Russell B. Van Dyke

Maternal Viral Load, Zidovudine Treatment, and the Risk of Transmission of Human Immunodeficiency Virus Type 1 from Mother to Infant

BACKGROUND AND METHODS A placebo-controlled trial has shown that treatment with zidovudine reduces the rate at which human immunodeficiency virus type 1 (HIV-1) is transmitted from mother to infant. We present data from that trial showing the number of infected infants at 18 months of age and the relation between the maternal viral load, the risk of HIV-1 transmission, and the efficacy of zidovudine treatment. Viral cultures were obtained, and HIV-1 RNA was measured by two assays in samples of maternal blood obtained at study entry and at delivery. RESULTS In 402 mother-infant pairs, the rate of transmission of HIV-1 was 7.6 percent (95 percent confidence interval, 4.3 to 12.3 percent) with zidovudine treatment and 22.6 percent (95 percent confidence interval, 17.0 to 29.0 percent) with placebo (P<0.001). In the placebo group, a large viral burden at entry or delivery or a positive culture was associated with an increased risk of transmission (the transmission rate was greater than 40 percent in the highest quartile of the RNA level). In both groups, transmission occurred at a wide range of maternal plasma HIV-1 RNA levels. Zidovudine reduced plasma RNA levels somewhat (median reduction, 0.24 log). Zidovudine was effective regardless of the HIV-1 RNA level or the CD4+ count at entry. In the zidovudine group, however, after we adjusted for the base-line HIV-1 RNA level and CD4+ count, the reduction in viral RNA from base line to delivery was not significantly associated with the risk of transmission of HIV-1. CONCLUSIONS A high maternal plasma concentration of virus is a risk factor for the transmission of HIV-1 from an untreated mother to her infant. The reduction in such transmission after zidovudine treatment is only partly explained by the reduction in plasma levels of viral RNA. To prevent HIV-1 transmission, initiating maternal treatment with zidovudine is recommended regardless of the plasma level of HIV-1 RNA or the CD4+ count.

Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant

BACKGROUND AND METHODS A placebo-controlled trial has shown that treatment with zidovudine reduces the rate at which human immunodeficiency virus type 1 (HIV-1) is transmitted from mother to infant. We present data from that trial showing the number of infected infants at 18 months of age and the relation between the maternal viral load, the risk of HIV-1 transmission, and the efficacy of zidovudine treatment. Viral cultures were obtained, and HIV-1 RNA was measured by two assays in samples of maternal blood obtained at study entry and at delivery. RESULTS In 402 mother-infant pairs, the rate of transmission of HIV-1 was 7.6 percent (95 percent confidence interval, 4.3 to 12.3 percent) with zidovudine treatment and 22.6 percent (95 percent confidence interval, 17.0 to 29.0 percent) with placebo (P<0.001). In the placebo group, a large viral burden at entry or delivery or a positive culture was associated with an increased risk of transmission (the transmission rate was greater than 40 percent in the highest quartile of the RNA level). In both groups, transmission occurred at a wide range of maternal plasma HIV-1 RNA levels. Zidovudine reduced plasma RNA levels somewhat (median reduction, 0.24 log). Zidovudine was effective regardless of the HIV-1 RNA level or the CD4+ count at entry. In the zidovudine group, however, after we adjusted for the base-line HIV-1 RNA level and CD4+ count, the reduction in viral RNA from base line to delivery was not significantly associated with the risk of transmission of HIV-1. CONCLUSIONS A high maternal plasma concentration of virus is a risk factor for the transmission of HIV-1 from an untreated mother to her infant. The reduction in such transmission after zidovudine treatment is only partly explained by the reduction in plasma levels of viral RNA. To prevent HIV-1 transmission, initiating maternal treatment with zidovudine is recommended regardless of the plasma level of HIV-1 RNA or the CD4+ count.

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.

Long-Term Effectiveness of Highly Active Antiretroviral Therapy on the Survival of Children and Adolescents with HIV Infection: A 10-Year Follow-Up Study

BACKGROUND Previous observational studies found highly active antiretroviral therapy (HAART) to be associated with improved survival among human immunodeficiency virus (HIV)-infected children and adolescents. However, these studies had limited follow-up of HIV-infected children undergoing HAART. Given that HIV infection is chronic and that exposure to HAART is likely to be life-long, there is a need to evaluate the long-term effect of HAART on survival in this population. METHODS The study included 1236 children and adolescents who were perinatally infected with HIV, who were on study or enrolled after January 1996 in a United States-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C), and who were not receiving HAART at baseline; subjects were observed for a maximum of 10 years through June 2006. A weighted Cox regression model was used to estimate the effect of HAART on survival, appropriately adjusted for time-varying confounding by severity. RESULTS At the end of the 10-year follow-up period (median duration of follow-up, 6.3 years; interquartile range, 4.3-9.8 years), 70% of participants had initiated HAART. Lower CD4 cell percentages, total lymphocyte counts, and albumin levels were associated with an increased probability of initiating HAART. Eighty-five deaths were observed, and the mortality hazard ratio associated with HAART, compared with non-HAART regimens, was 0.24 after adjusting for measured confounding by severity (95% confidence interval, 0.11-0.51). CONCLUSIONS The use of HAART was highly effective in reducing mortality during the period 1996-2006 among children and adolescents infected with HIV. With improved long-term survival, continued follow-up is necessary to evaluate the effects of prolonged use of HAART on potential adverse events, immune function, growth, sexual maturation, and quality of life in this population.

Oral Acyclovir Suppression and Neurodevelopment after Neonatal Herpes

BACKGROUND Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Safety of the maternal–infant zidovudine regimen utilized in the Pediatric Aids Clinical Trial Group 076 Study

Objective:To determine the safety of the zidovudine (ZDV) regimen utilized in the Pediatric AIDS Clinical Trial Group (ACTG) 076 study. Design:ACTG 076 was a randomized, double-blind, placebo-controlled trial which demonstrated that a ZDV regimen could prevent mother-to-child HIV-1 transmission. Infants were followed through 18 months of age and women were followed through 6 months postpartum. Methods:Maternal complications, pregnancy outcomes, growth and development of the uninfected infants, and HIV-1 disease progression in the women were monitored prospectively. Results:Maternal therapy was well tolerated. There was no serious pattern of adverse pregnancy outcomes associated with ZDV use. Amongst the ZDV-exposed infants, the only recognized toxicity was anemia within the first 6 weeks of life; the risk for anemia was not associated with premature delivery, duration of maternal treatment, degree of maternal immunosuppression, or maternal anemia. ZDV treatment was not associated with an increased incidence of newborn structural abnormalities. At 18 months of age, uninfected infants did not differ in growth parameters or immune function. No childhood neoplasias were reported in either group. In the women, at 6 months postpartum, there were no differences in clinical, immunologic, or virologic disease progression. Conclusion:There were no identified problems that would alter current recommendations for the routine use of ZDV for the prevention of mother–child HIV-1 transmission.

In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children.

Background:There is equivocal evidence of in utero nucleoside reverse transcriptase inhibitor (NRTI) exposure and the occurrence of mitochondrial dysfunction (MD) in HIV-uninfected children born of HIV-infected women. Methods:The primary analysis included 1037 HIV-uninfected children born in 1991–2002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C. Possible cases with unexplained signs of MD according to the Enquête Périnatale Française criteria were identified through retrospective review. Associations between overall in utero NRTI exposure, and trimester of first in utero NRTI exposure and possible MD were estimated with exact logistic regression. Results:Cases (n = 20) were significantly more likely to be male and to be born in earlier years than non-cases (n = 1017). There was no association between overall in utero NRTI exposure and MD. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) [odds ratio (OR), 3.76 versus 3TC unexposed; 95% confidence interval (CI), 1.09–11.78] and to zidovudine (ZDV) and 3TC in combination (ZDV/3TC) (OR, 3.29 vs. ZDV/3TC unexposed; 95% CI, 0.96–10.25) among cases than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC (OR, 10.57; 95% CI, 1.93–75.61) and ZDV/3TC (OR, 9.84; 95% CI, 1.77–71.68) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use. Conclusions:Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed.

Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: Results of a phase I/II trial

BACKGROUND Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. METHODS Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. RESULTS Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. CONCLUSIONS Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.

The Ariel Project: A Prospective Cohort Study of Maternal-Child Transmission of Human Immunodeficiency Virus Type 1 in the Era of Maternal Antiretroviral Therapy

In a prospective cohort study, clinical and biologic factors that contribute to maternal-child transmission of human immunodeficiency virus type 1 (HIV-1) were studied. HIV-infected pregnant women and their infants were evaluated prospectively according to a standardized protocol. Of 204 evaluable women, 81% received zidovudine during their pregnancy. The infection rate among the 209 evaluable infants was 9.1%. By univariate analysis, histologic chorioamnionitis, prolonged rupture of membranes, and a history of genital warts were significantly associated with transmission. Additional factors associated with transmission that approached significance included a higher maternal virus load at delivery and the presence of cocaine in the urine. In a logistic regression model, histologic chorioamnionitis was the only independent predictor of transmission. Despite a significantly higher transmission rate at one site, no unique viral genotype was found at any site. Thus, chorioamnionitis was found to be the major risk factor for transmission among women receiving zidovudine.

Treating Opportunistic Infections among HIV-Exposed and Infected Children: Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America

In 2001, CDC, the National Institutes of Health, and the Infectious Diseases Society of America convened a working group to develop guidelines for therapy of human immunodeficiency virus (HIV)-associated opportunistic infections to serve as a companion to the Guidelines for Prevention of Opportunistic Infections Among HIV-Infected Persons. In recognition of unique considerations related to HIV infection among infants, children, and adolescents, a separate pediatric working group was established. Because HIV-infected women coinfected with opportunistic pathogens might be more likely to transmit these infections to their infants than women without HIV infection, guidelines for treating opportunistic pathogens among children should consider treatment of congentially acquired infections among both HIV-exposed but uninfected children and those with HIV infection. In addition, the natural history of opportunistic infections among HIV-infected children might differ from that among adults. Compared with opportunistic infections among HIV-infected adults, which are often caused by reactivation of pathogens acquired before HIV infection when host immunity was intact, opportunistic infections among children often reflect primary acquisition of the pathogen and, among children with perinatal HIV infection, infection acquired after HIV infection has been established and begun to compromise an already immature immune system. Laboratory diagnosis of opportunistic infections can be more difficult with children. Finally, treatment recommendations should consider differences between adults and children in terms of drug pharmacokinetics, dosing, formulations, administration, and toxicities. This report focuses on treatment of opportunistic infections that are common in HIV-exposed and infected infants, children, and adolescents in the United States.