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.

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.

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.

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: 23­39), 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 35­49 years: OR: 0.28, 95% CI: 0.18­0.64, p = 0.003; participants over 50 years: OR: 0.18, 95% CI: 0.07­0.47, p = 0.0004), previous COVID-19 infection (OR: 0.31, 95% CI: 0.11­0.87, p = 0.03), and receiving vaccine information from healthcare workers (OR: 0.32, 95% CI: 0.10­1.0, p = 0.05). Unemployed (OR: 2.14, 95% CI: 1.1­4.2, p = 0.03) and self-employed individuals (OR: 2.98, 95% CI: 1.27­7.02, 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.

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.

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.

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.

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.

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.

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.

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 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.

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.

Performance of rapid antigen tests in identifying Omicron BA.4 and BA.5 infections in South Africa.

BACKGROUND: Concerns around accuracy and performance of rapid antigen tests continue to be raised with the emergence of new SARS-CoV-2 variants. OBJECTIVE: To evaluate the performance of two widely used SARS-CoV-2 rapid antigen tests during BA.4/BA.5 SARS-CoV-2 wave in South Africa (May - June 2022). STUDY DESIGN: A prospective field evaluation compared the SARS-CoV-2 Antigen Rapid test from Hangzhou AllTest Biotech (nasal swab) and the Standard Q COVID-19 Rapid Antigen test from SD Biosensor (nasopharyngeal swab) to the Abbott RealTime SARS-CoV-2 assay (nasopharyngeal swab) on samples collected from 540 study participants. RESULTS: Overall 28.52% (154/540) were SARS-CoV-2 RT-PCR positive with median cycle number value of 12.30 (IQR 9.30-19.40). Out of the 99 successfully sequenced SARS-CoV-2 positive samples, 18 were classified as BA.4 and 56 were classified as BA.5. The overall sensitivities of the AllTest SARS-CoV-2 Ag test and Standard Q COVID-19 Ag test were 73.38% (95% CI 65.89-79.73) and 74.03% (95% CI 66.58-80.31) and their specificities were 97.41% (95% CI 95.30-98.59) and 99.22% (95% CI 97.74-99.74) respectively. Sensitivity was >90% when the cycle number value was <20. The sensitivity of both rapid tests was >90% in samples infected with Omicron sub-lineage BA.4 and BA.5. CONCLUSION: Accuracy of tested rapid antigen tests that target the nucleocapsid SARS-CoV-2 protein, were not adversely affected by BA.4 and BA.5 Omicron sub-variants.

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.

Hepatocyte mARC1 promotes fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1. Results: We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. Impact and implications: We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD.

MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies.

BACKGROUND AND AIM: Enhanced hepatic de novo lipogenesis (DNL) has been proposed as an underlying mechanism for the development of NAFLD and insulin resistance. Max-like protein factor X (MLX) acts as a heterodimer binding partner for glucose sensing transcription factors and inhibition of MLX or downstream targets has been shown to alleviate intrahepatic triglyceride (IHTG) accumulation in mice. However, its effect on insulin sensitivity remains unclear. As human data is lacking, the aim of the present work was to investigate the role of MLX in regulating lipid and glucose metabolism in primary human hepatocytes (PHH) and in healthy participants with and without MLX polymorphisms. METHODS: PHH were transfected with non-targeting or MLX siRNA to assess the effect of MLX knockdown on lipid and glucose metabolism, insulin signalling and the hepatocellular transcriptome. A targeted association analysis on imputed genotype data for MLX on healthy individuals was undertaken to assess associations between specific MLX SNPs (rs665268, rs632758 and rs1474040), plasma biochemistry, IHTG content, DNL and gluconeogenesis. RESULTS: MLX knockdown in PHH altered lipid metabolism (decreased DNL (p < 0.05), increased fatty acid oxidation and ketogenesis (p < 0.05), and reduced lipid accumulation (p < 0.001)). Additionally, MLX knockdown increased glycolysis, lactate secretion and glucose production (p < 0.001) and insulin-stimulated pAKT levels (p < 0.01) as assessed by transcriptomic, steady-state and dynamic measurements. Consistent with the in vitro data, individuals with the rs1474040-A and rs632758-C variants had lower fasting plasma insulin (p < 0.05 and p < 0.01, respectively) and TG (p < 0.05 and p < 0.01, respectively). Although there was no difference in IHTG or gluconeogenesis, individuals with rs632758 SNP had notably lower hepatic DNL (p < 0.01). CONCLUSION: We have demonstrated using human in vitro and in vivo models that MLX inhibition favored lipid catabolism over anabolism and increased glucose production, despite increased glycolysis and phosphorylation of Akt, suggesting a metabolic mechanism that involves futile cycling.

Point-of-Care Viral Load Testing to Manage HIV Viremia During the Rollout of Dolutegravir-Based ART in South Africa: A Randomized Feasibility Study (POwER).

BACKGROUND: Data are required regarding the feasibility of conducting a randomized trial of point-of-care viral load (VL) testing to guide management of HIV viremia and to provide estimates of effect to guide potential future trial design. SETTING: Two public South African clinics during the dolutegravir-based antiretroviral therapy (ART) rollout. METHODS: We randomized adults receiving first-line ART, with recent VL ≥1000 copies/mL, in a 1:1 ratio to receive point-of-care Xpert HIV-1 VL versus standard-of-care laboratory VL testing after 12 weeks. Feasibility outcomes included proportions of eligible patients enrolled and completing follow-up and VL process outcomes. Estimates of effect were assessed using the trial primary outcome of VL <50 copies/mL after 24 weeks. RESULTS: From August 2020 to March 2022, we enrolled 80 eligible participants, an estimated 24% of those eligible. 47 of 80 (58.8%) were women, and the median age was 38.5 years (interquartile range [IQR], 33-45). 44 of 80 (55.0%) were receiving dolutegravir, and 36 of 80 (465.0%) were receiving efavirenz. After 12 weeks, point-of-care participants received VL results after median 3.1 hours (IQR 2.6-3.8), versus 7 days (IQR 6-8, P < 0.001) in standard of care. Twelve-week follow-up VL was ≥1000 copies/mL in 13 of 39 (33.3%) point-of-care participants and in 16 of 41 (39.0%) standard-of-care participants; 11 of 13 (84.6%) and 12 of 16 (75.0%) switched to second-line ART. After 24 weeks, 76 of 80 (95.0%) completed follow-up. 27 of 39 (69.2% [95% CI: 53.4 to 81.4]) point-of-care participants achieved VL <50 copies/mL versus 29 of 40 (72.5% [57.0 to 83.9]) standard-of-care participants. Point-of-care participants had median 3 (IQR, 3-4) clinical visits versus 4 (IQR, 4-5) in standard-of-care participants ( P < 0.001). CONCLUSIONS: It was feasible to conduct a trial of point-of-care VL testing to manage viremia. Point-of-care VL lead to quicker results and fewer clinical visits, but estimates of 24-week VL suppression were similar between arms. TRIAL REGISTRATION: Pan African Clinical Trials Registry: PACTR202001785886049.

Implementation and outcomes of dolutegravir-based first-line antiretroviral therapy for people with HIV in South Africa: a retrospective cohort study.

BACKGROUND: There are few data assessing the uptake of first-line dolutegravir among men and women living with HIV in low-income and middle-income countries, and subsequent clinical outcomes in non-trial settings. We aimed to determine dolutegravir uptake in women, and the effect of dolutegravir on clinical outcomes in routine care in South Africa. METHODS: In this cohort study, we analysed deidentified data from adults receiving first-line antiretroviral therapy (ART) at 59 South African clinics from Dec 1, 2019, to Feb 28, 2022, using two distinct cohorts. In the initiator cohort, we used Poisson regression models to assess the outcome of initiation with dolutegravir-based ART by gender, and associations between dolutegravir use and the outcomes of 12-month retention in care and viral suppression at less than 50 copies per mL. In the transition cohort, comprising adults who received non-dolutegravir-based first-line ART in December, 2019, we used Cox proportional hazards models to assess the outcome of transition to first-line dolutegravir by gender. We then used time-dependent propensity score matching to compare the outcomes of subsequent 12-month retention in care and viral suppression between people who transitioned to dolutegravir and those who had not yet transitioned at the same timepoint. In both the initiation and transition cohort, the primary viral load analysis was an intention-to-treat analysis, with a secondary as-treated analysis that excluded people who changed their ART regimen after baseline. FINDINGS: In the initiator cohort, between Dec 1, 2019, and Feb 28, 2022, 45 392 people were initiated on ART. 23 945 (52·8%) of 45 392 were non-pregnant women, 4780 (10·5%) were pregnant women, and 16 667 (36·7%) were men. The median participant age was 31·0 years (IQR 26·0-38·0) and 2401 (5·3%) were receiving tuberculosis treatment at time of ART initiation. 31 264 (68·9%) of 45 392 people were initiated on dolutegravir, 14 102 (31·1%) on efavirenz, and 26 (0·1%) on nevirapine. In a univariable Poisson regression model, pregnant women (risk ratio [RR] 0·57, 95% CI 0·49 to 0·66; risk difference -35·4%, 95% CI -42·3 to -28·5) and non-pregnant women (RR 0·78, 0·74 to 0·82; risk difference -18·4%, -21·6 to -15·2) were less likely to be initiated on dolutegravir than were men. In Poisson models adjusted for age, gender (including pregnancy), time, tuberculosis status, and initiation CD4 count, people initiated on dolutegravir were more likely to be retained in care at 12 months (adjusted RR 1·09, 95% CI 1·04 to 1·14; adjusted risk difference 5·2%, 2·2 to 8·4) and virally suppressed (adjusted RR 1·04, 95% CI 1·01 to 1·06; adjusted risk difference 3·1%, 1·2 to 5·1) compared with those initiated on non-dolutegravir-based regimens. For the transition cohort, on Dec 1, 2019, 180 956 people were receiving non-dolutegravir-based first-line ART at the study clinics, of whom 124 168 (68·6%) were women. The median age was 38 years (IQR 32-45), and the median time on ART was 3·9 years (2·0-6·4) years, with most people receiving efavirenz (178 624 [98·7%] people) and tenofovir (178 148 [98·4%]). By Feb 28, 2022, 121 174 (67·0%) of 180 956 people had transitioned to first-line dolutegravir at a median of 283 days (IQR 203-526). In a univariable Cox regression model the hazard of being transitioned to dolutegravir was lower in women than in men (hazard ratio 0·56, 95% CI 0·56 to 0·57). Among 92 318 propensity score matched people, the likelihood of retention in care was higher among the dolutegravir group compared with matched controls (adjusted RR 1·03, 95% CI 1·02 to 1·03; risk difference 2·5%, 95% CI 2·1 to 2·9). In the dolutegravir group, 33 423 (90·5%) of 36 920 people were suppressed at less than 50 copies per mL compared with 31 648 (89·7%) of 35 299 matched controls (adjusted RR 1·01, 95% CI 1·00 to 1·02; risk difference 0·8%, 95% CI 0·3 to 1·4). INTERPRETATION: Women were less likely to receive dolutegravir than men. As dolutegravir was associated with improved outcomes, roll-out should continue, with a particular emphasis on inclusion of women. FUNDING: Wellcome Trust, Africa Oxford Initiative, International Association of Providers of AIDS Care, and Bill & Melinda Gates Foundation. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.

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.