John W. Hargrove

The potential impact of male circumcision on HIV in Sub-Saharan Africa.

Background A randomized controlled trial (RCT) has shown that male circumcision (MC) reduces sexual transmission of HIV from women to men by 60% (32%−76%; 95% CI) offering an intervention of proven efficacy for reducing the sexual spread of HIV. We explore the implications of this finding for the promotion of MC as a public health intervention to control HIV in sub-Saharan Africa. Methods and Findings Using dynamical simulation models we consider the impact of MC on the relative prevalence of HIV in men and women and in circumcised and uncircumcised men. Using country level data on HIV prevalence and MC, we estimate the impact of increasing MC coverage on HIV incidence, HIV prevalence, and HIV-related deaths over the next ten, twenty, and thirty years in sub-Saharan Africa. Assuming that full coverage of MC is achieved over the next ten years, we consider three scenarios in which the reduction in transmission is given by the best estimate and the upper and lower 95% confidence limits of the reduction in transmission observed in the RCT. MC could avert 2.0 (1.1−3.8) million new HIV infections and 0.3 (0.1−0.5) million deaths over the next ten years in sub-Saharan Africa. In the ten years after that, it could avert a further 3.7 (1.9−7.5) million new HIV infections and 2.7 (1.5−5.3) million deaths, with about one quarter of all the incident cases prevented and the deaths averted occurring in South Africa. We show that a) MC will increase the proportion of infected people who are women from about 52% to 58%; b) where there is homogenous mixing but not all men are circumcised, the prevalence of infection in circumcised men is likely to be about 80% of that in uncircumcised men; c) MC is equivalent to an intervention, such as a vaccine or increased condom use, that reduces transmission in both directions by 37%. Conclusions This analysis is based on the result of just one RCT, but if the results of that trial are confirmed we suggest that MC could substantially reduce the burden of HIV in Africa, especially in southern Africa where the prevalence of MC is low and the prevalence of HIV is high. While the protective benefit to HIV-negative men will be immediate, the full impact of MC on HIV-related illness and death will only be apparent in ten to twenty years.

AIDS among older children and adolescents in Southern Africa: projecting the time course and magnitude of the epidemic.

Objective:An AIDS epidemic among older children and adolescents is clinically apparent in Southern Africa. We estimated the likely scale and time course of the epidemic in older survivors of vertical HIV infection. Design:We modelled demographic, HIV prevalence, mother-to-child transmission and child survival data to project HIV burden among older children in two Southern African countries at different stages of severe HIV epidemics. Using measured survival data for children, we estimate that 64% of HIV-infected infants are fast progressors with median survival 0.64 years and 36% are slow progressors with median survival 16.0 years. We confirmed model validity by comparing model predictions to available epidemiological data. Findings:Without treatment, HIV prevalence among 10-year-olds in South Africa is expected to increase from 2.1% in 2008 to 3.3% in 2020, whereas in Zimbabwe, it will decrease from 3.2% in 2008 to 1.6% in 2020. Deaths among untreated slow progressors will increase in South Africa from 7000/year in 2008 to 23 000/year in 2030, and in Zimbabwe from 8000/year in 2008 to peak at 9700/year in 2014. Drugs to prevent mother-to-child transmission could reduce death rate in 2030 to 8700/year in South Africa and to 2800/year in Zimbabwe in 2014. Conclusions:A substantial epidemic of HIV/AIDS in older survivors of mother-to-child transmission is emerging in Southern Africa. The lack of direct observations of survival in slow progressors has resulted in failure to anticipate the magnitude of the epidemic and to adequately address the clinical needs of HIV-infected older children and adolescents. Better HIV diagnostic and care services for this age group are urgently required.

Improved HIV-1 incidence estimates using the BED capture enzyme immunoassay.

Objective:To validate the BED capture enzyme immunoassay for HIV-1 subtype C and to derive adjustments facilitating estimation of HIV-1 incidence from cross-sectional surveys. Design:Laboratory analysis of archived plasma samples collected in Zimbabwe. Methods:Serial plasma samples from 85 women who seroconverted to HIV-1 during the postpartum year were assayed by BED and used to estimate the window period between seroconversion and the attainment of a specified BED absorbance. HIV-1 incidences for the year prior to recruitment and for the postpartum year were calculated by applying the BED technique to HIV-1-positive samples collected at baseline and at 12 months. Results:The mean window for an absorbance cut-off of 0.8 was 187 days. Among women who were HIV-1 positive at baseline and retested at 12 months, a proportion (ϵ) 5.2% (142/2749) had a BED absorbance < 0.8 at 12 months and were falsely identified as recent seroconverters. Consequently, the estimated BED annual incidence at 12 months postpartum (7.6%) was 2.2 times the contemporary prospective estimate. BED incidence adjusted for ϵ was 3.5% [95% confidence interval (CI), 2.6–4.5], close to the 3.4% estimated prospectively. Adjusted BED incidence at baseline was 6.0% (95% CI, 5.2–6.9) and, like the prospective estimates, declined with maternal age. Unadjusted BED incidence estimates were largely independent of age; the pooled estimate was 58% higher than adjusted incidence. Conclusion:The BED method can be used in an African setting, but further estimates of ϵ and of the window period are required, using large samples in a variety of circumstances, before its general utility can be gauged.

HIV decline in Zimbabwe due to reductions in risky sex? Evidence from a comprehensive epidemiological review

Background Recent data from antenatal clinic (ANC) surveillance and general population surveys suggest substantial declines in human immunodeficiency virus (HIV) prevalence in Zimbabwe. We assessed the contributions of rising mortality, falling HIV incidence and sexual behaviour change to the decline in HIV prevalence. Methods Comprehensive review and secondary analysis of national and local sources on trends in HIV prevalence, HIV incidence, mortality and sexual behaviour covering the period 1985–2007. Results HIV prevalence fell in Zimbabwe over the past decade (national estimates: from 29.3% in 1997 to 15.6% in 2007). National census and survey estimates, vital registration data from Harare and Bulawayo, and prospective local population survey data from eastern Zimbabwe showed substantial rises in mortality during the 1990s levelling off after 2000. Direct estimates of HIV incidence in male factory workers and women attending pre- and post-natal clinics, trends in HIV prevalence in 15–24-year-olds, and back-calculation estimates based on the vital registration data from Harare indicated that HIV incidence may have peaked in the early 1990s and fallen during the 1990s. Household survey data showed reductions in numbers reporting casual partners from the late 1990s and high condom use in non-regular partnerships between 1998 and 2007. Conclusions These findings provide the first convincing evidence of an HIV decline accelerated by changes in sexual behaviour in a southern African country. However, in 2007, one in every seven adults in Zimbabwe was still infected with a life-threatening virus and mortality rates remained at crisis level.

Male Circumcision for HIV Prevention in High HIV Prevalence Settings: What Can Mathematical Modelling Contribute to Informed Decision Making?

Experts from UNAIDS, WHO, and the South African Centre for Epidemiological Modelling report their review of mathematical models estimating the impact of male circumcision on HIV incidence in high HIV prevalence settings

Accuracy of serological assays for detection of recent infection with HIV and estimation of population incidence: a systematic review

We systematically reviewed the accuracy of serological tests for recent infections with HIV that have become widely used for measuring population patterns incidence of HIV. Across 13 different assays, sensitivity to detect recent infections ranged from 42-100% (median 89%). Specificity for detecting established infections was between 49.5% and 100% (median 86.8%) and was higher for infections of durations longer than 1 year (median 98%, range 31.5-100.0). For four different assays, comparisons were made between assay-derived population incidence estimates and a reference incidence estimate. The median percentage difference between the assay-derived incidence and reference incidence was 26.0%. Serological assays have reasonable sensitivity for the detection of recent infection with HIV, but are vulnerable to misclassifying established infections as recent-potentially leading to biases in incidence estimates. This conclusion is highly qualified by the apparent absence of a standardised approach to assay evaluation. There is an urgent need for an internationally agreed framework for evaluating and comparing these tests.

Determination of Mean Recency Period for Estimation of HIV Type 1 Incidence with the BED-Capture EIA in Persons Infected with Diverse Subtypes

The IgG capture BED enzyme immunoassay (BED-CEIA) was developed to detect recent HIV-1 infection for the estimation of HIV-1 incidence from cross-sectional specimens. The mean time interval between seroconversion and reaching a specified assay cutoff value [referred to here as the mean recency period (ω)], an important parameter for incidence estimation, is determined for some HIV-1 subtypes, but testing in more cohorts and new statistical methods suggest the need for a revised estimation of ω in different subtypes. A total of 2927 longitudinal specimens from 756 persons with incident HIV infections who had been enrolled in 17 cohort studies was tested by the BED-CEIA. The ω was determined using two statistical approaches: (1) linear mixed effects regression (ω(1)) and (2) a nonparametric survival method (ω(2)). Recency periods varied among individuals and by population. At an OD-n cutoff of 0.8, ω(1) was 176 days (95% CL 164-188 days) whereas ω(2) was 162 days (95% CL 152-172 days) when using a comparable subset of specimens (13 cohorts). When method 2 was applied to all available data (17 cohorts), ω(2) ranged from 127 days (Thai AE) to 236 days (subtypes AG, AD) with an overall ω(2) of 197 days (95% CL 173-220). About 70% of individuals reached a threshold OD-n of 0.8 by 197 days (mean ω) and 95% of people reached 0.8 OD-n by 480 days. The determination of ω with more data and new methodology suggests that ω of the BED-CEIA varies between different subtypes and/or populations. These estimates for ω may affect incidence estimates in various studies.

Genetic Variants in Nonclassical Major Histocompatibility Complex Class I Human Leukocyte Antigen (HLA)–E and HLA-G Molecules Are Associated with Susceptibility to Heterosexual Acquisition of HIV-1

Human leukocyte antigen (HLA)-E and HLA-G molecules act as powerful modulators of the innate immune response. The present study shows that the HLA-E(G) genetic variant (the HLA-E*0103 allele) alone is significantly (P = .001) associated with a 4.0-fold decreased risk of human immunodeficiency virus 1 (HIV-1) infection in Zimbabwean women. Furthermore, women carrying the combination of the protective HLA-E(G) homozygote and HLA-G*0105N heterozygote genotypes had a 12.5-fold decreased risk of HIV-1 infection (P = .03), compared with women carrying neither genotype. These associations remained significant after adjustment was made for other significant sociodemographic risk factors for HIV prevalence in this population. In conclusion, HLA-E and HLA-G polymorphisms can independently and synergistically influence susceptibility to heterosexual acquisition of HIV-1.

Significantly diminished long-term specificity of the BED capture enzyme immunoassay among patients with HIV-1 with very low CD4 counts and those on antiretroviral therapy.

Objective:To estimate the proportion who test as recent infections by the BED capture enzyme immunoassay (BED) among patients about to commence, and those receiving, antiretroviral therapy. Design:Cryopreserved plasma samples from HIV patients on the national antiretroviral treatment (ART) rollout program at Tygerberg Hospital HIV clinic, South Africa, were tested using the BED assay. Participants:Five hundred five patients qualifying for ART were included in this study. Method:All plasma samples from each patient were tested by BED. Basic demographic data, HIV-1 viral load, and CD4 count results were obtained from the laboratory database. Main Outcome:The proportion presenting as false recently infected is reported. Results:Among patients, with presumed long-term HIV-1 infections, about to commence ART, 11.2% [95% confidence interval (CI): 8.3 to 14.5%] tested recent by BED. The proportion was higher among patients with CD4 counts <50 cells per microliter [odds ratio 2.63, 95% CI: 1.39 to 5.00] and log10 HIV-1 viral load less than 4 [odds ratio 3.03, 95% CI: 1.05 to 9.09]. Proportions testing false recent increased from 11.2% before ART to 17%, 25%, 38%, and 56% at 0.5, 1, 1.5, and 2 years, respectively, after ART initiation. Conclusions:If the BED method is to be used for the accurate estimation of HIV incidence from cross-sectional surveys, it will be essential, before other statistical adjustment methods, to identify, at least, all cases who are on ART and all those with CD4 counts < 50 cells per microliter. The more general remaining problem is the unequivocal identification of all persons with long-term HIV infections.

Mortality among HIV-positive postpartum women with high CD4 cell counts in Zimbabwe.

Background:Whereas HAART initiated at CD4 cell counts 351–450 cells/μl reduces mortality, compared with starting at lower CD4 levels, there is currently no evidence for the advantages of initiating treatment at CD4 cell counts greater than 450 cells/μl. Methods:Mortality hazard, as a function of CD4 cell count, was estimated among postpartum HIV-positive women in Zimbabwe, using HIV-negative women as the reference group. Results:Mortality within 24 months postpartum was 54 times higher among women with CD4 cell counts less than 200 cells/μl, fell to 5.4 times higher for those with CD4 cell counts 400–600 cells/μl but fell little thereafter. For CD4 cell counts greater than 600 cells/μl the hazard was 6.2 (95% confidence interval 3.2–11.9). Conclusion:Early HAART initiation for all HIV-positive pregnant women may benefit individual mothers and infants, and simultaneously reduce population HIV incidence.