Roland Kupka

Anemia Is an Independent Predictor of Mortality and Immunologic Progression of Disease Among Women With Hiv in Tanzania

Objectives:To examine the association of anemia with mortality and disease progression among a cohort of women with HIV in Dar es Salaam, Tanzania. Methods:Time to all-cause death, AIDS-related death, and a 50% decrease in CD4 cell count among 1078 HIV-positive pregnant women enrolled in a clinical trial of vitamin supplementation from 1995-2003. Results:Adjusted models showed that anemia was associated with an increased risk of all-cause mortality (relative hazard [RH]: 2.06, 95% CI: 1.52 to 2.79 for moderate anemia and RH: 3.19, 95% CI: 2.23 to 4.56 for severe anemia) and AIDS-related mortality (RH: 2.21, 95% CI: 1.53 to 3.19 for moderate anemia and RH: 3.47, 95% CI: 2.25 to 5.33 for severe anemia), independent of CD4 cell count, World Health Organization clinical stage, age, pregnancy, vitamin supplementation, and body mass index. Anemia was also associated with a more rapid decline in CD4 counts, measured as time to a 50% drop in CD4 cell count from baseline. Erythrocyte characteristics suggestive of iron deficiency were also associated with all-cause and AIDS-related death and a 50% decline in CD4 cell count. Conclusions:Anemia is an independent predictor of mortality and disease progression in this cohort. Screening for anemia, coupled with prevention and treatment efforts, should be included in HIV care initiatives, particularly those that target women.

Role of selenium in Hiv infection

HIV infection is a global disease that disproportionately burdens populations with nutritional vulnerabilities. Laboratory experiments have shown that selenium has an inhibitory effect on HIV in vitro through antioxidant effects of glutathione peroxidase and other selenoproteins. Numerous studies have reported low selenium status in HIV-infected individuals, and serum selenium concentration declines with disease progression. Some cohort studies have shown an association between selenium deficiency and progression to AIDS or mortality. In several randomized controlled trials, selenium supplementation has reduced hospitalizations and diarrheal morbidity, and improved CD4(+) cell counts, but the evidence remains mixed. Additional trials are recommended to study the effect of selenium supplementation on opportunistic infections, and other HIV disease-related comorbidities in the context of highly active antiretroviral therapy in both developing and developed countries.

Water and sanitation associated with improved child growth

Objective: To examine the relation between household water and sanitation, and the risk of stunting and reversal of stunting in Khartoum and Crezira regions Sudan.Design: Prospective cohort study.Setting: A total of 25 483 children aged 6–72 months from rural Sudan enrolled in an 18-month field trial in 1988 to study the effect of vitamin A supplementation on child health and survival.Results: The mean height-for-age z-scores at baseline and the end of study were −1.66 and −1.55, respectively, for the group with water and sanitation facilities, and −2.03 and −1.94 for the group without water and sanitation, after adjustment for age, region, gender, mothers literacy, intervention group (vitamin A vs placebo), family wealth, breastfeeding and cleanliness. Among children of normal height-for-age at baseline, the risk of stunting (<−2 height-for-age z-score) was lowest in the group that came from homes that had both water and sanitation compared to children from homes without these facilities (multivariate RR=0.79, 95% CI 0.69–0.90). Among children stunted at baseline, those coming from homes with water and sanitation had a 17% greater chance of reversing stunting than those coming from homes without either facility (adjusted RR=1.17, 95% CI 0.99–1.38). We did not detect a synergistic association between access to water and sanitation.Conclusions: Water and sanitation are independently associated with improved growth of children.Sponsorship: None.

Zinc Nutrition and HIV Infection

The trace element zinc is involved in many important immune processes. A number of immunologic impairments owing to zinc deficiency are also evident in HIV disease, most notably a reduction in the number of circulating T lymphocytes. Observational epidemiologic studies have provided conflicting results on the role of zinc status in HIV disease progression. Randomized, placebo-controlled trials are needed to resolve this controversy. Studies must also address the role of zinc in vertical transmission of HIV from mother to child and its role in reducing the risk of adverse pregnancy outcomes, both of which are of considerable public health importance in developing countries.

Zinc supplementation to HIV-1-infected pregnant women: effects on maternal anthropometry, viral load, and early mother-to-child transmission.

Objective:To examine the effect of zinc supplementation to HIV-1-infected pregnant women on viral load, early mother-to-child transmission of HIV (MTCT), and wasting.Design:Double-blind placebo-controlled randomized clinical trial.Setting:Antenatal clinic in Dar es Salaam, Tanzania.Subjects:Four hundred HIV-1-infected pregnant women.Methods:Women 12–27 weeks of gestation were randomly assigned to receive a daily oral dose of 25 mg zinc or placebo from the day of the first prenatal visit until 6 weeks postdelivery. Weight and mid-upper arm circumference (MUAC) were measured monthly. HIV status of the babies was assessed at birth and at 6 weeks postpartum. Viral load was assessed in a random sample of 100 women at baseline and at the end of the study.Results:Zinc had no effects on maternal viral load or early MTCT. Supplementation was related to a significant threefold increase in the risk of wasting (reaching a MUAC value <22 cm) during an average 22 weeks of observation (RR=2.7, 95%CI=1.1, 6.4, P=0.03), and to a 4 mm decline in MUAC during the second trimester (P=0.02).Conclusions:Zinc supplementation to HIV-infected pregnant women offers no benefits on viral load or MTCT. The clinical relevance of an apparent decrease in MUAC associated with zinc supplementation is yet to be ascertained. These findings together with the lack of effect on fetal outcomes (reported previously) do not provide support for the addition of zinc supplements to the standard of prenatal care among HIV-infected women.Sponsorship:The US National Institute of Child Health and Human Development (NICHD R01 32257).

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.

C-reactive protein independently predicts Hiv-related outcomes among women and children in a resource-poor setting

Objective:To evaluate C-reactive protein (CRP) as a predictor of HIV-related outcomes among women and children in a resource-poor setting. Design:We measured serum CRP concentration among 606 HIV-infected women, all of whom were not taking highly-active antiretroviral therapy, 3 to 11 months after they gave birth, and assessed relationships of CRP to HIV-related endpoints, including maternal disease progression, mother-to-child transmission of HIV, and maternal and child mortality. Methods:We used Cox proportional hazards and regression models adjusted for age, sociodemographic characteristics, anthropometric measurements, hemoglobin, CD4 cell count, HIV viral load, and, for child outcomes, breastfeeding status. Results:Ninety-four women had a high CRP concentration (> 10 mg/l). During the follow-up, 56 women progressed to WHO stage 4 and 188 died, and a high maternal CRP concentration was associated with a 2.26-fold [95% confidence interval (CI), 1.64–3.12] greater risk of progression to stage 4 or death. Among children, 174 acquired HIV and 116 died by age 2 years, and a high maternal CRP concentration was associated with a 3.03-fold (95% CI, 1.85–4.96) greater risk of child mortality. In multivariate analyses among adults, a high maternal CRP concentration was associated with a 1.55-fold (95% CI, 1.08–2.23) greater risk of progression to stage 4 or death. A maternal CRP concentration was not significantly associated with mother-to-child transmission of HIV. Conclusions:A high maternal CRP concentration independently predicts HIV disease progression, maternal mortality, and child mortality in a resource-poor setting. C-reactive protein may be an important and inexpensive prognostic indicator for HIV-infected women and their children.

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.

Stunting and Wasting Are Associated with Poorer Psychomotor and Mental Development in HIV-Exposed Tanzanian Infants

Infants born to HIV-infected women are at increased risk of impaired neurodevelopment, but little research has attempted to identify modifiable risk factors. The objective of this prospective cohort analysis was to identify maternal, socioeconomic, and child correlates of psychomotor and mental development in the first 18 mo of life among Tanzanian infants born to HIV-infected women. We hypothesized that child HIV infection, morbidity, and undernutrition would be associated with lower developmental status when taking into consideration maternal health and socioeconomic factors. Baseline maternal characteristics were recorded during pregnancy, birth characteristics were collected immediately after delivery, infant micronutrient status was measured at 6 wk and 6 mo, and anthropometric measurements and morbidity histories were performed at monthly follow-up visits. The Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development, 2nd edition (BSID-II) were used to assess developmental functioning at 6, 12, and 18 mo of age. Multivariate repeated regression models with time-varying covariates were used to estimate adjusted mean MDI and PDI scores for each level of the variables. A total of 311 infants contributed ≥1 BSID-II assessments for 657 PDI and 655 MDI measurements. Of infants, 51% were male, 23% were born preterm, 7% were low birth weight, and 10% were HIV-positive at 6 wk. Preterm birth, child HIV infection, stunting, and wasting were independently associated with lower PDI and MDI scores. Strategies to lower mother-to-child transmission of HIV, prevent preterm birth, and enhance child growth could contribute to improved child psychomotor and mental development.