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.

Blood monocyte and dendritic cell profiles among people living with HIV with Mycobacterium tuberculosis co-infection.

BACKGROUND: Understanding the complex interactions of the immune response mediated by Mycobacterium tuberculosis and HIV co-infection is fundamental to disease biomarker discovery, vaccine, and drug development. Using flow cytometry, we characterized the frequencies and phenotypic differences in monocytes and dendritic cell populations using peripheral blood mononuclear cells from individuals with recurrent, active pulmonary tuberculosis with and without coexisting HIV infection (CAPRISA 011, Clinicaltrials.gov, NCT02114684, 29/01/2014) and compared them to samples from HIV positive individuals and healthy controls. Additionally, we assessed the associations between the frequency of monocyte and dendritic cell subsets and time to culture conversion and cavitary disease in patients with active TB using a cox proportional hazards and logistic regression models. RESULTS: Compared to healthy controls, the frequency of total monocytes (HLA-DR + CD14 +) was significantly higher in the TB/HIV and TB groups and the frequency of dendritic cells (HLA-DR + CD14-) was significantly higher in TB/HIV and HIV groups. We observed significant variation in the expression of CCR2, CD40, CD11b, CD86, CD163, CX3CR1 across different cell subsets in the four study groups. Increase in CCR2, CD11b and CD40 was associated with active TB infection, while decrease in CX3CR1 and increase in CD163 was associated with HIV infection. Expression of CX3CR1 (aHR 0.98, 95% CI 0.963 - 0.997, p = 0.019) on non-classical monocytes associated with longer time to TB culture conversion in the multivariable model correcting for randomization arm, age, sex, HIV status, lung cavitation, alcohol use, smoking and BMI. Higher surface expression of CD86 (aOR 1.017, 95% CI 1.001 - 1.032, p = 0.033) on intermediate monocytes associated with the presence of lung cavitation, while higher expression of transitional monocytes (aOR 0.944, 95% CI 0.892 - 0.999, p = 0.047) associated with the absence of lung cavitation in the multivariable model. CONCLUSION: These data provide valuable insight into the heterogenous role of monocyte and dendritic cells in TB and HIV infections.

Experience with Contraceptive Dosage Forms and Interest in Novel PrEP Technologies in Women.

New pre-exposure prophylaxis (PrEP) strategies tailored to the needs and expectations of individuals at risk of HIV acquisition are needed. In the CAPRISA 082 prospective cohort study in KwaZulu-Natal, South Africa, sexually active women aged 18 to 30 reported, through interviewer-administered questionnaires, on their prior contraceptive experience and interest in both approved and potential future PrEP dosage forms (oral PrEP, long-acting injectable PrEP, and PrEP implants) between March 2016 and February 2018. Univariable and multivariable Poisson regression models with robust standard errors were used to detect associations between women's prior and current contraceptive use and interest in PrEP options. Of 425 women enrolled, 381 (89.6%) had used at least one modern female contraceptive method previously, with injectable depot medroxyprogesterone acetate (DMPA) being used by 79.8% (n = 339). Women were more likely to show interest in a future PrEP implant if they were currently using (aRR 2.1, CI 1.43-3.07, p = 0.0001) or had ever used (aRR 1.65, CI 1.14-2.40, p = 0.0087) a contraceptive implant, and were more likely to choose an implant as their first choice method than the implant-naïve (current users aRR 3.2, CI 1.79-5.73, p < 0.0001; "ever" users aRR 2.12, CI 1.16-3.86, p = 0.0142). Women were more interested in injectable PrEP if they had used injectable contraceptives (current users aRR 1.24, CI 1.06-1.46, p = 0.0088; "ever" users aRR 1.72, CI 1.20-2.48, p = 0.0033); and were more interested in oral PrEP if they had ever used oral contraceptives (aRR 1.3, CI 1.06-1.59, p = 0.0114). This apparent relationship between women's contraceptive experience and their interest in novel forms of PrEP in an equivalent dosage form may play a future role in strengthening HIV prevention efforts in women at high risk of HIV acquisition.

Associations of Social Support with Sexual Practices, Health Behaviours, and Health Outcomes Among Adolescent Girls and Young Women: Evidence From a Longitudinal Study in KwaZulu-Natal, South Africa.

BACKGROUND: Several studies have reported on the benefits of social support for health behaviour, including risky sex. Social support may thus be an important resource for promoting individual health and well-being, particularly in regions where HIV rates are high and healthcare resources are scarce. However, prior research on the implications of social support for the health behaviour of young women has yielded mixed and inconclusive findings. Using prospective data from young women in South Africa, this study examines the associations of social support with subsequent sexual practices, health behaviour, and health outcomes. METHOD: We used two rounds of longitudinal data from a sample of n = 1446 HIV-negative emerging adult women, aged 18 to 29 years, who participated in a population-based HIV study in KwaZulu-Natal, South Africa. Applying the analytic template for outcome-wide longitudinal designs, we estimated the associations between combinations of social support (i.e. tangible, educational, emotional) and ten HIV risk-related outcomes. RESULTS: Combinations of tangible, educational, and emotional support, as well as tangible support by itself, were associated with lower risk for several outcomes, whereas educational and emotional support, by themselves or together, showed little evidence of association with the outcomes. CONCLUSION: This study highlights the protective role of tangible support in an environment of widespread poverty, and the additional effect of combining tangible support with non-tangible support. The findings strengthen recent evidence on the benefits of combining support in the form of cash and food with psychosocial care in mitigating risk behaviours associated with HIV and negative health outcomes among young women.

Clinical Evaluation of Severe Acute Respiratory Syndrome Coronavirus 2 Rapid Antigen Tests During the Omicron Wave in South Africa.

We evaluated the performance of nasal and nasopharyngeal Standard Q COVID-19 [coronavirus disease 2019] Ag tests (SD Biosensor) and the Panbio COVID-19 Ag Rapid Test Device (nasal; Abbott) against the Abbott RealTime severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assay during the Omicron (clades 21M, 21K, and 21L) wave in South Africa. Overall, all evaluated tests performed well, with high sensitivity (range, 77.78%-81.42%) and excellent specificity values (>99%). The sensitivity of rapid antigen tests increased above 90% in samples with cycle threshold <20, and all 3 tests performed best within the first week after symptom onset.

Impact of COVID-19 public health responses on income, food security and health services among key and vulnerable women in South Africa.

Globally, COVID-19 has impacted lives and livelihoods. Women living with HIV and/or at high risk of acquiring HIV are socially and economically vulnerable. Less is known of the impact of COVID-19 public health responses on women from key and vulnerable populations. The purpose of this cross-sectional survey conducted in four South African provinces with a high burden of HIV and COVID-19 from September to November 2021 was to advance understanding of the socio-economic and health care access impact of COVID-19 on women living with HIV or at high risk of acquiring HIV. A total of 2 812 women >15 years old completed the survey. Approximately 31% reported a decrease in income since the start of the pandemic, and 43% an increase in food insecurity. Among those accessing health services, 37% and 36% reported that COVID-19 had impacted their access to HIV and family planning services respectively. Economic and service disruptions were enhanced by living in informal housing, urbanisation and being in the Western Cape. Food insecurity was increased by being a migrant, having fewer people contributing to the household, having children and experience of gender-based violence. Family planning service disruptions were greater for sex workers and having fewer people contributing to the household. These differentiated impacts on income, food security, access to HIV and family planning services were mediated by age, housing, social cohesion, employment and household income, highlighting the need for improved structural and systemic interventions to reduce the vulnerability of women living with HIV or at high risk of acquiring HIV.

Poor rates of linkage to HIV care and uptake of treatment after home-based HIV testing among newly diagnosed 15-to-49 year-old men and women in a high HIV prevalence setting in South Africa.

Early antiretroviral therapy (ART) initiation is essential, but linkage to care following community-based services is often poor, and inadequately understood. This study examined factors influencing linkage to care following home-based HIV-testing services (HBHTS) in a hyper-endemic setting in South Africa. HBHTS was offered to participants (N = 10,236) enrolled in the second HIV Incidence Provincial Surveillance System survey (2015-2016), KwaZulu-Natal. Follow-up telephone surveys with 196 of the 313 individuals diagnosed HIV-positive through HBHTS were used to measure linkage to care (i.e., a clinic visit within 12 weeks) and ART-initiation. Among newly diagnosed individuals (N = 183), 55% linked to care, and 21% of those who were ART-eligible started treatment within 12 weeks. Linkage to care was less likely among participants who had doubted their HIV-diagnosis (aOR:0.46, 95%CI: 0.23-0.93) and more likely among participants who had disclosed their HIV-status (aOR:2.31, 95%CI: 1.07-4.97). Reasons for not linking to care included no time (61%), only wanting to start treatment when sick (48%), fear of side-effects (33%), and not believing the HIV-diagnosis (16%). Results indicate that HBHTS needs to be paired with targeted interventions to facilitate early linkage to care. Interventions are required to counter denial of HIV status and facilitate early linkage to care among healthier individuals.

Association of medical male circumcision and sexually transmitted infections in a population-based study using targeted maximum likelihood estimation.

BACKGROUND: Epidemiological theory and many empirical studies support the hypothesis that there is a protective effect of male circumcision against some sexually transmitted infections (STIs). However, there is a paucity of randomized control trials (RCTs) to test this hypothesis in the South African population. Due to the infeasibility of conducting RCTs, estimating marginal or average treatment effects with observational data increases interest. Using targeted maximum likelihood estimation (TMLE), a doubly robust estimation technique, we aim to provide evidence of an association between medical male circumcision (MMC) and two STI outcomes. METHODS: HIV and HSV-2 status were the two primary outcomes for this study. We investigated the associations between MMC and these STI outcomes, using cross-sectional data from the HIV Incidence Provincial Surveillance System (HIPSS) study in KwaZulu-Natal, South Africa. HIV antibodies were tested from the blood samples collected in the study. For HSV-2, serum samples were tested for HSV-2 antibodies via an ELISA-based anti-HSV-2 IgG. We estimated marginal prevalence ratios (PR) using TMLE and compared estimates with those from propensity score full matching (PSFM) and inverse probability of treatment weighting (IPTW). RESULTS: From a total 2850 male participants included in the analytic sample, the overall weighted prevalence of HIV was 32.4% (n = 941) and HSV-2 was 53.2% (n = 1529). TMLE estimates suggest that MMC was associated with 31% lower HIV prevalence (PR: 0.690; 95% CI: 0.614, 0.777) and 21.1% lower HSV-2 prevalence (PR: 0.789; 95% CI: 0.734, 0.848). The propensity score analyses also provided evidence of association of MMC with lower prevalence of HIV and HSV-2. For PSFM: HIV (PR: 0.689; 95% CI: 0.537, 0.885), and HSV-2 (PR: 0.832; 95% CI: 0.709, 0.975). For IPTW: HIV (PR: 0.708; 95% CI: 0.572, 0.875), and HSV-2 (PR: 0.837; 95% CI: 0.738, 0.949). CONCLUSION: Using a TMLE approach, we present further evidence of a protective association of MMC against HIV and HSV-2 in this hyper-endemic South African setting. TMLE has the potential to enhance the evidence base for recommendations that embrace the effect of public health interventions on health or disease outcomes.

Age-disparate partnerships and HSV-2 among adolescent girls and young women in South Africa: implications for HIV infection risk.

OBJECTIVE: There is an urgent need to understand high HIV-infection rates among young women in sub-Saharan Africa. While age-disparate partnerships have been characterised with high-risk sexual behaviours, the mechanisms through which these partnerships may increase HIV-risk are not fully understood. This study assessed the association between age-disparate partnerships and herpes simplex virus type-2 (HSV-2) infection, a factor known to increase HIV-infection risk. METHODS: Cross-sectional face-to-face questionnaire data, and laboratory HSV-2 and HIV antibody data were collected among a representative sample in the 2014/2015 household survey of the HIV Incidence Provincial Surveillance System in KwaZulu-Natal, South Africa. Among 15-24-year-old women who reported having ever had sex (n=1550), the association between age-disparate partnerships (ie, male partner ≥5 years older) and HSV-2 antibody status was assessed using multivariable Poisson regression models with robust variance. Analyses were repeated among HIV-negative women. RESULTS: HSV-2 prevalence was 55% among 15-24-year-old women. Women who reported an age-disparate partnership with their most recent partner were more likely to test HSV-2 positive compared with women with age-similar partners (64% vs 51%; adjusted prevalence ratio (aPR):1.19 (95% CI 1.07 to 1.32, p<0.01)). HSV-2 prevalence was also significantly higher among HIV-negative women who reported age-disparate partnerships (51% vs 40 %; aPR:1.25 (95% CI 1.05 to 1.50, p=0.014)). CONCLUSIONS: Results indicate that age-disparate partnerships are associated with a greater risk of HSV-2 among young women. These findings point towards an additional mechanism through which age-disparate partnerships could increase HIV-infection risk. Importantly, by increasing the HSV-2 risk, age-disparate partnerships have the potential to increase the HIV-infection risk within subsequent partnerships, regardless of the partner age-difference in those relationships.

Long-term adherence to antiretroviral therapy in a South African adult patient cohort: a retrospective study.

BACKGROUND: South Africa has the highest HIV prevalence and supports the largest antiretroviral therapy (ART) programme globally. With the introduction of a test and treat policy, ensuring long term optimal adherence to ART (≥95%) is essential for successful patient and public health outcomes. The aim of this study was to assess long-term ART adherence to inform best practices for chronic HIV care. METHOD: Long-term ART adherence was retrospectively analysed over a median duration of 5 years (interquartile range [IQR]: 5.3-6.5) in patients initially enrolled in a randomised controlled trial assessing tuberculosis and HIV treatment integration and subsequently followed post-trial in an observational cohort study in Durban, South Africa. The association between baseline patient characteristics and adherence over time was estimated using generalized estimating equations (GEE). Adherence was assessed using pharmacy pill counts conducted at each study visit and compared to 6 monthly viral load measurements. A Kaplan Meier survival analysis was used to estimate time to treatment failure. The McNemar test (with exact p-values) was used to determine the effect of pill burden and concurrent ART and tuberculosis treatment on adherence. RESULTS: Of the 270 patients included in the analysis; 54.8% were female, median age was 34 years (IQR:29-40) and median time on ART was 70 months (IQR = 64-78). Mean adherence was ≥95% for each year on ART. Stable patients provided with an extended 3-month ART supply maintained adherence > 99%. At study end, 96 and 94% of patients were optimally adherent and virologically suppressed, respectively. Time since ART initiation, female gender and primary breadwinner status were significantly associated with ≥95% adherence to ART. The cumulative probability of treatment failure was 10.7% at 5 years after ART initiation. Concurrent ART and tuberculosis treatment, or switching to a second line ART regimen with higher pill burden, did not impair ART adherence. CONCLUSION: Optimal long-term adherence with successful treatment outcomes are possible within a structured ART programme with close adherence monitoring. This adherence support approach is relevant to a resource limited setting adopting a test and treat strategy.

COVID-19 vaccine hesitancy in KwaZulu-Natal, South Africa: A survey of unvaccinated adults.

Background: Concerns and misconceptions surrounding coronavirus disease 2019 (COVID-19) vaccines may account for vaccine hesitancy and low uptake. Aim: To determine prevalence of COVID-19 vaccine hesitancy, vaccine-related misconceptions, and predictors of vaccine hesitancy among South Africans. Setting: Community setting in five districts in KwaZulu- Natal province. Methods: Between August 20, 2021, and September 27, 2021, we conducted a cross-sectional survey, interviewing 300 unvaccinated adults amid the national vaccination campaign. Predictors of hesitancy were identified through multivariable logistic regression analysis. Results: Participants had a median age of 29 years (IQR: 23-39), 86.7% were Black African, 63.2% were male, 53.3% resided in rural communities, and 59.3% (95% CI: 53.8% - 64.9%) were classified as vaccine hesitant. The primary reason for not vaccinating was a lack of trust in the vaccine (62.1%). Factors associated with reduced vaccine hesitancy included age (participants aged 35-49 years: OR: 0.28, 95% CI: 0.18-0.64, p = 0.003; participants over 50 years: OR: 0.18, 95% CI: 0.07-0.47, p = 0.0004), previous COVID-19 infection (OR: 0.31, 95% CI: 0.11-0.87, p = 0.03), and receiving vaccine information from healthcare workers (OR: 0.32, 95% CI: 0.10-1.0, p = 0.05). Unemployed (OR: 2.14, 95% CI: 1.1-4.2, p = 0.03) and self-employed individuals (OR: 2.98, 95% CI: 1.27-7.02, p = 0.01) were more likely to be vaccine hesitant. Conclusion: COVID-19 vaccine hesitancy rates are high in KwaZulu-Natal. Uptake could be enhanced by healthcare workers leading information campaigns with messages targeting younger individuals, the unemployed, and the self-employed. Contribution: This survey provides evidence to improve COVID-19 vaccination uptake in South Africa.

Effectiveness of ChAdOx1 nCoV-19 and BBIBP-CorV vaccines against COVID-19-associated hospitalisation and death in the Seychelles infected adult population.

BACKGROUND: The Seychelles COVID-19 vaccination campaign was initiated using two different vaccines during the first wave of the pandemic in 2021. This observational study estimated vaccine effectiveness against severe outcomes (hospitalisation and/or death) from individuals infected with COVID-19 in the Seychelles adult population during Beta and Delta variant transmission. METHODS: This nationwide retrospective cohort study included all Seychellois residents aged ≥ 18 years who tested positive by RT-PCR or rapid antigen test for COVID-19 between January 25, 2021, and June 30, 2021. We measured the relative risk (RR) of laboratory-confirmed SARS-CoV-2 hospitalisation and/or death among individuals partially or fully vaccinated with ChAdOx1 nCoV-19 (SII Covishield) or BBIBP-CorV (Sinopharm) vaccines compared to unvaccinated individuals using modified Poisson regression. Controlling for age, gender and calendar month, vaccine effectiveness was estimated as 1-RR ≥14 days after the first dose and ≥7 days after the second dose for each available vaccine versus an unvaccinated control group. RESULTS: A total of 12,326 COVID-19 infections were reported in adult Seychellois residents between January 25, 2021, and June 30, 2021. Of these, 1,287 individuals received one dose of either BBIBP-CorV (Sinopharm) or ChAdOx1-nCoV-19 (SII Covishield) vaccine, and 5,225 individuals received two doses. Estimated adjusted effectiveness of two doses of either Sinopharm or SII Covishield was high, at 70% (95% CI 58%-78%) and 71% (95% CI 62%-78%) respectively. Sinopharm maintained high levels of protection against severe outcomes in partially vaccinated individuals at 61% (95% CI 36%-76%), while the effectiveness of one dose of SII Covishield was low at 29% (95% CI 1%-49%). CONCLUSIONS: This observational study demonstrated high levels of protection of two doses of two vaccine types against severe outcomes of COVID-19 during the first wave of the pandemic driven by Beta (B.1.351) and Delta (B.1.617.2) variant predominance. One dose of ChAdOx1-nCoV-19 (Covishield SII) was found to be inadequate in protecting the general adult population against hospitalisation and/or death from COVID-19.

Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort study.

BACKGROUND: Dolutegravir (DTG) is recommended for second-line antiretroviral therapy (ART) after virological failure on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in people living with HIV in low-income and middle-income countries. We compared the effectiveness of DTG versus the previously recommended ritonavir-boosted lopinavir (LPV/r) regimen for second-line treatment in South Africa. METHODS: In this retrospective observational cohort study, we used routinely collected, de-identified data from 59 primary health-care facilities in eThekwini Municipality, KwaZulu-Natal, South Africa. We included people living with HIV aged 15 years or older with virological failure (defined as two consecutive viral loads of ≥1000 copies per mL at least 56 days apart) on first-line NNRTI-based ART containing tenofovir disoproxil fumarate (TDF) and who switched to second-line ART. Our primary outcomes were retention in care and viral suppression (<50 copies per mL) at 12 months after starting second-line treatment. We used modified Poisson regression models to compare these outcomes between second-line regimens (zidovudine [AZT]/emtricitabine or lamivudine [XTC]/DTG; TDF/XTC/DTG; and AZT/XTC/LPV/r). FINDINGS: We included 1214 participants in our study, of whom 729 (60%) were female and 485 (40%) were male, and whose median age was 36 years (IQR 30-42). 689 (57%) were switched to AZT/XTC/LPV/r, 217 (18%) to AZT/XTC/DTG, and 308 (25%) to TDF/XTC/DTG. Compared with AZT/XTC/LPV/r (75%), retention in care was higher with AZT/XTC/DTG (86%, adjusted risk ratio [aRR]=1·14, 95% CI 1·03-1·27; adjusted risk difference [aRD]=10·89%, 95% CI 2·01 to 19·78) but similar with TDF/XTC/DTG (77%, aRR=1·01, 0·94-1·10; aRD=1·04%, -5·03 to 7·12). Observed retention in care was lower with TDF/XTC/DTG than with AZT/XTC/DTG, although in multivariable analysis evidence for a difference was weak (aRR=0·89, 0·78-1·01, p=0·060; aRD=-9·85%, -20·33 to 0·63, p=0·066). Of 799 participants who were retained in care with a 12-month viral load test done, viral suppression was higher with AZT/XTC/DTG (59%; aRR=1·25, 1·06-1·47; aRD=11·57%, 2·37 to 20·76) and higher with TDF/XTC/DTG (61%; aRR=1·30, 1·14-1·48; aRD=14·16%, 7·14 to 21·18) than with AZT/XTC/LPV/r (47%). INTERPRETATION: These findings from routine care support further implementation of WHO's recommendation to use DTG instead of LPV/r in people living with HIV who experience virological failure while receiving first-line NNRTI-based ART. FUNDING: Bill & Melinda Gates Foundation. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.

Evaluating diagnostic accuracy of an RT-PCR test for the detection of SARS-CoV-2 in saliva.

BACKGROUND AND OBJECTIVE: Saliva has been proposed as a potential more convenient, cost-effective, and easier sample for diagnosing SARS-CoV-2 infections, but there is limited knowledge of the impact of saliva volumes and stages of infection on its sensitivity and specificity. METHODS: In this study, we assessed the performance of SARS-CoV-2 testing in 171 saliva samples from 52 mostly mildly symptomatic patients (aged 18 to 70 years) with a positive reference standard result at screening. The samples were collected at different volumes (50, 100, 300, and 500 µl of saliva) and at different stages of the disease (at enrollment, day 7, 14, and 28 post SARS-CoV-2 diagnosis). Imperfect nasopharyngeal (NP) swab nucleic acid amplification testing was used as a reference. We used a logistic regression with generalized estimating equations to estimate sensitivity, specificity, PPV, and NPV, accounting for the correlation between repeated observations. RESULTS: The sensitivity and specificity values were consistent across saliva volumes. The sensitivity of saliva samples ranged from 70.2% (95% CI, 49.3-85.0%) for 100 µl to 81.0% (95% CI, 51.9-94.4%) for 300 µl of saliva collected. The specificity values ranged between 75.8% (95% CI, 55.0-88.9%) for 50 µl and 78.8% (95% CI, 63.2-88.9%) for 100 µl saliva compared to NP swab samples. The overall percentage of positive results in NP swabs and saliva specimens remained comparable throughout the study visits. We observed no significant difference in cycle number values between saliva and NP swab specimens, irrespective of saliva volume tested. CONCLUSIONS: The saliva collection offers a promising approach for population-based testing.

Single-nucleotide polymorphisms in ABC drug transporters alter expression and circulating tenofovir in healthy South African women exposed to pre-exposure prophylaxis.

Aim: We investigated if single-nucleotide polymorphisms (SNPs) in ATP-binding cassette (ABC) drug transporters alter gene expression and tenofovir disposition in South African women taking Truvada® for HIV prevention. Materials & methods: In 393 women, real-time PCR was used to determine the associations between six SNPs in ABC transporter genes, mRNA expression and circulating-tenofovir. Results: Univariable and multivariable analyses showed that CT and TT relative to CC genotypes for the ABCC4(3463C/T) SNP had significantly higher tenofovir levels. In contrast, the AA genotype for the ABCC4(4976A/G) SNP showed significantly less tenofovir, while mRNA expression was increased. Conclusion: SNPs in the ABCC4 gene may differentially affect gene expression and circulating tenofovir. Their impact may inform on low pre-exposure prophylaxis efficacy and discern effective drugs in clinical trials of African women enriched for certain genotypes.

NK cell phenotypic profile during active TB in people living with HIV-evolution during TB treatment and implications for bacterial clearance and disease severity.

Natural killer (NK) cells, key effector cells of the innate immune system, play an important role in the clearance and control of Mycobacterium tuberculosis and HIV infections. Here, we utilized peripheral blood specimens from the Improving Retreatment Success CAPRISA 011 study to characterize NK cell phenotypes during active TB in individuals with or without HIV co-infection. We further assessed the effects of TB treatment on NK cell phenotype, and characterized the effects of NK cell phenotypes during active TB on mycobacterial clearance and TB disease severity measured by the presence of lung cavitation. TB/HIV co-infection led to the expansion of functionally impaired CD56neg NK cell subset. TB treatment completion resulted in restoration of total NK cells, NK cell subset redistribution and downregulation of several NK cell activating and inhibitory receptors. Higher percentage of peripheral CD56bright cells was associated with longer time to culture conversion, while higher expression of NKp46 on CD56dim NK cells was associated with lower odds of lung cavitation in the overall cohort and the TB/HIV co-infected participants. Together these results provide a detailed description of peripheral NK cells in TB and TB/HIV co-infection and yield insights into their role in TB disease pathology.

Clinical outcomes after extended 12-month antiretroviral therapy prescriptions in a community-based differentiated HIV service delivery programme in South Africa: a retrospective cohort study.

INTRODUCTION: There is an urgent need for more efficient models of differentiated antiretroviral therapy (ART) delivery for people living with HIV (PLHIV), with the World Health Organization calling for evidence to guide whether annual ART prescriptions and consultations (12M scripts) should be recommended in global guidelines. We assessed the association between 12M scripts (allowed temporarily during the COVID-19 pandemic) versus standard 6-month prescriptions and consultations (6M scripts) and clinical outcomes. METHODS: We performed a retrospective cohort study using routine, de-identified data from 59 public clinics in KwaZulu-Natal, South Africa. We included PLHIV aged ≥18 years with a recent suppressed viral load (VL) who had been referred for community ART delivery with 6M or 12M scripts. We used modified Poisson regression to compare 12-month retention-in-care (≤90 days late for all visits) and viral suppression (<50 copies/ml) between prescription groups. RESULTS: Among 27,148 PLHIV referred for community ART during Jun-Dec 2020, 57.4% received 12M scripts. The median age was 39 years and 69.4% were women. Age, sex, prior community ART use and time on ART were similar across groups. However, more of the 12M script group had dolutegravir-based regimens (60.0% vs. 46.3%). The median (interquartile range) number of clinic visits in the year of follow-up was 1(1-1) in the 12M group and 2(2-3) in the 6M group. Retention was 94.6% (95% confidence interval [CI]: 94.2%-94.9%) among those receiving 12M scripts and 91.8% (95% CI: 91.3%-92.3%) among those with 6M scripts. 17.1% and 16.9% of clients in the 12M and 6M groups were missing follow-up VL data, respectively. Among those with VLs, 92.4% (95% CI: 92.0%-92.9%) in the 12M group and 91.4% (95% CI: 90.8%-92.0%) in the 6M group were suppressed. After adjusting for age, sex, ART regimen, time on ART, prior community ART use and calendar month, retention (adjusted risk ratio [aRR]: 1.03, 95% CI: 1.01-1.05) and suppression (aRR: 1.00, 95% CI: 0.99-1.01) were similar across groups. CONCLUSIONS: Among PLHIV referred for community ART with a recent suppressed VL, the use of 12M scripts reduced clinic visits without impacting short-term clinical outcomes. 12M scripts should be considered for differentiated service delivery programmes.

Field evaluations of four SARS-CoV-2 rapid antigen tests during SARS-CoV-2 Delta variant wave in South Africa.

BACKGROUND: Rapid antigen tests detecting SARS-CoV-2 were shown to be a useful tool in managing the COVID-19 pandemic. Here, we report on the results of a prospective diagnostic accuracy study of four SARS-CoV-2 rapid antigen tests in a South African setting. METHODS: Rapid antigen test evaluations were performed through drive-through testing centres in Durban, South Africa, from July to December 2021. Two evaluation studies were performed: nasal Panbio COVID-19 Ag Rapid Test Device (Abbott) was evaluated in parallel with the nasopharyngeal Espline SARS-CoV-2 Ag test (Fujirebio), followed by the evaluation of nasal RightSign COVID-19 Antigen Rapid test Cassette (Hangzhou Biotest Biotech) in parallel with the nasopharyngeal STANDARD Q COVID-19 Ag test (SD Biosensor). The Abbott RealTime SARS-CoV-2 assay was used as a reference test. RESULTS: Evaluation of Panbio and Espline Ag tests was performed on 494 samples (31% positivity), while the evaluation of Standard Q and RightTest Ag tests was performed on 539 samples (13.17% positivity). The overall sensitivity for all four tests ranged between 60 and 72% with excellent specificity values (> 98%). Sensitivity increased to > 80% in all tests in samples with cycle number value < 20. All four tests performed best in samples from patients presenting within the first week of symptom onset. CONCLUSIONS: All four evaluated tests detected a majority of the cases within the first week of symptom onset with high viral load.

Clinical outcomes after the introduction of dolutegravir for second-line antiretroviral therapy in South Africa: a retrospective cohort study.

Background: Dolutegravir is now recommended for second-line anti-retroviral therapy (ART) in low- and middle-income countries. We compared outcomes with dolutegravir (DTG) versus the previous lopinavir/ritonavir (LPV/r) regimen in South Africa. Methods: We used routinely collected, de-identified data from 59 South African clinics. We included people living with HIV aged ≥ 15 years with virologic failure (two consecutive viral loads ≥1000 copies/mL) on first-line tenofovir disoproxil fumarate (TDF)-based ART and switched to second-line ART. We used modified Poisson regression models to compare outcomes of 12-month retention-in-care and viral suppression (<50 copies/ml) after switching to second-line regimens of zidovudine (AZT), emtricitabine/lamivudine (XTC), DTG and TDF/XTC/DTG and AZT/XTC/LPV/r. Findings: Of 1214 participants, 729 (60.0%) were female, median age was 36 years (interquartile range 30 to 42), 689 (56.8%) were switched to AZT/XTC/LPV/r, 217 (17.9%) to AZT/XTC/DTG and 308 (25.4%) to TDF/XTC/DTG. Retention-in-care was higher with AZT/XTC/DTG (85.7%, adjusted risk ratio (aRR) 1.14, 95% confidence interval (CI) 1.03 to 1.27; adjusted risk difference (aRD) 10.89%, 95%CI 2.01 to 19.78) but not different with TDF/XTC/DTG (76.9%, aRR 1.01, 95%CI 0.94 to 1.10; aRD 1.04%, 95%CI -5.03 to 7.12) compared to AZT/XTC/LPV/r (75.2%). Retention-in-care with TDF/XTC/DTG was not statistically significantly different from AZT/XTC/DTG (aRR 0.89, 95%CI 0.78 to 1.01; aRD -9.85%, 95%CI -20.33 to 0.63). Of 799 participants who were retained-in-care with a 12-month viral load, viral suppression was higher with AZT/XTC/DTG (59.3%, aRR 1.25, 95%CI 1.06 to 1.47; aRD 11.57%, 95%CI 2.37 to 20.76) and TDF/XTC/DTG (60.7%, aRR 1.30, 95%CI 1.14 to 1.48; aRD 14.16%, 95%CI 7.14 to 21.18) than with the AZT/XTC/LPV/r regimen (46.7%). Interpretation: DTG-based second-line regimens were associated with similar or better retention-in-care and better viral suppression than the LPV/r-based regimen. TDF/XTC/DTG had similar viral suppression compared to AZT/XTC/DTG. Funding: Bill & Melinda Gates Foundation, Africa Oxford Initiative.

Clinical Outcomes After Viremia Among People Receiving Dolutegravir vs Efavirenz-Based First-line Antiretroviral Therapy in South Africa.

Background: We aimed to compare clinical outcomes after viremia between dolutegravir vs efavirenz-based first-line antiretroviral therapy (ART) as evidence is lacking outside clinical trials in resource-limited settings. Methods: We conducted a retrospective cohort analysis with routine data from 59 South African clinics. We included people with HIV aged ≥15 years receiving first-line tenofovir disoproxil fumarate, lamivudine, dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, efavirenz (TEE) and with first viremia (≥50 copies/mL) between June and November 2020. We used multivariable modified Poisson regression models to compare retention in care and viral suppression (<50 copies/mL) after 12 months between participants on TLD vs TEE. Results: At first viremia, among 9657 participants, 6457 (66.9%) were female, and the median age (interquartile range [IQR]) was 37 (31-44) years; 7598 (78.7%) were receiving TEE and 2059 (21.3%) TLD. Retention in care was slightly higher in the TLD group (84.9%) than TEE (80.8%; adjusted risk ratio [aRR], 1.03; 95% CI, 1.00-1.06). Of 6569 participants retained in care with a 12-month viral load, viral suppression was similar between the TLD (78.9%) and TEE (78.8%) groups (aRR, 1.02; 95% CI, 0.98-1.05). However, 3368 participants changed ART during follow-up: the majority from TEE to first-line TLD (89.1%) or second-line (TLD 3.4%, zidovudine/emtricitabine/lopinavir-ritonavir 2.1%). In a sensitivity analysis among the remaining 3980 participants who did not change ART during follow-up and had a 12-month viral load, viral suppression was higher in the TLD (78.9%) than TEE (74.9%) group (aRR, 1.07; 95% CI, 1.03-1.12). Conclusions: Among people with viremia on first-line ART, dolutegravir was associated with slightly better retention in care and similar or better viral suppression than efavirenz.