Declining HIV prevalence and incidence in perinatal women in Harare, Zimbabwe.

BACKGROUND: In several recent papers it has been suggested that HIV prevalence and incidence are declining in Zimbabwe as a result of changing sexual behavior. We provide further support for these suggestions, based on an analysis of more extensive, age-stratified, HIV prevalence data from 1990 to 2009 for perinatal women in Harare, as well as data on incidence and mortality. METHODOLOGY/PRINCIPAL FINDINGS: Pooled prevalence, incidence and mortality were fitted using a simple susceptible-infected (SI) model of HIV transmission; age-stratified prevalence data were fitted using double-logistic functions. We estimate that incidence peaked at 5.5% per year in 1991 declining to 1% per year in 2010. Prevalence peaked in 1998/9 [35.9% (CI95: 31.3-40.7)] and decreased by 67% to 11.9% (CI95: 10.1-13.8) in 2009. For women <20y, 20-24y, 25-29y, 30-34y and ≥35y, prevalence peaked at 25.4%, 34.2%, 47.1%, 44.0% and 33.5% in 1993, 1996, 1997, 1998 and 1999, respectively, declining thereafter in every age group. Among women <25y, prevalence peaked in 1994 at 28.8% declining thereafter by 69% to 8.9% (CI95: 6.8-11.5) in 2009. CONCLUSION/SIGNIFICANCE: HIV prevalence declined substantially among perinatal women in Harare after 1998 consequent upon a decline in incidence starting in the early 1990s. Our model suggests that this was primarily a result of changes in behavior which we attribute to a general increase in awareness of the dangers of AIDS and the ever more apparent increases in mortality.

Mother to child transmission of HIV among Zimbabwean women who seroconverted postnatally: prospective cohort study.

OBJECTIVES: To estimate the rates and timing of mother to infant transmission of HIV associated with breast feeding in mothers who seroconvert postnatally, and their breast milk and plasma HIV loads during and following seroconversion, compared with women who tested HIV positive at delivery. DESIGN: Prospective cohort study. SETTING: Urban Zimbabwe. PARTICIPANTS: 14 110 women and infants enrolled in the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial (1997-2001). MAIN OUTCOME MEASURES: Mother to child transmission of HIV, and breast milk and maternal plasma HIV load during the postpartum period. RESULTS: Among mothers who tested HIV positive at baseline and whose infant tested HIV negative with polymerase chain reaction (PCR) at six weeks (n=2870), breastfeeding associated transmission was responsible for an average of 8.96 infant infections per 100 child years of breast feeding (95% CI 7.92 to 10.14) and varied little over the breastfeeding period. Breastfeeding associated transmission for mothers who seroconverted postnatally (n=334) averaged 34.56 infant infections per 100 child years (95% CI 26.60 to 44.91) during the first nine months after maternal infection, declined to 9.50 (95% CI 3.07 to 29.47) during the next three months, and was zero thereafter. Among women who seroconverted postnatally and in whom the precise timing of infection was known (≤90 days between last negative and first positive test; n=51), 62% (8/13) of transmissions occurred in the first three months after maternal infection and breastfeeding associated transmission was 4.6 times higher than in mothers who tested HIV positive at baseline and whose infant tested HIV negative with PCR at six weeks. Median plasma HIV concentration in all mothers who seroconverted postnatally declined from 5.0 log(10) copies/mL at the last negative enzyme linked immunosorbent assay (ELISA) to 4.1 log(10) copies/mL at 9-12 months after infection. Breast milk HIV load in this group was 4.3 log(10) copies/mL 0-30 days after infection, but rapidly declined to 2.0 log(10) copies/mL and <1.5 log(10) copies/mL by 31-90 days and more than 90 days, respectively. Among women whose plasma sample collected soon after delivery tested negative for HIV with ELISA but positive with PCR (n=17), 75% of their infants were infected or had died by 12 months. An estimated 18.6% to 20.4% of all breastfeeding associated transmission observed in the ZVITAMBO trial occurred among mothers who seroconverted postnatally. CONCLUSIONS: Breastfeeding associated transmission is high during primary maternal HIV infection and is mirrored by a high but transient peak in breast milk HIV load. Around two thirds of breastfeeding associated transmission by women who seroconvert postnatally may occur while the mother is still in the "window period" of an antibody based test, when she would test HIV negative using one of these tests. Trial registration Clinical trials.gov NCT00198718.

Improved HIV-1 incidence estimates using the BED capture enzyme immunoassay.

OBJECTIVE: To validate the BED capture enzyme immunoassay for HIV-1 subtype C and to derive adjustments facilitating estimation of HIV-1 incidence from cross-sectional surveys. DESIGN: Laboratory analysis of archived plasma samples collected in Zimbabwe. METHODS: Serial plasma samples from 85 women who seroconverted to HIV-1 during the postpartum year were assayed by BED and used to estimate the window period between seroconversion and the attainment of a specified BED absorbance. HIV-1 incidences for the year prior to recruitment and for the postpartum year were calculated by applying the BED technique to HIV-1-positive samples collected at baseline and at 12 months. RESULTS: The mean window for an absorbance cut-off of 0.8 was 187 days. Among women who were HIV-1 positive at baseline and retested at 12 months, a proportion (epsilon) 5.2% (142/2749) had a BED absorbance < 0.8 at 12 months and were falsely identified as recent seroconverters. Consequently, the estimated BED annual incidence at 12 months postpartum (7.6%) was 2.2 times the contemporary prospective estimate. BED incidence adjusted for epsilon was 3.5% [95% confidence interval (CI), 2.6-4.5], close to the 3.4% estimated prospectively. Adjusted BED incidence at baseline was 6.0% (95% CI, 5.2-6.9) and, like the prospective estimates, declined with maternal age. Unadjusted BED incidence estimates were largely independent of age; the pooled estimate was 58% higher than adjusted incidence. CONCLUSION: The BED method can be used in an African setting, but further estimates of epsilon and of the window period are required, using large samples in a variety of circumstances, before its general utility can be gauged.

The impact of safer breastfeeding practices on postnatal HIV-1 transmission in Zimbabwe.

OBJECTIVES: We assessed the association between exposure to an educational intervention that emphasized safer breastfeeding practices and postnatal HIV transmission among 437 HIV-positive mothers in Zimbabwe, 365 of whom did not know their infection status. METHODS: Mothers were tested for HIV and were encouraged--but not required--to learn their HIV status. Intervention exposure was assessed by a questionnaire, Turnbull methods were used to estimate postnatal HIV transmission, and multivariate Cox proportional hazard models were constructed to assess the association between intervention exposure and postnatal HIV transmission. RESULTS: Cumulative postnatal HIV transmission was 8.2%; each additional intervention contact was associated with a 38% reduction in postnatal HIV transmission. HIV-positive mothers who were exposed to both print and video materials were 79% less likely to infect their infants compared with mothers who had no exposure. These findings were similar for mothers who did not know their HIV status. CONCLUSIONS: The promotion of exclusive breastfeeding has the potential to reduce postnatal HIV transmission among women who do not know their HIV status, and child survival and HIV prevention programs should support this practice.

Child mortality according to maternal and infant HIV status in Zimbabwe.

BACKGROUND: HIV causes substantial mortality among African children but there is limited data on how this is influenced by maternal or infant infection status and timing. METHODS: Children enrolled in the ZVITAMBO trial were divided into 5 groups: those born to HIV-negative mothers (NE, n = 9510), those born to HIV-positive mothers but noninfected (NI, n = 3135), those infected in utero (IU, n = 381), those infected intrapartum (IP, n = 508), and those infected postnatally (PN, n = 258). Their mortality was estimated. RESULTS: Two-year mortality was 2.9% (NE infants), 9.2% (NI), 67.5% (IU), 65.1% (IP), and 33.2% (PN). Between 8 weeks and 6 months, mortality in IU infants quintupled (from 309 to 1686/1000 c-y). The median time from infection to death was 208, 380, and >500 days for IU, IP, and PN infants, respectively. Among NI children, advanced maternal disease was predictive of mortality. Acute respiratory infection was the major cause of death. CONCLUSIONS: Perinatally infected infants are at particular risk of death between 2 and 6 months: cotrimoxazole prophylaxis and early pediatric HAART should be scaled up. Uninfected infants of infected mothers have at least twice the mortality risk of infants born to uninfected mothers: all HIV-exposed infants should be targeted with child survival interventions. HIV-positive mothers with more advanced disease are not only more likely to infect their infants, but their infants are more likely to die, whether infected or not: provision of antiretroviral treatment to pregnant and lactating women is an urgent need for both mothers and their children.

Effects of infant sex on mother-to-child transmission of HIV-1 according to timing of infection in Zimbabwe.

We examined the relationship between sex and the risk of intrauterine, intrapartum and postnatal HIV transmission among 4495 infants born to HIV-infected mothers in Harare, Zimbabwe. Intrauterine transmission was 8.6%, and consistent with other studies was higher among girl than boy infants (AOR 1.53; 95% CI 1.23-1.91). Unlike previous studies, we observed no independent effect of infant sex on intrapartum or breastfeeding-associated HIV transmission. Sex-specific postnatal prevention strategies are not warranted in this population.

Mortality and morbidity among postpartum HIV-positive and HIV-negative women in Zimbabwe: risk factors, causes, and impact of single-dose postpartum vitamin A supplementation.

BACKGROUND: Vitamin A deficiency is common among women in resource-poor countries and is associated with greater mortality during HIV. METHODS: Fourteen thousand one hundred ten mothers were tested for HIV and randomly administered 400,000 IU vitamin A or placebo at less than 96 hours postpartum. The effects of vitamin A and HIV status on mortality, health care utilization, and serum retinol were evaluated. RESULTS: Four thousand four hundred ninety-five (31.9%) mothers tested HIV positive. Mortality at 24 months was 2.3 per 1000 person-years and 38.3 per 1000 person-years in HIV-negative and HIV-positive women, respectively. Vitamin A had no effect on mortality. Tuberculosis was the most common cause of death, and nearly all tuberculosis-associated deaths were among HIV-positive women. Among HIV-positive women, vitamin A had no effect on rates of hospitalization or overall sick clinic visits, but did reduce clinic visits for malaria, cracked and bleeding nipples, pelvic inflammatory disease, and vaginal infection. Among HIV-negative women, serum retinol was responsive to vitamin A, but low serum retinol was rare. Among HIV-positive women, serum retinol was largely unresponsive to vitamin A, and regardless of treatment group, the entire serum retinol distribution was shifted 25% less than that of HIV-negative women 6 weeks after dosing. CONCLUSIONS: Single-dose postpartum vitamin A supplementation had no effect on maternal mortality, perhaps because vitamin A status was adequate in HIV-negative women and apparently unresponsive to supplementation in HIV-positive women.

Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants: a prospective, randomized study.

BACKGROUND: Anemia is prevalent in infants in developing countries. Its etiology is multifactorial and includes vitamin A deficiency. OBJECTIVE: Our primary aim was to measure the effect of maternal or neonatal vitamin A supplementation (or both) on hemoglobin and anemia in Zimbabwean infants. Our secondary aim was to identify the underlying causes of postnatal anemia. DESIGN: A randomized, placebo-controlled trial was conducted in 14 110 mothers and their infants; 2854 infants were randomly selected for the anemia substudy, of whom 1592 were successfully observed for 8-14 mo and formed the study sample. Infants were randomly assigned within 96 h of delivery to 1 of 4 treatment groups: mothers and infants received vitamin A; mothers received vitamin A and infants received placebo; mothers received placebo and infants received vitamin A; and mothers and infants received placebo. The vitamin A doses were 400,000 and 50,000 IU in the mothers and infants, respectively. RESULTS: Vitamin A supplementation had no effect on hemoglobin or anemia (hemoglobin <105 g/L) in unadjusted or adjusted analyses. Infant HIV infection independently increased anemia risk >6-fold. Additional predictors of anemia in HIV-negative and -positive infants were male sex and lower total body iron at birth. In addition, in HIV-positive infants, the risk of anemia increased with early infection, low maternal CD4+ lymphocyte count at recruitment, and frequent morbidity. Six-month plasma ferritin concentrations <12 microg/L were a risk factor in HIV-negative but not in HIV-positive infants. Maternal HIV infection alone did not cause anemia. CONCLUSION: Prevention of infantile anemia should include efforts to increase the birth endowment of iron and prevent HIV infection.

HIV incidence among post-partum women in Zimbabwe: risk factors and the effect of vitamin A supplementation.

OBJECTIVE: To test whether post-partum vitamin A supplementation can reduce incident HIV among post-partum women and identify risk factors for HIV incidence. DESIGN: Randomized, placebo-controlled trial METHODS: Between November 1997 and January 2001, 14,110 women were randomly administered 400,000 IU vitamin A or placebo within 96 h post-partum. HIV incidence was monitored among 9562 HIV-negative women. RESULTS: Cumulative incidence was 3.4% [95% confidence interval (CI), 3.0-3.8] and 6.5% (95% CI, 5.7-7.4) over 12 and 24 months post-partum, respectively. Vitamin A supplementation had no impact on incidence [hazard ratio (HR), 1.08; 95% CI, 0.85-1.38]. However, among 398 women for whom baseline serum retinol was measured, those with levels indicative of deficiency (< 0.7 micromol/l, 9.2% of those measured) were 10.4 (95% CI, 3.0-36.3) times more likely to seroconvert than women with higher concentrations. Furthermore, among women with low serum retinol, vitamin A supplementation tended to be protective against incidence (HR, 0.29; 95% CI, 0.03-2.60; P = 0.26), although not significantly so, perhaps due to limited statistical power. Severe anaemia (haemoglobin < 70 g/l) was associated with a 2.7-fold (95%CI, 1.2-6.1) greater incidence. Younger women were at higher risk of HIV infection: incidence declined by 5.7% (2.8-8.6) with each additional year of age. CONCLUSION: Among post-partum women, a single large-dose vitamin A supplementation had no effect on incidence, although low serum retinol was a risk factor for seroconversion. Further investigation is required to determine whether vitamin A supplementation of vitamin-A-deficient women or treatment of anaemic women can reduce HIV incidence.

Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality.

BACKGROUND: Low maternal serum retinol level is a risk factor for mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality. The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency; neonatal dosing is under consideration. We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT, HIV-free survival, and mortality in HIV-exposed infants. METHODS: A total of 14,110 mother-infant pairs were enrolled < or =96 h after delivery, and both mother and infant, mother only, infant only, or neither received vitamin A supplementation in a randomized, placebo-controlled trial with a 2 x 2 factorial design. All but 4 mothers initiated breast-feeding. A total of 4495 infants born to HIV-positive women were included in the present analysis. RESULTS: Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months. However, the timing of infant HIV infection modified the effect that supplementation had on mortality. Vitamin A supplementation had no effect in infants who were polymerase chain reaction (PCR) positive [corrected] for HIV at baseline. In infants who were PCR negative at baseline and PCR positive at 6 weeks, neonatal supplementation reduced mortality by 28% (P=.01), but maternal supplementation had no effect. In infants who were PCR negative at 6 weeks, all 3 vitamin A regimens were associated with ~2-fold higher mortality (P< or =.05). CONCLUSIONS: Targeted vitamin A supplementation of HIV-positive children prolongs their survival. However, postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks. These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas.

Neonatal erythropoiesis and subsequent anemia in HIV-positive and HIV-negative Zimbabwean babies during the first year of life: a longitudinal study.

BACKGROUND: Anemia is common in HIV infection and independently associated with disease progression and mortality. The pathophysiology of HIV-related anemia is not well understood especially in infancy. METHODS: We conducted a longitudinal cohort study nested within the Zimbabwe Vitamin A for Mothers and Babies Project. We measured hemoglobin, erythropoietin (EPO), serum transferrin receptor (TfR) and serum ferritin at 6 weeks, 3 and 6 months of age and hemoglobin at 9 and 12 months in 3 groups of randomly selected infants: 136 born to HIV-negative mothers, and 99 born to HIV-positive mothers and who were infected themselves by 6 weeks of age, and 324 born to HIV-positive mothers but who did not become infected in the 6 months following birth. RESULTS: At one year of age, HIV-positive infants were 5.26 (adjusted odds ratio, P < 0.001) times more likely to be anemic compared to HIV-negative infants. Among, HIV-negative infants, EPO was or tended to be inversely associated with hemoglobin and was significantly positively associated with TfR throughout the first 6 months of life; TfR was significantly inversely associated with ferritin at 6 months; and EPO explained more of the variability in TfR than did ferritin. Among infected infants, the inverse association of EPO to hemoglobin was attenuated during early infancy, but significant at 6 months. Similar to HIV-negative infants, EPO was significantly positively associated with TfR throughout the first 6 months of life. However, the inverse association between TfR and ferritin observed among HIV-negative infants at 6 months was not observed among infected infants. Between birth and 6 months, mean serum ferritin concentration declined sharply (by approximately 90%) in all three groups of babies, but was significantly higher among HIV-positive compared to HIV-negative babies at all time points. CONCLUSION: HIV strongly increases anemia risk and confounds interpretation of hematologic indicators in infants. Among HIV-infected infants, the EPO response to anemia is attenuated near the time of infection in the first weeks of life, but normalizes by 6 months.

Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival.

OBJECTIVES: The promotion of exclusive breastfeeding (EBF) to reduce the postnatal transmission (PNT) of HIV is based on limited data. In the context of a trial of postpartum vitamin A supplementation, we provided education and counseling about infant feeding and HIV, prospectively collected information on infant feeding practices, and measured associated infant infections and deaths. DESIGN AND METHODS: A total of 14 110 mother-newborn pairs were enrolled, randomly assigned to vitamin A treatment group after delivery, and followed for 2 years. At baseline, 6 weeks and 3 months, mothers were asked whether they were still breastfeeding, and whether any of 22 liquids or foods had been given to the infant. Breastfed infants were classified as exclusive, predominant, or mixed breastfed. RESULTS: A total of 4495 mothers tested HIV positive at baseline; 2060 of their babies were alive, polymerase chain reaction negative at 6 weeks, and provided complete feeding information. All infants initiated breastfeeding. Overall PNT (defined by a positive HIV test after the 6-week negative test) was 12.1%, 68.2% of which occurred after 6 months. Compared with EBF, early mixed breastfeeding was associated with a 4.03 (95% CI 0.98, 16.61), 3.79 (95% CI 1.40-10.29), and 2.60 (95% CI 1.21-5.55) greater risk of PNT at 6, 12, and 18 months, respectively. Predominant breastfeeding was associated with a 2.63 (95% CI 0.59-11.67), 2.69 (95% CI 0.95-7.63) and 1.61 (95% CI 0.72-3.64) trend towards greater PNT risk at 6, 12, and 18 months, compared with EBF. CONCLUSION: EBF may substantially reduce breastfeeding-associated HIV transmission.

An education and counseling program for preventing breast-feeding-associated HIV transmission in Zimbabwe: design and impact on maternal knowledge and behavior.

International guidance on HIV and infant feeding has evolved over the last decade. In response to these changes, we designed, implemented, and evaluated an education and counseling program for new mothers in Harare, Zimbabwe. The program was implemented within the ZVITAMBO trial, in which 14,110 mother-baby pairs were enrolled within 96 h of delivery and were followed at 6 wk, 3 mo, and 3-mo intervals. Mothers were tested for HIV at delivery but were not required to learn their test results. Infant feeding patterns were determined using data provided up to 3 mo. Formative research was undertaken to guide the design of the program that included group education, individual counseling, videos, and brochures. The program was introduced over a 2-mo period: 11,362, 1311, and 1437 women were enrolled into the trial before, during, and after this period. Exclusive breast-feeding was recommended for mothers of unknown or negative HIV status, and for HIV-positive mothers who chose to breast-feed. A questionnaire assessing HIV knowledge and exposure to the program was administered to 1996 mothers enrolling after the program was initiated. HIV knowledge improved with increasing exposure to the program. Mothers who enrolled when the program was being fully implemented were 70% more likely to learn their HIV status early (<3 mo) and 8.4 times more likely to exclusively breast-feed than mothers who enrolled before the program began. Formative research aided in the design of a culturally sensitive intervention. The intervention increased relevant knowledge and improved feeding practices among women who primarily did not know their HIV status.

Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe.

BACKGROUND: Young infants are at risk of vitamin A deficiency. Supplementation of breastfeeding mothers improves the vitamin A status of their infants, but there are no data regarding its effect on infant mortality, and data on the effect of directly supplementing infants during the first few weeks of life are conflicting. OBJECTIVE: The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single, large doses of vitamin A during the immediate postpartum period. DESIGN: A randomized, placebo-controlled, 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants; 9208 of the mothers were HIV-negative at delivery, remained such during the postpartum year, and were retained in the current analysis. The infants were randomly assigned within 96 h of delivery to 1 of 4 treatment groups: mothers and infants received vitamin A (Aa), mothers received vitamin A and infants received placebo (Ap), mothers received placebo and infants received vitamin A (Pa), and both mothers and infants received placebo (Pp). The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU. The mother-infant pairs were followed to 12 mo. RESULTS: Hazard ratios (95% CI) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 (0.87, 1.58) and 1.08 (0.80, 1.46), respectively. Hazard ratios (95% CI) for the Aa, Ap, and Pa groups compared with the Pp group were 1.28 (0.83, 1.98), 1.27 (0.82, 1.97), and 1.18 (0.76, 1.83), respectively. These data indicate no overall effect. Serum retinol concentrations among a subsample of women were similar to reference norms. CONCLUSION: Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status.

Total body iron in HIV-positive and HIV-negative Zimbabwean newborns strongly predicts anemia throughout infancy and is predicted by maternal hemoglobin concentration.

One method of preventing postnatal iron deficiency is to ensure that the infant is born with a full endowment of iron. We calculated total body iron at birth (TBI) as the sum of hemoglobin iron (HbI) and body storage iron (BSI) in 2021 Zimbabwean newborns, and related TBI to subsequent anemia from 3 to 12 mo of age and to maternal and fetal characteristics. We estimated the mean +/- SD TBI to be 210 +/- 41 mg. There was an inverse dose-response association between TBI quartile and risk of anemia at all postnatal ages. The odds of anemia were >3 times higher in the lowest vs. highest TBI quartile (P < 0.001) at 6, 9 and 12 mo. Preterm birth and parity were not independently associated with TBI after controlling for birthweight. The predicted change in TBI per kilogram increase in birthweight was 68 mg (P < 0.001). After adjusting for birthweight, TBI increased by 25 mg with each 10-y decrement in maternal age (P = 0.033). Maternal hemoglobin was a strong linear predictor of TBI (P < 0.001). Maternal and infant HIV infection, especially among girls, was associated with apparently greater estimated TBI. We speculate that this is actually an artifact, explained by an inflammatory response, and that there was a sex difference in the response. We conclude that we can make satisfactory estimates of TBI and that the assumptions required for this approach are sufficiently robust to lead to an acceptable estimate of the prenatally acquired iron endowment. Babies born with low birthweight or to mothers with low hemoglobin are born with less TBI, which confers a substantially greater risk of anemia from 3 to 12 mo of age.