Management of active tuberculosis

The management of active TB-HIV co-infection involves prompt initiation of an appropriate multidrug TB regimen that is guided by DST, commencing cART and treatment monitoring. The ASHM Antiretroviral Guidelines, an Australian handbook and several international guidelines include a more complete discussion of the diagnosis and treatment of TB in patients with HIV infection. TB can be a rapidly progressive illness in advanced immunodeficiency. After collection of appropriate specimens for NAAT, culture and DST, empiric treatment for TB may be warranted while awaiting results in persons with clinical and radiographic features suggestive of HIV-TB co-infection. It is recommended that all patients initiated on TB treatment are screened at baseline for viral hepatitis and diabetes mellitus.⁵³ There are several specific issues related to the treatment of TB-HIV co-infection: when to start cART; shared toxicity and drug-drug interactions with cART (especially between the rifamycins); and the development of TB-associated immune reconstitution inflammatory syndrome (TB-IRIS).

Drug-susceptible tuberculosis

 In TB-HIV co-infection, the same standard regimen for drug-susceptible TB is used as in people without HIV infection.  A four-drug regimen of isoniazid, a rifamycin (rifampicin or rifabutin), pyrazinamide and ethambutol for 2 months (intensive phase), followed by isoniazid and a rifamycin for 4 months (continuation phase) is recommended. Some guidelines recommend that ethambutol can be ceased sooner than 2 months if drug susceptibility to isoniazid and rifampicin is confirmed.⁵⁴ The optimal duration of therapy depends on the site of disease and response to treatment. In patients with pulmonary disease, short-course therapy for 6 months is adequate, unless there is persistent culture-positive sputum after 2 months of therapy without drug-resistance, when therapy should be extended to 9 months. Concerns about relapse rates after short-course therapy have come from trials in countries with a high prevalence of TB and re-infection may be the explanation for this phenomenon. Irrespective of HIV status, patients with miliary, meningeal or skeletal disease should be treated for a total of 9 to 12 months. Three randomised controlled trials have evaluated 4-month regimens for drug sensitive TB, but all have had higher relapse rates and are not recommended. A meta-analysis demonstrated that increasing rifamycin duration to 8 months or more was associated with reduced relapse in patients with HIV infection with active TB.⁵⁵ However, the majority of patients were not on cART and it cannot be determined if relapse was due to re-infection or recurrence.

Treatment should be administered daily, as intermittent therapy (three times a week) in the intensive phase increases relapse rates. The choice of which rifamycin is guided by avoidance of drug-drug interactions and cost as their efficacy is considered equivalent. Pyridoxine supplementation is administered to reduce the risk of peripheral neuropathy caused by isoniazid and exacerbated by HIV infection and/or certain antiretroviral drugs. See Table 2 for the common side-effects of anti-tuberculosis agents.

Table 2. Side-Effects of commonly used anti-tuberculosis agents⁵⁴

In cases of marked immunodeficiency (CD4+ T cell count < 50/μL) where Mycobacterium avium complex (MAC) infection is in the differential diagnosis of a  diagnosis of TB, and in the absence of the result of a NAAT or culture, empirical therapy should cover both MAC and M. tuberculosis infections. This regimen involves the addition of clarithromycin or azithromycin to the standard four-drug TB therapy (See section on non-tuberculous mycobacterial infections).

Drug-resistant tuberculosis 

The management of DR-TB poses a major challenge to treatment due to the requirement for a longer duration of therapy, complex clinical management issues (including drug toxicity, monitoring and drug-drug interactions), and a paucity of evidence to guide decisions.  Drug-resistant TB includes mono-resistant (e.g. isoniazid-resistant, rifampicin-resistant TB, RR-TB) and poly-drug resistant TB; multidrug-resistant TB and resistance beyond MDR-TB. Currently, extensively drug-resistant TB (XDR-TB) is defined as MDR-TB with additional resistance to any quinolone and any second-line injectable agent. If the DST reveals resistance to any of the drugs in the standard initial TB regimen, expert consultation is essential.

The WHO treatment guidelines for DR-TB underwent a major revision in 2019 and are likely to change significantly each year, as new evidence emerges for shorter and more effective regimens and novel and repurposed drugs. Of note were recent studies showing that, in comparison with the previous WHO standard of care, a reduction in mortality in patients treated with bedaquiline in South Africa, and the results of a randomised trial of a shorter MDR-TB treatment regimen. The current WHO recommended treatment regimen for MDR-TB is at least four ‘effective’ second-line TB drugs administered over at least 18 months. The second line drugs have been re-classified into 3 groups on the basis of meta-analyses of evidence of efficacy and adverse events. Four or five drugs should be selected first from Group A (later generation fluoroquinolone, linezolid, bedaquiline) and then from group B (clofazimine, cycloserine) unless there is resistance or intolerance to 1 or more of the drugs in which case group C drugs are added (see table 3).  Bedaquiline is well tolerated, safe, and efficacious in patients with HIV infection and TB. However, patients must be monitored for QT prolongation. A shorter 9-11 month regimen is conditionally recommended by WHO based on a randomised controlled trial showing non-inferiority to standard longer regimens.⁶¹ However, this regimen has not been compared to updated regimens including bedaquiline and linezolid, and includes drugs with a high adverse event profile including injectable agents with risk of ototoxicity. Both the randomised trial and an observational study in African countries had higher mortality rates in patients with HIV infection than in patients without.⁶³ This regimen is not recommended in the Australian context. For isoniazid-mono-resistant tuberculosis, a four-drug regimen of a later generation fluoroquinolone (levofloxacin or moxifloxacin) together with rifampicin, pyrazinamide, and ethambutol is recommended for a duration of at least 6 months.⁵⁹ Several trials of new all oral regimens are underway, and treatment guidelines are likely to change frequently in the next few years.

Table 3. WHO grouping of medicines recommended for use in longer MDR-TB regimens⁵⁹ 

Antiretroviral therapy in patients with HIV infection and TB

All patients with HIV-associated TB should be treated with cART, regardless of CD4+ T cell count and ideally within 8 weeks.

 When to start cART

 The decision to commence cART is a balance between the risk of high mortality and morbidity in patients with a very low CD4+ T cell counts (especially counts < 50 /µL) and the potential for drug toxicity and interactions and TB-IRIS.  Several large randomised controlled trials have now been conducted and full recommendations are expanded in the ASHM guidelines.⁵²

• In patients with CD4+ T cell counts <50/µL, cART should be initiated as soon as possible but within 2 weeks of starting TB treatment, as this has improved survival, despite an increase in the risk of TB-IRIS by 2-3-fold.
• In patients with CD4+ T cell counts ≥50 cells/µL, cART should be initiated within 8 weeks of starting TB treatment.
• In patients with TB meningitis, optimal timing is less certain, but should be commenced between 2 and 8 weeks after starting TB treatment, regardless of CD4+ T cell count due to the higher rates of morbidity and mortality associated with TB-IRIS of the central nervous system (CNS).⁵⁵
• In all pregnant women with HIV infection and active TB, cART should be started as early as feasible, both for maternal health and for prevention of mother-to-child transmission of HIV infection.
• In patients with HIV infection and documented MDR-TB, cART should be initiated within 2 to 4 weeks of confirmation of TB drug resistance and initiation of second-line TB therapy.

 Drug toxicity and interactions

 Anti-tuberculosis treatment and cART have overlapping and additive toxicity profiles that include drug-induced liver injury (DILI), cutaneous reactions, renal impairment, neuropathy and neuropsychiatric adverse effects. A comprehensive review can be found in the DHHS and ASHM guidelines.^52,54 All drugs can cause DILI but it is more common from isoniazid, rifamycins, pyrazinamide, bedaquiline, nevirapine, efavirenz and protease inhibitors. HIV-TB co-infection has been associated with a five-fold increased risk of rash or drug fever. Renal impairment can be caused by different mechanisms; tenofovir disoproxil fumarate (tubular), injectable agents (tubular), rifampicin (interstitial). Peripheral neuropathy can occur with administration of isoniazid or may be a manifestation of HIV infection. All patients receiving isoniazid, and potentially linezolid, should also receive supplemental pyridoxine to reduce peripheral neuropathy.

When cART is used with anti-tuberculosis treatment, consideration of potential drug interactions is of paramount importance and a database such as http://www.hiv-druginteractions.org should be consulted.  After determining the drugs and doses to use, clinicians should monitor patients closely to assure good control of both TB and HIV infections. Suboptimal HIV suppression or suboptimal response to TB treatment should prompt assessment of drug adherence, subtherapeutic drug levels (consider therapeutic drug monitoring, TDM), and acquired drug resistance.

Rifamycins are potent inducers of the hepatic cytochrome P (CYP) 450 and uridine diphosphate gluconyltransferase (UGT) 1A1 enzymes and are associated with significant interactions with most antiretroviral drugs including all protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs; to a moderate extent), maraviroc and raltegravir. Rilpivirine, etravirine, and elvitegravir co-formulated with cobicistat should not be used with rifampicin. The nucleoside reverse transcriptase inhibitors (NRTIs) can be used with rifampicin without dose adjustments. The exception is Tenofovir alafenamide (TAF) which is more likely to have drug-drug interactions than TDF and caution is urged.

The cART regimen for which there is most experience of use in combination with first-line anti-tuberculosis treatment is: tenofovir disoproxil fumarate + emtricitabine + efavirenz. Alternatives include dolutegravir 50mg twice daily with rifampicin. Raltegravir levels are reduced by rifampicin, however it is unclear whether to adjust the dose as a phase II trial showed equivalent virologic response with raltegravir 400mg BD or 800mg in people taking rifampicin.

Other options for using cART in combination with anti-tuberculosis therapy are more problematic because rifampicin reduces the concentration of ritonavir-boosted protease inhibitors by 75-90%. Rifampicin is not recommended in combination with all protease inhibitors and the NNRTIs, etravirine, and rilpivirine. When rifampin is used with maraviroc or raltegravir, increased dosage of the antiretroviral drug is generally recommended. Rifabutin, a weaker enzyme inducer, is an alternative to rifampicin. Rifabutin has little effect on ritonavir boosted atazanavir or lopinavir, but moderately increases darunavir levels. However, all protease inhibitors increase serum concentrations of rifabutin and its metabolites. The dose of rifabutin should be decreased to avoid potential toxicity (uveitis, neutropenia). 

Bedaquiline should not be used with efavirenz and use with lopinavir-ritonavir requires careful monitoring. Dolutegravir, has no known interactions with bedaqualine and might be better tolerated. Delamanid has no known interactions with antiretroviral therapy.⁵⁴