James Okuma

Sex differences in antiretroviral treatment outcomes among HIV-infected adults in an urban Tanzanian setting.

Objective:To determine the relationship between sex and antiretroviral therapy (ART) outcomes in an urban Tanzanian setting. Design:Longitudinal analysis of a cohort of HIV-infected adult men and women on ART enrolled at the Management and Development for Health (MDH)-Presidents Emergency Plan For AIDS Relief (PEPFAR) HIV care and treatment program in Dar es Salaam, Tanzania. Methods:Clinical and immunologic responses to ART were compared between HIV-infected men and women enrolled from November 2004 to June 2008. Cox regression analyses were used to study sex differences with regard to mortality, immunologic failure (WHO, 2006) and loss to follow-up, after adjusting for other risk factors for the outcomes. Results:Four thousand, three hundred and eighty-three (34%) men and 8459 (66%) women were analyzed. Men were significantly more immunocompromised than women at enrollment in terms of stage IV disease (27 vs. 23%, P < 0.001) and mean CD4+ cell count (123 vs. 136 cells/μl, P < 0.001). In multivariate analyses, men had a significantly higher risk of overall mortality [hazard ratio 1.19, 95% confidence interval (CI) 1.05–1.30, P < 0.001], immunologic nonresponse defined as CD4 cell count less than 100 cells/μl after at least 6 months of initiating ART (hazard ratio 1.74, 95% CI 1.44–2.11, P < 0.001) and loss to follow-up (hazard ratio 1.19, 95% CI 1.10–1.30, P < 0.001) than that in women. Associations did not change significantly when restricting analyses to the period of good adherence for all patients. Conclusion:Nonadherence to care and advanced immunodeficiency at enrollment explained only 17% of the inferior mortality in HIV-infected men in this resource-limited setting. Additional study of behavioral and biologic factors that may adversely impact treatment outcomes in men is needed to reduce these sex disparities.

Effect of High-Dose vs Standard-Dose Multivitamin Supplementation at the Initiation of HAART on HIV Disease Progression and Mortality in Tanzania A Randomized Controlled Trial

CONTEXT Large randomized trials have previously shown that high-dose micronutrient supplementation can increase CD4 counts and reduce human immunodeficiency virus (HIV) disease progression and mortality among individuals not receiving highly active antiretroviral therapy (HAART); however, the safety and efficacy of such supplementation has not been established in the context of HAART. OBJECTIVE To test the hypothesis that high-dose multivitamin supplementation vs standard-dose multivitamin supplementation decreases the risk of HIV disease progression or death and improves immunological, virological, and nutritional parameters in patients with HIV initiating HAART. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, controlled trial of high-dose vs standard-dose multivitamin supplementation for 24 months in 3418 patients with HIV initiating HAART between November 2006 and November 2008 in 7 clinics in Dar es Salaam, Tanzania. INTERVENTION The provision of daily oral supplements of vitamin B complex, vitamin C, and vitamin E at high levels or standard levels of the recommended dietary allowance. MAIN OUTCOME MEASURE The composite of HIV disease progression or death from any cause. RESULTS The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3418 patients were enrolled (median follow-up, 15 months), and there were 2374 HIV disease progression events and 453 observed deaths (2460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96-1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1239 events per 1215 person-years vs 879 events per 1236 person-years; RR, 1.44; 95% CI, 1.11-1.87) vs standard-dose supplementation. CONCLUSION In adults receiving HAART, use of high-dose multivitamin supplements compared with standard-dose multivitamin supplements did not result in a decrease in HIV disease progression or death but may have resulted in an increase in ALT levels. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00383669.

Multiple micronutrient supplementation in Tanzanian infants born to HIV-infected mothers: a randomized, double-blind, placebo-controlled clinical trial

BACKGROUND Multiple micronutrients (vitamin B complex and vitamins C and E) were effective at reducing infectious disease morbidity, HIV disease progression, and poor pregnancy outcomes in HIV-infected women. OBJECTIVE The objective was to evaluate whether direct supplementation of these micronutrients to HIV-exposed infants reduces mortality and morbidity. DESIGN Infants born to HIV-infected women from Dar es Salaam, Tanzania, were randomly assigned to receive daily oral supplementation of multiple multivitamins (vitamin B complex and vitamins C and E) or placebo from age 6 wk for 24 mo. All-cause mortality, hospitalizations, and unscheduled clinic visits were recorded. Morbidities were recorded during monthly follow-up visits. All mothers received multiple micronutrients throughout the study. RESULTS A total of 1193 infants were randomly assigned to receive micronutrients and 1194 to receive placebo. There were 138 child deaths in the multivitamin group and 124 deaths in the placebo group (HR: 1.13; 95% CI: 0.88, 1.44; P = 0.33). Hospitalizations (RR: 0.83; 95% CI: 0.62, 1.13; P = 0.23), unscheduled clinic visits (RR: 0.97; 95% CI: 0.85, 1.10; P = 0.59), and maternal reports of diarrhea (RR: 0.97; 0.87, 1.10; P = 0.64) were not significantly different between the 2 groups. Fever (P = 0.02) and vomiting (P = 0.007) were significantly lower in the multivitamin group. Among 429 children whose mothers received antiretroviral (ARV) therapy, multivitamin use had no effect on mortality but was associated with a significant reduction in hospitalizations (P = 0.035), episodes of fever (P = 0.005), and episodes of fever and cough (P = 0.019). CONCLUSIONS In the setting of maternal micronutrient supplementation, supplementation of HIV-exposed infants with vitamin B and vitamins C and E does not reduce mortality. Studies of nutrition supplementation in ARV-exposed infants may be warranted.

A randomized trial to determine the optimal dosage of multivitamin supplements to reduce adverse pregnancy outcomes among HIV-infected women in Tanzania

BACKGROUND We previously reported that supplementation with multivitamins (vitamin B complex, vitamin C, and vitamin E) at multiples of the Recommended Dietary Allowance (RDA) significantly decreased the risk of adverse pregnancy outcomes among HIV-infected women. The minimum dosage of multivitamins necessary for optimal benefits is unknown. OBJECTIVE We investigated the efficacy of multivitamin supplements at single compared with multiple RDAs on decreasing the risk of adverse pregnancy outcomes among HIV-infected women. DESIGN We conducted a double-blind, randomized controlled trial among 1129 HIV-infected pregnant women in Tanzania. Eligible women between 12 and 27 gestational weeks were randomly assigned to receive daily oral supplements of either single or multiple RDA multivitamins from enrollment until 6 wk after delivery. RESULTS Multivitamins at multiple and single doses of the RDA had similar effects on the risk of low birth weight (11.6% and 10.2%, respectively; P = 0.75). We found no difference between the 2 groups in the risk of preterm birth (19.3% and 18.4%, respectively; P = 0.73) or small-for-gestational-age (14.8% and 12.0%, respectively; P = 0.18). The mean birth weights were similar in the multiple RDA (3045 + or - 549 g) and single RDA multivitamins group (3052 + or - 534 g; P = 0.83). There were no significant differences between the 2 groups in the risk of fetal death (P = 0.99) or early infant death (P = 0.19). CONCLUSION Multivitamin supplements at a single dose of the RDA may be as efficacious as multiple doses of the RDA in decreasing the risk of adverse pregnancy outcomes among HIV-infected women. This trial was registered at clinicaltrials.gov as NCT00197678.

Predictors of Stunting, Wasting and Underweight among Tanzanian Children Born to HIV-Infected Women.

Background/Objectives:Children born to human immunodeficiency virus (HIV)-infected women are susceptible to undernutrition, but modifiable risk factors and the time course of the development of undernutrition have not been well characterized. The objective of this study was to identify maternal, socioeconomic and child characteristics that are associated with stunting, wasting and underweight among Tanzanian children born to HIV-infected mothers, followed from 6 weeks of age for 24 months.Subjects/Methods:Maternal and socioeconomic characteristics were recorded during pregnancy, data pertaining to the infant’s birth were collected immediately after delivery, morbidity histories and anthropometric measurements were performed monthly. Multivariate Cox proportional hazards methods were used to assess the association between potential predictors and the time to first episode of stunting, wasting and underweight.Results:A total of 2387 infants (54.0% male) were enrolled and followed for a median duration of 21.2 months. The respective prevalence of prematurity (<37 weeks) and low birth weight (<2500 g) was 15.2% and 7.0%; 11.3% of infants were HIV-positive at 6 weeks. Median time to first episode of stunting, wasting and underweight was 8.7, 7.2 and 7.0 months, respectively. Low maternal education, few household possessions, low infant birth weight, child HIV infection and male sex were all independent predictors of stunting, wasting and underweight. In addition, preterm infants were more likely to become wasted and underweight, whereas those with a low Apgar score at birth were more likely to become stunted.Conclusions:Interventions to improve maternal education and nutritional status, reduce mother-to-child transmission of HIV, and increase birth weight may lower the risk of undernutrition among children born to HIV-infected women.

Dyslipidemia in an HIV-Positive Antiretroviral Treatment-Naive Population in Dar es Salaam, Tanzania.

Limited data are available on dyslipidemia in HIV-infected patients in resource-limited settings. We performed a cross-sectional analysis in antiretroviral therapy (ART)-naive, non-fasting HIV-infected patients in Tanzania between November 2004 to June 2008. Robust linear regression modeling was performed. Lipid parameters were assessed in 12,513 patients [65% women; median (interquartile range) age, 36 (30-42) years; CD4 count, 143 (51-290) cells/mm3]. Low high-density lipoprotein was prevalent in 67% and increased triglyceride in 28%. High triglyceride and low high-density lipoprotein levels were associated with low CD4 counts (P < 0.001). In this ART-naive Tanzanian population, dyslipidemia was highly prevalent and associated with advanced disease. The impact of ART on these changes requires further exploration.

HIV Infection and the incidence of malaria among HIV-exposed children from Tanzania

OBJECTIVE To determine whether human immunodeficiency virus (HIV) infection is associated with increased risk of malaria incidence and recurrence in children. METHODS Newborn infants of HIV-infected mothers were enrolled at 6 weeks and followed for 2 years. HIV status was assessed by enzyme-linked immunosorbant assay and confirmed by HIV DNA polymerase chain reaction. Malaria was defined as (1) physician-diagnosed clinical malaria; (2) probable malaria, in which laboratory testing is requested for parasitemia; and (3) blood smear-confirmed malaria. Cox proportional hazards models estimated hazard ratios (HRs) for development of first and second malaria episodes, and generalized estimating equation models estimated malaria rate differences per 100-child-years in relation to time-updated HIV status. RESULTS Child HIV infection was associated with clinical (HR, 1.34; 95% confidence interval [CI], 1.12-1.61), probable (HR, 1.47; 95% CI, 1.19-1.81), and confirmed (HR, 1.67; 95% CI, 1.18-2.36) malaria episodes. Per 100 child-years, HIV-infected children experienced 88 (95% CI, 65-113), 36 (95% CI, 19-53), and 20 (95% CI, 9-31) more episodes of clinical, probable, and confirmed malaria episodes, respectively, than HIV-uninfected children. Among children with ≥1 malaria episodes, those with HIV infection developed second clinical (HR, 1.28; 95% CI, 1.04-1.57), probable (HR, 1.60; 95% CI, 1.26-2.14), and confirmed (HR, 2.27; 95% CI, 1.06-3.89) malaria sooner than HIV-uninfected children. CONCLUSIONS HIV infection is a risk factor for the development of malaria. Proactive malaria disease prevention and treatment is warranted for all children, particularly those with HIV infection in settings of coendemicity.

The Contribution of Preterm Birth and Intrauterine Growth Restriction to Infant Mortality in Tanzania

BACKGROUND Our objectives were to examine the associations of neonatal and infant mortality with preterm birth and intrauterine growth restriction (IUGR), and to estimate the partial population attributable risk per cent (pPAR%) of neonatal and infant mortality due to preterm birth and IUGR. METHODS Participants were HIV-negative pregnant women and their infants enrolled in Dar es Salaam, Tanzania. Gestational age calculated from date of last menstrual period was used to define preterm, and small for gestational age (SGA) was used as proxy for IUGR. Survival of infants was ascertained at monthly follow-up visits. Cox proportional hazard models were used to estimate the associations of preterm and SGA with neonatal and infant mortality. RESULTS Study included 7225 singletons, of whom 15% were preterm and 21% were SGA; majority of preterm or SGA babies had birthweight ≥2500 g. Compared to term and appropriately sized babies (AGA), relative risks (RR) of neonatal mortality among preterm-AGA was 2.6 [95% CI 1.8, 3.9], RR among term-SGA was 2.3 [95% CI 1.6, 3.3], and the highest risk was among the preterm-SGA babies (RR 15.1 [95% CI 8.2, 27.7]). Risk associated with preterm was elevated throughout the infancy, and risk associated with SGA was elevated during the neonatal period only. The pPAR% of neonatal mortality for preterm was 22% [95% CI 17%, 26%] and for SGA it was 26% [95% CI 16%, 36%]. CONCLUSIONS Preterm and SGA birth substantially increased the risk of mortality. Interventions for prevention and management of these conditions are likely to reduce of infant mortality in Tanzania.

Mortality and Treatment Failure among HIV-Infected Adults in Dar Es Salaam, Tanzania

Objectives: Monitoring antiretroviral treatment (ART) outcomes is essential for assessing the success of HIV care and treatment programs in resource-limited settings (RLS). Methods: Longitudinal analyses of clinical and immunologic parameters in HIV-infected adults initiated on ART between November 2004 and June 2008 at Management and Development for Health (MDH)-Presidents Emergency Plan For AIDS Relief PEPFAR supported HIV care and treatment clinics in Tanzania. Results: A total of 12 842 patients were analyzed (65.9% female, median baseline CD4 count, 106 cells/mm3). Significant improvements in immunologic status were observed with an increase in CD4 count to 298 (interquartile range [IQR] 199-416), 372 (256-490) and 427 (314-580) cells/mm3, at 1, 2, and 3 years, respectively. Overall mortality was 13.1% (1682 of 12 842). Male sex, World Health Organization (WHO) stage III/IV, CD4 <200 cells/mm3, hemoglobin (Hgb) <8.5 g/dL, and stavudine (d4T)-containing regimens were independently associated with early and overall mortality. Conclusions: Closer monitoring of males and patients with advanced HIV disease following ART initiation may improve clinical and immunologic outcomes in these individuals.

Multivitamin Supplements Have No Effect on Growth of Tanzanian Children Born to HIV-Infected Mothers

Growth faltering and micronutrient deficiencies commonly coexist in HIV-exposed children in sub-Saharan Africa, and correcting deficiencies, such as those of vitamins B-complex, C, and E, may improve HIV-related endpoints and child growth. We therefore examined the effect of daily oral supplementation of vitamins B-complex, C, and E on growth among 2341 children born to HIV-infected mothers in Tanzania. HIV-infected women pregnant at ≤32 wk of gestation were enrolled in the study. Children were randomized at age 6 wk to receive multivitamins or placebo until age 104 wk. All women received the same types of vitamins pre- and postnatally. At 6 wk, 256 children (11.1%) were HIV infected and the mean (SD) Z-scores for length for age (LAZ), weight for length (WLZ), and weight for age (WAZ) were -0.39 ± 1.20, -0.21 ± 1.23, and -0.52 ± 1.11, respectively. There was no overall treatment effect on LAZ, WLZ, or WAZ profiles during the follow-up (P ≥ 0.15). There was no treatment effect from 6 to 104 wk on LAZ [(95% CI: -0.14, 0.13); P = 0.94], WLZ [(95% CI: -0.17, 0.13); P = 0.78], or WAZ [(95% CI: -0.15, 0.16); P = 0.97] or on the incidence of growth failure, defined as respective Z-scores < -2 (P ≥ 0.29). Among the subgroup of HIV-uninfected children, there was no treatment effect from 6 to 104 wk on LAZ, WLZ, and WAZ (P ≥ 0.71) or on the incidence of growth failure (P ≥ 0.16). Multivitamin supplements had no effect on growth among children born to HIV-infected women who were themselves receiving multivitamins.