Andrea Ruff

Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials.

BACKGROUND UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding. METHODS HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8-42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. These studies are registered with ClinicalTrials.gov, numbers NCT00074399, NCT00061321, and NCT00639938. FINDINGS 2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58-1.10; p=0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34-0.85; p=0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0.54). INTERPRETATION Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint-risk of HIV transmission at 6 months-suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high. FUNDING US National Institutes of Health; US National Institute of Allergy and Infectious Diseases; Fogarty International Center.

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.

A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children

HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.

Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.

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.

Biosynthesis and Metabolism of Carnitine

In the second segment of this three-part review of parasitic infections of the central nervous system in children, we consider parasitic infections which typically involve various tissues and organs in addition to the brain and spinal cord. Parasites capable of dissemination in immunocompetent hosts are discussed first, and, as in Part I, organisms are grouped according to their predominant geographic location. This is followed by a discussion of the unique aspects of toxoplasmosis, strongyloidiasis and infection with microsporidia in immunocompromised patients, with an emphasis on the central nervous system. (J Child Neurol 1995;10:77-87).

Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding: from animal studies to randomized clinical trials.

The major remaining challenge in the prevention of mother-to-child transmission is the reduction of the risk in settings where breast-feeding is common. This review gives an update on ongoing or planned antiretroviral intervention studies in resource-limited settings that are aimed at reducing the risk of mother-to-infant HIV transmission during lactation. These strategies include antiretroviral therapy given to the mother to reduce viral load in plasma and breast milk as well as antiretroviral regimens providing prophylaxis to uninfected infants during the period of breast-feeding. The rationale for the interventions based on animal models and human studies is described as well as the study designs of clinical trials. Potential risks and benefits of these interventions to mothers and infants are also highlighted. Laboratory studies nested within several of these trials will provide a better understanding of the pathogenesis of postnatal HIV transmission and its potential prevention using antiretroviral drugs.

A Human Milk Factor Inhibits Binding of Human Immunodeficiency Virus to the CD4 Receptor

ABSTRACT: Perinatal transmission of human immuno-deficiency virus (HIV) from infected mothers to their children occurs at rates reported as 20–50%. The role of breast feeding in perinatal transmission of viral infections has not been well established. We studied 34 milk and colostral samples obtained from HIV-seropositive and HIV-sero-negative women to determine if they contained anti-HIV activity. We found that all the samples contained a factor that inhibited the binding of HIV epitope-specific MAb to recombinant CD4 receptor molecules. The titers of inhibitory activity ranged from 1:200 to 1:10 000 and did not differ between HIV-seropositive and HIV-seronegative mothers. This milk factor also inhibited the binding of gp120 to CD4. Neither human sera nor bovine milk exhibited appreciable inhibitory activity. Fractionation of human milk indicated that the inhibitory activity was confined to the macromolecular fraction; little activity was found in isolated milk lipids or oligosaccharides. Chromatographic procedures indicated that the active macromolecule has an isoelectric point of 9.3–9.6. The active material did not bind to concanavalin A; however, the activity was partially destroyed by chemical and enzymatic treatments that removed sulfated residues. The active material may thus be a sulfated protein, glycoprotein, mucin, or glycosaminoglycan that inhibits the binding of CD4 to HIV envelope glycoproteins. The role of this factor in the natural history of HIV infection in infants and children should be the subject of additional investigations.

Selenium Deficiency and Cardiomyopathy in Acquired Immunodeficiency Syndrome

Selenium deficiency is common in patients with human immunodeficiency virus infection and may contribute to the development of cardiomyopathy. A 5-year-old boy with congenital human immunodeficiency virus infection developed cardiomyopathy. Evaluation for reversible causes of cardiomyopathy was notable for the diagnosis of selenium deficiency. Cardiac function improved on selenium supplementation. The role of selenium in cardiac dysfunction and the need for nutritional evaluation and supplementation of malnourished patients with acquired immunodeficiency syndrome is discussed.

Short-term effects of large-dose vitamin A supplementation on viral load and immune response in HIV-infected women

Vitamin A supplementation has been suggested for treatment and prevention of HIV infection. However, some in vitro data indicate that vitamin A may activate HIV. Randomly, 40 HIV-seropositive women of reproductive age were allocated to receive a single oral dose of 9900 micromol (300,000 IU) vitamin A or placebo. Plasma HIV-1 RNA concentration, total lymphocytes, selected lymphocyte subsets and activation markers, and in vitro lymphocyte proliferation to phytohemagglutinin (PHA) and Candida were measured before dosing and at various time points over an 8-week follow-up period. No differences were found between treatment groups in the frequency of signs or symptoms of acute vitamin A toxicity, nor were differences evident in any lymphocyte subset or activation marker at any time during follow-up. Mean and median viral load concentration at each time point and change in viral load from baseline to each follow-up point did not differ between treatment groups. No difference was measured between treatment groups in the proportion of women who responded to PHA or Candida. This study provides no evidence that high dose vitamin A supplementation of HIV-infected women is associated with significant clinical or immunologic adverse effects.