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.

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.

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.