Peter Iliff

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.

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 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.

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 (ϵ) 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 ϵ 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 ϵ and of the window period are required, using large samples in a variety of circumstances, before its general utility can be gauged.

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

BackgroundAnemia 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.MethodsWe 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.ResultsAt 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 ~90%) in all three groups of babies, but was significantly higher among HIV-positive compared to HIV-negative babies at all time points.ConclusionHIV 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.

Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy.

Background: Human immunodeficiency virus (HIV) remains a major cause of pediatric morbidity in Africa. In addition, HIV-exposed, but uninfected (HEU) infants can comprise a substantial proportion of all infants born in high prevalence countries and may also be a vulnerable group with special health problems. Methods: A total of 14,110 infants were recruited within 96 hours of birth between November 1996 and January 2000. Rates and causes of sick clinic visits and hospitalizations during infancy were investigated according to infant HIV infection group: infected-intrauterine, infected-intrapartum, postnatally-infected, HEU, and not-exposed (born to HIV-negative mother). Results: A total of 382 infected-intrauterine, 499 infected-intrapartum, 188 postnatally-infected, 2849 HEU, and 9207 not-exposed infants were included in the analysis. Compared with not-exposed infants, HIV-infected infants made 2.8 times more all-cause sick clinic visits and required 13.3 times more hospitalizations; they had 7.2 times more clinic visits and 23.5 times more hospitalizations for lower respiratory tract infection after the neonatal period and were 159.9 times more likely to be hospitalized for malnutrition during the second half of infancy. Compared with not-exposed infants, sick clinic visits were 1.2 times more common among HEU infants, were inversely associated with maternal CD4 cell count, and were significantly higher for all HEU infants except those whose mothers had a CD4 count ≥800 cells/&mgr;L, which was the mean value of HIV-negative women enrolled in the trial. Conclusions: Morbidity is extremely high among HIV-infected infants. Compared with not-exposed infants, morbidity is higher among HEU infants and increases with severity of maternal disease, but is significantly higher for all mothers with CD4 cell count <800 cells/&mgr;L.

Timing of mother-to-child transmission of HIV-1 and infant mortality in the first 6 months of life in Harare, Zimbabwe.

Objectives: To examine the risks of intra-uterine (IU), intra- and early post-partum (IP/ePP) and late post-partum (LPP) mother-to-child transmission (MTCT) of HIV-1 and infant mortality in the first 6 months of life. Methods: Whole blood was collected in ethylenediaminetetra-acetic acid at birth, 6 weeks, 3 and 6 months from 996 infants born to HIV-1 seropositive mothers. Polymerase chain reaction using Roche DNA amplification assay, version 1.5 (Roche Diagnostics Incorporation, Alameda, California, USA) was used to determine timing of MTCT. Logistic regression models determined risk factors for HIV-1 transmission and survival analyses examined mortality by timing of transmission. Results: Two hundred and forty-nine mothers (30.7%) transmitted HIV-1 infection to their infants by 6 months of age. Eighty-nine infants [9.4%; 95% confidence interval (CI), 7.7–11.5], 104 infants (16.0%; 95% CI, 10.8–21.2) and 21 infants (5.3%; 95% CI, 1.6–12.2) were infected IU, IP/ePP and LPP respectively. Low maternal CD4 cell count and arm circumference were risk factors for IP/ePP transmission. Infant mortality was higher among infected infants than uninfected (P < 0.001, log rank test). Timing of infection, birth weight and maternal CD4 cell counts were important factors in predicting infant death. Conclusion: In the first 6 months of life, IU and IP/ePP transmission contributed more than three-quarters of the 30.7% MTCT. Our data, in addition to serving as a historical comparison, may be useful in designing and evaluating the efficacy of short course antiretroviral trials aimed at reducing MTCT in developing countries.

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 log10 copies/mL at the last negative enzyme linked immunosorbent assay (ELISA) to 4.1 log10 copies/mL at 9-12 months after infection. Breast milk HIV load in this group was 4.3 log10 copies/mL 0-30 days after infection, but rapidly declined to 2.0 log10 copies/mL and <1.5 log10 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.

Maternal herpes simplex virus type 2 infection syphilis and risk of intra-partum transmission of HIV-1: Results of a case control study.

Background:Genital ulcer disease including that caused by Herpes simplex virus type 2 (HSV-2) and syphilis facilitates sexual transmission of HIV-1. The effect of these infections on intra-partum mother-to-child-transmission (MTCT) of HIV-1 is unknown. Methods:A case–control study was conducted using archived sera from HIV-1 positive women enrolled in ZVITAMBO, an MTCT trial. Cases were 509 women who transmitted HIV-1 to their infants intra-partum; controls were 1018 women whose infants remained uninfected at 12 months. Maternal serum collected at delivery, were tested for HSV-2 antibody. The 6-week post-partum sample was also tested for syphilis by RPR and TPHA to identify women with incubating or active syphilis at delivery. Rates of prevalent and incident HSV-2 and recently acquired syphilis were compared between cases and controls. Findings:Overall prevalence of maternal HSV-2 and active syphilis at delivery were 82.5% [95% confidence interval (CI), 80.6–84.5] and 4.0% (95% CI, 3.0–5.1), respectively. Prevalent HSV-2 was associated with increased intra-partum MTCT [adjusted odds ratio (OR), 1.50; 95% CI, 1.09–2.08]. The proportion of intra-partum transmissions potentially attributable to prevalent HSV-2 infection was 28.4% (95% CI, 7.3–44.7). Maternal infection with active syphilis at delivery was not associated with intra-partum MTCT (unadjusted OR, 0.89; 95%CI, 0.49–1.59; adjusted OR, 0.64; 95% CI, 0.34–1.20). Interpretation:HSV-2 infection is common among HIV-1-positive women and is associated with an increased risk of intra-partum MTCT. More than 25% of intra-partum MTCT may be attributable to maternal HSV-2 co-infection. Active maternal syphilis at the time of delivery is not associated with intra-partum MTCT risk.

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 μmol/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.