HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients

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.

Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis

“…Table 3 shows potential clinical predictors of conversion within the different AUC 0-24 /MIC quartiles for isoniazid, rifampicin, and pyrazinamide. A higher percentage of side effects was reported by patients with isoniazid AUC 0-24 /MIC in the highest quartile as previously reported [27]. No statistically significant interaction was found between isoniazid exposures, drug side effects, and the outcome of culture conversion.…”

Impact of the host environment on the antitubercular action of pyrazinamide

“…Absorption and clearance of PZA in the context of TB-HIV coinfection is less clear. Some studies report that co-infection with HIV reduces PZA plasma concentrations [69,71,72] ; while others state that no significant differences are observed between TB only and co-infected patients [73,74] . Factors that may influence disparate drug concentrations include nutritional status [75] , access to antiretroviral therapy, and state of immunosuppression.…”

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Weight band doses should be optimized accordingly. Moreover, fat-free mass is frequently more closely related to clearance and volume of distribution than total body weight [7,[9][10][11][12][13][14]. For these drugs (including rifampin, isoniazid, and pyrazinamide), wasted or stunted individuals have lower drug exposures due to a higher proportion of their total body weight being accounted for by fat-free mass.…”

“…The findings across different studies are not consistent. This may be due to methodological differences between the studies, or differences between the study populations such as disease severity and wasting, inflammatory and immune status, and the presence or absence of concomitant antiretroviral treatment [11,[66][67][68]. Reduced antituberculosis drug exposures have also been described in males compared to females [1,12].…”

“…Many antituberculosis drugs exhibit wide pharmacokinetic variability in patient cohorts [1][2][3][4][5][6][7][8][9][10][11][12][13]. Studies in patients with drug-susceptible tuberculosis (DS-TB) on a standard regimen of rifampin and isoniazid for 6 months with pyrazinamide and ethambutol for the first 2 months, suggest that such variability is clinically important.…”