Omicron infection enhances Delta antibody immunity in vaccinated persons.

The extent to which Omicron infection1-9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3-9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19-27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement.

Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women.

BACKGROUND: There are gaps in uptake of, adherence to, and persistence in the use of preexposure prophylaxis for human immunodeficiency virus (HIV) prevention among cisgender women. METHODS: We conducted a phase 3, double-blind, randomized, controlled trial involving adolescent girls and young women in South Africa and Uganda. Participants were assigned in a 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine-tenofovir alafenamide (F/TAF), or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF; active control); all participants also received the alternate subcutaneous or oral placebo. We assessed the efficacy of lenacapavir and F/TAF by comparing the incidence of HIV infection with the estimated background incidence in the screened population and evaluated relative efficacy as compared with F/TDF. RESULTS: Among 5338 participants who were initially HIV-negative, 55 incident HIV infections were observed: 0 infections among 2134 participants in the lenacapavir group (0 per 100 person-years; 95% confidence interval [CI], 0.00 to 0.19), 39 infections among 2136 participants in the F/TAF group (2.02 per 100 person-years; 95% CI, 1.44 to 2.76), and 16 infections among 1068 participants in the F/TDF group (1.69 per 100 person-years; 95% CI, 0.96 to 2.74). Background HIV incidence in the screened population (8094 participants) was 2.41 per 100 person-years (95% CI, 1.82 to 3.19). HIV incidence with lenacapavir was significantly lower than background HIV incidence (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.04; P<0.001) and than HIV incidence with F/TDF (incidence rate ratio, 0.00; 95% CI, 0.00 to 0.10; P<0.001). HIV incidence with F/TAF did not differ significantly from background HIV incidence (incidence rate ratio, 0.84; 95% CI, 0.55 to 1.28; P = 0.21), and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF (incidence rate ratio, 1.20; 95% CI, 0.67 to 2.14). Adherence to F/TAF and F/TDF was low. No safety concerns were found. Injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions. CONCLUSIONS: No participants receiving twice-yearly lenacapavir acquired HIV infection. HIV incidence with lenacapavir was significantly lower than background HIV incidence and HIV incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 1 ClinicalTrials.gov number, NCT04994509.).

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Host genetic variation at a locus near CHD1L impacts HIV sequence diversity in a South African population.

IMPORTANCE: It has been previously shown that genetic variants near CHD1L on chromosome 1 are associated with reduced HIV VL in African populations. However, the impact of these variants on viral diversity and how they restrict viral replication are unknown. We report on a regional association analysis in a South African population and show evidence of selective pressure by variants near CHD1L on HIV RT and gag. Our findings provide further insight into how genetic variability at this locus contributes to host control of HIV in a South African population.

High incidence of asymptomatic genital tract infections in pregnancy in adolescent girls and young women: need for repeat aetiological screening.

INTRODUCTION: Sexually transmitted infection (STI) prevalence and incidence estimates for pregnant adolescents are under-reported. We estimated prevalence and incidence of STIs in pregnant adolescents (15-19 years) in comparison with pregnant women 20-24 and >25 years. METHODS: Pregnant women registering at primary care clinics in Umlazi, a periurban subdistrict in KwaZulu-Natal, South Africa, were enrolled in an HIV incidence cohort study during February 2017-March 2018. Women were examined for abnormal vaginal discharge, received empirical treatment, tested for HIV-1 and had vaginal swabs taken at their first and a subsequent visit in the third trimester. Vaginal swabs were stored for STI testing at completion of study and tested for Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma genitalium using PCR. RESULTS: A total of 752 HIV-negative pregnant women were enrolled at a median gestational age of 17 weeks: 180 (23.9%), 291 (38.7%) and 281 (37.4%) in the 15-19, 20-24 and >25 years age groups. Pregnant adolescents had an STI prevalence of 26.7% at baseline, not significantly lower than the 20-24 (34.7%, OR 1.4; 95% CI 1.0 to 2.1, p=0.09) and >25 years (33.8%, OR 1.4; 95% CI 0.9 to 2.1, p=0.12) age groups. T. vaginalis (11.1%), C. trachomatis (7.8%) and N. gonorrhoeae (4.4%) were most prevalent in adolescents, a trend similar to the other age groups. Overall, 43.4% were symptomatic and treated at baseline. Overall, 40.7% (118 of 290) of women who tested negative for an STI at baseline tested positive at the repeat visit (incidence 19.5/100 person years). STI incidence in pregnant adolescents was 23.9/100 person years and comparable with older age groups (20.5/100 person years and 16.2/100 person years). At the repeat visit, 19.0% of all women with an STI were symptomatic and treated. Performance of syndromic management was poor at baseline (negative predictive value (NPV) 68.6%, positive predictive value (PPV) 34.0%) and at repeat visit (NPV 58.4%, PPV 34.3%). CONCLUSIONS: Prevalence of asymptomatic curable STIs in pregnant adolescents is high and comparable with women >20 years old. Adolescents remain at substantial risk of asymptomatic incident STIs during pregnancy.

Genital Immune Cell Activation and Tenofovir Gel Efficacy: A Case-Control Study.

Genital inflammation (GI) undermines topical human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) efficacy through unknown mechanisms. Here, associations between activated endocervical CD4 + T-cell numbers and higher deoxyadenosine triphosphate (dATP) concentrations suggest that competition for intracellular metabolites within HIV target cells may reduce the efficacy of antiretroviral-based PrEP in women with GI.

HIV prevention for the next decade: Appropriate, person-centred, prioritised, effective, combination prevention.

UNAIDS and a broad range of partners have collaborated to establish a new set of HIV prevention targets to be achieved by 2025 as an intermediate step towards the sustainable development target for 2030.The number of new HIV infections in the world continues to decline, in part due to the extraordinary expansion of effective HIV treatment. However, the decline is geographically heterogeneous, with some regions reporting a rise in incidence. The incidence target that was agreed for 2020 has been missed.A range of exciting new HIV prevention technologies have become available or are in the pipeline but will only have an impact if they are accessible and affordable and delivered within systems that take full account of the social and political context in which most infections occur. Most new infections occur in populations that are marginalised or discriminated against due to structural, legal, and cultural barriers.The new targets imply a new approach to HIV prevention that emphasises appropriate, person-centred, prioritised, effective, combination HIV prevention within a framework that reduces existing barriers to services and acknowledges heterogeneity, autonomy, and choice.These targets have consequences for people working in HIV programmes both for delivery and for monitoring and evaluation, for health planners setting local and national priorities, and for funders both domestic and global. Most importantly, they have consequences for people who are at risk of HIV exposure and infection.Achieving these targets will have a huge impact on the future of the HIV epidemic and put us back on track towards ending AIDS as a public health threat by 2030.

COVID-19: Impact on the HIV and Tuberculosis Response, Service Delivery, and Research in South Africa.

PURPOSE OF REVIEW: To describe how mitigation measures against COVID-19 have impacted HIV and TB research in South Africa. RECENT FINDINGS: South Africa has the highest number of COVID-19 (34%) cases in Africa, accounting for 43% of all reported COVID-19-related deaths on the continent. The country accounts for 20% of all people living with HIV and ranked third in the world for new TB infections in 2019. While South Africa's investments in its HIV and TB responses enabled it to pivot rapidly to respond to the emerging COVID-19 epidemic, it negatively impacted the HIV and TB response through temporary suspension of research, diversion of key resources for HIV and TB control, and patient access to health care facilities; the full extent of this has yet to emerge. Success in integrating responses to the colliding epidemics could potentially enhance survival outcomes and ensure gains made to date in HIV and TB are not reversed and we stay on track toward achieving the UN 2030 Sustainable Development Goals.

Age-Restriction of a Validated Risk Scoring Tool Better Predicts HIV Acquisition in South African Women: CAPRISA 004.

We examined the predictive ability of the VOICE risk screening tool among adolescent girls and young women at heightened HIV risk in urban and peri-urban Kwa-Zulu-Natal, South Africa. Using participant data from CAPRISA 004's control arm (N = 444), we applied the initial VOICE risk screening score (IRS), a modified risk score (MRS) based on predictive and non-predictive variables in our data, and age-restricted (AIRS and AMRS, respectively). We estimated incidence rates, 95% confidence bounds, sensitivity, specificity, negative and positive predictive values and area under the curve (AUC). The sample's HIV incidence rate was 9.1/100 Person-Years [95% CI 6.9-11.7], resulting from 60 seroconversions (60/660.7 Person-Years). The IRS' ≥ 8 cutpoint produced moderate discrimination [AUC = 0.66 (0.54-0.74), sensitivity = 63%, specificity = 57%]. Restricting to age < 25 years improved the score's predictive ability (AIRS: AUC = 0.69, AMRS: AUC = 0.70), owing mainly to male partner having other partners and HSV-2. The risk tool predicted HIV acquisition at a higher cutpoint in this sample than in the initial VOICE analysis. After age-stratification, fewer variables were needed for maintaining score's predictiveness. In this high incidence setting, risk screening may still improve the efficiency or effectiveness of prevention counseling services. However, PrEP should be offered to all prevention-seeking individuals, regardless of risk ascertainment.

Clinical Trials of Broadly Neutralizing Monoclonal Antibodies for Human Immunodeficiency Virus Prevention: A Review.

Passive immunization with broadly neutralizing antibodies (bnAbs) is a promising approach to reduce the 1.7 million annual human immunodeficiency virus (HIV) infections globally. Early studies on bnAbs showed safety in humans, but short elimination half-lives and low potency and breadth. Since 2010, several new highly potent bnAbs have been assessed in clinical trials alone or in combination for HIV prevention. Published data indicate that these bnAbs are safe and have a half-life ranging from 15 to 71 days. Only intravenous VRC01 has advanced to an efficacy trial, with results expected in late 2020. If bnAbs are shown to be effective in preventing HIV infection, they could fast-track vaccine development as correlates of protection, and contribute as passive immunization to achieving the goal of epidemic control. The purpose of the current review is to describe the current status and provide a synopsis of the available data on bnAbs in clinical trials for HIV prevention.

COVID-19 and global equity for health: The good, the bad, and the wicked.

Elvin Geng and co-authors discuss monitoring and achieving equity in provision of vaccines for COVID-19.

How will COVID-19 transform global health post-pandemic? Defining research and investment opportunities and priorities.

Michael Reid and co-authors introduce a Collection on the global health in the post-COVID-19 era.

Development of a prognostic tool exploring female adolescent risk for HIV prevention and PrEP in rural South Africa, a generalised epidemic setting.

OBJECTIVES: Adolescent females in sub-Saharan Africa bear a disproportionate burden of new HIV infections but have been excluded from prognostic research, such as developed risk calculators. This study examines whether validated risk calculators, which calculate HIV risk among sub-Saharan African women, can be modified to assess HIV risk among adolescent girls. The performance of selected risk variables from validated calculators and the literature was evaluated among adolescent females using modern advanced statistical tools. METHODS: Risk variables for the updated tool were selected from the CAPRISA 007 (CAP007) trial (2010-2012) questionnaires. An initially HIV-seronegative cohort of rural South African female high school students (n=1049) aged 14-25 years was selected. The number and characteristics of latent factors, or dimensions, underlying selected variables were assessed using exploratory factor analysis (EFA). The updated tool's effectiveness identifying trends in adolescent risk were assessed with latent class analysis (LCA). RESULTS: EFA identified two key latent factors: sexual behaviour and socioeconomic risk factors. Latent sexual behaviour risk influenced contraception use (0.883), perceived HIV risk (0.691) and pregnancy (-0.384). Latent socioeconomic risk influenced low HIV knowledge (0.371), financial dependence (0.532), prior HIV testing (-0.379) and alcohol use (-0.332). Using LCA, three underlying categories of adolescent females were identified: those with no, low and high risk of HIV (1.10%, 2.26% and 2.91% 1-year seroconversion rates, respectively). Herpes simplex virus serotype-2, condom contraception, alcohol use, pregnancy and age were significantly associated with higher risk class membership, while non-condom contraception was associated with lower risk class membership. CONCLUSIONS: Adolescent females are at unequal risk of acquiring HIV. Findings suggest the updated tool captures two main facets of adolescent characteristics and may identify differential risk. This work supports further investigation to inform development of targeted differentiated interventions and efficient prognostic tools for adolescents in high-risk settings.

Importance of early identification of PrEP breakthrough infections in a generalized HIV epidemic: a case report from a PrEP demonstration project in South Africa.

BACKGROUND: The World Health Organisation recommends the use of tenofovir-containing pre-exposure prophylaxis (PrEP) as an additional Human Immunodeficiency Virus (HIV) prevention choice for men and women at substantial risk of HIV infection. PrEP could fill an important HIV prevention gap, especially for sexually active young women who are limited in their ability to negotiate mutual monogamy or condom use. As PrEP is scaled up in high HIV incidence settings, it is crucial to consider the importance of early identification of HIV infection during PrEP use, to allow for rapid discontinuation of PrEP to reduce the risk of antiretroviral (ARV) resistance. The purpose of this case study is to provide this critical evidence. CASE PRESENTATION: This report describes a 20-year-old woman in a HIV sero-discordant relationship who initiated oral PrEP (tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC)) through a demonstration project (CAPRISA 084) in October 2017. Despite good adherence throughout her PrEP use, she tested HIV antibody positive at month nine of study participation. Retrospective testing showed increasing HIV viral load over time, and retrospective use of fourth-generation rapid HIV tests showed HIV detection (positive antigen/antibody) at month one. Sequencing confirmed a dominant wild type at month one with dual therapy resistance patterns emerging by month three (M184V and K65R mutations), which is suggestive of protracted PrEP use during an undetected HIV infection. The participant was referred to infectious diseases for further management of her HIV infection and was initiated on a first line, tenofovir-sparing regimen. At the time of this report (January 2020), the participant had been on ARV- therapy (ART) for 13 months and had no signs of either clinical, immunologic or virologic failure. CONCLUSIONS: This case report highlights the importance of appropriate HIV screening during wider oral PrEP scale-up in high HIV incidence settings to circumvent the consequences of prolonged dual therapy in an undiagnosed HIV infection and in turn prevent ARV resistance.

High incidence and persistence of hepatitis B virus infection in individuals receiving HIV care in KwaZulu-Natal, South Africa.

BACKGROUND: Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Tuberculosis (TB) are common infections in South Africa. We utilized the opportunity of care provision for HIV-TB co-infected patients to better understand the relationship between these coinfections, determine the magnitude of the problem, and identify risk factors for HBV infection in HIV infected patients with and without TB in KwaZulu-Natal, South Africa. METHODS: This retrospective cohort analysis was undertaken in 2018. In-care HIV infected patients were included in the analysis. Results from clinical records were analysed to determine the prevalence, incidence, persistence and factors associated with HBsAg positivity in HIV-infected patients with or without TB co-infection. RESULTS: A total of 4292 HIV-infected patients with a mean age of 34.7 years (SD: 8.8) were included. Based on HBsAg positivity, the prevalence of HBV was 8.5% (363/4292) [95% confidence interval (CI): 7.7-9.3] at baseline and 9.4% (95%CI: 8.6-10.3%) at end of follow-up. The HBV incidence rate was 2.1/100 person-years (p-y). Risk of incident HBV infection was two-fold higher among male patients (HR 2.11; 95% CI: 1.14-3.92), while severe immunosuppression was associated with a greater than two-fold higher risk of persistent infection (adjusted risk ratio (RR) 2.54; 95% CI 1.06-6.14; p = 0.004. Additionally, active TB at enrolment was associated with a two-fold higher risk of incident HBV infection (aHR 2.38; 95% CI: 0.77-7.35). CONCLUSION: The provision of HIV care and treatment in high HBV burden settings provide a missed opportunity for HBV screening, immunization and care provision.

Acceptability of HIV self-testing among men and women in KwaZulu-Natal, South Africa.

Successful implementation of Universal Test and Treat as a strategy to achieve the 90-90-90 target requires higher HIV testing rates. Currently, uptake of HIV testing is not optimal which has directed research initiatives towards identification of additional HIV testing methods. HIV self-testing (HIVST) has received growing attention as a complementary testing approach as it overcomes barriers that are commonly associated with current HIV testing methods. In sub-Saharan Africa, acceptability rates showed a gendered pattern of men benefitting more than women, with limited evidence to explain this difference. This study assessed whether men or women in KwaZulu-Natal displayed a higher acceptance of HIVST and also explored factors that influenced and motivated their acceptability. Participants were recruited through purposive sampling at two clinical research sites to participate and underwent qualitative assessments. The outcomes from focus group discussions coupled with findings from a scoping review informed the design and data collection instruments for in-depth interviews. A randomised cross-over study design exposed participants to HIV counselling and testing and HIVST, accompanied by before (baseline) and after in-depth interviews. HIVST was acceptable among most participants with acceptability higher in women. Men preferred HIVST due to convenience and efficiency, whilst women favoured HIVST due to its potential to provide autonomy and empowerment. Also, lack of HIV counselling and managing a positive HIV result as well as linkage to care were raised as deterrents of HIVST. As HIVST was acceptable by most participants, future research efforts should be directed towards evaluating the feasibility of its introduction into the public health sector.

Effect of Antiretroviral Therapy on the Memory and Activation Profiles of B Cells in HIV-Infected African Women.

Human immunodeficiency virus infection induces a wide range of effects in B cells, including skewed memory cell differentiation, compromised B cell function, and hypergammaglobulinemia. However, data on the extent to which these B cell abnormalities can be reversed by antiretroviral therapy (ART) are limited. To investigate the effect of ART on B cells, the activation (CD86) and differentiation (IgD, CD27, and CD38) profiles of B cells were measured longitudinally in 19 HIV-infected individuals before (median, 2 mo) and after ART initiation (median, 12 mo) and compared with 19 age-matched HIV-uninfected individuals using flow cytometry. Twelve months of ART restored the typical distribution of B cell subsets, increasing the proportion of naive B cells (CD27-IgD+CD38-) and concomitantly decreasing the immature transitional (CD27-IgD+CD38+), unswitched memory (CD27+IgD+CD38-), switched memory (CD27+IgD-CD38- or CD27-IgD-CD38-), and plasmablast (CD27+IgD-CD38high) subsets. However, B cell activation was only partially normalized post-ART, with the frequency of activated B cells (CD86+CD40+) reduced compared with pre-ART levels (p = 0.0001), but remaining significantly higher compared with HIV-uninfected individuals (p = 0.0001). Interestingly, unlike for T cell activation profiles, the extent of B cell activation prior to ART did not correlate with HIV plasma viral load, but positively associated with plasma sCD14 levels (p = 0.01, r = 0.58). Overall, ART partially normalizes the skewed B cell profiles induced by HIV, with some activation persisting. Understanding the effects of HIV on B cell dysfunction and restoration following ART may provide important insights into the mechanisms of HIV pathogenesis.