Bingxia Wang

HIV Preexposure Prophylaxis in the United States: Impact on Lifetime Infection Risk, Clinical Outcomes, and Cost-Effectiveness

BACKGROUND The combination of tenofovir and emtricitabine shows promise as HIV preexposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, the risks of developing drug resistance and toxicity, behavioral disinhibition, and drug costs. METHODS We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP among men who have sex with men and are at high risk of HIV infection (i.e., 1.6% mean annual incidence of HIV infection) in the United States. Base-case assumptions included 50% PrEP efficacy and monthly tenofovir-emtricitabine costs of

Loss to Care and Death Before Antiretroviral Therapy in Durban, South Africa

753. We used sensitivity analyses to examine the stability of results and to identify critical input parameters. RESULTS In a cohort with a mean age of 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased mean life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted quality-adjusted life-years). Discounted mean lifetime treatment costs increased from

CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment.

81,100 to

Routine voluntary HIV testing in Durban, South Africa : The experience from an outpatient department

232,700 per person, indicating an incremental cost-effectiveness ratio of

Scaling Up Antiretroviral Therapy in South Africa: The Impact of Speed on Survival

298,000 per quality-adjusted life-year gained. Markedly larger reductions in lifetime infection risk (from 44% to 6%) were observed with the assumption of greater (90%) PrEP efficacy. More-favorable incremental cost-effectiveness ratios were obtained by targeting younger populations with a higher incidence of infection and by improvements in the efficacy and cost of PrEP. CONCLUSIONS PrEP could substantially reduce the incidence of HIV transmission in populations at high risk of HIV infection in the United States. Although it is unlikely to confer sufficient benefits to justify the current costs of tenofovir-emtricitabine, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger populations or populations at higher risk of infection. Given recent disappointments in HIV infection prevention and vaccine development, additional study of PrEP-based HIV prevention is warranted.

Gag-Protease-Mediated Replication Capacity in HIV-1 Subtype C Chronic Infection: Associations with HLA Type and Clinical Parameters

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.

Clinical impact and cost-effectiveness of antiretroviral therapy in India: starting criteria and second-line therapy.

Objectives: To determine the rate of CD4 decline and the incidence of opportunistic infections (OIs) among antiretroviral therapy-naive South African HIV-infected patients and inform timing of OI prophylaxis. Methods: We used mixed-effect models to estimate CD4 cell decline by CD4 cell count strata in HIV-infected patients in the Cape Town AIDS Cohort between 1984 and 2000. Stratum-specific OI incidence per 100 person-years of observation was determined using incidence density analysis. Results: Nine hundred seventy-four patients with 2 or more CD4 cell counts were included. CD4 counts declined by 47.1 cells/&mgr;L per year in the stratum with more than 500 cells/&mgr;L stratum, 30.6 cells/&mgr;L per year in the stratum with 351 to 500 cells/&mgr;L, and 20.5 cells/&mgr;L per year in the stratum with 201 to 350 cells/&mgr;L. Tuberculosis and oral candidiasis were the only OIs that occurred frequently in the stratum with more than 200 CD4 cells/&mgr;L. Rates of chronic diarrhea, wasting syndrome, tuberculosis, and oral and esophageal candidiasis increased in the stratum with less than 200 cells/&mgr;L, and rates of all OIs were highest in the stratum with 50 cells/&mgr;L or less. Conclusions: CD4 cell count declines were dependent on CD4 strata and can inform timing of clinic visits and treatment initiation in South Africa. Incidence rates of OIs suggest that targeted OI prophylaxis could prevent substantial HIV-related morbidity in South Africa.

Cost-effectiveness of tenofovir as first-line antiretroviral therapy in India.

Objective:To evaluate the yield of a routine voluntary HIV testing program compared with traditional provider-referred voluntary counseling and testing (VCT) in a hospital-affiliated outpatient department (OPD) in Durban, South Africa. Design and Methods:In a prospective 14-week “standard of care” period, we compared OPD physician logs documenting patient referrals to the hospital VCT site with HIV test registers to measure patient completion of HIV test referral. The standard of care period was followed by a 12-week intervention during which all patients who registered at the OPD were given an educational intervention and offered a rapid HIV test at no charge as part of routine care. Results:During the standard of care period, OPD physicians referred 435 patients aged ≥18 years for HIV testing; 137 (31.5%) of the referred patients completed testing at the VCT site within 4 weeks. Among those tested, 102 (74.5%) were HIV infected. During the intervention period, 1414 adults accepted HIV testing and 1498 declined. Of those tested, 463 (32.7%, 95% confidence interval: 30.3 to 35.3) were HIV infected. Routine HIV testing in the OPD identified 39 new HIV cases per week compared with 8 new cases per week with standard of care testing based on physician referral to a VCT site (P < 0.0001). Conclusions:Routine voluntary HIV testing in an OPD in South Africa leads to significantly higher rates of detection of HIV disease. This strategy should be implemented more widely in high HIV prevalence areas where treatment is available.

Influence of Gag-Protease-Mediated Replication Capacity on Disease Progression in Individuals Recently Infected with HIV-1 Subtype C

BACKGROUND Only 33% of eligible human immunodeficiency virus (HIV)-infected patients in South Africa receive antiretroviral therapy (ART). We sought to estimate the impact of alternative ART scale-up scenarios on patient outcomes from 2007-2012. METHODS Using a simulation model of HIV infection with South African data, we projected HIV-associated mortality with and without effective ART for an adult cohort in need of therapy (2007) and for adults who became eligible for treatment (2008-2012). We compared 5 scale-up scenarios: (1) zero growth, with a total of 100,000 new treatment slots; (2) constant growth, with 600,000; (3) moderate growth, with 2.1 million; (4) rapid growth, with 2.4 million); and (5) full capacity, with 3.2 million. RESULTS Our projections showed that by 2011, the rapid growth scenario fully met the South African need for ART; by 2012, the moderate scenario met 97% of the need, but the zero and constant growth scenarios met only 28% and 52% of the need, respectively. The latter scenarios resulted in 364,000 and 831,000 people alive and on ART in 2012. From 2007 to 2012, cumulative deaths in South Africa ranged from 2.5 million under the zero growth scenario to 1.2 million under the rapid growth scenario. CONCLUSIONS Alternative ART scale-up scenarios in South Africa will lead to differences in the death rate that amount to more than 1.2 million deaths by 2012. More rapid scale-up remains critically important.

Loss to follow-up and mortality among HIV-infected people co-infected with TB at ART initiation in Durban South Africa.

ABSTRACT 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.