Delivery of index-linked HIV testing for children: learnings from a qualitative process evaluation of the B-GAP study in Zimbabwe.

BACKGROUND: Index-linked HIV testing for children, whereby HIV testing is offered to children of individuals living with HIV, has the potential to identify children living with undiagnosed HIV. The "Bridging the Gap in HIV Testing and Care for Children in Zimbabwe" (B-GAP) study implemented and evaluated the provision of index-linked HIV testing for children aged 2-18 years in Zimbabwe. We conducted a process evaluation to understand the considerations for programmatic delivery and scale-up of this strategy. METHODS: We used implementation documentation to explore experiences of the field teams and project manager who delivered the index-linked testing program, and to describe barriers and facilitators to index-linked testing from their perspectives. Qualitative data were drawn from weekly logs maintained by the field teams, monthly project meeting minutes, the project coordinator's incident reports and WhatsApp group chats between the study team and the coordinator. Data from each of the sources was analysed thematically and synthesised to inform the scale-up of this intervention. RESULTS: Five main themes were identified related to the implementation of the intervention: (1) there was reduced clinic attendance of potentially eligible indexes due to community-based differentiated HIV care delivery and collection of HIV treatment by proxy individuals; (2) some indexes reported that they did not live in the same household as their children, reflecting the high levels of community mobility; (3) there were also thought to be some instances of 'soft refusal'; (4) further, delivery of HIV testing was limited by difficulties faced by indexes in attending health facilities with their children for clinic-based testing, stigma around community-based testing, and the lack of familiarity of indexes with caregiver provided oral HIV testing; (5) and finally, test kit stockouts and inadequate staffing also constrained delivery of index-linked HIV testing. CONCLUSIONS: There was attrition along the index-linked HIV testing cascade of children. While challenges remain at all levels of implementation, programmatic adaptations of index-linked HIV testing approaches to suit patterns of clinic attendance and household structures may strengthen implementation of this strategy. Our findings highlight the need to tailor index-linked HIV testing to subpopulations and contexts to maximise its effectiveness.

Feasibility and Accuracy of HIV Testing of Children by Caregivers Using Oral Mucosal Transudate HIV Tests.

BACKGROUND: Children encounter multiple barriers in accessing facilities. HIV self-testing using oral mucosal transudate (OMT) tests has been shown to be effective in reaching hard-to-reach populations. We evaluated the feasibility and accuracy of caregivers conducting HIV testing using OMTs in children in Zimbabwe. METHODS: We offered OMTs to caregivers (>18 years) living with HIV to test children (2-18 years) living in their households. All caregivers were provided with manufacturer instructions. In Phase 1 (January-December 2018, 9 clinics), caregivers additionally received a demonstration by a provider using a test kit and video. In Phase 2 (January-May 2019, 3 clinics), caregivers did not receive a demonstration. We collected demographic data and assessed caregiver's ability to perform the test and interpret results. Caregiver performance was assessed by direct observation and scored using a predefined checklist. Factors associated with obtaining a full score were analyzed using logistic regression. RESULTS: Overall 400 caregivers (83.0% female, median age 38 years) who were observed tested 786 children (54.6% female, median age 8 years). For most tests, caregivers correctly collected oral fluid [87.1% without provider demonstrations (n = 629) and 96.8% with demonstrations (n = 157), P = 0.002]. The majority correctly used a timer (90.3% without demonstrations and 96.8% with demonstrations, P = 0.02). In multivariate logistic regression caregivers who obtained a full score for performance were more likely to have received a demonstration (odds ratio 4.14, 95% confidence interval: 2.01 to 8.50). CONCLUSIONS: Caregiver-provided testing using OMTs is a feasible and accurate HIV testing strategy for children. We recommend operational research to support implementation at scale.

Comparison of index-linked HIV testing for children and adolescents in health facility and community settings in Zimbabwe: findings from the interventional B-GAP study.

BACKGROUND: Index-linked HIV testing, whereby children of individuals with HIV are targeted for testing, increases HIV yield but relies on uptake. Community-based testing might address barriers to testing access. In the Bridging the Gap in HIV testing and care for children in Zimbabwe (B-GAP) study, we investigated the uptake and yield of index-linked testing in children and the uptake of community-based vs facility-based HIV testing in Zimbabwe. METHODS: B-GAP was an interventional study done in the city of Bulawayo and the province of Matabeleland South between Jan 29 and Dec 12, 2018. All HIV-positive attendees (index patients) at six urban and three rural primary health-care clinics were offered facility-based or community-based HIV testing for children (age 2-18 years) living in their households who had never been tested or had tested as HIV-negative more than 6 months ago. Community-based options involved testing in the home by either a trained lay worker with a blood-based rapid diagnostic test (used in facility-based testing), or by the child's caregiver with an oral HIV test. Among consenting individuals, the primary outcome was testing uptake in terms of the proportion of eligible children tested. Secondary outcomes were uptake of the different HIV testing methods, HIV yield (proportion of eligible children who tested positive), and HIV prevalence (proportion of HIV-positive children among those tested). Logistic regression adjusting for within-index clustering was used to investigate index patient and child characteristics associated with testing uptake, and the uptake of community-based versus facility-based testing. FINDINGS: Overall, 2870 index patients were linked with 6062 eligible children (3115 [51·4%] girls [sex unknown in seven], median age 8 years [IQR 5-13]). Testing was accepted by index patients for 5326 (87·9%) children, and 3638 were tested with a known test outcome, giving an overall testing uptake among 6062 eligible children of 60·0%. 39 children tested positive for HIV, giving an HIV prevalence among the 3638 children of 1·1% and an HIV yield among 6062 eligible children of 0·6%. Uptake was positively associated with female sex in the index patient (adjusted odds ratio [aOR] 1·56 [95% CI 1·38-1·77], p<0·0001) and child (aOR 1·10 [1·03-1·19], p=0·0080), and negatively associated with any financial cost of travel to a clinic (aOR 0·86 [0·83-0·88], p<0·0001), increased child age (6-9 years: aOR 0·99 (0·89-1·09); 10-15 years: aOR 0·91 [0·83-1·00]; and 16-18 years: aOR 0·75 [0·66-0·85]; p=0·0001 vs 2-5 years), and unknown HIV status of the mother (aOR 0·81 [0·68-0·98], p=0·027 vs HIV-positive status). Additionally, children had increased odds of being tested if community-based testing was chosen over facility-based testing at screening (1320 [73·9%] children tested of 1787 vs 2318 [65·5%] of 3539; aOR 1·49 [1·22-1·81], p=0·0001). INTERPRETATION: The HIV yield of index-linked testing was low compared with blanket testing approaches in similar settings. Index-linked HIV testing can improve testing uptake among children, although strategies that improve testing uptake in older children are needed. Community based testing by lay workers is a feasible strategy that can be used to improve uptake of HTS among children and adolescents. FUNDING: UK Medical Research Council, UK Department for International Development, Wellcome Trust.

Brief Report: Improving Early Infant Diagnosis Observations: Estimates of Timely HIV Testing and Mortality Among HIV-Exposed Infants.

BACKGROUND: Improving efforts toward elimination of mother-to-child transmission of HIV requires timely early infant diagnosis (EID) among all HIV-exposed infants, but the occurrence of timely EID and infant survival may be underascertained in routine, facility-bound program data. METHODS: From March 2015 to May 2015, we traced a random sample of HIV-positive mother and HIV-exposed infant pairs lost to follow-up for EID in facility registers in Zimbabwe. We incorporated updated information into weighted survival analyses to estimate incidence of EID and death. Reasons for no EID were surveyed from caregivers. RESULTS: Among 2651 HIV-positive women attending antenatal care, 1823 (68.8%) infants had no documented EID by 3 months of age. Among a random sample of 643 (35.3%) HIV-exposed infants lost to follow-up for EID, vital status was ascertained among 371 (57.7%) and updated care status obtained from 256 (39.8%) mothers traced. Among all HIV-infected mother-HIV-exposed infant pairs, weighted estimates found cumulative incidence of infant death by 90 days of 3.9% (95% confidence interval: 3.4% to 4.4%). Cumulative incidence of timely EID with death as a competing risk was 60%. The most frequently cited reasons for failure to uptake EID were "my child died" and "I didn't know I should have my child tested." CONCLUSIONS: Our findings indicate uptake of timely EID among HIV-exposed infants is underestimated in routine health information systems. High, early mortality among HIV-exposed infants underscores the need to more effectively identify HIV-positive mother-HIV exposed infant pairs at high risk of adverse outcomes and loss to follow-up for enhanced interventions.

Evaluating the effectiveness and cost-effectiveness of health facility-based and community-based index-linked HIV testing strategies for children: protocol for the B-GAP study in Zimbabwe.

INTRODUCTION: The number of new paediatric infections per year has declined in sub-Saharan Africa due to prevention-of-mother-to-child HIV transmission programmes; many children and adolescents living with HIV remain undiagnosed. In this protocol paper, we describe the methodology for evaluating an index-linked HIV testing approach for children aged 2-18 years in health facility and community settings in Zimbabwe. METHODS AND ANALYSIS: Individuals attending for HIV care at selected primary healthcare clinics (PHCs) will be asked if they have any children aged 2-18 years in their households who have not been tested for HIV. Three options for HIV testing for these children will be offered: testing at the PHC; home-based testing performed by community workers; or an oral mucosal HIV test given to the caregiver to test the children at home. All eligible children will be followed-up to ascertain whether HIV testing occurred. For those who did not test, reasons will be determined, and for those who tested, the HIV test result will be recorded. The primary outcome will be uptake of HIV testing. The secondary outcomes will be preferred HIV testing method, HIV yield, prevalence and proportion of those testing positive linking to care and having an undetectable viral load at 12 months. HIV test results will be stratified by sex and age group, and factors associated with uptake of HIV testing and choice of HIV testing method will be investigated. ETHICS AND DISSEMINATION: Ethical approval for this study was granted by the Medical Research Council of Zimbabwe, the London School of Hygiene and Tropical Medicine and the Institutional Review Board of the Biomedical Research and Training Institute. Study results will be presented at national policy meetings and national and international research conferences. Results will also be published in international peer-reviewed scientific journals and disseminated to study communities at the end of study.

Childhood fish oil supplementation modifies associations between traffic related air pollution and allergic sensitisation.

BACKGROUND: Studies of potential adverse effects of traffic related air pollution (TRAP) on allergic disease have had mixed findings. Nutritional studies to examine whether fish oil supplementation may protect against development of allergic disease through their anti-inflammatory actions have also had mixed findings. Extremely few studies to date have considered whether air pollution and dietary factors such as fish oil intake may interact, which was the rationale for this study. METHODS: We conducted a secondary analysis of the Childhood Asthma Prevention Study (CAPS) birth cohort, where children were randomised to fish oil supplementation or placebo from early life to age 5 years. We examined interactions between supplementation and TRAP (using weighted road density at place of residence as our measure of traffic related air pollution exposure) with allergic disease and lung function outcomes at age 5 and 8 years. RESULTS: Outcome information was available on approximately 400 children (~ 70% of the original birth cohort). Statistically significant interactions between fish oil supplementation and TRAP were seen for house dust mite (HDM), inhalant and all-allergen skin prick tests (SPTs) and for HDM-specific interleukin-5 response at age 5. Adjusting for relevant confounders, relative risks (RRs) for positive HDM SPT were RR 1.74 (95% CI 1.22-2.48) per 100 m local road or 33.3 m of motorway within 50 m of the home for those randomised to the control group and 1.03 (0.76-1.41) for those randomised to receive the fish oil supplement. The risk differential was highest in an analysis restricted to those who did not change address between ages 5 and 8 years. In this sub-group, supplementation also protected against the effect of traffic exposure on pre-bronchodilator FEV1/FVC ratio. CONCLUSIONS: Results suggest that fish oil supplementation may protect against pro-allergic sensitisation effects of TRAP exposure. Strengths of this analysis are that supplementation was randomised and independent of TRAP exposure, however, findings need to be confirmed in a larger experimental study with the interaction investigated as a primary hypothesis, potentially also exploring epigenetic mechanisms. More generally, studies of adverse health effects of air pollution may benefit from considering potential effect modification by diet and other factors. TRIAL REGISTRATION: Australia New Zealand Clinical Trial Registry. www.anzctr.org.au Registration: ACTRN12605000042640 , Date: 26th July 2005. Retrospectively registered, trial commenced prior to registry availability.

Facility-based delivery in the context of Zimbabwe's HIV epidemic--missed opportunities for improving engagement with care: a community-based serosurvey.

BACKGROUND: In developing countries, facility-based delivery is recommended for maternal and neonatal health, and for prevention of mother-to-child HIV transmission (PMTCT). However, little is known about whether or not learning one's HIV status affects one's decision to deliver in a health facility. We examined this association in Zimbabwe. METHODS: We analyzed data from a 2012 cross-sectional community-based serosurvey conducted to evaluate Zimbabwe's accelerated national PMTCT program. Eligible women (≥16 years old and mothers of infants born 9-18 months before the survey) were randomly sampled from the catchment areas of 157 health facilities in five of ten provinces. Participants were interviewed about where they delivered and provided blood samples for HIV testing. RESULTS: Overall 8796 (77 %) mothers reported facility-based delivery; uptake varied by community (30-100%). The likelihood of facility-based delivery was not associated with maternal HIV status. Women who self-reported being HIV-positive before delivery were as likely to deliver in a health facility as women who were HIV-negative, irrespective of when they learned their status - before (adjusted prevalence ratio (PRa) = 1.04, 95% confidence interval (CI) = 1.00-1.09) or during pregnancy (PRa = 1.05, 95% CI = 1.01-1.09). Mothers who had not accessed antenatal care or tested for HIV were most likely to deliver outside a health facility (69%). Overall, however 77% of home deliveries occurred among women who had accessed antenatal care and were HIV-tested. CONCLUSIONS: Uptake of facility-based delivery was similar among HIV-infected and HIV-uninfected mothers, which was somewhat unexpected given the substantial technical and financial investment aimed at retaining HIV-positive women in care in Zimbabwe.

Breastfeeding, asthma, and allergy: a tale of two cities.

BACKGROUND: The effect of breastfeeding duration on subsequent asthma and allergy remains the subject of much controversy. OBJECTIVE: To investigate whether differences in study design or disease-related exposure modification were the cause of the differences in study findings. METHOD: The data from two cohorts, the Childhood Asthma Prevention Study (CAPS) from Australia and the Barn Allergi Miljo Stockholm cohort from Sweden, which had reported different findings on the association between breastfeeding and asthma, were combined. For this analysis, the definitions for breastfeeding, asthma, and allergy were harmonized. Subjects were included if they had at least one parent with wheeze or asthma and had a gestational age of more than 36 wks (combined n = 882). The risk of disease-related exposure modification was assessed using survival analysis. RESULTS: Breastfeeding reduced the risk of asthma at 4/5 and 8 yrs of age in children with a family history of asthma. The effect was stronger in the Swedish cohort. Breastfeeding had no effect on the prevalence of sensitization to inhaled allergens in this cohort with a family history of asthma but was a risk factor for sensitization to cow's milk, peanuts, and eggs in the CAPS cohort at 4/5 yrs and in the combined cohort at 8 yrs. There was no evidence to support the existence of disease-related exposure modification in either cohort. CONCLUSION: These findings point to the importance of harmonization of features of study design, including subject selection criteria and variable definitions, in resolving epidemiological controversies such as those surrounding the impact of breastfeeding on asthma and allergic sensitization.

Why be smoke-free? A qualitative study of smoke-free restaurant owner and manager opinions.

This qualitative study captured the opinions of the owners and managers of smoke-free restaurants. The purpose of this study, initiated by local citizens who were members of a group called Healthy Alamance, was to identify the motivations and experiences of restaurant owners and managers who had committed to smoke-free indoor environments. Telephone interviews were attempted with all 80 owners/managers of smoke-free restaurants in Alamance County, North Carolina, and 87.5% of these restaurant owners/managers completed the interview. The investigators isolated economic factors, customer demands and considerations, and environmental issues as the three principal categories describing smoke-free restaurant owners' and managers' motivations for becoming smoke free. The results from this study can be used to assist communities working toward the development of a smoke-free restaurant campaign.

Effect of omega-3 fatty acid concentrations in plasma on symptoms of asthma at 18 months of age.

The objective of this study was to assess the relation between observed levels of omega-3 fatty acids in plasma and symptoms of asthma and atopy in children at 18 months of age. A total of 616 women at risk of having a child who would develop asthma because of a family history were recruited from the antenatal clinics of six hospitals in Sydney, Australia. Families were randomized to either active omega-3 supplemented or control group. The active group received a daily tuna fish oil supplement and omega-3-rich margarines and cooking oils and the control group received a placebo supplement with polyunsaturated margarines and cooking oils. When the children were 18 months of age an assessment of symptoms was carried out by a research nurse blinded to treatment group allocation. Atopy was measured by skin prick tests, blood was collected to determine serum immunoglobulin E (IgE), and plasma fatty acid concentrations. A total of 376 children (61.0% of total recruited) completed an assessment at 18 months and had blood taken to determine plasma fatty acid concentrations. Omega-3 fatty acid levels were expressed in quintiles of exposure 'as treated' without reference to treatment group allocation. Wheeze ever, doctor visits for wheeze, bronchodilator use and nocturnal coughing were significantly reduced in children in the higher exposure quintiles. Serum IgE was reduced in the highest quintile but not significantly so. There was no difference in diagnosed asthma or atopy between the exposure quintiles. Although wheeze at this age may not be a good indicator of asthma in later childhood, it is encouraging that some symptoms have been reduced in children with high omega-3 fatty acid concentrations in plasma.

The 4830C>A polymorphism within intron 5 affects the pattern of alternative splicing occurring within exon 6 of the thrombopoietin gene.

OBJECTIVE: A common variant in intron 5 of the thrombopoietin (TPO) gene (4830C>A) has been associated with risk of myocardial infarction (MI). To explore the molecular mechanism of this association, the ability of the intron to act as a transcription enhancer and to influence mRNA splicing was tested. METHOD AND RESULTS: In HepG2 cells the presence of intron 5 upstream of the TPO promoter decreased promoter activity to between 60% and 30%. This effect was orientation dependent; in the reverse orientation, intron 5 caused a twofold greater decrease in promoter activity compared to the forward orientation. However, the effects were similar with either the C or the 4830A allele. An in vitro exon trapping system was used to study the effect of the polymorphism on splicing events in exon 6. The full-length (TPO-1) and three previously reported splice variants (TPO-2, TPO-3, and TPO-5) were identified. The 4830A allele resulted in a small but statistically significant increase in production of the TPO-3 splice variant relative to the full-length transcript (10.6%+/-0.6%) compared to the 4830C allele (8.3%+/-0.6%) (p=0.02). Generation of TPO-5 was also slightly increased, but this did not reach significance. CONCLUSION: The identification of a potential "silencer" sequence in intron 5 of the TPO gene demonstrates the complexity of control of expression of the gene. Although the precise role of the different splice variants is not known, the finding that the 4830C>A sequence change alters their relative amounts, suggests a possible molecular mechanism whereby TPO genotype may influence the risk of MI.

Dietary antioxidant intake and incidence of early age-related maculopathy: the Blue Mountains Eye Study.

OBJECTIVE: To investigate associations between dietary intake, including modest supplement intake, of antioxidant vitamins and zinc at baseline and the 5-year incidence of early age-related maculopathy (ARM). DESIGN: Population-based cohort study. PARTICIPANTS: From 1992 through 1994, 3654 persons aged 49 years or more (82% of those eligible) living in two postcode areas west of Sydney, Australia, were examined for the Blue Mountains Eye Study baseline. Five years later, 2335 persons (75% of known survivors) were reexamined. METHODS: A 145-item Food Frequency Questionnaire (FFQ) was used to assess nutrient intakes. Of the 2335 people who attended a follow-up visit, 1989 (85%) had completed a FFQ at baseline. The nutrients examined in this study included: alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, lycopene, retinol, vitamin A, vitamin C, and zinc. MAIN OUTCOME MEASURES: Early ARM was assessed by masked grading of stereo retinal photographs. Definitions for incidence closely followed those used in the Beaver Dam Eye Study. RESULTS: Early ARM developed in 192 persons (8.7% 5-year incidence) who did not have either late or early ARM at baseline. Of these, 159 persons completed the FFQ at baseline. After adjusting for age, gender, family history of ARM, and smoking status at baseline, no associations, or any trends suggesting possible association, were found between baseline intake of the nutrients examined, apart from vitamin C, and the 5-year incidence of early ARM. Compared with the lowest quintile, increasing baseline intakes of vitamin C, from diet and supplements, was associated with an increased risk of incident early ARM (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.0-3.0; and OR, 2.3; 95% CI, 1.3-4.0 for the fourth and fifth quintiles, respectively). CONCLUSIONS: Our cohort study of an older population could not find evidence of protection associated with usual dietary antioxidant or zinc intakes (including use of supplements) on the 5-year incidence of early ARM.