Abstract
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.
Highlights
There are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients
Despite global initiatives prioritizing reductions of the incidence and mortality attributable to tuberculosis (TB), in 2014 there were an estimated 9.6 million new TB cases (12% of patients were coinfected with HIV-1) and 1.5 million deaths (27% of patients were coinfected with HIV-1) [1]
In the case of rifampin-susceptible pulmonary tuberculosis, World Health Organization (WHO) guidelines advocate a daily regimen of 2 months of intensive-phase therapy with the first-line drugs rifampin, isoniazid, pyrazinamide, and ethambutol followed by 4 months of continuation-phase therapy with rifampin and isoniazid
Summary
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. 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. There have been contrasting findings published regarding the effect of HIV-1 coinfection on anti-TB drug pharmacokinetics, with some studies showing reduced drug exposures [10,11,12] and others showing no significant difference between HIV-1-coinfected and -uninfected patients [5, 13,14,15]. These may be difficult to attribute to a specific anti-TB drug with any certainty, they are likely to contribute to suboptimal adherence [22] and may adversely affect treatment outcomes [19]
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