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

Abstract

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

Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a randomised non-inferiority trial

“…[11][12][13][14] These discrepancies led some authors to propose that, because cytochrome P450 enzymes in patients on rifampicin are presumably already induced at the time of antiretroviral therapy initiation, nevirapine should be started at full dose in these patients. 15,16 However, effi cacy and safety of this approach have not been assessed. In this study, we aimed to compare the effi cacy and safety of nevirapine-based and efavirenz-based antiretroviral therapies in patients co-infected with HIV and tuberculosis, with initiation of nevirapine at full dose.…”

Drug-Resistant Tuberculosis Treatment Complicated by Antiretroviral Resistance in HIV Coinfected Patients: A Report of Six Cases in Lesotho

“…8,14 The reduction of nevirapine concentrations with concomitant rifampicin use is greater than the reduction of efavirenz concentrations, 8,14 and currently, coadministration of nevirapine and rifampicin is not recommended. 15 However, clinical cohorts have shown excellent viral control with efavirenz regimens, despite coadministration of rifampicin, 14,16 and current guidelines suggest that dose adjustment of efavirenz is unnecessary. 15 To our knowledge, this study is the first published study describing HIV drug resistance in DR-TB patients with HIV coinfection.…”

Clinical management of tuberculosis and HIV-1 co-infection

“…This may explain some of the variability and high rates of clinical toxicity in some studies [177]. Based on available data, standard doses of efavirenz can be given to patients weighing ,60 kg, but in patients weighing .60 kg an increase to 800 mg daily can be considered although may be unnecessary [159,178]. Trough drug level monitoring where available can be performed 2 weeks after starting efavirenz to check adequacy.…”

“…Amongst the most potent inducers of CYP3A4 [156,157] are the rifamycin family and rifampicin (table 2) is the most powerful inducer of CYP3A4 known, with rifabutin less so (table 3) [158]. Rifampicin also induces other cytochromes such as CYP2C19 and CYP2D6 and increases activity of the drug transporter Pglycoprotein that contributes to the absorption, distribution and elimination of PI [159,160]. Rifabutin, unlike rifampicin, is also a substrate of the CYP3A4 enzyme [156] thus CYP3A4 inhibitors will increase the concentration of rifabutin but have no effect on rifampicin metabolism.…”