Randomized controlled trial of feeding a concentrated formula to infants born to women infected by human immunodeficiency virus.

OBJECTIVE: We tested the hypothesis that concentrated formula (CF) begun within the first 2 weeks of life increases growth in infants born to human immunodeficiency virus (HIV)-infected mothers. MATERIALS AND METHODS: HIV-exposed infants from the United States, the Bahamas, and Brazil were randomized in a double-blind, controlled trial to receive either a CF (87 kcal/100 mL [26 kcal/oz]) or a standard formula (SF; 67 kcal/100 mL [20 kcal/oz]) for 8 weeks. This article presents results for infants who were not determined to be HIV infected based on testing at 4 weeks. Primary outcomes were safety, tolerability, and growth in weight and length. RESULTS: Two thousand ninety-seven infants were enrolled, of whom 1998 were uninfected and had study formula dispensed. At weeks 4 and 8, uninfected infants receiving CF showed higher energy intake than those who were receiving SF (P < 0.001). By week 8, uninfected infants assigned to CF weighed more than infants receiving SF. There were no consistent differences in measures of tolerability, and rates of discontinuation or perceived formula intolerance were similar between treatment groups. CONCLUSIONS: A CF is well tolerated and results in increased weight gain compared with SF. Until the HIV status of an infant is reliably determined, early introduction of a CF in HIV-exposed children may have beneficial effects on growth. The role of early nutritional intervention remains to be determined for individuals living in countries with endemic malnutrition for whom formula feeding is a viable option.

Reduced lopinavir exposure during pregnancy.

BACKGROUND: Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy. METHODS: We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30-36 weeks gestation and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was > or = 52 microg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 microg h/ml). RESULTS: Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 microg h/ml [90% confidence interval (CI), 38.7-50.9] and 12-h post-dose concentration (C12h) was 1.6 microg/ml (90% CI, 1.1-2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 microg h/ml (90% CI, 49.7-85.4) and C12h was 4.6 microg/ml (90% CI, 3.7-5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54-0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 +/- 0.13. CONCLUSIONS: LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.

Declines in mortality rates and changes in causes of death in HIV-1-infected children during the HAART era.

CONTEXT: Introduction of highly active antiretroviral therapy has significantly decreased mortality in HIV-1-infected adults and children. Although an increase in non-HIV-related mortality has been noted in adults, data in children are limited. OBJECTIVES: To evaluate changes in causes and risk factors for death among HIV-1-infected children in Pediatric AIDS Clinical Trials Group 219/219C. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective cohort study designed to evaluate long-term outcomes in HIV-1-exposed and infected US children. There were 3553 HIV-1-infected children enrolled and followed up between April 1993 and December 2006, with primary cause of mortality identified in the 298 observed deaths. MAIN OUTCOME MEASURES: Mortality rates per 100 child-years overall and by demographic factors; survival estimates by birth cohort; and hazard ratios for mortality by various demographic, health, and antiretroviral treatment factors were determined. RESULTS: Among 3553 HIV-1-infected children followed up for a median of 5.3 years, 298 deaths occurred. Death rates significantly decreased between 1994 and 2000, from 7.2 to 0.8 per 100 person-years, and remained relatively stable through 2006. After adjustment for other covariates, increased risk of death was identified for those with low CD4 and AIDS-defining illness at entry. Decreased risks of mortality were identified for later birth cohorts, and for time-dependent initiation of highly active antiretroviral therapy (hazard ratio 0.54, P < 0.001). The most common causes of death were "End-stage AIDS" (N = 48, 16%) and pneumonia (N = 41, 14%). The proportion of deaths due to opportunistic infections (OIs) declined from 37% in 1994-1996 to 24% after 2000. All OI mortality declined during the study period. However, a greater decline was noted for deaths due to Mycobacterium avium complex and cryptosporidium. Deaths from "End-stage AIDS," sepsis and renal failure increased. CONCLUSIONS: Overall death rates declined from 1993 to 2000 but have since stabilized at rates about 30 times higher than for the general US pediatric population. Deaths due to OIs have declined, but non-AIDS-defining infections and multiorgan failure remain major causes of mortality in HIV-1-infected children.

Antibody responses to hepatitis A virus vaccine in HIV-infected children with evidence of immunologic reconstitution while receiving highly active antiretroviral therapy.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy. METHODS: A total of 235 children with CD4+ T cell percentages > or = 20% received 2 vaccine doses 24 weeks apart, and 117 received a third vaccine dose after 104 weeks. Anti-HAV antibody titers were measured at baseline and at 32, 104, and 112 weeks after the first vaccination. Subjects with antibody titers > or = 20 mIU/mL were defined as being seropositive. High and low antibody responses were defined as titers > or = 250 and <250 mIU/mL, respectively. RESULTS: Of 151 subjects who were HAV seronegative at baseline, 97% seroconverted after 2 vaccine doses, and 47% had low antibody responses. At 104 weeks, 90% of subjects had antibody titers > or = 20 mIU/mL, and those with low antibody responses were more likely to lose protective antibody titers. A third vaccine dose generated significantly higher antibody titers than those observed after the second vaccine dose. Undetectable HIV RNA at baseline was associated with higher anti-HAV antibody titers after the second vaccine dose. Antibody titers after the second and third vaccine doses were weakly correlated with CD4+ T cell percentages at the time when each vaccine dose was administered. In the 45 subjects who were HAV seropositive at baseline, responses to 2 and 3 vaccine doses were higher than those in subjects who were HAV seronegative at baseline, but the responses showed similar correlations. There were no serious adverse events associated with the vaccine. CONCLUSIONS: HIV-infected children with CD4+ T cell percentages > or = 20% responded better to the HAV vaccine if they had undetectable HIV RNA. The standard 2-dose immunization regimen generated low antibody titers with limited persistence. A third vaccine dose was safe and increased the antibody titers, suggesting that an increase in immunizations may be warranted in this population.

The rate of serious bacterial infections among HIV-infected children with immune reconstitution who have discontinued opportunistic infection prophylaxis.

OBJECTIVE: Receipt of highly active antiretroviral therapy is associated with a decrease in the incidence of opportunistic infections (OIs) among HIV-infected adults. The goal of Pediatric AIDS Clinical Trials Group protocol 1008 was to evaluate prospectively the incidence of serious bacterial infections (SBIs) and other OIs after discontinuation of OI and/or Pneumocystis jiroveci pneumonia (PCP) prophylaxis among HIV-infected pediatric subjects who experienced immune reconstitution while receiving stable antiretroviral therapy. METHODS: HIV-infected children and adolescents, 2 to 21 years of age, who had received OI and/or PCP prophylaxis for > or =6 months were enrolled if they had sustained responses (>16 weeks before study entry) to antiretroviral therapy, with CD4+ cell percentages of > or =20% for patients >6 years of age or > or =25% for patients 2 to 6 years of age. Prophylaxis was discontinued at entry. To identify whether any correlation existed between functional immune reconstitution and protection from OIs, subjects were immunized with the hepatitis A virus vaccine. The association between the humoral immune response and the likelihood of developing an OI was evaluated. RESULTS: A total of 235 HIV-infected subjects from 43 participating sites had a median follow-up period of 132 weeks, yielding 547 person-years of observation. Twenty SBIs were observed among 19 subjects, resulting in an incidence rate of 3.66 SBIs per 100 person-years (95% confidence interval: 2.24-5.66 SBIs per 100 person-years). Sixteen of the events were presumed bacterial pneumonia, with 4 proven SBIs. One participant experienced 2 separate pneumonia episodes, of presumed bacterial cause. Ten subjects who developed SBIs had baseline CD4+ cell counts of > or =750 cells per mm3, and 15 had CD4+ cell percentages of > or =25% at the time of their SBIs. Two subjects died as a result of non-SBI-related causes. There were no statistically significant differences in changes over time in CD4+ cell counts or CD4+ cell percentages between subjects who experienced primary end points and those who did not. There was no evidence that baseline protease inhibitor use, gender, race/ethnicity, age, or CD4+ cell count or percentage affected the time to development of a SBI. CONCLUSIONS: OI or PCP prophylaxis can be withdrawn safely for HIV-infected pediatric patients who experience CD4+ cell recovery while receiving stable antiretroviral therapy. More studies are needed to assess the association between antibody responses to neoantigens and the development of SBIs.