The rifampicin-resistant tuberculosis (RR-TB) programme has been subjected to dramatic and revolutionary advances over the past 5 years. ‘Rifampicin-resistant tuberculosis’ is used as a general term to encompass all the forms of RR-TB, including multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). Through the development of new drugs and simpler, shorter and more acceptable treatment regimens, the success rate for both MDR-TB and XDR-TB has shown a dramatic improvement.
A policy supporting decentralised and deinstitutionalised drug-resistant TB (DR-TB) treatment provision at lower levels of the health system was introduced in 2011; however, largely because of complicated regimens, including daily injectables, implementation has varied. South Africa has been a global leader in this field and the work carried out in this country has affected global policy. It was one of the first countries to roll out the updated 2018 World Health Organization (WHO) recommendations to use an injection-free RR-TB regimen. In November 2019, the National Department of Health (NDOH) published a clinical reference guide for the management of RR-TB,
The entry point into the DR-TB programme is when the patient is confirmed as GeneXpert-positive, rifampicin resistant. The patient is classified as ‘RR-TB’, and notified and enrolled in a DR-TB programme. Note that DR-TB is always a laboratory diagnosis. The only exception to this rule is a child with TB symptoms and a close contact with DR-TB. If no sputum sample is acquired, the source case’s laboratory results would be used to design an appropriate regimen. Following the GeneXpert, the most important next investigation is the DR-TB reflex test.
In South Africa, all patients with GeneXpert positive RR-TB must have a sputum sample sent for a DR-TB reflex test. This will automatically include the following:
If FLQ sensitive – will confirm susceptibility to levofloxacin (LFX) or moxifloxacin (MOX) If FLQ-resistant – will confirm susceptibility to linezolid (LZD), bedaquiline (BDQ) and clofazamine (CFZ).
Line Probe Assay results are available within 8–18 days and make it possible to classify RR-TB and give appropriate treatment regimen.
Drug-resistant tuberculosis has seen extraordinary progress in the development of effective medicines, including the development of new drugs (such as BDQ) and refashioning of known drugs (such as LZD and CFZ). The WHO currently defines three groups of drugs.
This group contains three key medicines that, if the bacilli are susceptible to them, are always included in the regimen.
This group contains two drugs that are excellent additions to a regimen.
Group C drugs are mostly used in rescue regimens or when Group A or B drugs are not tolerated.
Drugs with a lower efficacy include the first-line TB drugs: pyrazinamide (PZA), ethambutol (EMB) and high-dose INH (hINH).
New Group C drugs include delamanid (DLM), a recent addition to the DR-TB drug options and an important drug in children aged 3–6 years and XDR-TB.
Toxic drugs such as ethionamide (ETO), para-aminosalicylic acid (PAS) and amikacin (AM) may still be used but are poorly tolerated, whereas meropenem has to be given as intravenous infusion (IVI) twice a day for 6 months.
This section discusses the content of
Updated drug-resistant tuberculosis regimens for adults and adolescents.
Resistance pattern | Other criteria | Intensive phase | Continuation phase |
---|---|---|---|
Rif-resistant/FLQ sensitive/no more than one INH mutation | < 1-month exposure to second-line TB drugs in past |
4–6 months |
5 months |
Rif-resistant/FLQ sensitive |
> 1-month exposure to second-line TB drugs in past |
6–8 months |
12 months |
Rif-resistant and FLQ-resistant | Use when highly suspicious of FLQ-resistant TB (e.g. contact history) | 6–8 months |
12 months |
Rif-resistant and any of BDQ/CFZ or LZD-resistant | Failure on any RR-TB regimen |
Consult NCAC | Consult NCAC |
Rif-resistant (adjust regimen according to resistance pattern) | Confirmed or highly suspicious TB of meningitis | 12 months |
6 months |
BDQ, bedaquiline; LZD, linezolid; LFX, levofloxacin; CFZ, clofazamine; TZD, terizidone; DLM, delamanid; EMB, ethambutol; ETO, ethionamide; hINH, high-dose isoniazid; PZA, pyrazinamide; EPTB, extrapulmonary tuberculosis; FLQ, fluoroquinolones; INH, isoniazid; NCAC, National Clinical Advisory Committee; RR/MDR-TB, rifampicin-resistant/multidrug tuberculosis.
The MDR-TB short regimen is an option for any newly diagnosed RR-TB patient, who has had no previous exposure to second-line drugs, has no more than one INH mutation and is still relatively well clinically. It is made up of seven medicines:
bedaquiline as a 6-month course, but can be extended to 9 months in late converters
linezolid for 2 months
isoniazid for 4–6 months, which is stopped at 4 months if the acid-fast bacillus (AFB) is negative, followed by LFX, CFZ, PZA and EMB for 5 months.
Most patients will be on this regimen for 9 months, and those with late smear conversion may need 11 months to complete the regimen. We expect patients to be smear- and culture-negative at the end of 4 months or this regimen may have failed.
Any patient who is FLQ sensitive and does not qualify for short regimen will receive the basic long RR-TB regimen. This includes patients who have MDR-TB with dual mutation, patients who are injectable-resistant, patients with previous exposure to DR-TB drugs for > 1 month and complicated patients (e.g. extrapulmonary tuberculosis [EPTB] or extensive lung disease).
This regimen is longer but simpler. The five key drugs (Groups A and B) – BDQ, LFX, LZD, CFZ and terizidone (TZD) – are given for 6 months, followed by a continuation phase of 12 months with TZD, CFZ and LFX.
This regimen contains the biggest change from the interim guideline and is for patients with FLQ-resistant DR-TB (both XDR and pre-XDR FLQ-resistant). Owing to the addition of DLM, this regimen has been simplified dramatically and the duration is usually for no more than 18–20 months.
The regimen is similar to the MDR-TB long regimen, with LFX replaced by DLM. This is followed by a 12-month continuation phase of CFZ and TZD combined with one or two of LZD, BDQ or DLM. Patients with extensive disease would have four drugs in the continuation phase.
One of the great challenges of some of our newer drugs, such as BDQ, is that they do not cross the blood-brain barrier very well. The regimen for meningitis TB is therefore the most complicated one, with inclusion of many Group C drugs with good cerebrospinal fluid (CSF) penetration.
The intensive phase has been increased to 12 months and has the basic long MDR-TB regimen (depending on LPA results) but also DLM, PZA and HHINH (if a patient has
We already have patients with resistance to our new advanced drugs, including incidences of BDQ, CFZ and LZD resistance. These are key drugs to our regimens and any patient with suspected or proven resistance to any of these three will have a specific rescue regimen designed, which could include drugs such as DLM, mereponem, ETO, PAS and high-dose MOX. These regimens are designed by experts after having consultation with the National Clinical Advisory Committee (NCAC) at centres of excellence. It is imperative to request an extended-DST (eDST) through the National Health Laboratory Service (NHLS) on any patient where resistance to these drugs is suspected. The clinical reference guide
Being HIV-positive increases the chances of latent TB activation; conversely, TB leads to progression in HIV infection. Around 60% – 70% of patients with DR-TB can also have HIV infection, and this co-infection adds to the challenge of managing DR-TB successfully. This section discusses the content of
Antiretroviral regimens for patients on drug-resistant tuberculosis treatment.
Criteria/regimen prior to DR-TB treatment | Regimen choice at start of DR-TB treatment | Regimen choice when BDQ/LZD completed | Proviso |
---|---|---|---|
New patient – never exposed to ARV, ≥ 10 years old and ≥ 35 kg | TDF/3TC/DTG as fixed combination | TDF/3TC/DTG as fixed combination | Ensure there is adequate creatinine clearance (for TDF use). Use appropriate formula for eGFR/creatinine clearance calculation according to age |
Patient defaulted on 1TFE | TDF/FTC/LPV/r | AZT/3TC/DTG (second line). Change once HB ≥ 10 g/dL and LZD completed | |
Patient defaulted on AZT/3TC/LPV/r (second line) | TDF/FTC/LPV/r | AZT/3TC/LPV/r (second line). |
|
Patient already on 1TFE: VL LDL | TDF/FTC/DTG | TDF/FTC/DTG | VL result in last 3–6 months |
Patient already on 1TFE: VL > 1000 | TDF/FTC/LPV/r | AZT/3TC/DTG (second line). Change once HB > 10 g/dL and LZD completed | Ensure there is adequate creatinine clearance (for TDF use) |
Patient already on AZT/3TC/LPV/r | TDF/FTC/LPV/r | AZT/3TC/LPV/r (second line). |
Ensure there is adequate creatinine clearance (for TDF use) |
Note: For more details on the regimens for children and patients on ABC, see the clinical reference guide.
ARV, antiretroviral; AZT, zidovudine; FTC, emtricitabine; DR-TB, drug-resistant tuberculosis; VL, viral load; TDF, tenofovir; 3TC, lamivudine; DTG, dolutegravir; HB, haemoglobin; LPV/r, lopinavir/ritonavir; BDQ, bedaquiline; LZD, linezolid; eGFR, estimated glomerular filtration rate; VL LDL, viral load lower than detectable; 1TFE, first line with Tenofovir/Emitracitabine and Efavirenz.
Fortunately, the new antiretroviral (ARV) guidelines
Patients who have defaulted treatment are usually restarted on the same regimen, but we have to make allowance for drug interactions with the DR-TB treatment.
For those patients already on ARVs, the modification to the antiretroviral therapy (ART) regimen will depend on the last viral load (VL), preferably taken in the last 3 months. Always check the VL and CD4 cell count at baseline.
As we cannot use AZT, start patient on TDF, emtricitabine (FTC) and LPV/r; but as soon as LZD is stopped and HB ≥ 10 g/dL, the patient can be switched to the new second-line ARV regimen: AZT, 3TC and DTG.
The guidelines recommend that patients with VL 50–1000 are to be discussed with NCAC.
It is not possible to cover all of the information contained in the clinical reference guide
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