Megan Valentine

Morbidity and mortality among a cohort of human immunodeficiency virus type 1-infected and uninfected pregnant women and their infants from Malawi, Zambia, and Tanzania

Background: Morbidity and mortality patterns among pregnant women and their infants (before antiretroviral therapy was widely available) determines HIV-1 diagnostic, monitoring, and care interventions. Methods: Data from mothers and their infants enrolled in a trial of antibiotics to reduce mother-to-child-transmission of HIV-1 at 4 sub-Saharan African sites were analyzed. Women were enrolled during pregnancy and follow-up continued until the infants reached 12 months of age. We describe maternal and infant morbidity and mortality in a cohort of HIV-1-infected and HIV-1-uninfected mothers. Maternal and infant factors associated with mortality risk in the infants were assessed using Cox proportional hazard modeling. Results: Among 2292 HIV-1-infected mothers, 166 (7.2%) had a serious adverse event (SAE) and 42 (1.8%) died, whereas no deaths occurred among the 331 HIV-1 uninfected mothers. Four hundred twenty-four (17.8%) of 2383 infants had an SAE and 349 (16.4%) died before the end of follow-up. Infants with early HIV-1 infection (birth to 4–6 weeks) had the highest mortality. Among infants born to HIV-1-infected women, maternal morbidity and mortality (P = 0.0001), baseline CD4 count (P = 0.0002), and baseline plasma HIV-1 RNA concentration (P < 0.0001) were significant predictors of infant mortality in multivariate analyses. Conclusions: The high mortality among infants with early HIV-1 infection supports access to HIV-1 diagnostics and appropriate early treatment for all infants of HIV-1-infected mothers. The significant association between stage of maternal HIV-1 infection and infant mortality supports routine CD4 counts at the time of prenatal HIV-1 testing.

Effect of influenza immunization on immunologic and virologic characteristics of pediatric patients infected with human immunodeficiency virus

OBJECTIVES We evaluated the responses of HIV-infected children to a single dose of split-virus influenza vaccine and the relationship to viral load and other characteristics. METHODS Fifty-three HIV-infected children ages 1.8 to 13.2 years were given influenza vaccine for the 1994 to 1995 influenza season (Wyeth-Ayerst: A/Texas H1N1, A/Shangdong H3N2 and B/Panama). Immunologic and virologic factors were assessed at the time of and 2 to 10 weeks after immunization. RESULTS The differences between pre- and postimmunization CD4+ counts, CD4+:CD8+ ratios and viral load were not significant. Thirty-one of 53 children (58.4%) had a > 2-fold increase and 16 of 53 (30%) had a 4-fold rise in their postimmunization antibody titers for at least one component of the vaccine. Influenza immunization in the 1993 to 1994 flu season and administration of intravenous immunoglobulin around the time of immunization was not associated with immune response to the vaccine. Factors that were negatively associated with antibody response included increased time between samples (P = 0.004) and decreased preimmunization CD4+:CD8+ ratio (P = 0.02). CONCLUSIONS Influenza immunization in this population is safe, and a positive antibody response to influenza immunization is not associated with significant clinical events or change in HIV-1 plasma viral burden.

Evaluation of surrogate markers and clinical outcomes in two-year follow-up of eighty-six human immunodeficiency virus-infected pediatric patients

OBJECTIVES To evaluate the prognostic value of surrogate markers (HIV RNA copy number, CD4 counts and CDC clinical and immunologic categories) in HIV-infected children through a 2-year period. METHODS Eighty-six HIV-infected children followed by the Duke Pediatric HIV Clinic in the fall of 1994 were evaluated for plasma HIV RNA concentration (viral load), CD4 lymphocyte percentage, age, antiretroviral treatment status and CDC clinical and immunologic categories. Follow-up evaluations were performed for approximately 2 years, and the time to progression to a new CDC category C diagnosis or death was noted. RESULTS Of 86 children 22 had progression to new Category C diagnosis or death. Seven children died, 17 had a new Category C diagnosis and 2 had both. Among children who progressed, the median CD4 percentage at entry was 3% (absolute count, 75 cells/mm3), whereas children who had no disease progression entered with a median of 29% (868 cells/mm3). The overall median viral load at study entry was 4.58 log10 copies/ml (38,019 copies/ml, with a range of 1.7 to 6.78 logs). Children who had no disease progression had a median log copy number of 4.43, whereas 5.18 was the median for children whose disease progressed. Log copy number declined over time in children < 3 years of age, whereas it remained fairly consistent for children 3 years or older. Progression rates were determined by entry plasma HIV RNA concentration quartiles [quartile boundaries < 4.18, 4.58, > 5.08 log RNA copy/ml (< 15,136, 38,019 and > 120,226 copies/ml, respectively)]. Progression rates by quartile were 0 of 21, 4 of 22, 5 of 21 and 13 of 22. Kaplan-Meier survival curves defined by CD4% less than or greater than 15 and log RNA less than or greater than 5.0 (100,000) revealed that patients with CD4% less than 15 and plasma HIV RNA concentration > 5 log10 copies/ml did least well: 11 of 12 (92%) had a progression event at a median of 179 days. Patients with a high CD4 percentage and high viral load, or a low CD4 percentage and low viral load did similarly; 5 of 14 (36%) and 4 of 12 (33%) had progression events, respectively. Patients with high CD4 percentage and low viral load did best: only 2 of 48 (4%) had a progression event. CONCLUSIONS The two most significant prognostic indicators of disease progression were the initial CD4 percentage and the plasma HIV RNA concentration, and a combination of CD4 percentage and virus load best predicted which children had progression events. Progression was less common in children who had < 100,000 HIV RNA copies/ml initially (6 of 60 vs. 16 of 26; P < 0.001; relative risk 0.16). Therefore it seems reasonable that in a child for whom complete suppression is not possible, a threshold of 100,000 (5 log10 copies/ml) can be used to mandate a change in therapy.

Predictors of Stillbirth in Sub-Saharan Africa

OBJECTIVE: To describe the incidence and predictors of stillbirth in a predominantly human immunodeficiency virus (HIV)-infected African cohort. METHODS: Human Immunodeficiency Virus (HIV) Prevention Trials Network (HPTN) 024 was a randomized controlled trial of empiric antibiotics to reduce chorioamnionitis-related perinatal HIV transmission. A proportion of HIV-uninfected individuals were enrolled to reduce community-based stigma surrounding the trial. For this analysis, only women who gave birth to singleton infants were included. RESULTS: Of 2,659 women enrolled, 2,434 (92%) mother– child pairs met inclusion criteria. Of these, 2,099 (86%) infants were born to HIV-infected women, and 335 (14%) were born to HIV-uninfected women. The overall stillbirth rate was 32.9 per 1,000 deliveries (95% confidence interval [CI] 26.1–40.7). In univariable analyses, predictors for stillbirth included previous stillbirth (odds ratio [OR] 2.3, 95% CI 1.2–4.3), antenatal hemorrhage (OR 14.4, 95% CI 4.3–47.9), clinical chorioamnionitis (OR 20.9, 95% CI 5.1–86.2), and marked polymorphonuclear infiltration on placental histology (OR 2.9, 95% CI 1.7–5.2). When compared with pregnancies longer than 37 weeks, those at 34–37 weeks (OR 1.7, 95% CI 0.8–3.4) and those at less than 34 weeks (OR 22.8, 95% CI 13.6–38.2) appeared more likely to result in stillborn delivery. Human immunodeficiency virus infection was not associated with a greater risk for stillbirth in either univariable (OR 1.5, 95% CI 0.7–3.0) or multivariable (adjusted OR 1.11, 95% CI 0.38–3.26) analysis. Among HIV-infected women, however, decreasing CD4 cell count was inversely related to stillbirth risk (P=.009). CONCLUSION: In this large cohort, HIV infection was not associated with increased stillbirth risk. Further work is needed to elucidate the relationship between chorioamnionitis and stillbirth in African populations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00021671 LEVEL OF EVIDENCE: II

Immune reconstitution in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy: a cohort study

Background. Highly active antiretroviral therapy (HAART) has brought about rapid declines in HIV-1 RNA concentrations and an increase in CD4+ counts in HIV-1-infected children. These changes are often accompanied by clinical improvement; however, the extent to which immune reconstitution occurs is not known. Design. We compared two cohorts (n = 35) of HIV-1-infected children to evaluate the effects of HAART on immune recovery. Cohort 1 (C1) included clinically well children receiving HAART with a CD4 >22% at study initiation. Before HAART all children had moderately to severely suppressed immune function by CDC criteria (CD4 <25%) or CDC Category B or C disease. Cohort 2 (C2) included children with no current or past evidence of immunosuppression based on CDC criteria (CD4 >25%) and no evidence of clinical disease. Children in C2 were receiving a non-HAART regimen. Methods. Immunophenotyping was performed to characterize CD4+ and CD8+ subsets with regard to maturation and activation. T cell rearrangement excision circles (TRECs) were measured to quantify recent thymic emigrants. Results. No difference was found in percent CD4+ or percent CD8+ T cells or maturation markers between C1 and C2. There was significantly less expression of activation markers in both CD4+ and CD8+ cells in C1. There was no difference in TREC production between C1 and C2. Conclusion. Moderately to severely suppressed HIV-1-infected children receiving HAART are able to reconstitute their immune systems to a degree that is indistinguishable from that of stable, CDC Class A1 HIV-1-infected children with regard to CD4+ and CD8+ T cell subsets, expression of cellular maturation markers and TREC production.

Treatment of trichomoniasis in pregnancy in sub-Saharan Africa does not appear to be associated with low birth weight or preterm birth

OBJECTIVES To determine whether treatment of trichomoniasis increases the risk of prematurity. DESIGN Sub-analysis of a randomised trial. SETTING We analysed data from HPTN trial of antenatal and intrapartum antibiotics to reduce chorioamnionitis-related perinatal HIV transmission. SUBJECTS Pregnant women from four sites in Africa. OUTCOME MEASURES Gestational age at the time of delivery or mean birth weight. RESULTS Of 2,428 women-infant pairs included, 428 (18%) had trichomoniasis at enrolment. There were no differences in infant age or birth weight between women with or without trichomoniasis. By randomisation group, there were no differences in gestational age at birth or birth weight. Of the 428 women diagnosed with trichomoniasis, 365 (83%) received antibiotics and 63 (15%) did not. In analysis of actual use of antibiotics, women with trichomoniasis who received no treatment were more likely to deliver a preterm infant when the symphysis-fundal height was used to estimate gestational age (36% v. 23%; p=0.03), but not when the Ballard score was used (16% v. 21%; p=0.41). There were no differences in mean birth weight between groups. CONCLUSIONS In pregnant women in sub-Saharan Africa, most of whom were HIV-infected, neither trichomoniasis nor its treatment appears to influence the risk of preterm birth or a low-birth-weight infant.

Risk Factors for Late Postnatal Transmission of Human Immunodeficiency Virus Type 1 in Sub-Saharan Africa

Background: We conducted secondary data analyses of a clinical trial (HIVNET 024) to assess risk factors for late postnatal transmission (LPT) of human immunodeficiency virus type 1 (HIV-1) through breast-feeding. Methods: Data regarding live born, singleton infants of HIV-1-infected mothers were analyzed. The timing of HIV-1 transmission through 12 months after birth was defined as: in utero (positive HIV-1 RNA results at birth), perinatal/early postnatal (negative results at birth, positive at 4–6 week visit), or LPT (negative results through the 4–6 week visit, but positive assays thereafter through the 12-month visit). HIV-1-uninfected infants were those with negative HIV-1 enzyme immunoassay results at 12 months of age, or infants with negative HIV-1 RNA results throughout follow-up. Results: Of 2292 HIV-1-infected enrolled women, 2052 mother/infant pairs met inclusion criteria. Of 1979 infants with HIV-1 tests, 404 were HIV-1-infected, and 382 had known timing of infection (LPT represented 22% of transmissions). Further analyses of LPT included infants who were breast-feeding at the 4–6 week visit (with negative HIV-1 results at that visit) revealed 6.9% of 1317 infants acquired HIV-1 infection through LPT by 12 months of age. More advanced maternal HIV-1 disease at enrollment (lower CD4+ counts, higher plasma viral loads) were the factors associated with LPT in adjusted analyses. Conclusions: In this breast-feeding population, 6.9% of infants uninfected at 6 weeks of age acquired HIV-1 infection by 12 months. Making interventions to decrease the risk of LPT of HIV-1 available and continuing research regarding the mechanisms of LPT (so as to develop improved interventions to reduce such transmission) remain essential.

Population Attributable Fractions for Late Postnatal Mother-to- Child Transmission of HIV-1 in Sub-Saharan Africa

Objectives:Assess population attributable fractions (PAFs) for late postnatal transmission (LPT) of HIV-1 in a cohort of HIV-1-exposed infants. Methods:We used data established from a risk factor analysis of LPT (negative HIV-1 results through the 4-6 week visit, but positive assays thereafter through the 12-month visit) from a perinatal clinical trial conducted in 3 sub-Saharan countries. PAFs were calculated as the proportions of excess LPTs attributed to identified risk factors. Results:For the cohort of 1317 infants, 206 (15.6%) had only low maternal CD4+ counts (<200 cells/mm3), 332 (25.2%) had only high maternal plasma viral loads (VLs) (>50,000 copies/mL), and 81 (6.2%) had both low CD4+ counts and high VLs. Their PAFs were 26.0% [95% confidence interval (CI): 12.0% to 36.0%], 37.0% (95% CI: 22.0% to 51.0%), and 16.0% (95% CI: 6.0% to 25.0%), respectively. Conclusions:Our PAF analysis illustrates the public health impact of the substantial proportion of LPTs accounted for by high-risk women with both low CD4+ counts and high VLs. In light of these results, access to and use of antiretroviral therapy by high-risk HIV-1-infected pregnant women is essential. Additional strategies to reduce LPT for those not meeting criteria for antiretroviral therapy should be implemented.

Selected hematologic and biochemical measurements in African HIV-infected and uninfected pregnant women and their infants: the HIV Prevention Trials Network 024 protocol

BackgroundReference values for hematological and biochemical assays in pregnant women and in newborn infants are based primarily on Caucasian populations. Normative data are limited for populations in sub-Saharan Africa, especially comparing women with and without HIV infection, and comparing infants with and without HIV infection or HIV exposure.MethodsWe determined HIV status and selected hematological and biochemical measurements in women at 20–24 weeks and at 36 weeks gestation, and in infants at birth and 4–6 weeks of age. All were recruited within a randomized clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV (HPTN024). We report nearly complete laboratory data on 2,292 HIV-infected and 367 HIV-uninfected pregnant African women who were representative of the public clinics from which the women were recruited. Nearly all the HIV-infected mothers received nevirapine prophylaxis at the time of labor, as did their infants after birth (always within 72 hours of birth, but typically within just a few hours at the four study sites in Malawi (2 sites), Tanzania, and Zambia.ResultsHIV-infected pregnant women had lower red blood cell counts, hemoglobin, hematocrit, and white blood cell counts than HIV-uninfected women. Platelet and monocyte counts were higher among HIV-infected women at both time points. At the 4–6-week visit, HIV-infected infants had lower hemoglobin, hematocrit and white blood cell counts than uninfected infants. Platelet counts were lower in HIV-infected infants than HIV-uninfected infants, both at birth and at 4–6 weeks of age. At 4–6 weeks, HIV-infected infants had higher alanine aminotransferase measures than uninfected infants.ConclusionNormative data in pregnant African women and their newborn infants are needed to guide the large-scale HIV care and treatment programs being scaled up throughout the continent. These laboratory measures will help interpret clinical data and assist in patient monitoring in a sub-Saharan Africa context.Trial RegistrationnicalTrials.gov Identifier NCT00021671.

Timing of maternal and neonatal dosing of nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024

Objective:Despite a growing emphasis worldwide on complex and potent antiretroviral drug regimens for the prevention of mother-to-child transmission of HIV-1 (MTCT), two-dose nevirapine (NVP) prophylaxis remains an important choice in many settings. We analyzed data from a multicenter clinical trial to determine whether timing of maternal or infant NVP was associated with MTCT between delivery and 6 weeks of age (intrapartum/early postnatal transmission; I/EP). Methods:HIVNET 024 was a placebo-controlled, double-blind trial of empiric antibiotics to reduce chorioamnionitis-associated MTCT. This secondary analysis used data collected in the original randomized trial. Enrolled women were instructed to self-administer NVP at labor onset; infants were to receive a dose within 72 h of birth. Results:Data regarding 1491 mother–infant pairs were analyzed. The overall I/EP HIV-1 transmission rate was 8.1% at 6 weeks. Almost all women (93%) ingested NVP within 24 h of delivery; 90% of infants were given NVP within 48 h after delivery. Variations in mother or infant dose timing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women ingesting NVP ≤ 2 h before delivery, early NVP administration to the infant (< 4 h after birth) was not associated with lower MTCT risk when compared with later administration (≥ 4 h). Conclusion:Variations in the timing of maternal and infant NVP doses (within reasonable proximity to delivery) do not appear to affect the risk of MTCT.