Author(s): Abiy Habtewold aff1 aff2 , Eyasu Makonnen aff2 , Wondwossen Amogne aff3 aff4 , Getnet Yimer aff1 aff2 , Getachew Aderaye aff3 , Leif Bertilsson aff1 , Jürgen Burhenne aff5 , Eleni Aklillu [*] aff1
CYP2B6; efavirenz; Ethiopia; HIV/AIDS; rifampicin; sub-Saharan Africa; treatment guideline; tuberculosis
Tuberculosis (TB) is the most common opportunistic infection and cause of death in HIV-infected patients. HIV infected individuals with active TB need to be treated with both anti-TB and antiretroviral therapy (ART). However, the high pill burden, significant drug-drug interactions and additive toxicities from concomitant antiretroviral (ARV) and anti-TB drugs use remain challenging [1-3 ]. Rifampicin (RIF), a cornerstone first-line anti-TB drug in resource-limited countries, is a potent inducer of drug metabolizing enzymes and transporter proteins, and this may reduce plasma exposure of antiretroviral drugs including protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Despite its long-term auto-induction effect [4-7 ], efavirenz (EFV) is the preferred NNRTI to be used with RIF-based anti-TB therapy because of its proved efficacy, simpler dosing schedule, better side-effect profile and reduced impact on its pharmacokinetics compared with nevirapine or protease inhibitors [8-10 ].
CYP2B6, the major EFV-metabolizing enzyme, is induced by EFV and RIF. Therefore, coadministration of RIF with EFV may result in additive effect to induce CYP2B6 enzyme and this may further reduce systemic EFV exposure. Earlier studies in white population [11 ] and in healthy volunteers [12 ] reported that RIF coadministration decreases plasma exposures of EFV. In a relatively small number of patients, a previous study suggested to increase the EFV dose from 600 to 800 mg/day to compensate for the effect of RIF induction, particularly in patients with baseline bodyweight [greater than]50 kg [11 ]. Using pharmacokinetic simulation of nonclinical data to predict human EFV exposure in healthy volunteers, Rekic et al. suggested increasing the EFV dose during concomitant RIF treatment mainly in patients weighing [greater than]50 kg regardless of CYP2B6 genotype [13 ]. However, studies from diverse populations, mainly in black and Asian populations, reported no effect of RIF on EFV plasma concentration or increase in plasma EFV concentration during RIF-based anti-TB treatment [ 14-20 ]. The extent of EFV auto-induction over time and EFV plasma exposure varies between populations, partly due to CYP2B6 pharmacogenetic variations [21 ]. Therefore findings on EFV-RIF drug interaction study from one population may not be extrapolated to others. Besides, the impact of RIF coadministration on EFV-based ART virologic suppression and immunologic recovery is understudied.
The current TB-HIV treatment guidelines are inconsistent as to whether or not to increase the dose of EFV during concomitant RIF-based anti-TB therapy. The International Antiviral Society-USA panel recommend increasing the dose of EFV from 600 to 800 mg/day when coadministered with RIF in patients with pretreatment bodyweight of [greater than]50 kg [22 ]. Recently, the US FDA approved a revised EFV package label recommending a 800-mg EFV dose for patients receiving RIF-based anti-TB treatment who weigh [greater than]50 kg [23 ]. The British HIV Association guidelines for the treatment of TB-HIV coinfection recommend increasing dose of EFV from 600...