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U.S. Department of Health and Human Services

  

Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

Rifampin and Antiretroviral Therapy

The most important drug-drug interactions in the treatment of HIV-related tuberculosis are those between rifampin and the NNRTIs, efavirenz and nevirapine.  Rifampin is the only rifamycin available in most of the world, and initial antiretroviral regimens in areas with high rates of tuberculosis consist of efavirenz or nevirapine (in combination with nucleoside analogues).  Furthermore, because of its potency and durability on randomized clinical trials, efavirenz-based therapy is a preferred option for initial antiretroviral therapy in developed countries.

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Rifampin and Efavirenz

Rifampin causes a measurable, though modest, decrease in efavirenz concentrations 11, 12 (Table 2).  Increasing the dose of efavirenz from 600 mg daily to 800 mg daily compensates for the effect of rifampin 11, 12, but it does not appear that this dose increase is necessary to achieve excellent virological outcomes of therapy 12.  Trough concentrations of efavirenz, the best predictor of its virological activity, remain well above the concentration necessary to suppress HIV in vitro among patients on concomitant rifampin 13.  A testament to the potency of efavirenz against HIV is that the standard dose of efavirenz results in very high rates of complete viral suppression despite 10-fold interpatient differences in trough concentrations.  Therefore, it is unlikely that the 20% decrease in serum concentrations resulting from rifampin will have a clinically-significant effect on antiretroviral activity.  In several cohort studies, antiretroviral therapy of standard-dose efavirenz + 2 nucleosides was well-tolerated and highly efficacious in achieving complete viral suppression among patients receiving concomitant rifampin-based tuberculosis treatment 14, 15.  Furthermore, there was no apparent benefit from a higher dose of efavirenz (800 mg daily) in one randomized trial 12, and a small observational study documented high serum concentrations and neurotoxicity among 7 of 9 patients receiving the 800 mg dose with rifampin 16.  Therefore, this combination – efavirenz-based antiretroviral therapy and rifampin-based tuberculosis treatment, at their standard doses – is the preferred treatment for HIV-related tuberculosis (Table 1).  Some experts recommend the 800 mg dose of efavirenz for patients weighing > 60 kg.

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Alternatives to Efavirenz-Based Antiretroviral Therapy

Alternatives to efavirenz-based antiretroviral therapy are needed for patients with HIV-related tuberculosis: efavirenz cannot be used during pregnancy (at least during the first trimester), some patients are intolerant to efavirenz, and some are infected with NNRTI-resistant strains of HIV.

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Rifampin and Nevirapine

Rifampin decreases serum concentrations of nevirapine by 20-55% 17, 18 (Table 1).  The common toxicities of nevirapine – skin rash and hepatitis – overlap common toxicities of some first-line antituberculosis drugs.  Furthermore, nevirapine-based regimens are not recommended for patients with higher CD4 cell counts (> 350 cells/mm3 for men, > 250 cells/mm3 for women) because of increased risk of severe hypersensitivity reactions.  Therefore, there are concerns about the efficacy and safety of using nevirapine-based antiretroviral therapy during rifampin-based tuberculosis treatment.  At present, there have been no studies comparing efavirenz vs. nevirapine-based antiretroviral therapy among patients being treated for tuberculosis.  Trough serum concentrations of nevirapine among patients on concomitant rifampin often exceed the concentration necessary to suppress HIV in vitro 17, 19.  Several cohort studies have shown high rates of viral suppression among patients receiving nevirapine-based antiretroviral therapy 17, 20.  The risk of hepatitis among such patients was also comparable to patients receiving first-line tuberculosis treatment without antiretroviral therapy 20.  Despite the interaction with rifampin, nevirapine-based antiretroviral therapy appears to be reasonably effective and well-tolerated among patients being treated for tuberculosis.

These studies are neither adequately powered nor reported in sufficient detail to fully answer the concerns about the efficacy and safety of nevirapine-based antiretroviral therapy during tuberculosis treatment.  However, the collected experience is sufficient to make nevirapine an alternative for patients unable to take efavirenz and who do not have access to rifabutin.  Some investigators have suggested using an increased dose of nevirapine among patients on rifampin 18.  However, a recent randomized trial comparing standard dose nevirapine (200 mg twice-daily) to a higher dose (300 mg twice daily) among patients on rifampin demonstrated an increased risk of nevirapine hypersensitivity among patients randomized to the higher dose of nevirapine 21.  Therefore, the standard dose of nevirapine should be used among patients on rifampin (200 mg daily for 2 weeks, followed by 200 mg twice-daily).

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Other Antiretroviral Regimens for Use With Rifampin

For patients who are infected with NNRTI-resistant HIV, neither efavirenz nor nevirapine will be effective.  Unfortunately, there is little clinical experience with alternatives to NNRTI-based therapy among patients being treated with rifampin.  Standard doses of protease inhibitors cannot be given with rifampin (Table 1); the > 90% decreases in trough concentrations of the protease inhibitors would surely make them ineffective 22-24.  Most protease inhibitors are given with low-dose ritonavir (100-200 mg per dose of the other protease inhibitor).  However, low-dose ritonavir does not overcome the effects of rifampin; serum concentrations of indinavir, lopinavir, and atazanavir were decreased by > 90% when given with the standard ritonavir boosting dose (100 mg) in the presence of rifampin 23-25, and a once-daily regimen of ritonavir-boosted saquinavir (saquinavir 1600 mg + ritonavir 200 mg) resulted in inadequate concentrations of saquinavir 26, 27.  Therefore, standard protease inhibitor regimens, whether boosted or not, cannot be given with rifampin.

The dramatic effects of rifampin on serum concentrations of other protease-inhibitors can be overcome with high-doses of ritonavir (400 mg twice-daily, “super-boosted protease inhibitors”) or by doubling the dose of the co-formulated form of lopinavir/ritonavir 23.  However, high rates of hepatoxicity occurred among healthy volunteers treated with rifampin and ritonavir-boosted saquinavir (saquinavir 1000 mg + ritonavir 100 mg twice-daily 28)  and those treated with rifampin and lopinavir/ritonavir (either as lopinavir 400 mg + 400 mg ritonavir twice-daily or as lopinavir 800 mg + ritonavir 200 mg twice-daily) 23, 29.    

Whether patients with HIV-related tuberculosis will have the same high rates of hepatotoxicity when treated with super-boosted protease inhibitors or double-dose lopinavir/ritonavir has not been adequately studied.  Among patients receiving rifampin-based tuberculosis treatment, the combination of ritonavir-boosted saquinavir (400 mg of each, twice daily) was not well-tolerated 30.  The initial positive experience with super-boosted lopinavir among young children (see below) suggests that these regimens may be tolerable and effective among at least some patients with HIV-related tuberculosis.  However, these regimens should only be used with close clinical and laboratory monitoring for possible hepatoxicity, when there is a pressing need to start antiretroviral therapy.

Regimens composed entirely of nucleoside analogues are less active than combinations of two classes of antiretroviral drugs (e.g., NNRTI + nucleosides) 31.  A regimen of zidovudine, lamivudine, and the nucleotide agent, tenofovir, has been reported to be active among patients on rifampin-based tuberculosis treatment 32.  However, this regimen has not been compared to standard initial antiretroviral therapy (e.g., efavirenz + 2 nucleosides).  Finally, a quadruple regimen of zidovudine, lamivudine, abacavir, and tenofovir has been reported to be as active as an efavirenz-based regimen in an initial small trial 33. While these regimens of nucleosides and nucleotides cannot be recommended as preferred therapy among patients receiving rifampin, their lack of predicted clinically-significant interactions with rifampin make them an acceptable alternative, for patients unable to take NNRTIs or those with NNRTI-resistant HIV 32, 34.

Rifampin has substantial interactions with the recently-approved CCR5-receptor antagonist, maraviroc 35.  An increased dose of maraviroc has been recommended to allow concomitant use of rifampin and maraviroc, but there is no reported clinical experience with this combination. Rifampin decreases the trough concentrations of raltegravir, the recently-approved integrase inhibitor, by ~ 60% 36.  Because the antiviral activity of raltegravir 200 mg twice daily was very similar to the activity of the licensed dose (400 mg twice-daily), the current recommendation is to use the standard dose of raltegravir in a patient receiving concomitant rifampin.  However, this combination should be used with caution – there is very little clinical experience with using concomitant raltegravir and rifampin.  Finally, rifampin is predicted to substantially decrease the concentrations of etravirine (a second-generation NNRTI 37 currently available through an expanded access program).  Additional drug-interaction studies will be needed to further evaluate whether these new agents can be used among patients receiving rifampin-based tuberculosis treatment.

 


Released October 2008
Centers for Disease Control and Prevention
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
Division of Tuberculosis Elimination - http://www.cdc.gov/tb

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