Strategies to Close the PrEP Uptake Gap Among Transgender People and Men Who Have Sex with Men in Tshwane, South Africa: Perspectives from the Community.

HIV Pre-exposure Prophylaxis (PrEP) uptake among transgender (TG) people and gay men and other men who have sex with men (MSM) remains low, despite South Africa being the first African country to approve PrEP. This mixed-methods study used a two-phase explanatory sequential design: (1) quantitative analysis of cross-sectional surveys followed by (2) qualitative in-depth interviews. This study explored facilitators and barriers to PrEP uptake to identify strategies to increase utilization in these key populations. We conducted 202 cross-sectional surveys and 20 in-depth interviews between July 2021 and March 2022 in Soshanguve, Tshwane, Gauteng. Quantitative data were analyzed using univariate logistic regression; thematic analysis was performed for qualitative data. Findings show high willingness to use PrEP but low PrEP uptake. We outline strategies to facilitate PrEP use: (1) demystify daily PrEP by deploying community-engaged PrEP education campaigns; (2) capitalize on existing peer networks; and (3) expand accessible and culturally responsive PrEP service delivery models. We provide feasible recommendations to close the PrEP uptake gap in these key populations in South Africa.

Incidence of Respiratory Syncytial Virus-Associated Lower Respiratory Tract Illness in Infants in Low- and Middle-Income Regions During the Coronavirus Disease 2019 Pandemic.

Background: Incidence data of respiratory syncytial virus-associated lower respiratory tract illness (RSV-LRTI) are sparse in low- and middle-income countries (LMICs). We estimated RSV-LRTI incidence rates (IRs) in infants in LMICs using World Health Organization case definitions. Methods: This prospective cohort study, conducted in 10 LMICs from May 2019 to October 2021 (largely overlapping with the coronavirus disease 2019 [COVID-19] pandemic), followed infants born to women with low-risk pregnancies for 1 year from birth using active and passive surveillance to detect potential LRTIs, and quantitative reverse-transcription polymerase chain reaction on nasal swabs to detect RSV. Results: Among 2094 infants, 32 (1.5%) experienced an RSV-LRTI (8 during their first 6 months of life, 24 thereafter). Seventeen (0.8%) infants had severe RSV-LRTI and 168 (8.0%) had all-cause LRTI. IRs (95% confidence intervals [CIs]) of first RSV-LRTI episode were 1.0 (.3-2.3), 0.8 (.3-1.5), and 1.6 (1.1-2.2) per 100 person-years for infants aged 0-2, 0-5, and 0-11 months, respectively. IRs (95% CIs) of the first all-cause LRTI episode were 10.7 (8.1-14.0), 11.7 (9.6-14.0), and 8.7 (7.5-10.2) per 100 person-years, respectively. IRs varied by country (RSV-LRTI: 0.0-8.3, all-cause LRTI: 0.0-49.6 per 100 person-years for 0- to 11-month-olds). Conclusions: RSV-LRTI IRs in infants in this study were relatively low, likely due to reduced viral circulation caused by COVID-19-related nonpharmaceutical interventions. Clinical Trials Registration: NCT03614676.

Prevalence and incidence of sexually transmitted infections among South African women initiating injectable and long-acting contraceptives.

BACKGROUND: South Africa is among the countries with the highest prevalence of sexually transmitted infections (STIs), including Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). In 2017, there were an estimated 6 million new CT, 4.5 million NG and 71 000 Treponema pallidum infections among South African men and women of reproductive age. METHODS: We evaluated STI prevalence and incidence and associated risk factors in 162 women aged 18-33 years old, residing in eThekwini and Tshwane, South Africa who were part of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial. Women were randomised to use depot medroxyprogesterone acetate (n = 53), copper intrauterine device (n = 51), or levonorgestrel (n = 58) implant. Lateral vaginal wall swab samples were collected prior to contraceptive initiation and at months one and three following contraceptive initiation for STI testing. RESULTS: There were no significant differences in STI incidence and prevalence across contraceptive groups. At baseline, 40% had active STIs (CT, NG, Trichomonas vaginalis (TV), Mycoplasma genitalium (MG) or herpes simplex virus-2 shedding across all age groups- 18-21 years (46%), 22-25 years (42%) and 26-33 years (29%). The incidence of STIs during follow-up was exceptionally high (107.9/100 women-years [wy]), with younger women (18-21 years) more likely to acquire CT (75.9/100 wy) compared to 26-33 year olds (17.4/100 wy; p = 0.049). TV incidence was higher in the 26-33 year old group (82.7/100 wy) compared to the 18-21 year olds (8.4/100 wy; p = 0.01). CONCLUSIONS: Although the study participants received extensive counselling on the importance of condom use, this study highlights the high prevalence and incidence of STIs in South African women, especially amongst young women, emphasising the need for better STI screening and management strategies.

The Importance of the Individual in PrEP Uptake: Multilevel Correlates of PrEP Uptake Among Adolescent Girls and Young Women in Tshwane, South Africa.

Adolescent girls and young women (AGYW) account for 25% of new HIV infections in South Africa. Pre-exposure prophylaxis (PrEP) is approved by the South African Government, but the factors that promote PrEP uptake among AGYW are not well understood. This study examines multilevel factors associated with PrEP uptake among AGYW in six clinic catchment areas in Tshwane (Pretoria), South Africa. After consent/assent, PrEP-eligible AGYW (n = 448) completed a questionnaire assessing factors at the individual, network/interpersonal, and community levels and were prescribed PrEP in study clinics, if interested. A multivariable model, adjusting for clustering, assessed factors associated with PrEP uptake over a 9-month period. At the individual level, multiple partners in the past 3 months (OR = 0.47), perceived risk of HIV (OR = 0.71), and PrEP-related shame (OR = 0.63) were correlated with lower odds of PrEP uptake (ps ≤ 0.05). The findings highlight modifiable factors that should be addressed to support PrEP uptake efforts.

ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19.

Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19.

Efficacy of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination against SARS-CoV-2 variants of concern: Final analysis of a randomized, placebo-controlled, phase 1b/2 study in South African adults (COV005).

COVID-19 vaccine efficacy (VE) has been observed to vary against antigenically distinct SARS-CoV-2 variants of concern (VoC). Here we report the final analysis of VE and safety from COV005: a phase 1b/2, multicenter, double-blind, randomized, placebo-controlled study of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination in South African adults aged 18-65 years. South Africa's first, second, and third waves of SARS-CoV-2 infections were respectively driven by the ancestral SARS-CoV-2 virus (wild type, WT), and SARS-CoV-2 Beta and Delta VoCs. VE against asymptomatic and symptomatic infection was 90.6% for WT, 6.7% for Beta and 77.1% for Delta. No cases of severe COVID-19 were documented ahead of unblinding. Safety was consistent with the interim analysis, with no new safety concerns identified. Notably, South Africa's Delta wave occurred ≥ 9 months after primary series vaccination, suggesting that primary series AZD1222 vaccination offers a good durability of protection, potentially due to an anamnestic response. Clinical trial identifier: CT.gov NCT04444674.

Clinical outcomes of intrauterine device insertions by newly trained providers: The ECHO trial experience.

Objectives: To assess the rates of failed insertion, expulsion, and perforation when intrauterine device (IUD) insertions were done by newly trained clinicians, and to examine factors that may affect these outcomes. Study design: We evaluated skill-based outcomes following IUD insertion at 12 African sites in a secondary analysis of the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial. Before trial initiation, we provided competency-based IUD training to clinicians and offered ongoing clinical support. We used Cox proportional hazards regression to examine factors associated with expulsion. Results: Among 2582 IUD acceptors who underwent first attempted IUD insertion, 141 experienced insertion failure (5.46%) and seven had uterine perforation (0.27%). Perforation was more common among breastfeeding women within three months postpartum (0.65%) compared with non-breastfeeding women (0.22%). We recorded 493 expulsions (15.5 per 100 person-years, 95% confidence interval [CI] 14.1─16.9): 383 partial and 110 complete. The risk of IUD expulsion was lower among women older than 24 years (aHR 0.63, 95% CI 0.50─0.78) and may be higher among nulliparous women. (aHR 1.65, 95% CI 0.97─2.82). Breastfeeding (aHR 0.94, 95% CI 0.72─1.22) had no significant effect on expulsion. IUD expulsion rate was highest during the first three months of the trial. Conclusions: IUD insertion failure and uterine perforation rates in our study were comparable to those reported in the literature. These results suggest that training, ongoing support, and opportunities to apply new skills were effective in ensuring good clinical outcomes for women receiving IUD insertion by newly trained providers. Implications: Data from this study support recommendations to program managers, policymakers, and clinicians that IUDs can be inserted safely in resource-constrained settings when providers receive appropriate training and support.

Prospective acceptability of a multipurpose technology (MPT) implant in preclinical development to prevent HIV and unplanned pregnancy: Qualitative insights from women end users and health care providers in South Africa and Zimbabwe.

BACKGROUND: Given the high rates of both HIV and unintended pregnancies in sub-Saharan Africa, the SCHIELD program aims to develop a multipurpose technology implant for HIV and pregnancy prevention. An end-user evaluation was undertaken with young women and health care providers to assess preferences for modifiable implant attributes to improve future adoption and rollout. METHODS: Focus group discussions were conducted with potential women end users, and health care providers experienced in implant insertion or removal participated in in-depth interviews. All participants were recruited from Harare, Zimbabwe, or Soshanguve, South Africa. The purposively stratified sampled women were either implant experienced or implant naïve and were categorized into three groups: nulliparous, postpartum, or engaged in transactional sex. Topics covered included duration (six months to three years), biodegradability, removability, and independent rod retrievability (per indication). Data were analyzed using Dedoose software and summarized into emerging themes. RESULTS: Participants identified three key areas that could facilitate rollout, uptake, and adherence of an implant for HIV and pregnancy prevention. First, discreetness was the most salient topic and was associated with implant characteristics such as anatomical location, flexibility, and biodegradability. Second, the ability to independently retrieve the HIV or pregnancy prevention component was preferred, as life circumstances may change and was favored by all participants, except for young women in Soshanguve. Third, there is a need for proper counseling, sensitization, provider training, and health campaigns to facilitate rollout of a 2-in-1 implant. CONCLUSIONS: A 2-in-1 implant was seen as highly desirable by most young women and health care providers. Participants discussed potential concerns and barriers to uptake of a biodegradable implant with dual HIV prevention and contraceptive properties, identifying key implant attributes that product developers can modify while still in preclinical stages.

Incorporating end-users' voices into the development of an implant for HIV prevention: a discrete choice experiment in South Africa and Zimbabwe.

BACKGROUND: Input from end-users during preclinical phases can support market fit for new HIV prevention technologies. With several long-acting pre-exposure prophylaxis (PrEP) implants in development, we aimed to understand young women's preferences for PrEP implants to inform optimal design. METHODS: We developed a discrete choice experiment and surveyed 800 young women in Harare, Zimbabwe and Tshwane, South Africa between September-November 2020. Women aged 18-30 years who were nulliparous, postpartum, or exchanged sex for money, goods or shelter in prior year were eligible; quotas were set for each subgroup. The DCE asked participants to choose between two hypothetical implants for HIV prevention in a series of nine questions. Implants were described by: size, number of rods and insertion sites, duration (6-months, 1-year, 2-years), flexibility, and biodegradability. Random-parameters logit models estimated preference weights. RESULTS: Median age was 24 years (interquartile range 21-27). By design, 36% had used contraceptive implants. Duration of protection was most important feature, with strong preference for a 2-year over 6-month implant. In Zimbabwe, the number of rods/insertion sites was second most important and half as important as duration. Nonetheless, to achieve an implant lasting 2-years, 74% were estimated to accept two rods, one in each arm. In South Africa, preference was for longer, flexible implants that required removal, although each of these attributes were one-third as important as duration. On average, biodegradability and size did not influence Zimbabwean women's choices. Contraceptive implant experience and parity did not influence relative importance of attributes. CONCLUSIONS: While duration of protection was a prominent attribute shaping women's choices for PrEP implants, other characteristics related to discreetness were relevant. Optimizing for longest dosing while also ensuring minimal detection of implant placement seemed most attractive to potential users.

Durability of ChAdOx1 nCoV-19 (AZD1222) vaccine and hybrid humoral immunity against variants including omicron BA.1 and BA.4 6 months after vaccination (COV005): a post-hoc analysis of a randomised, phase 1b-2a trial.

BACKGROUND: COVID-19 vaccine rollout is lagging in Africa, where there has been a high rate of SARS-CoV-2 infection. We aimed to evaluate the effect of SARS-CoV-2 infection before vaccination with the ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days. METHODS: We did an unmasked post-hoc immunogenicity analysis after the first and second doses of AZD1222 in a randomised, placebo-controlled, phase 1b-2a study done in seven locations in South Africa. AZD1222 recipients who were HIV-uninfected, were stratified into baseline seropositive or seronegative groups using the serum anti-nucleocapsid (anti-N) immunoglobulin G (IgG) electroluminescence immunoassay to establish SARS-CoV-2 infection before the first dose of AZD1222. Binding IgG to spike (anti-S) and receptor binding domain (anti-RBD) were measured before the first dose (day 0), second dose (day 28), day 42, and day 180. Neutralising antibody (NAb) against SARS-CoV-2 variants D614G, beta, delta, gamma, and A.VOI.V2, and omicron BA1 and BA.4 variants, were measured by pseudovirus assay (day 28, day 42, and day 180). This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132. FINDINGS: Of 185 individuals who were randomly assigned to AZD1222, we included 91 individuals who were baseline seropositive and 58 who were baseline seronegative, in the final analysis. In the seropositive group, there was little change of anti-S IgG (and anti-RBD IgG) or neutralising antibody (NAb) titres at day 42 compared with at day 28. Anti-S (and anti-RBD) IgG geometric mean concentrations (GMCs) were higher throughout in the seropositive compared with the seronegative group, including at day 180 (GMCs 517·8 [95% CI 411·3-651·9] vs 82·1 [55·2-122·3] BAU/mL). Also D614G NAb geometric mean titres (GMTs) were higher in the seropositive group than the seronegative group, as was the percentage with titres of at least 185 (80% putative risk reduction threshold [PRRT] against wild-type-alpha COVID-19), including at day 180 (92·0% [74·0-99·0] vs 18·2% [2·3-51·8). Similar findings were observed for beta, A.VOI.V2, and gamma. For delta, BA.1, and BA.4, NAb GMTs and the proportion with titres above the PRRT were substantially higher in the seropositive compared with seronegative group at day 28 and day 42, but no longer differed between the groups by day 180. INTERPRETATION: A single dose of AZD1222 in the general African population, where COVID-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2. FUNDING: The Bill & Melinda Gates Foundation, the South African Medical Research Council, the UK Research and Innovation, the UK National Institute for Health Research, and the South African Medical Research Council. TRANSLATION: For the Zulu translation of the abstract see Supplementary Materials section.

Stigma in the health clinic and implications for PrEP access and use by adolescent girls and young women: conflicting perspectives in South Africa.

BACKGROUND: Globally, an urgent need exists to expand access to HIV prevention among adolescent girls and young women (AGYW), but the need is particularly acute in sub-Saharan Africa. Oral pre-exposure prophylaxis (PrEP) offers an effective HIV prevention method. In many countries, however, accessing PrEP necessitates that AGYW visit their local health clinic, where they may face access challenges. Some countries have implemented youth-friendly services to reduce certain challenges in local health clinics, but barriers to access persist, including clinic stigma. However, evidence of clinic stigma toward AGYW, particularly with respect to PrEP service delivery, is still limited. This mixed methods study explores stigma toward AGYW seeking clinic services, in particular PrEP, from the perspective of both clinic staff (clinical and nonclinical) and AGYW who seek services at clinic sites in Tshwane province, South Africa. METHODS: Six focus group discussions were conducted with AGYW (43 total participants) and four with clinic staff (42 total participants) and triangulated with survey data with AGYW (n = 449) and clinic staff (n = 130). Thematic analysis was applied to the qualitative data and descriptive statistics were conducted with the survey data. RESULTS: Four common themes emerged across the qualitative and quantitative data and with both AGYW and clinic staff, although with varying degrees of resonance between these two groups. These themes included (1) clinic manifestations of stigma toward AGYW, (2) concerns about providing PrEP services for AGYW, (3) healthcare providers' identity as mothers, and (4) privacy and breaches of confidentiality. An additional theme identified mainly in the AGYW data pertained to stigma and access to healthcare. CONCLUSION: Evidence is needed to inform strategies for addressing clinic stigma toward AGYW, with the goal of removing barriers to PrEP services for this group. While awareness has increased and progress has been achieved around the provision of comprehensive, youth-friendly sexual and reproductive health services, these programs need to be adapted for the specific concerns of young people seeking PrEP services. Our findings point to the four key areas noted above where programs seeking to address stigma toward AGYW in clinics can tailor their programming.

High Levels of Pretreatment HIV-1 Drug Resistance Mutations Among South African Women Who Acquired HIV During a Prospective Study.

BACKGROUND: Pretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: HIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database. RESULTS: We sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs. CONCLUSIONS: The high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.

Brief Report: Quantifiable Plasma Tenofovir Among South African Women Using Daily Oral Pre-exposure Prophylaxis During the ECHO Trial.

BACKGROUND: HIV endpoint-driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. METHODS: ECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16-35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification. RESULTS: Of 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83-104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83). CONCLUSIONS: Over a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end. CLINICAL TRIAL NUMBER: NCT02550067.

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.

Female and male partner perspectives on placebo Multipurpose Prevention Technologies (MPTs) used by women in the TRIO study in South Africa and Kenya.

BACKGROUND: Male partner awareness and acceptance of microbicide and family planning product use has been shown to increase women's own acceptance and adherence of a product. However, little is known about preferences regarding potential Multipurpose Prevention Technology (MPT) product delivery forms. As part of the TRIO study, men's reactions to their female partner's TRIO product use and comparisons of men's and women's views of TRIO product attributes and use acceptability were explored to better understand product preferences. METHODS: Women in TRIO used three placebo products that represented potential MPTs: daily oral tablets, monthly vaginal rings, and monthly dual injections. Male partners (N = 39) and women (N = 88) completed in-depth interviews on their own and their partner's experiences with these products. Qualitative coding and analyses followed a conceptual model of HIV prevention product acceptability, and here, we explored themes of disclosure, trust and infidelity as they informed barriers and facilitators to product use. RESULTS: Men expressed a desire to know of their partner's product use decisions and be informed and educated on the products to better support their partners, in some cases, expressing a high level of concern regarding maximizing the ease of product adherence for their partner. They also wanted to understand the effects of products on sexual encounters with their partner, but in some cases, wanted more knowledge in order to control their partner's product use decisions. Similarly to women, men found long-acting, discreet products that have little to no effect on sexual encounters or libido the most acceptable for their female partners' use. Product use was most acceptable to men if they were informed of use without inadvertent discovery. CONCLUSIONS: Men's product attribute preferences often aligned with women's opinions of the same products. To support women's correct use of MPTs, further research is needed to determine the best strategy for achieving male partner acceptance and support of product use, particularly for less familiar delivery forms, such as the vaginal ring.

Genital inflammatory status and the innate immune response to contraceptive initiation.

PROBLEM: Data on the effects of contraceptives on female genital tract (FGT) immune mediators are inconsistent, possibly in part due to pre-existing conditions that influence immune mediator changes in response to contraceptive initiation. METHODS: This study included 161 South African women randomised to injectable depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD), or levonorgestrel (LNG) implant in the Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial. We measured thirteen cytokines and antimicrobial peptides previously associated with HIV acquisition in vaginal swabs using Luminex and ELISA, before, and at 1 and 3 months after contraceptive initiation. Women were grouped according to an overall baseline inflammatory profile. We evaluated modification of the relationships between contraceptives and immune mediators by baseline inflammation, demographic, and clinical factors. RESULTS: Overall, LNG implant and copper IUD initiation were associated with increases in inflammatory cytokines, while no changes were observed following DMPA-IM initiation. However, when stratifying by baseline inflammatory profile, women with low baseline inflammation in all groups experienced significant increases in inflammatory cytokines, while those with a high baseline inflammatory profile experienced no change or decreases in inflammatory cytokines. CONCLUSION: We conclude that pre-contraceptive initiation immune profile modifies the effect of contraceptives on the FGT innate immune response.

Immunogenicity and safety of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine in people living with and without HIV-1 infection: a randomised, controlled, phase 2A/2B trial.

BACKGROUND: There is a paucity of data on COVID-19 vaccines in people living with HIV-1, who could be at increased risk of severe illness and death from COVID-19. We evaluated the safety and immunogenicity of a Matrix-M adjuvanted recombinant spike protein nanoparticle COVID-19 vaccine (NVX-CoV2373; Novavax) in HIV-negative people and people living with HIV-1. METHODS: In this randomised, observer-blinded, multicentre, placebo-controlled phase 2A/B trial in South Africa, participants aged 18-84 years, with and without underlying HIV-1, were enrolled from 16 sites and randomly assigned (1:1) to receive two intramuscular injections of NVX-CoV2373 or placebo, 21 days apart. People living with HIV-1 were on stable antiretroviral therapy and had an HIV-1 viral load of less than 1000 copies per mL. Vaccine dosage was 5 µg SARS-CoV-2 recombinant spike protein with 50 µg Matrix-M adjuvant, whereas 0·9% saline was used as placebo injection (volume 0·5 mL each). All study staff and participants remained masked to study group assignment. We previously reported an interim analysis on the efficacy and safety of the NVX-CoV2373 vaccine (coprimary endpoints). In this Article, we present an expanded safety analysis for the full cohort of participants and report on the secondary objective of vaccine immunogenicity in the full cohort of people living with HIV-1 and in HIV-negative individuals overall and stratified by baseline SARS-CoV-2 serostatus. This trial is registered with ClinicalTrials.gov, NCT04533399, and the Pan-African Clinical Trials Registry, PACTR202009726132275. FINDINGS: Participants were enrolled between Aug 17 and Nov 25, 2020. The safety analysis set included 4164 HIV-negative participants (2089 in the intervention group and 2075 in the placebo group) and 244 people living with HIV-1 (122 in the intervention group and 122 in the placebo group). 1422 (34·1%) of 4164 HIV-negative people and 83 (34·0%) of 244 people living with HIV-1 were categorised as baseline SARS-CoV-2-positive (ie, anti-spike IgG reactive at enrolment or had a reactive SARS-CoV-2 nucleic acid amplification test by 14 days after the second study vaccination). In the NVX-CoV2373 group, solicited local and systemic adverse events were more common in HIV-negative participants (427 [30·6%] local and 401 [28·7%] systemic) than in people living with HIV-1 (20 [25·3%] local and 20 [25·3%] systemic) among those who were baseline SARS-CoV-2-seronegative (naive). Of the serious adverse events that occurred among HIV-negative people (of whom, two [0·1%] were baseline SARS-CoV-2-negative and four [0·6%] were baseline SARS-CoV-2-positive) and people living with HIV-1 (for whom there were no serious adverse events) in the NVX-CoV2373 group, none were assessed as related to the vaccine. Among participants who were baseline SARS-CoV-2-negative in the NVX-CoV2373 group, the anti-spike IgG geometric mean titres (GMTs) and seroconversion rates (SCRs) were lower in people living with HIV-1 (n=62) than in HIV-negative people (n=1234) following the first vaccination (GMT: 508·6 vs 1195·3 ELISA units [EU]/mL; SCR: 51·6% vs 81·3%); and similarly so 14 days after the second vaccination for GMTs (14 420·5 vs 31 631·8 EU/mL), whereas the SCR was similar at this point (100·0% vs 99·3%). In the NVX-CoV2373 group, anti-spike IgG GMTs 14 days after the second vaccination were substantially higher in those who were baseline SARS-CoV-2-positive than in those who were baseline SARS-CoV-2-seronegative for HIV-negative participants (100 666·1 vs 31 631·8 EU/mL) and for people living with HIV-1 (98 399·5 vs 14 420·5 EU/mL). This was also the case for angiotensin-converting enzyme 2 receptor-binding antibody and neutralising antibody titres. INTERPRETATION: The safety of the NVX-CoV2373 vaccine in people living with HIV-1 was similar to that in HIV-negative participants. However, people living with HIV-1 not previously exposed to SARS-CoV-2 had attenuated humoral immune responses to NVX-CoV2373 compared with their HIV-negative vaccine counterparts, but not so if they were baseline SARS-CoV-2-positive. FUNDING: Novavax and the Bill & Melinda Gates Foundation; investigational vaccine manufacturing support was provided by the Coalition for Epidemic Preparedness Innovations.

Lung and blood early biomarkers for host-directed tuberculosis therapies: Secondary outcome measures from a randomized controlled trial.

BACKGROUND: Current tuberculosis treatments leave most patients with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase all-cause post-TB mortality. Host-directed therapies (HDTs) may reduce lung inflammation and hasten eradication of infection. Biomarkers can accelerate tuberculosis regimen development, but no studies have yet examined early biomarkers of TB-HDTs. METHODS: Biomarkers of inflammation and microbicidal activity were evaluated as a part of a recent phase-2 randomized controlled trial of four HDTs in 200 patients with pulmonary tuberculosis and baseline predictors of poor outcome, including CC-11050 (PDE4i), everolimus (mTORi), auranofin (oral gold salt), and ergocalciferol (vitamin D). Two of the 4 arms (CC-11050 and everolimus) showed superior recovery of lung function at day 180 compared to control; none showed accelerated eradication of MTB infection. Patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on entry and day 56. PET signals were analyzed according to total, maximal, and peak glycolytic activity; CT was analyzed according to total modified Hounsfield units to assess radiodensity. Mycobactericidal activity in ex vivo whole blood culture was measured on days 42, 84, and 140. C-reactive protein (CRP) was measured at multiple time points. RESULTS: All PET/CT parameters showed highly significant reductions from baseline to day 56; however, only maximal or peak glycolytic activity showed further experimental reduction compared to controls, and only in everolimus recipients. CRP dropped precipitously during early treatment, but did so equally in all arms; over the entire period of treatment, the rate of decline of CRP tended to be greater in CC-11050 recipients than in controls but this fell short of statistical significance. Whole blood mycobactericidal activity in ex-vivo culture was enhanced by auranofin compared to controls, but not by other HDTs. CONCLUSIONS: None of these early biomarkers correctly predicted HDT effects on inflammation or infection across all four experimental arms. Instead, they each appear to show highly specific responses related to HDT mechanisms of action.

Immunological non-inferiority of a new fully liquid presentation of the MenACWY-CRM vaccine to the licensed vaccine: results from a randomized, controlled, observer-blind study in adolescents and young adults.

A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.

ART initiation among women newly diagnosed with HIV in a contraceptive trial in sub-Saharan Africa.

Current guidelines recommend starting antiretroviral therapy (ART) as soon as possible after HIV diagnosis to reduce morbidity, mortality and onward HIV transmission. We examined factors influencing ART initiation by women who seroconverted during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial. ECHO, conducted between 2015 and 2018, enrolled HIV-negative, sexually active women, aged 16-35 years, from four African countries. Follow-up was 12-18 months, with quarterly HIV testing. Women with incident HIV infection received extensive counselling by trial staff and referral to local facilities for HIV care. Of 304 women with ≥90 days follow-up time since HIV diagnosis, 186(61.2%) initiated ART within 90 days, 69(22.7%) initiated after 90 days, and 49(16.1%) had not initiated by the end of the study. There were no statistically significant differences in characteristics among women who initiated ART ≤90 days versus those who did not. Frequent reasons for delayed or non-initiation of ART included not feeling ready to start ART and being newly diagnosed. In a large clinical trial, ART initiation was modest within 90 days of HIV diagnosis and grew to 84% with longer observation. Despite extensive counselling on the importance of early ART initiation, personal barriers delayed some women from starting ART.