South African General Practitioner. 2021;2(4):143-145
https://doi.org/10.36303/SAGP.2021.2.4.0085
Open Access article distributed under the terms of the Creative Commons License [CC BY-NC-ND 4.0]
http://creativecommons.org/licenses/by-nc-nd/4.0
1 KwaZulu-Natal Department of Health, Benedictine Hospital, South Africa
2 KwaZulu-Natal Department of Health, Thulasizwe Hospital, South Africa
Corresponding author, email: thulasizwemdrtb@gmail.com
Morbidity and mortality due to tuberculosis (TB) remain serious challenges in South Africa (SA) and globally. Despite the spirited fight against the disease, TB mortality, especially among people living with HIV (PLHIV), remains unacceptably high. However, recent developments in TB diagnosis and treatment provide ammunition for TB epidemic control. The novel use of molecular diagnostic tests enables rapid TB bacteriological confirmation, and hence the opportunity to initiate treatment on the same day as sample collection. In addition, molecular diagnostic tests provide Mycobacterium tuberculosis (MTB) resistance/sensitivity to rifampicin, which is a proxy to multi-drug resistant TB (MDR-TB). Appropriate treatment for drug-resistant TB (DR-TB) may therefore be initiated while awaiting further drug sensitivity tests. The availability of effective anti-TB drugs through the decentralised, deinstitutionalised TB programme is yet another opportunity to control the epidemic. Introduction of the standardised, effective, bedaquiline-based injectable-free DRTB treatment regimen has resulted in remarkably improved DR-TB management with high treatment success rates. There is also an opportunity to explore TB preventive treatment (TPT), which remains a key TB control measure for PLHIV and younger children. These key changes in TB management are a strong incentive for clinicians to better manage TB patients and control the epidemic.
Keywords: tuberculosis, management, molecular diagnostic tests, rapid TB bacteriological confirmation
Introduction
The tuberculosis (TB) burden remains a big challenge to healthcare systems globally and in South Africa in particular. Despite decreasing TB case notification in SA, TB remains a major cause of death, especially among people living with HIV (PLHIV) where it claimed 36 000 lives compared to only 22 000 deaths among HIV-negative people in 2019.1 The emergence of drug-resistant TB (DR-TB), which carries a higher mortality rate compared to drug-sensitive TB (DS-TB)2 is another major public health concern. Thus, it is critical for high-quality TB control measures to be implemented.
The TB prevalence survey of 2018 estimated that 737 per 100 000 South Africans had TB with a male preponderance of 1.6 to 1 compared to females.3 The same survey found that two-thirds of those with TB reported not having sought medical care, hence a lower TB notification rate. Therefore, active TB case finding needs to be scaled up to diagnose and treat TB early, which are both critical for TB control.
TB is caused by Mycobacterium tuberculosis (MTB) complex, which includes the predominant M. tuberculosis and other species like M. bovis, M. africanum and M. canettii which account for fewer TB cases.4 Transmission of MTB is airborne through droplets generated through coughing, sneezing, singing and even talking.5,6
It is vital to understand the microbiology of MTB which aids comprehension of TB microbiological diagnosis and treatment.
MTB is aerobic, non-motile, slow-growing with a waxy cell wall that confers resistance to desiccation, hence its persistence in air droplets and dust.5,6 The mycobacterial cell wall – which consists of a capsule, lipoarabinomannan (LAM), mycolic acids and a lipid bilayer – serves to protect mycobacterium from toxic chemicals, including medicines.6,7
Tools for rapid microbiological TB diagnosis: is same-day TB diagnosis and treatment now a reality?
Recent changes in the diagnostic approach enable rapid microbiological confirmation of MTB infection. Microbiological confirmation of TB within hours, using a single spot sputum sample, is now possible with the expanded use of molecular testing.
Xpert MTB/RIF assay, a semi-automated two-hour long molecular test which simultaneously detects MTB and its sensitivity/ resistance to rifampicin (R) by targeting the rpo B gene of MTB, is now recommended as an initial diagnostic test for TB;8 thus, TB can be diagnosed quickly, enabling patients to be initiated on appropriate TB treatment on the same day. Xpert MTB/RIF use has been expanded to include diagnosis of extra-pulmonary TB through testing specimens like cerebrospinal fluid (CSF), aspirates (gastric, nasopharyngeal, lymph node, pleural) and stool, albeit with a lower sensitivity compared to sputum analysis.8 Xpert MTB/RIF Ultra which is more sensitive compared to Xpert MTB/ RIF, showed a sensitivity of about 89% for CSF analysis; 75% for pleural fluid and 70% for lymph node fluid; 9 thus, TB can be diagnosed with more certainty in extra-pulmonary cases.
The lateral flow urine LAM test (LF-LAM) is an antigenic point-ofcare test now available in South Africa. This test is useful for ruling
in disseminated TB through detection of LAM released from dead bacilli that are subsequently excreted in urine.8 WHO strongly recommends the use of LF-LAM to diagnose disseminated TB in HIV-positive patients with clinically advanced disease or low CD4 counts below 100. The sensitivity and specificity of LF-LAM in adults with advanced HIV regardless of symptoms is 47% and 90% respectively.8 Despite limited data on children, emerging evidence shows similar sensitivity and specificity among paediatric patients.8
South Africa uses a patient-centred approach in the management of both DS-TB and DR-TB. Thus, decentralisation of DSTB management has been in practice for more than a decade, whereas DR-TB decentralisation and deinstitutionalisation policy has been recently adapted.10 This patient-centred approach goes a long way to enhance the quality of TB care in the country.
Early TB diagnosis and treatment is critical for better individual patient outcomes as well as curtailing TB transmission, given that patients become non-infectious within two weeks of starting appropriate TB treatment.4 Therefore, we now have a unique opportunity to control the TB epidemic since we have highly sensitive molecular tests (Xpert MTB/RIF and Xpert MTB/RIF Ultra) as well as LF-LAM for patients with severe HIV infection, which both enable prompt bacteriological TB confirmation and initiation on appropriate TB treatment.
Standard regimen for DS-TB in adults consists of a two-month long intensive phase with rifampicin/isoniazid/pyrazinamide/ ethambutol (RHZE) and a four-month long continuation phase of the two most effective anti-TB drugs (RH) – these medicines come as fixed-dose combinations (FDCs) which promote adherence through minimising pill burden and prevents unintended monotherapy,4 thus avoiding the development of drug resistance. Similarly, children aged eight years and above, weighing 30 kg or more, receive the same regimen as adults. In contrast, paediatric TB patients below eight years and weighing less than 30 kg, with uncomplicated TB, receive RHZ to avoid possible ethambutol-induced optic neuritis, whereas children below eight years with complicated TB receive RHZE.11 Owing to its superior CSF bioavailability, ethionamide is notably recommended for use in treatment of children below the age of eight years with TB meningitis or miliary TB.12
As is the case with other sub-Saharan countries, SA has high rates of TB/HIV coinfection,1 therefore, a significant number of patients receive concurrent TB and HIV treatments. Thus, attention must be paid to common drug-drug interactions that can lead to acquisition of HIV drug resistance.
Rifampicin, being a potent liver enzymes inducer, interacts negatively with dolutegravir (DTG), an HIV integrase inhibitor, which has been in use in SA since 2019 as part of the preferred first-line anti-retroviral therapy (ART) regimen and in some cases
as part of the second-line ART regimen. Rifampicin induces both UDP-glucuronosyltransferase 1A1 (UGT1A1) and CYP3A, both enzymes which metabolise DTG;13 thus reducing its bioavailability. DTG should therefore be boosted by prescribing it as 50 mg given 12 hours apart when being used concurrently with rifampicin in contrast to the normal 50 mg daily dosing.
Similar to DTG, lopinavir boosted with ritonavir (LPV/r) – an HIV protease inhibitor – needs doubling of its usual dose when used concurrently with rifampicin in adults, whereas additional ritonavir (RTV) must be given to achieve an LPV:RTV ratio of 1:1 when used to treat HIV in children who are receiving rifampicin for concurrent TB treatment.14
SA has rolled out the decentralised DR-TB treatment programme that uses the standardised second-line injectable-free drug regimens, which are associated with better treatment success rates close to 70%.15 All patients with rifampicin-resistant TB (proxy for MDR-TB) should be commenced on either the 9–11-month long standardised MDR-TB short-course regimen consisting of seven drugs (bedaquiline/clofazimine/linezolid/ levofloxacin/high-dose isoniazid/pyrazinamide/ethambutol) OR an 18–20-month long MDR-TB treatment regimen comprising of five drugs (bedaquiline/clofazimine/linezolid/levofloxacin/ terizidone).15 The long MDR-TB treatment regimen is reserved for patients who do not meet the criteria to be on the short-course regimen.15 Patients diagnosed with pre-XDR and XDR-TB are put on individualised DR-TB treatment regimens based on the resistance patterns.
TB preventive treatment (TPT) remains a key TB control measure for PLHIV and children under the age of five. All patients’ contacts exposed to infectious TB should be screened to rule out active TB disease and appropriate investigations should be done on all symptomatic TB presumptive cases. Contact screening should, however, be prioritised for contacts of sputum-positive cases, DR-TB patients, and those in congregate settings where transmission is high.11 Notably, DR-TB contacts diagnosed with active TB disease should be treated based on the resistance pattern of the source patient while awaiting further tests, including drug sensitivity testing.15
Asymptomatic DR-TB contacts should either be closely monitored and assessed to exclude active TB; or be initiated on the appropriate TB preventive regimen based on the resistance pattern of the source patient, as shown in Table I, provided that they are in the high-risk category.15 Adult DR-TB contacts should be followed up at least every six months for 24 months post initial exposure, whereas children should be followed up more frequently, at least every two to three months for 24 months.15 Tables I and II show the TPT regimens for various TB exposure categories.
Table I: DS-TB contacts prophylaxis11
*Vitamin B6 (pyridoxine) should be administered together with INH to prevent peripheral neuropathy
Table II: DR-TB contacts prophylaxis15
* Given with pyridoxine (vitamin B6): 25–50 mg per day
** Dosing in younger children (i.e. less than 3 years of age) is still being established
Above all, persons on preventive therapy should be closely monitored for drug-induced adverse events or active disease and should be managed appropriately should these be diagnosed.
Conclusion
The availability of both tests that rapidly confirm TB bacteriologically and effective TB treatment drug regimens that are backed by sound TB policy-guidelines should be seized to bring the TB epidemic under control in SA.
The authors declare no conflict of interest. The views and opinions are those of the authors and not necessarily the views and opinions of their place of employment.
K Chipango https://orcid.org/0000-0003-0535-6017
ND Zulu https://orcid.org/0000-0002-8525-950X
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