HIV-1 coinfection does not reduce exposure to rifampicin, isoniazid, and pyrazinamide in South African tuberculosis outpatients
journal contributionposted on 2020-10-01, 14:41 authored by Neesha Rockwood, Graeme Meintjes, Maxwell Chirehwa, Lubbe Wiesner, Helen McIlleron, Robert J Wilkinson, Paolo Denti
There are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0-24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0-24 The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat-free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients.
AdultAnti-HIV AgentsAntiretroviral Therapy, Highly ActiveAntitubercular AgentsArea Under CurveBiological AvailabilityCoinfectionFemaleHIV InfectionsHIV-1HumansIsoniazidLopinavirMaleModels, StatisticalMycobacterium tuberculosisOutpatientsProspective StudiesPyrazinamideRifampinRitonavirSouth AfricaTuberculosis, PulmonaryWilkinson, R FC0012180605 Microbiology1108 Medical Microbiology1115 Pharmacology and Pharmaceutical SciencesMicrobiology