The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 g/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.Tuberculosis (TB) remains one of the most important opportunistic infections in human immunodeficiency virus (HIV)-infected individuals. The burden of effectively treating HIV-TB-coinfected patients is a well-recognized global public health problem. A decreased risk of death has been observed in patients starting combination antiretroviral therapy (CART) compared with those not receiving CART after the diagnosis of TB (2, 9, 13). In India, there are effective treatments available for both HIV disease and TB through the government program. Concomitant administration of CART and anti-TB medications is often complicated because of drug-drug interactions and the adverse-effect profile (17,30,36).Efavirenz (EFV) is a potent nonnucleoside reverse transcriptase inhibitor for the treatment of HIV type 1 (HIV-1) infection. EFV has been recommended as a first-line option in antiretroviral therapy (ART) and the preferential choice in TB-and HIV-coinfected patients, despite induction of the cytochrome P-450 system by rifampin (RMP). The available pharmacokinetic data provide evidence of a 13 to 25% reduction in EFV levels when it is coadministered with RMP (20), which is lower than those of nevirapine (40...

Several risk factors for drug concentration variations were identified. Two-hour post-dosing drug concentrations mimicked Cmax. A high proportion of TB patients had RMP Cmax below the expected range, which is a matter of concern.

Nevirapine blood concentrations are affected by many factors, most notably age ≤ 3 years; a combination of young age, stunting and CYP2B6 GG or GT genotype could potentially result in sub-therapeutic nevirapine concentrations. Dosing recommendations for children should be reviewed in the light of these findings.

This is the first study to show that rs11045819, rs4149032 and rs4149033 polymorphisms in the SLCO1B1 gene did not influence RMP concentrations in Indian patients.

Access to antiretroviral therapy has expanded in many developing countries, including India. The standard first-line regimens consist of a combination of two nucleoside reverse transcriptase inhibitors and a nonnucleoside reverse transcriptase inhibitor, in a fixed drug combination. Data regarding resistance to these drugs are scarce, especially in children. We evaluated the pattern of polymorphism and potential drug resistance mutations (DRMs) in HIV-1 isolates from 48 children naive to antiretroviral therapy attending the outpatient clinics of the Tuberculosis Research Center in Chennai. The samples were subjected to genotyping of reverse transcriptase (RT) and protease genes. All the samples showed significant polymorphisms in both RT and protease genes, but none had major DRMs. The currently recommended generic first-line antiretroviral drug combination is an appropriate treatment strategy for HIV-1-infected children in India.