AIDS Clinical Trials Group Study A5349/Tuberculosis Trials Consortium Study 31 (S31) is a phase III trial comparing two short-course TB treatment regimens containing high dose daily rifapentine (RPT) to standard TB treatment. RPT is a known CYP inducer and efavirenz (EFV) is a CYP substrate; thus, there is a potential risk of decreased EFV exposure and consequently increased risk of virologic failure. The pharmacokinetics (PK) of this combination have not been evaluated. An objective of S31 was to evaluate the effect of RPT on EFV PK, initially among a subset of participants on stable EFV-containing antiretroviral therapy (ART) at the time of initiation of RPT-containing TB treatment.
This substudy included participants already suppressed on at least two months of EFV-containing (600mg) ART, and randomized to one of two regimens containing daily RPT (1200mg), isoniazid (H), pyrazinamide, and either ethambutol or moxifloxacin. Mid interval EFV concentrations were measured in plasma samples collected at weeks 0 (pre-RPT/H), 4, and 8 during concomitant RPT/H. EFV apparent oral clearance (CL/F) was modeled using Bayesian estimation; population PK priors were taken from previous EFV PK studies. Week 4 and 8 EFV concentrations were combined to estimate EFV CL/F during RPT/H therapy. The geometric mean ratio (GMR) and 90% confidence interval (CI) of the pre and during RPT/H EFV CL/F values were calculated. The protocol specified that >80% of participants should have EFV concentrations ≥1 mg/L for enrollment to continue.
Of 23 evaluable participants, 52% were female, 91% Black/African, and median age was 37 years (25-53). All 23 had HIV-1 RNA <200 copies/mL at randomization, 16/16 (100%) had HIV-1 RNA <200 copies/mL at week 8; the median baseline CD4+ count was 401 cells/mm3 (118-998). The GMR for EFV CL/F was 0.88 (0.75-0.96). The number of participants with EFV concentrations ≥ 1 mg/L at both week 4 and 8, was 21 (91%). Median (IQR) RPT concentrations were 14.7 mg/L (12.2-19.25 mg/L).
The CL/F of EFV decreased slightly with RPT/H. However, the proportion of participants with EFV concentrations ≥1mg/L did not cross below the pre-specified threshold of 80%. Plasma HIV-RNA levels during RPT/H indicated maintenance of viral suppression. These data provide preliminary support for co-administration of high-dose RPT/H with EFV-containing ART. Evaluation of EFV PK in participants starting ART after initiation of study RPT-containing TB treatment is underway.