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Pharmacy Peer Review: Antiretroviral Therapy
Antiretroviral Therapy – Is 3 a Crowd?
There have been huge advances in the pharmacologic treatments of Human Immunodeficiency Virus (HIV) in recent years. It has evolved from a once fatal diagnosis to become a manageable, chronic condition where people living with HIV have a life expectancy that is comparable to those without HIV1. Current antiretroviral (ARV) medication is now more readily available and provides maximal virologic efficacy, yields high genetic barriers to resistance, has more tolerable side effect profiles and a reduced pill burden in comparison to older agents. HIV treatment is instigated to achieve the following goals: • HIV RNA suppression • To restore and preserve immunologic function • To reduce HIV-associated morbidity and mortality • To prevent onward transmission2 In 1987, the first drug to treat HIV, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), was approved to be used as monotherapy. However, it was quickly established that AZT did not maintain viral RNA suppression and therefore lead to the emergence of drug resistance, failure of therapy and patient deterioration3 .
In the early 1990s research progressed to the idea of treating HIV with three drug regimens, known as “triple therapy”. By targeting different stages of the HIV replication life cycle, “triple therapy” was shown to rapidly reduce HIV RNA levels, sustain an undetectable viral load and improve patients’ immune function, assessed by means of CD4 lymphocyte count monitoring. Over the past 30 years, antiretroviral therapy has mainly consisted of a two-drug NRTI backbone plus a drug from one other class such as Protease Inhibitors (PI), NonNucleotide Reverse Transcriptase Inhibitors (NNRTI) or Integrase Inhibitors (INI). In the past decade attempts have been made to reduce from three active antiretroviral drugs to two
Written by Conor Moran, Infectious Diseases Pharmacist, Mater Misericordiae University Hospital
drug maintenance therapy. The emergence of new antiviral agents with increased viral potency combined with the desire to reduce drug exposure has driven the exploration of dual therapy HIV regimes in recent years. People living with HIV (PLWH) are living longer since the introduction of highly effective three drug antiretroviral therapy. In 2018, 51% of HIV positive Americans were over the age of 504. The Pharmacokinetic and Clinical Observations in People Over Fifty (POPPY) Study highlighted the increasing burden of comorbidities in older people living with HIV (PLWH) in the UK and Ireland5. Lifelong treatment with antiretroviral therapy poses challenges such as polypharmacy and long-term toxicities of ARVs. Drug-drug interactions pose a risk to an ARV regimen by decreasing ARV concentrations by methods such as induction or inhibition of the metabolic pathway, chelation of drug and polyvalent cations or by reduction of stomach acidity. This can lead to loss of treatment efficacy and cause subsequent viral breakthrough. Similarly,
Table 1: studies comparing dual agents with three drug regimens
the ARV regimen can have a detrimental effect on concomitant medication a patient may be taking therefore dual ARV therapy may help to avoid unwanted drug-drug interactions in the future.
Adverse effects have been reported with most ARVs and to achieve and sustain HIV RNA suppression over a lifetime, both short-term and long-term toxicities must be anticipated and managed. Long-term complications of ARVs can be underestimated and may take years of real world prescribing experience to uncover because of the selective inclusion criteria of clinical trials and the relatively short follow up time. ARVs have been associated with long term adverse effects such as renal disease, decreased bone mineral density, CNS toxicity, fat distribution and weight gain. Not only can such complications lead to poor health status and a diminished quality of life but ARV related adverse effects that ultimately result in increased morbidity and mortality may contribute to the burden on healthcare resources and costs associated with HIV. Reducing HIV treatment from three to two antiretroviral drugs will lower the exposure of patients to long term toxicities; specifically if one or both NRTIs are removed from the regime. NRTIs are linked to an increase risk of renal impairment, reduction in bone mineral density and an increase in cardiovascular risk.
Development of resistance to ARVs is a major impediment to optimum treatment of HIV. Resistance mutations develop when viral suppression is not maintained due to suboptimal drug concentrations. Resistance mutations can affect more than one drug in the class (and often render the entire ARV class obsolete); this is known as cross resistance. Protection of ARV classes for future treatment options by avoiding prescribing them is a commonly used strategy and in practice this would be easier to achieve with a dual ARV regimen6 . Lower pill burden is also an advantage of dual therapy and is associated with higher rates of adherence to HIV treatment and better virologic outcomes7. The research also showed that oncedaily regimes had better adherence than twice-daily regimes, however they did not have advantages in terms of virologic suppression. Many first-world countries have access to several combination single tablet antiretroviral regimens however this is not equitable around the world. In this scenario dual therapy as two tablets may still prove preferable and beneficial to patients. Dual therapy provides an opportunity for cost-effective prescribing as several ARVs used in clinical practice have expired patents, allowing for the production of generic versions. Lamivudine was first licenced in Europe in 1996, Ritonavir in 1997 and Darunavir in 2007; generic versions of each are available on the Irish market. Dual therapy single tablet antiretroviral regimes are likely to be covered by patents for the foreseeable future; therefore prescribing individual medicines including a generic should be considered.
These clinical trial results were reassuring and supported the use of dual therapy in certain circumstances and supported their introduction to guidelines. Dolutegravir and Lamivudine is recommended as a first line treatment option in the European AIDS Clinical Society (EACS) Guidelines provided patients have a baseline viral load <500,000 copies/ml and are HBsAg negative13. Raltegravir/Darunavir/r is listed as an alternative regimen, while Dolutegravir/Rilpivirine is listed as an option for suppressed switch - that is switching a patient who has already achieved HIV RNA suppression. The introduction of dual therapy treatment options is mirrored in worldwide HIV guidelines such as the US Center for Disease Control and Prevention (CDC) Guidelines, Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) and British HIV Association (BHIVA) Guidelines. In January 2021 the US Food and Drug Authority (FDA) approved the first long-acting (LA) injectable antiretroviral regimen Cabotegravir (CAB)/Rilpivirine (RPV) and in February 2021 this was incorporated into the US HIV treatment guidelines14. The panel recommends the CAB/RPV monthly intramuscular injection can be used as an optimisation strategy for patients currently on antiretroviral therapy who fit the following criteria: • Suppressed HIV RNA for at least 3 months
• No baseline resistance to either medication
• Do not have active Hepatitis B (unless on HBV treatment) • Are not pregnant or planning pregnancy • Are not receiving medication that may interact with oral or injectable CAB or RPV • Tolerate a four week lead in of oral therapy with CAB and RPV before initiation of the longacting IM injectable CAB/RPV LA injectable has been approved by the European Medicines Agency but has not been incorporated in the EACS guidelines. Dual antiretroviral therapy has been incorporated into HIV guidelines around the world for both treatment initiation and switch therapy; however, it is important to note it’s place in prescribing in HIV. Patients should be carefully selected and each clinical scenario assessed on an individual basis. At present, those with a history of poor adherence, documented resistance, Hepatitis B, tuberculosis or who are pregnant should not be treated with dual antiviral therapy. The potential benefits of reduced renal and bone toxicity, adherence and tolerability and reduced cost are predicted. At present more real world data is required to assess benefits of dual therapy long term. Studies of two-drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation and onward transmission15 .
Dual antiretroviral therapy represents a suitable long-term option for people living with HIV in clinical practice. While there is no need to urgently switch patients on stable three drug antiretroviral regimes; dual therapy is worth considering in future treatment decisions.
Table 1: studies comparing dual agents with three drug regimens
Trial Name Treatment arms studied
NEAT001/ANRS1438 Darunavir/r & Raltegravir v Darunavir/r & Tenofovir DF/Emtricitabine
SWORD 1&29
GEMINI 1&210 Dolutegravir & Rilpivirine v Current 3 Drug Antiretrovial Regimen (2 NNRTIs & a third agent) Dolutegravir & Lamivudine v Dolutegravir & Tenofovir DF/Emtricitabine
TANGO11 Dolutegravir & Lamivudine v Current Tenofovir AF Based 3 Drug Antiretroviral Regimen • Non-inferiority Vs a TAF based regimen supporting it as a simplification strategy for patients who are virally suppressed at Week 48 • No breakthrough resistance seen in either arm
FLAIR12 Cabotegravir & Rilpivirine (Long Acting Injectable) v Abacavir/Lamivudine/Dolutegravir • Non-inferiority between study arms at Week 48 • Long acting injectable CAB & RPV well tolerated
Conclusion
• Non-inferiority between study arms at Week 48 • Dual therapy arm was less efficacious if starting with CD4 cell count <200/mm3
• Non-inferiority between study arms at Week 148
• Non-inferiority between study arms at Week 48 • Similar tolerability profile supports the role of
DTG/3TC in treatment naïve patients at Week 48
References available on request
Launching our powder Launching our powder for concentrate for solution for concentrate for solution for infusion for infusion
Anidulafungin 100mg Anidulafungin 100mg
PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information. Additional information is available upon request. Anidulafungin Fresenius Kabi 100mg powder for concentrate for solution for infusion. Active ingredients: Each vial contains 100mg anidulafungin. Indications: Treatment of invasive candidiasis in adults. Posology and method of administration: Treatment should be initiated by a physician experienced in management of invasive fungal infections. Obtain specimens for fungal culture prior to therapy; treatment can be started before results are known and adjusted accordingly. Single 200mg loading dose on day 1 PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information. Additional information is available upon request. Anidulafungin Fresenius Kabi 100mg powder for concentrate for followed by 100mg daily thereafter. Treatment duration based on patient’s clinical response. In general, antifungal therapy should continue for at least 14 days after last positive culture. Insufficient data to support 100mg dose solution for infusion. Active ingredients: Each vial contains 100mg anidulafungin. Indications: Treatment of invasive candidiasis in adults. Posology and method of administration: Treatment should be initiated by a physician for longer than 35 days of treatment. No dosing adjustments required for adults with renal insufficiency (including those on dialysis) or hepatic impairment, or for weight, gender, ethnicity, HIV positivity or elderly. Safety and experienced in management of invasive fungal infections. Obtain specimens for fungal culture prior to therapy; treatment can be started before results are known and adjusted accordingly. Single 200mg loading dose on day 1 efficacy have not been established in children and adolescents below 18 years of age. Method of administration: For intravenous use only. Reconstitute with water for injections to a concentration of 3.33mg/ml and subsequently followed by 100mg daily thereafter. Treatment duration based on patient’s clinical response. In general, antifungal therapy should continue for at least 14 days after last positive culture. Insufficient data to support 100mg dose dilute to 0.77mg/ml (see SmPC). Rate of infusion should not exceed 1.1mg/min (equivalent to 1.4ml/min when reconstituted and diluted per instructions). Must not be given as bolus injection. Contraindications: Hypersensitivity for longer than 35 days of treatment. No dosing adjustments required for adults with renal insufficiency (including those on dialysis) or hepatic impairment, or for weight, gender, ethnicity, HIV positivity or elderly. Safety and to the active substance, any of the excipients or other medicinal products of the echinocandin class. Special warnings and precautions for use: Has not been studied in patients with Candida endocarditis, osteomyelitis or efficacy have not been established in children and adolescents below 18 years of age. Method of administration: For intravenous use only. Reconstitute with water for injections to a concentration of 3.33mg/ml and subsequently meningitis. Efficacy has only been evaluated in a limited number of neutropenic patients. Monitor patients with increased hepatic enzymes during treatment for evidence of worsening hepatic function and evaluate for risk/ dilute to 0.77mg/ml (see SmPC). Rate of infusion should not exceed 1.1mg/min (equivalent to 1.4ml/min when reconstituted and diluted per instructions). Must not be given as bolus injection. Contraindications: Hypersensitivity benefit of continued therapy. Anaphylactic reactions (including shock) have been reported; if these reactions occur discontinue anidulafungin and administer appropriate treatment. Infusion-related adverse events reported to the active substance, any of the excipients or other medicinal products of the echinocandin class. Special warnings and precautions for use: Has not been studied in patients with Candida endocarditis, osteomyelitis or (infrequent when infusion rate does not exceed 1.1mg/min). Care when co-administering anidulafungin and anaesthetic agents – may be exacerbation of infusion-related reactions. Patients with rare hereditary problems of meningitis. Efficacy has only been evaluated in a limited number of neutropenic patients. Monitor patients with increased hepatic enzymes during treatment for evidence of worsening hepatic function and evaluate for risk/ fructose intolerance should not take unless strictly necessary. Not recommended during pregnancy unless maternal benefit clearly outweighs potential foetal risk. Unknown whether anidulafungin is excreted in human milk. benefit of continued therapy. Anaphylactic reactions (including shock) have been reported; if these reactions occur discontinue anidulafungin and administer appropriate treatment. Infusion-related adverse events reported Undesirable effects: Frequency of all cause adverse reactions from 840 subjects receiving 100mg anidulafungin - Very common (≥1/10): Hypokalaemia, diarrhoea, nausea. Common (≥1/100 to <1/10): Hyperglycaemia, convulsion, (infrequent when infusion rate does not exceed 1.1mg/min). Care when co-administering anidulafungin and anaesthetic agents – may be exacerbation of infusion-related reactions. Patients with rare hereditary problems of headache, hypotension, hypertension, bronchospasm, dyspnoea, vomiting, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, increased blood bilirubin, cholestafructose intolerance should not take unless strictly necessary. Not recommended during pregnancy unless maternal benefit clearly outweighs potential foetal risk. Unknown whether anidulafungin is excreted in human milk. sis, rash, pruritis, increased blood creatinine. Uncommon (≥1/1000 to <1/100): Coagulopathy, flushing, hot flush, upper abdominal pain, gamma-glutamyltransferase increased, urticaria, infusion site pain. Frequency not known:Undesirable effects: Frequency of all cause adverse reactions from 840 subjects receiving 100mg anidulafungin - Very common (≥1/10): Hypokalaemia, diarrhoea, nausea. Common (≥1/100 to <1/10): Hyperglycaemia, convulsion, Anaphylactic shock or anaphylactic reaction. Legal Category: POM Marketing Authorisation Number: PA2059/071/001. Marketing Authorisation Holder: Fresenius Kabi Deutschland GmbH, Else-Kroener Strasse 1, Bad Homburg headache, hypotension, hypertension, bronchospasm, dyspnoea, vomiting, increased alanine aminotransferase, increased blood alkaline phosphatase, increased aspartate aminotransferase, increased blood bilirubin, cholestav.d.H 61352, Germany Further Information: See the SmPC for further details. Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance.GB@ Fresenius-Kabi.com. Date of Preparation: March 2021 API/Anidulafungin/01 sis, rash, pruritis, increased blood creatinine. Uncommon (≥1/1000 to <1/100): Coagulopathy, flushing, hot flush, upper abdominal pain, gamma-glutamyltransferase increased, urticaria, infusion site pain. Frequency not known: Anaphylactic shock or anaphylactic reaction. Legal Category: POM Marketing Authorisation Number: PA2059/071/001. Marketing Authorisation Holder: Fresenius Kabi Deutschland GmbH, Else-Kroener Strasse 1, Bad Homburg v.d.H 61352, Germany Further Information: See the SmPC for further details. Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited via email Pharmacovigilance.GB@ Fresenius-Kabi.com. Date of Preparation: March 2021 API/Anidulafungin/01
Fresenius Kabi Limited
Fresenius Kabi Ireland Unit 3B Fingal Bay Fresenius Kabi Limited Balbriggan, Co. DublinFresenius Kabi Ireland Ireland Unit 3B Fingal Bay Balbriggan, Co. Dublin Ireland
Website: www.fresenius-kabi.com/ie/
Email: FK-enquiries.ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030 Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030
Date of Prep: April 2021 Job Code: IV/ANI/01/21 Date of Prep: April 2021
Job Code: IV/ANI/01/21
