Issues to consider in treating TB and HIV

The medications used to treat tuberculosis and HIV have many potential drug interactions and overlapping toxicities which can complicate treatment.1 [ref] As a result, previous treatment guidelines have recommended delaying antiretroviral therapy (ART) for people receiving treatment for TB. Subsequent studies have shown that beginning ART as soon as possible after initiating TB treatment does not pose more significant risks than deferring it; in fact, delaying ART can seriously increase the risk of mortality, especially in patients with advanced HIV disease.

The SAPIT study (Starting ARV therapy at three Points in Tuberculosis therapy) was a randomised, prospective comparison of immediate versus deferred antiretroviral therapy in TB patients. ART was begun early (as soon as possible after TB treatment to a maximum of two months), later (after the first two-month phase of treatment, by month three or four), or sequentially (after TB treatment was completed). An analysis in 2008 found that patients who initiated antiretroviral therapy within four months of starting TB treatment were 55% less likely to die than patients who deferred antiretroviral treatment until the end of a course of TB treatment, and the "sequential" arm of the trial was halted. Further results presented in 2010 showed no significant survival difference between starting ART within two months of starting TB treatment and starting two to four months later.[ref] [ref]

However, other studies have found that deferring ART by two or three months is a serious threat to survival, especially in those with low CD4 cell counts. A large prospective South African study showed that people with HIV had a 50% greater risk of death if they did not start ART within three months of TB treatment, and that a CD4 count below 100 cells/mm3 was an independent risk factor for death in TB patients not taking ART. The risk of immune reconstitution inflammatory syndrome was negligible.2 The CAMbodian Early vs Late Introduction of Antiretroviral drugs (CAMELIA) study found that deferring ART by more than eight weeks, versus starting within two weeks, increased risk of death by 34%. The CAMELIA patients had very advanced disease, with a mean CD4 cell count of 25 cells/mm3 at baseline.3

A 2006 retrospective study found that, in HIV/TB co-infected patients who began TB treatment at the same time as ART, response to HIV treatment was comparable to patients without TB beginning ART. The study also found that the co-infected patients had similar rates of relapse following the end of tuberculosis treatment to a group of HIV-negative patients with tuberculosis.4

The 2009 WHO guidance recommends antiretroviral treatment with an efavirenz-based regimen for everyone with TB regardless of CD4 count, with antiretroviral therapy to be initiated soon after TB treatment.

Although guidelines still do not address the issue, there is evidence that use of d4T (stavudine) alongside isoniazid greatly increases the risk of serious toxicities including lactic acidosis and peripheral neuropathy during the first two months of antiretroviral treatment. A review of 1845 South African patients who took d4T alongside TB treatment found that initiation of the two drugs within a two-week interval increased the risk of serious d4T toxicity sevenfold during the first two months of ART.5

The most recent revision of the Centers for Disease Control and Prevention (CDC) guidelines on treating tuberculosis and HIV recommend the use of rifabutin (Mycobutin) instead of rifampicin. In addition it recommends that with adjustment of dosages in some cases, both antiretroviral and anti-tuberculosis treatment can be given together.

However, rifabutin is not available in every country. In addition, UK doctors have pointed out that rifabutin has not been tested in controlled trials amongst HIV-positive people, and patients given the drug have not been followed up for as long as those given rifampicin.

Furthermore, it has not been tested in people who already have isoniazid-resistant tuberculosis. Despite a retrospective cohort study finding similar outcomes in HIV-positive patients treated with rifampicin and rifabutin, a prospective study has shown that rifabutin-based therapy results in high rates of treatment failure and relapse in patients with low CD4 cell counts.6 7

If antiretroviral therapy is administered at the same time as ART, the antiretroviral regimens may need to be modified to be compatible with rifampicin-based tuberculosis treatment. The following dose adjustments are necessary:

  • Efavirenz (Sustiva): while the CDC recommends increasing the efavirenz dose to 800mg daily, there are few published data on efavirenz metabolism in non-Western populations. In some countries experts do not recommend increasing the efavirenz dose when given with rifampicin for fear of increased toxicity. Three-year follow-up of Indian patients treated with efavirenz and rifampicin or efavirenz alone showed no significant difference in outcomes, although a significantly higher risk of liver toxicity in those who received both drugs.8
  • Nevirapine (Viramune): nevirapine clearance varies between ethnic groups but no dose adjustments are considered necessary. A randomised study conducted in Thailand showed a higher rate of drug sensitivity if the dose was increased to 600mg, and no difference in viral load outcomes after 24 weeks, but data from Thailand may not be applicable to all ethnic groups, since Thais tend to have higher nevirapine levels.9 Another Thai study showed that trough levels of nevirapine did not differ according to rifampicin treatment status after 8-12 weeks of nevirapine treatment.10
  • Protease inhibitors: most protease inhibitor levels are significantly reduced when given with rifampicin and should not be used, unless boosted by ritonavir (Norvir). For people taking ritonavir-boosted protease inhibitors, rifabutin is recommended at a substantially reduced dosage. However, there are data from a small US study in HIV-positive patients suggesting that dose reduction may be inappropriate in patients taking Kaletra because of below-average rifabutin exposure. The investigators suggest that a rifabutin dose of 450mg five times a week may be necessary.11
  • When antiretroviral therapy consists of both protease inhibitors and a NNRTI, drug interactions are complex and appropriate dose adjustments are unknown.

There is also a risk of additive side-effects and drug toxicity when antiretrovirals are combined with tuberculosis treatment. For example, hepatitis is a common side effect of nevirapine, isoniazid, rifampicin, and pyrazinamide. In patients with preexisting liver disease, frequent clinical and laboratory monitoring should be performed to detect drug-induced liver injury. A South African study showed that concomitant TB treatment and antiretroviral therapy with either efavirenz or nevirapine increased the risk of liver toxicity eight-fold compared to ART treatment alone.ref]  Drinking alcohol increases the risk of liver toxicity. In resource-limited settings where d4T is still commonly used, co-administration with isoniazid poses a particularly high risk of peripheral neuropathy.

TB drug levels may also be affected by HIV infection itself. A study in Botswana revealed that 84% of HIV-positive patients had low rifampicin levels, with the risk of low levels greatly elevated in those with CD4 counts below 200 cells/mm3. However, treatment failure was most strongly predicted by low pyrazinamide levels, a drug also more likely to achieve suboptimal levels in HIV-positive patients.12

TB may develop after starting antiretroviral therapy despite immune reconstitution. An analysis of 37,000 patients in European, American and other cohorts found that the risk of developing TB remained high six months after starting ART for people with a poor virological or immunological response.13

However the incidence of TB declines as time on antiretroviral lengthens: a South African study of 346 patients on ART found that TB incidence declined from 3.5 cases per 100 persons years of follow-up during the first year of ART to 1.1 cases per 100 years in the fourth year of ART.14

A similar study in over 900 South African children found that TB incidence fell from 3.7 cases per 100 child years in untreated children to 1.76 cases per 100 child years in children receiving ART who had viral load below 400 copies/ml after a median of eleven months of treatment.15

References

  1. Jack C et al. Integration of antiretroviral therapy into an existing tuberculosis directly observed therapy program in a resource constrained setting (START study). Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract P783, 2003
  2. Lawn SD et al. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS 19: 2109 – 2116, 2005
  3. Blanc FX et al. Significant enhancement in survival with early (2 weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART) in severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. Eighteenth International AIDS Conference, Vienna, abstract THLBB106, 2010
  4. Breen RAM et al. Virological response to highly active antiretroviral therapy is unaffected by antituberculosis therapy. J Infect Dis 193: 1437-1440, 2006
  5. Westreich D et al. Tuberculosis treatment and risk of stavudine substitution in first-line antiretroviral therapy. Clin Infect Dis 48 (11):1617-23, 2009
  6. Burman W et al. Acquired rifamycin-resistance with twice-weekly treatment of HIV-related tuberculosis. Am J Respir Crit Care Med 173: 350-356, 2005
  7. Vargas A et al. Rifabutin versus rifampin in the treatment of tuberculosis in HIV patients. Third International AIDS Society Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, abstract TuPe7, 2005
  8. Patel K et al. TB co-infection treated at onset of therapy does not affect long-term risk of treatment failure among HIV-1 patients initiating efavirenz (EFV)-based combination antiretroviral treatment (cART). Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract MOAB103, 2007
  9. Avihingsanon A et al. 24-week efficacy and safety of nevirapine: 400 mg versus 600 mg based HAART in HIV-infected patients with active tuberculosis receiving rifampicin. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract MOAB102, 2007
  10. Manosuthi W et al. Comparison of plasma levels of nevirapine, liver function, virological and immunological outcomes in HIV-1 infected patients receiving and not receiving rifampicin: preliminary results. 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, abstract H-414, Washington DC, 2005
  11. Boulanger C et al. Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis. Clin Infect Dis 49: 1305-1311, 2009
  12. Chideya S et al. Incidence of sub-therapeutic tuberculosis drug concentrations and associated treatment outcomes among predominantly HIV-infected tuberculosis patients, Botswana. Fourth International AIDS Society Conference on HIV Treatment and Pathogenesis, Sydney, abstract MOAB104, 2007
  13. The Antiretroviral Cohort Collaboration. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 41: 1772 – 1782, 2005
  14. Lawn S et al. Tuberculosis among HIV-infected patients receiving HAART: long-term incidence and risk factors in a South African cohort. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 68, 2006
  15. Martinson N et al. Incidence of tuberculosis in HIV-infected children: the influence of HAART. Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, abstract 22, 2006
This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.