Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Recommendations

Managing Drug Interactions with Antiretrovirals and Rifampin

Rifampin and NNRTIs
In areas with high rates of both tuberculosis and HIV, initial antiretroviral drug regimens usually include efavirenz or nevirapine in combination with NRTIs (often in fixed-dose combinations). Thus, drug-drug interactions involving rifampin and the NNRTIs are of high importance in these settings. Furthermore, efavirenz-based therapy is a preferred option for initial antiretroviral therapy in developed countries because of its potency, availability in a once-daily co-formulation with tenofovir and emtricitabine, and durability of efficacy in randomized clinical trials.¹

Rifampin and efavirenz
Initial studies evaluating the effects of rifampin on efavirenz pharmacokinetics demonstrated a modest decrease in efavirenz concentrations,^21,22,23 but subsequent prospective studies have failed to show statistically significant reductions in concentrations of efavirenz during rifampin therapy.^{24 (Table 2)} Further, there is significant inter-patient variability in the effect that rifampin has on efavirenz concentrations. In patients with certain genetic polymorphisms that result in slow metabolism of efavirenz (e.g., CYP 2B6 516 G>T), high concentrations of efavirenz are common, even among patients also taking rifampin.^25,26,27

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?
Alternatives to efavirenz-based antiretroviral treatment are needed for some patients with HIV-related tuberculosis who are taking rifampin. Efavirenz is often avoided during the first trimester of pregnancy, some patients are intolerant of efavirenz, and some are infected with NNRTI-resistant strains of HIV. Additionally, efavirenz cannot be used in HIV-infected children under the age of 3 years because appropriate dosing has not been determined for that age group (see section: Children). Alternatives discussed below include other NNRTIs, protease inhibitors, triple and quadruple NRTI regimens, integrase inhibitors, and CCR5 antagonists.

Rifampin and Nevirapine
Nevirapine is typically given to adults at a dose of 200 mg once a day for the first two weeks of treatment (initiation) followed by 200 mg twice daily or 400 mg once daily (extended release formulation) (maintenance therapy). This dosing strategy (of initiation followed by maintenance therapy) is used for two reasons: (1) Nevirapine induces its own metabolism, and, in most cases, its concentrations decline with continued dosing; and (2) High initial nevirapine concentrations have been associated with toxicities, such as skin rash. In the U.S., initiation of nevirapine-based antiretroviral treatment is not recommended for adult or adolescent patients with higher CD4 cell counts (> 400 cells/mm³ for men, > 250 cells/mm³ for women) because of increased risk of severe hypersensitivity reactions, including hepatotoxicity.¹ The World Health Organization, though, recommends nevirapine as an option for women with CD4 cell counts up to 350 cells/mm³.³⁶ Taking nevirapine-based antiretroviral therapy together with tuberculosis treatment is complicated both by pharmacokinetic interactions related to rifampin and by overlapping toxicities of nevirapine and the first-line antituberculosis drugs, notably skin rash and hepatotoxicity.

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
Rilpivirine, a second-generation NNRTI, was approved by the United States Food and Drug Administration in May of 2011 and is available as a fixed-dose combination with tenofovir and emtricitabine. Rifampin reduces rilpivirine AUC by 80% and trough concentrations by 89%, so the two drugs should not be co-administered.⁴⁶ Rifampin is also predicted to substantially reduce the concentration of etravirine, another second-generation NNRTI, though this interaction has never been tested.⁴⁷

Rifampin and Protease Inhibitors
Protease inhibitor-based antiretroviral regimens remain an important option for the treatment of HIV infection. Unfortunately, when co-administered with rifampin, concentrations of many standard-dose protease inhibitors are severely diminished (>90%) compromising HIV treatment efficacy.^48-52 The Guideline Development Group did not find studies evaluating drug interaction involving rifampin and darunavir. Several pharmacokinetic studies have been conducted to evaluate either higher doses of the protease inhibitor or higher doses of the pharmacologic boosting agent, ritonavir, or both.^{49, 51, 53, 54} Two strategies for dosing boosted protease inhibitors together with rifampin have been evaluated: super-boosting (giving standard-dose protease inhibitor plus a higher-than-usual dose of ritonavir) versus double dosing (doubling the dose of both the protease inhibitor and ritonavir). While these strategies may result in adequate protease inhibitor concentrations,^{51, 55} several studies involving healthy volunteers have reported unacceptable rates of hepatotoxicity. ^{51, 56-58}

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
Regimens composed entirely of NRTIs are less effective than combinations of two classes of antiretroviral drugs (e.g., NNRTI + NRTI).^60-63 For example, virologic suppression achieved with zidovudine and lamivudine combined with efavirenz is superior to that observed with zidovudine, lamivudine, and abacavir, regardless of pre-treatment viral load.⁶⁰ Similarly, among adults receiving zidovudine and lamivudine plus either abacavir or nevirapine, the nevirapine-based regimen results in better immunologic and virologic responses than the triple-NRTI regimen, particularly among those with baseline HIV viral levels > 100,000 copies/mL.^{61, 62} A regimen of zidovudine, lamivudine, and the nucleotide agent, tenofovir, has been reported to be effective among some patients on rifampin-based tuberculosis treatment. ⁶³ However, this regimen has not been compared to standard initial antiretroviral therapy (e.g., efavirenz + 2 NRTIs) among patients taking rifampin. Finally, a quadruple drug regimen of zidovudine, lamivudine, abacavir, and tenofovir was reported to be as active as an efavirenz-based regimen in initial small trials,^{64, 65} but a subsequent larger study suggested that a quadruple nucleos(t)ide regimen of tenofovir, emtricitabine, zidovudine, and abacavir was less active than tenofovir-emtricitabine plus either efavirenz or ritonavir-boosted atazanavir.⁶⁶ While these regimens of nucleosides and nucleotides alone cannot be recommended as preferred therapy among patients receiving rifampin because they have not been rigorously evaluated, the lack of predicted clinically-significant interactions between these agents and rifampin make them an acceptable alternative during tuberculosis therapy for patients with lower plasma HIV RNA levels (<100,000 copies/mL) who are unable to take NNRTIs. ^{64, 67} However, among patients who have HIV that is known to be resistant to NNRTIs or who have failed a first-line regimen (but for whom resistance testing is not available), this strategy may be inadvisable because these patients are at high risk of having HIV with NRTI resistance mutations.

Rifampin with Integrase Inhibitors
Raltegravir, the first-in-class integrase inhibitor, is increasingly being used in both treatment-naïve and treatment-experienced adults with HIV. In pharmacokinetic studies among HIV-uninfected healthy volunteers, rifampin decreased the trough concentrations of raltegravir 400 mg twice daily by ~ 60%.⁶⁸ Doubling the dose of raltegravir to 800 mg twice daily improved overall raltegravir exposures, but trough concentrations were still reduced by 53% when compared to raltegravir 400 mg twice daily without rifampin.⁶⁸ However, in dose-ranging studies among patients with HIV infection, the antiviral activity of raltegravir 200 mg twice daily was very similar to the activity of the licensed 400 mg twice-daily dose, suggesting that the drug can still be effective even at reduced concentrations.⁶⁹ And, in a recent trial of once-daily dosing (800 mg) versus twice-daily dosing (400 mg) among treatment-naïve adults with HIV, low raltegravir trough concentrations in the daily dosing arm (but not the twice-daily arm) were associated with virologic failure.⁷⁰ Thus, given the reductions in trough concentrations when raltegravir is given with rifampin, it is recommended to double the dose of raltegravir to 800 mg twice daily in adults taking rifampin for tuberculosis.Though there have not yet been published prospective studies evaluating this regimen, raltegravir 800 mg twice-daily given with rifampin has been shown to be effective in some clinical reports.^{71, 72} Raltegravir doses of 800 mg twice-daily and 400 mg twice daily have been tested in a clinical trial among patients with HIV receiving rifampin-containing TB treatment.⁷³ Pending the availability of full trial results, this combination (of raltegravir 800mg twice daily and rifampin-containing TB therapy) should be used with caution, particularly among patients with high HIV viral loads who are just beginning antiretroviral therapy. There is little clinical experience with use of concomitant raltegravir and rifampin, and safety and tolerability have yet to be explored in larger trials. While awaiting the efficacy data from the study evaluating double-dose raltegravir among patients with HIV and TB taking rifampin, clinicians may prefer to use rifabutin (where rifabutin is available). Elvitegravir co-formulated with cobicistat, tenofovir, and emtricitabine (Stribild™, or the “Quad” pill) was recently approved by the Food & Drug Administration. Stribild should not be given together with rifampin, as rifampin is expected to reduce concentrations of both elvitegravir and cobicistat.

Rifampin and CCR5-receptor Antagonists
Rifampin has substantial interactions with the CCR5-receptor antagonist, maraviroc. An increased dose of maraviroc has been recommended to allow concomitant use of rifampin and maraviroc, ³⁶ but there is no reported clinical experience with this combination. Additional clinical studies will be needed to further evaluate whether or not these new agents can be used among patients receiving rifampin-containing tuberculosis treatment.