Review Effectiveness and Safety of Antiretrovirals with Rifampicin: Crucial Issues for High-Burden Countries

Antiviral Therapy 2009 14:1039–1043 (doi: 10.3851/IMP1455)

Review Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries

Gary Maartens1*, Eric Decloedt1 and Karen Cohen1

1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

*Corresponding author: e-mail: [email protected]

Coadministration of antitubercular and antiretroviral reassuring data on the effectiveness of standard doses therapy is common in high-burden countries where tuber- of efavirenz with concomitant rifampicin, but the largest culosis is the commonest opportunistic infection. Con- cohort study found a higher risk of virological failure with comitant use of rifampicin and many antiretroviral drugs nevirapine. The drug–drug interaction between rifampicin is complicated by drug–drug interactions caused by the and ritonavir-boosted protease inhibitors is more marked potent induction by rifampicin of genes involved in drug than with the NNRTIs, and therapeutic concentrations metabolism and transport, which could result in sub- have only been achieved with adjusted doses of lopinavir/ therapeutic antiretroviral drug concentrations. This review ritonavir or with saquinavir/ritonavir (400/400 mg every focuses on drug–drug interactions involving antiretrovirals 12 h). The major barrier to using adjusted dose protease used in resource-limited settings: the non-nucleoside inhibitors with rifampicin is the high rates of hepatotox- reverse transcriptase inhibitors (NNRTIs) efavirenz or icity seen in healthy volunteers. The alternative strategy nevirapine, and ritonavir-boosted protease inhibitors. The followed in resource-rich settings is to replace rifampicin reduction of nevirapine concentrations with concomi- with rifabutin, but even if the price of rifabutin were to be tant rifampicin is greater than with efavirenz, particu- dramatically reduced it would be difficult to implement in larly during the lead-in dose period when subtherapeutic high-burden countries where standardized antitubercular concentrations occur in the majority of patients. There is regimens with fixed-dose combinations are used.

Introduction

Tuberculosis is the commonest opportunistic infection in This review focuses on recent information regarding HIV-infected patients globally, and is especially common the pharmacokinetics, effectiveness and safety of con- in sub-Saharan Africa, where the majority of new cases comitant use of ART and antitubercular therapy. Only of tuberculosis in the highest burden countries are HIV- those ART regimens currently recommended by the infected [1]. Access to antiretroviral therapy (ART) is World Health Organization (WHO) in high-burden rapidly expanding in resource-limited settings. Although countries will be considered, namely a first-line regi- ART reduces the incidence of tuberculosis by approxi- men based on the non-nucleoside reverse transcriptase mately 80%, incidence rates remain considerably higher inhibitors (NNRTIs) efavirenz or nevirapine and a sec- than in the general population [1]. Coadministration of ond-line regimen based on ritonavir-boosted protease antitubercular therapy and ART is therefore common in inhibitors [3]. Wherever possible, studies on patients high-burden countries. Rifampicin is a key component coinfected with HIV and tuberculosis were reviewed of antitubercular therapy. Concomitant use of rifampicin in preference to studies examining interactions with and many antiretroviral drugs is complicated by drug– rifampicin alone (because interactions might be modi- drug interactions caused by the potent induction by fied by other antitubercular agents, notably isoniazid, rifampicin of many genes involved in drug metabolism which inhibits many cytochrome P450 enzymes [4]) or and transport [2], which might result in subtherapeutic those conducted on healthy volunteers (because disease- antiretroviral drug concentrations with loss of antiviral related factors could alter pharmacokinetics). Tubercu- efficacy and the development of resistance. Overlapping losis immune reconstitution inflammatory syndrome is toxicity between drugs used for HIV and tuberculosis a further complication of using ART in patients with could also complicate management. tuberculosis, but is beyond the scope of this review.

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First-line ART regimens The WHO and the US Centers for Disease Control and Prevention (CDC) recommend as an option increas- Pharmacokinetics ing the efavirenz dose by 33% when coadministered Nevirapine is metabolized largely by the cytochrome with rifampicin [3,21]. A Thai study reported no differ- P450 isoenzyme CYP3A4 with some metabolism occur- ence in efavirenz concentrations in patients randomized ring by CYP2B6, whereas efavirenz is metabolized vir- to either standard or increased doses of efavirenz with tually exclusively by CYP2B6. An in vitro study found concomitant rifampicin [22]; however, because their that rifampicin induced the expression of CYP2B6 by body weights were approximately 50 kg, dose increases 8.8-fold and CYP3A4 by 55.1-fold [5]. Therefore, one continue to be recommended for patients weighing would anticipate that with concomitant rifampicin >60 kg [3,21]. A South African study found no differ- the magnitude of the reduction in drug concentrations ence in efavirenz concentrations in patients above or would be greater with nevirapine than with efavirenz, below 60 kg taking antitubercular therapy and standard which is indeed the case. doses of efavirenz [18], suggesting that adjusted doses Pharmacokinetic studies of patients coinfected with are not necessary. tuberculosis and HIV conducted in South Africa [6], The metabolism of efavirenz is extensively influenced Spain [7] and Thailand [8,9] have shown significant by pharmacogenetic factors. The cytochrome P450 2B6 reductions in the trough concentrations (16–34%) single nucleotide polymorphism 516G>T, which impairs and/or area under the curve (31–40%) of nevirapine metabolism, resulting in high efavirenz concentrations, when coadministered with rifampicin-based antituber- occurs commonly in Southern Africa [18,23], West Africa cular therapy. A population pharmacokinetic model [24] and India [20]. Patients who are homozygous for predicted that increasing the nevirapine dose by 50% this polymorphism have high efavirenz concentrations, would overcome the enzyme induction from rifampicin even in the presence of rifampicin-based antitubercular [10]. This prediction was supported by an Indian therapy [18,20], and routine efavirenz dose increases in study of seven patients on rifampicin who had trough such patients could result in adverse effects. nevirapine concentrations <3 mg/l; all concentrations increased into the therapeutic range after a 50% Effectiveness and tolerability increase in the dose of nevirapine [11]. Nevirapine con- Only a few studies have compared the effectiveness of centrations <3 mg/l are considered subtherapeutic, as NNRTI-based ART in cohorts with and without con- this concentration is associated with an increased risk comitant rifampicin-based antitubercular therapy. A of virological failure [12]. small Thai study reported no difference in virologi- Two studies, conducted in Malawi and Thailand, cal suppression with nevirapine-based ART [9], and evaluated nevirapine concentrations in tuberculo- a small study from Botswana reported no difference sis patients pre-induced with rifampicin during the in virological suppression with either efavirenz- or 2-week nevirapine lead-in dose (200 mg daily) phase. nevirapine-based ART, and no difference in efficacy The proportion of patients with subtherapeutic nevi- between efavirenz and nevirapine [25]. A recent large rapine concentrations was 59% and 79% at week 2, South African study showed that efavirenz was equally improving to 14% and 23% on full doses at week 4 effective in patients with and without tuberculosis, but for Malawian and Thai patients, respectively [13,14]. nevirapine was associated with a higher risk of virologi- The Thai study included an arm starting nevirapine at cal failure, although >80% of patients on nevirapine full doses (200 mg every 12 h), followed by increasing achieved virological suppression at 6 months [26]. Inter- the dose by 50%. This study was unfortunately stopped estingly, patients who started antitubercular therapy early because of a higher rate of hypersensitivity reac- when they were established on nevirapine-based ART tions in the high-dose arm, but the difference was not did not have a higher risk of failure, suggesting that statistically significant. subtherapeutic nevirapine concentrations during the Concomitant rifampicin has not been shown to lead-in dose phase [13,14] accounted for the increased consistently reduce efavirenz concentrations. A risk of failure. The South African study also showed pharmacokinetic study in 12 participants found that efavirenz was more effective than nevirapine in decreases in efavirenz area under the curve of 26% patients without tuberculosis [26], which a number of [15] and a retrospective analysis of a therapeutic drug other large cohorts have also reported [27–29]. monitoring database found that efavirenz concentra- A small randomized controlled trial comparing tions were significantly lower (by 35%) with concomi- efavirenz with nevirapine in Thai patients on rifampicin- tant rifampicin [16], but prospective pharmacokinetic based antitubercular therapy was recently published studies conducted in Spain [17], South African adults [30]. The trial found no difference in the proportion of [18] and children [19], and India [20] have not shown patients with virological suppression at 48 weeks, but significant reductions in efavirenz concentrations. had limited power. A larger trial addressing the same

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question is underway in Mozambique, but results are of all ritonavir-boosted protease inhibitors at standard only expected in 2011. doses are reduced by >90% when coadministered with There is contradictory data on the tolerability of rifampicin [21]. The CDC guidelines on managing drug NNRTI-based ART with concomitant antitubercular interactions in the treatment of HIV-related tuberculo- therapy. Two studies have reported more hepatotoxicity sis recommends one of two options to deal with the with efavirenz [31], and with either nevirapine or efa- protease-inhibitor–rifampicin interaction [21]. The virenz [25], but two other studies found no significantly first and preferred option is to replace rifampicin with increased rate of adverse events with nevirapine [9], or rifabutin, which is the only recommendation given in with either nevirapine or efavirenz [26]. the current US guidelines on managing opportunistic infections [34]. Rifabutin is a much less potent inducer Research questions than rifampicin and has minimal effects on ritonavir- Adequately powered randomized clinical trials should boosted protease inhibitor concentrations. Rifabutin be conducted on first-line ART regimens in patients is currently very expensive, but even if the price of on rifampicin-based antitubercular therapy to evalu- rifabutin were to be dramatically reduced, it would be ate efficacy and tolerability, and much could be learned difficult to implement in high-burden countries where from large cohort studies. There is also a need for more standardized antitubercular regimens are administered studies in children. by healthcare workers, often using fixed-dose combi- There is much more clinical and pharmacokinetic nations. Furthermore, a recent Cochrane systematic data on the interaction between rifampicin and efa- review of rifabutin in tuberculosis concluded that there virenz, than with nevirapine. However, as summarized was insufficient evidence for its efficacy in HIV-infected above, the reduction of nevirapine concentrations with patients [35]. Finally, the concentrations of rifabutin rifampicin is greater than that seen with efavirenz. are markedly increased by ritonavir-boosted protease Nevirapine is the most widely used NNRTI in first-line inhibitors necessitating a dose reduction and adminis- ART regimens in high-burden countries [32], which is tration three times a week [21], which will be difficult likely to remain the case because it is cheaper than efa- to implement in clinics where daily administration of virenz and considered to be safer in pregnancy. Thus, the other antitubercular drugs is used. the greatest need is for studies on nevirapine. It is our The second option given in the CDC guidelines to view that further studies should be conducted omitting compensate for the inducing effect of rifampicin is to the lead-in dose of nevirapine, with adequate power to increase the dose of the protease inhibitor. This can be assess the risk of toxicity. It is standard practice to omit achieved by increasing the ritonavir dose to 400 mg the lead-in dose of nevirapine when switching from every 12 h with either saquinavir [36,37] or lopinavir efavirenz, which is a less potent inducer of cytochrome [38], or by doubling the dose of lopinavir/ritonavir P450 isoenzymes than rifampicin. A large study of Cam- [38]. Studies in South African children coinfected with bodian patients switching from efavirenz to nevirapine, tuberculosis and HIV found that increasing the ritona- without the lead-in dose, concluded that there did not vir component to give a lopinavir:ritonavir ratio of 1:1 appear to be more adverse events than when nevirapine resulted in adequate trough lopinavir concentrations is initiated with increasing doses [33]. [39], but doubling the dose of lopinavir/ritonavir (in the usual formulation of 4:1) did not [40]. Recommendations Efavirenz, in standard doses, is the preferred NNRTI Effectiveness and tolerability for concomitant use with rifampicin. If efavirenz is una- We are not aware of any cohort studies comparing the vailable or inappropriate (for example, during the first effectiveness of adjusted doses of boosted protease- trimester of pregnancy), then nevirapine could be used. inhibitor-based ART in cohorts with and without con- Consideration should be given to omitting the lead-in comitant rifampicin-based antitubercular therapy, or of dose of nevirapine, as when switching from efavirenz to any randomized controlled trials. nevirapine, together with close monitoring for toxicity. The major barrier to using adjusted dose protease inhibitors and rifampicin-based antitubercular therapy Second-line ART regimens is hepatotoxicity. Three recent studies in healthy volunteers exploring the interaction between rifampicin Pharmacokinetics and adjusted doses of ritonavir-boosted saquinavir, The drug–drug interaction between rifampicin and lopinavir (tablet formulation) and atazanavir, were protease inhibitors is more severe than with NNRTIs. prematurely terminated because of very high inci- Rifampicin induces both CYP3A4 and the transmem- dences of hepatotoxicity [41–43]. The study examin- brane efflux pump P-glycoprotein [2], and protease inhib- ing the interaction between boosted saquinavir and itors are substrates of both. The trough concentrations rifampicin [41] found different rates of hepatotoxicity

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depending on the sequence in which the drugs were be very closely monitored. Middle income countries administered: 2 of 14 participants in the arm given should consider substituting rifampicin with rifabutin. boosted saquinavir initially followed by rifampicin, and 9 of 14 participants in the arm given rifampicin Disclosure statement initially followed by boosted saquinavir. In the prematurely discontinued lopinavir and atazanavir studies, GM has received speakers honoraria from Abbott rifampicin was commenced first. It has been hypoth- Laboratories and Merck Sharp & Dohme. ED and KC esized [43] that prior induction of the liver enzymes declare no competing interests. by rifampicin could give rise to high concentrations of toxic intermediate metabolites when the boosted pro- References tease inhibitor is introduced. 1. Corbett EL, Marston B, Churchyard GJ, De Cock KM. 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Accepted for publication 7 July 2009

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