Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review

Abstract

Aims: Efavirenz (EFV) and rifampicin-isoniazid (RH) are cornerstone drugs in human immunodeficiency virus (HIV)-tuberculosis (TB) coinfection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries.

Methods: We conducted a systematic review of studies conducted in the high TB/HIV-burden countries between 1990 and 2016 on EFV pharmacokinetics during RH coadministration in coinfected patients. Two reviewers conducted article screening and data collection.

Results: Of 119 records retrieved, 22 were included (two conducted in children), reporting either EFV mid-dose or pre-dose concentrations. In 19 studies, median or mean concentrations of RH range between 1000 and 4000 ng ml^-1 , the so-called therapeutic range. The proportion of patients with subtherapeutic concentration of RH ranged between 3.1 and 72.2%, in 12 studies including one conducted in children. The proportion of patients with supratherapeutic concentration ranged from 19.6 to 48.0% in six adult studies and one child study. Five of eight studies reported virological suppression >80%. The association between any grade hepatic and central nervous system adverse effects with EFV/RH interaction was demonstrated in two and three studies, respectively. The frequency of the CYP2B6 516G > T polymorphism ranged from 10 to 28% and was associated with higher plasma EFV concentrations, irrespective of ethnicity.

Conclusions: Anti-TB drug coadministration minimally affect the EFV exposure, efficacy and safety among TB-HIV coinfected African and Asian patients. This supports the current 600 mg EFV dosing when coadministered with anti-TB drugs.

Keywords: HIV/AIDS < infectious diseases; adverse drug reactions; antiretrovirals < infectious diseases; genetics and pharmacogenetics; pharmacokinetics.

Figure 1

Flow chart showing the selection of relevant papers

Figure 2

Proportion of patients with subtherapeutic efavirenz (EFV) plasma concentration. †Child studies; S, on and off rifampicin–isoniazid (RH) EFV subtherapeutic concentrations assessed in the same patient; P, on and off RH EFV subtherapeutic concentrations assessed in different patient groups (HIV‐TB coinfected vs. HIV only). n, sample size on which the EFV subtherapeutic frequencies either with or without RH coadministration is based; n1, sample size on which the EFV subtherapeutic frequencies during ART without RH coadministration is based; n2, sample size on which the EFV subtherapeutic frequencies during ART with RH coadministration is based; ref = reference number

Figure 3

Proportion of patients with supratherapeutic efavirenz plasma concentration. †Child studies; EFV, efavirenz; RH, rifampicin and isoniazid; S, on and off RH subtherapeutic EFV concentrations assessed in the same patient; P, on and off RH subtherapeutic EFV concentrations assessed in different patient groups (HIV‐TB coinfected vs. HIV only). n, Sample size on which the EFV subtherapeutic frequencies either with or without RH coadministration is based; n1, Sample size on which the EFV subtherapeutic frequencies during ART without RH coadministration is based; n2, Sample size on which the EFV subtherapeutic frequencies during ART with RH coadministration is based; ref, reference number

Figure 4

Efavirenz plasma concentrations on and off rifampicin coadministration among patients with CYP2B6 homozygous slow and extensive metabolizer genetic polymorphism, CYP2B6 G516 T. (A) Slow metabolizer genetic polymorphism; (B) extensive metabolizer genetic polymorphism. On‐R, on rifampicin; Off‐R, off rifampicin; SM, slow metabolizer; EM, extensive metabolizer; EFV, efavirenz; Ref, reference number; C12, efavirenz mid‐dose concentrations; Cmin, minimum efavirenz concentration; A, C12; mean; B, C12; median; C, Cmin; median; D, Cmin; mean