BACKGROUND Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others. METHODS In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF–FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF–FTC in preventing HIV acquisition and to evaluate safety. RESULTS HIV infections occurred in 33 women in the TDF–FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P = 0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF–FTC group (P = 0.04, P<0.001, and P = 0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF–FTC group (4.7%) than in the placebo group (3.0%, P = 0.051). Less than 40% of the HIV-uninfected women in the TDF–FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. The study was stopped early, on April 18, 2011, because of lack of efficacy. CONCLUSIONS Prophylaxis with TDF–FTC did not significantly reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. Despite substantial counseling efforts, drug adherence appeared to be low. (Supported by the U.S. Agency for International Development and others; FEM-PrEP ClinicalTrials.gov number, NCT00625404.)

The study of cell-population heterogeneity in a range of biological systems, from viruses to bacterial isolates to tumor samples, has been transformed by recent advances in sequencing throughput. While the high-coverage afforded can be used, in principle, to identify very rare variants in a population, existing ad hoc approaches frequently fail to distinguish true variants from sequencing errors. We report a method (LoFreq) that models sequencing run-specific error rates to accurately call variants occurring in <0.05% of a population. Using simulated and real datasets (viral, bacterial and human), we show that LoFreq has near-perfect specificity, with significantly improved sensitivity compared with existing methods and can efficiently analyze deep Illumina sequencing datasets without resorting to approximations or heuristics. We also present experimental validation for LoFreq on two different platforms (Fluidigm and Sequenom) and its application to call rare somatic variants from exome sequencing datasets for gastric cancer. Source code and executables for LoFreq are freely available at http://sourceforge.net/projects/lofreq/.

Age-related macular degeneration (AMD) is a major cause of blindness, but presents differently in Europeans and Asians. Here, we perform a genome-wide and exome-wide association study on 2,119 patients with exudative AMD and 5,691 controls, with independent replication in 4,226 patients and 10,289 controls, all of East Asian descent, as part of The Genetics of AMD in Asians (GAMA) Consortium. We find a strong association between CETP Asp442Gly (rs2303790), an East Asian-specific mutation, and increased risk of AMD (odds ratio (OR)=1.70, P=5.60 × 10−22). The AMD risk allele (442Gly), known to protect from coronary heart disease, increases HDL cholesterol levels by 0.17 mmol l−1 (P=5.82 × 10−21) in East Asians (n=7,102). We also identify three novel AMD loci: C6orf223 Ala231Ala (OR=0.78, P=6.19 × 10−18), SLC44A4 Asp47Val (OR=1.27, P=1.08 × 10−11) and FGD6 Gln257Arg (OR=0.87, P=2.85 × 10−8). Our findings suggest that some of the genetic loci conferring AMD susceptibility in East Asians are shared with Europeans, yet AMD in East Asians may also have a distinct genetic signature.

BackgroundAs pre-exposure prophylaxis (PrEP) moves closer to availability in developing countries, practical considerations for implementation become important. We conducted a consultation with district-level community stakeholders experienced in HIV-prevention interventions with at-risk populations in Bondo and Rarieda, Kenya to generate locally grounded approaches to the future rollout of oral PrEP to four populations: fishermen, widows, female sex workers, and serodiscordant couples.MethodsThe 20 consultation participants represented the Ministry of Health, faith- and community-based organizations, health facilities, community groups, and nongovernmental organizations. Participants divided into breakout groups and followed a structured discussion guide asking them to identify barriers to implementing HIV-prevention interventions (including PrEP) with each population. Questions also solicited solutions for addressing these barriers, as well as other facilitators for PrEP implementation. In particular, questions focused on how to encourage people to screen for PrEP eligibility by having HIV and other blood tests and how to encourage compliance with ongoing HIV testing.ResultsThe barriers and facilitators/solutions discussants provided were frequently population-specific, but there were also broad-level similarities across populations. Service delivery barriers to HIV-prevention interventions concerned the need for staff trained to address the needs of particular populations. Service delivery facilitators to provision of ongoing HIV testing consisted of offering testing options besides facility-based testing. Stigma was the main community-level barrier for all groups, whereas barriers at the level of target populations included mobility; lifestyle and life circumstances, especially cultural norms among fishermen and widows; and fears, lack of awareness, and misinformation. Proposed facilitators and strategies for addressing community- and population-level barriers included topic-specific education within the populations and community, involvement of partners and family members, mass HIV testing, and peer educators. Barriers to PrEP uptake included non-adherence to pill taking and missing clinic visits. For drug adherence, facilitators were counselling and involving family members. Discussants suggested that client reminders, e.g., home visits, were needed to encourage clients to keep their clinic appointments.ConclusionsStrategies for encouraging eligibility screening and ongoing HIV testing will have local and population-specific aspects. Our results nonetheless apply to similar populations throughout sub-Saharan Africa and reach beyond oral PrEP to other ARV-based PrEP formulations.

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