A research and development (R&D) roadmap for broadly protective coronavirus vaccines: A pandemic preparedness strategy.

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 26 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

High HIV incidence among young women in South Africa: Data from a large prospective study.

INTRODUCTION: South Africa has the highest national burden of HIV globally. Understanding drivers of HIV acquisition in recently completed, prospective studies in which HIV was an endpoint may help inform the strategy and investments in national HIV prevention efforts and guide the design of future HIV prevention trials. We assessed HIV incidence and correlates of incidence among women enrolled in ECHO (Evidence for Contraceptive Options and HIV Outcomes), a large, open-label randomized clinical trial that compared three highly effective. reversible methods of contraception and rates of HIV acquisition. METHODS: During December 2015 to October 2018, ECHO followed sexually active, HIV-seronegative women, aged 16-35 years, seeking contraceptive services and willing to be randomized to one of three contraceptive methods (intramuscular depot medroxyprogesterone acetate, copper intrauterine device, or levonorgestrel implant) for 12-18 months at nine sites in South Africa. HIV incidence based on prospectively observed HIV seroconversion events. Cox proportional hazards regression models were used to define baseline cofactors related to incident HIV infection. RESULTS: 5768 women were enrolled and contributed 7647 woman-years of follow-up. The median age was 23 years and 62.5% were ≤24 years. A total of 345 incident HIV infections occurred, an incidence of 4.51 per 100 woman-years (95%CI 4.05-5.01). Incidence was >3 per 100 woman-years at all sites. Age ≤24 years, baseline infection with sexually transmitted infections, BMI≤30, and having new or multiple partners in the three months prior to enrollment were associated with incident HIV. CONCLUSIONS: HIV incidence was high among South African women seeking contraceptive services. Integration of diagnostic management of sexually transmitted infections alongside delivery of HIV prevention options in health facilities providing contraception services are needed to mitigate ongoing risks of HIV acquisition for this vulnerable population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02550067 was the main Clinical Trial from which this secondary, non-randomized / observational analysis was derived with data limited to just South African sites.

Estimating the Population Size of Female Sex Workers in Three South African Cities: Results and Recommendations From the 2013-2014 South Africa Health Monitoring Survey and Stakeholder Consensus.

BACKGROUND: Robust population size estimates of female sex workers and other key populations in South Africa face multiple methodological limitations, including inconsistencies in surveillance and programmatic indicators. This has, consequently, challenged the appropriate allocation of resources and benchmark-setting necessary to an effective HIV response. A 2013-2014 integrated biological and behavioral surveillance (IBBS) survey from South Africa showed alarmingly high HIV prevalence among female sex workers in South Africa's three largest cities of Johannesburg (71.8%), Cape Town (39.7%), and eThekwini (53.5%). The survey also included several multiplier-based population size estimation methods. OBJECTIVE: The objective of our study was to present the selected population size estimation methods used in an IBBS survey and the subsequent participatory process used to estimate the number of female sex workers in three South African cities. METHODS: In 2013-2014, we used respondent-driven sampling to recruit independent samples of female sex workers for IBBS surveys in Johannesburg, Cape Town, and eThekwini. We embedded multiple multiplier-based population size estimation methods into the survey, from which investigators calculated weighted estimates and ranges of population size estimates for each city's female sex worker population. Following data analysis, investigators consulted civil society stakeholders to present survey results and size estimates and facilitated stakeholder vetting of individual estimates to arrive at consensus point estimates with upper and lower plausibility bounds. RESULTS: In total, 764, 650, and 766 female sex workers participated in the survey in Johannesburg, Cape Town, and eThekwini, respectively. For size estimation, investigators calculated preliminary point estimates as the median of the multiple estimation methods embedded in the IBBS survey and presented these to a civil society-convened stakeholder group. Stakeholders vetted all estimates in light of other data points, including programmatic experience, ensuring inclusion only of plausible point estimates in median calculation. After vetting, stakeholders adopted three consensus point estimates with plausible ranges: Johannesburg 7697 (5000-10,895); Cape Town 6500 (4579-9000); eThekwini 9323 (4000-10,000). CONCLUSIONS: Using several population size estimates methods embedded in an IBBS survey and a participatory stakeholder consensus process, the South Africa Health Monitoring Survey produced female sex worker size estimates representing approximately 0.48%, 0.49%, and 0.77% of the adult female population in Johannesburg, Cape Town, and eThekwini, respectively. In data-sparse environments, stakeholder engagement and consensus is critical to vetting of multiple empirically based size estimates procedures to ensure adoption and utilization of data-informed size estimates for coordinated national and subnational benchmarking. It also has the potential to increase coherence in national and key population-specific HIV responses and to decrease the likelihood of duplicative and wasteful resource allocation. We recommend building cooperative and productive academic-civil society partnerships around estimates and other strategic information dissemination and sharing to facilitate the incorporation of additional data as it becomes available, as these additional data points may minimize the impact of the known and unknown biases inherent in any single, investigator-calculated method.

Increased Access to Antiretroviral Therapy Is Associated with Reduced Maternal Mortality in Johannesburg, South Africa: An Audit from 2003-2012.

OBJECTIVE: To assess the impact of expanded access to antiretroviral treatment (ART) on maternal mortality in Johannesburg, South Africa between 2003 and 2012. METHODS: Audit of patient files, birth registers and death certificates at a tertiary level referral hospital. Cause of death was assigned independently, by two reviewers. We compared causes of deaths and the maternal mortality ratios (MMR, deaths/100,000 live births) over three periods corresponding to changes in government policy on ART provision: period one, 2003-2004 (pre-ART); period two, 2005-2009 (ART eligibility with CD4 count <200cells/µL or WHO stage 4 disease); and period three, 2010-2012 (eligibility with CD4 count <350 cells/µL). RESULTS: There were 232 deaths and 80,376 deliveries in the three periods. The proportion of pregnant women tested for HIV rose from 43.4% in 2003 to 94.6% in 2012. MMR was 301, 327 and 232 in the three periods, (p = 0.10). The third period MMR was lower than the first and second combined (p = 0.03). Among HIV-positive women, the MMR fell from 836 in the first time period to 431 in the third (p = 0.008) but among HIV negative women it remained unchanged over the three periods, averaging 148. Even in the third period, however, the MMR among HIV-infected women was 3-fold higher than in other women. Mortality from direct obstetric causes such as hemorrhage did not decline over time, but deaths from tuberculosis and HIV-associated malignancy did. In 38.3% of deaths, women had not attended antenatal care. CONCLUSION: Higher coverage of HIV testing and ART has substantially reduced MMR in this hospital setting. Though the gap in MMR between women with and without HIV narrowed, a third of deaths still remain attributable to HIV. Lowering overall MMR will require further strengthening of HIV services, increased antenatal care coverage, and improved care for obstetric emergencies at all levels of care.

Field evaluation of Standard Diagnostics' Bioline HIV/Syphilis Duo test among female sex workers in Johannesburg, South Africa.

BACKGROUND: Point-of-care tests provide immediate results with the opportunity for same-day interventions with improved public health outcomes. A dual HIV/syphilis test enables early treatment of both diseases. METHODS: We conducted a field evaluation of the Standard Diagnostics' SD Bioline HIV/Syphilis Duo test (SD Bioline) among female sex workers. SD Bioline was conducted on finger-prick blood according to manufacturer's instructions and compared with (i) Genscreen HIV1/2 (third generation) and Vironostika Ag/Ab (fourth generation) assays for HIV, and (ii) Treponema pallidum particle agglutination (TPPA) and rapid plasma reagin (RPR) assays for syphilis. A negative TPPA test was considered negative, a TPPA-confirmed RPR titre ≤1:4 as past infection and a TPPA-confirmed RPR titre ≥1:8 as active syphilis. Sensitivity, specificity, positive and negative predictive values were calculated. RESULTS: Of 263 women recruited, 14 (5.3%) declined an HIV test. Among the remaining 249 women, 187 (75.1%) were HIV positive, 51 (20.5%) had syphilis antibodies with seven (2.8%) active infections. For HIV, the sensitivity and specificity were 98.9% (95% CI 95.8% to 99.8%) and 100% (95% CI 92.7% to 100%). For syphilis, the sensitivity and specificity were 66.7% (95% CI 52.0% to 78.9%) and 98.0% (95% CI 94.5% to 99.3%). Sera with high TPPA titres were more likely to test positive. CONCLUSIONS: In field conditions, while the SD Bioline test has high sensitivity and specificity for HIV and high specificity for syphilis, the test has lower sensitivity for syphilis than reported from laboratory evaluations. As the dual test detects only two thirds of syphilis cases, it should only be used in areas with weak screening programmes.

High pregnancy intentions and missed opportunities for patient-provider communication about fertility in a South African cohort of HIV-positive women on antiretroviral therapy.

High fertility intentions amongst HIV-positive women have been reported elsewhere. Less is known about how clinical and HIV treatment characteristics correlate with fertility intentions. We use cross-sectional baseline data from a prospective cohort study to assess pregnancy intentions and patient-provider communication around fertility. Non-pregnant, HIV-positive women aged 18-35 on ART were recruited through convenience sampling at Johannesburg antiretroviral (ART) treatment facilities. Among the 850 women in this analysis, those on efavirenz had similar fertility intentions over the next year as women on nevirapine-based regimens (33% vs. 38%). In multivariate analysis, recent ART initiation was associated with higher current fertility intentions; there was no association with CD4 cell count. Forty-one percent of women had communicated with providers about future pregnancy options. Women on ART may choose to conceive at times that are sub-optimal for maternal, child and partner health outcomes and should be routinely counseled around safer pregnancy options.

Concurrent sexual partnerships and human immunodeficiency virus risk among South African youth.

BACKGROUND: To estimate the prevalence of concurrency (more than 1 sex partner overlapping in time), the attitudes/behaviors of those engaged in concurrency, length of relationship overlap, and the association between concurrency and human immunodeficiency virus (HIV) among South Africans aged 15 to 24 years. METHODS: A cross-sectional, nationally representative, household survey of HIV infection, and sexual attitudes and behaviors was conducted among 11,904 15 to 24 year old South Africans in 2003. Analyses were conducted among sexually experienced youth. RESULTS: Men were more likely to report having concurrent (24.7%) than serial partners (5.7%) in the past 12 months, but concurrency was not associated with HIV. Among women, concurrency and serial monogamy were equally common (4.7%), and concurrency, defined by respondent reports of multiple ongoing partners, was associated with HIV in multivariate analysis (odds ratio, 3.4; 95% confidence interval, 1.8-6.5). Median length of relationship overlap was approximately 4 months for women and 3 months for men. Compared to serial monogamists, concurrents reported less consistent condom use, and female concurrents were more likely to report transactional sex and problems negotiating condoms and refusing intercourse. CONCLUSIONS: Concurrency is a common partnership pattern among those youth with multiple partners, especially men. For women, having concurrent relationships may be associated with relationship power imbalances and less ability to protect against HIV. Given the prevalence and likely significance of concurrency in the spread of HIV throughout a sexual network, our findings underscore the need for prevention efforts targeting fidelity.

Enhancing global control of alcohol to reduce unsafe sex and HIV in sub-Saharan Africa.

Sub-Saharan Africa carries a massive dual burden of HIV and alcohol disease, and these pandemics are inextricably linked. Physiological and behavioural research indicates that alcohol independently affects decision-making concerning sex, and skills for negotiating condoms and their correct use. More than 20 studies in Africa have reported higher occurrence of HIV among people with problem drinking; a finding strongly consistent across studies and similar among women and men. Conflation of HIV and alcohol disease in these setting is not surprising given patterns of heavy-episodic drinking and that drinking contexts are often coterminous with opportunities for sexual encounters. HIV and alcohol also share common ground with sexual violence. Both perpetrators and victims of sexual violence have a high likelihood of having drunk alcohol prior to the incident, as with most forms of violence and injury in sub-Saharan Africa. Reducing alcohol harms necessitates multi-level interventions and should be considered a key component of structural interventions to alleviate the burden of HIV and sexual violence. Brief interventions for people with problem drinking (an important component of primary health care), must incorporate specific discussion of links between alcohol and unsafe sex, and consequences thereof. Interventions to reduce alcohol harm among HIV-infected persons are also an important element in positive-prevention initiatives. Most importantly, implementation of known effective interventions could alleviate a large portion of the alcohol-attributable burden of disease, including its effects on unsafe sex, unintended pregnancy and HIV transmission.

Bone mineral density in young women aged 19-24 after 4-5 years of exclusive and mixed use of hormonal contraception.

BACKGROUND: Use of depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) and low-dose combined oral contraceptives (COCs) has been associated with loss of bone mineral density (BMD) in adolescents. However, the effect of using a combination of these methods over time in this age group is limited. The aim of this cross-sectional study was to investigate BMD in young women (aged 19-24 years) with a history of mixed hormonal contraceptive use. STUDY DESIGN: BMD was measured at the spine, hip and femoral neck using dual X-ray absorptiometry. Women were classified into three groups: (1) injectable users (DMPA, NET-EN or both) (n=40), (2) mixed COC and injectable users (n=13) and (3) non-user control (n=41). RESULTS: Women in the injectables-only user group were found to have lower BMDs compared to the non-user group at all three sites, and there was evidence of a difference in BMD between these two groups at the spine after adjusting for body mass index (p=.042), hip (p=.025) and femoral neck (p=.023). The mixed COC/injectable user group BMD values were lower than those for controls; however, there was no evidence of a significant difference between this group and the non-user group at any of the three sites. CONCLUSION: This study suggests that BMD is lower in long-term injectable users but not when women have mixed injectable and COC use.

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

OBJECTIVES: To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. METHODS: Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. RESULTS: Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. CONCLUSION: Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

Sexual violence and reproductive health outcomes among South African female youths: a contextual analysis.

OBJECTIVES: We studied whether female youths from communities with higher sexual violence were at greater risk of negative reproductive health outcomes. METHODS: We used data from a 2003 nationally representative household survey of youths aged 15-24 years in South Africa. The key independent variable was whether a woman had ever been threatened or forced to have sex. We aggregated this variable to the community level to determine, with control for individual-level experience with violence, whether the community-level prevalence of violence was associated with HIV status and adolescent pregnancy among female, sexually experienced, never-married youths. RESULTS: Youths from communities with greater sexual violence were significantly more likely to have experienced an adolescent pregnancy or to be HIV-positive than were youths from communities experiencing lower sexual violence. Youths from communities with greater community-level violence were also less likely to have used a condom at their last sexual encounter. Individual-level violence was only associated with condom nonuse. CONCLUSIONS: Programs to reduce adolescent pregnancies and HIV risk in South Africa and elsewhere in sub-Saharan Africa must address sexual violence as part of effective prevention strategies.

Vulnerability of women in southern Africa to infection with HIV: biological determinants and priority health sector interventions.

OBJECTIVE: To review biomedical determinants of women's vulnerability to infection with HIV and interventions to counter this, within the southern African context. RESULTS: Apart from number of exposures, if any, several factors influence the efficiency of HIV transmission during sex. Acute HIV infection, with extraordinarily high semen viral load, in conjunction with concurrent partnerships maximizes this efficiency. Delaying sexual debut and avoiding HIV exposure among biologically and socially vulnerable youth is critical. Reducing unintended pregnancies keeps girls in school and prevents vertical (also possibly horizontal) transmission. Female condoms, especially newer versions, are an under-exploited prevention technology. Control of sexually transmitted infections (STI), which facilitate HIV acquisition and transmission, remains important, especially among the most at-risk populations. Pathogens, such as herpes simplex virus type 2, which contribute most to HIV transmission in southern Africa must be targeted, although the importance of bacterial vaginosis and Trichomonas vaginalis is under-recognized. Also, heavy episodic alcohol use affects sexual decision-making and condom skills. Moreover, prevailing social contexts, partly a consequence of poor leadership, constrain the behavioural 'choices' available for girls and women. CONCLUSIONS: Priority health sector interventions for preventing HIV are: male and female condom programming; prevention and control of STI; outreach to most vulnerable populations; HIV testing in all patient-provider encounters; male circumcision; and the integration of HIV prevention within sexual and reproductive health services. Future interventions during acute HIV infection and microbicides will reduce women's biological vulnerability. Far-reaching measures, such as sexual equity and alcohol control, create conditions necessary for achieving sustained prevention results. These are, however, contingent on stronger, more informed cultural and political leadership.

Keep them in school: the importance of education as a protective factor against HIV infection among young South African women.

OBJECTIVE: To identify risk factors for HIV infection among young women aged 15-24 years reporting one lifetime partner in South Africa. Design In 2003, we conducted a nationally representative household survey of sexual behaviour and HIV testing among 11 904 young people aged 15-24 years in South Africa. This analysis focuses on the subset of sexually experienced young women with only one reported lifetime sex partner (n = 1708). METHODS: Using the proximate determinants framework and the published literature we identified factors associated with HIV in young women. The associations between these factors and HIV infection were explored in multivariable logistic regression models. RESULTS: Of the young women, 15% reporting one lifetime partner were HIV positive. In multivariable analyses, young women who had not completed high school were more likely to be infected with HIV compared with those that had completed high school (AOR 3.75; 95% CI 1.34-10.46). CONCLUSIONS: Young South African women in this population were at high risk of HIV infection despite reporting only having one lifetime partner. Few individual level factors were associated with HIV infection, emphasizing the importance of developing HIV prevention interventions that address structural and partner level risk factors.

Contraception use and pregnancy among 15-24 year old South African women: a nationally representative cross-sectional survey.

BACKGROUND: Adolescent reproductive health has not continued to receive the attention it deserves since the start of the HIV epidemic. In South Africa, high numbers of adolescent women report pregnancies that are unwanted and yet few have accessed available termination of pregnancy services. Enabling contraception use is vital for meeting the goals of HIV prevention. METHODS: A nationally representative survey of South African 15-24 year olds was undertaken. Participants completed a questionnaire on sexual behaviour and provided an oral fluid sample for HIV testing. Analysis of the data was restricted to women (n = 6217), particularly those who reported being sexual active in the last 12 months (n = 3618) and was conducted using svy methods in the program STATA 8.0 to take account of sampling methods. Univariate and multivariate analyses were conducted to explore factors associated with contraceptive use. RESULTS: Two thirds of all women reported having ever been sexually active and among these 87% were sexually active in the past 12 months. Among women who reported currently being sexually active, 52.2% reported using contraceptives. There was evidence of association between contraceptive use and being employed or a student (vs unemployed); fewer sex partners; type of last sex partner; having talked to last partner about condom use and having ever been pregnant. CONCLUSION: Specific emphasis must be placed on encouraging young women to use contraceptive methods that offer protection against pregnancy and STIs/HIV. Our consistent finding of a relationship between discussing condom use with partners and condom use indicates the importance of involvement of male partners in women's contraceptive decisions.

Predictors of condom use among young adults in South Africa: the Reproductive Health and HIV Research Unit National Youth Survey.

OBJECTIVES: We examined correlates of condom use among a national random probability sample of sexually experienced young adults aged 15 to 24 years (n = 7686) in South Africa. METHODS: Using data from the Reproductive Health and HIV Research Unit National Youth Survey, we conducted gender-stratified bivariate and multivariate logistic regression analyses to determine predictors of whether respondents had used a condom during their most recent sexual intercourse. RESULTS: Condom use at sexual debut and talking with one's first sexual partner about condoms were the most significant predictors of condom use at most recent intercourse. Other significant predictors included high condom use self-efficacy, optimism about the future, and reported behavior change attributable to HIV/AIDS. Young adults who were married or had been involved in a relationship for 6 months or more were significantly less likely to have used a condom during their most recent sexual intercourse. CONCLUSIONS: Our findings point to the importance of exposing youths to sexuality education before their sexual debut as well as voluntary counseling and testing and programming that supports young adults, particularly young women, in making informed decisions about sexual intercourse and condoms.

Highly efficient HIV transmission to young women in South Africa.

BACKGROUND: Young women in sub-Saharan Africa are at very high risk of HIV acquisition, and high prevalence levels have been observed among women reporting one lifetime partner and few sexual contacts. Such findings have led to hypotheses that the probability of HIV transmission from men to women must be far higher than previously appreciated. METHODS: We used the data from a cross-sectional national household survey of HIV among South African women aged 15-24 years to estimate the per-partnership transmission probability from men to women. Estimates were obtained using maximum likelihood methods and a transmission probability model allowing for random error in the self-reported number of lifetime partners. Sensitivity analyses were employed to assess the robustness of the per-partnership transmission probability estimates to the assumed HIV prevalence in male partners. RESULTS: HIV prevalence in women was 21.2% (95% confidence interval 17.9-24.5). The mean reported number of lifetime partners was 2.3. A significant increase in prevalence was observed with increasing lifetime partner numbers (P = 0.02). For a range of plausible values of the partner prevalence, the estimated per-partnership transmission probability varied from 0.74 to 1.00 with 95% confidence intervals ranging from 0.56 to 1.00. DISCUSSION: The per-partnership probability of HIV transmission from men to women in this population was very high. Before this, the majority of studies examining per-partnership transmission probabilities estimated values below 50%. Identifying the factors that may drive the efficient spread of HIV in sub-Saharan Africa is essential for the development of effective prevention interventions.

Challenge of evaluating a national HIV prevention programme: the case of loveLife, South Africa.

Although 50% of all new global HIV infections occur among young people, our knowledge to date of the impact of adolescent HIV prevention interventions in developing country settings is limited. During 1999, a national HIV prevention programme for youth, called loveLife, was launched in South Africa. This paper describes the challenges faced in trying to evaluate such a national programme and the types of evidence that could be used to better understand the effect of programmes of national scale. A range of methods were planned to evaluate the programme, including national household surveys and programme monitoring data. Given the urgent need to scale-up programmes in an effort to reduce new HIV infections, a range of evidence should be assessed to measure the effect of large-scale, complex behavioural interventions as an alternative to randomised controlled trials.

Factors associated with self-efficacy for condom use and sexual negotiation among South african youth.

OBJECTIVES: To use logistic regression modeling to identify factors associated with high self-efficacy for sexual negotiation and condom use in a sample of South African youth. METHODS: The Reproductive Health and HIV Research Unit (RHRU) National Youth Survey examined a nationally representative sample of 7409 sexually active South African youth aged 15 to 24 years. We used logistic regression modeling in this sample to identify factors associated with the main outcome of high self-efficacy. RESULTS: Among female respondents (n = 3890), factors associated with high self-efficacy in the adjusted model were knowing how to avoid HIV (odds ratio [OR] = 2.30, 95% confidence interval [CI]: 1.05 to 5.00), having spoken with someone other than a parent or guardian about HIV/AIDS (OR = 1.46, 95% CI: 1.01 to 2.10), and having life goals (OR = 1.28, 95% CI: 1.10 to 1.48). Not using condoms during their first sexual encounter (OR = 0.61, 95% CI: 0.50 to 0.76), a history of unwanted sex (OR = 0.66, 95% CI: 0.51 to 0.86), and believing that condom use implies distrust in one's partner (OR = 0.57, 95% CI: 0.51 to 0.86) were factors associated with low self-efficacy among female respondents. Male respondents (n = 3519) with high self-efficacy were more likely to take HIV seriously (OR = 4.03, 95% CI: 1.55 to 10.52), to believe they are not at risk for HIV (OR = 1.38, 95% CI: 1.12 to 1.70), to report that getting condoms is easy (OR = 1.85, 95% CI: 1.23 to 2.77), and to have life goals (OR = 1.30, 95% CI: 1.10 to 1.54). Not using condoms during their first sexual experience (OR = 0.51, 95% CI: 0.39 to 0.67), a history of having unwanted sex (OR = 0.47, 95% CI: 0.34 to 0.64), believing condom use is a sign of not trusting one's partner (OR = 0.63, 95% CI: 0.46 to 0.87), and refusing to be friends with HIV-infected persons (OR = 0.52, 95% CI: 0.32 to 0.85) were factors associated with low self-efficacy among male respondents in the fully adjusted model. CONCLUSIONS: We used the social cognitive model (SCM) to identify factors associated with self-efficacy for condom use and sexual negotiation. Many of these factors are modifiable and suggest potential ways to improve self-efficacy and reduce HIV sexual risk behavior in South African youth.