, and managing stress. 2
The WHO recommends starting antihypertensive medication for individuals who have an SBP of ≥140mmHg, or a DBP of ≥90mmHg. For those with existing CVD and an SBP between 130mmHg139mmHg, treatment is also recommended. Additionally, individuals without CVD but with high CV risk factors such as diabetes or CKD, and an SBP in the 130mmHg-139mmHg range, should also begin treatment.1
When starting anti-hypertensive therapy, the WHO suggests conducting laboratory tests to screen for comorbidities and secondary hypertension, provided these tests do not delay the initiation of treatment. CVD risk assessment should be carried out if feasible but should not hinder treatment initiation.1
For first-line pharmacological treatment, the WHO recommends using drugs from one of three classes:1
1 Thiazide and thiazide-like diuretics.
2 Angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEis).
3 Long-acting dihydropyridine calcium channel blockers (CCBs).
Anti-hypertensives: Who and what?
According to the ESH guidelines, the pharmacological treatment of hypertension involves a stepwise approach, starting with combination therapy for most patients. The initial combination typically includes an ACEi or ARB with a CCB or a thiazide/ thiazide-like diuretic. If well tolerated, the dosage can be increased to achieve up to 60% control of BP. 2
For patients requiring further control, a triple combination therapy is recommended, adding
another agent to the initial combination, potentially achieving up to 90% control.2
Monotherapy should be reserved for selected patients, such as those with low-risk hypertension, high-normal BP with very high CV risk, or frail and elderly patients. Beta-blockers (BBs) can be used as monotherapy or at any step of combination therapy. 2
In cases of true resistant hypertension, where BP remains uncontrolled despite the use of three anti-hypertensive agents, additional therapies such as spironolactone or other mineralocorticoid receptor antagonists can be considered. Renal denervation may be an option for patients with an estimated glomerular filtration rate >40ml/min/1.73 m². 2
International guidelines recommend ARBs or ACEis as firstline therapies for patients with various comorbidities
Peresuodei et al conducted a systematic review comparing the safety and efficacy of ARBs and ACEis in the management of hypertension. The review included 10 studies and data of >1.6 million patients. 3 ARBs work by competitively binding to angiotensin-2 receptors, preventing its activation, while ACEis block the conversion of angiotensin (AT)-1 into the active form, AT-2. 3
The team found that ARBs and ACEis are equally safe and effective in managing hypertension. However, in terms of tolerability, the review noted that ARBs were better tolerated than ACEis. 3
Patients on ACEis were more likely to experience dry cough and angioedema compared to those on ARBs. Overall, ARBs had a lower rate of adverse effects (AEs). 3
According to Dézsi, the introduction of ARBs represents a significant milestone in the management of hypertension, expanding personalised treatment options, particularly for patients intolerant to ACEis. 4
International guidelines recommend ARBs or ACEis as first-line therapies for patients with various comorbidities, including microalbuminuria, renal dysfunction, CKD, metabolic syndrome, diabetes, atherosclerosis, stable angina, a history of myocardial infarction (MI), atrial fibrillation (AFib), and heart failure (HF). 4
A large-scale observational study involving >3 million patients commencing anti-hypertensive treatment with either an ARB or ACEi found no significant difference in effectiveness between the two classes in preventing acute MI, HF, stroke, or composite CV events. However, ARBs demonstrated a better safety profile, with lower risks of acute pancreatitis, angioedema, cough, and gastrointestinal bleeding. 5
Currently, guidelines do not specify which ARB should be used for patients with various comorbidities, although several studies have indicated that certain ARBs can provide additional beneficial effects. 4 Among ARBs, telmisartan is unique, as it is the only ARB approved for reducing CV morbidity in patients with atherothrombotic CV disease. This approval is based on findings from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, which demonstrated that telmisartan offers similar reductions in composite endpoints of CV death, MI, stroke, or HF hospitalisations compared to ramipril. Additionally, the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease reported that telmisartan was linked to reduced CV hospitalisations, lower left ventricular hypertrophy, and decreased incidence of both macrovascular and microvascular events, including microalbuminuria. A combined analysis with data from the Prevention Regimen for Effectively Avoiding Second Strokes study also revealed telmisartan’s significant benefits in reducing CV death, MI, and stroke. Furthermore, telmisartan has been shown to significantly reduce the recurrence of AFib compared to carvedilol, amlodipine, and ramipril.4
A meta-analysis of eight trials found that telmisartan outperformed other ARBs in reducing fasting plasma glucose and increasing adiponectin levels. At an 80mg dose, telmisartan lowered fasting plasma insulin levels and improved insulin resistance, measured by the homeostasis model assessment, and was associated with a 16% reduction in the risk of newonset diabetes compared to placebo. 4 The Angiotensin II Receptor Blockade in Obese Patients with Hypertension and Insulin Resistance study demonstrated
that telmisartan significantly improved the hyperinsulin response to glucose loading in obese patients with hypertension and insulin resistance, along with improvements in vascular inflammation, reductions in visceral fat, and increases in serum adiponectin. 4
Telmisartan also shows promise in improving proteinuria and preventing progression to end-stage renal disease (ESRD). It significantly reduced urinary albumin/protein excretion and the urinary albumin/protein to creatinine ratio by 20% and 14%, respectively, compared to other ARBs and ACEis, resulting in an overall reduction of 40%. 4
Furthermore, telmisartan appears to protect against hypertension-related cognitive decline through angiotensin 1 receptor blockade and partial activation of PPAR- γ in the hippocampus, significantly restoring cognitive functions impaired by chronic stress and reducing forgetfulness. 4
Effective antihypertensive treatment must sustain BP control, particularly in the last six hours of the dosing period or following a missed dose. Early morning BP surges and 24-hour mean BP are associated with CV events and targetorgan damage. 6
A key advantage of telmisartan is its long half-life, providing 24-hour protection. Lacourcière et al compared telmisartan’s long half-life with the shorter half-life valsartan during the last six hours of treatment and after a missed dose. 6,8
In their study, participants received once-daily telmisartan (40mg-80mg) or valsartan (80mg-160mg) for eight weeks. Results showed that during the last six hours of treatment, telmisartan reduced DBP by 7.6mmHg compared to 5.8mmHg with valsartan, with SBP reductions of 11.1mmHg for telmisartan versus 9.1mmHg for valsartan. 6
After a missed dose, telmisartan reduced 24-hour mean DBP by 7.2mmHg versus 5.5mmHg with valsartan, and SBP reductions were 10.7mmHg with telmisartan compared to 8.7mmHg with valsartan. The authors concluded that telmisartan consistently provided greater BP reductions, especially in the last hours of the dosing interval, making it particularly beneficial for patients with poor adherence to treatment. 6
In the Study of Micardis (telmisartan) in Overweight/Obese Patients with Type 2 Diabetes and Hypertension, 840 patients were randomised to receive telmisartan 80mg or valsartan 160mg daily for four weeks, followed by HCTZ 12.5mg for six weeks.7
Results showed that telmisartan/HCTZ
significantly reduced mean BP in the last six hours of the dosing interval compared to valsartan/HCTZ, with greater reductions in SBP and DBP.7
Overall, telmisartan combined with HCTZ provided more significant BP reductions, particularly during early morning hours, making it a more effective option for managing high-risk patients with hypertension and type 2 diabetes.7
Fixed-dose combination of telmisartan/HCTZ
The fixed-dose combination of telmisartan and hydrochlorothiazide (HCTZ) is used for adults whose BP is inadequately controlled with telmisartan alone. Studies demonstrate that adding HCTZ to telmisartan significantly improves BP control, with reductions in ambulatory SBP and diastolic DBP of 21.5/14.6mmHg over 24-hours, 21.8/14.9mmHg during the day, and 20.4/13.7mmHg at night. 8,9,10,11
Concerns have been raised regarding the metabolic side effects of thiazide diuretics, particularly their impact on glucose tolerance. Combining ARBs with HCTZ can mitigate some of the metabolic effects associated with thiazide diuretics. For instance, ARBs reduce the risk of hypokalaemia, and their use may also counterbalance the tendency of thiazides to cause hyperglycaemia and new-onset diabetes. Studies have shown that ARBs are linked to fewer cases of new-onset diabetes compared to certain other agents.12
Losartan has demonstrated benefits in reducing the relative risk of the composite endpoint of death, MI, or stroke by 13% in the
Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. Greater benefits were observed in diabetic patients, where mortality was reduced by 39%.4
The Evaluation of Losartan in the Elderly (ELITE) I and II trials showed that, in elderly patients living with HF, treatment with losartan provided similar outcomes to captopril regarding all-cause mortality, sudden death, and resuscitated arrests. In the ELITE I study, losartan also showed a lower mortality rate, primarily due to a greater reduction in sudden cardiac death. Additionally, using a 150mg dose of losartan provided further benefits compared to the 50mg dose, reducing the rate of death or HF hospitalisation and improving left ventricular ejection fraction. 4
Post-hoc analyses indicate that losartan, valsartan, and candesartan are associated with a 20%-35% reduction in the incidence of new-onset AFib. Losartan also effectively reduced the maximum and total duration of paroxysmal AFib in patients with sick sinus syndrome, without causing significant haemodynamic changes. 4
Studies have shown that losartan reduces the risk of ESRD by 28% and lowers urinary protein excretion by 35% in patients with diabetic nephropathy, compared to placebo. 4
Treatment with losartan has also been shown to enhance erectile function, sexual satisfaction, and frequency of sexual activity in hypertensive patients. In diabetic patients, losartan alone or in combination with tadalafil significantly improved erectile dysfunction (ED), with the greatest benefit observed in those with mild to moderate ED. 4
Additionally, losartan uniquely lowers serum uric acid (SUA) levels, which are
associated with an increased risk of gout. Compared with a low dose (50mg), highdose losartan (150mg) reduced SUA by -0.27mg/dl. High-dose losartan reduced the incidence of hyperuricaemia.13
A real-world study assessed the effectiveness of combining losartan 50mg with HCTZ 12.5mg in managing isolated systolic hypertension among patients with various comorbidities. The analysis included 15 846 patients diagnosed with SBP >140mmHg and DBP <90mmHg, excluding those with diabetes or CKD. The most prevalent CV risk factor was hypercholesterolaemia (48.1%), followed by obesity (16.3%). Other conditions included cerebrovascular diseases (9.6%), ischaemic heart disease (7.9%), and left ventricular hypertrophy (4.6%). The proportion of patients with complications varied by age: 62% for ≤64 years, 69% for 65-74 years, and 67% for ≥75 years. Mean BP improved from 156/78mmHg initially to 140/72 mmHg at one month and 134/72mmHg at six months.14
Laboratory values for total cholesterol, uric acid, haemoglobin A1c, and serum potassium remained stable. Adverse effects such as orthostatic hypotension and significant BP drops were rare. This combination therapy proved effective and safe in achieving the recommended BP target of <140mmHg.14
Role of
Amlodipine is a widely used CCB that effectively lowers blood pressure by inhibiting calcium influx into vascular smooth muscle cells, leading to vasodilation. It is particularly beneficial for patients with isolated systolic hypertension, a common condition in the elderly. Amlodipine has a favourable side effect profile and is welltolerated by most patients. Additionally, it has been shown to reduce the risk of CV events, including stroke and MI.15
According to the 2024 European Society of Cardiology (ESC), combination therapy including a CCB combined with either a thiazide diuretic or a renin-angiotensin system blockers (ACEis or ARBs) should be considered in patients of African descent who require BP-lowering treatment.16
The ESC recommends BBs in specific situations, such as managing angina, HF, or post-MI, and for controlling heart rate, where they play a crucial role in therapy. In these cases, second-generation (cardio-selective) and third-generation (vasodilating) BBs are recommended. However, BBs are generally less effective than ACEis, ARBs, CCBs, or diuretics in preventing stroke and have a higher discontinuation rate due to side effects. Additionally, the use of BBs
and diuretics, particularly in combination, is linked to an increased risk of new-onset diabetes in susceptible patients.1
A key advantage of telmisartan is its long half-life, providing 24-hour protection
In conclusion, patient selection is crucial in hypertension management, and telmisartan offers significant advantages, particularly for those with comorbidities such as atherosclerosis, diabetes, and CKD. Its long half-life ensures sustained BP control, particularly in the last hours of the dosing interval, making it beneficial for patients with adherence challenges.
Telmisartan also provides additional CV protection, reducing the risk of MI, stroke, and HF hospitalisations, while improving insulin resistance and reducing proteinuria.
Patients with hypertension who struggle with early morning BP surges or those who require better 24-hour BP control may particularly benefit from telmisartan. Furthermore, its fixed-dose combination with HCTZ enhances blood pressure control while minimising metabolic side effects at lower doses. Overall, telmisartan is an excellent option for high-risk patients requiring both BP management and CV protection.
Losartan is beneficial for patients with diabetes and CVD, while CCBs are effective in reducing BP by relaxing blood vessels, and BBs are often used for patients with HF or arrhythmias.
1. World Health Organization. Global report on hypertension: the race against a silent killer. 2023 [Internet]. Available at https://www.who.int/ publications/i/item/9789240081062
2. European Society of Hypertension. 2024 European Society of Hypertension clinical practice guidelines for the management of arterial hypertension. European Journal of Internal Medicine, 2024.
3. Peresuodei TS, et al A Comparative Study of the Safety and Efficacy Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on the Management of Hypertension: A Systematic
Review. Cureus, 2024.
4. Dézsi CA. The Different Therapeutic Choices with ARBs. Which One to Give? When? Why? Am J Cardiovasc Drugs, 2016.
5. Chen RJ, et al Comparative First-Line Effectiveness and Safety of ACE (Angiotensin-Converting Enzyme) Inhibitors and Angiotensin Receptor Blockers. A Multinational Cohort Study. Hypertension, 2021.
6. Lacourcière Y, Krzesinskib J-M, Whitec WB, et al Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Pressure Monitoring, 2004.
7. Sharma AM, Davidson J, Koval S, Lacourcière Y. Telmisartan/hydrochlorothiazide versus valsartan/ hydrochlorothiazide in obese hypertensive patients with type 2 diabetes: the SMOOTH study. Cardiovascular Diabetology, 2007.
8. Gosse P. A review of telmisartan in the treatment of hypertension: blood pressure control in the early morning hours. Vasc Health Risk Manag, 2006.
9. Professional Information. Telmisartan/ Hydrochlorothiazide 40 mg/12.5 mg tablets. 2023 [Internet]. Available at: www.hpra.ie/img/ uploaded/swedocuments/Licence_PA2315-107001_12042023131159.pdf
10. Fogari R, et al. Effectiveness of hydrochlorothiazide in combination with telmisartan and olmesartan in adults with moderate hypertension not controlled with monotherapy: a prospective, randomized, open-label, blinded end point (PROBE), parallel-arm study. Curr Ther Res Clin Exp, 2008.
11. Kjeldsen SE, et al Telmisartan and hydrochlorothiazide combination therapy for the treatment of hypertension. Curr Med Res Opin, 2010.
12. Weir MR, Bakris GL. Combination therapy with Renin-Angiotensin-aldosterone receptor blockers for hypertension: how far have we come? J Clin Hypertens (Greenwich), 2008.
13. Ferreira JP, Zannad F, Kiernan MS, Konstam MA. High- versus low-dose losartan and uric acid: An analysis from HEAAL. Journal of Cardiology, 2023.
14. Suzuki H, et al Antihypertensive effectiveness of combination therapy with losartan/ hydrochlorothiazide for ‘real world’ management of isolated systolic hypertension. Therapeutic Advances in Cardiovascular Disease, 2015.
15. Bulsara KG, et al. Amlodipine. [Updated 2024 Apr 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519508/
16. McEvoy JW, et al 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. European Heart Journal, 2024. SF
It is estimated that ~10% of adults ≥75-years have atrial fibrillation (AFib). AFib results in uncoordinated contractions of the heart’s atria, which can lead to the formation of blood clots. These clots increase the risk of stroke five-fold and can also contribute to cognitive decline, renal impairment, and mesenteric ischaemia.1
Studies show that ~20% of strokes occur in patients with known AFib who were either inadequately anticoagulated or inappropriately treated with antiplatelet drugs.1
Stroke recovery can be complicated by venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE). The risk of VTE is highest within the first three months following a stroke, decreasing rapidly afterward. 2
Although symptomatic PE occurs in only about 1% of stroke survivors within the first two- to four-weeks, it remains a significant cause of preventable death, accounting for up to 30% of post-stroke fatalities. Strokerelated VTE has also been linked to increased disability at six months and lower survival rates at 30-days and one-year post-stroke.2
It is therefore extremely important to evaluate patients’ stroke risk, and
those identified as high-risk should start treatment with non-vitamin K oral anticoagulants (NOACs) as the primary antithrombotic therapy, according to Giskes et al 1
NOACs are direct-acting medications that specifically target either thrombin (factor IIa) or activated factor X (Xa). Evidence indicates that NOACs are at least as effective as, if not superior to, warfarin in reducing the risk of stroke, with similar or lower rates of bleeding compared to warfarin.1
NOACs reduce stroke risk by ~70% and mortality by ~30%. Intracranial haemorrhage (ICH) rates are significantly lower with NOACs compared to warfarin, and the incidence of major gastrointestinal (GI) bleeding is comparable between NOACs and warfarin.1
NOACs offer practical benefits in clinical
settings, including fewer food and drug interactions and the absence of the need for frequent monitoring. They achieve full anti-coagulation within one to two hours of dosing due to their rapid onset.1
Are NOACs universally suitable for all patients?
In South Africa, the available NOACs include dabigatran, a direct inhibitor of factor IIa, and apixaban and rivaroxaban, which are direct inhibitors of factor Xa.1
All three NOACs are indicated for the prevention of VTE in patients undergoing hip or knee replacement surgery, the reduction of stroke and SE risk in patients living with AFib, and the treatment and prevention of recurrent DVT PE. 3,4,5
Dabigatran, apixaban, and rivaroxaban each serve these purposes, with slight variations. Apixaban additionally reduces
Table 1: Comparison of the mode of action, pharmacokinetics, and clinical characteristics of apixaban vs rivaroxaban
8
Feature Apixaban
Mechanism of action
Direct oral Factor Xa inhibitor, inhibits both free and clot-bound Factor Xa
Bioavailability ~50% absolute oral bioavailability. Food has no significant effect on bioavailability
Absorption Rapid absorption with maximum plasma concentration occurring three to four-hours post-administration
Pharmacokinetics
Dose-proportional increase in exposure for oral doses up to 10mg
Half-life ~12-hours
Elimination Multi-pathway elimination: Metabolism, biliary excretion, and direct intestinal excretion. ~27% cleared renally
Metabolism Metabolised by CYP-independent pathways
Distribution Plasma protein consistent across patients (87%8)
Drug Interactions Limited clinically relevant drug interactions, enabling fixed dosing without therapeutic drug monitoring
Pharmacodynamics Pharmacodynamic effects closely correlated with plasma concentration. No monitoring required during treatment
Clinical efficacy and safety Effective for various thromboembolic conditions, including stroke prevention in AFib and post-surgical thromboprophylaxis
Rivaroxaban7
Direct oral Factor Xa inhibitor, selectively inhibits Factor Xa, preventing the conversion of prothrombin to thrombin in the coagulation cascade
~100% absolute oral bioavailability for the 10mg dose. No significant food effect for 10mg dose
Rapid absorption with maximum plasma concentration occurring two- to four-hours post-administration
Linear pharmacokinetics with no significant accumulation beyond steady state
Five- to nine-hours in young individuals and 11- to 13-hours in elderly patients
Elimination via metabolism and renal excretion (66% total elimination), 30%-40% excreted as unchanged drug in urine
Metabolised via CYP 3A4, CYP 2J2, and CYP-independent pathways
High plasma protein binding (92%95%), mainly to serum albumin. Volume of distribution ~50l
Substrate of P-glycoprotein and breast cancer resistance protein
Dose-dependent inhibition of Factor Xa activity. Prothrombin time (PT) prolonged in a dosedependent manner. No monitoring required during treatment
Demonstrated efficacy in preventing VTE in orthopaedic surgery patients and AFib
Coagulation parameters No need for monitoring coagulation parameters PT prolonged dose-dependently. Anti-factor Xa activity influenced but no standard calibration for monitoring
the risk of mortality in patients living with NVAFib with one or more risk factors. 3,4,5 Rivaroxaban and apixaban are currently among the most prescribed NOACs. However, their distinct pharmacokinetic and pharmacodynamic profiles can influence their safety and effectiveness differently. 6
Deciding to anticoagulate a patient involves assessing the need for anticoagulant therapy. The CHA2DS2-VASc score has expanded eligibility for anticoagulants to 90%-95% of patients, compared to the previous 66% with the CHADS2 score.9
Given the low bleeding rates of NOACs,
most patients living with NVAFib should receive anticoagulant therapy. Exceptions are patients with active bleeding, recurrent bleeding from anticoagulants, or a CHA2DS2-VASc score of 0. For patients who had major bleeding with warfarin, alternatives like apixaban or rivaroxaban should be considered before eliminating anticoagulation.9
According to Bonde et al, clinical guidelines do not endorse a particular NOAC over others for stroke prevention in AFib. As a result, there is considerable variability in the choice of NOACs, leading to similar patients
potentially receiving different NOACs depending on the treatment facility.7
Patient profiles that can aid in tailoring anticoagulation therapy include:9,10
_ Apixaban is preferred due to its consistent efficacy in reducing bleeding outcomes, including intracranial bleeding. For younger patients with good kidney function and no bleeding history, apixaban offers significant protection from stroke.
_ Apixaban is favoured over rivaroxaban for patients with a high bleeding risk due to its lower incidence of bleeding complications.
_ Apixaban is recommended as it is associated with a lower rate of GI bleeding compared to rivaroxaban.
_ Apixaban is suitable for patients with chronic kidney disease (CKD), including those with end-stage renal disease, as it does not require dose adjustment based on CKD stage.
_ Rivaroxaban, with its once-daily dosing, can be beneficial for improving patient adherence compared to medications requiring multiple daily doses. However, comparisons between once-daily and twice-daily dosing regimens reveal that despite a higher percentage of prescribed doses being taken with once-daily dosing, twice-daily dosing ensures a greater degree of continuity in drug action.
therapy?
For the prevention of VTE following elective hip or knee replacement surgery, the recommended dose of apixaban is 2.5mg taken orally twice daily. The first dose should be administered 12- to 24-hours post-surgery. For hip replacement surgery, the treatment duration is recommended to be 32- to 38- days, while for knee replacement surgery, it is 10- to 14-days. 4
According to Agnelli et al, the decision to extend treatment is challenging. In the Apixaban for the Extended Treatment of Venous Thromboembolism (AMPLIFY-EXT) the team set about evaluating the efficacy and safety of two doses of apixaban compared to placebo in patients with VTE who had completed six- to 12-months of initial anticoagulation therapy and were uncertain about continuing treatment.11
Agnelli et al evaluated the efficacy and safety of two apixaban doses (2.5mg and 5mg twice daily) compared to placebo. The study medications were administered for 12 months.11
The results showed that among 2486 randomised patients (with 2482 included
in the intention-to-treat analysis), the rate of symptomatic recurrent VTE or death from VTE was significantly lower in both apixaban groups compared to the placebo group.11
Specifically, 8.8% of placebo recipients experienced these outcomes, while only 1.7% of those receiving either the 2.5mg or 5mg dose of apixaban did. The difference between apixaban and placebo was 7.2 percentage points for the 2.5mg dose and seven percentage points for the 5mg dose, with both comparisons reaching statistical significance.11
Regarding bleeding risks, major bleeding occurred in 0.5% of the placebo group, 0.2% in the 2.5mg apixaban group, and 0.1% in the 5mg apixaban group. Clinically relevant non-major bleeding rates were slightly higher in the apixaban groups compared to placebo. The rate of death from any cause was also lower in the apixaban groups compared to the placebo group.11
In conclusion, extended treatment with apixaban, whether at a treatment dose of 5mg or a prophylactic dose of 2.5mg, effectively reduced the risk of recurrent VTE without increasing the rate of major bleeding.11
For the prevention of stroke and SE in patients with NVAFib, the recommended dose is 5mg taken orally twice daily. However, for patients who meet at least two of the following criteria: Age ≥80-years, body weight of ≤60kg, or serum creatinine levels of ≥1.5mg/dl or higher – the recommended dose is 2.5mg twice daily. 4
In the Apixaban Versus Aspirin in Patients with Atrial Fibrillation (AVERROES) trial, 5599 patients living with AFib and at least one additional stroke risk factor, who were unsuitable for VKA therapy, were enrolled at 522 sites across 36 countries.12
Patients were randomised to receive apixaban (n=2808) or aspirin (n=2791). After a mean follow-up of 13-months, the trial was stopped early due to the clear benefit of apixaban, which significantly (55%) reduced the risk of stroke or SE compared to aspirin with similar major bleeding risk.12
Following the double-blind phase, an open-label extension was initiated, allowing participants to continue receiving apixaban. Of the 5599 participants, 58.5% continued apixaban treatment during the open-label extension, with a median follow-up of three years.12
During this period, the annual rates of stroke or SE, haemorrhagic stroke, and major bleeding were 1.0%, 0.3%, and 1.2%, respectively. These event rates were consistent with those observed during the initial trial phase.12
An analysis of all patients who received apixaban from the start of AVERROES to the end of the extension showed similar results, supporting the long-term efficacy and safety of apixaban in patients living with AFib.12
In a retrospective cohort study by Ray et al, the team compared major ischaemic and haemorrhagic outcomes between apixaban and rivaroxaban in patients ≥65-years (n=581 451). Follow-up was four years.13
The primary outcome was a composite of major stroke/SE and haemorrhagic (ICH and other significant bleeding) events. Secondary outcomes included non-fatal extracranial bleeding and total mortality.13
~20% of strokes occur in patients who are inadequately or inappropriately treated
Results showed that the adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years compared to 13.4 for apixaban, indicating a higher risk associated with rivaroxaban. Rivaroxaban also had an increased risk for both major ischaemic events (8.6 vs 7.6 per 1000 person-years) and haemorrhagic events (7.5 vs 5.9). Additionally, patients on rivaroxaban experienced higher rates of non-fatal extracranial bleeding (39.7 vs 18.5) and total mortality (44.2 vs 41).13
In conclusion, both apixaban and rivaroxaban offer significant benefits in managing patients living with AFib. Apixaban is generally preferred in patients at higher risk of bleeding, particularly those with CKD or a history of GI bleeding. For extended treatment, apixaban effectively reduces the risk of recurrent VTE without increasing major bleeding, providing a safe and efficient option for long-term anticoagulation therapy. Tailoring patient selection based on individual risk profiles remains essential.
References
1. Giskes K, Lowres N, Hespe C, Freedman B.
Stroke Risk Mitigation Prescribing and Monitoring Anticoagulation in Atrial Fibrillation. Modern Medicine, 2024.
2. Tøndel BG, Morelli VM, Hansen JB, Braekkan SK . Risk factors and predictors for venous thromboembolism in people with ischemic stroke: A systematic review. J Thromb Haemost, 2022.
3. Professional Information. Pradaxa. 2022. [Internet]. https://pi-pil-repository.sahpra.org. za/wp-content/uploads/2022/08/pi-pradaxa17aug2022.pdf
4. Professional Information. Apixaban. 2024 [Internet]. Available at: https://pi-pil-repository. sahpra.org.za/wp-content/uploads/2024/04/ Final_PIL_Apixaban-Accord_Applicant-1.pdf
5. Professional Information. Xarelto. 2022 [Internet]. Available at: https://pi-pil-repository. sahpra.org.za/wp-content/uploads/2022/05/ approved-xarelto-15-and-20-pi-05.2022.pdf
6. Bonde AN, Martinussen T, Lee CJ-Y, et al. Rivaroxaban Versus Apixaban for Stroke Prevention in Atrial Fibrillation. An Instrumental Variable Analysis of a Nationwide Cohort. Circ Cardiovasc Qual Outcomes, 2020.
7. Professional Information. Ixarola. 2022 [Internet]. Available at: https://pi-pil-repository. sahpra.org.za/wp-content/uploads/2022/05/ approved-ixarola-15-20-pil-05.2022.pdf
8. Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clinical Pharmacokinetics, 2019.
9. Schaefer JK, McBane RD, Wysokinski WE. How to choose appropriate direct oral anticoagulant for patients with nonvalvular atrial fibrillation. Ann Hematol, 2016.
10. Vrijens B, Heidbuchel H. Non-vitaman K antagonist oral anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace, 2015.
11. Agnelli G, Buller HR, Cohen A, et al Apixaban for Extended Treatment of Venous Thromboembolism. NEJM, 2013.
12. Benz AP, Eikelboom JW, Yusuf S, et al. LongTerm Treatment with Apixaban in Patients with Atrial Fibrillation: Outcomes during the OpenLabel Extension following AVERROES. Thromb Haemost, 2021.
13. Ray WA, Chung CP, Stein M, et al Association of Rivaroxaban vs Apixaban with Major Ischemic or Hemorrhagic Events in Patients with Atrial Fibrillation. JAMA, 2021. SF
This article was independently sourced by Specialist Forum
Click for the quiz
Atrial fibrillation (AFib), characterised by chaotic and irregular electrical activity in the upper chambers of the heart, is the most common heart dysrhythmia worldwide. The prevalence of AFib is increasing due to the growing ageing population. Between 2010 and 2019, the global prevalence of AFib increased from 33.5 million to 59 million. This trend is expected to continue in the coming decades.1,2
Non-valvular AFib (NVAF) - AFib without rheumatic valvular disease - is the most common type and is a strong independent predictor of stroke. Apart from stroke (5-fold), individuals living with AFib are at increased risk of myocardial infraction (MI, 2-fold), heart failure, as well as dementia and cognitive decline.1,2
NOACs compared to warfarin
The main goal in managing AFib is stroke prevention. Oral anticoagulants (OACs) are recommended to mitigate the risk of stroke and reduce overall mortality. Before the development of direct OACs or non-vitamin K antagonists (NOACs) such as apixaban, dabigatran, and rivaroxaban, vitamin K antagonists (VKAs) such as warfarin, was the standard of care for stroke prevention in individuals living with NVAF. However, since the launch of NOACs more than a decade ago, numerous studies have shown that these agents are not only more convenient for patients, but also have similar or better efficacy and safety profiles than warfarin.1,3
The largest observational study to date comparing NOACs (apixaban, dabigatran, rivaroxaban) and warfarin titled A nticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients), included 434 046 participants living with NVAF. The study compared the safety and efficacy of NOACs compared to warfarin in reducing the risk of stroke/systemic embolism (SE) and major bleeding (MB). 3
The study matched six cohorts: 100 977 patient pairs for apixabanwarfarin, 36 990 for dabigatran-warfarin, 125 068 for rivaroxaban-warfarin, 37 314 for apixaban-dabigatran, 107 236 for
apixaban-rivaroxaban, and 37 693 for dabigatran-rivaroxaban. Results showed that compared to warfarin, apixaban (hazard ratio [HR] 0.64), dabigatran (HR 0.82), and rivaroxaban (HR 0.79) were associated with lower rates of stroke/SE. Apixaban (HR 0.60) and dabigatran (HR 0.71) had lower rates of MB compared to warfarin, while rivaroxaban (HR 1.06) had a higher rate compared to warfarin. 3
Apart from the lower rates of stroke/ SE, and MB shown with apixaban and dabigatran, NOACs are associated with fewer monitoring requirements, less frequent follow-up, more immediate drug onset and offset effects (important for peri-procedural and acute bleeding management), as well as fewer drug and food interactions.4
As mentioned, prior to the launch of NOACs, VKAs were the only options for OACs in patients living with AFib. Since the launch of NOACs, these agents are increasingly being used. However, caution Kefale et al (2021), switching from one OAC to another, can negatively affect clinical outcomes and healthcare costs. 5
The team conducted a comprehensive review on the patterns of OAC switching in patients living with NVAF patients, possible rationales for switching, associated clinical outcomes, and predictors of switching. 5
They found that switching rates differed notably between specific OACs: Dabigatran users had the highest rates, while apixaban users had lower rates.
Switching was highest within the first three months of OAC initiation but continued to increase with longer follow-up. For VKAs, switching rates ranged from 2.7% to 33.8% within a year, while NOAC rates
were 4.9%-14.9% combined. The highest recorded switching rate for DOACs was 19.6% within 24 months. Notably, patients on VKAs frequently switched to apixaban, rivaroxaban or dabigatran. 5
The team found that the decision to switch is influenced by various clinical or patientrelated factors. A 2021 Danish study involving 50 623 participants found that clinical events contributing to switches from VKAs to NOACs included thrombotic complications, bleeding, anaemia, new contraindications, and procedures to restore sinus rhythm.5
Another study investigating switching from warfarin to a NOAC, found that among patients initially treated with warfarin, 3.7% switched due to ease of use. Ease-of-use issues included unstable international normalised ratio (INR), frequent monitoring, poor adherence, dietary restrictions, and side effects. 5
In terms of clinical outcomes, Kefale et al found that switching from warfarin to dabigatran resulted in a reduced rate of gastrointestinal (GI) bleeding with a hazard ratio (HR) of 0.69 and intracranial haemorrhage (ICH) with an HR of 0.53. It was also associated with a 43% reduction in all-cause mortality. However, there was no significant difference in the rate of ischaemic stroke (IS, HR 1.19). 5
An Italian study examined the effectiveness and safety of switching from a VKA to a NOAC in patients with a CHA2DS2-VASc score ≥2. These patients had been on a VKA for at least six months before switching and were followed for at least six months postswitching. Switchers experienced a 50% lower risk of CV events (HR 0.5) and a 50% lower risk of bleeding (HR 0.5).5
Another study focused on switching from apixaban to warfarin found that a
higher proportion of switchers experienced major bleeding (8.2% vs 2.2%) and stroke/ SE (3.2% vs 1.4%) compared to those who continue apixaban. 5
A large retrospective cohort study with 55 749 patients assessed the clinical outcomes of switching from warfarin to rivaroxaban. Patients who switched to rivaroxaban (n=11 845) were matched with warfarin-only users (n=43 904) using propensity scoring. Switchers had an increased risk of GI bleeding compared to non-switchers (HR 1.55), which was notably higher in the first 90-days following switching (HR 2.33). There were no significant differences in the rates of IS (HR 1.06), ICH (HR 1.04), or MI (HR 1.08).5
Strategy for switching from warfarin to DOACs
According to Abdelnabi et al, it is safe to promptly initiate NOACs once the INR is ≤2. If the INR is between 2 and 2.5, NOACs can also be started immediately or the following day. However, if the INR is >2.5, it is recommended to consider both the actual INR level and the half-life of warfarin (36–48 hours) to determine the appropriate starting time.6
For apixaban, indicated in South Africa for the prevention of stroke/SE in adult patients living with NVAF who have one or more risk factors such as prior stroke or transient ischaemic attack, age ≥75 years, hypertension, diabetes, or symptomatic HF (New York Heart Association Class ≥II), the following is recommended:7
_ Switching treatment from parenteral OACs to apixaban (and vice versa) can be done at the next scheduled dose, avoiding simultaneous administration _ When switching from a VKA to apixaban, discontinue VKA therapy and start apixaban when the INR is <2 _ When switching from apixaban to VKA therapy, continue apixaban for at least two days after starting VKA therapy. Co-administration should continue until the INR is ≥2, with an INR check prior to the next apixaban dose.
Is it safe to switch from one NOAC to another?
According to Deitelzweig et al, switching between NOACs happens frequently in clinical practice. Patients may switch from one NOAC to another for various reasons as mentioned above. In addition, they may also switch NOACs due to restrictions such as formulary exclusion or increased out-of-pocket costs associated with formulary tier increase.1
To answer the question posed above, the team evaluated stroke/SE and MB risks among patients living with NVAF continuing or switching to a different NOAC (apixaban
and rivaroxaban). The study included data from 264 026 privately insured individuals.1
The study outcomes were stroke/SE and MB events during the follow-up period (10.5 months for apixaban-to-rivaroxaban switchers and 11.5 months for apixaban continuers1). Stroke/SE events included IS, haemorrhagic stroke (HS), and SE. MB events included GI bleeding, ICH, and MB at other key sites.1
Among apixaban initiators, the incidence rate of stroke/SE and MB was 1.53 and 4.59, respectively, for those who switched from apixaban to rivaroxaban, compared to 0.75 and 2.44 for those who continued on apixaban. Patients switching from apixaban to rivaroxaban had a higher risk of stroke/ SE (HR 1.99) and MB (HR 1.80) compared to apixaban continuers. Specifically, these switchers were at higher risk of IS, HS (HR 2.12), GI bleeding (HR 2.15), and other bleeding (HR 1.50).1
Among rivaroxaban initiators, the incidence rate of stroke/SE and MB was 0.61 and 2.01, respectively, for those who switched to apixaban, compared to 0.78 and 3.89 for those who continued on rivaroxaban. Patients switching from rivaroxaban to apixaban had a similar risk of stroke/SE (HR 0.74) but a lower risk of MB (HR 0.49), GI bleeding (HR 0.44), and other bleeding (HR 0.59.1
The findings of the sensitivity analysis were consistent with those of the main analysis. Among patients who initiated the standard dose of apixaban, those who switched to rivaroxaban had a higher risk of stroke/ SE (HR 1.69) and MB (HR 1.76) compared to apixaban continuers. Conversely, among patients who initiated the standard dose of rivaroxaban, those who switched to apixaban had a similar risk of stroke/SE (HR 0.76), but a lower risk of MB (HR 0.82) compared to rivaroxaban continuers.1
The authors concluded that switching from apixaban to rivaroxaban was associated with a higher risk of stroke/SE and MB vs continuous apixaban treatment, while switching from rivaroxaban to apixaban was associated with a similar risk of stroke/ SE and a lower risk of MB vs continuous rivaroxaban treatment. These findings may aid physicians and patients in making informed decisions when considering a switch between apixaban or rivaroxaban.1
Key messages
Efficacy and safety profiles: NOACs (apixaban, dabigatran, rivaroxaban) have shown comparable or better efficacy in reducing stroke/SE and MB compared to warfarin. 3
Reasons for switching : Common reasons for switching include adverse effects, poor
anticoagulation control with warfarin, and specific patient preferences. Patients may also switch due to formulary restrictions or changes in drug coverage, impacting both clinical outcomes and healthcare costs.1,5
Switching patterns and timing : Switching rates vary significantly depending on the OAC used initially, with higher rates observed within the first three months and continuing over time. 5
Safety of switching : It is generally safe to switch from one NOAC to another, however, clinical outcomes such as stroke/SE and MB risks should be carefully monitored during the transition.1
Timing of switching : When switching from warfarin to NOACs, it is recommended to start NOACs promptly once the INR is ≤2 to minimise the risk of bleeding or thrombotic events. 6
Specific considerations for apixaban : When switching from VKAs to apixaban, ensuring the INR is <2 before starting apixaban is recommended to avoid overlapping anticoagulation effects.7
Risk of adverse events: Switching from apixaban to rivaroxaban has been associated with a higher risk of stroke/SE and MB compared to continuous apixaban treatment, whereas switching from rivaroxaban to apixaban showed a lower risk of MB.1
Shared decision-making : Informed decision-making involving both physicians and patients is crucial when considering a switch between OACs to balance risks, benefits, and patient preferences.1
1. Deitelzweig S, Kang A, Jiang J, et al. Clinical Impact of Switching or Continuation of Apixaban or Rivaroxaban among Patients with NonValvular Atrial Fibrillation. J Clin Med, 2024.
2. Linz L Gawalko M, Betz K, et al. Atrial fibrillation: epidemiology, screening and digital health. The Lancet, 2024.
3. Lip GYH, Keshishian A, Li X, et al. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. The ARISTOPHANES Study. Stroke, 2018.
4. Chen A, Stecker E, Warden BA. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. Jour Amer Heart Assoc, 2020.
5. Kefale AT, Peterson GM, Bezabhe WM, Bereznicki LR. Switching of oral anticoagulants in patients with nonvalvular Atrial fibrillation: A narrative review. Br J Clin Pharmacol, 2022.
6. Abdelnabi M, Benjanuwattra J, Okasha O, et al Switching from Warfarin to Direct-Acting Oral Anticoagulants: It is time to move forward! Egypt Heart J, 2022.
7. Professional information. Eliquis. 2023. [Internet]. Available at: https://labeling.pfizer. com/ShowLabeling.aspx?id=12118 SF
for the PREVENTION of Stroke and Systemic Embolism in your patients with NON-VALVULAR ATRIAL FIBRILLATION2 &
& for the TREATMENT of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) and PREVENTION of Recurrent DVT and PE.2 for the PREVENTION OF VENOUS THROMBOEMBOLIC EVENTS after elective knee and hip replacement surgery2 For ELIQUIS ® (apixaban) prescribing information, scan the QR code
References: 1. Data on file, IQVIA MIDAS® Q2’23 Sell-In/Sell-Out data 2. Pfizer Laboratories (Pty) Ltd. ELIQUIS® (apixaban) 2,5 mg and 5 mg Film-coated Tablets. Approved Package Insert – 11 July 2022. To access the ELIQUIS ® (apixaban) website, scan the QR code
S4 ELIQUIS® 2,5mg and 5mg Film-coated Tablets (Reg. No’s: 47/8.2/0463, 0464). Each film-coated tablet contains either 2,5 mg or 5 mg apixaban, respectively
To report an adverse event, please contact ZAF.AEReporting@pfizer.com . If you wish to contact Pfizer for any other purpose, please use contact details: +2711 320 6000 or 0860 734 937 (SA) . Monday-Friday 09h00-17h00.
Pfizer Laboratories (Pty) Ltd. Company Reg. No. 1954/000781/07. Building 2, 1st Floor, Maxwell Office Park, Magwa Crescent, Waterfall City, Midrand, Johannesburg, South Africa. Tel. No: 0 860 PFIZER (734937). Copyright © 2023. Pfizer Laboratories (Pty) Ltd. All rights rese rved P P - ELI - Z A F - 0493
The advent of non-vitamin K antagonist oral anticoagulants (NOACs) such as apixaban represented a pivotal advancement in stroke management among patients living with atrial fibrillation (AFib). NOACs have also been shown to be effective in the prevention and treatment of venous thromboembolism (VTE). These agents offer benefits such as no routine coagulation monitoring, minimal food interactions, and fewer drug interactions compared to vitamin K antagonists (VKAs) such as warfarin.1,2
Several landmark phase 3 trials have demonstrated the efficacy and safety of NOACs reducing the risk of stroke and mortality in patients living with AFib, as well as VTE. 3,4,5,6
Granger et al conducted a randomised, double-blind study comparing apixaban (5mg twice daily) with warfarin (target
international normalised ratio [INR] 2.0 to 3.0) in patients (n=18 201) with one additional stroke risk factor. 3
Over a median follow-up of 1.8 years, apixaban significantly reduced the primary outcome (ischaemic or haemorrhagic stroke or systemic embolism) compared to warfarin (1.27% vs 1.60% per year).
Apixaban also lowered major bleeding (2.13% vs 3.09% per year), and all-cause mortality (3.52% vs 3.94%) rates. 3
Haemorrhagic stroke incidence was significantly lower with apixaban (0.24% vs 0.47% per year). The study authors concluded that in patients living with AFib, apixaban was superior to warfarin in
preventing stroke or systemic embolism, with lower bleeding and mortality. 3
In a trial comparing rivaroxaban (20mg daily) to warfarin in patients (n= with 14 264) at risk of stroke, rivaroxaban showed noninferiority to warfarin for stroke or systemic embolism prevention, with fewer intracranial and fatal bleedings. In the per-protocol analysis, stroke or systemic embolism rates were 1.7% with rivaroxaban versus 2.2% with warfarin, while major bleeding rates were similar. 4
In another trial, dabigatran (110mg or 150mg twice daily) was compared to warfarin in patients (n=18 113) at risk of stroke. Dabigatran 110mg showed noninferiority for stroke or systemic embolism (1.53% vs 1.69% per year for warfarin) and lower major bleeding rates (2.71% vs 3.36% per year). Dabigatran 150mg demonstrated superiority for stroke prevention (1.11% per year) and similar major bleeding rates (3.11% per year) compared to warfarin. Haemorrhagic stroke rates were significantly lower with both doses of dabigatran. 5
Cohen et al conducted a study comparing the effectiveness and safety of apixaban versus warfarin in patients with VTE who were at increased risk of bleeding or recurrent VTE. Results showed that apixaban patients had a lower risk of recurrent VTE, major bleeding, and clinically relevant non-major bleeding compared to warfarin patients. 6
Subgroup analyses revealed consistent findings across various patient groups at increased risk of bleeding or recurrences. Importantly, there were no significant interactions between treatment and subgroup strata on VTE, major bleeding, and clinically relevant non-major bleeding. 6
The study concluded that apixaban demonstrated superior outcomes in terms of reduced VTE recurrence and bleeding risk compared to warfarin, with consistent effects observed across different patient subgroups. 6
NOACs vary in pharmacokinetics and dosing regimens, depending on the indication. For instance, rivaroxaban is administered once daily for stroke prophylaxis, twice daily for acute VTE treatment, and once daily for VTE secondary prevention. In contrast, dabigatran and apixaban are consistently given twice daily, irrespective of the indication.7
Despite the effectiveness and safety of NOACs in decreasing the risk of stroke among patients living with AFib and VTE,
real-world studies show that the prescribing of anticoagulant therapy frequently deviates from the dosing regimen as recommended by medical regulatory bodies, potentially diminishing the protective benefits of NOACs. 6,8
Another challenge is suboptimal patient adherence to anticoagulation therapy. Patient adherence involves three key components: Initiation, implementation, and discontinuation. Initiation marks the beginning of treatment, implementation refers to following the dosing regimen as prescribed, and discontinuation signifies the end of therapy.9
Apixaban is superior to warfarin in terms of reduced VTE recurrence and bleeding risk
A study evaluating patient adherence to warfarin revealed widespread nonadherence, with ~92% of patients having at least one missed or extra dose over a mean period of 32 weeks. Additionally, 36% missed >20% of their prescribed doses, and 4% took more than 10% extra doses.9
This poor adherence significantly impacted anticoagulation control, with missing one to two doses per week associated with up to a two-fold increased likelihood of sub-therapeutic INR values. Conversely, taking extra doses was linked to an increased risk of excessively high INR levels. Adhering to appropriate dosing regimens can protect patients from unfavourable outcomes, stresses BeyerWestendorf et al 8,9
Which dosing regimen can improve patient adherence: Once- or twice-daily?
Traditionally, it was believed that reducing the frequency of dosing (eg once-daily dosing) could enhance adherence. According to Vrijens and Hedibuchel, this idea originated from concentrating solely on the number of doses taken, without considering when the doses were actually taken.9
Comparisons between once-daily and twice-daily dosing regimens reveal that
despite a higher percentage of prescribed doses being taken with once-daily dosing, twice-daily dosing ensures a greater degree of continuity in drug action.9
Furthermore, stress Vrijens and Hedibuchel, while once-daily dosing may appear to simplify dosing regimens and improve patient adherence, it requires nearperfect adherence to achieve intended pharmacodynamic and clinical outcomes. In contrast, twice-daily dosing, depending on the agent’s pharmacokinetics, is more forgiving of variations in dose timing or occasional missed doses9
A crucial aspect to consider when prescribing an agent is that patients undergoing once-daily NOAC treatment face a greater risk of gastrointestinal (GI) bleeding compared to those on warfarin regimens. This increased risk is believed to be linked to the peak level of drug concentration, which is anticipated to be higher in once-daily regimens than in twicedaily regimens.10
According to Ido et al, opting for twicedaily dosing over once-daily dosing could theoretically reduce the peak level of drug concentration in both the gut lumen and blood plasma. This adjustment may lead to a narrower range of drug concentration within the twice-daily regimen compared to the once-daily regimen, potentially contributing to an improved safety profile.10
To test this theory, Ido et al assessed the effect of once-daily versus twice-daily regimens on GI bleeding in a real-world setting. This study was conducted as a single-center prospective observational registry. It enrolled adult patients (aged ≥18 years) living with AFib who were prescribed apixaban, dabigatran, rivaroxaban, and a fourth NOAC not yet approved in South Africa.10
Patients (n=2216) were categorised into two groups based on their regimen: The twice-daily regimen group (comprising dabigatran and apixaban users) and the once-daily regimen group (consisting of rivaroxaban and the as yet unapproved NOAC).10
The primary endpoint was GI bleeding, defined as any bleeding within the GI tract identified through medical records, irrespective of site or severity. Secondary endpoints included all-cause mortality, stroke, major bleeding, and any bleeding.10
Stroke was characterised by a neurological deficit persisting for at least 24 hours, attributed to acute focal injury of the central nervous system by a vascular cause. Major bleeding was defined per the International Society on Thrombosis and Haemostasis (ISTH) criteria, involving
clinically evident bleeding accompanied by a decrease in haemoglobin level of at least 2g/dL, transfusion of at least two units of packed red cells, occurrence at a critical site, or resulting in death.10
Any bleeding constituted a composite of major bleeding and clinically relevant non-major bleeding, following ISTH criteria. Clinical events were monitored through questioning, physical examination, and laboratory tests at outpatient visits conducted every two to four months. Follow-up was about two years.10
Ido et al showed that the incidence of GI bleeding was notably lower in the twicedaily regimen group compared to the oncedaily regimen (3.5 per 100 person-years vs 6.2 per 100 person-years.10
Furthermore, the occurrence of major bleeding was significantly reduced in patients receiving the twice-daily regimen. However, no significant differences were observed in all-cause mortality, stroke, or any bleeding between the two regimens groups.10
In the overall study population, the risk of GI bleeding was lower in the twice-daily regimen. Importantly, the superiority of the twice-daily regimen was consistently observed across various subgroups.10
Clemens et al compared the risk-benefit balance between twice- and once-daily dosing regimens of NOACs. They conducted a rigorous, stepwise meta-analysis with predefined quality criteria for heterogeneity to derive common estimates for twice- and once-daily dosing regimens.11
Comparing twice- and once-daily versus regimens, the hazard ratios (HR) for stroke and systemic embolism were 0.75 for dabigatran 150mg twice-daily and 0.91 for apixaban twice daily.11
For ischaemic stroke, the HR of twiceversus once-daily versus was 0.85. In terms of intracranial haemorrhage, the HR for twice-daily versus rivaroxaban once-daily was 0.57.11
The authors concluded that twicedaily dosing regimen appears to offer a more balanced risk-benefit profile concerning stroke prevention and intracranial haemorrhage.11
Once-daily dosing does not improve adherence
The key question remains: Does oncedaily dosing improve patient adherence? A recent study by Hwang et al assessed the impact of once- or twice-daily dosing on adherence and clinical outcomes in patients living with AFib. The study compared adherence levels and clinical outcomes among patients (n=33 515)
prescribed different NOACs with varying dosing regimens.12
High adherence was defined as a proportion of days covered of the index NOAC of 80% or higher. Clinical outcomes included stroke, acute myocardial infarction, death, and a composite outcome measure.12
The study found that 95% of patients achieved high adherence to NOAC therapy, with no significant differences observed based on dosing regimen. Across all dosing regimens, the mean proportion of days covered for NOACs was ~96%.12
Notably, adherence was highest among apixaban users, followed by rivaroxaban users, and lowest among dabigatran users, irrespective of dosing frequency. Adverse outcomes were more prevalent among patients with low adherence to NOAC therapy, regardless of the dosing regimen.12
Conventional wisdom favouring once-daily dosing regimens for enhanced adherence may not apply to patients living with AFib treated with NOACs
It seems that the conventional wisdom favouring once-daily dosing regimens for enhanced adherence may not apply to patients living with AFib undergoing treatment with NOACs.
Studies comparing NOACs suggest that twice-daily dosing offers better drug action continuity, and a more balanced risk-benefit profile with the latter, especially regarding stroke prevention, intracranial haemorrhage and GI bleeding.
In conclusion, while NOAC therapy has significantly advanced stroke management in AFib patients and VTE treatment, optimising dosing regimens and ensuring patient adherence remain pivotal for favorable outcomes.
The selection between once- and twice-daily dosing should carefully weigh factors like drug continuity, safety, and patient preferences, aiming to maximise therapeutic benefits while minimising risks.
References
1. Ho THQ, Ton MT, Nguyen VL, et al. Selection of
Non-vitamin K Antagonist Oral. Anticoagulant for Stroke Prevention in Atrial Fibrillation Based on Patient Profile: Perspectives from Vietnamese Experts. Part 1. European Cardiology Review, 2023.
2. Renta G, de Caterina R. The new oral anticoagulants in atrial fibrillation: Once daily or twice daily? Vascular Pharmacology, 2013.
3. Granger CB, Alexander JH, McMurray JJV, et al Apixaban versus warfarin in patients with atrial fibrillation, NEJM, 2011.
4. Patel MR, Mahaffey KW, Garg J, et al Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. NEJM, 2011.
5. Connolly SJ, Ezekowitz MD, Yusuf S, et al Dabigatran versus warfarin in patients with atrial fibrillation. NEJM, 2019.
6. Cohen AT, Sah J, Dhamane AD, et al. Effectiveness and Safety of Apixaban vs Warfarin in Patients with Venous Thromboembolism with Risk Factors for Bleeding or for Recurrences. Adv Ther, 2023.
7. Patti G, Haas S. Non-Vitamin K Antagonist Oral Anticoagulants and Factors Influencing the Ischemic and Bleeding Risk in Elderly Patients with Atrial Fibrillation: A Review of Current Evidence. J Cardiovasc Pharmacol, 2020.
8. Beyer-Westendorf J, Fay M, Amara W. The Importance of Appropriate Dosing of Nonvitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation. TH Open, 2021.
9. Vrijens B, Heidbuchel H. Non-vitamin K antagonist oral anticoagulants: considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. Europace, 2015.
10. Ido T, Sasaki S, Sotomi Y, Hirata A, et al Twice- or once-daily dosing of direct oral anticoagulants and gastrointestinal bleeding in patients with atrial fibrillation. Am Heart J Plus, 2022.
11. Clemens A, Noack H, Brueckmann M, Lip GY. Twice- or once-daily dosing of novel oral anticoagulants for stroke prevention: a fixed-effects meta-analysis with predefined heterogeneity quality criteria. PLoS One. 2014
12. Hwang H-J, Sohn S, Jin E-S, Bae Y-J. Adherence and clinical outcomes for twicedaily versus once-daily dosing of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: Is dosing frequency important? PLoS ONE, 2023. SF
EZETIMIBE 10 mg & ROSUVASTATIN 5, 10, 20 mg
ONE effective, complementary and well-tolerated lipid-lowering fixed dose combination with TWO active ingredients 1,2
Indicated for* Primary hypercholesterolaemia
Homozygous familial hypercholesterolaemia (HoFH) Prevention of cardiovascular events
This article was independently sourced by Specialist Forum.
High blood cholesterol levels, better known as hypercholesterolaemia (HC), is a lipid disorder and a recognised risk factor for cardiovascular (CV), cerebrovascular (stroke), and peripheral vascular (ischaemic heart disease and atherosclerosis) diseases. Recent data indicates that ~28.5 million adults (≥20-years) are affected by elevated levels of total serum cholesterol, accounting for a reported prevalence of 11.9%.1,2
CVD is the leading cause of mortality globally, contributing to ~30% of global fatalities. In 2017, 17.8 million deaths were attributed to CVD, a significant 21.1% increase from 2007. Projections indicate a continued upward trajectory, with estimated annual mortality expected to approach nearly 24 million by 2030.1
Definition and classification of hypercholesterolaemia
HC is defined as low-density lipoproteincholesterol (LDL-C) levels >4.9mmol/l, surpassing >4.1mmol/l with at least one major risk factor, or >3.3mmol/l with two CV risk factors. These risk factors include age (men aged ≥45-years and women aged ≥55-years or a positive family history of premature atherosclerotic CVD (ASCVD, occurring in men <55-years years and women <65-years), hypertension, diabetes, smoking, and low high-density lipoprotein-C (HDL-C) levels (<1mmol/l in men and <1.4mmol/l in women). 3
HC can be classified as either primary (genetic or familial) or secondary (acquired). In familial cases, genetic mutations in the LDL receptor gene are responsible for ~85% of cases. Other contributing factors include defects in apolipoprotein B, mutations in the proprotein convertase subtilisin/kexin type 9 gene resulting in gain-of-function, mutations in the LDL receptor adaptor protein, and polygenic HC. 2
Acquired causes of HC include diseases such as hypothyroidism, diabetes, nephrotic syndrome, and cholestasis. Furthermore, certain pharmacotherapies such as cyclosporine and thiazide diuretics, along with high dietary cholesterol intake and smoking, have been associated with an increased risk of developing HC. 2
As mentioned, age is a significant risk factor for HC, with older individuals exhibiting a higher risk of developing HC regardless of gender. However, HC are often undetected in younger age groups, including teenagers and young adults
between 18- and 25-years. A 2020 study showed that the prevalence of HC in this age group is 23.7%. 2
Who should be screened?
The European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) recommend risk factor screening, including a lipid profile, for men ≥40- years, and in women ≥50-years or post-menopausal, particularly in the presence of other risk factors.4
In addition, all individuals with evidence of ASCVD and type 2 diabetes (T2DM) –irrespective of age – and those with a family history of premature CVD, arterial hypertension, central obesity (defined as an increased waist circumference of ≥94cm for men and ≥80cm for women, or with a BMI ≥25 kg/m2), autoimmune chronic inflammatory conditions (eg rheumatoid arthritis, systemic lupus erythematosus, and psoriasis), chronic kidney disease (CKD), characterised by an estimated glomerular filtration rate <60mL/min/1.73 m2, should be screened for dyslipidaemias. 4
Furthermore, recommend the ESC/ EAS, individuals with clinical signs of genetic dyslipidaemias (eg xanthomas [fatty deposits that build up under the skin, resulting in small, yellowish bumps or nodules], xanthelasmas [yellowish patches or deposits that form on the eyelids], and premature arcus cornealis [a grayish or white ring around the edge of the cornea]), warrant attention as they may indicate severe lipoprotein disorders, particularly familial HC (FHC). 4
In a South African context, it is important to note that antiretroviral therapies can accelerate atherosclerosis in patients with peripheral artery disease (PAD) or elevated carotid intima-media thickness or plaques. Additionally, screening the offsprings of individuals living with severe dyslipidaemia, including FHC, familial combined hyperlipidaemia, or chylomicronaemia, is recommended. Similarly, screening relatives of patients with premature CVD for significant lipoprotein disorders is advisable. 4
Who is at risk of adverse events?
Patients at very high risk are those with documented CVD through invasive or non-invasive testing, previous myocardial infarction, acute coronary syndrome, coronary revascularisation procedures, ischaemic stroke, PAD, T2DM, type 1 diabetes with target organ damage, and moderate to severe CKD. Additionally, those with a calculated 10-year risk SCORE ≥10% are included in the very highrisk category. 4
High-risk individuals may have markedly elevated single risk factors or a calculated SCORE ≥5% and <10% for 10-year risk of fatal CVD. Moderate-risk individuals have a SCORE ≥1% and <5% at 10 years, with various factors modulating this risk. Lowrisk individuals have a SCORE <1%. 4 Guidelines recommend tailoring preventive measures based on the overall CV risk level. Recommendations for lipid analysis target levels differ according to risk level, with less stringent targets for lowerrisk individuals. 4
A reduction of LDL-C levels by 1mmol/l correlates with a 22% reduction in CVD mortality and morbidity. For patients at very high CV risk, the LDL-C treatment target is <1.8mmol/L or a ≥50% reduction from baseline LDL-C, achievable with monotherapy. 4
High-risk individuals should aim for an LDL-C level <2.5mmol/l, with secondary targets based on clinical judgement. Moderate-risk individuals should consider an LDL-C target of <3mmol/l. 4
Lowering LDL-C reduces the risk of CVD
Statins, which inhibit cholesterol synthesis, are recommended as first-line therapy due to their safety and efficacy in lowering LDL-C levels. Statins inhibit cholesterol synthesis, leading to increased LDL receptor expression and decreased circulating LDL-C.1,4
Several meta-analyses have explored the efficacy and safety of statins for primary and secondary prevention of CV morbidity and mortality. In the meta-analyses conducted by the Cholesterol Treatment Trialists, which included data from 170 000 participants across 26 randomised trials of statins, a reduction in all-cause mortality by 10% and in coronary artery disease mortality by 20% per 1mmol/L reduction in LDL-C was observed.4
There was also a 23% reduction in major CV events (MACE) and a 17% reduction in stroke risk per 1mmol/L reduction in LDL-C. These proportional reductions in MACE rates remained consistent across all examined subgroups. While the benefits were noticeable within the first year, they became more pronounced in subsequent years.4
While many patients achieve target LDL-C levels with statin monotherapy, some high-risk individuals or those with exceptionally high LDL-C levels may require additional treatment. Furthermore, some patients may be intolerant to statins or unable to tolerate higher doses. In such scenarios, combination therapy becomes a viable option to manage HC effectively. 4
The addition of non-statin therapies, either ezetimibe or a proprotein convertase subtilisin/kexin type 9 inhibitor to statin therapy, has shown to enhance CV outcomes.1
Ezetimibe works by inhibiting cholesterol absorption at the brush border of the intestine, likely through interaction with the Niemann-Pick C1-Like 1 protein. By doing so, it decreases the amount of lipoprotein cholesterol circulated to the liver. 4
Consequently, the liver responds by up-regulating LDL receptors, resulting in increased clearance of LDL from the bloodstream. When used alone, ezetimibe reduces LDL-C levels in patients with HC by 15%-22%. 4
An American College of Cardiology/ American Heart Association scientific report, recommend adding a non-statin in patients with a very high-risk of ASCVD, defined as individuals with a history of multiple major ASCVD events or specific high-risk conditions, if LDL-C levels remain ≥1.8mmol/l despite statin therapy.5
For patients with severe primary HC (LDL-C level ≥4.9mmol/l), high-intensity statin therapy is recommended. If LDL-C levels remain elevated (≥2.6mmol/l) despite statin therapy, ezetimibe may be added.5
How safe and effective is combination therapy?
According to the ESC/EAD, combining ezetimibe with a statin can further lower LDL-C levels by an additional 15%-20%.
A 2008 study showed that concurrent use of ezetimibe and a statin reduces the occurrence of ischaemic CV – especially in patients with less severe aortic stenosis –by up to 46%. Furthermore, a 2011 study yielded positive results in patients living with CKD treated with combination ezetimibe and a statin. 4
Ballantyne et al conducted a study to assess the efficacy and safety of rosuvastatin 40mg alone or in combination with ezetimibe 10mg in patients (n=469) at high risk of coronary heart disease. Patients were randomly assigned to receive either rosuvastatin alone or in combination with ezetimibe for six weeks. 6
The primary endpoint was the percentage of patients achieving an LDL-C goal of (<2.586mmol/l) at week six. Secondary endpoints included the percentage of patients achieving other lipid goals, changes in lipid, lipoprotein, and inflammatory parameters from baseline, and safety and tolerability. 6
The study found that significantly more patients receiving rosuvastatin/ezetimibe achieved LDL-C goals (<2.5mmol/l) compared to those receiving rosuvastatin alone (94.0% vs 79.1%), as well as the optional LDL-C goal (<1.8mmol/l) for very high-risk patients (79.6% vs 35.0%). 6
The combination of rosuvastatin/ ezetimibe also resulted in significantly greater reductions in LDL-C compared to rosuvastatin alone (69.8% vs 57.1%). Other components of the lipid/lipoprotein profile were also significantly improved with rosuvastatin/ezetimibe. 6
After six weeks of treatment, median percent decrease in high-sensitivity C-reactive protein (hs-CRP) was significantly higher with combination therapy than monotherapy (-46.4% vs -28.6%). Total cholesterol decreased by -42% vs -51% in the monotherapy group versus the combination therapy group from baseline. HDL-C increased by +9% and +11% respectively, and triglycerides decreased by -25% in the monotherapy versus 35% combination groups. 5,6
Apolipoprotein A1 increased in the monotherapy group (+3%) and combination group (+2%) while apolipoprotein B decreased by 46% in the monotherapy group compared to 57% in the combination group. 6
Both treatments were generally well tolerated, with rosuvastatin 40mg
effectively improving the atherogenic lipid profile in this high-risk population. Combining rosuvastatin with ezetimibe enabled greater decreases in LDL-C and allowed more patients to achieve LDL-C goals. In conclusion, rosuvastatin plus ezetimibe may improve the management of high-risk patients who cannot achieve goal on maximal statin monotherapy, concluded Ballantyne et al 5
The Efficacy and Safety of Ezetimibe and Rosuvastatin Combination Therapy Versus Those of Rosuvastatin Monotherapy in Patients with Primary Hypercholesterolemia study, by Kim et al was a multicentre, randomised, doubleblind study, which comprised a main study and an extension study.7
In the main study, the effectiveness and safety of combining rosuvastatin (at doses of 5mg, 10mg, and 20mg) with ezetimibe (10mg) were compared with rosuvastatin monotherapy (at the same doses).7
Participants who achieved LDL-C goals in the main study consented to participate further and were enrolled in the extension study. In the extension study, ezetimibe (10mg) was also administered to participants who had previously received rosuvastatin monotherapy in the main study, and the same treatment was continued for participants who had received the combination of rosuvastatin with ezetimibe.7
At the end of the main study (week eight), LDL-C levels were significantly lower in participants receiving combination therapy compared to those receiving rosuvastatin monotherapy (56.4% vs -45.1%).7
A higher percentage of participants achieved the LDL-C goal at week eight in the combination treatment group compared to the monotherapy group (94.15% vs 86.63%), observed not only in the pooled group but also in the subgroups stratified by rosuvastatin doses. 6
Other lipid profiles also significantly improved in the combination therapy
group, and these improvements continued in the extension study (see Table 1). Apolipoprotein A-1/apolipoprotein B ratio decreased by -40.3% and -49.1% in the combination therapy and monotherapy groups, respectively. The change from baseline in triglycerides were -9.37% versus 19.86% and HDL-C increased by 9.3% and 10.8% in the monotherapy and combination groups, respectively. 6,7
Additional subgroup analyses were conducted based on the presence of diabetes, demonstrating that the efficacy of combination therapy was sustained in patients with this disease.7
Furthermore, in participants living with diabetes, the combination of rosuvastatin 5mmg and ezetimibe exhibited a higher percentage change in LDL-C compared to rosuvastatin 10mg or 20mg alone. 6
The combination therapy of rosuvastatin and ezetimibe was generally well tolerated. The increased dosage of rosuvastatin was also well tolerated in the combination treatment. 6
The authors concluded that combining ezetimibe (10mg) with varying doses of rosuvastatin commonly used in clinical practice improved the lipid profile and allowed more participants to reach the LDL-C goal in primary HC compared to rosuvastatin monotherapy. 6
Additionally, the effectiveness of combination therapy was maintained for an extended period. Additional beneficial changes were also achieved with combination therapy even in patients who responded well to rosuvastatin monotherapy.6
Combination therapy with rosuvastatin/ ezetimibe presents a promising approach for managing high-risk patients with HC who struggle to achieve target goals with maximal statin therapy alone.
Rosuvastatin/ezetimibe combination therapy not only significantly improves
lipid profiles but also enables a higher percentage of patients to reach LDL-C goals compared to rosuvastatin monotherapy. The efficacy of rosuvastatin/ezetimibe combination therapy was sustained over an extended period, demonstrating its potential as a long-term management strategy. Furthermore, the safety profile of rosuvastatin/ezetimibe combination therapy was favourable, with both agents generally well-tolerated. These findings underscore the importance and effectiveness of combination therapy in optimising CV risk reduction in patients with HC, particularly those at high risk of MACE.
1. Soppert J, Lehrke M, Marx N, et al. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Advanced Drug Delivery Reviews, 2020.
2. Al-Zahrani J, Shubair MM, Al-Ghamdi S, et al The prevalence of hypercholesterolemia and associated risk factors in Al - Kharj population, Saudi Arabia: a cross - sectional survey. BMC Cardiovasc Disord, 2021.
3. Ibrahim MA, Asuka E, Jialal I. Hypercholesterolemia. [Updated 2023 Apr 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459188/
4. Reiner Z, Catapano AL, de Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias. The European Heart Journal, 2011.
5. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines, Circulation, 2019.
6. Ballantyne CM, Weiss R, Moccetti, et al Efficacy and Safety of Rosuvastatin 40 mg Alone or in Combination with Ezetimibe in Patients at High Risk of Cardiovascular Disease (Results from the EXPLORER Study). The American Journal of Cardiology, 2007.
7. Kim W, Yoon YE, Shin S-H, et al Efficacy and Safety of Ezetimibe and Rosuvastatin Combination Therapy Versus Those of Rosuvastatin Monotherapy in Patients with Primary Hypercholesterolemia. Clinical Therapeutics, 2018. SF
Ulcerative colitis (UC) is the most prevalent form of inflammatory bowel disease (IBD) globally. It is characterised by inflammation that is confined to the mucosa and submucosa of the colon. The disease usually begins in the rectum and progresses proximally in a continuous pattern.1
The recent Global Burden of Disease study report agestandardised UC prevalence rates in sub-Saharan Africa ranging from 9.9 to 11.2 per 100 000 population. According to Watermeyer et al, these figures stand in stark contrast to traditionally high-incidence regions (eg North America), where the prevalence was 442 per 100 000 population in 2017. 2 UC has a bimodal pattern of incidence. The main onset peaks between 15- and 30-years. A second, and the smaller peak
of incidence occurs between the 50- and 70-years. Though some studies show a slight predilection for men, most studies show no gender differences.1
The primary symptom of UC is bloody diarrhoea, with or without mucus. Other associated symptoms include urgency, tenesmus, abdominal pain, malaise, weight loss, and fever - depending on the disease’s extent and severity (see Table 2).1
The disease typically begins gradually, with
patients experiencing periods of spontaneous remission followed by relapses. Up to 90% of patients will have one or more relapses after the first attack, and early relapse or active disease. Factors that can exacerbate UC include smoking cessation and the use of non-steroidal anti-inflammatory drugs1,3 Between 10% and 30% of patients present with extra-intestinal manifestations (EIMs). EIMs associated with disease activity include episcleritis, scleritis, uveitis, peripheral arthropathies, erythema nodosum, and pyoderma gangrenosum.1
EIMs that are independent of colitis activity include axial arthropathies, sacroiliitis, and ankylosing spondylitis. A significant hepatic EIM is primary sclerosing cholangitis, which is linked to an increased risk of colorectal cancer (CCa).1
Differentiating UC from Crohn’s disease (CD) can be difficult, because between 5%-15% of IBD patients have non-specific symptoms. The British Society of Gastroenterology (BSG) recommends that in individuals suspected of having UC, stool cultures and Clostridium difficile toxin assays should be performed to exclude infectious causes. 3
While flexible sigmoidoscopy is commonly used to diagnose UC initially, a full ileocolonoscopy is recommended within the first year to confirm the diagnosis, assess disease extent, and help predict future disease progression. This helps differentiate UC from CD and aids in risk stratification, which can be used to guide treatment
decisions. During the initial endoscopy, biopsy specimens should be taken from multiple sites, including the ileum and rectum.3
Rectal sparing in UC is rare but can occur in up to 3% of patients - often in those receiving empirical topical therapy. Other features, like caecal patches and backwash ileitis, can be seen in UC but may require small bowel evaluation to exclude CD if they are inconsistent with typical UC patterns. 3
Histologically, no single feature is diagnostic of UC, but a combination of basal plasmacytosis, crypt atrophy, villous irregularity, and mucus depletion is suggestive of UC. In cases with uneven inflammation or long-standing disease, this may vary. 3
Traditionally, according to the Montreal classification, UC is divided into three subgroups: Proctitis, left-sided or extensive. See Table 1. 3
Disease severity is measured by
Table 1: Montreal classification of UC and associated risks 3
Classification Description
E1 (proctitis) Disease limited to the rectum
E2 (left-sided disease) Disease distal to the splenic flexure
E3 (extensive colitis) Disease extends proximal to the splenic flexure
Associated risks
Lower risk of medication usage, colectomy, and colorectal cancer compared to more extensive disease
Higher risk of medication usage, colectomy, and colorectal cancer
Highest risk of medication usage, colectomy, and colorectal cancer
Table 2: Modified Truelove and Witts severity criteria 4
Erythrocyte sedimentation rate (mm/h) or C-reactive protein (mg/L)
Table 3: ECCO treatment recommendations for UC: Mild, moderate, severe, and remission 5
Category
Mild UC 5-aminosalicylates (5-ASA) eg mesalamine or sulfasalazine in oral or topical form
Moderate to severe UC
Oral CS or budesonide MMX for flare control
Severe UC Hospital admission, intravenous (IV) CS eg hydrocortisone or methylprednisolone
Remission Maintenance therapy with 5-ASA or thiopurines eg azathioprine or mercaptopurine. Biologics are another option
Oral corticosteroids (CS) eg prednisolone or budesonide for exacerbations
Thiopurines eg azathioprine or mercaptopurine, methotrexate, or calcineurin inhibitors eg tacrolimus
assessment of clinical and biochemical parameters (see Table 2). 4
How is UC managed?
The latest European Crohn’s and Colitis Organisation (ECCO) guidelines emphasise that the primary goal of UC treatment is to preserve health-related quality of life (HRQoL) and prevent disability. Achieving rapid symptom relief is essential, but endoscopic healing, when possible, is also crucial, as it contributes to better longterm outcomes. Medical therapy is the cornerstone of UC management and aims to induce and maintain remission. 5,6
Therapy should be personalised based on the characteristics of the disease or the severity of disease activity. See Table 3 for ECCO treatment recommendations. The prognosis during the first decade after diagnosis is often generally good, and most patients will achieve remission, however, UC has a no cure and patients will require lifelong treatment,1,5,6
What is new in the medical management of UC?
Topical CS, with adjustment based on response
Biologic therapies (TNF inhibitors, vedolizumab, or ustekinumab) or JAK inhibitors (tofacitinib)
IV cyclosporine or infliximab if no improvement with CS Surgery (colectomy) for patients not responding to medical treatment
Adjust dose or continue with biologics or thiopurines. Maintenance CS in some cases
As mentioned, topical and oral mesalamine is recommended as first-line therapy for mildto-moderate UC, used for both induction and maintenance of remission. In cases where UC extends to at least the rectosigmoid, international guidelines recommend combining oral and rectal mesalamine.5,6 Standard oral mesalamine has limitations, as it is predominantly absorbed in the small intestine, meaning only a small fraction reaches the colon where the inflammation occurs. To address this, several modified-release formulations have been developed. These include pHdependent release, where mesalamine is encapsulated in a film that dissolves at a specific pH (eg S-coated tablets, which release at pH ≥7 in the colon) and timedependent, slow-release formulations, such as ethylcellulose-coated microspheres, which begin releasing mesalamine in the duodenum and continue into the colon, regardless of pH. 6
The latest advancement is multi-matrix system (MMX) mesalamine. This system provides gradual, controlled release throughout the entire colon. The MMX coating, which resists drug release until it reaches the pH of 7 in the terminal ileum, contains both hydrophilic and lipophilic matrices. This dual system ensures that mesalamine is gradually diffused over the entire colon, making it potentially more effective for localised treatment of inflammation compared to other formulations.6
Although guidelines do not favour one
mesalamine formulation over another, the MMX system offers a promising approach to enhance drug delivery to the inflamed regions of the colon. 6
D’Amico et al recently (2024) conducted a review to summarise the current understanding of MMX mesalamine in the treatment of mild-to-moderate UC. The efficacy of MMX mesalamine in treating mild-to-moderate UC has been evaluated in several clinical trials, including phase II and III studies. Initial phase II trials compared MMX mesalamine (3.6g/day) with a 4g mesalamine enema in patients living with left-sided UC. After eight weeks, the clinical remission rates were 60% for MMX mesalamine and 50% for enemas. Although both treatments showed statistically significant improvement, MMX mesalamine demonstrated higher patient adherence (97%) compared to the enemas (87.5%). 6
Subsequent dose-ranging studies found that higher doses of MMX mesalamine (2.4g and 4.8g daily) were more effective. In an eight-week trial, 31% of participants in the 2.4g group and 18% in the 4.8g group achieved remission, compared to none in the 1.2g group. 6
In the Phase III Study of MMX Mesalamine for the Induction of Remission in Mildto-Moderate Ulcerative Colitis, 34.1% of participants on 2.4g/day and 29.2% on 4.8g/day achieved clinical and endoscopic remission at week eight, significantly higher than the 12.9% in the placebo group. 6
The Phase III Study of MMX Mesalamine for the Induction of Remission in Mild-toModerate Ulcerative Colitis: Comparison with Placebo and a Reference Mesalamine confirmed these findings, with 40.5% of participants on 2.4g/day and 41.2% on 4.8g/day achieving remission, compared to 22.1% on placebo. 6
An extended trial also demonstrated that patients who failed to achieve remission in previous trials could still reach clinical and endoscopic remission after eight more weeks of high-dose MMX mesalamine. For maintenance of remission, a 12-month study showed that 64.4% of patients on 2.4g/day and 68.5% on 1.2g twice daily remained in clinical and endoscopic remission. Furthermore, pooled data from >1300 patients indicated that MMX mesalamine led to faster symptom resolution compared to placebo, with significant reductions in stool frequency and rectal bleeding. 6
Real-world studies have demonstrated the effectiveness of MMX mesalamine in managing UC. In a study of UC patients
in clinical remission, 2.4g/day of MMX mesalamine was used for maintenance over 12-months. After six-months, 76.5% of patients remained recurrence-free, and 64.4% maintained remission at the 12-month mark. The study found that adherence played a significant role, with higher recurrence rates in patients with <80% adherence (52.2%) compared to those with 80% or more (31.2%). 6
A prospective cohort study assessed the efficacy of MMX mesalamine for maintaining remission after mucosal healing. Over the first six-months, 79.1% of patients remained in remission, with a mean time to relapse of 14-weeks, and an additional 7% relapsed in the second semester.6
A post-hoc analysis of patients who received 4.8g/day of MMX mesalamine for eight weeks showed that patients achieving clinical and endoscopic remission had significant improvements in HRQoL compared to partial responders. 6
Furthermore, a retrospective cohort study of patients treated with MMX mesalamine evaluated real-world outcomes. High rates of clinical remission (80.3%-88.6%) and biochemical remission (74.2%-85.7%) were observed with MMX monotherapy for both induction and maintenance phases. In the group receiving both oral MMX mesalamine and topical therapy, 87.3% of patients were able to stop the topical therapy after induction. 6
MMX mesalamine is considered safe and well-tolerated due to its local effect in the colon and minimal systemic absorption. In two pivotal Phase III induction trials, data showed that the incidence of treatmentemergent adverse events (AEs) in the MMX mesalamine groups was similar to that in the placebo group, with no evidence of a dose-response relationship for any safety parameters. 6
Most AEs were mild or moderate in intensity, and patients on MMX mesalamine were less likely to discontinue the study due to adverse events compared to those on placebo. The most common AEs were gastrointestinal (GI) disorders, such as abdominal pain, worsening of UC, diarrhoea, flatulence, and nausea. 6
GI-related AEs were reported in 18.1%, 11.7%, and 24.0% of patients in the MMX mesalamine 2.4g/day, 4.8g/day, and placebo groups, respectively. Importantly, no cases of kidney failure or interstitial nephritis were observed among patients, although interstitial nephritis is a known risk of mesalazine therapy, typically occurring within 12-months of treatment
initiation. Monitoring creatinine levels is recommended at the start of therapy and at six- and 12-months. 6
In long-term studies, including those lasting 12-months, MMX mesalamine demonstrated consistent safety, with no new or unexpected concerns. Data from pooled trials with >2800 patients showed that 54% experienced treatment-emergent AEs, with only 9% discontinuing therapy. The most frequent AEs were abdominal pain, headache, diarrhoea, and urinary tract infections, with mild-to-moderate severity in most cases. 6
The new MMX mesalamine formulation represents a significant advancement in the treatment of mild-to-moderate UC. Its dual hydrophilic-lipophilic matrix ensures gradual, controlled release of mesalamine throughout the entire colon, offering improved localised delivery compared to traditional formulations. Clinical trials have demonstrated its efficacy, showing higher remission rates and better patient adherence compared to alternative treatments. This controlled release improves patient outcomes and supports long-term management strategies for UC.
1. Lynch WD, Hsu R. Ulcerative Colitis. [Updated 2023 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459282/
2. Watermeyer G, Katsidzira L, Nsokolo B, et al Challenges in the diagnosis and management of IBD: a sub-Saharan African perspective. Therapeutic Advances in Gastroenterology, 2023.
3. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut, 2019.
4. Segal JP, Jean-Frédéric A, LeBlanc B, et al Ulcerative colitis: an update. Clinical Medicine, 2021.
5. Raine T, Bonovas S, Burisch, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. Journal of Crohn’s and Colitis, 2022.
6. D’Amico F, Lusetti F, Peyrin-Biroulet L, Danese S. MMX mesalamine in ulcerative colitis: Major advantages towards classical mesalamine formulations. Digestive and Liver Disease, 2021. SF
Gastroesophageal reflux disease (GORD) is a prevalent condition affecting approximately 25% of the Western population, with a lower incidence in Asia. It is most commonly seen in individuals aged 60- to 70-years and is increasingly recognised in older adults.
GORD presents with a variety of symptoms, including heartburn, dysphagia, and nocturnal choking. Atypical symptoms such as chronic cough and laryngitis are also associated with the condition. Alarm symptoms, which necessitate urgent referral, include dysphagia, odynophagia, weight loss, and gastrointestinal bleeding.
Diagnosis of GORD is multifaceted, involving empiric trials, endoscopy, and pH monitoring to evaluate acid exposure and symptom correlation. Manometry is also utilised to assess motility disorders related to GERD. The Montreal definition of GERD differentiates between non-erosive reflux disease (NERD) and erosive oesophagitis.
Treatment
The treatment of GORD aims to enhance lower oesophageal sphincter pressure, improve oesophageal acid clearance, facilitate gastric emptying, and protect the oesophageal lining. A threephase structure treatment approach is recommended and include:
1 Lifestyle modifications:
Recommendations include elevating the head of the bed, reducing fat intake, quitting smoking, avoiding lying down after meals, losing weight, limiting alcohol, and wearing loose clothing. While these changes may not completely alleviate symptoms, they can significantly improve them.
2 Pharmacologic intervention :
Standard or high-dose antisecretory therapy is employed, with proton pump inhibitors (PPIs) proving more effective than H2 receptor antagonists in healing erosive oesophagitis and providing
symptom relief. Timing of medication administration is crucial, particularly for PPIs, which should be taken before meals for optimal effectiveness. Potential reasons for PPI therapy failure include adherence issues and weakly acidic reflux.
3 Surgical intervention : This is considered for patients unresponsive to pharmacologic treatment or those with severe complications. Laparoscopic fundoplication is presented as an effective option for refractory GORD, offering high patient satisfaction and long-term symptom relief, although it may lead to side effects like bloating and dysphagia. Alternative treatments, such as magnetic sphincter augmentation, show promise in improving quality of life and reducing PPI dependence.
considerations and unmet needs
In pregnancy, 66% of women experience heartburn, typically resolving post-delivery. Treatment during pregnancy should prioritise lifestyle changes, followed by antacids and H2 receptor blockers, or histamine-2 receptor antagonists, which are generally safe.
Unmet needs in GORD management include breakthrough symptoms and the necessity for improved medication adherence. The introduction of dexlansoprazole, a newer PPI, is highlighted for its superior acid control and longer duration of action, making it a promising option for GORD patients. Other treatment options include potassium-competitive acid blockers, pain modulators, and baclofen
for reducing transient lower oesophageal sphincter relaxation.
Endoscopic treatments are described as relatively new and may benefit select patients with well-documented GORD responsive to PPIs. The presentation includes case studies that illustrate the complexities of GORD management, emphasising the need for lifestyle changes, appropriate medication use, and potential surgical or endoscopic interventions for refractory cases.
A multifaceted approach is required to effectively manage GORD, integrating both medical and surgical options while addressing the challenges of longterm PPI therapy and the necessity for individualised patient care. By adopting a comprehensive treatment strategy, healthcare professionals can significantly improve the quality of life for patients suffering from GORD.
This webinar was sponsored by Adcock and is accredited for one (1) CPD point. Once you have watched the replay, send an e-mail to john.woodford@newmedia.co.za and request to have your CPD point allocated to your profile on the HPCSA database. Include the webinar name and your HPCSA number in your e-mail. SF
• the MOST POWERFUL inhibitory effect on the proton pump of ALL available PPIs.4
• TRUE once-daily dosing.5
reflux disease - comparative efficacy and outcomes of dexlansoprazole MR. Ther Clin Risk Manag 2015;11:1649-56. doi: 10.2147/TCRM.S66680. 6. Dexilant Professional Information. Takeda (Pty) Ltd, South Africa; August 2021. 7. Sharma P, Shaheen NJ, Perez MC, et al. Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-release formulation--results from two randomized
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) primarily affecting the colon and rectum. The disease is characterised by symptoms such as frequent diarrhoea mixed with blood and mucus, abdominal pain, and weight loss. The goal of diagnosis is to differentiate UC from other conditions that present similarly, such as Crohn’s disease, infectious colitis, or malignancy.
Diagnosis begins with a thorough history and physical examination. Key factors include the duration, frequency, and characteristics of diarrhea, as well as associated symptoms like weight loss or fever.
A history of recent antibiotic use could indicate a Clostridium difficile infection, which might mimic UC symptoms. An evaluation of stool characteristics, including presence of blood or mucus, and any nocturnal diarrhea is crucial.
A family history of IBD or colorectal cancer, alongside other systemic symptoms like joint pain or skin lesions, can provide additional diagnostic clues.
The physical examination might reveal anaemia, abdominal tenderness, or perianal abnormalities. Digital rectal examination, while not always pleasant, can sometimes uncover hidden pathologies. Extra-intestinal manifestations such as eye inflammation, skin lesions, or joint pain can also suggest underlying IBD.
Diagnosing UC involves ruling out other conditions with similar presentations. Tests such as faecal calprotectin are useful to differentiate IBD from irritable bowel syndrome, as elevated levels indicate intestinal inflammation.
Endoscopy, including colonoscopy, is essential for visualising the colon and rectum, assessing the extent of inflammation, and identifying mucosal changes characteristic of UC. The Mayo score is used to classify disease
severity from mild to severe based on endoscopic findings.
The goals of treatment are to control inflammation, induce and maintain remission, and improve the patient’s quality of life while minimising side effects. Long-term management often requires a multidisciplinary approach involving gastroenterologists, dietitians, and other specialists to address the various aspects of the disease and its impact on daily life.
The treatment of UC aims to induce and maintain remission while preventing complications. The management approach is tailored to the disease severity and the patient’s response to previous treatments.
Initial treatment often involves 5-aminosalicylic acid compounds, which are effective for inducing and maintaining remission in mild to moderate cases. These can be administered orally or rectally depending on the extent of the disease.
For moderate to severe cases, corticosteroids (CS) such as prednisone or budesonide are used to quickly induce remission. However, due to potential side effects like weight gain, hypertension, and osteoporosis, CS are not suitable for longterm use. Their use is typically limited to short-term management and bridging to other therapies.
Immunomodulators, including azathioprine and 6-mercaptopurine, are effective for maintaining remission and reducing steroid dependency, but they take several weeks to become effective and require regular
monitoring due to potential side effects. Methotrexate may be used in some cases, though its application is less common.
Biologics such as anti-TNF agents (eg infliximab, adalimumab) offer targeted therapy by addressing specific immune responses involved in UC. These are particularly useful in severe cases or when patients are unresponsive to conventional therapies. Newer options like integrin inhibitors and small molecules are emerging, offering additional choices for managing UC.
In summary, managing UC effectively involves accurate diagnosis, targeted therapy, and regular monitoring to adjust treatment as needed and address potential complications.
The webinar is accredited for one (1) CPD point. Once you have watched the replays, send an e-mail to john.woodford@ newmedia.co.za and request to have your CPD point allocated to your profile on the HPCSA database. Include the webinar name and your HPCSA number in your e-mail. SF
Dr Nazeer Ahmed Ismail Chopdat Click
An option for patients who are virologically suppressed (VL < 50 copies / mL) while receiving a regimen of NNRTI + two NRTIs, and who have never experienced virological failure, is a switch to the two-drug combination of DTG + RPV.2
This article was independently sourced by Specialist Forum
During the mid-1990s, the standard approach to treating HIV shifted towards antiretroviral (ARV) regimens incorporating three active drugs from different classes. This approach was effective in suppressing viral replication and minimised the development of resistance.1
Despite the effectiveness of triple therapy, the potential risk of adverse effects (AEs) associated with the long-term use of any medication, required consideration of using the minimum number of drugs necessary.1
According to van Welzen et al, questions have been raised over the past few years about whether there is a need to hold on to the mantra that combination ARV therapy (ART) should always consist of three drugs. These questions resulted in renewed interest in the use of monotherapy or dual ART due to its potential to reduce overall therapy exposure, mitigate specific drug toxicities, and lower costs.1,2
It is unlikely that monotherapy will play a role in the near future, while dual therapy on the other hand is increasingly being incorporated in guidelines, state van Welzen et al 2
In 2018 a single-tablet dual regimen consisting of dolutegravir (DTG), an integrase strand transfer inhibitor (InSTI), and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) was approved, followed in 2020 by a single-pill combination consisting of DTG and lamivudine (3TC). DTG/3TC was the first dual regimen approved as first-line therapy for treatment-naïve people living with HIV (PLWHIV).2,3
In 2022, the two dual regimens (DTG 50mg/3TC 300mg and DTG 50mg/RPV 25mg) became available in South Africa.
Single-pill DTG/3TC is indicated for treatment naïve adults aged ≥18-years living with HIV-1, who have no known or suspected resistance to either ARV component.4,5
Single-pill DTG/RPV is indicated for the treatment of HIV-1 in adults who are virologically suppressed (<50 copies/ml), on a stable protease inhibitor (PI), or NNRTI based regimens for at least six months, without known or suspected resistance to either ARV component. Co-administration with any other HIV-1 ARVs is not recommended.6
The 2023 Southern African HIV Clinicians Society (SAHCS) guidelines recommend switching most patients to a DTG-based regimen if possible. Another first-line option is RPV.7
According to the SAHCS guidelines, consideration for first-line dual regimen comprising DTG/3TC depends on several factors. Importantly, hepatitis B must be excluded before considering this regimen as patients with hepatitis B must receive TDF + 3TC (or emtricitabine [FTC]) to prevent rapid emergence of 3TC/FTC resistance.7
Furthermore, Ghandi et al caution that DTG/3TC should only be used when HIV RNA level is <500 000 copies/mL and should not be used for rapid ART initiation when laboratory results are not yet available.8
The SAHCS guidelines do not contain any recommendations regarding dual therapy with DTG/RPV, but several studies, which will
be discussed below, have shown that DTG/ RPV are non-inferior compared to continuing triple therapy.1,7
According to Gibas et al, switching to a dual regimen is a viable option for individuals who have achieved virological suppression. There are multiple rationales behind this switch, state the authors, including the avoidance of AEs associated with certain NRTIs (eg bone and renal effects of tenofovir disoproxil fumarate, or the cardiovascular effects of abacavir).1
Even when there are no apparent contraindications to triple therapy, the adoption of dual therapy to reduce lifetime exposure to ARVs can be considered, provided it does not compromise virological efficacy or safety, add the authors.1
Various factors such as payer or insurance restrictions, cost considerations, pill size, drug interactions, and drug intolerance may influence the decision to switch.1
However, for some people living with HIV (PLWHIV), maintaining triple therapy may be preferable for several reasons. This preference may be based on satisfaction with the current therapy, payer or formulary restrictions favouring triple therapy regimens, concerns about potential drug interactions, or simply personal choice.1
How effective is dual therapy compared to triple therapy?
Several clinical trials have been conducted to evaluate the efficacy and safety of DTG/3TC and DTG/RPV compared to standard combination ART in both treatment-experienced and treatmentna ï ve PLWHIV.9-18
The Antiretroviral Strategy to Promote Improvement and Reduce Exposure (ASPIRE) study investigated the feasibility of adopting DTG/3TC as a dual maintenance therapy for HIV treatment.9
The study compared the efficacy of DTG/3TC to standard combination ART and found comparable treatment failure rates at week 24 between the two groups, demonstrating the non-inferiority of DTG/3TC. Adherence rates and viral load suppression were similar between the groups, with minimal viral blips observed.9
The authors concluded that DTG/3TC showed promise as a simplified treatment option with efficacy and safety comparable to traditional combined ART, suggesting its potential as a viable regimen for certain PLWHIV.9
The Switching to dolutegravir/lamivudine (DTG/3TC) fixed-dose combination (FDC) is non-inferior to continuing a tenofovir alafenamide (TAF)-based regimen (TBR) in maintaining virological suppression through 96 weeks. The TANGO study evaluated the efficacy and safety of switching to DTG/3TC in virologically suppressed adults living with HIV-1.10
This phase III randomised, open-label study compared the outcomes of switching to once-daily DTG/3TC versus continuing a tenofovir alafenamide (TAF)-based regimen over 148 weeks. Results at week 96 showed non-inferior virologic failure and virologic success rates between the DTG/3TC group and the TAF-based regimen group. No resistance was observed with DTG/3TC, and lipid profile improvements favoured DTG/3TC.10
The study authors concluded that switching to DTG/3TC maintained virologic suppression non-inferiorly to TAF-based regimens, with a favourable safety profile and low risk of resistance, making it a robust option for treatment-experienced adults.10 Similarly, Osiyemi et al investigated the efficacy of switching to DTG/3TC compared to continuing TAF-based regimens at week 144 in virologically suppressed adults living with HIV-1.11
The study found that switching to DTG/3TC maintained virologic suppression
as effectively as continuing TAF-based regimens. Although drug-related AEs were more frequent with DTG/3TC, they became comparable post-week 48.11
Lipid value changes generally favoured DTG/3TC, with no clinically significant impact on renal function. Overall, switching to DTG/3TC demonstrated non-inferior and durable efficacy, good safety, and tolerability over 144 weeks, making it a viable option for treatment-experienced adults.11
Furthermore, the An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine with Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects (GEMINI 1 and GEMINI 2) trials evaluated the efficacy of DTG/3TC compared to standard triple ART regimens in treatment-naïve PLWHIV.12
Results from the GEMINI-1 and GEMINI-2 trials demonstrated non-inferiority of DTG/3TC to standard triple ART in achieving viral suppression at week 48 and week 96.12
Few participants experienced virologic failure or met virologic withdrawal criteria, and no treatment-emergent resistance mutations were observed with DTG/3TC.12
Additionally, DTG/3TC exhibited a favourable safety profile and led to improvements in renal and bone biomarkers. These findings support the long-term efficacy and safety of DTG/3TC as an option for treatment-naïve PLWHIV.12
Rojas et al investigated the efficacy and safety of switching to DTG/3TC versus maintaining triple therapy in virologically suppressed adults living with HIV at 48 weeks.13
The study found similar proportions of participants with HIV ≥50 copies/ml between the dual and triple therapy groups, demonstrating non-inferiority of DTG/3TC.13
AEs occurred in a comparable percentage of participants in both groups, with no significant difference in drug discontinuation due to AEs. These findings support DTG/3TC as a safe and effective simplified therapy switch option for selected PLWHIV.13
Lastly, in the Regimen Switch to Dolutegravir/Lamivudine Fixed Dose Combination from Current Antiretroviral Regimen in HIV-1 Infected and Virologically Suppressed Adults or SALSA trial conducted by Llibre et al (2023), the efficacy and safety of switching to DTG/3TC versus continuing various triple or quadruple regimens were investigated in adults living with HIV-1. Participants with HIV-1 RNA <50 copies/ml and no prior virologic failure were randomly assigned (1:1) to either switch to once-daily fixed-dose DTG/3TC or maintain their current regimen.14
At week 48, the study found that only one participant in the DTG/3TC group and three in the triple or quadruple therapy group had HIV-1 RNA ≥50 copies/ml, confirming the non-inferiority of DTG/3TC.14
None of the participants met confirmed virologic withdrawal criteria, eliminating the need for resistance testing. While AE rates were more prevalent with DTG/3TC (20%) compared to triple or quadruple therapy (6%) up to week 48, they became comparable post-week 24 (5% versus 2%, respectively).14
Furthermore, DTG/3TC resulted in improvements in proximal tubular renal function and bone turnover biomarkers, with both groups showing minimal changes in lipids and inflammatory biomarkers.14
These findings highlight the effectiveness, safety, and resistance-preventing potential of DTG/3TC as a viable switch option for maintaining virologic suppression in treatment-experienced PLWHIV. The study suggests that DTG/3TC could be a promising alternative for those seeking simplified treatment regimens without compromising efficacy or safety.14
The identically designed Regimen Switch to Dolutegravir + Rilpivirine from Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults (SWORD 1 and SWORD 2) studies conducted across 12 countries, investigated the feasibility and efficacy of switching virologically suppressed adults living with HIV-1 to a DTG/RPV regimen compared to continuing a standard triple or quadruple regimen.15 Participants on their first or second ART regimen, with stable plasma HIV-1 RNA levels (<50 copies/ml) for at least six months, were randomly assigned in a 1:1 ratio. The primary endpoint was achieving HIV-1 RNA levels <50 copies/ml at week 48 among those who received at least one dose of the study medication.15
Results from the SWORD-1 and SWORD-2 studies demonstrated the non-inferiority of DTG/RVP compared to standard triple therapy in maintaining virological suppression through 48 weeks. Both treatment groups achieved high rates of viral suppression, with similar outcomes between DTG/RVP and standard therapy.15 AEs were reported more frequently in the DTG/RVP group, with nasopharyngitis and headache being common, but overall, the safety profile was consistent with the components of the regimen.15
In the 100-week analysis of SWORD-1
and SWORD-2, the combination of DTG/ RVP effectively maintained virological suppression, with 89% and 93% of participants in the early-switch and lateswitch groups achieving the primary efficacy endpoint, respectively.16
The incidence of drug-related AEs was higher in the early-switch group but remained manageable, supporting the use of DTG/RVP as an alternative to traditional three-drug regimens while reducing overall ART exposure.16
Palacios et al (2023) conducted an observational study to evaluate the realworld efficacy and safety of DTG/RPV in individuals with diverse treatment histories.17
Despite extensive ART experience and prior virological failures, DTG/RPV demonstrated high rates of HIV-RNA suppression at 48 weeks, with minimal AEs and favourable changes in lipid and liver profiles.17
The study confirmed the effectiveness and safety of DTG/RPV in a real-world setting, supporting its use as a viable switch therapy option for individuals with longstanding HIV infection.17
Moyle et al (2024) assessed the efficacy of switching to DTG/RVP in individuals with virological suppression and Lys103Asn mutations who had previously received other treatment regimens.18
Virological suppression was maintained in the majority of participants at week 48, indicating the potential effectiveness of DTG/RVP. Although more AEs were observed in the DTG/RVP group, the overall proportion of participants reporting AEs was similar between groups, highlighting the need for further investigation through larger trials to validate the efficacy and safety of DTG/RVP.18
The landscape of HIV treatment has evolved significantly since the mid-1990s, shifting from complex multidrug regimens towards simpler, more tolerable treatment options.
The advent of dual therapy, particularly DTG-based dual therapy, has emerged as a promising strategy to maintain virological suppression while reducing pill burden and potential AEs associated with traditional ART. Clinical trials, real-world studies, and observational analyses have consistently demonstrated the efficacy and safety of switching to DTG-based dual therapy, either with 3TC or RPV, in various patient populations living with HIV-1.
These studies have shown that DTGbased dual therapy maintains virological suppression comparable to standard triple therapy over extended durations, with favourable safety profiles and minimal risk
of resistance.
Furthermore, the flexibility and simplicity offered by dual therapy regimens like DTG/3TC or DTG/RPV have made them increasingly incorporated into treatment guidelines and recommendations.
The ability to tailor therapy based on individual patient needs, such as avoiding specific drug toxicities or addressing treatment preferences, underscores the importance of dual therapy options in the management of HIV.
However, while dual therapy presents a viable alternative for many PLWHIV, it may not be suitable for everyone.
Considerations such as prior treatment history, comorbidities (including hepatitis B coinfection), and potential drug interactions must be carefully evaluated when making treatment decisions.
1. Gibas KM, Kelly SG, Arribas JR, et al Two-drug regimens for HIV treatment. Lancet HIV, 2022.
2. van Welzen BJ, Oomen PGA and Hoepelman AIM. Dual Antiretroviral Therapy—All Quiet Beneath the Surface? Front Immunol, 2021.
3. Zamora FJ, Dowers E, Yasin F, Ogbuagu O. Dolutegravir and Lamivudine Combination for the Treatment Of HIV-1 Infection. HIV AIDS (Auckl), 2019.
4. Cipla Press Release. Dual therapy HIV treatment introduced in SA for the first time. 2022. [Internet]. Accessed 8 April 2024. Available at: https://www.cipla.co.za/hiv/ dual-therapy-hiv-treatment-introducedin-sa-for-the-first-time#:~:text=The%20 combinations%20of%20dolutegravir%20 %2F%20lamivudine,patient%2Dcentric%20 management%20of%20HIV
5. Professional Information . Lomida. 2021.
6. Professional Information. Daliduo. 2022.
7. Nel J, Meintjies G, Osih R, et al. Southern African HIV Clinicians Society Guidelines for Antiretroviral Therapy in Adults: 2023 Update. [Internet]. Accessed 5 April 2024. Available at: https://sahivsoc.org/Guidelines/ Index#:~:text=This%202023%20update%20 to%20the,than%20efavirenz%2D%20or%20 lopinavir%2Dritonavirbased
8. Gandhi RT, Bedimo R, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society–USA Panel. JAMA, 2023.
9. Taiwo BO, Marconi VC, Berzins B, et al. Dolutegravir Plus Lamivudine Maintains Human Immunodeficiency Virus-1 Suppression Through Week 48 in a Pilot Randomized Trial. Clinical Infectious Diseases, 2018.
10. van Wyk J, Ajana F, Bisshop F, et al Switching to DTG/3TC Fixed-Dose Combination (FDC) is Noninferior to Continuing a TAF-Based Regimen in Maintaining Virological Suppression Through 48
Weeks (TANGO Study). HIV Medicine, 2021.
11. Osiyemi O, De Wit S, Ajana F, et al. Efficacy and Safety of Switching to Dolutegravir/Lamivudine Versus Continuing a Tenofovir AlafenamideBased 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Results Through Week 144 From the Phase 3, Noninferiority TANGO Randomized Trial. Clin Infect Dis, 2022.
12. Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in antiretroviral treatment naive adults with HIV-1 infection: 96-week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr, 2020.
13. Rojas J, de Lazzari E, Negredo E, et al, on behalf of the DOLAM study group. Efficacy and safety of switching to dolutegravir plus lamivudine versus continuing triple antiretroviral therapy in virologically suppressed adults with HIV at 48 weeks (DOLAM): a randomised non-inferiority trial. Lancet HIV, 2021.
14. Llibre JM, Hung C-C, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, noninferiority SWORD-1 and SWORD-2 studies. Lancet, 2018.
15. Llibre JM, Brites C, Cheng CY, et al. Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial. Clin Infect Dis, 2023.
16. Aboud M, Orkin C, Podzamczer D, Bogner JR, et al Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV, 2019.
17. Palacios R, Gómez-Ayerbe C, Casado JL, et al Efficacy and safety of dolutegravir/rilpivirine in real-world clinical practice. GeSIDA study 1119. HIV Med, 2023.
18. Moyle G, Assoumou L, de Castro N, et al Switching to dolutegravir plus rilpivirine versus maintaining current antiretroviral therapy regimen in virologically suppressed people with HIV-1 and the Lys103Asn (K103N) mutation: 48-week results from a randomised, open-label pilot clinical trial. The Lancet HIV, 2014. SF
Reydin – a TLD regimen by Cipla.1
Patients currently on TDF +FTC/3TC and EFV or NVP should be switched to TLD regardless of whether their VL is suppressed or not suppressed. 2 S4 Reg. No. 52/20.2.8/0451.450. Reydin. Each
South Africa has the world’s largest population of people living with HIV (PLWHIV, 7.6 million). Since the report of the country’s first case in 1982, South Africa has made significant strides in mitigating rates of HIV infection and mortality. A recent report by the Human Sciences Research Council (HSRC) shows that the prevalence of HIV in South Africa has decreased from 14% in 2017 to 12.7% in 2022.1,2
HIV prevalence in the country varies significantly across regions, genders, ethnicity and age groups. The prevalence ranges from 8% in the Western Cape to 22% in KwaZulu-Natal. Women (20%) are significantly more affected than men (12%) and regarding ethnicity, HIV prevalence is highest among individuals from African descent (20%), followed by Coloured people (5%), and lowest among people from European, Indian and Asian descent (1%). 2
Furthermore, the HSRC report highlight that in comparison to men within the same age bracket, women between 15- to 19-years have roughly double the HIV prevalence (5.6% versus 3%). Similarly, among those aged 20- to 24-years, women showed a twofold higher prevalence compared to men (8% versus 4%). In the age group 25- to 29-years, women had a three-fold higher prevalence compared to men (20% versus 6%).2
Since 2010, there has been a 51% reduction in HIV-related deaths globally. According to Lamprecht et al, mortality attributed to HIVand AIDS-related causes in South Africa saw a significant decline following the introduction and subsequent widespread availability of antiretroviral therapy (ART).3,4
ART was only rolled-out in the South African public sector in 2004, resulting in an estimated 330 000 unnecessary deaths. The good news is that the roll-out of ART in South Africa has subsequently led to a yearly reduction in mortality by 27% among adults aged between 25- and 49-years. The leading causes of HIV-related mortality in the country are pneumonia and tuberculosis (pulmonary and extrapulmonary) regardless of HIV-serostatus. The roll-out of ART also resulted in a yearly decrease of 35% in poor health reporting among adults aged 25- to 49-years.4,5
The first antiretroviral (ARV) drug, azidothymidine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI) originally developed to treat cancer, was approved by the American Food and Drug Administration for the treatment of HIV and AIDS in 1987.6
However, some individuals taking AZT alone experienced rapid drug resistance development within days as the virus replicates rapidly and is prone to errors, which resulted in mutations, prompting researchers to develop new agents.7
The introduction of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs eg tenofovir disoproxil fumarate [TDF]), brought about a revolutionary shift in the treatment of HIV. 8 In 1996, the first non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved and in 2007, the development
of entry and integrase strand transfer inhibitors (InSTIs) provided alternatives for patients resistant to traditional drugs.9
The availability of new agents also complicated the treatment of HIV. Clinicians now had to carefully weigh various factors such as dosing frequency, dietary requirements, potential for drug interactions, short- and long-term toxicities, as well as the lifelong costs associated with treatment, when selecting regimens.10
It soon became apparent that streamlined treatment strategies were required, involving the use of combination therapy – both for the initial and long-term treatment of PLWHIV.10
A second-generation InSTI, dolutegravir (DTG) was developed in 2013. DTG and lamivudine (3TC) combination was the firstever fixed-dose combination (FDC) two-drug regimen approved for the treatment of HIV-1 infection in treatment-naïve patients.8,10
The World Health Organization (WHO) has advocated for the use of combinations containing DTG as the preferred first- and second-line treatment options for all PLWHIV – including pregnant women and those of childbearing potential – since 2018.11
In 2019, the first generic once-a-day FDC three-drug regimen containing 3TC, TDF, DTG was launched in South Africa. This FDC is approved for the treatment of PLWHIV >18-years.12,13
What do the latest guidelines recommend?
Current guidelines published by the International AIDS Society, the WHO, the South African National Department of Health (SANDoH) and the Southern African HIV Clinicians Society (SAHCS) recommend initiating HIV treatment with a combination of two NRTIs along with either an InSTI, a PI, or a NNRTI. 10,11,14,15
Among these options, InSTIs – DTG in particular – are favoured as the preferred drug class, while others are reserved as alternative agents for specific clinical scenarios. According to the WHO, DTG is superior to alternative agents in terms of efficacy, ease of administration, and reduced risk of side effects.10,11
Additionally, DTG boasts a significant genetic barrier against the development of drug resistance, a crucial advantage considering increasing resistance observed in regimens containing EFV and nevirapine (NVP).11
In 2023, the SANDoH updated the ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy and Breastfeeding, Adolescents, Children, Infants and Neonates. The updated guidelines recommend an initial ART
regimen for all adult and adolescent men and women, including pregnant women ≥30kg and ≥10-years of age, with TDF/3TC/ DTG (TLD). For children (0- to <10-years of age), initial combination therapy includes abacavir (ABC)/3TC/DTG (ALD).14
The guidelines recommend that individuals – regardless of the regimen that they are currently on – should be assessed for switching to a DTG regimen. TLD as firstline therapy in treatment-naïve patients and switching to a DTG regimen (for all patients if possible) is also supported by the 2023 updated SAHCS HIV guidelines.14,15.
Guidelines recommend initiating HIV treatment with a combination of two NRTIs, with either an INSTI, a PI or a NNRTI
According to the WHO, clinical and observational studies support switching from TLE comprising TDF, 3TC and efavirenz (EFV) to TLD without viral load testing or regardless of the viral load.16
Switching from TLE to TLD offers several advantages:17,18,19,20,21,22
_ Superior potency: TLD has demonstrated greater potency, leading to a faster suppression of viral load compared to EFV-based regimens.
A 2023 study showed that viral load suppression was achieved in 55.71 % of participants in the TLE group after six months of ART while in the TLD group, 88.57% achieved virologic suppression. The findings were consistent at 12 months and 95.71% of participants had achieved viral load suppression as compared to 80% in the TLE group.17
_ Enhanced durability: DTG possesses a significantly higher genetic resistance barrier compared to NNRTIs, thereby reducing the likelihood of resistancerelated treatment failures.18
_ Better tolerance and fewer side effects: DTG is a very well tolerated drug, with lower overall incidence of AEs (<5%) when compared with EFV. The most common reported AEs associated with DTG are gastrointestinal symptoms
(nausea, vomiting), hypersensitivity skin reactions, and central nervous system effects (insomnia, dizziness) which are most often mild and self-limited. Discontinuation rates observed in clinical trials and in programme data are low.19
_ Improved convenience: TLD comes in a smaller tablet format taken just once daily, enhancing convenience for patients.20
_ Reduced drug interactions: DTG is associated with fewer drug interactions, simplifying its administration alongside commonly used medications. 21
_ Given its better tolerability and fewer side effects compared to TLE, switching to TLD is expected to improve treatment adherence and retention, especially with proper patient education and preparation. 22
_ More cost-effective: The prices of DTG formulations are 10%-15% less expensive than current EFV formulations in lowand middle-income countries. With generic competition and increased purchase volumes, further price reductions are expected.19
Individuals eligible for switching to TLD (adults) or ALD (children and adolescents), according to SAHCS include:23
Switching to TLD from a first-line NNRTI regimen (EFV or nevirapine):
_ Patients on TDF/EFV/emtricitabine (TEE), TLE, or NVP-based regimens can switch to TLD, regardless of viral load (suppressed or unsuppressed) or recent viral load result.
_ Patients previously on an EFV- or a NVP-based regimen who interrupted treatment can restart on TLD.
Switching to DTG from a second-line boosted PI-containing regimen:
_ Patients on any two NRTIs plus lopinavir/ ritonavir (LPV/r) or atazanavir/ritonavir ATV/r with a viral load <50 copies/ml in the last six months can switch to TLD.
_ Patients on LPV/r or ATV/r-based regimens with a viral load >50 copies/ ml should continue current management per guidelines.
Children and adolescents: >10 years and >35 kg:
_ Same as adults. Additionally:
• Adolescent patients transitioning from ABC-based first-line regimens (NNRTI- or PI-based) can move to TLD, regardless of viral load.
20 kg – 35 kg:
_ Patients on ABC/3TC/EFV with a viral load <50 copies/ml in the last six months can switch to ABC/3TC/DTG.
_ Patients on ABC/3TC/EFV with viral load >50 copies/ml needing a regimen switch should switch to AZT/3TC/DTG, with repeat viral load at three months.
_ Patients on ABC/3TC plus LPV/r or ATV/r with a viral load <50 copies/ml in the last six months can switch to ABC/3TC/DTG.
_ Patients on LPV/r or ATV/r-based regimens with viral load >50 copies/ml should continue current management. <20 kg:
_ These patients are currently not eligible for DTG 50mg tablets, unless recommended by expert opinion. SAHCS cautions that recommendations assume no contraindications to DTG or TLD. Patients with unsuppressed viral loads switching to DTG should receive additional adherence support and evaluate for potential causes of the raised viral load (eg drug interactions, poor absorption). 23
Switching to TLD represents a critical advancement in HIV treatment. With the world’s largest population of PLWHIV, South Africa’s commitment to improving treatment outcomes and reducing transmission rates is evident.
The introduction of TLD offers several advantages over previous regimens, including superior potency, enhanced durability, improved convenience, better tolerance, and fewer side effects. These benefits not only contribute to better treatment adherence but also reduce the risk of drug resistance and the need for costly second-line regimens. Furthermore, guidelines endorse DTGbased regimens as the preferred first-line and second-line treatments for all HIV populations, including pregnant women and those of childbearing potential. This endorsement underscores the efficacy, safety, and feasibility of switching to TLD for a wide range of patients.
References
1. World Health Organization. HIV Country Profile. Updated 2023. [Internet]. Available at: https://cfs.
hivci.org/
2. Human Sciences Research Council. New HIV Survey Highlights Progress and Ongoing Disparities in South Africa’s HIV Epidemic. 2023. Accessed 26 March 2024. [Internet]. Available at: https:// hsrc.ac.za/press-releases/hsc/new-hiv-surveyhighlights-progress-and-ongoing-disparities-insouth-africas-hiv-epidemic/
3. World Health Organization. HIV Statistics, Globally and by WHO Region, 2023. Accessed 26 March 2024. [Internet]. Available at: https://cdn.who.int/media/ docs/default-source/hq-hiv-hepatitis-and-stislibrary/j0294-who-hiv-epi-factsheet-v7.pdf
4. Lamprecht DJ, Martinson N, Variava E. Effect of HIV on Mortality Among Hospitalised Patients in South Africa. South Afr J HIV Med, 2023.
5. Burger C, Burger R, van Doorslaer E . The Health Impact of Free Access to Antiretroviral Therapy in South Africa. Social Science & Medicine, 2022.
6. Forsythe SS, McGreevey W, Whiteside A, et al Twenty Years of Antiretroviral Therapy for People Living With HIV: Global Costs, Health Achievements, Economic Benefits. Global Health Policy, 2019.
7. National Institute of Allergy and Infectious Diseases. Antiretroviral Drug Discovery and Development. 2024. Accessed 27 March 2024. [Internet]. Available at: https://www.niaid.nih. gov/diseases-conditions/antiretroviral-drugdevelopment#:~:text=Scientists%20funded%20 by%20NIH’s%20National,drugs%20to%20treat%20 HIV%2FAIDS
8. Tseng A, Seet J, Phillips EJ. The Evolution of Three Decades of Antiretroviral Therapy: Challenges, Triumphs and the Promise of the Future. Br J Clin Pharmacol, 2015.
9. Weichseldorfer M, Reitz M, Latinovic OS. Past HIV-1 Medications and the Current Status of Combined Antiretroviral Therapy Options for HIV-1 Patients. Pharmaceutics, 2021.
10. Zamora FJ, Dowers E, Yasin F, Ogbuagu O. Dolutegravir and Lamivudine Combination for the Treatment Of HIV-1 Infection. HIV AIDS (Auckl), 2019.
11. World Health Organization. WHO Recommends Dolutegravir as Preferred HIV treatment option in all populations. 2019. Accessed 28 March 2024. [Internet]. Available at: https://www.who.int/news/item/22-072019-who-recommends-dolutegravir-as-preferredhiv-treatment-option-in-all-populations
12. UNITAID. South Africa to Introduce State-of-theArt HIV treatment. 2019. [Internet]. Accessed 5 April 2024. Available at: https://unitaid.org/news-blog/ south-africa-to-introduce-state-of-the-art-hivtreatment/
13. Professional Information. Reydin. 2018. [Internet]. Accessed 5 April 2024. Available at: https://www. sahpra.org.za/wp-content/uploads/2019/08/ Reydin_PIL_Cipla_MCC-format-31-August-2018.pdf
14. SA National Department of Health. 2023
ART Clinical Guidelines for the Management of HIV in Adults, Pregnancy and Breastfeeding, Adolescents, Children, Infants and Neonates. 2023. Accessed 28 March 2024. [Internet]. Available at: https://knowledgehub.health.gov.za/system/
files/elibdownloads/2023-07/National%20 ART%20Clinical%20Guideline%20AR%204.5%20 20230713%20Version%204%20WEB.pdf
15. Nel J, Meintjies G, Osih R, et al. Southern African HIV Clinicians Society Guidelines for Antiretroviral Therapy in Adults: 2023 Update. [Internet]. Accessed 5 April 2024. Available at: https://sahivsoc.org/ Guidelines/Index#:~:text=This%202023%20 update%20to%20the,than%20efavirenz%2D%20 or%20lopinavir%2Dritonavirbased
16. World Health Organization. Update on the Transition to Dolutegravir-based Antiretroviral Therapy: report of a WHO meeting. 2022. [Internet]. Accessed 5 April 2024. Available at: https://www. who.int/publications/i/item/9789240053335
17. Mahale PR, Patel BS, Kasmani N. Treatment Outcomes of Dolutegravir- Versus Efavirenz-Based Highly Active Antiretroviral Therapy Regimens Among Treatment-Naive People Living With HIV. Cureus, 2023.
18. McCluskey S, Pepperell T, Hill A, et al. Adherence, resistance, and viral suppression on dolutegravir in sub-Saharan Africa: implications for the TLD era. AIDS, 2021.
19. World Health Organization. Dolutegravir (DTG) and the fixed dose combination (FDC) of tenofovir/ lamivudine/dolutegravir (TLD). April 30 2018. Briefing note. Updated 2018. [Internet]. Accessed 14 May 2024. Available at: https://www.researchgate.net/ profile/Mondli_Alfred/post/With_the_introduction_ of_the_new_HIV_drug_it_would_make_the_ immune_system_to_be_stronger_Wouldnt_it_ trigger_other_hidden_infections_to_it_patients/ attachment/5e8d010ff155db0001f37906/AS %3A877816417640448%401586299151110/ download/DTG-TLD-arv_briefing_2018.pdf
20. Twimukye A, Laker M, Odongpiny EAL, et al Patient experiences of switching from Efavirenzto Dolutegravir-based antiretroviral therapy: a qualitative study in Uganda. BMC Infectious Diseases, 2021.
21. Song I, Borland J, Chen S, Guta P. Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir. Eur J Clin Pharmacol, 2014.
22. Bangalee A, Hanley S, Bangalee V. Dolutegravir as First-line Antiretroviral Therapy In South Africa: Beware the One-Size-Fits-All Approach. SAMJ, 2022.
23. SAHCS. Use of Dolutegravir-based Regimens for First- And Second-line Antiretroviral Therapy. Updated 2022. [Internet]. Available at: https:// sahivsoc.org/Files/SAHCS%20clinical%20 statement_TLD%20switching_20220513.pdf SF
South Africa’s antiretroviral therapy (ART) armamentarium recently received a significant boost with the introduction of a new single-tablet formulation incorporating rilpivirine (RPV), emtricitabine (FTC), and tenofovir alafenamide (TAF). This development marks a significant milestone in the ongoing battle against HIV, offering patients and healthcare providers a convenient and effective alternative treatment option.1,2
RPV is a second-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) and plays a crucial role in inhibiting viral replication in people living with HIV (PLWHIV). Both FTC and TAF belong to the class of nucleoside reverse transcriptase inhibitors (NRTIs). 3,4
NNRTIs like RPV exert their therapeutic effects by binding permanently to the reverse transcriptase enzyme of HIV, thereby disrupting its function, and hindering viral replication. On the other hand, NRTIs such as FTC and TAF function by incorporating themselves into the viral DNA chain, thereby inhibiting its elongation and preventing further viral replication. 4
Clinical consideration when prescribing ART regimens
Despite significant advances in the development of new antiretrovirals (ARVs), it is essential to recognise that HIV is a complex disease with varying presentations and treatment responses among affected individuals. Daar emphasises the need for personalised treatment approaches, considering factors such as age and comorbidities when selecting ARV regimens. 5
Iacob et al emphasise the importance of vigilant monitoring once an ARV regimen has been selected, with a keen focus on both its effectiveness and potential adverse effects (AEs). Changes to the regimen is necessary in instances of drug toxicity and the development of ARV resistance. 6
Furthermore, the authors underscore the variability of patient factors. Apart from age and comorbidities, social status, lifestyle, ability to understand the treatment plan, and unique genetic makeup are influential determinants in tailoring ARV regimens. Consequently, the adaptability of ARV regimens to accommodate these factors necessitates a continuous process of evaluation and adjustment. 6
What are some of the AEs associated with ARVs used as first-line treatment?
Dolutegravir (DTG), an integrase strand transfer inhibitor (InSTI), in combination with a NRTI backbone are recommended as the preferred first-line regimen for PLWHIV who are initiated on ART, according to guidelines published by the World Health Organization, the Southern African HIV Clinicians Society (SAHCS), and the South African National Department of Health. 4,7,8
In South Africa, the preferred firstline ART regimen is tenofovir disoproxil
fumarate (TDF)-lamivudine (3TC)-DTG for adults and adolescents. SAHCS recommends efavirenz (EFV) and RPV as alternative first-line options – particularly in cases where DTG is contraindicated or not tolerated. 4,8
DTG is generally well-tolerated, with mild side effects such as headaches and insomnia. While DTG may cause a slight elevation in serum creatinine levels, this is not indicative of renal damage and does not warrant treatment discontinuation. However, caution is advised regarding potential drug interactions, particularly with anticonvulsants and anti-arrhythmic drugs. 4,7
permanently to the reverse transcriptase enzyme of HIV, disrupting its function and hindering viral replicating
EFV may cause neuropsychiatric events such as insomnia, vivid dreams, rash, and dizziness particularly during the initial weeks of treatment. Rare but serious AEs, including psychosis and Stevens-Johnson syndrome, have also been reported. Monitoring for these symptoms is crucial, and switching to an alternative agent may be warranted if they persist or worsen. 4
Furthermore, EFV has been associated with late-onset encephalopathy syndrome, characterised by subacute encephalopathy and cerebellar dysfunction, which may manifest months or years after initiating treatment. Other potential AEs include drug-induced hepatitis and gynaecomastia. 4
RPV should not be co-administered with proton pump inhibitors, including esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Histamine H2-receptor antagonists can be coadministered if properly spaced.9 Additionally, avoid co-administration with anticonvulsants like carbamazepine, oxcarbazepine, phenobarbital, and phenytoin, anti-mycobacterials such as rifabutin, rifampicin, and rifapentine, systemic dexamethasone (multiple doses), and Hypericum perforatum (St John’s wort), as they may significantly decrease
RPV plasma concentrations due to CYP3A enzyme induction.9
Furthermore, RPV cannot be coadministered with rifampin-based tuberculosis treatment and should not be started in patients with a viral load >100 000 copies/ml. RPV has a lower incidence of neuropsychiatric events and rashes compared to EFV. 4
TDF can cause tubular wasting syndrome (TWS) in rare cases. TWS is characterised by phosphate and potassium depletion. Monitoring for symptoms such as muscle weakness is crucial, and assessment of potassium and phosphate levels is recommended. TDF is associated with renal and bone toxicities and precautions should be taken, particularly in patients with impaired kidney function. 4
TAF is a prodrug of tenofovir and has been described as ‘a magic bullet’. TAF was developed to reduce renal toxicity and the negative impact on bone mineral density associated with TDF. Compared to TDF, TAF is associated with greater weight gain, adverse lipid profile effects, and drug interactions. TAF (25mg) is not recommended with ritonavir-containing protease inhibitor (PI) regimens. 4,10 3TC and FTC are well-tolerated and despite minor differences, are considered interchangeable. However, rare instances of pure red cell aplasia have been reported with both agents, necessitating consideration of alternative agents in such cases. 4
Is switching to once-daily single-tablet RPV-FTCTAF safe and effective?
RPV was approved by the American Food and Drug Administration for the treatment of PLWHIV in May 2011, and a once-daily single-tablet containing RPV/FTC/TDF was approved in August 2011 as an alternative first-line option for treatment-naïve patients.9
In South Africa, the new once-daily single-tablet formulation containing RPV/ FTC/TAF, is indicated for the treatment of adults and adolescents (aged ≥12-years with a body weight of at least 35kg) living with HIV-1.1
Orkin et al (2017) conducted a study to assess the efficacy, safety, and tolerance of switching to a single-tablet regimen incorporating RVP/ FTC/TAF from a regimen containing RVP/FTC/ TDF in adult patients who had achieved viral suppression.11
This was a randomised, doubleblind, multi-centre, placebo-controlled, non-inferiority trial conducted across
11 countries in North America and Europe. Participants, who had been virally suppressed for at least six months and had adequate kidney function, were randomly assigned to receive either the new singletablet regimen or to continue their current regimen with matching placebo, once daily for 96 weeks.11
Both participants and study staff were unaware of the treatment assignments. The primary endpoint was the proportion of participants maintaining viral suppression (HIV-1 RNA <50 copies/ ml) at week 48. The study involved 630 participants, with 316 assigned to the TAF group and 314 to the TDF group.11
At week 48, non-inferiority of TAF to TDF was demonstrated, with similar rates of viral suppression observed in both groups. AEs were comparable between the two groups, with fewer participants experiencing drug-related AEs in the TAF group.11
According to Orkin et al, their findings support the use of TAF-based regimens, including co-formulation with RVP and FTC, as a suitable option for both initial and ongoing treatment of HIV-1.11
DeJesus et al (2017) assessed the efficacy, safety, and tolerability of switching from a regimen of EFV/FTC/TDF to a regimen of RPV/FTC/TAF. Conducted as a randomised, double-blind, placebocontrolled trial across multiple sites, 875 PLWHIV were enrolled, meeting specific criteria including viral suppression and adequate renal function.12
The primary endpoint was the proportion of participants with plasma HIV-1 RNA <50 copies/ml at week 48. Results showed that the TAF regimen was non-inferior to the TDF regimen in maintaining viral suppression, with a 90% suppression rate observed.12
Additionally, the switch was welltolerated, with comparable rates of treatment-related AEs between groups. These findings support the recommendation of TAF-based regimens for both initial and ongoing treatment of HIV-1 infection.12
Hagins et al (2018) evaluated the efficacy, safety, and tolerability of switching to the RPV/FTC/TAF option for adults from either RPV/FTC/TDF or EFV/FTC/TDF.
The team conducted two randomised, double-blind, active-controlled, noninferiority trials were conducted: Study 1216 for participants on RPV/FTC/TDF and Study 1160 for those on EFV/FTC/TDF. 2
Virologically suppressed adults were randomised (1:1) to switch to RPV/FTC/ TAF or continue their current regimen for
96 weeks. Efficacy was assessed by HIV-1 RNA <50 copies/ml, and bone and renal endpoints were evaluated at week 96. 2
In Study 1216 (n=630) and Study 1160 (n=875), switching to RPV/FTC/TAF showed non-inferior efficacy to continuing baseline therapy at week 96. No participant on RPV/ FTC/TAF developed treatment-emergent resistance, while two on EFV/FTC/TDF and one on RPV/FTC/TDF did. RPV/FTC/TAF groups exhibited significant improvements in bone mineral density and renal tubular markers compared to continuing baseline therapy. 2
TAF is a prodrug of tenofovir and has been described as ‘a magic bullet’
The introduction of the once-daily singletablet formulation containing RPV/FTC/ TAF represents a significant advancement in South Africa’s ART landscape. This formulation potentially offers a more effective treatment option for PLWHIV. The clinical trials conducted by Orkin et al and DeJesus et al demonstrated the efficacy, safety, and tolerability of switching to the RPV/FTC/TAF regimen from previous ART regimens containing TDF.
These studies revealed non-inferiority in maintaining viral suppression with RPV/ FTC/TAF compared to existing regimens, along with comparable rates of AEs. Furthermore, Hagins et al highlighted the benefits of RPV/FTC/TAF in improving bone mineral density and renal function, further supporting its use as a suitable option for both initial and ongoing HIV treatment.
References
1. Professional Information. Tavirant. 2023.
2. Hagins D, Orkin C, Daar ES, et al Switching to Co-formulated Rilpivirine (RPV), Emtricitabine (FTC) And Tenofovir Alafenamide from Either RPV, FTC And Tenofovir Disoproxil Fumarate (TDF) Or Efavirenz, FTC And TDF: 96-week Results from Two Randomized Clinical Trials. HIV Med, 2018.
3. Moorhouse MA, Cohen K. The Role of Rilpivirine
in Southern Africa. South Afr J HIV Med, 2019.
4. Nel J, Meintjies G, Osih R, et al. Southern African HIV Clinicians Society Guidelines for Antiretroviral Therapy in Adults: 2023 Update. [Internet]. Accessed 5 April 2024. Available At: Https://Sahivsoc.Org/Guidelines/ Index#:~:text=this%202023%20update%20 to%20the,than%20efavirenz%2d%20or%20 lopinavir%2dritonavirbased
5. Daar ES. Novel Approaches to HIV Therapy. F1000res, 2017.
6. Iacob SA, Iacob DG, Jugulete G. Improving the Adherence to Antiretroviral Therapy, A Difficult but Essential Task for a Successful HIV Treatment-clinical Points of View and Practical Considerations. Front Pharmacol, 2017.
7. World Health Organization. Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a Public Health Approach. 2021. [Internet]. Accessed 6 April 2024. Available At: Https://Www.Who.Int/Publications/I/ Item/9789240031593
8. SA National Department of Health. 2023 ART Clinical Guidelines for the Management of HIV In Adults, Pregnancy and Breastfeeding, Adolescents, Children, Infants and Neonates. 2023. [Internet]. Accessed 6 April 2024. Available At: Https://Knowledgehub.Health. Gov.Za/System/Files/Elibdownloads/2023-07/ National%20art%20clinical%20guideline%20 ar%204.5%2020230713%20version%204%20 web.Pdf
9. Sharma M, Saravolatz LD. Rilpivirine: A New Non-Nucleoside Reverse Transcriptase Inhibitor. J Antimicrob Chemother, 2013.
10. Di Perri G. Tenofovir Alafenamide (TAF) Clinical Pharmacology. Infez Med, 2021.
11. Orkin C, Dejesus E, Ramgopal M, et al Switching from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Coformulated with Rilpivirine and Emtricitabine in Virally Suppressed Adults With HIV-1 Infection: A Randomised, Double-blind, Multicentre, Phase 3b, Non-inferiority Study. Lancet HIV, 2017.
12. Dejesus E, Ramgopal M, Crofoot G, et al Switching from Efavirenz, Emtricitabine, And Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide Coformulated with Rilpivirine and Emtricitabine in Virally Suppressed Adults With HIV-1 Infection: A Randomised, Double-blind, Multicentre, Phase 3b, Non-inferiority Study. Lancet HIV, 2017. SF
Tobramycin 3 mg/ml or mg/g
Ophthalmic Solution/Ointment
Broad spectrum, bactericidal action suitable for mild, moderate and severe bacterial infections caused by both susceptible Gram-positive and Gram-negative pathogens.1
Scan the QR code for the full Professional Information
References: 1. TOBREX® Approved Professional Information 05 December 2021. 2. Wilhelmus KR, Gilbert ML, Osato MS. Tobramycin in Ophthalmology. Surv Ophthalmol. 1987;32(2):111-122.
For full prescribing information, refer to the Professional Information approved by the South African Health Products Regulatory Authority.
S4 TOBREX® Eye Drops Reg. No. P/15.1/58. TOBREX® Eye Ointment: Reg. No. P/15.1/205. COMPOSITION: TOBREX® Eye Drops: A sterile ophthalmic solution containing 3 mg tobramycin base per ml, preserved with 0,01% (m/v) benzalkonium chloride. TOBREX® Eye Ointment: A sterile ophthalmic ointment containing 3 mg tobramycin base per g preserved with chlorobutanol 0,5% (m/m). Holder of Certificate of Registration: Novartis South Africa (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View, 2090. Tel. (011) 347 6600. Co. Reg. No. 1946/020671/07. Novartis Adverse Drug Reaction Reporting: Email: patientsafety.sacg@novartis.com. Web: https://psi.novartis.com/. Tel: 0861 929-929. Fax: 011 929-2262. Marketed and Distributed by Adcock Ingram Limited. Co. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021. Customer Care: 0860 ADCOCK/232625. www.adcock.com. ZA2302214617 Exp.: 02/2025.
This article was independently sourced by Specialist Forum
Conjunctivitis, commonly known as ‘pink eye’, seldom leads to permanent visual impairment or structural harm, but its economic impact is significant, largely due to missed work or school days and direct medical costs such as consultations, tests, and treatment. Conjunctivitis is defined as inflammation or infection of the conjunctiva – a thin mucous membrane that lines the inside of the eyelids and the surface of the eye up to the limbus, where the sclera and cornea meet.1,2
The conjunctiva has two portions: The bulbar portion, which covers the eye’s surface, and the tarsal portion, which covers the eyelids. Normally transparent, it can turn pink or red when inflamed, hence the colloquial term ‘pink eye’. Most cases of paediatric conjunctivitis are caused by either bacterial or viral infections or allergies. Bacterial conjunctivitis (50%-70%) are the leading cause in children.1
Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the top three culprits. H. influenzae cause of bacterial ~70% of conjunctivitis. Viral conjunctivitis is mainly caused by adenoviruses.
Allergic conjunctivitis affects one in five children. It is classified as a type 1 hypersensitivity reaction, caused by airborne allergens like pollen, dander, dust, or moulds.1
Conjunctivitis can vary in severity, from mild redness accompanied by tearing to more severe cases with purulent discharge,
subconjunctival haemorrhage, and oedema of the conjunctiva or eyelid.1
Symptoms of bacterial conjunctivitis typically include redness in the eyes and a notable discharge, often yellowishgreen. Those affected by acute bacterial conjunctivitis frequently report waking up with their eyes glued shut due to the discharge. During examination, mucopurulent discharge is commonly observed along the edges of the eyelids, which quickly returns even after wiping, usually within minutes.1
Neonatal conjunctivitis, also known as ophthalmia neonatorum, is conjunctivitis that occurs during the first 28 days of life. Around 40% of neonatal conjunctivitis is caused by Chlamydia trachomatis Symptoms typically manifest between five days to two weeks after birth.1
Neonates with bacterial conjunctivitis commonly exhibit purulent discharge, which may progress to purulent discharge and the development of yellow-white membranes, known as pseudomembranes, visible on the
tarsal conjunctiva whereas those with viral conjunctivitis, mainly caused by the herpes simplex virus, tend to have a watery discharge.1 Conjunctivitis caused by Neisseria gonorrhoeae is characterised by significant redness and swelling, lid oedema, and purulent discharge, typically occurring earlier than chlamydial conjunctivitis, around two to five days after birth.1
Patients with viral conjunctivitis often report a sudden onset of symptoms, which include a burning or gritty sensation, along with watery discharge. Initially affecting one eye it spreads to the other within 24 to 48 hours. This presentation may be accompanied by a viral prodrome, including fever, swollen lymph nodes (particularly around the ears), sore throat, and upper respiratory tract infection. Clinical examination typically reveals prominent redness in the conjunctiva, watery discharge, and a follicular pattern on the inner surface of the eyelids.1
The typical presentation of allergic
conjunctivitis involves bilateral symptoms such as watery discharge, chemosis (swelling of the eye surface membranes because of accumulation of fluid), and morning crusting along the eyelid margins. It often coincides with peak allergen season. A key distinguishing factor is itching, which may accompany other atopic symptoms such as nasal congestion, coughing, or sneezing.1
Helpful features to differentiate allergic conjunctivitis include symptoms like photophobia, eye pain, and blurry vision are atypical and should prompt referral to an ophthalmologist. Conditions like blepharitis and meibomian gland dysfunction can mimic allergic conjunctivitis and should be considered in the differential diagnosis.1
Preventative measures
Prompt diagnosis and treatment of infectious conjunctivitis are crucial for mitigating the public health and economic consequences of community transmission. Furthermore, individuals with underlying systemic conditions may initially manifest with conjunctivitis. For instance, certain types of neonatal conjunctivitis are linked to conditions like pneumonia, otitis media, or Kawasaki disease. 2
Preventing infectious conjunctivitis involves several strategies, including prophylactic treatments, vaccination programmes, and interrupting transmission chains. Neonatal conjunctivitis can often be prevented through prenatal screening and treatment of expectant mothers, as well as prophylactic treatment of infants at birth. Childhood vaccinations also offer protection against viral conjunctivitis. 2
Hygiene also plays an important role in prevention. Individuals with viral conjunctivitis should be advised to wash their hands frequently with soap and water (rather than relying solely on sanitiser), use separate towels and pillows to prevent cross-contamination, and refrain from close contact with others during the contagious period. This advice is particularly important for individuals in professions with a high risk of transmission, such as healthcare workers and childcare providers. 2
While the duration of infectivity can vary, many experts consider the contagious period to extend for about seven days from the onset of symptoms in the second eye if both are affected. After seven to 10 days of infection, recovering virus from infected cases becomes increasingly difficult. These precautions help minimise the spread of the virus and protect both the individual and the community from further transmission. 2
Treatment of conjunctivitis is most effective when targeted at the underlying cause. Early identification and intervention can preserve sight and, in certain cases, even save lives. The American Academy of Ophthalmology (AAO) cautions that the indiscriminate use of topical antibiotics or corticosteroids should be avoided due to potential adverse events (AEs). 2
A Cochrane Review evaluated the benefits and AEs of antibiotic therapy in the management of acute bacterial conjunctivitis. The review included 21 eligible randomised controlled trials, with a total of 8805 participants. 3
The analysis found that antibiotics significantly improved clinical cure, with a 26% increase compared to placebo. Similarly, microbiological cure was also enhanced with antibiotic therapy. Participants receiving antibiotics had a lower risk of treatment incompletion and were less likely to experience persistent clinical infection. No serious systemic AEs were reported in either the antibiotic or placebo groups. 3
Overall, the findings suggest that the use of topical antibiotics can modestly improve the resolution of acute bacterial conjunctivitis compared to placebo. Given the absence of serious side effects, antibiotics may be considered to achieve better clinical and microbiological efficacy. This can contribute to quicker recovery and may facilitate individuals’ return to work or school, enhancing their quality of life. 3
In the management of neonatal conjunctivitis, several key factors are essential:4
_ Prevent cross-contamination by practicing frequent hand washing and wearing gloves
_ Irrigate the affected eye with sterile isotonic saline to aid in cleansing
_ Systemic treatment is necessary for specific types of conjunctivitis, including staphylococcal, gonococcal, Chlamydia, Pseudomonas, and herpetic conjunctivitis
_ Avoid eye patching, as it may exacerbate the condition
_ Consider consulting with a paediatric infectious disease or ophthalmologic specialists for guidance in complex cases
_ Chemical conjunctivitis typically resolves within 24 to 72 hours and may benefit from lubrication and artificial tears
_ Gonococcal conjunctivitis is a medical emergency due to its severity. Thirdgeneration cephalosporins are the firstline antibiotics, as there is resistance to penicillin, and it can occur even in
infants born to mothers with positive maternal gonococcal infection, despite appropriate prophylaxis.
According to the AAO, sexual abuse should be considered in children presenting with gonococcal or chlamydial conjunctivitis. Gonococcal conjunctivitis requires systemic antibiotic therapy, with saline lavage aiding comfort and inflammation resolution. If corneal involvement is present, topical treatment akin to bacterial keratitis management is added. Daily monitoring until conjunctivitis resolves is essential, including history review, visual acuity assessment, and slit-lamp examination. 2 Chlamydial conjunctivitis management involves systemic therapy due to the likelihood of concurrent infections in other sites like the nasopharynx, genital tract, or lungs. Empirical antibiotic treatment may be warranted for patients displaying typical signs and symptoms, with systemic therapy being the primary approach. 2
HSV conjunctivitis is typically a short-term, acute condition, often requiring treatment when corneal involvement is suspected. Topical options may be applied multiple times daily. Oral medications are also effective, with higher doses sometimes necessary for apparent resistant cases. 2 Combining oral and topical antiviral treatments can effectively prevent HSV blepharoconjunctivitis progression. Lower oral antiviral doses are utilised for long-term prophylaxis against recurrent HSV conjunctivitis and keratitis. Topical corticosteroids should be avoided as they can worsen HSV infections. 2 Follow-up within a week of treatment initiation is recommended, including history review, visual acuity assessment, and slitlamp examination. Neonatal cases require immediate consultation due to the potential life-threatening nature of systemic HSV infection. 2
Recommendations for managing allergic conjunctivitis include a range of preventive measures and symptomatic treatments such as wearing sunglasses to shield against airborne allergens, utilising cold compresses and refrigerated artificial tears for relief, avoiding eye rubbing, and minimising exposure to known allergens. 2 Implementing hypoallergenic bedding, using eyelid cleansers, frequent laundering, and pre-bedtime bathing can further alleviate symptoms. Over-the-counter antihistamine/vasoconstrictor agents or second-generation topical histamine
H1-receptor antagonists are effective for mild cases, with refrigerated storage enhancing their efficacy. 2
Mast-cell stabilisers are prescribed for frequent or persistent cases, with newer medications combining antihistamine and mast-cell stabilising properties. Topical mast-cell inhibitors aid in allergic rhinitis management, along with nasal sprays and aerosols. In inadequately controlled cases, a short-term course of topical corticosteroids may be added cautiously. 2
Oral antihistamines, though common, can exacerbate dry eye syndrome; hence, cooled artificial tears are advised concurrently. Severe cases may require topical cyclosporine or tacrolimus. These approaches aim to provide effective relief while minimising long-term complications and rebound symptoms. 2
Which antibiotic to choose
The choice of antibiotic is often empirical, with a five- to seven-day course of a broad-spectrum topical antibiotic being effective. Microbiological testing should inform treatment decisions, which may involve compounded topical antibiotics tailored to the specific pathogens identified. These measures are crucial for effectively managing moderate to severe bacterial conjunctivitis and minimising the risk of complications, especially in vulnerable populations such as neonates. 2 According to Hutnik et al, a systematic review concluded that selecting the best topical antibiotics for ocular infections is not straightforward. Factors such as local microbiological resistance patterns, cost, dosing schedules, and individual patient considerations like allergies and adherence play crucial roles alongside efficacy. 5
The authors added that while results from RCT vary, many indicate comparable clinical and microbiological efficacy across various topical antibiotics. In South Africa, the primary treatment for acute bacterial conjunctivitis involves chloramphenicol eye drops or ointment as the first-line approach. Treatment duration should not exceed five days to mitigate the risk of side effects and resistance development. 5,6 It should also be noted that prolonged or frequent use of chloramphenicol has been associated with serious complications such as optic neuropathies, blood dyscrasias, and aplastic anaemia. 6 If there is an inadequate response to chloramphenicol or if resistant organisms are confirmed, alternative treatments may be considered. These include topical fusidic acid eye drops, aminoglycoside eye drops or ointment (such as tobramycin),
and fluoroquinolone eye drops or ointment (such as ciprofloxacin). 6
Safety and efficacy of tobramycin eye drops or ointment in paediatric patients Tobramycin (0.3%) ointment is suitable for children aged ≥2-months.7
The safety and efficacy of tobramycin eye drops, or ointment in paediatric patients have been shown in numerous studies. Timewell et al conducted a study to compare the safety and efficacy of tobramycin and gentamicin sulfate solutions and ointments in paediatric patients <20-years with acute superficial ocular inflammations of presumed bacterial origin. 8,9
Efficacy analysis showed that both tobramycin and gentamicin were effective in treating the infections, with 98% of eyes in the tobramycin group and 95% in the gentamicin group classified as cured or improved by the investigator at the end of the treatment period. 8
The study concluded that both tobramycin and gentamicin were equally efficacious in treating external ocular infections in paediatric populations, with tobramycin demonstrating a trend towards fewer treatment-related side effects, consistent with previous reports. Therefore, tobramycin is considered a valuable addition to the ophthalmologist’s treatment options for bacterial superficial ocular infections. 8
Knowing when to refer a patient with conjunctivitis to an ophthalmologist is crucial for ensuring appropriate management and timely intervention. While certain symptoms and clinical findings may suggest specific causes of conjunctivitis, there is significant overlap in clinical practice, emphasising the importance of careful assessment.1
Referral should be considered if patients present with:1
_ Moderate to severe pain
_ Vision loss
_ Constant blurred vision
_ Severe purulent discharge
_ Photophobia, especially if disproportionate to other symptoms or present in cases of allergic conjunctivitis. Moreover, patients with symptoms persisting beyond seven to 10 days, recurrent symptoms, or inadequate response to treatment should also be referred for further assessment.1
While many cases of allergic conjunctivitis can be managed without referral, suspicion
of vernal conjunctivitis warrants immediate referral, as it can pose a risk to vision.1
Bacterial conjunctivitis, commonly known as ‘pink eye’, rarely lead to permanent visual impairment, but carries significant economic burden due to missed work or school days and direct medical costs. Understanding the spectrum of conjunctivitis causes, including bacterial, viral, and allergic, is crucial for appropriate management. Tobramycin, a widely used antibiotic, has demonstrated efficacy and safety in treating bacterial conjunctivitis in pediatric populations. Careful consideration of referral to ophthalmology is essential, especially in cases with severe symptoms, prolonged duration, or poor response to treatment, to ensure timely and comprehensive evaluation and management.
1. Mahoney MJ, Bekibele R, Notermann SL, et al. Pediatric Conjunctivitis: A Review of Clinical Manifestations, Diagnosis, and Management. Children (Basel), 2023.
2. Ambrus A, Daly M, Lum FC. American Academy of Ophthalmology. Conjunctivitis Preferred Practice Pattern ®. Updated 2023. [Internet]. Available at: https://www.aao. org/education/preferred-practice-pattern/ conjunctivitis-ppp-2023
3. Chen YY, Liu SH, Nurmatov U, et al Antibiotics versus placebo for acute bacterial conjunctivitis. Cochrane Database Syst Rev, 2023.
4. Makker K, Nassar GN, Kaufman EJ. Neonatal Conjunctivitis. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441840/
5. Hutnik C, Mohammad - Shahi MH . Bacterial conjunctivitis. Clinical Ophthalmology, 2010.
6. Van Eyk AD. Pharmaceutical options for ophthalmic conjunctivitis. SAFP, 2019.
7. Professional information. Tobramycin. 2023. [Internet]. Available at: https://www.drugs.com/ monograph/tobramycin-eent.html
8. Timewell RM, Rosenthal AL, Smith JP, Cagle GD. Safety and Efficacy of Tobramycin and Gentamicin Sulfate in the Treatment of External Ocular Infections of Children. J Ped Ophthalmol Strab, 1983. SF
Convenient twice daily dosage1 from 6 months (in AOMT**) to adults, including the elderly1,2 Scan the QR code for
CILODEX® treating patients for over 15 years.1
* AOE: Acute Otitis Externa ** AOMT: Acute Otitis Media with Tympanotomy Tubes. References: 1. Cilodex® Approved Professional Information, 13 April 2022. 2. Daniel SJ, et al. Guidelines for the treatment of tympanostomy tube otorrhoea. J Otolaryngol 2005;34(S2):S60-S63. For full prescribing information, refer to the Professional Information approved by the South African Health Products Regulatory Authority. S4 CILODEX® Ear Drops, suspension. 1 ml of suspension contains 3 mg ciprofloxacin (as hydrochloride) and 1 mg dexamethasone preserved with benzalkonium chloride 0,01% (m/v). A39/16.2/0544. Novartis SA (Pty) Ltd. Magwa Crescent West, Waterfall City, Jukskei View, 2090. Tel. (011) 347 6600. Co. Reg. No. 1946/020671/07. Novartis Adverse Drug Reaction Reporting: Email: patientsafety.sacg@novartis.com. Web: www.novartis.com/report. Tel: 0861 929-929. Marketed and Distributed by Adcock Ingram Limited. Co. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Customer Care: 0860 ADCOCK/232625. www.adcock.com FA-11222356 Exp.: 07/2026.
Paediatric pain often remains inadequately treated, a phenomenon known as oligoanalgesia, particularly affecting younger patients and those living with cognitive impairments. Contributing factors include difficulties in pain recognition due to limited visual and behavioural cues, reduced pain perception, insufficient awareness of available pain relief options, incorrect dosing of medications, and concerns about potential side effects or toxicity of analgesics.1
Studies indicate that individuals experiencing pain during early life often exhibit enduring alterations in pain perception and associated behaviours. Likewise, unmanaged or severe pain can contribute to the development of hyperalgesia later in life, underscoring the critical significance of implementing comprehensive pain management strategies in paediatric populations.1
This article was independently sourced by Specialist Forum
Otalgia a leading source of pain
Otalgia is a common complaint among children seen in primary care or emergency settings, often ranking as one of the primary reasons for evaluation. 2
In non-verbal children, signs suggestive of otalgia include:3
_ Tugging or pulling at the ear(s)
_ Fussiness and crying
_ Difficulty sleeping
_ Fever, particularly in infants and younger children
_ Fluid draining from the ear
_ Clumsiness or issues with balance
_ Difficulty hearing or responding to quiet sounds.
Most patients presenting with otalgia typically receive one of three common diagnoses: Acute otitis media (AOM) and its subtypes including otitis media with effusion (OME), or otitis externa (OE).1,5
However, in rare instances, more severe diseases associated with ear pain may arise
due to the spread of infection to nearby anatomical structures, such as mastoiditis, meningitis, malignant otitis externa, or venous sinus thrombosis. Additionally, otalgia can be a symptom of basilar skull fracture or epidural haematoma following head trauma.1
Streptococcus pneumoniae is the predominant bacterial organism responsible for OM, followed by nontypeable Haemophilus influenzae and Moraxella catarrhalis. Among viral pathogens associated with otitis media, respiratory syncytial virus, coronaviruses, influenza viruses, adenoviruses, human metapneumovirus, and picornaviruses are the most common culprits. 5
Understanding acute otitis media AOM, or infection of the middle ear space, is one of the most common reasons for paediatric consultations. About 50% of children will experience at least one ear
infection by the time they reach their second birthday. The most prevalent age range for children to develop AOM is between three- to 24-months. 4,5
Multiple risk factors contribute to the development of AOM in children. The primary risk factor is a previous upper respiratory tract infection. Additional factors include being male, adenoid hypertrophy causing obstruction, allergies, attending daycare, exposure to environmental smoke, pacifier usage, immunodeficiency, gastroesophageal reflux, a family history of recurrent childhood AOM, and other genetic predispositions. 5
Diagnosing AOM in children can be challenging due to the presence of nonspecific symptoms alongside otalgia. These symptoms may include pulling or tugging at the ears, irritability, headache, disturbed sleep, poor feeding, vomiting, or diarrhoea. Fever, typically low-grade, is present in ~60% of cases. Diagnosis relies primarily on clinical examination, with no requirement for laboratory tests or imaging. 5
According to guidelines, the diagnosis of AOM is confirmed by clinical findings such as moderate to severe bulging of the tympanic membrane or new onset of otorrhea not caused by OE. Additionally, mild tympanic membrane bulging accompanied by recent otalgia or erythema supports the diagnosis. 5
Acute chronic suppurative OM (CSOM) is another important subtype of AOM. Acute CSOM is also referred to as chronic OM and indicates a stage of ear pathology marked by persistent infection within the middle ear, accompanied by the absence of an intact tympanic membrane.1,6
This condition involves ongoing inflammation affecting both the middle ear and mastoid cavity. A hallmark indication is the presence of chronic or enduring otorrhea lasting from two to six weeks, often observed through a perforated tympanic membrane. 6
Acquired hearing loss is a characteristic manifestation observed in individuals affected by this condition. If left untreated, this hearing impairment can exacerbate existing morbidity and mortality risks. 6
The predominant micro-organisms associated with CSOM include S. aureus, including methicillin-resistant strains. Additionally, pathogens such as Pseudomonas aeruginosa, various species of Proteus and Klebsiella, as well as Bacteroides and Fusobacterium species, are recognised culprits in causing the disease. 6
Decoding otitis media with effusion
OME is the leading cause of acquired hearing loss in childhood, typically affecting children between the ages of one- and sixyears. Its prevalence peaks around age two and declines after >5-years. OME tends to be more common during the winter months, aligning with increased rates of upper respiratory infections among patients during this time.7
OME is characterised by the presence of fluid in the middle ear without signs of acute infection. As fluid accumulates in the middle ear and Eustachian tube, it exerts pressure on the tympanic membrane. This pressure interferes with the proper vibration of the tympanic membrane, reduces sound conduction, and consequently leads to hearing impairment in patients.7
Risk factors for OME include passive smoking, bottle feeding, daycare attendance, and atopy. Both children and adults can develop OME, but the underlying causes differ between these populations. In younger children, the eustachian tube is positioned more horisontally, making them more susceptible to OME. As children grow into adulthood, the tube elongates and angles downward, reducing the risk of OME.7
Treatment goals of AOM are to manage pain and address the infection
OE – also referred to as swimmer’s ear –can affect individuals from all age groups. Around 10% of individuals will experience OE during their lifetime of which 95% will experience acute OE. It is rare in patients <2-years and typically peaks around the ages of seven- to 14-years. OE generally occurs during the summer months and in tropical climates, potentially due to increased humidity levels. 8
Multiple factors can contribute to the development of OE. Among these, swimming is one of the most prevalent risk factors, increasing the risk fivefold compared to non-swimmers. Additionally, other factors include for example high
humidity levels, trauma to the ear or the use of external devices such as cotton swabs, earplugs, or hearing aids and dermatologic conditions like eczema and psoriasis as well as stress. 8
When are antibiotics appropriate for AOM?
The treatment goals of AOM are twofold: To manage pain and address the infection using antibiotic therapy. Pain control can be achieved using non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen. Treatment options are discussed in more detail below. 5
According to Shahbaznejad et al, watchful waiting approach is appropriate for healthy children aged six- to 23-months who have mild symptoms and have a confirmed diagnosis of unilateral AOM, as well as for children aged ≥2-years and older with either bilateral or unilateral AOM, or those who do not fully meet the diagnostic criteria. This approach can be pursued for up to 48 hours if appropriate follow-up is ensured.9
However, children aged ≥6-months with specific criteria, such as a bulging tympanic membrane, fever ≥39°C, moderate to severe systemic illness, severe otalgia, or those who have been significantly ill for 48 hours or more, should be treated promptly with antimicrobial agents. Furthermore, children <2-years old with bilateral AOM, regardless of additional signs or symptoms, should also receive antimicrobial treatment.9
Administering oral antibiotics to children increases the risk of systemic AEs. This is particularly concerning because the routine use of oral antibiotics for common infections like AOM can foster the development of antimicrobial resistance.10 In contrast, topical antibiotic treatments do not subject children to systemic AEs and may exert less selective pressure on commensal microbes, potentially mitigating the development of resistance.10
When should tympanostomy tubes be considered?
Around 40% of children experience six or more recurrences (defined as three or more episodes in six months, or four or more in one year) of AOM by the time they are seven years old. By the age of three, ~7% of children undergo tympanostomy tube insertion surgery for various OM issues.11 The most common reasons for this procedure are chronic OME, recurrent acute AOM, and persistent AOM despite antibiotic therapy. However, tympanostomy tube insertion carries certain risks and remains
a controversial practice, especially for children with OME lasting less than three months and those with recurrent AOM.11
Tympanostomy tube insertion is not recommended for children with recurrent AOM who do not have middle ear effusion (MEE) in either ear. This is due to the condition’s favourable natural history and strong evidence showing that these children do not experience a reduced incidence of AOM after the procedure. In contrast, children with recurrent AOM accompanied by unilateral or bilateral MEE may be considered for bilateral tympanostomy tube insertion.11
Persistent MEE can indicate underlying eustachian tube dysfunction, potentially predisposing these children to future AOM recurrences. Additional benefits of tympanostomy tube insertion include the possibility of treating future episodes with topical rather than systemic antibiotics and experiencing less pain and hearing loss.11
Current clinical practice guidelines for the treatment of AOM recommend using topical antibiotics after tympanostomy tube placement. Studies have shown that topical antibiotics are more effective than oral antibiotics for treating AOM with otorrhea.12 Generally, antibiotic drops are safe and well-tolerated, with proven efficacy compared to placebo. Some studies suggest that topical antibiotic drops containing steroids may further alleviate inflammation and secretions, expediting pain relief. Regardless of the specific antibiotic used, between 65% to 90% of cases experience clinical resolution within seven to 10 days. 8
Randomised clinical trials have shown that topical treatments, including antibiotics alone, antibiotics with corticosteroids, and fluoroquinolones with corticosteroids, shorten the duration of otorrhea in paediatric AOM patients with tympanostomy tubes. Topical treatments can achieve local drug concentrations over 1 000 times higher than oral administrations and have reduced side effects.12
In South Africa, fixed-dose combination ciprofloxacin 0.3% (broad-spectrum antibiotic), and dexamethasone 0.1% (glucocorticoid) topical eardrops are approved for the treatment of AOM in patients with tympanotomy tubes and acute OE caused by strains of bacteria susceptible to ciprofloxacin.13
Dohar et al found that ciprofloxacin 0.3%/ dexamethasone 0.1% used twice daily for seven days, resulted in significantly faster resolution of otorrhea and cure of AOM compared to oral antibiotics taken every 12 hours for 10 days.14
Giles et al evaluated ciprofloxacin 0.3%/ dexamethasone 0.1% for the prevention of early post-operative otorrhea following tympanostomy tube placement. All patients received ciprofloxacin 0.3%/ dexamethasone 0.1% or no treatment for five days post-operatively and returned at two weeks.15
Physician-observed otorrhea was reported in 4.95% patients receiving ciprofloxacin 0.3%/dexamethasone 0.1% and 39.39% patients receiving no treatment. Treatment decreased otorrhea in all groups, while the greatest benefit was observed in patients with bilateral effusion (93% reduction). Ciprofloxacin 0.3%/dexamethasone 0.1% treatment also decreased the rate of clinically diagnosed OM and effusion following tympanostomy tube placement.15
Paediatric pain management remains a significant concern in healthcare settings, often necessitating emergency department visits. Oligoanalgesia, the inadequate treatment of pain, poses a particular challenge, especially among younger populations and those with cognitive impairments.
The management of otalgia, a common complaint among children, involves addressing various conditions such as AOM, OME, and OE, each requiring tailored treatment approaches.
Amid debates over the necessity of antibiotics, especially in cases of AOM, careful consideration of the risks and benefits is paramount. Topical antibiotic treatments offer a promising alternative, minimising systemic AEs and potentially reducing selective pressure on commensal microbes, thus aiding in the fight against antimicrobial resistance.
1. Webb TL, Sanders JE. Emergency Medicine Residents’ Association. Pain Management Guide. Chapter 12: Paediatric Pain. 2021. [Internet]. Available at: https://www.emra.org/books/ pain-management/pediatric-pain
2. Greenes D. Evaluation of earache in children. 2024. [Internet]. Available at: https://www.uptodate.com/contents/ evaluation-of-earache-in-children
3. National Institute on Deafness and Other Communication Disorders. Ear Infections in Children. [Internet]. 2022. Available at: https://www.nidcd.nih.gov/health/ ear-infections-children
4. Paul CR, Moreno MA. Acute Otitis Media. JAMA Paediatrics, 2020.
5. Danishyar A, Ashurst JV. Acute Otitis Media.
[Updated 2023 Apr 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih. gov/books/NBK470332/
6. Rosario DC, Mendez MD. Chronic Suppurative Otitis. [Updated 2023 Jan 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK554592/
7. Searight FT, Singh R, Peterson DC. Otitis Media With Effusion. [Updated 2023 May 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK538293/
8. Medina-Blasini Y, Sharman T. Otitis Externa. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih. gov/books/NBK556055/
9. Shahbaznejad L, Talaei E, Hosseinzadeh F, et al. Comparing Watchful Waiting Approach vs. Antibiotic Therapy in Children with Nonsevere Acute Otitis Media: A Randomized Clinical Trial. Int J Pediatr, 2021.
10. Hullegie S, Venekamp RP, van Dongen TMA, et al. Topical or oral antibiotics for children with acute otitis media presenting with ear discharge: study protocol of a randomised controlled noninferiority trial. BMJ Open, 2021.
11. Outhoff K. Grommets - an update on common indications for tympanostomy tube placement. South African Family Practice, 2017.
12. Kono M, Umar N, Takeda S, et al. Novel Antimicrobial Treatment Strategy Based on Drug Delivery Systems for Acute Otitis Media. Front Pharmacology, 2021.
13. Professional information. Cilodex. 2008. [Internet]. Available at: https://medapps.sahpra. org.za:6006/Home/Details/?id=CfDJ8F00HIJM3 pdAiDjIE0sZJwcB5GckG0wXxXjoIoC8JNvznGutT AnIzzkw0JO9lgQVF_-1uRuYDenIbGpD8A1WqnK Rn9rpbpzJKK66Oxt5lF4NRFvkECW7pqMYFUCO tVL1PA
14. Dohar J, Giles W, Roland P, et al Topical Ciprofloxacin/dexamethasone superior to Oral Amoxicillin/clavulanic Acid in Acute Otitis media with Otorrhea through Tympanostomy Tubes. Pediatrics, 2006.
15. Giles W, Dohar J, Iverson K, et al. Ciprofloxacin/ dexamethasone drops decrease the incidence of physician and patient outcomes of otorrhea after tube placement. Int J Pediatr Otorhinolaryngol, 2007. SF
This article was independently sourced by Specialist Forum
Attention deficit hyperactivity disorder (ADHD) is a common condition encountered in child and adolescent psychiatry, affecting between 5%-10% of South African children. However, recent studies suggest that ADHD-related symptoms might affect as many as 25.4% of South African children.1,2
Studies reveal that ADHD often runs in families, with a heritability estimated at 74%. Preterm-born children also exhibit a higher risk (~3-fold) of ADHD, and extremely pretermborn children have a ~4-fold increased risk.1,3
ADHD and comorbidities
ADHD often co-occurs with other neurodevelopmental and psychiatric disorders. Learning disorders, such as reading disorders and dyscalculia, affect 15%-50% and 5%-30% of children with ADHD, respectively. Autism spectrum disorder is observed in 70%-85% of ADHD cases, despite previously being considered an exclusion criterion in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.1
Other comorbidities include Tourette’s disorder (20%), obsessive-compulsive disorder (5%), developmental co-ordination disorder (30%-50%), enuresis (17%), and sleep disorders (25%-70%).1
Psychiatric comorbidities like depression and anxiety disorders are reported in up to 45%, while oppositional defiant disorder and conduct disorder coexist in 27%-55% of individuals living with ADHD.1
ADHD increases the risk of substance misuse disorders, with a ~1.5-fold increase (~2.4-fold for smoking) during adolescence. Additionally, there is a ~1.23-fold increase in the risk of obesity among adolescent girls with ADHD. Neurological comorbidities include a higher frequency of migraine (~3-fold) and epilepsy (~2.3- to ~3-fold) compared to children without ADHD.1
ADHD is characterised by symptoms of
inattention and hyperactivity/impulsivity. Diagnosis requires symptoms to be present in two or more settings before the age of 12 for at least six months, impairing social, academic, or occupational functioning. For adolescents, five symptoms per dimension are needed for diagnosis.1
The National Institute for Health and Care Excellence (NICE) guidelines recommend that ADHD diagnosis should be performed by specialists such as child psychiatrists or paediatricians, involving comprehensive clinical and psychosocial assessments. Assessment should include detailed observer reports, mental state examinations, and evaluations of developmental and psychiatric history. 4
Rating scales like Conners’ and the Strengths and Difficulties Questionnaire can be useful supplementary tools, particularly when there is uncertainty about symptoms. Observations in settings such as schools are also beneficial. 4
The assessment should consider the individual’s specific needs, coexisting conditions, social and familial circumstances, educational or occupational
situations, and physical health. 4
In children and adolescents, parental or caregiver mental health should also be assessed to ensure a thorough understanding of the individual’s well-being and context.4
According to Prof Renata Schoeman, undiagnosed or untreated ADHD can lead to children being unfairly labeled as naughty or unteachable. Addressing ADHD’s impact on educational performance, self-esteem, relationships, and productivity is crucial, as is raising awareness about comorbid conditions like anxiety, depression, and substance abuse. 5
The NICE guidelines recommend considering medication for children aged ≥5-years and adolescents living with ADHD if significant impairment persists despite environmental modifications. 4
Informed discussions with the individual and their caregivers about ADHD and a baseline assessment are essential. For adolescents benefiting from medication but still facing significant impairment, cognitive-behavioural therapy (CBT) is
recommended. CBT should address social skills, problem-solving, self-control, active listening, and expressing feelings. 4
options
Psychostimulants, such as amphetamines (AMPs) and methylphenidate (MPH), are recommended as first-line pharmacotherapies for children and adolescents living with ADHD. Numerous studies have shown that AMPs and MPH are highly effective in treating core ADHD symptoms.1,6
A recent network meta-analysis of double-blind randomised controlled trials involving >10 000 children and adolescents showed significant effect sizes for stimulants in reducing core ADHD symptoms as evaluated by clinicians. Additional studies indicate that stimulants not only address core symptoms effectively but also enhance overall quality of life and reduce functional impairment.7
Stimulants work by increasing central dopamine and norepinephrine activity, enhancing executive and attentional functions. AMPs inhibit dopamine and norepinephrine transporters, inhibit vesicular monoamine transporter 2, and suppress monoamine oxidase activity. 6
Research also suggests that stimulants may lower the risk of emergency hospital admissions related to trauma, suicidal events, substance abuse, criminal behaviour, and unintentional injuries.7
The NICE guidelines recommend MPH as first-line pharmacological treatment for children aged ≥5-years and adolescents with ADHD. If a six-week trial of MPH at an adequate dose is not beneficial, switching to lisdexamfetamine is recommended. 4
In South Africa, lisdexamfetamine dimesilate is indicated in cases where treatment with MPH and atomoxetine proves ineffective. It is not recommended for children <13-years, as the currently available formulations lack the flexibility required to achieve optimal dosage for individuals aged six- to 12-years. 8 NICE recommends dexamphetamine for patients who respond well to lisdexamfetamine but struggle with its extended duration of effects.
In South Africa, dexamphetamine is indicated for children and adolescents aged six- to -17-years. 4,9
However, it is not indicated in all children and adolescents living with ADHD and should only be used if symptoms do not improve with MPH. Furthermore, it should be used as part of a treatment programme, which typically includes psychological, educational and social measures.9
How effective and safe are amphetamines?
According to Mechler et al, individuals living with ADHD may exhibit a very high response rate when treated with either AMP or MPH, with positive outcomes observed when both stimulants are considered.7
AMPs demonstrate an improvement in overall ADHD core symptom severity based on parent ratings (standardised mean difference [SMD] −0.57), teacher ratings (SMD −0.55), and clinician ratings (SMD −0.84).10
Furthermore, a higher proportion of responders, as assessed by the Clinical Global Impression-Improvement scale, was observed when children were treated with AMPs compared to placebo (risk reduction 3.36).10
Commonly reported adverse events included decreased appetite, insomnia/ trouble sleeping, abdominal pain, nausea/ vomiting, headaches, and anxiety.10
One of the main concerns regarding AMPs is the risk of recreational misuse to induce euphoria or enhance cognitive performance. Lisdexamfetamine is often believed to have lower abuse potential compared to dexamphetamine.11
However, it should be noted that lisdexamfetamine is an inactive prodrug of dexamphetamine. Inactive lisdexamfetamine is almost entirely (>98%) converted to dexamphetamine in the bloodstream.11
A recent study by Dolder et al showed no differences in peak ratings of potentially abuse-related subjective drug effects (eg drug liking, drug high, stimulation, happy, well-being, and self-confidence) between lisdexamfetamine and dexamphetamine.11
Modified-release formulations recommended
NICE recommends modified-release (MR) once-daily stimulant formulations. While MR once-daily formulations are generally preferred for their practical benefits, immediate-release (IR) formulations might be suitable during initial titration or when more flexible dosing regimens are necessary.4
Many of the newer MR innovations including long-acting (LA) or extended release (ER/XR) MPH formulations differ from the initial wax-matrix, continuousrelease preparation by incorporating both an IR component for swift onset of action and an ER/XR component for sustained effects throughout the day.12
Newer MPH formulations utilise various technologies to ensure symptom management for at least eight hours, with differing ratios of IR and ER/XR MPH components.12
The IR MPH bolus of the new formulations range from 22% to 50% of the total MPH
dose. MPH MR provides 50% of the racemic MPH dose immediately, using a 50:50 mixture of IR and enteric-coated beads to delay MPH delivery.12
In essence, MR formulations facilitate rapid action upon administration, enabling once-daily dosing and eliminating the necessity for a second dose during school or work hours.12
In South Africa, MPH MR is indicated for the treatment of children ≥6-years, adolescents, as well as adults with ADHD onset in childhood as part of a comprehensive approach when remedial measures alone prove insufficient.13
Dextroamphetamine, administered orally, is also available as either an IR or MR formulation. Both contain enantiomer, d-amphetamine and l-amphetamine salts in a 3:1 ratio.14
The average half-lives of the IR and MR formulations are similar. The IR formulation’s duration of action is four- to six-hours, while the MR formulation’s effects last between eight- to 12-hours.14
The management of ADHD in children and adolescents has seen significant advancements with the development of MR formulations. These formulations offer a combination of IR and ER components. This innovative design provides rapid onset of action while maintaining therapeutic effects throughout the day, allowing for once-daily dosing and reducing the need for additional doses during school or work hours.
Research supports the effectiveness of these formulations in managing core ADHD symptoms and improving overall quality of life for those affected. MR formulations are particularly advantageous for their practicality and consistency in symptom control, ensuring better adherence and minimising the potential for missed doses. They also offer flexibility in addressing individual patient needs and optimising treatment outcomes. The integration of MR stimulant formulations represents a valuable tool in the comprehensive management of ADHD.
Scan the QR code on page 3 for the reference list. SF