A qualitative evaluation and conceptual framework on the use of the Birth weight and Age-at-death Boxes for Intervention and Evaluation System (BABIES) matrix for perinatal health in Uganda.

BACKGROUND: Perinatal mortality (newborn deaths in the first week of life and stillbirths) continues to be a significant global health threat, particularly in resource-constrained settings. Low-tech, innovative solutions that close the quality-of-care gap may contribute to progress toward the Sustainable Development Goals for health by 2030. From 2012 to 2018, the Saving Mothers, Giving Life Initiative (SMGL) implemented the Birth weight and Age-at-Death Boxes for Intervention and Evaluation System (BABIES) matrix in Western Uganda. The BABIES matrix provides a simple, standardized way to track perinatal health outcomes to inform evidence-based quality improvement strategies. METHODS: In November 2017, a facility-based qualitative evaluation was conducted using in-depth interviews with 29 health workers in 16 health facilities implementing BABIES in Uganda. Data were analyzed using directed content analysis across five domains: 1) perceived ease of use, 2) how the matrix was used, 3) changes in behavior or standard operating procedures after introduction, 4) perceived value of the matrix, and 5) program sustainability. RESULTS: Values in the matrix were easy to calculate, but training was required to ensure correct data placement and interpretation. Displaying the matrix on a highly visible board in the maternity ward fostered a sense of accountability for health outcomes. BABIES matrix reports were compiled, reviewed, and responded to monthly by interprofessional teams, prompting collaboration across units to fill data gaps and support perinatal death reviews. Respondents reported improved staff communication and performance appraisal, community engagement, and ability to track and link clinical outcomes with actions. Midwives felt empowered to participate in the problem-solving process. Respondents were motivated to continue using BABIES, although sustainability concerns were raised due to funding and staff shortages. CONCLUSIONS: District-level health systems can use data compiled from the BABIES matrix to inform policy and guide implementation of community-centered health practices to improve perinatal heath. Future work may consider using the Conceptual Framework on Use of the BABIES Matrix for Perinatal Health as a model to operationalize concepts and test the impact of the tool over time.

Virologic, immunologic and clinical response of infants to antiretroviral therapy in Kampala, Uganda.

BACKGROUND: Antiretroviral therapy (ART) is known to save lives. Among HIV-infected infants living in resource constrained settings, the short and long term benefits of ART are only partially known. This study was designed to determine the virologic, immunologic and clinical outcomes of antiretroviral therapy in a cohort of HIV-infected infants receiving care from an outpatient clinic in Kampala, Uganda. METHODS: A prospective cohort of HIV-infected infants receiving treatment at the Baylor-Uganda clinic was analyzed. Patients were diagnosed, enrolled and followed up at the clinic. HIV viral load, CD4 cell counts and clinical progress were assessed during follow-up. Descriptive statistical analysis and logistic regression modeling to determine predictors of treatment success were conducted. RESULTS: Of 91 HIV-infected infants enrolled into the cohort, 53 (58.2%) infants were female; 43 (47.3%) were 6 months of age or younger, and 50 (55.6%) had advanced HIV/AIDS disease (Clinical stage 3 or 4). Eighty four infants started ART and 78 (92.9%) completed 6 months of treatments. Fifty six (71.8%) infants attained virologic suppression by month-6 of ART, and at month-12 of ART, the cumulative probability of attaining viral suppression was 83.1%. None of the baseline infant factors (age, sex, WHO stage, CD4 cell percent, weight for age, or height for age z-score) predicted treatment success. There was an increase in CD4 cells from a baseline mean of 23% to 30% at month-6 of treatment (p<0.001) and by month-24 of ART, the mean CD4 percent was 36%. A total of 7 patients died while on ART and another 7 experienced adverse events that were related to treatment. CONCLUSION: Our results show that, even among very young patients from resource constrained settings, ART dramatically suppresses HIV replication, allows immune recovery and clinical improvement, and is safe. However, baseline characteristics do not predict recovery in this age group.

Addressing the First Delay in Saving Mothers, Giving Life Districts in Uganda and Zambia: Approaches and Results for Increasing Demand for Facility Delivery Services.

Saving Mothers, Giving Life (SMGL), a 5-year initiative implemented in selected districts in Uganda and Zambia, was designed to reduce deaths related to pregnancy and childbirth by targeting the 3 delays to receiving appropriate care at birth. While originally the "Three Delays" model was designed to focus on curative services that encompass emergency obstetric care, SMGL expanded its application to primary and secondary prevention of obstetric complications. Prevention of the "first delay" focused on addressing factors influencing the decision to seek delivery care at a health facility. Numerous factors can contribute to the first delay, including a lack of birth planning, unfamiliarity with pregnancy danger signs, poor perceptions of facility care, and financial or geographic barriers. SMGL addressed these barriers through community engagement on safe motherhood, public health outreach, community workers who identified pregnant women and encouraged facility delivery, and incentives to deliver in a health facility. SMGL used qualitative and quantitative methods to describe intervention strategies, intervention outcomes, and health impacts. Partner reports, health facility assessments (HFAs), facility and community surveillance, and population-based mortality studies were used to document activities and measure health outcomes in SMGL-supported districts. SMGL's approach led to unprecedented community outreach on safe motherhood issues in SMGL districts. About 3,800 community health care workers in Uganda and 1,558 in Zambia were engaged. HFAs indicated that facility deliveries rose significantly in SMGL districts. In Uganda, the proportion of births that took place in facilities rose from 45.5% to 66.8% (47% increase); similarly, in Zambia SMGL districts, facility deliveries increased from 62.6% to 90.2% (44% increase). In both countries, the proportion of women delivering in facilities equipped to provide emergency obstetric and newborn care also increased (from 28.2% to 41.0% in Uganda and from 26.0% to 29.1% in Zambia). The districts documented declines in the number of maternal deaths due to not accessing facility care during pregnancy, delivery, and the postpartum period in both countries. This reduction played a significant role in the decline of the maternal mortality ratio in SMGL-supported districts in Uganda but not in Zambia. Further work is needed to sustain gains and to eliminate preventable maternal and perinatal deaths.

Addressing the Second Delay in Saving Mothers, Giving Life Districts in Uganda and Zambia: Reaching Appropriate Maternal Care in a Timely Manner.

BACKGROUND: Between June 2011 and December 2016, the Saving Mothers, Giving Life (SMGL) initiative in Uganda and Zambia implemented a comprehensive approach targeting the persistent barriers that impact a woman's decision to seek care (first delay), ability to reach care (second delay), and ability to receive adequate care (third delay). This article addresses how SMGL partners implemented strategies specifically targeting the second delay, including decreasing the distance to facilities capable of managing emergency obstetric and newborn complications, ensuring sufficient numbers of skilled birth attendants, and addressing transportation challenges. METHODS: Both quantitative and qualitative data collected by SMGL implementing partners for the purpose of monitoring and evaluation were used to document the intervention strategies and to describe the change in outputs and outcomes related to the second delay. Quantitative data sources included pregnancy outcome monitoring data in facilities, health facility assessments, and population-based surveys. Qualitative data were derived from population-level verbal autopsy narratives, programmatic reports and SMGL-related publications, and partner-specific evaluations that include focus group discussions and in-depth interviews. RESULTS: The proportion of deliveries in any health facility or hospital increased from 46% to 67% in Uganda and from 63% to 90% in Zambia between baseline and endline. Distance to health facilities was reduced by increasing the number of health facilities capable of providing basic emergency obstetric and newborn care services in both Uganda and Zambia-a 200% and 167% increase, respectively. Access to facilities improved through integrated transportation and communication services efforts. In Uganda there was a 6% increase in the number of health facilities with communication equipment and a 258% increase in facility deliveries supported by transportation vouchers. In Zambia, there was a 31% increase in health facilities with available transportation, and the renovation and construction of maternity waiting homes resulted in a 69% increase in the number of health facilities with associated maternity waiting homes. CONCLUSION: The collective SMGL strategies addressing the second delay resulted in increased access to delivery services as seen by the increase in the proportion of facility deliveries in SMGL districts, improved communication and transportation services, and an increase in the number of facilities with associated maternity waiting homes. Sustaining and improving on these efforts will need to be ongoing to continue to address the second delay in Uganda and Zambia.

Addressing the Third Delay in Saving Mothers, Giving Life Districts in Uganda and Zambia: Ensuring Adequate and Appropriate Facility-Based Maternal and Perinatal Health Care.

BACKGROUND: Saving Mothers, Giving Life (SMGL) is a 5-year initiative implemented in participating districts in Uganda and Zambia that aimed to reduce deaths related to pregnancy and childbirth by targeting the 3 delays to receiving appropriate care: seeking, reaching, and receiving. Approaches to addressing the third delay included adequate health facility infrastructure, specifically sufficient equipment and medications; trained providers to provide quality evidence-based care; support for referrals to higher-level care; and effective maternal and perinatal death surveillance and response. METHODS: SMGL used a mixed-methods approach to describe intervention strategies, outcomes, and health impacts. Programmatic and monitoring and evaluation data-health facility assessments, facility and community surveillance, and population-based mortality studies-were used to document the effectiveness of intervention components. RESULTS: During the SMGL initiative, the proportion of facilities providing emergency obstetric and newborn care (EmONC) increased from 10% to 25% in Uganda and from 6% to 12% in Zambia. Correspondingly, the delivery rate occurring in EmONC facilities increased from 28.2% to 41.0% in Uganda and from 26.0% to 29.1% in Zambia. Nearly all facilities had at least one trained provider on staff by the endline evaluation. Staffing increases allowed a higher proportion of health centers to provide care 24 hours a day/7 days a week by endline-from 74.6% to 82.9% in Uganda and from 64.8% to 95.5% in Zambia. During this period, referral communication improved from 93.3% to 99.0% in Uganda and from 44.6% to 100% in Zambia, and data systems to identify and analyze causes of maternal and perinatal deaths were established and strengthened. CONCLUSION: SMGL's approach was associated with improvements in facility infrastructure, equipment, medication, access to skilled staff, and referral mechanisms and led to declines in facility maternal and perinatal mortality rates. Further work is needed to sustain these gains and to eliminate preventable maternal and perinatal deaths.

Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial.

BACKGROUND: WHO 2013 guidelines recommend universal treatment for HIV-infected children younger than 5 years. No paediatric trials have compared nucleoside reverse-transcriptase inhibitors (NRTIs) in first-line antiretroviral therapy (ART) in Africa, where most HIV-infected children live. We aimed to compare stavudine, zidovudine, or abacavir as dual or triple fixed-dose-combination paediatric tablets with lamivudine and nevirapine or efavirenz. METHODS: In this open-label, parallel-group, randomised trial (CHAPAS-3), we enrolled children from one centre in Zambia and three in Uganda who were previously untreated (ART naive) or on stavudine for more than 2 years with viral load less than 50 copies per mL (ART experienced). Computer-generated randomisation tables were incorporated securely within the database. The primary endpoint was grade 2-4 clinical or grade 3/4 laboratory adverse events. Analysis was intention to treat. This trial is registered with the ISRCTN Registry number, 69078957. FINDINGS: Between Nov 8, 2010, and Dec 28, 2011, 480 children were randomised: 156 to stavudine, 159 to zidovudine, and 165 to abacavir. After two were excluded due to randomisation error, 156 children were analysed in the stavudine group, 158 in the zidovudine group, and 164 in the abacavir group, and followed for median 2·3 years (5% lost to follow-up). 365 (76%) were ART naive (median age 2·6 years vs 6·2 years in ART experienced). 917 grade 2-4 clinical or grade 3/4 laboratory adverse events (835 clinical [634 grade 2]; 40 laboratory) occurred in 104 (67%) children on stavudine, 103 (65%) on zidovudine, and 105 (64%), on abacavir (p=0·63; zidovudine vs stavudine: hazard ratio [HR] 0·99 [95% CI 0·75-1·29]; abacavir vs stavudine: HR 0·88 [0·67-1·15]). At 48 weeks, 98 (85%), 81 (80%) and 95 (81%) ART-naive children in the stavudine, zidovudine, and abacavir groups, respectively, had viral load less than 400 copies per mL (p=0·58); most ART-experienced children maintained suppression (p=1·00). INTERPRETATION: All NRTIs had low toxicity and good clinical, immunological, and virological responses. Clinical and subclinical lipodystrophy was not noted in those younger than 5 years and anaemia was no more frequent with zidovudine than with the other drugs. Absence of hypersensitivity reactions, superior resistance profile and once-daily dosing favours abacavir for African children, supporting WHO 2013 guidelines. FUNDING: European Developing Countries Clinical Trials Partnership.

Anthropometric measurements and lipid profiles to detect early lipodystrophy in antiretroviral therapy experienced HIV-infected children in the CHAPAS-3 trial.

BACKGROUND: Few studies have investigated objective markers of lipodystrophy in African children. We compared body circumferences, skin-fold thickness (SFT) and lipids in antiretroviral therapy (ART)-naive and stavudine (d4T)-exposed children with HIV-uninfected controls. METHODS: In the CHAPAS-3 trial, HIV-infected children (ART-naive or on d4T for ≥2 years without clinical lipodystrophy) were randomized to d4T, abacavir or zidovudine with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor. Mid-upper-arm circumference (MUAC) and calf circumference (CC), SFT (biceps, triceps, sub-scapular and supra-iliac) and fasting lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL] and triglycerides [TRIG]) were measured at randomization in all HIV-infected children, and in HIV-uninfected controls. Age- and sex-adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) using Dutch reference data were compared across groups using linear regression. RESULTS: Of 496 children, 49% were male, 299 (median age 2.5 years [IQR 1.5-4.0]) were ART-naive, 109 (median age 6 years [IQR 5.5-7.0]) were ART-experienced and 88 (median age 2.2 years [IQR 1.5-3.0]) were control children. Overall, 100% and 95% of ART-experienced children had been on d4T plus 3TC and nevirapine, respectively, for a median 3.5 years (IQR 2.6-4.2). Mean (sd) weight-for-age z-scores and MUAC z-scores were -1.51 (1.29) versus -0.90 (0.88) versus -0.33 (1.15) and -1.56 (1.25) versus -1.24 (0.97) versus -0.65 (1.06) in ART-naive versus -experienced versus controls, respectively (all P<0.02). The mean (sd) of SSF was lower in the ART-experienced (-0.78 [1.28]) than in the ART-naive (-0.32 [1.09]; P<0.0001) children and controls (-0.29 [0.88]; P<0.002). ART-experienced children had higher mean fasting TC, LDL and HDL but lower TRIG compared to ART-naive children (P-values <0.0001), and higher TC and HDL but lower TRIG compared to controls (P-values <0.01). CONCLUSIONS: In ART-experienced children on d4T-containing regimens, we observed lower SFT and higher TC and LDL values compared to ART-naive children and HIV-uninfected controls.

Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda.

BACKGROUND: Antiretroviral therapy (ART) is known to cause a number of adverse effects. The objective of this study was to determine the frequency and outcome of ART-related adverse events among patients aged 6 weeks to 18 years. METHODS: We followed up a cohort of 378 HIV-infected children and adolescents who started ART at the Baylor-Uganda Clinic during the period July 2004 to July 2009. Patients were started on zidovudine or stavudine, plus lamivudine, and efavirenz or nevirapine. Adverse events were recorded as they occurred. Descriptive analyses and Kaplan-Meier survival analysis were carried out. RESULTS: Of 126 adverse events reported among 107 (28.3%) patients, dizziness (17.5%), diarrhea (13.5%), and nausea and vomiting (14.3%) were the most frequent. Anxiety/night mares, skin rashes, nail discoloration, and lipodystrophy each contributed between 5% and 10%; whereas anorexia, abdominal pain, hepatitis, and somnolence contributed 1%-5%. Amnesia, lactic acidosis, gynaecomastia, cardiomyopathy, and peripheral neuropathy were rare, each contributing less than 1% of the total events. The overall probability of remaining free of adverse events was 77.1% (95% confidence interval: 72.38 to 81.13) at month 6 of ART.Among infants and young children, neurologic events could not be determined. Laboratory abnormalities were present at baseline and during follow-up, and hemoglobin levels increased significantly during the first 6 months of ART. There was no association between adverse events and baseline patient characteristics. CONCLUSION: Close to one-third of children on ART experience adverse events. Most events occur within the first 3 months of ART and are not associated with baseline patient characteristics.

Prospective long-term outcomes of a cohort of Ugandan children with laboratory monitoring during antiretroviral therapy.

BACKGROUND: Treatment of HIV-1 infected Ugandan children with antiretroviral therapy (ART) is increasing, but few prospective long-term studies evaluating the treatment process have been reported. In this study, we sought to determine prospectively how consistent monitoring of HIV-1 RNA levels affects the ART treatment process. METHODS: One hundred eight children initiating ART were enrolled into this study. These children had comprehensive laboratory monitoring, including HIV-1 RNA level determination and genotype analysis (where appropriate), CD4% plus absolute counts and safety laboratory measurements performed before starting therapy and at regular intervals after receiving ART. Kaplan-Meier statistics were used to examine predictors of survival and virologic failure. Viral genotype analysis was performed on samples obtained from children having virologic failure to determine the emergence of mutations. RESULTS: Clinically, there was no difference in the 3-year survival between our cohort receiving consistent laboratory monitoring and a matched historical clinic cohort not routinely receiving laboratory monitoring. However, 34% of children receiving ART demonstrated virologic failure. Eleven of these children received second-line ART, and all responded with an undetectable HIV-1 RNA level and an increase in CD4 count. Children remaining on a failing antiretroviral regimen accumulated resistance mutations. CONCLUSIONS: Our prospective long-term findings support the general use of monitoring HIV-1 RNA levels for the management of children on ART and the adoption of a clearer definition for virologic failure and better guidelines for managing children with unsuppressed HIV-1 RNA levels.

Differences in factors associated with initial growth, CD4, and viral load responses to ART in HIV-infected children in Kampala, Uganda, and the United Kingdom/Ireland.

BACKGROUND: Few studies have directly compared response to antiretroviral therapy (ART) between children living in well-resourced and resource-limited settings. In resource-limited settings non-HIV contributors could reduce the beneficial effects of ART. We compare predictors of short-term immunological, virological, and growth response to ART in HIV-infected children in the United Kingdom/Ireland and Kampala. METHODS: We analyzed prospective cohort data from 54 UK/Irish hospitals (the Collaborative HIV Paediatric Study) and Mulago Hospital, Kampala, Uganda. Six- and 12-month responses are described among children initiating combination ART (> or = 3 drugs, > or = 2 classes). Six months post-ART, predictors of viral load (VL) suppression <400 copies/mL, CD4% increases > 10%, and height- and weight-for-age z-score increases > or = +0.5 were investigated using logistic regression. RESULTS: In all, 582 UK/Irish children (76% black African) were younger than 876 Kampala children at ART initiation (median 5.0 vs 7.6 years), with higher CD4% (14%, 8%), lower VL (172,491 and 346,809 copies/mL), and less stunting (-0.8, -2.8) and wasting (-0.6, -2.8). Post-ART, median 12-month changes in the United Kingdom/Ireland and Kampala in CD4% (+12%, +13%) and weight (+0.4, +0.5) were similar, but growth was less in Kampala (+0.20, +0.06, P < 0.001). Younger children in both cohorts had better immunological, weight, and growth responses (all P < 0.001). However, lower pre-ART CD4% predicted better immunological response in the United Kingdom/Ireland but poorer response in Kampala (heterogeneity P = 0.004). Although 70% children in both cohorts had suppressed < 400 copies/mL at 6 months, adolescents starting ART in the United Kingdom/Ireland had somewhat poorer VL responses than those in Kampala (P = 0.15). CONCLUSIONS: Overall immunological and virologic ART responses were similar in children in both cohorts. Poorer CD4 recovery in more immunosuppressed Kampala children and blunted growth responses likely reflect higher background malnutrition and infection rates in Uganda, suggesting the need for earlier HIV diagnosis, nutritional support, cotrimoxazole prophylaxis, and ART.