Ellen R. Cooper

Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission.

Context: The Women and Infants Transmission Study is a prospective natural history study that has been enrolling HIV‐1‐infected pregnant women and their infants since 1989. Objective: Toevaluate the impact of different antiretroviral regimens on perinatal HIV‐1 transmission at the population level. Design: Prospective cohort study. Plasma HIV‐1 RNA levels were serially measured in 1542 HIV‐1‐infected women with singleton live births between January 1990 and June 2000. Main Outcome Measure: HIV‐1 status of the infant. Results: HIV‐1 transmission was 20.0% (95% confidence interval [CI], 16.1%‐ 23.9%) for 396 women who not receiving prenatal antiretroviral therapy; 10.4% (95% CI, 8.2%‐12.6%) for 710 receiving zidovudine monotherapy; 3.8% (95% CI, 1.1%‐ 6.5%) for 186 receiving dual antiretroviral therapy with no or one highly active drug (Multi‐ART); and 1.2% (95% CI, 0‐2.5%) for 250 receiving highly active antiretroviral therapy (HAART). Transmission also varied by maternal delivery HIV RNA level: 1.0% for <400; 5.3% for 400 to 3499; 9.3% for 3500 to 9999; 14.7% for 10,000 to 29,999; and 23.4% for >30,000 copies/mL (p = .0001 for trend). The odds of transmission increased 2.4‐fold (95% CI, 1.7‐3.5) for every log10 increase in delivery viral load. In multivariate analyses adjusting for maternal viral load, duration of therapy, and other factors, the odds ratio for transmission for women receiving Multi‐ART and HAART compared with those receiving ZDV monotherapy was 0.30 (95% CI, 0.09‐1.02) and 0.27 (95% CI, 0.08‐0.94), respectively. Conclusion: Levels of HIV‐1 RNA at delivery and prenatal antiretroviral therapy were independently associated with transmission. The protective effect of therapy increased with the complexity and duration of the regimen. HAART was associated with the lowest rates of transmission.

Cytomegalovirus Infection and HIV-1 Disease Progression in Infants Born to HIV-1–Infected Women

Background and Methods Cytomegalovirus (CMV) has been implicated as a cofactor in the progression of human immunodeficiency virus type 1 (HIV-1) disease. We assessed 440 infants (75 of whom were HIV-1–infected and 365 of whom were not) whose CMV status was known, who were born to HIV-1–infected women, and who were followed prospectively. HIV-1 disease progression was defined as the presence of class C symptoms (according to the criteria of the Centers for Disease Control and Prevention [CDC]) or CD4 counts of less than 750 cells per cubic millimeter by 1 year of age and less than 500 cells per cubic millimeter by 18 months of age.

Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine.

Zidovudine (ZDV) therapy during pregnancy and to the neonate reduced perinatal HIV transmission by nearly 70% in Pediatric AIDS Clinical Trials Group (PACTG) protocol 076. ZDV has been reported as positive in several in vitro carcinogenicity screening tests. We evaluated the short-term risk for tumors in 727 children with known ZDV exposure enrolled into the PACTG 076/219 and the Women and Infants Transmission Study (WITS). ZDV exposure in utero (antepartum) occurred in 97% and 99% of infants in PACTG 076/219 or WITS, respectively. Mean follow-up was 38.3 months with 366.9 person years follow-up for PACTG 076/219 and 14.5 months with 743.7 person years follow-up for WITS. No tumors of any nature were observed; relative risk was 0 (95% confidence interval [CI], 0-17.6). These data are reassuring regarding the short-term lack of tumors for ZDV-exposed infants observed to date. Longitudinal, standardized follow-up for infants with in utero antiretroviral exposure is necessary to assess long-term carcinogenicity.

Encephalopathy and progression of human immunodeficiency virus disease in a cohort of children with perinatally acquired human immunodeficiency virus infection

OBJECTIVE To describe the incidence, predictors, and survival of children with human immunodeficiency virus (HIV) encephalopathy followed in the Women and Infants Transmission Study cohort. STUDY DESIGN Retrospective review of clinical and immunologic staging of perinatally HIV-infected infants, based on the 1994 Centers for Disease Control and Prevention Classification System. RESULTS Data were available for 128 HIV-infected children, with a median follow-up of 24 months. HIV encephalopathy was diagnosed in 27 (21%) of children. Median survival after diagnosis was 14 months. Of children with encephalopathy, 74% had at least moderate immunosuppression by the time of diagnosis. Encephalopathy represented the first acquired immunodeficiency syndrome-defining condition in 67%, and the only one in 26% of children. Hepatosplenomegaly or lymphadenopathy during the first 3 months of life was diagnosed in 63%, in contrast to 29% of those without encephalopathy (p value = 0.001). Cardiomyopathy was present in 30% of the children with encephalopathy versus 2% of those without encephalopathy. High viral load in infancy was associated with increased risk of encephalopathy but was not predictive of age at onset. CONCLUSIONS Encephalopathy in children with HIV is common and is associated with high viral load, immunodeficiency, and shortened survival. Encephalopathy was more likely to develop in infants with early signs and symptoms of HIV, although age at onset could not be predicted.

Maternal and Infant Factors Predicting Disease Progression in Human Immunodeficiency Virus Type 1-Infected Infants

Background. Infants with perinatally acquired human immunodeficiency virus type 1 (HIV-1) infection have widely variable courses. Previous studies showed that a number of maternal and infant factors, when analyzed separately, are associated with infant HIV-1 disease progression. In this study, clincal, virologic, and immunologic characteristics in the mothers and infants were examined together to determine the predictors of disease progression by 18 months of age and the associations with rapid progression during the first 6 months of life. Methods. One hundred twenty-two HIV-1-infected women whose infants were HIV-1 infected were identified from the Women and Infants Transmission Study (WITS) cohort. WITS is a longitudinal natural history study of perinatal HIV-1 infection carried out in 6 sites in the continental United States and in Puerto Rico. The women were enrolled during pregnancy and their infants were enrolled at the time of delivery and followed prospectively by a standardized protocol. Virologic and immunologic studies were performed in laboratories certified by National Institutes of Health-sponsored quality assurance programs. Maternal factors in pregnancy were used as potential predictors of infant disease progression (progression to Centers for Disease Control and Prevention [CDC] Clinical Class C disease or death by 18 months of age) or as correlates of progression at <6 months of age. Infant factors defined during the first 6 months of life were used as potential predictors of progression during 6 to 18 months of age and as correlates of progression at <6 months of age. Results. Progression by 18 months of age occurred in 32% of infants and by 6 months of age in 15%. Maternal characteristics that, by univariate analysis, were significant predictors of infant disease progression by 18 months of age were elevated viral load, depressed CD4+%, and depressed vitamin A. CD8+%, CD8+ activation markers, zidovudine (ZDV) use, hard drug use, and gestational age at delivery were not. When examined in a combined multivariate analysis of maternal characteristics, only vitamin A concentration independently predicted infant progression. Infant characteristics during the first 6 months of life that, by univariate analysis, were associated with disease progression included elevated mean viral load at 1 to 6 months of age, depressed CD4+%, CDC Clinical Disease Category B, and growth delay. Early HIV-1 culture positivity (<48 hours), CD8+%, CD8+ activation markers, and ZDV use during the first month of life did not predict progression. Multivariate analysis of infant characteristics showed that the only independent predictors were progression to CDC Category B by 6 months of age (odds ratio [OR], 5.80) and mean viral load from 1 to 6 months of age (OR, 1.99). The final combined maternal and infant analysis included the significant maternal and infant characteristics in a multivariate analysis. It showed that factors independently predicting infant progression by 18 months of age were progression to CDC Category B by 6 months of age (OR, 5.80) and elevated mean HIV-1 RNA copy number at 1 to 6 months of age (OR, 1.99). The characteristics associated with rapid progression to CDC Category C disease or death by 6 months of age were also examined. The only maternal characteristic associated with progression by 6 months in multivariate analysis was low maternal CD4+%. The infant characteristics associated with progression by 6 months of age in multivariate analysis were depressed mean CD4+% from birth through 2 months and the presence of lymphadenopathy, hepatomegaly, or splenomegaly by 3 months. Infant ZDV use was not assocciated with rapid progression. Conclusion. The strongest predictors of progression by 18 months are the presence of moderate clinical symptoms and elevated RNA copy number in the infants in the first 6 months of life. In contrast, progression by 6 months is associated with maternal and infant immune suppression, and the presence of infant clinical symptoms. The difference suggests that the key pathogenetic mechanisms responsible for progression may vary with age. These observations help provide direction for future pathogenesis research and assist in clinical care.

Disease progression in a cohort of infants with vertically acquired HIV infection observed from birth: the Women and Infants Transmission Study (WITS).

BACKGROUND The Women and Infants Transmission Study is an ongoing prospective cohort study of HIV-infected pregnant women and their infants. We used the 1994 U.S. Centers for Disease Control and Prevention (CDC) classification system for HIV infection in children to describe HIV disease progression in 128 HIV-infected children, and examined maternal and infant characteristics associated with disease course. METHODS The Kaplan-Meier method was used to calculate probabilities of entry into CDC clinical classes A, B, and C (mild, moderate, and severe HIV disease); CDC immunologic stages 2 and 3; and death. Relative risks of progression for selected predictor events were estimated using the Cox proportional hazards model. RESULTS With a median 24 months of follow-up, the median ages at entry into clinical classes A, B and C were 5, 11, and 48 months, respectively. Increased risk of progression to class C was seen in infants who had: onset of class B events (p < .001); progression to immunologic stage 2 (p < .001) or 3 (p < .001); early culture positivity (in first 48 hours, p < .01; in first 7 days, p = .03); and early appearance (within the first 3 months of life) of lymphadenopathy, hepatomegaly, or splenomegaly (p < .001). CONCLUSIONS Reaching specific clinical or immunologic stages were strong predictors of progression to AIDS or death. Early onset of clinical signs (onset of lymphadenopathy, hepatomegaly, or splenomegaly < or =3 months of age), and early culture positivity (within the first 48 hours or within the first week of life), defined the infant with highest risk of disease progression.

Seroreversion in human immunodeficiency virus-exposed but uninfected infants

The goal of this study was to describe seroreversion (SR) in a cohort of human immunodeficiency virus-exposed but uninfected infants. Groups of patients who seroreverted very early or late were examined for salient clinical and immunologic characteristics of the mother or infant. The mean time (± s.d.) to seroreversion by enzyme-linked immunoabsorbent assay (ELISA) was 50.1 ± 14.8 weeks, or 11.6 months (n = 84); the range of times to antibody loss by ELISA was 17.9 to 82.0 weeks. The mean time to seroreversion by Western blot was 68.3 ± 12.6 weeks, or 15.8 months (n = 51), with a range of 44.9 to 94.1 weeks. Initial anti-human immunodeficiency virus titer as measured by cord blood ELISA optical density (OD) was found to relate significantly to mean time to seroreversion. No relationship to time to seroreversion was demonstrated for gestational age, maternal or neonatal serum immunoglobulin concentrations, maternal CD4 cell counts, maternal alchol consumption, infantile diarrhea or failure to thrive. The lengthy time to seroreversion seen here demonstrates the 1994 revised Centers for Disease Control and Prevention definition of human immunodeficiency virus infection (based on seropositivity by both ELISA and confirmatory tests persisting beyond 18 months of age) to be accurate in our population. We recommend Western blot testing be used as confirmation for positive ELISAs only after 18 months of age.

Transitioning HIV-Infected Youth Into Adult Health Care

With advances in antiretroviral therapy, most HIV-infected children survive into adulthood. Optimal health care for these youth includes a formal plan for the transition of care from primary and/or subspecialty pediatric/adolescent/family medicine health care providers (medical home) to adult health care provider(s). Successful transition involves the early engagement and participation of the youth and his or her family with the pediatric medical home and adult health care teams in developing a formal plan. Referring providers should have a written policy for the transfer of HIV-infected youth to adult care, which will guide in the development of an individualized plan for each youth. The plan should be introduced to the youth in early adolescence and modified as the youth approaches transition. Assessment of developmental milestones is important to define the readiness of the youth in assuming responsibility for his or her own care before initiating the transfer. Communication among all providers is essential and should include both personal contact and a written medical summary. Progress toward the transition should be tracked and, once completed, should be documented and assessed.

Cardiac Effects of Antiretroviral Therapy in HIV-Negative Infants Born to HIV-Positive Mothers: NHLBI CHAART-1 (National Heart, Lung, and Blood Institute Cardiovascular Status of HAART Therapy in HIV-Exposed Infants and Children Cohort Study)

OBJECTIVES The aim of this study was to investigate the possible effects of antiretroviral therapy (ART) in utero on cardiac development and function in human immunodeficiency virus (HIV)-negative children. BACKGROUND ART reduces vertical HIV transmission. Long-term cardiotoxicity after in utero exposure to ART is unknown in children but has occurred in young animals. METHODS Using a prospective multisite cohort study design, echocardiograms taken between birth and 24 months were compared in 2 groups of HIV-negative infants of HIV-positive mothers: 136 infants exposed to ART (ART+) and 216 unexposed infants (ART-). RESULTS Mean left ventricular (LV) mass z-scores were consistently lower in ART+ girls than in ART- girls: differences in mean z-scores were -0.46 at birth (p = 0.005), -1.02 at 6 months (p < 0.001), -0.74 at 12 months (p < 0.001), and -0.79 at 24 months (p < 0.001). Corresponding differences in z-scores for boys were smaller: 0.13 at 1 month (p = 0.42), -0.44 at 6 months (p = 0.01), -0.15 at 12 months (p = 0.37), and -0.21 at 24 months (p = 0.21). Septal wall thickness and LV dimension were smaller than expected in ART+ infants, but LV contractility was consistently about 1 SD higher at all ages (p < 0.001). In ART+ infants, LV fractional shortening was higher than in ART- infants; girls showed a greater difference. CONCLUSIONS Fetal exposure to ART is associated with reduced LV mass, LV dimension, and septal wall thickness z-scores and increased LV fractional shortening and contractility up to age 2 years. These effects are more pronounced in girls than in boys. Fetal ART exposure may impair myocardial growth while improving depressed LV function.

HIV postexposure prophylaxis for children and adolescents.

HIV postexposure prophylaxis (PEP) is now a well-established part of the management of health care workers after occupational exposures to HIV. Use of PEP for adults exposed to HIV after sexual contact or injection drug use in nonoccupational settings remains controversial with limited data available. There is even less information available concerning HIV PEP for children and adolescents after accidental needlestick injuries or sexual assault. The objective was to describe the current practice of and associated problems with HIV PEP for children and adolescents at an urban academic pediatric emergency department. A retrospective review of all children and adolescents offered HIV PEP between June 1997-June 1998 was conducted. Ten pediatric and adolescent patients were offered HIV PEP, six patients after sexual assault, four patients after needle stick injuries. There were two small children 2 and 3 years of age and eight adolescents. Of these 10 patients, eight were started on HIV PEP. The regimens used for PEP varied; zidovudine, lamivudine, and indinavir were prescribed for in seven patients and zidovudine, lamivudine, and nelfinavir for one other. All 10 patients were HIV negative by serology at baseline testing and all available for follow-up testing (5 of 10) remained HIV negative at 4 to 28 weeks. Only two patients completed the full course of 4 weeks of antiretroviral therapy. Financial concerns, side effects, additional psychiatric and substance abuse issues as well as the degree of parental involvement influenced whether PEP and clinical follow-up was completed. HIV PEP in the nonoccupational setting for children and adolescents presents a medical and management challenge, and requires a coordinated effort at the initial presentation to the health care system and at follow-up. The difficulties encountered in the patients in our series need to be considered before initiating prophylaxis. A provisional management approach to HIV PEP in children and adolescents is proposed.