Browsing by Author "Davies, Mary-Ann"
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- ItemOpen AccessA longitudinal analysis of neonatal and infant diagnostic HIV-PCR uptake and associations during three sequential policy periods in Mitchell’s Plain, Cape Town(2018) Kalk, Emma; Davies, Mary-AnnBackground: Despite technological and programmatic advances in the prevention of vertical transmission of HIV and early infant diagnosis (EID), paediatric HIV continues to have a significant impact on infant and child survival in low- and middle-income countries. Many EID programmes follow the WHO recommendation of initial infant HIV testing with a nucleic acid assay at 4-6 weeks old. In general this strategy has been poorly implemented with substantial attrition after birth such that, according to UNAIDS, only 51% of HIV-exposed infants received a virological test in the first two months of life in 2015. In addition, there is concern about the sensitivity of the nucleic acid assays at six weeks in the context of exposure to prolonged multidrug antiretroviral therapy as infant post-exposure prophylaxis, and in breast milk. HIV-PCR testing at birth has been promoted as a means of maximizing the number of infants who receive an HIV test as well as identifying in utero-infected infants in whom HIV infection may follow an aggressive course. Evidence from pilot studies and modelling data was sufficiently compelling for the WHO to include a conditional recommendation for the addition of a birth HIV-PCR (either routine or targeted at high risk groups) to its EID algorithms in 2015. The Western Cape introduced targeted birth HIV testing for high risk infants in August 2014 and expanded this in line with the South African National Prevention of Mother-to-Child Transmission Guidelines, to include all HIV-exposed infants in December 2015. Methods: Between 2013 and 2016 we conducted an implementation science project to iteratively assess the implementation and effectiveness of the vertical transmission prevention of HIV in a chain of referral facilities in Cape Town (i.e. from primary to tertiary care). The e-register provided a single longitudinal record for each woman (linked to her infant after birth) and enabled assessment of HIV testing and treatment from first antenatal visit through delivery to infant HIV testing. Using a cohort of HIV-exposed live infants from this database, a protocol was designed (Section A: Protocol) to assess the implementation and outcome of effectively three different EID policy periods in the facility chain. i.e. an initial period of birth HIV-PCR at the clinician’s discretion if evidence of HIV infection; a period of targeted birth testing of high risk infants and lastly, of routine birth HIV-PCR for all HIV-exposed infants. A critical review of the literature appraised published assessments of birth HIV testing programmes in low- and middle-income countries (Section B: Literature Review) with the aim of assessing in utero transmission rates, follow-up testing and transmission rates and the resources required for implementation. Studies that modelled the impact of birth HIV testing were specifically reviewed. The manuscript (Section C: Manuscript) presented an analysis of the HIV-infected/exposed mother/infant dyads from the e-register of the Closing the Gaps study. Using this database adherence to guidelines in each period was assessed as well as the outcome of HIV-PCR at four delivery sites and the impact of the policies on return for follow-up EID. Results: South Africa is the first country in sub-Saharan Africa to implement birth HIV testing and most of the studies in support of this strategy were generated here. There was limited literature which highlighted the need for further investigation into the implementation and effectiveness of such programmes. No prospective data addressed targeted birth testing and those reporting on more routine birth HIV-PCR demonstrated success in timeous diagnosis and treatment although significant additional project resources were required. The retrospective laboratory data indicated that receipt of a birth HIV-PCR reduced the likelihood for follow-up at later testing time-points. This is important as the modelling studies suggested that the clinical and financial benefits of adding birth testing to existing algorithms would be lost if follow-up was poor. In the cohort of 2012 HIV-exposed infants in the study presented in the manuscript, the proportion who received birth testing increased with the progression of the EID policies but guideline implementation was poor, especially in primary care, with only 60% of infants being tested as recommended. The proportion of infants with positive HIV-PCR decreased as the pool of HIV-exposed infants undergoing testing expanded, being highest during the periods of targeted birth testing. In concurrence with the South African literature, receipt of a birth HIV-PCR decreased the likelihood of follow-up testing at 6-10 weeks. Among infants tested at 6-10 weeks old, the proportion who were positive for the first time at this time- point increased with the introduction of routine birth testing for all HIV-exposed infants, emphasizing the importance of the follow-up EID time-points. Conclusion: Virological testing at birth effectively increased the number of HIV-exposed infants who received an HIV test and was effective in identifying in utero infection in high risk infants (who could start treatment early with the attendant benefits.) The Western Cape EID policies were incompletely implemented in the study facilities over this time with many infants not being tested as indicated. Birth HIV-PCR decreased follow-up testing, an unintended consequence of serious concern. Adherence to the provincial and national guidelines needs to be re-enforced at delivery sites and at the primary care facilities where follow-up EID occurs.
- ItemOpen AccessA longitudinal analysis of the completeness of maternal HIV testing, including repeat testing, during pregnancy, and the predictors thereof, in Mitchell’s Plain, Cape Town(2019) De Beer, Shani; Davies, Mary-Ann; Kalk, EmmaHIV testing during pregnancy is the gateway to the HIV-related services that are part of the prevention of mother-to-child transmission (PMTCT) cascade. The virtual elimination of vertical HIV transmission cannot be achieved without universal antenatal care (ANC) HIV testing. Furthermore, women are at an increased risk of HIV infection and subsequent mother-to-child transmission (MTCT) during pregnancy. Emphasis has thus been placed on repeat testing during pregnancy among women who have a HIV-negative result at their first ANC test. Very little has been published on the current uptake and adherence to antenatal and repeat HIV testing in sub-Saharan Africa (SSA) countries. In line with the World Health Organization Guidelines, the Western Cape Prevention of Mother-to-Child Transmission of HIV (PMTCT) Clinical Guidelines in 2014 recommended a repeat HIV test between 32 - 34 weeks gestation and again at delivery in addition to testing at “booking” (< 20 weeks gestation), meaning that there were three “testing windows” during which pregnant women not previously diagnosed as HIV-infected should undergo testing. Between 2013 and 2016 the Closing the Gaps study established an electronic PMTCT register (e-register) that consolidated routine care data from a primary healthcare facility and its secondary and tertiary referral sites in Cape Town, South Africa. This provided a single longitudinal record, from antenatal care to delivery, for each pregnant woman which enabled the longitudinal assessment of maternal HIV testing uptake and treatment. Utilizing these data, we conducted a retrospective sub-analysis investigating the implementation of PMTCT HIV testing guidelines (until delivery), in Cape Town, for the period 1 July 2014 - 31 December 2016. The main objectives of the study were to assess the coverage and timing of initial HIV testing during pregnancy, the completion of HIV testing at “booking” and within the recommended testing windows (including delivery), HIV prevalence and incidence at the recommended testing windows, and the predictors of missed testing opportunities. The research protocol (Part A) was designed to describe the proposed significance, objectives and methodology of the study. The literature review (Part B) critically evaluated available literature on: antenatal and repeat HIV testing proportions, HIV positivity, the feasibility and acceptability of repeat iv testing, and the predictors of testing completeness within different SSA countries, for the period 2010 - June 2018. Its aim was to inform this study. The need for post-Option B+ implementation, longitudinal studies that analyze antenatal and repeat HIV testing coverage and implementation within SSA was identified. In Part C I present the methods, results and interpretation thereof for the analysis of individual-level, longitudinal, maternal HIV-testing patient data from the Closing the Gaps study e-register as a manuscript to be submitted for publication. Among 8558 women who delivered at either the primary care facility or its referral sites, 7213 were not diagnosed HIV-positive prior to their first visit and thus eligible for testing in pregnancy. Among these women, 91% received ≥1 HIV test and 85% “booked” >5 days before delivery with 98% testing completeness at “booking”. Only 49% of women eligible for testing “booked” ≤22 weeks gestation. Among women that “booked” ≤22 weeks gestation who weren’t diagnosed HIV-positive before delivery and delivered >5 days after the start of the third trimester, 10% received tests in all three recommended windows. Thirty-one percent of women that had not been diagnosed HIV-positive before delivery had an uncertain (i.e. last tested ≥3 months before delivery) or unknown (i.e. never tested) HIV status after delivery. Out of the women that had a known HIV status at delivery, 21% were HIV-positive of whom 95% were known HIV-positive before current pregnancy and 4% were diagnosed at “booking”. Overall, HIV incidence in those with ≥2 HIV tests during pregnancy/at delivery was estimated to be 0.2% between “booking” and delivery. Women who enrolled after 2014 were less likely to miss ≥1 of the three recommended tests (aOR: 0.70; CI: 0.55 - 0.90) and not test at delivery (aOR: 0.63; CI: 0.55 - 0.71) compared to those who enrolled in 2014. Conclusion: In our study, HIV testing completion at “booking” was high, but women tended to “book” late during pregnancy resulting in late initial testing and missed opportunities for early HIV diagnosis. Implementation of repeat HIV testing is poor, particularly at delivery. HIV incidence between first negative ANC test and delivery is very low and therefore future studies to assess the most cost-effective number and timing of HIV tests, and feasibility of implementation, should be considered. Overall, maternal HIV testing within the PMTCT programme in Cape Town has matured post 2014 with improved implementation over time.
- ItemOpen AccessAdherence to antiretroviral therapy in young children in Cape Town, South Africa, measured by medication return and caregiver self-report : a prospective cohort study(2010) Davies, Mary-Ann; Boulle, Andrew; Eley, BrianExcellent adherence to antiretroviral therapy (ART) is necessary if HIV-infected children are to experience the dramatically improved outcomes that this treatment affords. However, there is very limited data on adherence to antiretroviral therapy in Africa, with few studies that examine the predictive value of low technology measures of adherence in terms of viral and immune outcomes. In addition there are no long terms studies of adherence in young children in Africa.
- ItemOpen AccessAdherence to antiretroviral therapy in young children in Cape Town, South Africa, measured by medication return and caregiver self-report: a prospective cohort study(BioMed Central Ltd, 2008) Davies, Mary-Ann; Boulle, Andrew; Fakir, Tanzeem; Nuttall, James; Eley, BrianBACKGROUND:Antiretroviral therapy (ART) dramatically improves outcomes for children in Africa; however excellent adherence is required for treatment success. This study describes the utility of different measures of adherence in detecting lapses in infants and young children in Cape Town, South Africa. METHODS: In a prospective cohort of 122 HIV-infected children commenced on ART, adherence was measured monthly during the first year of treatment by medication return (MR) for both syrups and tablets/capsules. A questionnaire was administered to caregivers after 3 months of treatment to assess experience with giving medication and self-reported adherence. Viral and immune response to treatment were assessed at the end of one year and associations with measured adherence determined. RESULTS: Medication was returned for 115/122 (94%) children with median age (IQR) of 37 (16 - 61) months. Ninety-one (79%) children achieved annual average MR adherence [greater than or equal to] 90%. This was an important covariate associated with viral suppression after adjustment for disease severity (OR = 5.5 [95%CI: 0.8-35.6], p = 0.075), however was not associated with immunological response to ART. By 3 months on ART, 13 (10%) children had deceased and 11 (10%) were lost to follow-up. Questionnaires were completed by 87/98 (90%) of caregivers of those who remained in care. Sensitivity of poor reported adherence (missing [greater than or equal to] 1 dose in the previous 3 days) for MR adherence <90% was only 31.8% (95% CI: 10.7% - 53.0%). Caregivers of 33/87 (38.4%) children reported difficulties with giving medication, most commonly poor palatability (21.8%). Independent socio-demographic predictors of MR adherence [greater than or equal to] 90% were secondary education of caregivers (OR = 4.49; 95%CI: 1.10 - 18.24) and access to water and electricity (OR = 2.65; 95%CI: 0.93 - 7.55). Taking ritonavir was negatively associated with MR adherence [greater than or equal to] 90% (OR = 0.37; 95%CI: 0.13 - 1.02). CONCLUSION: Excellent adherence to ART is possible in African infants and young children and the relatively simple low technology measure of adherence by MR strongly predicts viral response. Better socio-economic status and more palatable regimens are associated with better adherence.
- ItemOpen AccessAntiretroviral treatment for children(Health and Medical Publishing Group, 2006) Eley, Brian; Davies, Mary-Ann; Apolles, Patti; Cowburn, Carol; Buys, Heloise; Zampoli, Marco; Finlayson, Heather; King, Spasina; Nuttall, JamesObjective: To describe the response of children during their first year on highly active antiretroviral therapy (HAART). Design: Retrospective, descriptive. Setting. Tertiary, referral hospital. Subjects: All HIV-infected children commenced on HAART from 1 August 2002 until 31 December 2004. Outcome measures: Children were retrospectively restaged using the WHO 4-stage clinical classification and CDC immunological staging system. After commencing HAART, patients were assessed at monthly intervals for the first 6 months and thereafter mostly 3-monthly. Baseline and 6- monthly CD4 counts and viral loads were performed. Results. Of 409 children commenced on HAART, 50.6% were < 2 years old, 62.7% had severe clinical disease and 76.6% had severe immune suppression. After 1 year, 65.8% were alive and continued HAART at the hospital, 11.2% had been transferred to another antiretroviral site, 15.4% had died, 4.6% were lost to follow-up and treatment had been discontinued in 2.9%. Kaplan-Meier survival estimate for 407 children at 1 year was 84% (95% confidence interval (CI) 80 - 87%). On multivariate analysis, survival was adversely affected in children with WHO stage 4 v. stage 2 and 3 disease (adjusted hazard ratio (HR): 5.26 (95% CI 2.25 - 12.32), p = 0.000), age < 12 months (adjusted HR: 2.46 (95% CI 1.48 - 4.09), p = 0.001) and CD4 absolute count (per 100 cell increase) (adjusted HR: 0.93 (95% CI 0.88 - 0.98), p = 0.013). In a separate multivariate model including only children with an initial viral load (N = 367), viral load r 1 million copies/ml (adjusted HR: 1.84 (95% CI 1.03 - 3.29)) and taking a protease inhibitor (PI)-based regimen (adjusted HR: 2.25 (95% CI 1.10 - 4.61)) were additionally independently associated with poorer survival; however, young age was not a significant predictor of mortality, after adjusting for viral load (p = 0.119). After 1 year of HAART 184/264 (69.7%) of children had a viral load < 400 copies/ml. Comparative analysis showed significant improvements in growth, immunological status and virological control. Conclusion: HAART can improve the health of many HIVinfected children with advanced disease, including those aged less than 2 years in resource-limited settings.
- ItemOpen AccessClinical mentorship of nurse initiated antiretroviral therapy in Khayelitsha, South Africa: a quality of care assessment(Public Library of Science, 2014) Green, Ann; de Azevedo, Virginia; Patten, Gabriela; Davies, Mary-Ann; Ibeto, Mary; Cox, VivianIntroduction To combat the AIDS epidemic and increase HIV treatment access, the South African government implemented a nurse-based, doctor-supported model of care that decentralizes administration of antiretroviral treatment (ART) for HIV positive patients through nurse initiated and managed ART. Médecins Sans Frontières (MSF) implemented a mentorship programme to ensure successful task-shifting, subsequently assessing the quality of clinical care provided by nurses. METHODS: A before-after cross-sectional study was conducted on nurses completing the mentorship programme in Khayelitsha, South Africa, from February 2011-September 2012. Routine clinical data from 229 patient folders and 21 self-assessment questionnaires was collected to determine the number of patients initiated on ART by nurses; quality of ART management before-after mentorship; patient characteristics for doctor and nurse ART initiations; and nurse self-assessments after mentorship. RESULTS: Twenty one nurses were authorized by one nurse mentor with one part-time medical officer's support, resulting in nurses initiating 77% of ART eligible patients. Improvements in ART management were found for drawing required bloods (91% vs 99%, p = 0.03), assessing adherence (50% vs 78%, p<0.001) and WHO staging (63% vs 91%, p<0.001). Nurse ART initiation indicators were successfully completed at 95-100% for 11 of 16 indicators: clinical presentation; patient weight; baseline blood work (CD4, creatinine, haemoglobin); STI screening; WHO stage, correlating medical history; medications prescribed appropriately; ART start date; and documented return date. Doctors initiated more patients with TB/HIV co-infection and WHO Stage 3 and 4 disease than nurses. Nurse confidence improved for managing HIV-infected children and pregnant women, blood result interpretation and long-term side effects. CONCLUSIONS: Implementation of a clinical mentorship programme in Khayelitsha led to nurse initiation of a majority of eligible patients, enabling medical officers to manage complex cases. As mentorship can increase clinical confidence and enhance professional development, it should be considered essential for universal ART access in resource limited settings.
- ItemOpen AccessClinical mentorship of nurse-initiated Antiretroviral Therapy (ART) in Khayelitsha, South Africa: a quality of care assessment(2013) Green, Ann; Cox, Vivian; Davies, Mary-AnnSouth Africa’s National Strategic Plan calls for task shifting of HIV care from doctors to nurses by 2016 to increase access to ART. There is little research demonstrating sustainable success of competent HIV management by nurses after training and mentorship. In February 2011, Medecins Sans Frontieres (MSF) partnered with the City of Cape Town Department of Health to implement a NIMART mentorship programme and assess quality of clinical care provided by nurse graduates. A before-after cross-sectional study was conducted on nurses completing mentorship from February 2011-September 2012. Routine clinical data from 229 patient folders and 21 selfassessment questionnaires was collected to determine the number of patients initiated on ART by individual nurses; quality of ART-management before and after mentorship; patient characteristics for doctor and nurse ART-initiations; and nurse self-assessments. 21 nurses were authorized by one nurse mentor with one part-time medical officer’s support, resulting in nurses initiating 77% of eligible patients. Improvements in ART management were found for drawing required bloods (91% vs 99%, p=0.03), assessing adherence (50% vs 78%, p<;0.001) and WHO staging (63% vs 91%, p<;0.001). Nurse ART initiation indicators were successfully completed 95-100% of the time for 10 out of 16 indicators: clinical presentation, past medical history, prior ART history, WHO stage, STI screening, patient weight, baseline blood work (CD4 count, creatinine, and haemoglobin), treatment plan, and medications prescribed. Doctors initiated more patients with TB/HIV co-infection and Stage 3 or 4 disease than nurses; 24% of patients initiated by nurses were seen or discussed with a doctor in the month prior to initiation. Nurse confidence improved for the management of HIV-infected children and pregnant women, blood result interpretation, and long-term side effects following completion of the mentorship programme.
- ItemOpen AccessCohort Profile: The Western Cape Pregnancy Exposure Registry (WCPER)(2022-06) Kalk, Emma; Heekes, Alexa; Slogrove, Amy; Phelanyane, Florence; Davies, Mary-Ann; Myer, Landon; Euvrard, Jonathan; Kroon, Max; Petro, Greg; Fieggen, Karen; Stewart, Chantal; Rhoda, Natasha; Gebhardt, Stefan; Osman, Ayesha; Anderson, Kim; Boulle, Andrew; Mehta, UshmaPurpose: The Western Cape Pregnancy Exposure Registry (PER) was established at two public sector healthcare sentinel sites in the Western Cape province, South Africa, to provide ongoing surveillance of drug exposures in pregnancy and associations with pregnancy outcomes. Participants: Established in 2016, all women attending their first antenatal visit at primary care obstetric facilities were enrolled and followed to pregnancy outcome regardless of the site (ie, primary, secondary, tertiary facility). Routine operational obstetric and medical data are digitised from the clinical stationery at the healthcare facilities. Data collection has been integrated into existing services and information platforms and supports routine operations. The PER is situated within the Provincial Health Data Centre, an information exchange that harmonises and consolidates all health-related electronic data in the province. Data are contributed via linkage across a unique identifier. This relationship limits the missing data in the PER, allows validation and avoids misclassification in the population-level data set. Findings to date: Approximately 5000 and 3500 pregnant women enter the data set annually at the urban and rural sites, respectively. As of August 2021, >30 000 pregnancies have been recorded and outcomes have been determined for 93%. Analysis of key obstetric and neonatal health indicators derived from the PER are consistent with the aggregate data in the District Health Information System. Future plans: This represents significant infrastructure, able to address clinical and epidemiological concerns in a low/middle-income setting.
- ItemOpen AccessA comparison of death recording by health centres and civil registration in South Africans receiving antiretroviral treatment(Journal of the International AIDS Society, 2015-12-16) Johnson, Leigh F; Dorrington, Rob E; Laubscher, Ria; Hoffmann, Christopher J; Wood, Robin; Fox, Matthew P; Cornell, Morna; Schomaker, Michael; Prozesky, Hans; Tanser, Frank; Davies, Mary-Ann; Boulle, AndrewIntroduction: There is uncertainty regarding the completeness of death recording by civil registration and by health centres in South Africa. This paper aims to compare death recording by the two systems, in cohorts of South African patients receiving antiretroviral treatment (ART). Methods: Completeness of death recording was estimated using a capture-recapture approach. Six ART programmes linked their patient record systems to the vital registration system using civil ID numbers, and provided data comparing the outcomes recorded in patient files and in the vital registration. Patients were excluded if they had missing/invalid IDs or had transferred to other ART programmes. Results: After exclusions, 91 548 patient records were included. Of deaths recorded in patients files after 2003, 94.0% (95% CI: 93.3-94.6%) were recorded by civil registration, with completeness being significantly higher in urban areas, older adults and females. Of deaths recorded by civil registration after 2003, only 35.0% (95% CI: 34.2-35.8%) were recorded in patient files, with this proportion dropping from 60% in 2004-2005 to 30% in 2010 and subsequent years. Recording of deaths in patient files was significantly higher in children and in locations within 50km of the health centre. When the information from the two systems was combined, an estimated 96.2% of all deaths were recorded (93.5% in children and 96.2% in adults). Conclusions: South Africa’s civil registration system has achieved a high level of completeness in the recording of mortality. However, the fraction of deaths recorded by health centres is low and information from patient records is insufficient by itself to evaluate levels and predictors of ART patient mortality. Previously-documented improvements in ART mortality over time may be biased if based only on data from patient records.
- ItemOpen AccessA description of HIV-exposed uninfected infants in the IeDEA Southern Africa Cohort and an examination of growth outcomes(2014) Morden, Erna; Davies, Mary-AnnSince the successful use of antiretroviral therapy for the prevention of mother-to-child transmission of human immunodeficiency virus (HIV), there has been a steady increase in the number of infants born to HIV-infected mothers who remain uninfected. The characteristics of these HIV-exposed uninfected infants are not well known, including growth and other health outcomes. The International Epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) research strategy 2011-2016 includes specific studies in pregnant women, infants, children and adolescents. This study addresses one of the IeDEA-SA objectives, namely to establish and describe a sub-cohort of HIV-infected pregnant women and their exposed infants. Part A, the protocol, includes background information on sites contributing to this cohort of HIV-exposed uninfected (HEU) infants. It also details the aims, objectives and methodology of this study. Part B, the literature review, discusses what is known about HIV-exposed uninfected infants to date. It includes maternal disease factors, the use of antiretroviral therapy and the association between feeding modality and growth, focussing on studies conducted on the African continent. Part C, the manuscript, details the methodology, results and their interpretation of longitudinal analysis of growth among HEU infants in the IeDEA-SA collaboration. This cohort of HEU infants included 2621 infants from two South African sites. The median birth WAZ was -0.65 (IQR -1.46; 0.0), 51% were male and there was a median of 2 visits per infant. The feeding modalities practised were as follows: 0.5% exclusive breastfeeding, 7.9% unknown breastfeeding exclusivity, 78.6% mixed breastfeeding and 10.6% formula feeding. Mothers with a CD4 <200 cells/μl delivered infants with a lower birth WAZ (adjusted ß -0.253 [95% CI -0.043; -0.072], p = 0.006) compared to mothers with a CD4 ≥500 cells/≧l. Similarly, iv mothers who did not receive antiretroviral (ARVs) drugs delivered infants with a lower birth WAZ (adjusted ß -0.49 [95% CI -0.78; -0.20], p = 0.001) compared to mothers who received antenatal ARVs. Antenatal maternal ARVs and CD4 cell count did not have an effect on postnatal growth. Mixed effects models using maximum likelihood estimation for the longitudinal analysis of growth showed that exposure to breast milk positively influenced growth, albeit the effect was small. Infants with a birth weight <2 500g (ß 0.069 [95% CI 0.061; 0.078], p <0.0001) experienced faster growth within the first 28 weeks of life compared to infants with a birth weight ≥2 500g. In this cohort of South African HEU infants, less severe maternal disease and the use of ARVs positively impacted birth weight. Mixed feeding was common, and any breastfeeding may have a positive effect on longitudinal growth.
- ItemRestrictedGrowth and mortality outcomes for different antiretroviral therapy initiation criteria in children ages 1–5 Years: a causal modeling analysis(Lippincott, Williams & Wilkins, 2016) Schomaker, Michael; Davies, Mary-Ann; Malateste, Karen; Renner, Lorna; Sawry, Shobna; N’Gbeche, Sylvie; Technau, Karl-Günter; Eboua, François; Tanser, Frank; Sygnaté-Sy, Haby; Phiri, Sam; Madeleine, Amorissani-Folquet; Cox, Vivian; Koueta, Fla; Chimbete, Cleophas; Lawson-Evi, Annette; Giddy, Janet; Amani-Bosse, Clarisse; Wood, Robin; Egger, Matthias; Leroy, ValerianeBackground: There is limited evidence regarding the optimal timing of initiating antiretroviral therapy (ART) in children. We conducted a causal modeling analysis in children ages 1–5 years from the International Epidemiologic Databases to Evaluate AIDS West/Southern-Africa collaboration to determine growth and mortality differences related to different CD4-based treatment initiation criteria, age groups, and regions. Methods: ART-naïve children of ages 12–59 months at enrollment with at least one visit before ART initiation and one follow-up visit were included. We estimated 3-year growth and cumulative mortality from the start of follow-up for different CD4 criteria using g-computation. Results: About one quarter of the 5,826 included children was from West Africa (24.6%).The median (first; third quartile) CD4% at the first visit was 16% (11%; 23%), the median weight-for-age z-scores and height-for-age z-scores were −1.5 (−2.7; −0.6) and −2.5 (−3.5; −1.5), respectively. Estimated cumulative mortality was higher overall, and growth was slower, when initiating ART at lower CD4 thresholds. After 3 years of follow-up, the estimated mortality difference between starting ART routinely irrespective of CD4 count and starting ART if either CD4 count <750 cells/mm3 or CD4% <25% was 0.2% (95% CI = −0.2%; 0.3%), and the difference in the mean height-for-age z-scores of those who survived was −0.02 (95% CI = −0.04; 0.01). Younger children ages 1–2 and children in West Africa had worse outcomes. Conclusions: Our results demonstrate that earlier treatment initiation yields overall better growth and mortality outcomes, although we could not show any differences in outcomes between immediate ART and delaying until CD4 count/% falls below 750/25%.
- ItemOpen AccessGrowth of HIV-exposed uninfected infants in the first 6 months of life in South Africa: The IeDEA-SA collaboration(Public Library of Science, 2016) Morden, Erna; Technau, Karl-Günter; Giddy, Janet; Maxwell, Nicola; Keiser, Olivia; Davies, Mary-AnnBACKGROUND: HIV-exposed uninfected (HEU) infants are a growing population in sub-Saharan Africa especially with the increasing coverage of more effective prevention of mother-to-child transmission (PMTCT) antiretroviral therapy regimens. This study describes the characteristics of South African HEU infants, investigates factors impacting birth weight and assesses their growth within the first 28 weeks of life. METHODS: This is a retrospective cohort based on routine clinical data from two South African PMTCT programmes. Data were collected between 2007 and 2013. Linear regression assessed factors affecting birth weight-for-age z-scores (WAZ) while growth (longitudinal WAZ) was assessed using mixed effects models. RESULTS: We assessed the growth of 2621 HEU infants (median birth WAZ was -0.65 (IQR -1.46; 0.0) and 51% were male). The feeding modalities practised were as follows: 0.5% exclusive breastfeeding, 7.9% breastfeeding with unknown exclusivity, 0.08% mixed breastfeeding and 89.2% formula feeding. Mothers with CD4 <200 cells/μl delivered infants with a lower birth WAZ (adjusted ß -0.253 [95% CI -0.043; -0.072], p = 0.006) compared to mothers with aCD4 ≥500 cells/μl. Similarly, mothers who did not receive antiretroviral drugs delivered infants with a lower birth WAZ (adjusted ß -0.39 [95% CI -0.67; -0.11], p = 0.007) compared to mothers who received antenatal antiretrovirals. Infants with a birth weight <2 500g (ß 0.070 [95% CI 0.061; 0.078], p <0.0001) experienced faster growth within the first 28 weeks of life compared to infants with a birth weight ≥2 500g. Infants with any breastfeeding exposure experienced slower longitudinal growth compared to formula fed infants (adjusted ß -0.012 [95% CI 0.021; -0.003], p = 0.011). CONCLUSION: Less severe maternal disease and the use of antiretrovirals positively impacts birth weight in this cohort of South African HEU infants. Formula feeding was common with breastfed infants experiencing marginally slower longitudinal growth.
- ItemOpen AccessHow accurately do routinely reported HIV viral load suppression proportions reflect progress towards the 90-90-90 target in the population on ART in Khayelitsha, South Africa?(2018) Euvrard, Jonathan George; Davies, Mary-Ann; Schulz, TanjaBackground: In 2016, Khayelitsha reported almost 89% viral load (VL) suppression but less than 56% completion on routine quarterly reports, casting doubt on the validity of reported suppression. Objectives: To assess the validity of reported VL suppression as a measure of progress towards the 90-90-90 target and identify barriers to routine VL completion. Methods: A retrospective cohort study including all patients on antiretroviral treatment (ART) in Khayelitsha with a routine VL expected between 1 July 2015 and 30 June 2016 was conducted. ART programme and laboratory data were obtained and a sample of 1 035 patient folders were reviewed. Suppression was calculated using laboratory data and compared to reported suppression. A VL cascade from “expected” to “done”, “filed”, “noted” and “captured” was constructed to reflect the steps a VL must complete to be included in reported suppression and successful progression to each step was estimated. Logistic regression models were used to calculate adjusted odds ratios (aOR) with 95% confidence intervals (95%CI) for completion among different patient groups. Results: Using laboratory data, VL suppression was estimated to be 82%, 87%, 89% and 91% at the 50, 200, 400 and 1 000 copies/mL thresholds respectively, but reported suppression would have been 80%, 86%, 88% and 89% at those thresholds. Of 22 991 patients with a routine VL due in the study period, 84% were done, 79% filed, 76% noted, and 55% captured. Routine VL were more likely to be done among children< 15 years old (aOR 1.89, 95%CI 1.45–2.48) and pregnant women (aOR 1.90, 95%CI 1.28–2.81) compared to adult men, adjusted for facility. Conclusion: Despite low reported completion, actual completion was high and reported suppression was similar to suppression calculated using laboratory data, thus providing an accurate measure of progress towards the 90-90-90 target. More work is needed to reach the 16% of patients missed by routine testing. Most of the VL done were available to the clinician at the next assessment, and further research is needed to assess how effectively these VL results are used in clinical decision-making.
- ItemOpen AccessInitial experience of a public sector antiretroviral treatment programme for HIV-infected children and their infected parents(2004) Eley, Brian; Nuttall, James; Davies, Mary-Ann; Smith, Lara; Cowburn, Carol; Buys, Heloise; Hussey, GregoryObjective. To describe the initial experience of treating HIVinfected children and their infected parents with antiretroviral therapy. Design. Prospective, cohort study. Setting. Tertiary, referral hospital. Patients. HIV-infected children and their parents. Methods. This report focuses on the early response of children to highly active antiretroviral therapy (HAART). Children were followed up at 4-weekly intervals. Monitoring included initial and yearly viral load measurements, baseline and 6- monthly CD4 counts and 4-weekly adherence checks. Results. Between August 2002 and June 2003, 80 children were enrolled in the programme, representing a follow-up period of 23.9 patient-years. Seventy-five children had severe clinical disease, severe immune suppression, or a combination of the two. The response of children who had received HAART for ≥ 6 months (N = 17) was assessed. There was no change in mass z-score (p = 0.11) or length z-score (p = 0.37), but a significant increase in CD4 percentage (p < 0.0001) during the first 6 months of therapy. Six-month viral loads were available for 12 children. There was a significant drop in viral load (p = 0.001) and 9 achieved undetectable levels by 6 months. Most children achieved ≥ 85% adherence. By June 2002, 67 children (84%) were relatively well, 1 had B-cell lymphoma, 7 (8.8%) had died, 4 (5%) were lost to follow-up and 1 was withdrawn from the programme. Of 57 children who completed 3 months of HAART, 12 were admitted a total of 17 times for infectious complications. There were no severe drug reactions. Three of 7 mothers on HAART received treatment through the programme. Conclusion. These initial results suggest that many HIVinfected children in the public sector will benefit from antiretroviral therapy. However, both ambulatory and inpatient facilities are required to manage children on HAART comprehensively
- ItemOpen Access"Injury-prone areas" Repeat Presentations for Injuries in Childhood(2019) Peters, Shrikant Maurice; Davies, Mary-AnnBackground: Injury remains a leading cause of childhood morbidity and mortality in the developing world. Probability of injury occurrence is influenced by agent, host and environmental factors. Studies of repeat injuries in childhood thus provide insight into factors in the epidemiological triad predisposing children to injury. Objectives: The study objectives were to determine the proportion of children and the factors associated with repeat presentations to Red Cross War Memorial Children’s Hospital Trauma Unit (RCWMCH TU) for all non-transport related injuries in childhood. Methods: This was a retrospective cohort study using data from RCWMCH TU. We included children aged 0-10 years with first presentation from January 1997 to June 2013, and followed up until the earliest of age 13 years or June 2016. We assessed individual and population-level factors associated with repeat injury using multilevel Poisson regression. Child Dependency Ratios were derived from the 2011 national census. Results: Between 1997 and 2013, 72 490 children under 10 years of age (59% male) presented to RCWMCH TU for the first time with injuries. After the initial injury, 9 417 (13%) presented with a repeat injury by 2016 and before age 13 years. After adjusting for health Sub-District, distance from RCWMCH TU and age at first presentation, factors associated with reduced repeat presentation were: injury identified as due to abuse (adjusted incidence rate ratio [aIRR] 0.6; 95% confidence interval [CI]: 0.4 - 0.7), fluid burn (aIRR 0.6; 95% CI: 0.6 - 0.7), foreign body ingestion (aIRR 0.7; 95% CI: 0.7 - 0.9), moderate and severe (vs minor) initial injury (aIRR 0.9; 95% CI: 0.8 - 0.9) and (aIRR 0.7; 95% CI: 0.6 - 0.8 respectively), whilst boys were more likely to have repeat injury presentations (aIRR 1.4; 95% CI: 1.4 - 1.5). Conclusion: Repeat presentations constituted a substantial proportion of disease burden. Factors associated with repeat presentations were identified, strengthening the argument that injuries arise due to sustained exposure to host, agent and environmental risk factors. While it is reassuring that children with initial injuries due to abuse and severe initial injuries are less likely to present again, injury prevention education should not neglect patients with minor and unintentional injuries. The findings of this study suggest that post-injury health promotion activities should not exclude patients who present with minor injuries, and that targeted education and further research is indicated for specific injuries, including those due to non-height falls and injuries sustained whilst playing sport.
- ItemOpen AccessKnowledge, attitudes and perceptions of antibiotic use and antibiotic resistance among private sector patients and prescribers in South Africa(2017) Farley, Elise; Boyles, Tom H; Stewart, Annemie; Davies, Mary-AnnAntibiotic resistance (ABR), alternately referred to as antimicrobial resistance, has been labelled as the next big global health crisis. If current levels of ABR continue along the same trajectories, by 2050 ABR will cost the lives of 10 million people a year, ABR cannot be stopped but it can be slowed down. ABR occurs because the bacteria evolve to protect themselves from antibiotics. One of the main causes of ABR is the misuse and over prescription of antibiotics. The primary objective of the study is to ascertain the level of knowledge, attitudes and perceptions of appropriate antibiotic use and ABR, among prescribers and patients in private health care in South Africa. The secondary objective of the study is to explore associations between knowledge, attitudes and perceptions of prescribers and patients regarding antibiotic use and resistance. This project consists of three main sections, a proposal, literature review and a journal ready article. All sections focus on ABR. The proposal lays a foundation for the need for the research, and explains how the research will be conducted. The literature review explores the existing evidence on the topic, and the final section is a secondary analysis of cross sectional study data, in which private practice patients and prescribers in South Africa completed a once-off anonymous survey. Data was analysed using Stata,T-tests, chi-squared tests and logistic regression models were used to assess associations between knowledge, attitudes and perceptions of both patients and prescribers. We found that mean knowledge scores among patients (n=403, mean 9 out of 14, standard deviation [SD] 3) and providers (n=175, median 5 maximum 7, IQR 4, 6), were suboptimal and that poor knowledge was associated with perceptions and behaviours as well as prescribing practices that could lead to ABR. Associations between knowledge, attitudes and perceptions of patients and prescribers were explored in multivariate logistic regression models. After adjusting for education and sex, a 1-unit increase in patient knowledge score was associated with the belief that antibiotics will work less well in future if we over-use them now (aOR 1.3; 95% CI: 1.18, 1.43; pvalue <0.001). Prescribers with higher knowledge scores were less likely to report that they prescribe antibiotics when not necessary as antibiotics cannot harm the patient (aOR 0.55; 95% CI: 0.33, 0.91; pvalue 0.02). We also identified a large proportion (58%) of patients who were interested in alternatives to antibiotics and a large proportion (91%) of prescribers wanting educational material to facilitate conversations about resistance with patients. Our study demonstrates gaps in patient and prescriber knowledge that are associated with potentially harmful perceptions and destructive behaviours regarding antibiotic use. These associations, together with our finding that patients and prescribers would like more education on ABR, suggest that educational tools and patient-provider communication tools could promote rational antibiotic use.
- ItemOpen AccessMonitoring of antiretroviral therapy and mortality in HIV programmes in Malawi, South Africa and Zambia: mathematical modelling study(Public Library of Science, 2013) Estill, Janne; Egger, Matthias; Johnson, Leigh F; Gsponer, Thomas; Wandeler, Gilles; Davies, Mary-Ann; Boulle, Andrew; Wood, Robin; Garone, Daniela; Stringer, Jeffrey S AObjectives Mortality in patients starting antiretroviral therapy (ART) is higher in Malawi and Zambia than in South Africa. We examined whether different monitoring of ART (viral load [VL] in South Africa and CD4 count in Malawi and Zambia) could explain this mortality difference. Design: Mathematical modelling study based on data from ART programmes. METHODS: We used a stochastic simulation model to study the effect of VL monitoring on mortality over 5 years. In baseline scenario A all parameters were identical between strategies except for more timely and complete detection of treatment failure with VL monitoring. Additional scenarios introduced delays in switching to second-line ART (scenario B) or higher virologic failure rates (due to worse adherence) when monitoring was based on CD4 counts only (scenario C). Results are presented as relative risks (RR) with 95% prediction intervals and percent of observed mortality difference explained. RESULTS: RRs comparing VL with CD4 cell count monitoring were 0.94 (0.74-1.03) in scenario A, 0.94 (0.77-1.02) with delayed switching (scenario B) and 0.80 (0.44-1.07) when assuming a 3-times higher rate of failure (scenario C). The observed mortality at 3 years was 10.9% in Malawi and Zambia and 8.6% in South Africa (absolute difference 2.3%). The percentage of the mortality difference explained by VL monitoring ranged from 4% (scenario A) to 32% (scenarios B and C combined, assuming a 3-times higher failure rate). Eleven percent was explained by non-HIV related mortality. CONCLUSIONS: VL monitoring reduces mortality moderately when assuming improved adherence and decreased failure rates.
- ItemOpen AccessMonitoring the South African National Antireteoviral Treatment Programme, 2003-2007: The IeDEA Southern Africa Collaboration(2009) Cornell, Morna; Technau, Karl; Fairall, Lara; Wood, Robin; Moultrie, Harry; Van Cutsem, Gilles; Giddy, Janet; Mohapi, Lerato; Eley, Brian; MacPhail, Patrick; Prozesky, Hans; Rabie, Helena; Davies, Mary-Ann; Maxwell, Nicola; Boulle, AndrewObjectives: To introduce the combined South African cohorts of the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterize patients accessing these services; and to describe changes in services and patients 2003-2007. Design & setting Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. Subjects ART-naïve adults and children (<16 years old) who initiated ART with ≥3 antiretroviral drugs before 2008. Results: Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median (IQR) range was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5) respectively. Of adults, 68% were female. Median CD4 cell count was 102 cells/µL (44-164) and was lower among males than females (86, 34-150 vs 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/µL, p<0.001) and for those in Stage IV (39-89 cells/µL, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5%-16.0%, p<0.001). Conclusions: IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increasing enrolment. Late presentation, especially of men and children, remains a concern. Investment in sentinel sites ensures good individual-level data while freeing most sites to continue with simplified reporting.
- ItemOpen AccessNoma in northwest Nigeria: a neglected disease in neglected populations(2020) Farley, Elise Sarah; Mehta, Ushma; Lenglet, Annick; Davies, Mary-AnnBackground Noma, also known as cancrum oris, is a gangrenous infection of the oral cavity, which causes widespread orofacial destruction. If untreated, noma has a reported 90% mortality rate within weeks after the onset of first symptoms. Noma progresses through distinct stages defined by the World Health Organisation (WHO); Stage 0: simple gingivitis; Stage 1: acute necrotizing gingivitis; Stage 2: oedema; Stage 3: gangrene; Stage 4: scarring. Stage 5: sequelae. It is unclear how many patients with the early stages of noma will progress to the later stages of disease. Treatment in the early reversible stages with antibiotics, wound debridement and nutritional support greatly reduces morbidity and mortality. Acute noma is most often reported in children aged between two and five years. Many patients who survive the acute stages of the disease suffer into adulthood with disfigurement and disability of varying degrees. Noma is thought to be most prevalent in developing countries in Africa and Asia. Estimates for noma prevalence and incidence vary. In 1998, the WHO estimated an annual incidence of 140,000 cases of acute noma and 770,000 noma survivors living with sequelae. Two Nigerian studies estimated the burden of disease ranged from seven cases per 1,000 children aged between one and 16 years (2003) to 6.4 per 1,000 children (2003). A study from 2019 estimated the period prevalence of noma from 2010 to 2018 was 1.6 per 100,000 population at risk in Nigeria. These estimates are based on expert opinion, number of hospital admissions and retrospectively collected hospital-based data and it is unclear which stages of noma were included. Risk factors for the disease include poor oral hygiene, malnutrition, comorbidities and low socioeconomic status. Despite its ancient history (reported by Hippocrates (460 - 370 BC)), noma-related literature remains mainly confined to case reports and case series. By employing both qualitative and quantitative methods, we sought to examine the biopsychosocial features of noma, its epidemiology and treatment in northwest Nigeria in order to inform advocacy and prevention efforts. The three overarching objectives to fulfil this aim were to assess the distribution of noma among children in northwest Nigeria; identify factors associated with noma (including factors influencing health-seeking behaviour and risk factors for the development of noma) and gain an understanding of the biomedical and non-biomedical care provided to noma patients in this setting. The knowledge gained through this thesis will support the assessment of the need for advocacy around noma, effective resource allocation and the planning of intervention strategies. Methods We conducted a scoping literature review, three quantitative studies (risk factors, outcomes, prevalence) and two qualitative studies (language and beliefs and traditional healing practices) in northwest Nigeria. Data were collected from patient caretakers at the Noma Children's Hospital, hospital staff, children and traditional healers in villages within Sokoto and Kebbi States. Data collection methods included quantitative surveys, oral screenings, anthropometric measurements, quality of life questionnaires, qualitative in-depth interviews and focus group discussions. Consenting adult respondents answered questionnaires and participated in interviews, and where applicable, data was collected from assenting children. Quantitative analyses included descriptive statistics as well as univariable and multivariable risk factor analyses. Qualitative data was manually coded and analysed thematically. Findings We included 74 cases (noma patients presenting at the hospital in the year preceding data collection) and 222 controls (both median age of five years (inter-quartile range 3, 15 years)) in the risk factor study. Vaccination coverage for polio and measles was below 7% in both cases and controls. The multivariable analysis identified the child being fed pap every day (adjusted odds ratio (aOR) 9.8; 95% confidence interval (CI 1.5, 62.7) as a risk factor. The mother being the primary caretaker (aOR 0.08; CI 0.01, 0.5) and the caretaker being married (aOR 0.006; CI 0.0006, 0.5) were protective factors. Of the 37 patients with noma sequelae included in the outcomes study, 21 (56.8%) were male and 22 (62.9%) were aged six years or older. Fifteen patients (40.5%) had two to three surgeries. The most frequently used surgical procedure was a deltopectoral flap (n=16 patients; 43.2%). Trismus was released in 12 patients (32.4%), of these; none had a normal mouth opening at the follow-up visit. Despite this finding, all respondents reported that the surgery had improved their quality of life. In the cross-sectional study assessing the prevalence of all stages of noma, we included 3,499 households and 7,122 children aged <15 years; 4,239 (59.8%) were aged 0 to 5 years. Simple gingivitis was identified in 3.1% (n=181; CI 2.6-3.8), acute necrotizing gingivitis in 0.1% (n=10; CI 0.1-0.3), and oedema in 0.05% (n=3; CI 0.02-0.2). No cases of late-stage noma were detected. Naming of the disease differed between caretakers and healthcare workers in the language and beliefs study. Beliefs about the causes of noma were varied (spirits, animals, insects, previous infections). Noma patient caretakers spoke of the mental health strain due to stigmatization as a key issue. Difficulty in accessing care was evident. A lack of trust in the health system was mentioned as a barrier to care. Traditional healers offered specialised forms of care for specific conditions and referral guidance. They viewed the stages of noma as different conditions with individualised remedies and were willing to refer noma patients. Caretakers trusted traditional healers. Conclusion Social conditions and childhood feeding practices are associated with the occurrence of noma in northwest Nigeria. This thesis has shown that following their last surgical intervention, noma patients do experience some improvements in their quality of life, but continue to face functional challenges that inhibit their daily life. We found many, widely distributed, early-stage noma cases in northwest Nigeria indicating a large population at risk of progressing to the later stages of disease. Caretaker and practitioner perspectives may enlighten efforts to improve case finding, and to understand barriers to accessing health care. Differences in disease naming illustrated the difference in beliefs about the disease. Traditional healers could play a crucial role in the early detection of noma and the health-seeking decision-making process of patients. Intervention programmes should include traditional healers through training and referral partnerships. In conclusion, this thesis provides a unique view of the biopsychosocial features, epidemiology and treatment options for noma in northwest Nigeria. Noma is a disease, which is indicative of a weak health system and socio-economic environments of extreme deprivation. Intervention programmes should include widespread health system improvements that could address a host of risk factors for noma, and simultaneously other childhood diseases. These include increasing access to quality health care (including vaccinations), ensuring effective referral mechanisms, predominantly in rural areas, and the creation of a robust surveillance network. Health financing initiatives would need to be paired with these improvements. Nutritional programs aimed at caretakers of young children and community-based oral health initiatives could be effective mechanisms to curb the number of noma cases. Awareness-building initiatives targeting healthcare workers and community members are necessary to improve the detection and timely management of noma in endemic settings. The combined findings of this thesis highlight the neglected nature of noma and make a strong case for placing noma on the WHO neglected tropical diseases list. This initiative could foster awareness among policy-makers and governments and direct much needed funding to facilitate further research, surveillance and targeted health interventions that would contribute to the eradication of noma.
- ItemOpen AccessOutcomes and effectiveness of antiretroviral therapy for HIV-infected children in South African treatment cohorts(2013) Davies, Mary-Ann; Boulle, Andrew; Eley, BrianSince 2004, increasing numbers of children in sub-Saharan Africa have commenced antiretroviral therapy (ART). This thesis reviews the outcomes of published studies of paediatric ART cohorts in Africa, describes outcomes for children receiving ART in South Africa and examines determinants of mortality and generalizability across the Southern African region. Temporal trends in characteristics at ART initiation are also examined. The measurement of treatment success in resource-limited settings is reviewed, by examining virological failure, and assessing the diagnostic accuracy of immunological criteria for identifying virological failure.The results chapter is presented in the form of published or submitted papers based on data from the International epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEASA) collaboration. The first paper reviews paediatric ART studies from Africa published before 2008. Together with the literature review in chapter 1, it provides the background to this thesis. The second paper reports on mortality (8%) and retention in care (81%) by 3 years after ART start for > 6,000 children who initiated ART in South Africa. The generalizable prognostic models in the third paper suggest that mortality during the first year on ART ranges from <2% to >45%, with the majority of children being in the group with the best prognosis. The fourth paper reports that 1 in 5 children meet criteria for confirmed virological failure by 3 years on ART. The risk is greater with triple ART containing nevirapine or unboosted ritonavir (in comparison with lopinavir/ritonavir or efavirenz). The fifth and sixth papers demonstrate that immunological criteria have low sensitivity and positive predictive value for virological failure. Targeted viral load measurement reduces the number of false positive virological failure diagnoses. The final paper shows that increasing numbers of children have initiated ART with a decline in disease severity at therapy start from 2005-2010. However, even in 2010 a substantial number of children started ART with advanced disease. The thesis concludes that access to ART for children has increased, with good outcomes. HIV cohort research is important in evaluating the safety and effectiveness of different models of care, treatment and monitoring strategies.