Background The antiviral activity of pegylated interferon-alpha-2a has not been studied in untreated HIV-1-infected subjects without chronic hepatitis C virus (HCV) infection. Methods Untreated HIV-1-infected volunteers without HCV received weekly pegylated interferon alfa-2a (180 μg) for twelve weeks. Changes in HIV-1 RNA (pVL), CD4+ T-cell counts, pharmacokinetics, pharmacodynamic measurements of 2’,5’ oligoadenylate synthetase (OAS) activity, and induction of interferon inducible genes (IFIG) were measured. Nonparametric statistical analysis was performed. Results Eleven subjects completed 12 weeks of therapy. Median pVL decline and change in CD4 T-cell counts at week 12 were 0.61 log10 cp/mL [90% CI:0.20,1.18] and −44 (− 95, 85) cells/mm3, respectively. There was no correlation between pVL declines and concurrent pegylated interferon plasma concentrations. However, subjects with larger increases in OAS exhibited greater decreases in pVL at weeks 1 and 2 (estimated Spearman correlations -0.75 [-0.93,-0.28]) and -0.61 [-0.87,-0.09], respectively). Subjects with higher baseline IFIG levels had smaller week 12 declines in pVL (0.66[0.06,0.91]), while those with larger IFIG induction exhibited larger declines in pVL (-0.74 [-0.93,-0.21]). Conclusion Pegylated interferon alfa-2a was well tolerated and had significant anti-HIV-1 activity in HIV-1-monoinfected patients. The anti-HIV-1 effect correlated with OAS protein (weeks 1 and 2) and IFIG induction (week 12), but not with pegylated interferon concentrations.

Background Drug-drug interactions complicate management of co-infection with HIV-1 and Mycobacterium tuberculosis. Bedaquiline (formerly TMC207), an investigational agent for the treatment of tuberculosis, is metabolized by cytochrome P450 (CYP) 3A which may be induced by the antiretroviral drug efavirenz. Methods This was a Phase I pharmacokinetic drug interaction trial. Each healthy volunteer received two 400 mg doses of bedaquiline, the first alone, and the second with concomitant steady-state efavirenz. Plasma pharmacokinetic sampling for bedaquiline and its N-monodesmethyl metabolite (M2) was performed over 14 days after each bedaquiline dose. Steady-state efavirenz pharmacokinetics were also determined. Efavirenz metabolizer status was based on CYP2B6 composite 516/983 genotype. Results Thirty-three of 37 enrolled subjects completed the study. Geometric mean ratios (GMR) for bedaquiline with efavirenz versus bedaquiline alone were 0.82 (90% CI 0.75 to 0.89) for the 14-day area under the concentration-time curve (AUC0-336h) and 1.00 (90% CI 0.88 to 1.13) for the maximum concentration (Cmax). For M2, the GMR was 1.07 (90% CI 0.97 to 1.19) for AUC0-336h and 1.89 (90% CI 1.66 to 2.15) for Cmax. There were no Grade 3 or 4 clinical adverse events. One subject developed asymptomatic Grade 3 serum transaminase elevation, prompting study drug discontinuation. Efavirenz concentrations stratified by CYP2B6 genotype were similar to historical data. Conclusions Single-dose bedaquiline was well-tolerated alone and with steady-state efavirenz. The effect of efavirenz on bedaquiline concentrations is unlikely to be clinically significant.

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Objectives We compared the pharmacokinetics of lopinavir (LPV) and ritonavir (RTV) between female and males. Methods This two-step, multicenter, pharmacokinetic study enrolled HIV-infected adults on lopinavir/ritonavir (LPV/r) capsules (400/100mg BID) plus 1 or more NRTIs. All subjects underwent 12 hour pharmacokinetic sampling. The PK sampling was repeated in subjects receiving the LPV/r tablet formulation. Results Step 1 enrolled 37 women and 40 men; step 2 included 42 subjects from step 1 plus 35 new participants (39 women and 38 men). LPV pharmacokinetics in females and males were not significantly different with either formulation. Females had significantly higher median RTV AUC0–12h with both the soft gel capsule and tablet formulations (SGC:5395 vs. 4119 ng*hr/ml, p=0.026; tablet 5310 vs. 3941 ng*hr/ml, p=0.012), higher median Cmax (SGC:802 vs. 635 ng/mL, p=0.032; tablet: 773 vs. 570 ng/ml, p=0.006)) and lower median CL/F (SGC:18.54 vs. 24.31 L/hour, p=0.026; tablet: 18.83 vs. 25.37 L/hour, p=0.012). RTV CL/F was slower in females after weight adjustment with both formulations. Conclusion The pharmacokinetics of LPV in the SGC and tablet formulations are comparable in HIV infected subjects. Females had higher RTV AUC0–12h and lower CL/F with both formulations. The mechanism of the sex difference in RTV CL/F warrants elucidation.

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