Return to Table of Contents RecommendationsManaging Drug Interactions with Antiretrovirals and RifampinRifampin and NNRTIs Rifampin and efavirenz When given at the standard dose of 600 mg daily, the trough concentration of efavirenz (which is the best predictor of its virological activity) remains well above the concentration necessary to suppress HIV in vitro among the vast majority of patients on concomitant rifampin.28, 29 More importantly, multiple cohort studies and a randomized controlled trial have shown that the standard adult efavirenz dose (600 mg daily) together with 2 NRTIs is well-tolerated and highly efficacious in achieving complete viral suppression among adults on concomitant rifampin-based tuberculosis treatment.30,31 Furthermore, in certain populations, a higher dose of efavirenz (800 mg daily) has been associated with high serum concentrations and neurotoxicity.32 There is limited evidence that sub-therapeutic efavirenz concentrations may be more likely among patients who weigh more than 60 kilograms and who are taking standard-dose efavirenz together with rifampin;33,34 however, findings of sub-therapeutic concentrations in such persons have not been consistent.25,30 Recently, the FDA approved a revised label for Sustiva® (efavirenz). The revision recommends that, if efavirenz is co-administered with rifampin, then the dose of efavirenz should be increased to 800 mg in patients who weigh over 50 kg. This recommendation is based on pharmacokinetic modeling using data from several trials. No prospective trial has shown a reduction in anti-viral treatment failure with this strategy, or an increase in failure without it, Moreover, few published studies have evaluated this increased efavirenz dose or compared the 600 mg and 800 mg dose among patients who weigh over 50 kg.21, 35 Therefore, because of its potency, simplicity, and proven clinical efficacy, use of efavirenz 600mg with 2 NRTIs, along with rifampin-based tuberculosis treatment is the preferred strategy for co-treatment of HIV and tuberculosis (Table 1a). Some clinicians may increase the dose of efavirenz to 800mg in persons weighing >50kg. We consider that data are insufficient to support a definitive statement in this regard. What if efavirenz cannot be used? Rifampin and Nevirapine Several studies have found that rifampin reduces serum concentrations of nevirapine by 20-55%. 37-40 (Table 1a). Decreases in serum concentrations caused by rifampin raise concerns about the efficacy of nevirapine-based antiretroviral therapy during rifampin-based tuberculosis treatment. Fortunately, results from recent prospective studies provide information for dosing strategies that may be helpful in this situation. One study conducted in South Africa found that patients who initiated nevirapine-based antiretroviral therapy during tuberculosis treatment (200 mg once daily for two weeks, then 200 twice daily) had a nearly two-fold higher risk of having a detectable HIV viral load after six months compared to those taking nevirapine who did not have tuberculosis.30 Those patients who were already on nevirapine at maintenance doses (200 mg twice daily) when they started tuberculosis treatment did not have a higher risk of HIV virologic failure. This suggests that if nevirapine is initiated when the patient has already been receiving rifampin-containing tuberculosis treatment, the lead-in period puts patients at risk of virologic failure because of suboptimal nevirapine concentrations during the first two weeks of therapy. A pharmacokinetic study in Uganda confirmed that concentrations of nevirapine were often subtherapeutic when patients were receiving either 200 mg once daily or 200 mg twice daily, together with rifampin-based tuberculosis treatment.41 Among Thai patients with advanced HIV, virologic and immunologic responses to nevirapine-based antiretroviral therapy when given at a dose of 200 mg twice daily were similar for those receiving rifampin-containing tuberculosis treatment and those who were not.42 However, in a head-to-head comparison of antiretroviral therapy containing nevirapine 200 twice daily versus efavirenz 600 mg once daily, 65% of patients taking nevirapine and 70% of patients taking efavirenz had HIV viral loads less than 50 copies/mL after 48 weeks of treatment, and rates of hepatotoxicity were similar in the two groups.43 Similarly, among patients in India randomized to receive either nevirapine (200 mg once daily for 14 days followed by 200 mg twice-daily) or efavirenz 600 mg daily together with rifampin-containing tuberculosis treatment, those receiving nevirapine were more likely to suffer virologic failure, severe toxicity, or death, and the trial was stopped early.44 Together, these data demonstrate that efavirenz is more effective and less toxic than nevirapine for HIV-TB patients receiving antiretroviral therapy and rifampin-containing tuberculosis treatment. However, giving nevirapine twice daily with rifampin (with no once-daily lead-in phase) may be an alternative when efavirenz cannot be used. Increasing the maintenance dose to 300 mg twice daily may cause higher rates of hepatotoxicity.45 Drug interaction studies with rifampin and the new 400 mg once-daily extended release formulation of nevirapine have not been performed, so this combination cannot be recommended. In light of these recent findings, for patients already receiving rifampin-containing tuberculosis therapy, we recommend that if nevirapine must be used,1 it should be initiated without the once-daily lead-in dosing. That is, ART should be initiated with twice-daily nevirapine dosing (adult dose, 200 mg twice daily) and twice-daily dosing should continue throughout co-treatment. Close monitoring of adherence and plasma HIV RNA is warranted. Therapeutic drug monitoring, if available, should be considered. Rifampin and other NNRTIs Rifampin and Protease Inhibitors It is unclear if HIV-infected patients with tuberculosis will have the same high rates of hepatotoxicity as healthy HIV-uninfected volunteers when treated with super-boosted protease inhibitors (standard-dose protease inhibitors given together with high doses of ritonavir) or double-dose protease inhibitor/ritonavir combinations. Clinical experience with these strategies has recently been growing as clinicians and treatment programs try to find ways to treat patients who have NNRTI-resistant HIV and require tuberculosis treatment.59 In a small study in South Africa among adults with HIV (but not tuberculosis) who were already taking standard-dose lopinavir/ritonavir 400mg/100mg twice-daily with suppressed viral loads, rifampin 600 mg daily was started, and lopinavir/ritonavir dosing was gradually increased over two weeks to a maximum dose of 800mg/200mg twice-daily (double dose).55 Therapeutic lopinavir concentrations were achieved, and the regimen was relatively well-tolerated, though two of twenty-one patients had grade 3 or 4 hepatotoxicity. These initial positive clinical and experimental experiences with double-dose lopinavir/ritonavir suggest that these regimens may be tolerable and effective among at least some patients with HIV-related tuberculosis, but prospective data to guide patient and dose selection are still limited. Higher-dose lopinavir/ritonavir should only be used with close clinical and laboratory monitoring for possible hepatotoxicity in cases where there is a pressing need to start antiretroviral therapy and no other antiretroviral drug options are available. Rifampin and triple or quadruple nucleos(t)ide regimens Rifampin with Integrase Inhibitors Rifampin and CCR5-receptor Antagonists |