Insertive condom-protected and condomless vaginal sex both have a profound impact on the penile immune correlates of HIV susceptibility

The penis is the primary site of HIV acquisition in heterosexual men. Elevated penile inflammatory cytokines increase sexual acquisition risk, and topically applied cytokines enhance foreskin HIV susceptibility in an explant model. However, the impact of penile-vaginal sex on these immune parameters is undefined. Heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the collection of penile swabs, semen, cervico-vaginal secretions, and blood after a period of abstinence, and repeated sampling up to 72 hours after either condomless (n = 30) or condom-protected (n = 8) penile-vaginal sex. Soluble immune parameters were quantified by multiplex immunoassay. Co-primary immune endpoints were penile levels of IL-8 and MIG, cytokines previously linked to penile HIV acquisition. One hour after sex there were dramatic increases in penile IL-8 and MIG levels, regardless of condom use, with a gradual return to baseline by 72 hours; similar patterns were observed for other chemoattractant chemokines. Penile cytokine changes were similar in circumcised and uncircumcised men, and repeated measures ANOVA and ANCOVA models demonstrated that the degree of change after condomless sex was explained by cytokine levels in their partners’ cervico-vaginal secretions. This may have important implications for the biology of penile HIV acquisition.

CAPRISA 018: a phase I/II clinical trial study protocol to assess the safety, acceptability, tolerability and pharmacokinetics of a sustained-release tenofovir alafenamide subdermal implant for HIV prevention in women

IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interval for the phase II trial.The phase II component (Group 4) will assess extended safety, PK, tolerability and acceptability of the implant in 490 at risk women, randomised in a 1:1 ratio to the TAF implant and placebo tablet or to the placebo implant and an oral pre-exposure prophylaxis tablet. Safety will be assessed by calculating the percentage change in creatinine clearance from baseline at weeks 4, 12, 24, 36, 72, 96 and 120, compared with the percentage change in the control group.Ethics and disseminationThe South African Health Products Regulatory Authority and the University of KwaZulu-Natal’s Biomedical Research Ethics Committee have approved the trial. Results will be disseminated through open access peer reviewed publications, conference presentations, public stakeholder engagement and upload of data into the clinical trials registry.Trial registration numberPACTR201809520959443.

A comparison of two population-based household surveys in Uganda for assessment of violence against youth

Violence is associated with health-risk behaviors, potentially contributing to gender-related HIV incidence disparities in sub-Saharan Africa. Previous research has demonstrated that violence, gender, and HIV are linked via complex mechanisms that may be direct, such as through forced sex, or indirect, such as an inability to negotiate safe sex. Accurately estimating violence prevalence and its association with HIV is critical in monitoring programmatic efforts to reduce both violence and HIV. We compared prevalence estimates of violence in youth aged 15–24 years from two Ugandan population-based cross-sectional household surveys (Uganda Violence Against Children Survey 2015 [VACS] and Uganda Population-based HIV Impact Assessment 2016–2017 [UPHIA]), stratified by gender. UPHIA violence estimates were consistently lower than VACS estimates, including lifetime physical violence, recent intimate partner physical violence, and lifetime sexual violence, likely reflecting underestimation of violence in UPHIA. Multiple factors likely contributed to these differences, including the survey objectives, interviewer training, and questionnaire structure. VACS may be better suited to estimate distal determinants of HIV acquisition for youth (including experience of violence) than UPHIA, which is crucial for monitoring progress toward HIV epidemic control.

Human Immunodeficiency Virus Preexposure Prophylaxis in Adolescents and Young Adults

Human immunodeficiency virus (HIV) prevention holds the promise of decreasing the burden of HIV infections worldwide. Access to HIV prevention services, including preexposure prophylaxis (PrEP), is a key strategy in reducing HIV transmission, but it continues to be underused. PrEP, a once-daily medication for HIV prevention, is approved for adolescents. A pediatrician’s role is critical in identifying and increasing access for adolescents and young adults to PrEP services and reducing HIV acquisition in youth.

Mycobacterium tuberculosis infection, immune activation, and risk of HIV acquisition

BackgroundAlthough immune activation is associated with HIV acquisition, the nature of inflammatory profiles that increase HIV risk, which may include responses to M. tuberculosis (Mtb) infection, are not well characterized.MethodsWe conducted a nested case-control study within the Step MRKAd5 HIV-1 vaccine study. PBMCs from the last HIV-negative sample from incident HIV cases and controls who did not acquire HIV were stimulated with Mtb-specific antigens (ESAT-6/CFP-10) and analyzed by flow cytometry with intracellular cytokine staining.Combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS) determined overall Mtb-antigen-specific T cell activation. We measured inflammatory profiles with five Correlates of TB Risk (CoR) peripheral blood transcriptomic signatures. Conditional logistic regression analyses, adjusted for known predictors of HIV acquisition, were employed to assess whether either cellular markers of TB-associated immune activation or transcriptomic predictors of TB disease states were associated with HIV acquisition.ResultsAmong 465 participants, latent Mtb infection (LTBI) prevalence (21.5% controls vs 19.1% cases, p=0.51) and Mtb antigen-specific polyfunctional CD4+ T cell COMPASS scores (aOR 0.96, 95% CI 0.77, 1.20) were not higher in those who acquired HIV. Two CoR signatures, Sweeney3 (aOR 1.38 (1.07, 1.78) per SD change) and RESPONSE5 (0.76 (0.60, 0.95)), were associated with HIV acquisition in multivariable analysis. The Sweeney3 signature best predicted odds of acquiring HIV in unadjusted and adjusted analyses, including when restricted to LTBI-negative participants.ConclusionsLTBI and Mtb polyfunctional antigen-specific CD4+ T cell immune activation were not identified as risk factors for HIV acquisition, but transcriptomic analyses demonstrated that two CoR signatures predicted HIV risk after adjustment for known behavioral and clinical risk factors. CoR signatures can demonstrate host gene expression associated with HIV acquisition, but the observed effects are likely not mediated through Mtb infection.

Impact of Dapivirine and Placebo Vaginal Rings on the Microbiota of Adolescent, Lactating, and Postmenopausal Females

Background A 25 mg dapivirine vaginal ring has been demonstrated to reduce risk of HIV acquisition in nonpregnant adult women. In this secondary analysis of studies conducted in US adolescent, lactating, and postmenopausal females, vaginal microbiota was assessed prior to and after ring use, and between dapivirine and placebo ring users. Methods Vaginal fluid swabs were collected before and after product use for the evaluation of microbiota using Nugent’s criteria, quantitative culture, and qPCR. Results Vaginal ring use did not impact bacterial vaginosis prevalence among the three populations and was associated with minimal shifts in microbiota. Adolescents in both arms demonstrated an increased prevalence of Lactobacillus crispatus and a decrease in quantity of Megasphaera lornae. Postmenopausal active and placebo ring users demonstrated an increased prevalence of lactobacilli and non-albicans yeast while dapivirine ring users demonstrated an increased prevalence of Candida albicans, and increased quantity of Group B Streptococcus (GBS) and non-albicans yeasts. Prevotella species were increased in lactating women while P. timonensis increased in prevalence and concentration among adolescent and postmenopausal women and P. bivia increased in prevalence among adolescent dapivirine ring users. Conclusions Dapivirine vaginal ring use was associated with minimal changes in the vaginal microbiota that are likely not clinically significant.

Evaluation of the impact of human immunodeficiency virus pre-exposure prophylaxis on new human immunodeficiency virus diagnoses during the COVID-19 pandemic

Aims The national PrEP programme launched in Ireland in November 2019 with tenofovir/emtricitabine free to those meeting eligibility criteria. We assessed the impact of the first year of the PrEP programme on new HIV diagnoses in the largest sexual health and HIV service in Ireland. Methods A free PrEP service was established in November 2019. We reviewed the number of new diagnoses of HIV between November 2018–2019, before the introduction of the national PrEP programme and compared this with the number of new HIV diagnosis between November 2019–2020. Results There were 95 new HIV diagnoses (63.3% MSM) between November 2018 and 2019 and 73 new HIV diagnoses (65.7% MSM) between November 2019 and 2020. There was a statistically significant decline in new HIV diagnoses between the 2 years ( P = 0.0003). 546 patients were prescribed PrEP as of December 2020.106 patients (19.4%) changed their PrEP dosing regimen due to lockdown. 178 individuals (32.6%) had a rectal infection diagnosed. Conclusion There has been a reduction in new HIV diagnoses in our cohort (although this has occurred during a global pandemic). It is too early to say if PrEP reduces late presentations of HIV based on our findings. A significant number of rectal infections were identified in the PrEP clinic suggesting ongoing risk despite pandemic restrictions. Further research into sexual practices during COVID-19 is needed to assess if this had an impact on the lower rates of HIV acquisition.

Beyond bacterial vaginosis: vaginal lactobacilli and HIV risk

HIV incidence continues to be unacceptably high in Eastern and Southern Africa, with women disproportionately affected. An increased per-contact risk of HIV acquisition among African, Caribbean, and other Black (ACB) women has been associated with the higher prevalence of bacterial vaginosis (BV) in these communities, wherein the vaginal microbiota is predominated by diverse pro-inflammatory anaerobic bacteria. However, while the vaginal microbiota in BV-free women is typically predominated by one of several different Lactobacillus spp., the degree of HIV protection afforded by a Lactobacillus-predominant vaginal microbiota also varies considerably. Specifically, L. crispatus is associated with an immunoregulatory genital immune environment, exclusion of BV-associated bacteria, and reduced HIV risk. In contrast, less HIV protection or exclusion of BV-associated bacteria and fewer immune benefits have been associated with L. iners—which is unfortunately the most common Lactobacillus species among ACB women. These species-specific clinical differences are underpinned by substantial genomic differences between Lactobacillus species: for instance, the much smaller genome of L. iners lacks the coding sequence for D-lactic acid dehydrogenase and cannot produce the D-lactate isomer that enhances HIV trapping in mucus but encodes for epithelial cell toxins and stress resistance proteins that may enhance bacterial survival in the context of microbiota and environmental fluctuations. While more studies are needed to elucidate whether differences in HIV protection between Lactobacillus species are due to direct genital immune effects or the exclusion of proinflammatory BV-associated bacteria, the current body of work suggests that for BV treatment to succeed as an HIV prevention strategy, it may be necessary to induce a vaginal microbiota that is predominated by specific (non-iners) Lactobacillus species.

Roll-out of HIV pre-exposure prophylaxis: a gateway to mental health promotion

HIV remains a pressing global health problem, with 1.5 million new infections reported globally in 2020. HIV pre-exposure prophylaxis (PrEP) can lower the likelihood of HIV acquisition among populations at elevated risk, yet its global roll-out has been discouragingly slow. Psychosocial factors, such as co-occurring mental illness and substance use, are highly prevalent among populations likely to benefit from PrEP, and have been shown to undermine persistence and adherence. In this analysis, we review the high burden of mental health problems among PrEP candidates and contend that inattention to mental health stands to undermine efforts to implement PrEP on a global scale. We conclude that integration of mental health screening and treatment within PrEP scale-up efforts represents an important strategy for maximising PrEP effectiveness while addressing the high burden of mental illness among at-risk populations. As implementers seek to integrate mental health services within PrEP services, efforts to keep access to PrEP as low-threshold as possible should be maintained. Moreover, programmes should seek to implement mental health interventions that are sensitive to local resource constraints and seek to reduce intersecting stigmas associated with HIV and mental illness.