Unintended pregnancy and contraception use among African women living with HIV: Baseline analysis of the multi-country US PEPFAR PROMOTE cohort.

BACKGROUND: About 90% of unintended pregnancies are attributed to non-use of effective contraception-tubal ligation, or reversible effective contraception (REC) including injectables, oral pills, intra-uterine contraceptive device (IUCD), and implant. We assessed the prevalence of unintended pregnancy and factors associated with using RECs, and Long-Acting-Reversible-Contraceptives (LARCs)-implants and IUCDs, among women living with HIV (WLHIV) receiving antiretroviral therapy (ART). METHODS: We conducted cross-sectional analyses of the US-PEPFAR PROMOTE study WLHIV on ART at enrollment. Separate outcome (REC and LARC) modified-Poisson regression models were used to estimate prevalence risk ratio (PRR) and corresponding 95% confidence interval (CI). RESULTS: Of 1,987 enrolled WLHIV, 990 (49.8%) reported their last/current pregnancy was unintended; 1,027/1,254 (81.9%) non-pregnant women with a potential to become pregnant reported current use of effective contraception including 215/1,254 (17.1%) LARC users. Compared to Zimbabwe, REC rates were similar in South Africa, aPRR = 0.97 (95% CI: 0.90-1.04), p = 0.355, lower in Malawi, aPRR = 0.84 (95% CI: 0.78-0.91), p<0.001, and Uganda, 0.82 (95% CI: 0.73-0.91), p<0.001. Additionally, REC use was independently associated with education attained, primary versus higher education, aPRR = 1.10 (95% CI: 1.02-1.18), p = 0.013; marriage/stable union, aPRR = 1.10 (95% CI: 1.01-1.21), p = 0.039; no desire for another child, PRR = 1.10 (95% CI: 1.02-1.16), p = 0.016; infrequent sex (none in the last 3 months), aPRR = 1.24 (95% CI: 1.15-1.33), p<0001; and controlled HIV load (≤ 1000 copies/ml), PRR = 1.10 (95% CI: 1.02-1.19), p = 0.014. LARC use was independently associated with country (Zimbabwe ref: South Africa, PRR = 0.39 (95% CI: 0.26-0.57), p<0.001; Uganda, PRR = 0.65 (95% CI: 0.42-1.01), p = 0.054; and Malawi, aPRR = 0.87 (95% CI: 0.64-1.19), p = 0.386; HIV load (≤ 1000 copies/ml copies/ml), aPRR=1.73 (95% CI: 1.26-2.37), p<0.001; and formal/self-employment, aPRR = 1.37 (95% CI: 1.02-1.91), p = 0.027. CONCLUSIONS: Unintended pregnancy was common while use of effective contraception methods particularly LARCs was low among these African WLHIV. HIV viral load, education, sexual-activity, fertility desires, and economic independence are pertinent individual-level factors integral to the multi-level barriers to utilization of effective contraception among African WLHIV. National programs should prioritize strategies for effective integration of HIV and reproductive health care in the respective African countries.

Incidence and prevalence of hypertension among HIV-TB co-infected participants accessing treatment: A five-year prospective cohort analysis.

INTRODUCTION: Hypertension is a leading risk factor for cardiovascular disease among people living with human immunodeficiency virus (PLWH). This study determined incidence and prevalence of hypertension among PLWH receiving antiretroviral therapy (ART). METHOD: We prospectively followed-up 642 HIV and tuberculosis (TB) co-infected study participants from 2005-2013. We defined hypertension as two consecutive elevated systolic and/or diastolic blood pressure measurements above 139/89 mmHg or current use of antihypertensive therapy. RESULTS: Of 507 participants analyzed, 53% were women. Median [interquartile range (IQR)] age, body mass index (BMI), and CD4 count was 34 (28.0-40.0) years, 22.7 (20.5-25.4) kg/m2, and 145 (69.0-252.0) cells/mm3, respectively. Incidence [95% confidence interval (CI)] of both systolic and diastolic hypertension overall, in men, and in women over 40 years was 1.9 (1.4-2.6), 5.9 (3.6-9.6), and 5.0 (2.7-9.3) per 100 person-years (PY), respectively. Risk of developing hypertension was higher in men [(adjusted hazard ratio (aHR) 12.04, 95% CI: 4.35-33.32)] and women over 40 years (aHR 8.19, 95% CI 2.96-22.64), and in men below 40 years (aHR 2.79, 95% CI 0.95-8.23). CONCLUSION: Higher incidence rates of hypertension among older men and women accessing ART highlight opportunities to expand current integrated HIV-TB care models, to include cardiovascular disease risk screening and care to prevent premature death.

Safety of a second homologous Ad26.COV2.S vaccine among healthcare workers in the phase 3b implementation Sisonke study in South Africa.

The Sisonke 2 study provided a homologous boost at least 6 months after administration of the priming dose of Ad26.COV2.S for healthcare workers enrolled on the Sisonke phase 3b implementation study. Safety monitoring was via five reporting sources: (i.) self-report through a web-link; (ii.) paper-based case report forms; (iii.) a toll-free telephonic reporting line; (iv.) healthcare professionals-initiated reports; and (v.) active linkage with National Disease Databases. A total of 2350 adverse events were reported by 2117 of the 240 888 (0.88%) participants enrolled; 1625 of the 2350 reported events are reactogenicity events and 28 adverse events met seriousness criteria. No cases of thrombosis with thrombocytopaenia syndrome were reported; all adverse events including thromboembolic disorders occurred at a rate below the expected population rates apart from one case of Guillain Barre Syndrome and one case of portal vein thrombosis. The Sisonke 2 study demonstrates that two doses of Ad26.COV2.S is safe and well tolerated; and provides a feasible model for national pharmacovigilance strategies for low- and middle-income settings.

Breastfeeding Among Women Living With HIV in the Era of Lifelong ART: An Observational Multicountry Study in Eastern and Southern Africa.

BACKGROUND: Lifelong antiretroviral treatment (ART) use is recommended for pregnant and breastfeeding (BF) women living with HIV (WLWH) to prevent perinatal HIV transmission and improve maternal health. We address 2 objectives in this analysis: (1) determine timing and factors associated with BF cessation and (2) assess the impact of BF on health of WLWH on ART. SETTING: This multicountry study included 8 sites in Uganda, Malawi, Zimbabwe, and South Africa. METHODS: This was a prospective study of WLWH on lifelong ART. These women initially participated from 2011 to 2016 in a randomized clinical trial (PROMISE) to prevent perinatal HIV transmission and subsequently reenrolled in an observational study (PROMOTE, 2016-2021) to assess ART adherence, safety, and impact. RESULTS: The PROMOTE cohort included 1987 women on ART. Of them, 752 breastfed and were included in analyses of objective 1; all women were included in analyses of objective 2. The median time to BF cessation varied by country (11.2-19.7 months). Country of residence, age, and health status of women were significantly associated with time to BF cessation (compared with Zimbabwe: Malawi, adjusted hazard ratio [aHR] 0.50, 95% confidence interval [95% CI]: 0.40 to 0.62, P < 0.001; South Africa, aHR 1.49, 95% CI: 1.11 to 2.00, P = 0.008; and Uganda, aHR 1.77, 95% CI: 1.37 to 2.29, P < 0.001). Women who breastfed had lower risk of being "unwell" compared with women who never breastfed (adjusted rate ratio 0.87, 95% CI: 0.81 to 0.95 P = 0.030). CONCLUSION: Women on lifelong ART should be encouraged to continue BF with no concern for their health. Time to BF cessation should be monitored for proper counseling in each country.

Safety and pharmacokinetics of escalating doses of neutralising monoclonal antibody CAP256V2LS administered with and without VRC07-523LS in HIV-negative women in South Africa (CAPRISA 012B): a phase 1, dose-escalation, randomised controlled trial.

BACKGROUND: Young women in sub-Saharan Africa continue to bear a high burden of HIV infection. Combination anti-HIV monoclonal antibodies are a potential HIV prevention technology that could overcome adherence challenges of daily oral pre-exposure prophylaxis. In this phase 1 clinical trial we aimed to determine the safety and pharmacokinetic profile of the broadly neutralising monoclonal antibody CAP256V2LS. METHODS: CAPRISA 012B, a first-in-human dose-escalation phase 1 trial evaluated the safety, pharmacokinetics, and neutralisation activity of CAP256V2LS alone and in combination with VRC07-523LS in young HIV-negative women in Durban, South Africa. Groups 1 and 2 were open label with CAP256V2LS administered at 5 mg/kg and 10 mg/kg intravenously and 5 mg/kg, 10 mg/kg, and 20 mg/kg subcutaneously. In group 3, participants were randomly allocated to receive a combination of CAP256V2LS and VRC07-523LS at 10 mg/kg and 20 mg/kg subcutaneously comixed with ENHANZE, a recombinant human hyaluronidase. Once safety was established in the first three participants, dose escalation took place sequentially following review of safety data. Primary endpoints were the proportion of participants with mild, moderate, and severe reactogenicity or adverse events, graded as per the Division of AIDS toxicity grading. The trial is registered on the Pan African Clinical Trial Registry, PACTR202003767867253, and is recruiting. FINDINGS: From July 13, 2020, to Jan 13, 2021, 42 HIV-negative women, aged 18-45 years, were enrolled. All 42 participants, eight with intravenous and 34 with subcutaneous administration, completed the trial. There were no serious adverse events or dose-limiting toxicities. Most commonly reported symptoms following intravenous administration were headaches in seven (88%) and nausea in four (50%) participants. Commonly reported symptoms following subcutaneous administration were headache in 31 (91%), chills in 25 (74%), and malaise or fatigue in 19 (56%) participants. Adverse events included transient lymphocytopenia in eight (19%), proteinuria in nine (21%), elevated aspartate aminotransferase in ten (24%), and alanine aminotransferase in five (12%) participants. INTERPRETATION: CAP256V2LS administered alone and in combination with VRC07-523LS was safe with favourable pharmacokinetics and neutralisation activity, supporting further assessment in larger clinical studies. FUNDING: European and Developing Countries Clinical Trials Partnership, South African Medical Research Council, and South African Department of Science and Innovation.

Using joint models to study the association between CD4 count and the risk of death in TB/HIV data.

BACKGROUND: The association structure linking the longitudinal and survival sub-models is of fundamental importance in the joint modeling framework and the choice of this structure should be made based on the clinical background of the study. However, this information may not always be accessible and rationale for selecting this association structure has received relatively little attention in the literature. To this end, we aim to explore four alternative functional forms of the association structure between the CD4 count and the risk of death and provide rationale for selecting the optimal association structure for our data. We also aim to compare the results obtained from the joint model to those obtained from the time-varying Cox model. METHODS: We used data from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) AIDS Treatment programme, the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) study, an open-label, three armed randomised, controlled trial between June 2005 and July 2010 (N=642). In our analysis, we combined the early and late integrated arms and compared results to the sequential arm. We utilized the Deviance Information Criterion (DIC) to select the final model with the best structure, with smaller values indicating better model adjustments to the data. RESULTS: Patient characteristics were similar across the study arms. Combined integrated therapy arms had a reduction of 55% in mortality (HR:0.45, 95% CI:0.28-0.72) compared to the sequential therapy arm. The joint model with a cumulative effects functional form was chosen as the best association structure. In particular, our joint model found that the area under the longitudinal profile of CD4 count was strongly associated with a 21% reduction in mortality (HR:0.79, 95% CI:0.72-0.86). Where as results from the time-varying Cox model showed a 19% reduction in mortality (HR:0.81, 95% CI:0.77-0.84). CONCLUSIONS: In this paper we have shown that the "current value" association structure is not always the best structure that expresses the correct relationship between the outcomes in all settings, which is why it is crucial to explore alternative clinically meaningful association structures that links the longitudinal and survival processes.

INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection in patients with drug-susceptible tuberculosis on a rifampicin-based treatment regimen: a phase 2b open-label randomised controlled trial.

INTRODUCTION: Cotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries. METHODS AND ANALYSIS: This is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled. ETHICS AND DISSEMINATION: The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov; Trial registration number: NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789).

Impact of Motivational Enhanced Adherence Counseling and Point-of-Care Viral Load Monitoring on Viral Load Outcome in Women on Life-Long ART: A Randomized Pilot Study.

We piloted the combined effectiveness of point-of-care viral load monitoring plus motivational enhanced adherence counseling (intervention) compared with routine care (control) in women identified at risk of virologic failure in the PROMOTE study in Zimbabwe. In an unblinded randomized study, consenting women with last viral load ≥200 copies/ml and/or pill count outside 90-110% range were randomized 1 : 1 to receive the intervention or continue routine care, comprising laboratory-based VL monitoring and standard EAC, from trained nurses and counsellors. Viral load was measured 0, 3, 6, and 12 months after enrolment. We compared viral suppression <200 copies/ml at 6 and 12 months between the arms through Fisher's exact test and sought associated factors by logistic regression with a 95% confidence interval (CI). Between December 2018 and July 2019, 50 women were enrolled (25 intervention and 25 controls) and followed until November 2020. At entry, 60% of the women were virally suppressed, 52% intervention vs. 68% control arm. Viral suppression was balanced between the two arms (p value = 0.248). At month 6 post study entry (primary endpont), 64% of the women retained in care were virally suppressed, 54% intervention vs. 76% control arm (p value = 0.124). At month12 post study entry (secondary endpoint), 69% of the women retained in care were virally suppressed, 67% intervention vs. 71% control arm women (p value = 0.739). More intervention women completed all scheduled sessions by month 6. Control group women were more likely to be virally suppressed at both timepoints. Only 25% had treatment switch by 12 months. Despite intense adherence support and viral load monitoring, sustained viral suppression remained elusive in women identified at risk of viral failure. These findings highlight the continued need for effective adherence intervention for women with unsuppressed HIV viral loads, efficient treatment switch strategies, as well as drug level monitoring.

Detection of differentially culturable tubercle bacteria in sputum from drug-resistant tuberculosis patients.

Several studies described the presence of non-replicating, drug-tolerant differentially culturable tubercle bacteria (DCTB) in sputum from patients with active tuberculosis (TB). These organisms are unable to form colonies on agar but can be recovered in liquid media supplemented with culture filtrate as a source of growth factors. Herein, we undertook to investigate the response of DCTB during the treatment of individuals with drug-resistant TB. A cohort of 100 participants diagnosed with rifampicin-resistant TB were enrolled and prospectively followed to monitor response to therapy using routine culture and limiting dilution assays, supplemented with culture filtrate (CF) to quantify DCTB. Fifteen participants were excluded due to contamination, and of the remaining 85 participants, 29, 49, and 7 were infected with rifampicin mono-resistant (RMR), multidrug-resistant (MDR), or extremely drug-resistant (XDR) TB, respectively. Analysis of baseline sputum demonstrated that CF supplementation of limiting dilution assays detected notable amounts of DCTB. Prevalence of DCTB was not influenced by smear status or mycobacterial growth indicator tube time to positivity. CF devoid of resuscitation promoting factors (Rpfs) yielded a greater amount of DCTB in sputum from participants with MDR-TB compared with those with RMR-TB. A similar effect was noted in DCTB assays without CF supplementation, suggesting that CF is dispensable for the detection of DCTB from drug-resistant strains. The HIV status of participants, and CD4 count, did not affect the amount of DCTB recovered. During treatment with second-line drug regimens, the probability of detecting DCTB from sputum specimens in liquid media with or without CF was higher compared with colony forming units, with DCTB detected up to 16 weeks post treatment. Collectively, these data point to differences in the ability of drug-resistant strains to respond to CF and Rpfs. Our findings demonstrate the possible utility of DCTB assays to diagnose and monitor treatment response for drug-resistant TB, particularly in immune compromised individuals with low CD4 counts.

Pregnancy rates and outcomes in a longitudinal HIV cohort in the context of evolving antiretroviral treatment provision in South Africa.

BACKGROUND: In South Africa, women continue to face a high burden of Human Immunodeficiency Virus (HIV) infection and the possible complications thereof during pregnancy. We assessed pregnancy incidence rates and outcomes in a longitudinal HIV cohort study over a 15-year period. METHODS: We evaluated pregnancies among women ≥ 18 years between 2004 and 2019 in the CAPRISA 002 study. We analysed pregnancy rates following HIV acquisition, CD4 counts and HIV viral load dynamics and pregnancy outcomes. We used linear regression to assess if the mean CD4 and log10 viral load close to delivery increases or decreases linearly across three different timepoints. RESULTS: In total 245 women enrolled into the HIV negative study phase, 225 into the HIV infection phase and 232 in the antiretroviral therapy (ART) phase. Median follow-up time was 2.0 years [Interquartile Range (IQR) 0.8-2.0] during the HIV negative phase, 2.6 years; (IQR) 1.2-4.8] during HIV infection and 3.7 years (IQR 1.8-5.0) on ART, with maximum follow-up time of 2, 10 and 6 years respectively. Overall, 169 pregnancies occurred in 140 women, of which 16 pregnancies were observed during acute or early HIV infection [Incidence Rate (IR) 8.0 per 100 women-years; 95% confidence interval (CI): 4.6-12.9], 48 during established infection [IR 9.3; (CI 6.8-12.3)] and 68 on ART [IR 8.9; (CI: 7.0 - 11.4)]. Birth outcomes from 155/169 (91.7%) pregnancies were 118 (76.1%) full term live births, 17 (10.9%) premature live births, 9 (5.8%) therapeutic/elective miscarriages, 8 (5.1%) spontaneous miscarriages and 3 (1.9%) spontaneous foetal deaths or stillbirths. Six mother-to-child transmission events occurred, with four documented prior to 2008. Over time, mean CD4 count in pregnant women increased from 395 cells/µL (2004-2009) to 543 cells/µL (2010-2014) and to 696 cells/µL (2015-2019), p < 0.001. Conversely, the viral load declined from 4.2 log10 copies/ml to 2.5 log10 copies/ml and to 1.2 log10 copies/ml (p < 0.001) for the corresponding periods. CONCLUSIONS: Pregnancy rates following HIV acquisition were high, emphasising a need for timeous ART provision and contraception counselling in women recently diagnosed with HIV. CD4 count and HIV viral load trajectories reflect improvements in treatment guidance for pregnant women over time.

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial.

BACKGROUND: Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data. METHODS AND FINDINGS: In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting. CONCLUSIONS: We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

Viral suppression among pregnant adolescents and women living with HIV in rural KwaZulu-Natal, South Africa: a cross sectional study to assess progress towards UNAIDS indicators and Implications for HIV Epidemic Control.

BACKGROUND: South Africa has made significant progress in scaling up antiretroviral therapy (ART) to achieve the aspirational goal of HIV epidemic control. The aim of this study was to determine the prevalence of HIV, assess progress towards each of the Joint United Nations Programme on HIV/AIDS (UNAIDS) indicators and determine factors associated with achieving viral suppression among pregnant adolescents and women living with HIV in rural KwaZulu-Natal, South Africa. METHODS: Pregnant adolescents and women, 12 years and older seeking antenatal care at six primary health care clinics were enrolled in a cross-sectional study. Following written informed consent, structured questionnaires were administered, and finger-prick blood samples were collected for HIV antibody testing and viral load measurement. Viral suppression was defined as HIV viral load of < 400 copies per mL. RESULTS: Between Dec 2016 and March 2017, among the 546 enrolled participants, data for 545 were analysed. The overall HIV prevalence was 40.2% [95% Confidence Interval (CI) 36.1-44.3]. Age-stratified prevalence increased from 22.1% (95% CI, 15.9-30.0) in the 14-19 year age group to 63.9% (95% CI, 55.1-71.9) among women ≥ 30 years (Χ2 trend P < 0.0001). Of the HIV positive participants, 84.5% (95% CI, 79.0-88.8) knew their HIV positive status, 98.3% (95% CI 95.1-99.4) who knew their status were on ART, and of those on ART, 95.9% (95% CI 91.8-98.0) were virally suppressed. Among all HIV-positives 90.8% (95% CI, 86.3-94.0) had achieved viral suppression, whilst those in the 14-19 year age group were least likely to be virally suppressed at 82.8% (95% CI 65.5-92.4) compared to those in the older age groups. Married women compared to those unmarried were more likely to have achieved viral suppression (PRR) of 1.11 (95% CI 1.05-1.18), P < 0.001. CONCLUSIONS: The proportion of HIV positive pregnant women achieving viral suppression was encouraging though far short of the target towards achieving epidemic control. Importantly, adolescent pregnant women were less likely to know their HIV status and to achieve viral suppression, underscoring the public health implications of sustained risk of HIV transmission. Thus, greater effort and strong social support are essential to improve HIV knowledge of status and care continuum towards the goal to achieving HIV epidemic control. To "fast-track" the response to achieve HIV epidemic control and end the AIDS epidemic, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set ambitious HIV testing and treatment targets for people living with HIV. Meeting these targets through scaling up testing for HIV, initiating and sustaining antiretroviral therapy (ART) to maintain viral suppression provides both therapeutic and preventive benefits with the potential to reduce HIV transmission. Viral suppression among pregnant adolescents and women living with HIV is crucial for the prevention of mother-to-child transmission of HIV including onward transmission to sexual partners. As a public health approach, in South Africa all pregnant women are offered routine HIV testing and immediate initiation of lifelong ART irrespective of CD4 cell count. It is, therefore, important to ascertain progress towards reaching the targets. The proportion of HIV positive pregnant adolescents and women achieving viral suppression was encouraging though far short of the target towards achieving epidemic control. Importantly, pregnant adolescents were less likely to know their HIV status and to achieve viral suppression, underscoring the public health implications of sustained risk of HIV transmission. Thus, greater effort and strong social support are essential to improve HIV knowledge of status and care continuum towards the goal to achieving HIV epidemic control.

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.

Effects of long-term antiretroviral therapy in reproductive-age women in sub-Saharan Africa (the PEPFAR PROMOTE study): a multi-country observational cohort study.

BACKGROUND: We report the long-term impact of ART in women of reproductive age (15-49 years) in Africa who have been using ART for up to 10 years. We assess outcomes of retention, adherence, maternal health, fertility intentions, and safety. METHODS: This longitudinal, multicountry study (PROMOTE) enrolled women who initiated ART in an earlier perinatal clinical trial, PROMISE. PROMISE occurred from 2011 to 2016 and PROMOTE follow-up started in 2016 and is ongoing. The PROMOTE study was done at eight sites in four countries: Malawi (Blantyre and Lilongwe), South Africa (Durban and Soweto), Uganda (Kampala), and Zimbabwe (Harare, Seke North, and St Mary's). After baseline enrolment, women and their children are followed up every 6 months to collect information on medical history, antiretroviral therapy (ART) use, adherence, and health information, and to do physical examinations and laboratory tests. Obesity was defined as a body-mass index of 30 kg/m2 or more. Data analyses were restricted to summaries of the main long-term outcomes (retention, adherence, maternal health, fertility intentions, and safety). We used descriptive and stratified analyses, and estimated rates using person-years of follow-up and computed probabilities based on Kaplan-Meier methods. FINDINGS: PROMOTE enrolled 1987 mothers and 2522 children. The median follow-up time for mothers was 41·8 (IQR 35·8-42·0) months and for children was 35·7 (23·8-42·0) months. Overall retention rates were 96·5% for mothers and 94·3% for children at 12 months, and, at 42 months, were 88·9% for mothers and 85·4% for children. 1115 (89·1%) of 1252 women had an undetectable viral load at 42 months, which varied by site (81·7-93·8%). Reported maternal health improved over time, with the proportion of women with excellent to very good health increasing from 67·5% at baseline to 87·5% at 42 months, the proportion of unwell participants who visited a health centre declining from 14·7% to 2·8%, and the proportion of those admitted to hospital declining from 1·5% to 1·0%. The desire to have more children was consistently high at some sites. The proportion of women with obesity was high in South Africa and increased over time from 40·2% at baseline to 52·8% at 42 months. The overall pregnancy rate was 17·6 (95% CI 16·5-18·7) per 100 women-years, and mortality rates were 2·4 (1·4-3·9) per 1000 person-years for mothers and 3·4 (2·2-5·10) per 1000 person-years for children (0-9 years). INTERPRETATION: The findings from this multicountry study are reassuring. These findings show that African women can consistently use ART for a long period after initiation, and long-term benefits can be maintained. Services to support maternal HIV care, treatment, and reproductive health should be strengthened. FUNDING: US President's Emergency Plan for AIDS Relief.

Recurrent Subclinical Tuberculosis Among Antiretroviral Therapy-Accessing Participants: Incidence, Clinical Course, and Outcomes.

BACKGROUND: Undiagnosed asymptomatic subclinical tuberculosis (TB) remains a significant threat to global TB control, accounting for a substantial proportion of cases among people living with human immunodeficiency virus (HIV)/AIDS (PLWHA). We determined incidence, progression, and outcomes of subclinical TB in antiretroviral therapy (ART)-accessing PLWHA with known previous TB in South Africa. METHODS: A total of 402 adult PLWHA previously treated for TB were enrolled in the prospective Centre for the AIDS Programme of Research in South Africa TRuTH (TB Recurrence Upon TB and HIV treatment) Study. Participants were screened for TB with quarterly clinical and bacteriologic evaluation and biannual chest radiographs over 36 months. Those with suspected or confirmed TB were referred to the National TB Programme. Participants received HIV services, including ART. Incidence rate of TB was estimated using Poisson regression and descriptive statistical analyses summarized data. RESULTS: A total of 48 of 402 (11.9%) bacteriologically confirmed incident recurrent TB cases were identified, comprising 17 of 48 (35.4%) subclinical TB cases and 31 of 48 (64.5%) clinical TB cases. Age, sex, and body mass index were similar among subclinical, clinical, and no TB groups. Incidence rates (95% Confidence Interval [CI]) of recurrent TB overall, in clinical and subclinical TB groups were 2.3 (1.7-3.0), 1.5 (1.1-2.2), and 0.9 (0.5-1.4) per 100 person-years, respectively. In the subclinical TB group, 14 of 17 (82.4%) were diagnosed by TB culture only, 11 of 17 (64.7%) received TB treatment, and 6 of 17 (35.3%) resolved TB spontaneously. CONCLUSIONS: High incidence rates of recurrent subclinical TB in PLWHA highlight inadequacies of symptom-based TB screening in high TB-HIV burden settings.

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study.

BACKGROUND: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]). INTERPRETATION: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. FUNDING: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

Mortality in HIV and tuberculosis patients following implementation of integrated HIV-TB treatment: Results from an open-label cluster-randomized trial.

BACKGROUND: HIV-TB treatment integration reduces mortality. Operational implementation of integrated services is challenging. This study assessed the impact of quality improvement (QI) for HIV-TB integration on mortality within primary healthcare (PHC) clinics in South Africa. METHODS: An open-label cluster randomized controlled study was conducted between 2016 and 2018 in 40 rural clinics in South Africa. The study statistician randomized PHC nurse-supervisors 1:1 into 16 clusters (eight nurse-supervisors supporting 20 clinics per arm) to receive QI, supported HIV-TB integration intervention or standard of care (control). Nurse supervisors and clinics under their supervision, based in the study health districts were eligible for inclusion in this study. Nurse supervisors were excluded if their clinics were managed by municipal health (different resource allocation), did not offer co-located antiretroviral therapy (ART) and TB services, services were performed by a single nurse, did not receive non-governmental organisation (NGO) support, patient data was not available for > 50% of attendees. The analysis population consists of all patients newly diagnosed with (i) both TB and HIV (ii) HIV only (among patients previously treated for TB or those who never had TB before) and (iii) TB only (among patients already diagnosed with HIV or those who were never diagnosed with HIV) after QI implementation in the intervention arm, or enrolment in the control arm. Mortality rates was assessed 12 months post enrolment, using unpaired t-tests and cox-proportional hazards model. (Clinicaltrials.gov, NCT02654613, registered 01 June 2015, trial closed). FINDINGS: Overall, 21 379 participants were enrolled between December 2016 and December 2018 in intervention and control arm clinics: 1329 and 841 HIV-TB co-infected (10·2%); 10 799 and 6 611 people living with Human Immunodeficiency Virus (HIV)/ acquired immunodeficiency syndrome (AIDS) (PLWHA) only (81·4%); 1 131 and 668 patients with TB only (8·4%), respectively. Average cluster sizes were 1657 (range 170-5782) and 1015 (range 33-2027) in intervention and control arms. By 12 months, 6529 (68·7%) and 4074 (70·4%) were alive and in care, 568 (6·0%) and 321 (5·6%) had completed TB treatment, 1078 (11·3%) and 694 (12·0%) were lost to follow-up, with 245 and 156 deaths occurring in intervention and control arms, respectively. Mortality rates overall [95% confidence interval (CI)] was 4·5 (3·4-5·9) in intervention arm, and 3·8 (2·6-5·4) per 100 person-years in control arm clusters [mortality rate ratio (MRR): 1·19 (95% CI 0·79-1·80)]. Mortality rates among HIV-TB co-infected patients was 10·1 (6·7-15·3) and 9·8 (5·0-18·9) per 100 person-years, [MRR: 1·04 (95% CI 0·51-2·10)], in intervention and control arm clusters, respectively. INTERPRETATION: HIV-TB integration supported by a QI intervention did not reduce mortality in HIV-TB co-infected patients. Demonstrating mortality benefit from health systems process improvements in real-world operational settings remains challenging. Despite the study being potentially underpowered to demonstrate the effect size, integration interventions were implemented using existing facility staff and infrastructure reflecting the real-world context where most patients in similar settings access care, thereby improving generalizability and scalability of study findings. FUNDING: Research reported in this publication was supported by South African Medical Research Council (SAMRC), and UK Government's Newton Fund through United Kingdom Medical Research Council (UKMRC).

Safety and Pharmacokinetics of Monoclonal Antibodies VRC07-523LS and PGT121 Administered Subcutaneously for Human Immunodeficiency Virus Prevention.

BACKGROUND: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa. METHODS: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals. RESULTS: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 µg/mL and 3.86 µg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 µg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 µg/mL and 0.22 µg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected. CONCLUSIONS: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.

Acquired HIV drug resistance and virologic monitoring in a HIV hyper-endemic setting in KwaZulu-Natal Province, South Africa.

BACKGROUND: Introduction of tenofovir (TDF) plus lamivudine (3TC) and dolutegravir (DTG) in first- and second-line HIV treatment regimens in South Africa warrants characterization of acquired HIV-1 drug resistance (ADR) mutations that could impact DTG-based antiretroviral therapy (ART). In this study, we sought to determine prevalence of ADR mutations and their potential impact on susceptibility to drugs used in combination with DTG among HIV-positive adults (≥ 18 years) accessing routine care at a selected ART facility in KwaZulu-Natal, South Africa. METHODS: We enrolled adult participants in a cross-sectional study between May and September 2019. Eligible participants had a most recent documented viral load (VL) ≥ 1000 copies/mL after at least 6 months on ART. We genotyped HIV-1 reverse transcriptase and protease genes by Sanger sequencing and assessed ADR. We characterized the effect of ADR mutations on the predicted susceptibility to drugs used in combination with DTG. RESULTS: From 143 participants enrolled, we obtained sequence data for 115 (80%), and 92.2% (95% CI 85.7-96.4) had ADR. The proportion with ADR was similar for participants on first-line ART (65/70, 92.9%, 95% CI 84.1-97.6) and those on second-line ART (40/44, 90.9%, 95% CI 78.3-97.5), and was present for the single participant on third-line ART. Approximately 89% (62/70) of those on first-line ART had dual class NRTI and NNRTI resistance and only six (13.6%) of those on second-line ART had major PI mutations. Most participants (82%) with first-line viraemia maintained susceptibility to Zidovudine (AZT), and the majority of them had lost susceptibility to TDF (71%) and 3TC (84%). Approximately two in every five TDF-treated individuals had thymidine analogue mutations (TAMs). CONCLUSIONS: Susceptibility to AZT among most participants with first-line viraemia suggests that a new second-line regimen of AZT + 3TC + DTG could be effective. However, atypical occurrence of TAMs in TDF-treated individuals suggests a less effective AZT + 3TC + DTG regimen in a subpopulation of patients. As most patients with first-line viraemia had at least low-level resistance to TDF and 3TC, identifying viraemia before switch to TDF + 3TC + DTG is important to avoid DTG functional monotherapy. These findings highlight a need for close monitoring of outcomes on new standardized treatment regimens.