Adeodata Kekitiinwa

Predictors of long-term viral failure among ugandan children and adults treated with antiretroviral therapy.

Background:HIV RNA viral load testing is costly and is generally unavailable in resource-limited settings. We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART). Methods:From April 2004 to June 2005, consecutive treatment-naive patients beginning ART at a university clinic in Uganda were enrolled. Clinical information, CD4 cell count, and HIV RNA level were collected at baseline and every 3 to 6 months. Independent predictors of viral failure were identified using multivariate logistic regression. Genotypic drug resistance for 8 patients with viral failure at 12 months was measured at baseline and at 6 and 12 months. Results:Five hundred twenty-six adults and 250 children (0 to 18 years of age) were started on first-line ART regimens and followed for 12 months. Outcomes could not be assessed in 13% of patients (79 died and 21 were withdrawn). Children were almost twice as likely to have viral failure compared with adults (26% vs. 14%; P = 0.0001). In adults, the sole independent predictor of viral failure was treatment with stavudine (d4T)/lamivudine (3TC)/nevirapine (NVP) versus zidovudine (ZDV)/3TC/efavirenz (EFV) (odds ratio [OR] = 2.59, 95% confidence interval [CI]: 1.20 to 5.59). In children, independent predictors of viral failure included male gender (OR = 2.44, 95% CI: 1.20 to 4.93), baseline CD4% <5 (OR = 2.69, 95% CI: 1.28 to 5.63), and treatment with d4T/3TC/NVP versus ZDV/3TC/EFV (OR = 2.46, 95% CI: 1.23 to 4.90). All 8 patients with viral breakthrough and genotypic drug resistance results had nonnucleoside reverse transcriptase inhibitor (NNRTI)- and 3TC-associated mutations. Conclusions:These data demonstrate the effectiveness of ART in a low-resource setting. Children and patients of all ages taking the d4T/3TC/NVP regimen were more likely to have viral failure. Our data suggest that viral failure occurring 6 months or more after the start of ART regimens commonly used in Uganda is likely to be associated with NNRTI- and 3TC-resistant virus.

Effects of trimethoprim-sulfamethoxazole and insecticide-treated bednets on malaria among HIV-infected Ugandan children

Background:Trimethoprim–sulfamethoxazole (TMP/SMX) prophylaxis and insecticide-treated bednets reduce malaria risk among HIV-infected adults. The efficacy of TMP/SMX may be diminished where antifolate resistance to malaria is high. We evaluated the efficacy of these interventions for malaria prevention among Ugandan children. Methods:We concurrently followed 300 HIV-infected children aged 1–10 years and a community-based cohort of 561 healthy children aged 1–11 years over 11 months in Kampala, Uganda. The HIV-infected children received TMP/SMX prophylaxis and insecticide treated bednets. In the community cohort, insecticide-treated bednets were introduced during the observation period. Children from both cohorts were followed using a standardized protocol to measure the incidence of malaria. Results:Only nine episodes of malaria were diagnosed among HIV-infected children (incidence = 0.07/person-year) in comparison with 440 episodes among children from the community (incidence = 0.90/person-year; P < 0.0001). The use of insecticide-treated bednets was associated with a 43% reduction in malaria incidence (P < 0.001), and a combination of TMP/SMX and use of insecticide-treated bednets with a 97% reduction in malaria incidence (P < 0.001). The prevalence of five mutations associated with antifolate resistance was high among malaria cases detected in both the HIV (100%) and community cohorts (75%). Malaria accounted for only 4% of febrile episodes in the HIV cohort in comparison with 33% in the community-based cohort (P < 0.0001). Conclusion:In a malaria endemic area with a high level of molecular markers of antifolate resistance, the combined use of TMP/SMX prophylaxis and insecticide-treated bednets was associated with a dramatic reduction in malaria incidence among HIV-infected children.

A Randomized Trial of Prolonged Co-trimoxazole in HIV-Infected Children in Africa

BACKGROUND Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole. METHODS We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolescents in Uganda and Zimbabwe. Eligible participants were older than 3 years of age, had been receiving ART for more than 96 weeks, were using insecticide-treated bed nets (in malaria-endemic areas), and had not had Pneumocystis jirovecii pneumonia. Coprimary end points were hospitalization or death and adverse events of grade 3 or 4. RESULTS A total of 758 participants were randomly assigned to stop or continue co-trimoxazole (382 and 376 participants, respectively), after receiving ART for a median of 2.1 years (interquartile range, 1.8 to 2.3). The median age was 7.9 years (interquartile range, 4.6 to 11.1), and the median CD4 T-cell percentage was 33% (interquartile range, 26 to 39). Participants who stopped co-trimoxazole had higher rates of hospitalization or death than those who continued (72 participants [19%] vs. 48 [13%]; hazard ratio, 1.64; 95% confidence interval [CI], 1.14 to 2.37; P = 0.007; noninferiority not shown). There was no evidence of variation across ages (P=0.93 for interaction). A total of 2 participants in the prophylaxis-stopped group (1%) died, as did 3 in the prophylaxis-continued group (1%). Most hospitalizations in the prophylaxis-stopped group were for malaria (49 events, vs. 21 in the prophylaxis-continued group) or infections other than malaria (53 vs. 25), particularly pneumonia, sepsis, and meningitis. Rates of adverse events of grade 3 or 4 were similar in the two groups (hazard ratio, 1.20; 95% CI, 0.83 to 1.72; P=0.33), but more grade 4 adverse events occurred in the prophylaxis-stopped group (hazard ratio, 2.04; 95% CI, 0.99 to 4.22; P=0.05), with anemia accounting for the largest number of events (12, vs. 2 with continued prophylaxis). CONCLUSIONS Continuing co-trimoxazole prophylaxis after 96 weeks of ART was beneficial, as compared with stopping prophylaxis, with fewer hospitalizations for both malaria and infection not related to malaria. (Funded by the United Kingdom Medical Research Council and others; ARROW Current Controlled Trials number, ISRCTN24791884.).

High Risk of Neutropenia in HIV-Infected Children following Treatment with Artesunate plus Amodiaquine for Uncomplicated Malaria in Uganda

BACKGROUND Artemisinin-based combination therapies are rapidly being adopted for the treatment of malaria in Africa; however, there are limited data on their safety and efficacy among human immunodeficiency virus (HIV)-infected populations. METHODS We compared malaria treatment outcomes between cohorts of HIV-infected and HIV-uninfected children in Uganda who were observed for 18 and 29 months, respectively. Malaria was treated with artesunate plus amodiaquine, and outcomes were assessed using standardized guidelines. HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis and antiretroviral therapy in accordance with current guidelines. RESULTS Twenty-six HIV-infected participants experiencing 35 episodes of malaria and 134 HIV-uninfected children experiencing 258 episodes of malaria were included in the study. Twelve HIV-infected children were receiving antiretroviral therapy, 11 of whom were receiving zidovudine. Malaria treatment was highly efficacious in both the HIV-infected and HIV-uninfected cohorts (28-day risk of recrudescence, 0% and 3.6%, respectively); however, there was a trend towards increased risk of recurrent malaria among the HIV-uninfected children (2.9% vs. 13.2%; p = .08). Importantly, the risk of neutropenia 14 days after initiation of treatment with artesunate plus amodiaquine was higher among HIV-infected children than among HIV-uninfected children (45% vs. 6%; p < .001). The severity of all episodes of neutropenia in HIV-uninfected children was mild to moderate, and 16% of episodes of neutropenia in the HIV-infected cohort were severe or life-threatening (neutrophil count, <750 cells/mm(3)). In the HIV-infected cohort, the risk of neutropenia was significantly higher among children who received antiretroviral therapy than among those who did not receive antiretroviral therapy (75% vs. 26%; p < .001). CONCLUSIONS Artesunate plus amodiaquine was highly efficacious for malaria treatment in HIV-infected children but was associated with a high risk of neutropenia, especially in the context of concurrent antiretroviral use. Our findings highlight an urgent need for evaluation of alternative antimalarial therapies for HIV-infected individuals.

Growth in HIV-infected children receiving antiretroviral therapy at a pediatric infectious diseases clinic in Uganda.

Antiretroviral therapy (ART) improves growth and survival of HIV-infected individuals. We designed a retrospective cohort study to assess clinical factors associated with growth in HIV-infected children on ART in Uganda between July 2003 and March 2006. Height and weight measurements taken pre- and post-ART initiation for at least 6 months were age- and gender-standardized to CDC 2000 reference. We analyzed medical records of 749 children receiving ART. Descriptive and logistic regression analyses were conducted to identify covariates associated with risk of either stunting or being underweight. Longitudinal regression analysis with a mixed model using autoregressive covariance structure was used to compare change in height and weight before and after initiation of ART. The mean age of the study population at first visit was 7.5 years. Mean height-for-age, weight-for-age, and weight-for-height percentiles at first visit were 8.6, 7.7, and 7.9, respectively. At last visit mean height-for-age, weight-for-age, and weight-for-height percentiles were 8.6, 13.3, and 13.8, respectively. Baseline weight-for-age z score of 1 or more was protective against stunting (odds ratio [OR] 0.25, confidence interval [CI] 0.18-0.35) while baseline height-for-age z score of 1 or more was protective against becoming underweight (OR 0.75, CI 0.63-0.88). Children in World Health Organization (WHO) stages II, III, and IV at baseline were 1.5 times more likely to become underweight (OR 1.51, CI 1.07-2.14). Initiation of ART resulted in improvement in mean standardized weight-for-age z score and weight-for-age percentiles (p < 0.001). Weight-for-age percentile and z score improved significantly after initiation of ART. This pediatric population gained weight more rapidly than height after initiation of ART.

Bacteraemia in severely malnourished children in an HIV-endemic setting

Abstract Background: HIV infection predisposes children with malnutrition to recurrent bacterial infections and a high risk of bacteraemia. Methods: A cross-sectional descriptive study to determine the prevalence, causative organisms, antibiotic sensitivity and factors associated with bacteraemia in malnourished children was undertaken at Mulago Hospital, Kampala. The prevalence of HIV infection was also determined. A total of 134 children aged 6–59 months with severe malnutrition were recruited. Results: Sixty-one (45.5%) had oedematous malnutrition and 73 (54.5%) had severe wasting. Fifty-nine (44.0%) were HIV-infected. The prevalence of bacteraemia was 22%. The predominant organisms isolated were gram-negative enteric bacilli (77%) with Salmonella species and E. coli contributing 67% of the isolates. Hypoglycaemia was significantly associated with bacteraemia (p=0.007). Most organisms were resistant to cotrimaxazole (93.3%), ampicillin (76.7%), gentamicin (66.7%) and chloramphenicol (60%). All isolates were sensitive to ceftriaxone. Sensitivity to ciprofloxacin was 97%. There was no strong association between HIV infection and bacteraemia. The relative risk of death in malnourished children with bacteraemia was ten times higher than in those without bacteraemia. Conclusions: Nearly a quarter (22%) of children admitted with severe malnutrition had bacteraemia and gram-negative organisms were the predominant cause. Forty-four per cent were HIV-infected. Most of the bacteria were sensitive to ceftriaxone and ciprofloxacin and resistant to commonly used antibiotics. In the absence of culture and sensitivity, ciprofloxacin or ceftriaxone should be considered as first-line antibiotics for severely malnourished children.

Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study.

With widespread use of antiretroviral therapy (ART) and prolonged survival of HIV‐infected children, toxicities like lipodystrophy are becoming more evident. Little is known about lipodystrophy in children in Uganda yet there is increased use of ART. The aim of this study was to determine the prevalence and factors associated with fat redistribution and metabolic abnormalities among HIV‐infected children on highly active antiretroviral therapy (HAART) in Uganda.

Hospitalization for severe malnutrition among HIV-infected children starting antiretroviral therapy.

Objective:To describe early hospitalization for severe malnutrition in HIV-infected children initiating antiretroviral therapy (ART). Design:Randomized trial of induction-maintenance and monitoring strategies in HIV-infected children. Setting:Three tertiary hospitals in Uganda and one in Zimbabwe. Participants:1207 HIV-infected children, median age 6 years (range, 3 months to 17 years). Intervention:Abacavir, lamivudine and nevirapine or efavirenz were given; children in induction-maintenance arms also received zidovudine to week 36. Pre-ART inpatient/outpatient nutritional rehabilitation for children with baseline severe malnutrition. Main outcome measures:Hospitalization for severe malnutrition and change in CD4 cell percentage by week 12 after ART. Mortality and change in weight-for-age Z-score (WAZ) by week 24 after ART. Results:Thirty-nine of 1207 (3.2%) children were hospitalized for severe malnutrition (20 with oedema), median 28 days [interquartile range (IQR) 14, 36] after ART for marasmus and 26 days (IQR 14, 56) after ART for kwashiorkor. Hospitalized children had lower baseline and greater 24-week rise in WAZ than nonhospitalized children (P < 0.001). Twenty-nine of 39 (74%) children admitted for severe malnutrition had underlying infections. Of 220 children with advanced disease (baseline WAZ and CD4 cell Z-scores both <−3), 7.3% [95% confidence interval (CI) 3.8, 10.7] developed kwashiorkor and 3.6% (95% CI 1.2, 6.1) developed marasmus by week 12. CD4 cell percentage rise was similar among groups (P = 0.37). Twenty-four-week mortality was 32, 20 and 1.7% among children hospitalized with marasmus, kwashiorkor and not hospitalized, respectively, (P < 0.001). Conclusion:One in nine children with advanced HIV required early hospitalization for severe malnutrition after ART, with a 15-fold increase in 6-month mortality compared with nonhospitalized children. Integration of HIV/malnutrition services and further research to determine optimal ART timing, role of supplementary feeding and antimicrobial prophylaxis are urgently required.

The pharmacokinetics and acceptability of lopinavir/ritonavir minitab sprinkles, tablets, and syrups in african HIV-infected children

Background:Guidelines recommend lopinavir/ritonavir (LPV/r) as first- and second-line therapy for young and older HIV-infected children, respectively. Available formulations have limitations making their widespread use complex. Methods:An open-label comparative bioavailability (randomized crossover) study compared a novel twice-daily minitab sprinkle formulation (40 mg/10 mg, Cipla Pharmaceuticals) versus innovator syrup in HIV-infected Ugandan infants aged 3 to <12 months (cohort A) and children aged 1–4 years (cohort B) and versus Cipla tablets (100/25 mg) in children aged 4 to <13 years (cohort C). Twelve-hour intensive pharmacokinetic sampling after observed LPV/r intake (plus 2 nucleoside reverse transcriptase inhibitors) following World Health Organization 2010 dosing with food was performed 4 weeks after enrollment. Children then switched formulation; sampling was repeated at week 8. Acceptability data were also collected. Results:Seventy-seven infants/children were included in cohort A (n = 19)/B (n = 26)/C (n = 32). Among 132 evaluable pharmacokinetic profiles, there were 13/21/25 within-child comparisons in cohort A/B/C. For minitabs versus syrup, geometric mean [95% confidence interval (CI)] AUC0–12h was 88.6 (66.7–117.6) versus 77.6 (49.5–121.5) h·mg/L in cohort A [geometric mean ratio (GMR) (90% CI) = 1.14 (0.71 to 1.85)] and 138.7 (118.2 to 162.6) versus 109.1 (93.7 to 127.1) h·mg/L in cohort B [GMR (90% CI) = 1.27 (1.10 to 1.46)]. For minitabs versus tablets, geometric mean (95% CI) AUC0–12h was 83.1 (66.7 to 103.5) versus 115.6 (103.0 to 129.7) h·mg/L; GMR (90% CI) = 0.72 (0.60 to 0.86). Subtherapeutic levels (<1.0 mg/L) occurred in 0 (0%)/2 (15%) minitabs/syrup in infants (P = 0.48), no children aged 1–4 years and 4 (16%)/1 (4%) minitabs/tablets (P = 0.35). About 13/17 (76%) and 19/26 (73%) caregivers of infants and children aged 1–4 years, respectively, chose to continue minitabs after week 8, mainly for convenience; only 7/29 (24%) older children (five <6 years) remained on minitabs. Conclusions:LPV/r exposure from minitabs was comparable with syrup, but lower than tablets, with no significant differences in subtherapeutic concentrations. Minitabs were more acceptable than syrups for younger children, but older children preferred tablets.

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.