Drug-drug interactions between bedaquiline and the antiretrovirals lopinavir/ritonavir and nevirapine in HIV-infected patients with drug-resistant TB.

OBJECTIVES: Bedaquiline is a new anti-TB drug, which is metabolized by cytochrome P450 (CYP) 3A4. Concomitant ART is important for all HIV-infected patients treated for TB, but several antiretrovirals inhibit or induce CYP3A4. Single-dose drug-drug interaction studies found no significant interactions with nevirapine or lopinavir/ritonavir, but these findings could be misleading, especially because of bedaquiline's long terminal t1/2. We evaluated the effect of nevirapine and lopinavir/ritonavir on bedaquiline exposure. METHODS: We conducted a parallel-group pharmacokinetic study of three groups of participants who were on bedaquiline as part of therapy for drug-resistant TB: no ART (HIV seronegative); nevirapine-based ART; and lopinavir/ritonavir-based ART. Non-compartmental analyses were done and exposure of bedaquiline and its M2 metabolite compared between the no-ART group and the two ART groups. RESULTS: We enrolled 48 participants: 17 in the no-ART group, 17 in the nevirapine group and 14 in the lopinavir/ritonavir group. The following median bedaquiline pharmacokinetic parameters were significantly higher in the lopinavir/ritonavir group than in the no-ART group: AUC(0-48) (67 002 versus 34 730 ng ·â€Šh/mL; P = 0.003); Tmax (6 versus 4 h; P = 0.003); and t1/2 (55 versus 31 h; P = 0.004). On multivariate analysis, bedaquiline exposure was increased by lopinavir/ritonavir, male sex and time on bedaquiline. Bedaquiline exposure was not significantly different between the nevirapine group and the no-ART group. M2 metabolite exposure was not significantly different in either of the antiretroviral groups compared with the no-ART group. CONCLUSIONS: Lopinavir/ritonavir significantly increased bedaquiline exposure. The clinical significance of this interaction remains to be determined.

Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug-resistant tuberculosis.

Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug-drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67-99%) and M2 clearance to 119% (92-156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17-35%) and M2 clearance to 59% (44-69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.

The role of the infectious diseases unit at Groote Schuur Hospital in addressing South Africa's greatest burden of disease.

BACKGROUND: The greatest burden of disease in South Africa (SA) comes from infectious diseases (ID), with human immunodeficiency virus (HIV) and tuberculosis (TB) dominating the health landscape. However, other infections including community-acquired and imported infections and the rise in hospital-acquired infections pose a considerable threat to public health. METHODS AND OBJECTIVES: We used a prospective cross-sectional study to examine the profile of patients referred to the Infectious Diseases Unit at Groote Schuur Hospital (GSH) between 2008 and 2011. RESULTS: A total of 2 142 patient consultations were performed, the majority at the request of secondary hospital level medical teams; 80% of patients were HIV-infected (with a median CD4 count of 128/mm3). Approximately half of antiretroviral-naïve, HIV-infected patients started antiretroviral therapy in hospital. TB, predominantly extrapulmonary, was the most common diagnosis. Imported infections, notably severe falciparum malaria, accounted for a large number of the 81 different diagnoses in HIV-seronegative patients. Over half of all patients had co-morbidity complicating their clinical presentation. In-hospital mortality was 5.8%, with overwhelming sepsis the cause in 40% of deaths, largely due to hospital-acquired infection, particularly in the HIV-infected cohort. CONCLUSION: The overwhelming burden of ID in SA is revealed in this experience at GSH, a tertiary level referral hospital serving the Cape metropolitan area. The needs of the population warrant a reappraisal of human resource capacity and training in ID in SA.