Pharmacokinetics of rifampicin and isoniazid in patients with HIV-tuberculosis coinfection receiving efavirenz-based antiretroviral treatment: an ANRS12292-RIFAVIRENZ sub-study

Abstract

Background: Increasing rifampicin dosing is considered a potent strategy for shortening TB treatment duration. Although previous data among patients with HIV-TB coinfection has shown that doubling rifampicin dosing had a small effect on EFV concentrations, its effect on the pharmacokinetics (PK) of antituberculosis drugs remains lacking in this population.

Objectives: To compare the PK of rifampicin and isoniazid with and without EFV co-administration in patients with HIV-TB coinfection using two rifampicin dosing regimens (10 and 20 mg/kg/day) and EFV dosing (600 and 800 mg q24h).

Methods: Ninety-seven patients were assigned to three arms in a randomized clinical trial conducted in Uganda. Plasma concentrations of rifampicin, isoniazid, and acetyl-isoniazid were measured. PK parameters were estimated, and statistical comparisons were made using geometric mean ratios, 90% CIs and the pre-set 0.80-1.25 interval.

Results: Doubling rifampicin dosing increased its Cmax and AUClast almost 3-fold. Adding EFV decreased rifampicin AUClast by 34%-40%. Isoniazid AUClast was unaffected with EFV 600 mg q24h but decreased with EFV 800 mg q24h by 23%. EFV increased acetyl-isoniazid concentrations, suggesting enhanced acetylation activity. At 10 mg/kg of rifampicin, 88% of patients had Cmax below the therapeutic range. However, at 20 mg/kg of rifampicin, 87% of patients achieved therapeutic concentrations, ensuring effective treatment.

Conclusions: The study highlights the importance of adjusting rifampicin dosing to achieve therapeutic levels in patients with coinfection. Doubling rifampicin dosing in patients with HIV-TB coinfection increases the percentage of patients with Cmax within the therapeutic range. Additionally, while EFV slightly affects rifampicin and isoniazid PK, these changes are not clinically significant, supporting the efficacy and safety of the combined regimen.