Background The combination of tenofovir and emtricitabine (TDF/FTC) shows promise as HIV pre-exposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, risk of resistance and toxicity, behavioral disinhibition, and drug costs. Methods We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP in high-risk (1.6% average annual HIV incidence) men who have sex with men (MSM) in the United States. Base case assumptions included: 50% PrEP efficacy and $753 monthly TDF/FTC costs. We used sensitivity analyses to examine the stability of results and to identify critical input parameters. Results In a cohort with mean age 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased average life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted, quality-adjusted life-years or QALYs). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio (ICER) of $298,000 per QALY gained. Markedly larger reductions in lifetime infection risk (from 43.5% to 5.8%) were observed assuming greater (90%) PrEP efficacy. More favorable ICERs were obtained by targeting younger, higher-incidence populations and with improvements in the efficacy and cost of PrEP. Conclusions PrEP could substantially reduce HIV transmission in high-risk populations in the United States. Although it is unlikely to confer sufficient benefits to justify current TDF/FTC costs, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger or higher-risk populations. Given recent disappointments in HIV prevention and vaccine development, further study of PrEP-based HIV prevention is warranted.

The mechanisms underlying HIV-1 control by protective HLA class I alleles are not fully understood and could involve selection of escape mutations in functionally important Gag epitopes resulting in fitness costs. This study was undertaken to investigate, at the population level, the impact of HLA-mediated immune pressure in Gag on viral fitness and its influence on HIV-1 pathogenesis. Replication capacities of 406 recombinant viruses encoding plasma-derived Gag-protease from patients chronically infected with HIV-1 subtype C were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. Viral replication capacities varied significantly with respect to the specific HLA-B alleles expressed by the patient, and protective HLA-B alleles, most notably HLA-B*81, were associated with lower replication capacities. HLA-associated mutations at low-entropy sites, especially the HLA-B*81-associated 186S mutation in the TL9 epitope, were associated with lower replication capacities. Most mutations linked to alterations in replication capacity in the conserved p24 region decreased replication capacity, while most in the highly variable p17 region increased replication capacity. Replication capacity also correlated positively with baseline viral load and negatively with baseline CD4 count but did not correlate with the subsequent rate of CD4 decline. In conclusion, there is evidence that protective HLA alleles, in particular HLA-B*81, significantly influence Gag-protease function by driving sequence changes in Gag and that conserved regions of Gag should be included in a vaccine aiming to drive HIV-1 toward a less fit state. However, the long-term clinical benefit of immune-driven fitness costs is uncertain given the lack of correlation with longitudinal markers of disease progression.

Objective To examine the loss to care and mortality rates before starting antiretroviral therapy (ART) among ART eligible HIV-infected patients in Durban, South Africa. Design Retrospective cohort study. Methods We reviewed data from ART eligible adults (≥18 years) at an urban HIV clinic that charges a monthly fee from July to December 2006. ART eligibility was based on CD4 count ≤200 cells per microliter or clinical criteria and a psychosocial assessment. Patients who did not start ART and were lost within 3 months were phoned. Correlates of loss to care were evaluated using logistic regression. Results During the study period, 501 patients registered for ART training. Mean time from initial CD4 count to first ART training was 3.6 months (interquartile range 2.3−3.9 months). Four hundred eight patients (81.4%) were in care and on ART at 3-month follow-up, and 11 (2.2%) were in care but had not initiated ART. Eighty-two ART eligible patients (16.4%) were lost before ART initiation. Of these, 28 (34.1%) had died; two thirds of deaths occurred before or within 2 months after the first ART training. Despite multiple attempts, 32 patients (39%) were unreachable by phone. Lower baseline CD4 counts (≤100 cells/μL) and unemployment were independently associated with being lost. Conclusions Loss to care and death occur frequently before starting ART at an HIV clinic in Durban, South Africa. This delay from CD4 count to ART training, even among those with the lowest CD4 counts, highlights the need for interventions that improve linkage to care and prioritize ART initiation for those with low baseline CD4 counts.