To examine rates of and risk factors for heterosexual transmission of human immunodeficiency virus (HIV), the authors conducted a prospective study of infected individuals and their heterosexual partners who have been recruited since 1985. Participants were recruited from health care providers, research studies, and health departments throughout Northern California, and they were interviewed and examined at various study clinic sites. A total of 82 infected women and their male partners and 360 infected men and their female partners were enrolled. Over 90% of the couples were monogamous for the year prior to entry into the study; < 3% had a current sexually transmitted disease (STD). The median age of participants was 34 years, and the majority were white. Over 3,000 couple-months of data were available for the follow-up study. Overall, 68 (19%) of the 360 female partners of HIV-infected men (95% confidence interval (CI) 15.0-23.3%) and two (2.4%) of the 82 male partners of HIV-infected women (95% CI 0.3-8.5%) were infected. History of sexually transmitted diseases was most strongly associated with transmission. Male-to-female transmission was approximately eight-times more efficient than female-to-male transmission and male-to-female per contact infectivity was estimated to be 0.0009 (95% CI 0.0005-0.001). Over time, the authors observed increased condom use (p < 0.001) and no new infections. Infectivity for HIV through heterosexual transmission is low, and STDs may be the most important cofactor for transmission. Significant behavior change over time in serodiscordant couples was observed.

SUMMARY. , an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistanceassociated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log 10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.Keywords: GS-9857, hepatitis C virus, NS3/4A protease inhibitor.Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC 0-24 , area under the plasma concentration vs time curve up to 24 h; AUC inf , area under the plasma concentration vs time curve extrapolated to infinity; AUC last , area under the plasma concentration vs time curve from zero to the last quantifiable concentration; BMI, body mass index; C 24 , observed plasma concentration at 24 h postdose; C last , last observed quantifiable plasma drug concentration; CL/F, apparent oral clearance of drug following administration; C max , maximum plasma concentration; DAA, direct-acting antiviral; ECG, electrocardiogram; EC 50 , dose or systemic exposure required to produce 50% of the maximal drug induced anti-HCV activity; E max , maximal anti-HCV activity; HCV, hepatitis C virus; LC/MS/MS, liquid chromatography tandem mass spectroscopy; LLOQ, lower limit of quantification; MedDRA, Medical Dictionary for Regulatory Activities; NS, nonstructural protein; PK, pharmacokinetics; PD, pharmacodynamics; RAV, resistance-associated variant; RNA, ribonucleic acid; t 1/2 , elimination half-life; T last , time of last observed quantifiable plasma drug concentration; T max , time of maximum plasma concentration; ULN, upper limit of normal; k z , terminal elimination rate constant.Correspondence: Eric Lawitz, MD, The

These results provide little evidence of HCV sexual transmission but are consistent with infrequent sexual transmission. They corroborate the importance of injection drug use and transfusion of blood or blood products in transmitting HCV and underscore the importance of ascertaining parenteral exposures when examining sexual transmission of HCV.

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