Evolutionary analyses of HIV-1 protein-coding sequences : adaptation to host cytotoxic immune responses and purifying selection at synonymous sites

Includes abstract.Includes bibliographical references (p. 136-165).This thesis exposes previously ignored evolutionary characteristics of the synonymous sites of virus nucleotide sequences and contributes new findings to the understanding of the evolution of HIV-1 in relation to the human immune response

Factors associated with Nevirapine adherence in the prevention of mother-to-child transmission of HIV in the Free State province of South Africa and discrepancies between service records and cord-blood surveillance

Includes bibliographical references.Sub-Saharan Africa holds 90% of the HIV-infected children worldwide and most of them are infected through vertical transmission. The elimination of mother-to-child transmission of HIV in this region can be achieved through complementing prophylaxis regimens with effective service delivery. The latter should involve reaching all those at risk and optimizing adherence through adequate and routine follow-up. A study set out to assess the effectiveness of preventing mother-to-child transmission (PMTCT) programs in four African countries including South Africa using the simple nevirapine-based PMTCT regimen, found that prophylaxis coverage for the PMTCT of HIV was on average poor, at only 50% among HIV-exposed infants during 2007-2008. Incomplete HIV testing in pregnancy accounted for 46% of missed opportunities for PMTCT intervention. In addition, discrepancies were found between data from cord-blood samples, which are the gold standard measure of ingestion of the prophylaxis by mothers and routinely collected data on the provision of prophylaxis at antenatal clinics. Clinic records overestimated adherence to prophylaxis which could mislead decisions about service delivery. Adherence to the simple nevirapine regimen, data and service quality should be investigated in order to identify needs for strengthening the effectiveness of WHO Option B guidelines which are being rolled out in resource-poor settings. This project set out to assess the extent of clinic-level PMTCT prophylaxis coverage in the resource-limited setting of the Free State province. Adherence to treatment as well as accuracy of clinic records so as to inform better service implementation were measured. A total of 1572 mother-infant pairs were included in a cross-sectional survey carried out in rural antenatal and delivery services from two health districts between 2007 and 2008. HIV testing and nevirapine prophylaxis data were collected by nurses and compared to anonymously linked cord-blood tests which confirmed true HIV status and ingestion of nevirapine. Logistic regression was used to assess variables from the clinic surveillance data: age, gravidity, mode of delivery, timing of HIV testing and number of antenatal visits during pregnancy, as potential predictors of adherence to nevirapine. The Kappa statistic revealed a disagreement of 10% in HIV test results and 20% in nevirapine intake between clinic records and cord-blood. The clinic records under-estimated maternal HIV prevalence by 9% (22% records versus 31% cord-blood) in mothers aged between 12 and 43 years. Also, cord-blood surveillance revealed that 19.4% of the HIV positive women recorded to have been offered nevirapine during labor, did not actually ingest it. The more frequently a woman sought antenatal care during pregnancy, the more likely she was to ingest nevirapine. Women who had at least 4 antenatal visits were 4.5 times more likely to adhere than women who attended services only once. Even though this is the simplest regimen for preventing vertical HIV transmission, compliance to the entire antenatal cascade during pregnancy is important in improving adherence to therapy and preventing missed opportunities for intervention. Inaccurate collection of routine clinic data negatively impacts on routinely reported data outcomes. Major improvements need to be undertaken both at the service provider and user levels in order to ensure that the effectiveness of the new Option-B guidelines are optimal in remote settings

Hospital acquired COVID-19 infections amongst patients before the rollout of COVID-19 vaccinations, a scoping review

Background Hospital settings are at increased risk of spreading Coronavirus Disease 2019 (COVID-19) infections, hence non-pharmaceutical prevention interventions (NPPIs) and prioritized vaccination of healthcare workers and resident patients are critical. The status of COVID-19 hospital acquired infections (HAIs) in low-income settings is unclear. We aimed to identify and summarize the existing evidence on COVID-19 HAIs amongst patients, prior to the rollout of vaccines in countries worldwide. Methods We conducted a scoping review of English peer-reviewed literature in PubMed, Web of Science and Scopus using a combination of selected search terms. Full texts articles presenting results on COVID-19 HAIs in hospitalised patients before the rollout of vaccines in countries worldwide were eligible. Data extracted from eligible articles included estimates of COVID-19 HAIs, country, and type of hospital setting, and was summarized narratively. Quality assessment of included articles was not possible. Results Literature searches generated a total of 5920 articles, and 45 were eligible for analysis. Eligible articles were from Europe, North America, Asia, and Brazil and none were from low-income countries. The proportion of COVID-19 HAIs ranged from 0% when strict NPPIs were applied, to 65% otherwise. The estimates of COVID-19 HAIs did not differ by country but were lower in studies conducted after implementation of NPPIs and in specialized hospital settings for operative surgery. Studies conducted before the implementation of NPPIs or in long-term care and psychiatric wards often reported high estimates of HAI. Although there was no clear trend in general wards, those situated in academic hospitals managed to reduce HAI rates under strict NPPI protocols. Operative surgery settings, unlike psychiatric settings, effectively prevented COVID-19 HAI using tailored NPPIs. Conclusion The available evidence shows a high risk of COVID-19 HAIs, the feasibility of preventing HAIs in different healthcare settings and the importance of appropriately tailored NPPIs. There were no data from low-income settings, therefore, it is unclear whether the reported NPPI approaches could be equally effective elsewhere. We recommend routine monitoring of COVID-19 HAIs in countries with low vaccination coverage, to identify and close gaps in NPPIs and understand gains made from vaccinating healthcare workers and hospitalized patients

Quality and turnaround times of viral load monitoring under prevention of mother-to-child transmission of HIV Option B+ in six South African districts with a high antenatal HIV burden

BACKGROUND : Barriers to monitoring maternal HIV viral load (VL) and achieving 90% viral suppression during pregnancy and breastfeeding still need to be understood in South Africa (SA). OBJECTIVES : To measure quality of VL care and turnaround times (TATs) for returning VL results to women enrolled in the prevention of mother-to-child transmission of HIV (PMTCT) programme in primary healthcare facilities. METHODS : Data were obtained from a 2018 cross-sectional evaluation of the PMTCT Option B+ programme in six SA districts with high antenatal and infant HIV prevalence. Quality of VL care was measured as the proportion of clients reporting that results were explained to them. TATs for VL results were calculated using dates abstracted from four to five randomly selected facility-based client records to report overall facility ‘short TAT’ (≥80% of records with TAT ≤7 days). Logistical regression and logit-based risk difference statistics were used. RESULTS : Achieving overall short TAT was uncommon. Only 50% of facilities in one rural district, zero in one urban metro district and 9 - 38% in other districts had short TAT. The significant difference between districts was influenced by the duration of keeping results in facilities after receipt from the laboratory. Expected quality of VL care received ranged between 66% and 85%. Client-related factors significantly associated with low quality of care, observed in two urban districts and one rural district, included lower education, recent initiation of antiretroviral treatment and experiencing barriers to clinic visits. Experiencing clinic visit barriers was also negatively associated with short TATs. CONCLUSIONS : We demonstrate above-average quality of care and delayed return of results to PMTCT clients. Context-specific interventions are needed to shorten TATs.The President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC). The publication of this manuscript was funded by the South African Medical Research Council.http://www.samj.org.zadm2022Paediatrics and Child Healt

Infrastructural and human-resource factors associated with return of infant HIV test results to caregivers: secondary analysis of a nationally representative situational assessment, South Africa, 2010

Abstract Background In June 2015, South Africa introduced early infant HIV diagnosis (EID) at birth and ten weeks postpartum. Guidelines recommended return of birth results within a week and ten weeks postpartum results within four weeks. Task shifting was also suggested to increase service coverage. This study aimed to understand factors affecting return of EID results to caregivers. Methods Secondary analysis of data gathered from 571 public-sector primary health care facilities (PHCs) during a nationally representative situational assessment, was conducted. The assessment was performed one to three months prior to facility involvement in the 2010 evaluation of the South African programme to prevent mother-to-child HIV transmission (SAPMTCTE). Self-reported infrastructural and human resource EID-related data were collected from managers and designated staff using a structured questionnaire. The main outcome variable was ‘EID turn-around-time (TAT) to caregiver’ (caregiver TAT), measured as reported number of weeks from infant blood draw to caregiver receipt of results. This was dichotomized as either short (≤3 weeks) or delayed (> 3 weeks) caregiver TAT. Logit-based risk difference analysis was used to assess factors associated with short caregiver TAT. Analysis included TAT to facility (facility TAT), defined as reported number of weeks from infant blood draw to facility receipt of results. Results Overall, 26.3% of the 571 PHCs reported short caregiver TAT. In adjusted analyses, short caregiver TAT was less achieved when facility TAT was > 7 days (versus ≤7 days) (adjusted risk difference (aRD): − 0.2 (95% confidence interval − 0.3-(− 0.1)), p = 0.006 for 8–14 days and − 0.3 (− 0.5-(− 0.1)), p = 0.006 for > 14 days), and in facilities with staff nurses (compared to those without) (aRD: − 9.4 (− 16.6-(− 2.2), p = 0.011). Conclusion Although short caregiver TAT for EID was only reported in approximately 26% of facilities, these facilities demonstrate that achieving EID TAT of ≤3 weeks is possible, making timely ART initiation within 3 weeks of diagnosis feasible within the public health sector. Our adjusted analyses underpin the need for quick return of results to facilities. They also raise questions around staff mentoring: we hypothesise that facilities with staff nurses were likely to have fewer professional nurses, and thus inadequate senior support

Factors associated with non-attendance at scheduled infant follow-up visits in an observational cohort of HIV-exposed infants in South Africa, 2012–2014

Abstract Background Since 2001 the South African guidelines to improve child health and prevent vertical HIV transmission recommended frequent infant follow-up with HIV testing at 18 months postpartum. We sought to understand non-attendance at scheduled follow-up study visits up to 18 months, and for the 18-month infant HIV test amongst a nationally representative sample of HIV exposed uninfected (HEU) infants from a high HIV-prevalence African setting. Methods Secondary analysis of data drawn from a nationally representative observational cohort study (conducted during October 2012 to September 2014) of HEU infants and their primary caregivers was undertaken. Participants were eligible (N = 2650) if they were 4–8 weeks old and HEU at enrolment. All enrolled infants were followed up every 3 months up to 18 months. Each follow-up visit was scheduled to coincide with each child’s routine health visit, where possible. The denominator at each time point comprised HEU infants who were alive and HIV-free at the previous visit. We assessed baseline maternal and early HIV care characteristics associated with the frequency of ‘Missed visits’ (MV-frequency), using a negative binomial regression model adjusting for the follow-up time in the study, and associated with missed visits at 18 months (18-month MV) using a logistic regression model. Results The proportion of eligible infants with MV was lowest at 3 months (32.7%) and 18 months (31.0%) and highest at 12 months (37.6%). HIV-positive mothers not on triple antiretroviral therapy (ART) by 6-weeks postpartum had a significantly increased occurrence rate of ‘MV-frequency’ (adjusted incidence rate ratio, 1.2 (95% confidence interval (CI), 1.1–1.4), p  24 years had a significantly reduced rate of ‘MV-frequency’ (p ≤ 0.01) and risk of ‘18-month-MV’ (p < 0.01) compared to younger women. Shorter travel time to health facility lowered the occurrence of ‘MV-frequency’ (p ≤ 0.004). Conclusion Late initiation of maternal ART and infant prophylaxis under the Option- A policy and extended travel time to clinics (measured at 6 weeks postpartum), contributed to higher postnatal MV rates. Mothers older than 24 years had lower MV rates. Targeted interventions may be needed during the current PMTCT Option B+ (lifelong ART to pregnant and lactating women at HIV diagnosis) to circumvent these risk factors and reduce missed visits during HIV-care

Mixed-methods cross-sectional study of the prevention of vertical HIV transmission program users unaware of male partner’s HIV status, in six South African districts with a high antenatal HIV burden

DATA AVAILABILITY : The dataset is still being analyzed by the primary research team. Anyone needing to access the data should e-mail [email protected] for quantitative data or [email protected] for qualitative data and qualitative methodology. Any data sharing will be by individual request, and in consultation with researchers currently analyzing the data.SUPPLEMENTARY INFORMATION : ADDITIONAL FILE 1: COREQ Checklist for Qualitative Study ADDITIONAL FILE 2: Option B+ FGDs inclusion criteriaBACKGROUND : Elimination of vertical HIV Transmission (VHT) and maternal deaths are global health priorities. Male involvement is one of the most important factors that influences women’s decisions, including the uptake of Prevention of vertical HIV transmission (P-VHT). We sought to understand not knowing a male partner’s HIV status (MPHIVs) amongst women using services to prevent vertical HIV transmission in six South African districts with high antenatal HIV burden. METHODS : A mixed-methods cross-sectional study was conducted in six South African districts, and data collected through face-to-face interviews with women and focus group discussions (FGDs) with women or male partners. The quantitative data were analyzed using STATA SE-17.0 and an inductive approach was used for qualitative data analysis. RESULTS : Overall, 28.7% of women were unaware of their MPHIVs, while 25.3% and 46.0% knew the MPHIVs was positive or negative, respectively. In multivariable logistic regression, single marital status and unplanned pregnancy increased the odds of not knowing a MPHIVs while a woman’s disclosure of her HIV status to the male partner reduced the odds. FDGs highlighted complexities around MPHIVs disclosure, e.g., reluctance to test for HIV and potential interventions including healthcare worker (HCW) assisted HIV disclosure. CONCLUSION : User-informed interventions to address MPHIVs non-disclosure amongst women of child-bearing age, particularly those at risk of unstable sexual partners and unplanned pregnancies, should be strengthened.The President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC); a Ford Foundation Fellowship, administered by the National Academies of Sciences, Engineering, and Medicine, a PEO Scholar Award from the PEO Sisterhood, and NIMH R36MH127838.https://bmcpublichealth.biomedcentral.comam2024Paediatrics and Child HealthSDG-03:Good heatlh and well-bein

Longitudinal adherence to maternal antiretroviral therapy and infant Nevirapine prophylaxis from 6 weeks to 18 months postpartum amongst a cohort of mothers and infants in South Africa.

BACKGROUND: Despite improved policies to prevent mother-to-child HIV transmission (MTCT), adherence to maternal antiretroviral therapy (ART) and infant Nevirapine prophylaxis (NVP) is low in South Africa. We describe ART adherence amongst a cohort of HIV-positive mothers and HIV-exposed but uninfected infants from 6 weeks until 18 months post-delivery and identify risk factors for nonadherence. METHODS: Data were collected in 2012-2014 through a nationally representative survey of PMTCT effectiveness. Mother-infant pairs were enrolled during the infant's first immunization visit at 6 weeks. Mothers and HIV-exposed infants (2811 pairs) were followed to 18 months at 3-month intervals. Mothers who self-reported being on ART at 6 weeks postpartum (N = 1572 (55.9%)) and infants on NVP at 6 weeks (N = 2370 (84.3%)) were eligible for this analysis and information about their adherence was captured at each interview they attended thereafter. We defined nonadherence within each 3-month interval as self-report of missing > 5% of daily ART/NVP doses, estimated adherence using a Cox survival curve with Andersen & Gill setup for recurring events, and identified risk factors for nonadherence with an extended Cox regression model (separately for mothers and infants) in Stata 13. Results are not nationally representative as this is a subgroup analysis of the follow-up cohort. RESULTS: Amongst mothers on ART at 6 weeks postpartum, cumulative adherence to maternal ART until 18 months was 63.4%. Among infants on NPV at 6 weeks postpartum, adherence to NVP was 74.5%.. Risk factors for nonadherence to maternal ART, controlling for other factors, included mother's age (16-24 years vs. ≥34 years, adjusted Hazard Ratio (aHR): 1.9, 95% CI: 1.4-2.5), nondisclosure of HIV status to anyone (nondisclosure vs. disclosure: aHR: 1.7, 95% CI: 1.3-2.1), and timing of ART initiation (initiated ART after delivery vs. initiated ART before delivery: aHR: 1.6, 95% CI: 1.3-2.0). Provincial variation was seen in nonadherence to infant NVP, controlling for other factors. CONCLUSION: Maintaining ART adherence until 18 months postpartum remains a crucial challenge, with maternal ART adherence among the six week maternal ART cohort below 65% and infant NVP adherence among breastfeeding infants in this cohort below 75%.This is gravely concerning, given the global policy shift to lifelong ART amongst pregnant and lactating women, and the need for extended infant prophylaxis amongst mothers who are not virally suppressed. Our findings suggest that young mothers and mothers who do not disclose their status should be targeted with messages to improve adherence, and that late maternal ART initiation (after delivery) increases the risk of maternal nonadherence

Eliminating HIV transmission through breast milk from women taking antiretroviral drugs

publishedVersio

Prevalence of HIV-1 drug resistance amongst newly diagnosed HIV-infected infants age 4–8 weeks, enrolled in three nationally representative PMTCT effectiveness surveys, South Africa: 2010, 2011–12 and 2012–13

Abstract Background South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. Methods Three nationally representative surveys were conducted in 2010, 2011–12 and 2012–13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4–8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. Results Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45–58%]) of HIV PCR positive infants, 37% (95% CI [28–47%]) in 2010, 64% (95% CI [53–74%]) in 2011 and 63% (95% CI [47–77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. Conclusions These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years