BackgroundObservational studies suggest that male circumcision may provide protection against HIV-1 infection. A randomized, controlled intervention trial was conducted in a general population of South Africa to test this hypothesis.Methods and FindingsA total of 3,274 uncircumcised men, aged 18–24 y, were randomized to a control or an intervention group with follow-up visits at months 3, 12, and 21. Male circumcision was offered to the intervention group immediately after randomization and to the control group at the end of the follow-up. The grouped censored data were analyzed in intention-to-treat, univariate and multivariate, analyses, using piecewise exponential, proportional hazards models. Rate ratios (RR) of HIV incidence were determined with 95% CI. Protection against HIV infection was calculated as 1 − RR. The trial was stopped at the interim analysis, and the mean (interquartile range) follow-up was 18.1 mo (13.0–21.0) when the data were analyzed. There were 20 HIV infections (incidence rate = 0.85 per 100 person-years) in the intervention group and 49 (2.1 per 100 person-years) in the control group, corresponding to an RR of 0.40 (95% CI: 0.24%–0.68%; p < 0.001). This RR corresponds to a protection of 60% (95% CI: 32%–76%). When controlling for behavioural factors, including sexual behaviour that increased slightly in the intervention group, condom use, and health-seeking behaviour, the protection was of 61% (95% CI: 34%–77%).ConclusionMale circumcision provides a degree of protection against acquiring HIV infection, equivalent to what a vaccine of high efficacy would have achieved. Male circumcision may provide an important way of reducing the spread of HIV infection in sub-Saharan Africa. (Preliminary and partial results were presented at the International AIDS Society 2005 Conference, on 26 July 2005, in Rio de Janeiro, Brazil.)

Objective To assess the impact of Stepping Stones, a HIV prevention programme, on incidence of HIV and herpes simplex type 2 (HSV-2) and sexual behaviour.Design Cluster randomised controlled trial.Setting 70 villages (clusters) in the Eastern Cape province of South Africa.Participants 1360 men and 1416 women aged 15-26 years, who were mostly attending schools.Intervention Stepping Stones, a 50 hour programme, aims to improve sexual health by using participatory learning approaches to build knowledge, risk awareness, and communication skills and to stimulate critical reflection. Villages were randomised to receive either this or a three hour intervention on HIV and safer sex. Interviewers administered questionnaires at baseline and 12 and 24 months and blood was tested for HIV and HSV-2.Main outcome measures Primary outcome measure: incidence of HIV. Other outcomes: incidence of HSV-2, unwanted pregnancy, reported sexual practices, depression, and substance misuse.Results There was no evidence that Stepping Stones lowered the incidence of HIV (adjusted incidence rate ratio 0.95, 95% confidence interval 0.67 to 1.35). The programme was associated with a reduction of about 33% in the incidence of HSV-2 (0.67, 0.46 to 0.97; P=0.036)-that is, Stepping Stones reduced the number of new HSV-2 infections over a two year period by 34.9 (1.6 to 68.2) per 1000 people exposed. Stepping Stones significantly improved a number of reported risk behaviours in men, with a lower proportion of men reporting perpetration of intimate partner violence across two years of follow-up and less transactional sex and problem drinking at 12 months. In women desired behaviour changes were not reported and those in the Stepping Stones programme reported more transactional sex at 12 months.

IL-18 is synthesized as a precursor molecule without a signal peptide but requires the IL-1beta converting enzyme (ICE, caspase-1) for cleavage into a mature peptide. Human precursor IL-18 was expressed, purified, and cleaved by ICE into a 18-kD mature form. Mature IL-18 induced IL-8, macrophage inflammatory protein-1alpha, and monocyte chemotactic protein-1 in human peripheral blood mononuclear cells in the absence of any co-stimuli. Blocking IL-1 with IL-1 receptor antagonist resulted in a 50% reduction in IL-8. Neutralization of TNF with TNF binding protein resulted in a 66% reduction in IL-1beta, an 80% reduction of IL-8, and an 88% reduction in mean TNFalpha mRNA. In purified CD14+ cells but not CD3+/CD4+, IL-18 induced gene expression and synthesis of IL-8 and IL-1beta. TNFalpha production was induced in the non-CD14+ population and there was no induction of TNFbeta by IL-18. In purified natural killer cells, IL-18 induced IL-8 that was also inhibited by TNF binding protein. IL-18 did not induce antiinflammatory cytokines, IL-1Ra, or IL-10, although IL-18 induction of TNFalpha was inhibited by IL-10. In the presence of IFNgamma, IL-18-induced TNFalpha was enhanced and there was an increase in the mature form of IL-1beta. We conclude that IL-18 possesses proinflammatory properties by direct stimulation of gene expression and synthesis of TNFalpha from CD3+/CD4+ and natural killer cells with subsequent production of IL-1beta and IL-8 from the CD14+ population.

Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C. Methods This phase IIb double-blind, randomized test-of-concept study was conducted in sexually active HIV-1 sero-negative participants in SA. The co-primary endpoints were a vaccine-induced reduction in HIV-1 acquisition or viral-load setpoint. These were assessed independently in the modified intent-to-treat (MITT) cohort with two-tailed significance tests stratified by gender. Immunogenicity was assessed by interferon-gamma (IFNγ) ELISPOT in peripheral blood mononuclear cells. Following the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrollment and vaccination in this study was halted, treatment unblinding occurred and follow-up continued. This study is registered with the SA National Health Research Database (DOH-27-0207-1539) and ClinicalTrials.gov (NCT00413725). Results 801 of a scheduled 3000 participants were enrolled, of whom 360 (44.9%) were women, more than half (55.6%) had Ad5 titres > 200, and almost a third (29.3%) of men were circumcised. 62 MITT participants were diagnosed with HIV-1, 34 in the vaccine arm and 28 in the placebo arm, with infection rates of 4.54 and 3.70 per 100 person-years, respectively. There was no evidence of vaccine efficacy (VE); the hazard ratio adjusted for gender was 1.25 (95% CI: 0.76, 2.05). VE did not differ by Ad5 titre, gender, age, HSV-2 status, or circumcision. The geometric mean viral load setpoint was 20,483 copies/ml (N=33) in vaccinees and 34,032 copies/ml (N=28) in placebo recipients (p=0.39). The vaccine elicited IFNγ-secreting T cells recognizing both clade B (89.2%) and C (77.4%) antigens. Conclusion The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint however early stopping likely compromised our ability to draw conclusions. The high incidence rates seen in SA highlight the critical need for intensified efforts to develop an efficacious vaccine.

Interleukin (IL)-18, formerly called interferon ␥ (IFN-␥)-inducing factor, is biologically and structurally related to IL-1␤. A comparison of gene expression, synthesis, and processing of IL-18 with that of IL-1␤ was made in human peripheral blood mononuclear cells (PBMCs) and in human whole blood. Similar to IL-1␤, the precursor for IL-18 requires processing by caspase 1. In PBMCs, mature but not precursor IL-18 induces IFN-␥; in whole human blood stimulated with endotoxin, inhibition of caspase 1 reduces IFN-␥ production by an IL-1␤-independent mechanism. Unlike the precursor for IL-1␤, precursor for IL-18 was expressed constitutively in PBMCs and in fresh whole blood from healthy human donors. Western blotting of endotoxinstimulated PBMCs revealed processed IL-1␤ in the supernatants via an caspase 1-dependent pathway. However, in the same supernatants, only unprocessed precursor IL-18 was found. Unexpectedly, precursor IL-18 was found in freshly obtained PBMCs and constitutive IL-18 gene expression was present in whole blood of healthy donors, whereas constitutive IL-1␤ gene expression is absent. Similar to human PBMCs, mouse spleen cells also constitutively contained the preformed precursor for IL-18 and expressed steady-state IL-18 mRNA, but there was no IL-1␤ protein and no spontaneous gene expression for IL-1␤ in these same preparations. We conclude that although IL-18 and IL-1␤ are likely members of the same family, constitutive gene expression, synthesis, and processing are different for the two cytokines.

IPV was strongly associated with most of the identified HIV risk factors. Our findings provide further evidence of links between IPV and HIV among women and the importance of joint prevention.

Objectives-to describe prevalence of childhood experiences of adversity in rural South African youth and their associations with health outcomes.Methods-we analysed questionnaires and blood specimens collected during a baseline survey for a cluster randomized controlled trial of behavioral intervention, and also tested blood HIV and herpes simplex type 2 virus at 12 and 24 month follow up; 1,367 male and 1,415 female volunteers were recruited from 70 rural villages. CI 0.99, 4.72, p=0.05), and incident HSV2 infections (IRR 1.62, 95% CI 1.01, 2.59, p=0.04). In men emotional neglect was associated with depression (aOR 3.41 (95% CI1.87, 6.20, p<0.0001) and drug use (aOR 1.98 (95% CI 1.37, 2.88, p<0.0001). Sexual abuse was associated with alcohol abuse in men (aOR 3.68 (95% CI2.00, 6.77, p<0.0001) and depression (aOR 2.16 (95% CI1.34, 3.48, p=0.002) and alcohol abuse in women (aOR 3.94 (95% CI 1.90, 8.17, p<0.0001). Results-BothPractice implications-Childhood exposure to adversity is very common and influences the health of women and men. All forms of adversity, emotional, physical and sexual, enhance the risk of adverse health outcomes in men and women. Prevention of child abuse need to be included as part

Summary Background The incidence of HIV infection in young women in Africa is very high. We did a large-scale community-wide phylogenetic study to examine the underlying HIV transmission dynamics and the source and consequences of high rates of HIV infection in young women in South Africa. Methods We did a cross-sectional household survey of randomly selected individuals aged 15–49 years in two neighbouring subdistricts (one urban and one rural) with a high burden of HIV infection in KwaZulu-Natal, South Africa. Participants completed structured questionnaires that captured general demographic, socioeconomic, psychosocial, and behavioural data. Peripheral blood samples were obtained for HIV antibody testing. Samples with HIV RNA viral load greater than 1000 copies per mL were selected for genotyping. We constructed a phylogenetic tree to identify clusters of linked infections (defined as two or more sequences with bootstrap or posterior support ≥90% and genetic distance ≤4.5%). Findings From June 11, 2014, to June 22, 2015, we enrolled 9812 participants, 3969 of whom tested HIV positive. HIV prevalence (weighted) was 59.8% in 2835 women aged 25–40 years, 40.3% in 1548 men aged 25–40 years, 22.3% in 2224 women younger than 25 years, and 7.6% in 1472 men younger than 25 years. HIV genotyping was done in 1589 individuals with a viral load of more than 1000 copies per mL. In 90 transmission clusters, 123 women were linked to 103 men. Of 60 possible phylogenetically linked pairings with the 43 women younger than 25 years, 18 (30.0%) probable male partners were younger than 25 years, 37 (61.7%) were aged 25–40 years, and five (8.3%) were aged 41–49 years: mean age difference 8.7 years (95% CI 6.8–10.6; p<0.0001). For the 92 possible phylogenetically linked pairings with the 56 women aged 25–40 years, the age difference dropped to 1.1 years (95% CI –0.6 to 2.8; p=0.111). 16 (39.0%) of 41 probable male partners linked to women younger than 25 years were also linked to women aged 25–40 years. Of 79 men (mean age 31.5 years) linked to women younger than 40 years, 62 (78.5%) were unaware of their HIV-positive status, 76 (96.2%) were not on antiretroviral therapy, and 29 (36.7%) had viral loads of more than 50 000 copies per mL. Interpretation Sexual partnering between young women and older men, who might have acquired HIV from women of similar age, is a key feature of the sexual networks driving transmission. Expansion of treatment and combination prevention strategies that include interventions to address age-disparate sexual partnering is crucial to reducing HIV incidence and enabling Africa to reach the goal of ending AIDS as a public health threat. Funding President’s Emergency Program for AIDS Relief, US Centers for Disease Control and Prevention, South African Medical Research Council, and MAC AIDS Fund.