Mahrukh Bamji

Association of Human Immunodeficiency Virus (HIV) Load Early in Life with Disease Progression among HIV-Infected Infants

The utility of RNA virus load to predict progression of human immunodeficiency virus (HIV)-1 disease was assessed in 89 HIV-1-infected children. Of 22 virus load values during week 1 of life, 17 were below the detection threshold. Geometric mean virus load increased to approximately 7 x 10(5) copies/mL by week 4, was sustained throughout the first 6 months of life, and then declined to 1.6 x 10(5) copies/mL during the third year. Samples from week 1 of life had little predictive value, but virus load during days 7-30 strongly predicted progression to CDC-3 classification or death (P = .024; risk ratio = 1.6), and virus load during months 2-3 predicted progression to CDC-C or death within the first 6 months of life (P = .002, risk ratio = 11). Virus load was highly associated with imminent vulnerability to CDC-C or death (P = .002) during the first 18 months of life. Except for values from the first week of life, virus load at any age through 18 months is strongly associated with risk of HIV disease progression.

The effect of maternal viral load on the risk of perinatal transmission of HIV-1

Objective:To determine the effect of maternal viral load at delivery on the risk of perinatal transmission of HIV-1. Design:A nested case–control study within a prospectively followed cohort of HIV- 1-infected pregnant women and their infants. Setting:The multicenter New York City Perinatal HIV Transmission Collaborative Study. Participants:Fifty-one women who gave birth to HIV-1-infected infants were frequency-matched within CD4+ cell count quintiles with 54 non-transmitting mothers. Main outcome measures:Maternal quantity of HIV-1 viral RNA was assayed in plasma obtained near delivery using the nucleic acid sequence-based amplification assay system. Results:Viral RNA was detected in 73 (70%) out of 105 women and the median viral load was 16 000 RNA copies/ml in transmitters and 6600 in non-transmitters (P < 0.01). When adjusted for maternal CD4+ count near delivery, women with measurable viral load were nearly sixfold more likely to transmit HIV-1 than women with viral load below detection [adjusted odds ratio (AOR), 5.8; 95% confidence interval (CI), 2.2–15.5]. The odds ratio for perinatal transmission of log10 viral load, adjusted for CD4 count was 2.7 (95% CI, 1.5–5.1). When stratified by the stage of HIV-1 disease, the only group with significant association between log10 viral load and transmission were AIDS-free women with CD4+ count > 500 x 106/l (AOR, 9.1; 95% CI, 2.6–31.5). Conclusions:High maternal viral load increases the likelihood of perinatal transmission of HIV-1 in women without AIDS and advanced immunosuppression. HIV-1-infected pregnant women without advanced disease, shown by others to have the lowest risk of perinatal transmission, may benefit the most from efforts to identify and decrease viral load at delivery.

Timing of maternal-infant HIV transmission : associations between intrapartum factors and early polymerase chain reaction results

Objective:To investigate the hypothesis that labour and delivery events, perinatal characteristics, and maternal factors are only associated with intrapartum HIV transmission, and not with intrauterine HIV transmission. Methods:In the New York City Perinatal HIV Transmission Collaborative Study 276 infants of HIV-infected women were followed prospectively and had results of early polymerase chain reaction (PCR) tests available. Among infected children, intrauterine infection was presumed if HIV DNA was detected by PCR in samples collected from children aged ≤ 3 days, and intrapartum infection was presumed if HIV DNA was not detected in these early samples. The proportion of infants with presumed intrauterine and intrapartum infections were compared by selected intrapartum, perinatal and maternal characteristics. Results:Presumed intrapartum infection was found in 7% of infants delivered by Cesarean section and, among infants delivered vaginally, those with longer duration of membrane rupture (> 4 h) were significantly more likely to have presumed intrapartum HIV infection (22%) than those with shorter duration (9%; P = 0.02). There were no differences in presumed intrauterine HIV infection by mode of delivery or longer duration of membrane rupture. Infants born preterm and small for gestational age had significantly higher risks of presumed intrapartum infection, but only those who were small for gestational age had higher risks of intrauterine infection. Conclusion:Our results support the notion that selected intrapartum conditions, long duration of membrane rupture prior to delivery in particular, are independent risk factors for maternal–infant transmission, and suggest that preterm infants may be especially vulnerable to intrapartum HIV exposure.

Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children : Week 24 results of a randomized controlled trial-PACTG 377

One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen. All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens. Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (< or =400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HIV RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population.

Maternal predictors of perinatal human immunodeficiency virus transmission

&NA; This analysis sought to identify characteristics of pregnant human immunodeficiency virus type 1 (HIV‐1)‐infected women that predict mother‐to‐child HIV‐1 transmission. Pregnant and immediately postpartum women at risk for HIV were enrolled at obstetric and pediatric care settings in New York City from 1986 to 1992. Demographic and behavioral characteristics, clinical illness, T lymphocyte subsets, immunoglobulin concentration and syphilis serology were collected on the women. Infants were followed to determine HIV infection classification according to Centers for Disease Control and Prevention criteria for HIV‐1 in children. Transmission rates were calculated for women who gave birth more than 15 months before the analysis. Of 172 HIV‐1‐infected women with known outcome 49 (28%) had infected infants. The transmission rate (TR) was significantly higher among women with <280 CD4+ cells/&mgr;l (lowest CD4+ quartile) than with CD4+ counts >280 (48% vs. 22%; P = 0.004; odds ratio, 3.4; 95% confidence interval (1.5, 7.8)); a similar trend was seen by CD4+% quartile. No difference in TR was seen comparing women by CD8+ count quartile but marginally higher TR was seen among women with CD8+% ≥51% than with CD8+% <51% (TR = 41% vs. 24%; P = 0.076; odds ratio, 2.2; confidence interval (1.0, 5.1)). The highest TR, 62%, was seen in women with both CD8+ count above the median and CD4+ count in the lowest quartile. No significant difference in TR was seen between women with and without HIV‐related illness, although the TR was 53% among women hospitalized in the previous year for pneumonia compared with 25% in others (P = 0.03). TR was somewhat lower in women who delivered by cesarean section than vaginally (entire cohort: 18% vs. 32%, P = 0.11; prenatal enrollees only, 17% vs. 38%, P = 0.045). No factor or combination of factors was both highly sensitive and specific for predicting mother‐to‐child HIV transmission. A possible relationship between transmission and mode of delivery deserves further investigation.

Effect of supplementation with cholecalciferol and calcium on 2-y bone mass accrual in HIV-infected children and adolescents: a randomized clinical trial

BACKGROUND Skeletal abnormalities have been reported in HIV-infected children and adolescents. Although the etiology is not well understood, vitamin D deficiency may be involved. OBJECTIVE The study objective was to evaluate the effect of vitamin D and calcium supplementation on bone mass accrual in HIV-infected youth. DESIGN Perinatally HIV-infected children were randomly assigned to receive vitamin D (100,000 IU cholecalciferol given every 2 mo) and calcium (1 g/d) (supplemented group) or double placebo (placebo group) for 2 y. The total-body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), spine bone mineral content (SBMC), and spine bone mineral density (SBMD) were assessed by using dual-energy X-ray absorptiometry at baseline and at 2 annual follow-up visits. RESULTS Fifty-nine participants, aged 6-16 y, were randomly assigned to either the supplemented (n = 30) or the placebo (n = 29) group. At enrollment, supplemented and placebo groups did not differ with respect to age, sex, dietary intakes of vitamin D and calcium, mean baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, TBBMC, TBBMD, SBMC, or SBMD. Significant increases in serum 25(OH)D were observed in the supplemented group but not in the placebo group. TBBMC, TBBMD, SBMC, and SBMD increased significantly at 1 and 2 y in both groups. No between-group differences were observed at any time before or after adjustment for stage of sexual maturation by mixed linear model analysis. CONCLUSION One gram of calcium per day and oral cholecalciferol at a dosage of 100,000 IU every 2 mo administered to HIV-infected children and adolescents did not affect bone mass accrual despite significant increases in serum 25(OH)D concentrations. This trial was registered at clinicaltrials.gov as NCT00724178.

Prospective study of human immunodeficiency virus 1-related disease among 512 infants born to infected women in New York City

OBJECTIVE To determine the incidence of HIV-1-related clinical findings, mortality and predictors of death in a cohort of HIV-exposed infants followed from birth. METHODS Data were collected approximately bimonthly during the first and second year of life and used in Kaplan-Meier and Cox proportional hazards survival analyses to predict time to the development of symptoms and death. RESULTS One hundred sixteen infected and 396 uninfected infants were followed for a median of 26 months at 7 New York City hospitals from 1986 to 1995. Two or more nonspecific HIV-related symptoms, AIDS or death occurred in 83% of infected children by the first year. Fifty infected infants (43%) developed AIDS and 19 (38%) of these had Pneumocystis carinii pneumonia. Estimated median age at AIDS/death was 30 months and 64% of infected children remained alive and AIDS-free at 1 year. Estimated infant mortality among infected children was 160/1000 live births, and median survival after AIDS was 21 months; 55% of infected children survived > 12 months after diagnosis of AIDS. P. carinii pneumonia was the most common cause of death. Although birth CD4 values did not predict AIDS or death, CD4 counts as early as 6 months of age were highly correlated with both. Thirteen (68%) of 19 infants who remained AIDS-free up to 3 to 6 months of age with CD4 count < or = 1500 cells/microliters subsequently developed AIDS vs. 18 (30%) of 61 with CD4 count > 1500 (P = 0.0001). CONCLUSIONS Most HIV-1-infected infants develop disease in the first year of life. AIDS or death can be predicted by a threshold CD4 count of 1500 cells/microliters at 3 to 6 months of age.

Individual and contextual factors of sexual risk behavior in youth perinatally infected with HIV.

This study prospectively examines the effects of maternal and child HIV infection on youth penetrative and unprotected penetrative sex, as well as the role of internal contextual, external contextual, social and self-regulatory factors in influencing the sexual behaviors of HIV-infected (PHIV+), HIV-affected (uninfected with an HIV+ caregiver), and HIV unaffected (uninfected with an HIV- caregiver) youth over time. Data (N=420) were drawn from two longitudinal studies focused on the effects of pediatric or maternal HIV on youth (51% female; 39% PHIV+) and their caregivers (92% female; 46% HIV+). PHIV+ youth were significantly less likely to engage in penetrative sex than HIV- youth at follow-up, after adjusting for contextual, social, and self-regulatory factors. Other individual- and contextual-level factors such as youth alcohol and marijuana use, residing with a biological parent, caregiver employment, caregiver marijuana use, and youth self-concept were also associated with penetrative sex. Youth who used alcohol were significantly more likely to engage in unprotected penetrative sex. Data suggest that, despite contextual, social, and self-regulatory risk factors, PHIV+ youth are less likely to engage in sexual behavior compared to HIV- youth from similar environments. Further research is required to understand delays in sexual activity in PHIV+ youth and also to understand potential factors that promote resiliency, particularly as they age into older adolescence and young adulthood.

Incubation period of HIV-1 in perinatally infected children

Objectives:To estimate the distribution of the incubation period of HIV-1 among perinatally infected children and to test the hypothesis that this distribution has been changing over time. Design:An analysis of 190 perinatally HIV-1-infected children born between 1986 and 1997 in eight medical centers in New York City to women enrolled in a prospective cohort study. Methods:Non-parametric Kaplan–Meier method and parametric survival analysis. Results:Using the Kaplan–Meier method it was estimated that among perinatally HIV-1-infected children, 48% [95% confidence interval (CI), 41–56] developed AIDS by 3 years of age after which the rate was less than 3% per year. Using a parametric survival analysis for extrapolation, it was predicted that 33% (95% CI, 23–43) would remain AIDS-free at 13 years of age. Median age at onset of AIDS was estimated to be 4.1 years (95% CI, 1.9–6.4) by parametric survival analysis. The year of birth was significantly associated with AIDS-free survival, suggesting an increase in the time to AIDS over the years. This association remained significant (P = 0.03) after adjustment for those maternal characteristics that have also changed over time: timing of enrollment (prepartum versus postpartum), zidovudine, alcohol, and hard drug (heroin, cocaine or methadone) use during pregnancy. Conclusions:Although a substantial proportion of perinatally HIV-1-infected children develop AIDS very early in life, a significant and increasing percentage of them are expected to survive into adolescence without developing AIDS. Further research is needed to determine the factors associated with the lengthening survival to AIDS.

Human immunodeficiency virus 1-specific Iga capture enzyme immunoassay for early diagnosis of human immunodeficiency virus 1 infection in infants

A simplified human immunodeficiency virus 1 (HIV-1)-specific IgA capture enzyme immunoassay (IgA-CEIA) was evaluated and compared with IgA-Western blot assay for early diagnosis of HIV-1 infection in infants born to seropositive women. A total of 232 coded sera collected prospectively from 70 infants were tested. All 25 sera from 10 HIV-1-negative in-