Paul Palumbo

Failure of Antepartum Maternal Cultures to Predict the Infant's Risk of Exposure to Herpes Simplex Virus at Delivery

Abstract In 414 pregnant women with a history of recurrent genital herpes simplex infection, we studied the correlation between asymptomatic viral shedding in late pregnancy and at the time of delivery. Antepartum cultures for asymptomatic reactivation of herpes simplex virus were positive in 17 of the 414 women (4.1 percent). None of these women had positive cultures at the time of delivery. Cultures of specimens obtained at delivery from 5 of 354 asymptomatic mother–infant pairs (1.4 percent) were positive for asymptomatic excretion of herpes simplex virus. None of these women had had antepartum cultures that documented asymptomatic excretion of herpes simplex virus, despite the fact that culturing was repeatedly performed during the four weeks before delivery. Asymptomatic shedding of herpes simplex virus occurred with the same frequency at delivery, whether or not any episodes of symptomatic recurrence were noted during the pregnancy (1.4 vs. 1.3 percent). We conclude that antepartum maternal cultures...

Impact of zidovudine use on risk and risk factors for perinatal transmission of HIV

Objectives:To evaluate the impact of perinatal zidovudine use on the risk of perinatal transmission of HIV and to determine risk factors for transmission among women using perinatal zidovudine. Design:Prospective cohort study of 1533 children born to HIV-infected women between 1985 and 1995 in four US cities. Methods:The association of potential risk factors with perinatal HIV transmission was assessed with univariate and multivariate statistics. Results:The overall transmission risk was 18% [95% confidence interval (CI), 16–21]. Factors associated with transmission included membrane rupture > 4 h before delivery [relative risk (RR), 2.1; 95% CI, 1.6–2.7], gestational age < 37 weeks (RR, 1.8; 95% CI, 1.4–2.2), maternal CD4+ lymphocyte count < 500 × 106cells/l (RR, 1.7; 95% CI, 1.3–2.2), birthweight < 2500 g (RR, 1.7; 95% CI, 1.3–2.1), and antenatal and neonatal zidovudine use (RR, 0.6; 95% CI, 0.4–0.9). For infants exposed to zidovudine antenatally and neonatally, the transmission risk was 13% overall but was significantly lower following shorter duration of membrane rupture (7%) and term delivery (9%). The transmission risk declined from 22% before 1992 to 11% in 1995 (P < 0.001) in association with increasing zidovudine use and changes in other risk factors. Conclusions:Perinatal HIV transmission risk has declined with increasing perinatal zidovudine use and changes in other factors. Further reduction in transmission for women taking zidovudine may be possible by reducing the incidence of other potentially modifiable risk factors, such as long duration of membrane rupture and prematurity.

Distinct Risk Factors for Intrauterine and Intrapartum Human Immunodeficiency Virus Transmission and Consequences for Disease Progression in Infected Children

Predictors and prognosis of intrauterine and intrapartum human immunodeficiency virus (HIV) transmission were investigated among 432 children of HIV-infected women in the Perinatal AIDS Collaborative Transmission Study. Timing of transmission was inferred from polymerase chain reaction or viral culture within 2 days of birth. Proportions of infections due to intrauterine transmission were similar among women using (29%) or not using zidovudine (30%). Preterm delivery was strongly associated with intrapartum transmission (relative risk, 3.7; 95% confidence interval [CI], 2.2-6.1), particularly among infants delivered longer after membrane rupture, but was not associated with intrauterine transmission. Progression to AIDS or death increased 2.5-fold (95% CI, 1.1-5.8) among intrauterine infected children, adjusting for preterm delivery, and maternal CD4 cell count. Early transmission appears unlikely to explain instances of zidovudine failure. Preterm infants may be more vulnerable to HIV acquisition at delivery, especially if membrane rupture is prolonged. Intrauterine infection does not appear to increase risk of preterm delivery.

Sequelae of maternally derived cytomegalovirus infections in premature infants

Eighteen of 106 (17%) infants of seropositive mothers, with birth weights less than 1500 gm, acquired cytomegalovirus from a maternal source. Neutropenia, lymphocytosis, thrombocytopenia, and hepatosplenomegaly developed in some infants concomitant with the onset of CMV excretion. Infected infants who excreted CMV at less than 7 weeks of age had longer oxygen requirements than infants who did not excrete CMV until they were older. Passively derived maternal antibody to CMV fell more rapidly over the first few months of life in sick premature infants than would be expected in term infants. Among six infected premature infants, five had undetectable antibody titers when CMV excretion began. Loss of passively acquired antibody and early excretion of virus appear to be associated with symptomatic CMV infections in premature infants of seropositive mothers.

Viral measurement by polymerase chain reaction-based assays in human immunodeficiency virus-infected infants.

Serial samples from human immunodeficiency virus-infected infants in the first year of life were analyzed by quantitative human immunodeficiency virus polymerase chain reaction assays. Very high, persistent levels of plasma RNA and proviral DNA were detected throughout the study period, suggesting the absence of an effective immune response. Most patients had normal CD4 lymphocyte counts and were symptom free for the first 3 to 6 months despite high levels of viral replication. These findings support the evaluation of early intervention (before symptoms develop) and efforts to establish the predictive value of these assays.

Trends in Opportunistic Infections in the Pre–and Post–Highly Active Antiretroviral Therapy Eras Among HIV-Infected Children in the Perinatal AIDS Collaborative Transmission Study, 1986–2004

OBJECTIVE. We sought to determine the impact of highly active antiretroviral therapy on the incidence and prevalence of opportunistic infections in HIV-infected children. METHODS. Children born from 1986 to 1998 were monitored until 2004 in the Perinatal AIDS Collaborative Transmission Study, sponsored by the Centers for Disease Control and Prevention. We determined the pre–highly active antiretroviral therapy and post–highly active antiretroviral therapy (before and after January 1, 1997, respectively) incidence rates of opportunistic infections among HIV-infected children and characterized the temporal decreases in percentages of CD4+ cells and the mortality rates among patients with and those without incident opportunistic infections. RESULTS. The overall opportunistic infection incidence declined from 14.4 to 1.1 cases per 100 patient-years; statistically significant reductions were seen in the incidence of the most common opportunistic infections, including Pneumocystis jiroveci pneumonia (5.8 vs 0.3 cases per 100 patient-years), recurrent bacterial infections (4.7 vs 0.2 cases per 100 patient-years), extraocular cytomegalovirus infection (1.4 vs 0.1 cases per 100 patient-years), and disseminated nontuberculous mycobacterial infection (1.3 vs 0.2 cases per 100 patient-years). Kaplan-Meier analysis of time from birth to the first opportunistic infection illustrated more-rapid acquisition of opportunistic infections by HIV-infected children born in the pre–highly active antiretroviral therapy era than by those born later. In the first 3 years of life, there was a faster decline in the percentage of CD4+ cells among children with opportunistic infections. The mortality rate was significantly higher among children with opportunistic infections. CONCLUSIONS. Reduction in the incidence of opportunistic infections and prolongation of the time to the first opportunistic infection were noted during the post–highly active antiretroviral therapy era. Children who experienced opportunistic infections had higher mortality rates than did those who did not. Younger children (<3 years) who experienced opportunistic infections had faster declines in percentages of CD4+ T cells.

Dyslipidemia among perinatally HIV-infected children enrolled in the PACTS-HOPE cohort, 1999-2004: a longitudinal analysis.

Background: Protease inhibitor (PI)-containing regimens have led to improved survival among HIV-infected children. However, adverse effects, including dyslipidemia, may put children at risk for cardiovascular disease. Methods: Serum cholesterol and triglyceride levels were recorded on perinatally HIV-infected children participating in the PACTS-HOPE cohort (1999-2004). Hypercholesterolemia (HC) was defined as cholesterol ≥200 mg/dL and hypertriglyceridemia (HT) as triglycerides ≥150 mg/dL. HC and HT were modeled over time using generalized estimating equations. Results: For 178 children, 47% met criteria for HC and 67% for HT at least once during the study period. In generalized estimating equation models, PI use, undetectable viral load, and immunologic category 3 were independent predictors of HC. HT was significantly associated with PI use and body mass index (BMI) ≥90th percentile for age and gender. Among children on PI-containing regimens, HC was significantly associated with multiple PIs and undetectable viral load; HT was predicted by body mass index ≥90th percentile and ritonavir use. The prevalence of clinical lipodystrophy was 5.6% (10/178). Conclusions: Children on PI-containing regimens have a higher risk of both HC and HT. Lipid levels should be measured regularly in children on antiretroviral treatment. Interventions such as diet, exercise, or lipid-lowering drug therapy may benefit some children.

Quantitative RNA testing for diagnosis of HIV-infected infants.

Quantitative HIV RNA testing was used for diagnosis in 156 HIV-exposed non-breast-fed infants at less than 6 months of age (54 infected, 102 uninfected) enrolled in the Perinatal AIDS Collaborative Transmission Study. Sensitivity was 29% in the first week, 79% at 8 to 28 days of age, and >90% at 29 days of age and thereafter; specificity was 100% in all periods, except at 29 to 60 days of age, when specificity was 93%. Neither sensitivity nor specificity was significantly affected by maternal or infant zidovudine (ZDV) treatment, even though infant viral loads were lower during the first 6 weeks in infants who received perinatal ZDV prophylaxis (p = .005). Paired analysis of DNA and RNA measurements revealed no advantage for either test. Quantitative RNA testing can be used for diagnosis in HIV-exposed infants, recognizing the chance for a false-positive test result. It may be most useful as a confirmatory test in infants with another positive diagnostic test result.

Maternal versus paternal inheritance of HLA class I alleles among HIV-infected children: consequences for clinical disease progression

Objective: When children acquire HIV infection from their mothers (with whom they share at least 50% of their HLA alleles), they acquire virus with a history of encounter with maternal HLA-mediated immune responses. We investigated whether maternal HLA selection pressures on the virus would adversely influence clinical outcomes of HIV-infected children. Methods: We tested whether time to AIDS diagnosis or death, among a cohort of 59 HIV-infected children in New York City followed from birth for up to 12 years, was associated with maternally- or paternally-inherited child HLA class I alleles, and with HLA similarity between mother and child. Results: HIV-infected children with an HLA allele usually associated with slow disease experienced a slower progression to AIDS or death only if the allele was paternally inherited. If the allele was present in the mother, no association was observed. Children who were homozygous or who shared both alleles with their mothers at more than one HLA class I locus were more likely to progress to AIDS or death than other children (relative hazard, 3.46; 95% confidence interval, 1.24–9.71). Conclusion: Genetic similarity between mother and child may compromise the childs capacity to control HIV replication when the virus is acquired from the mother. HLA-mediated selective pressures on the virus in a transmitting mother–infant pair may undermine future HLA-mediated viral control in the child.

Trends in Bacteremia in the Pre- and Post-Highly Active Antiretroviral Therapy Era Among HIV-Infected Children in the US Perinatal AIDS Collaborative Transmission Study (1986–2004)

OBJECTIVE. HIV-infected children are at high risk for bacteremia. Highly active antiretroviral therapy has reduced rates of opportunistic infections; less is known about its effect on pediatric bacteremia rates. Thus, we sought to determine its impact on bacteremia incidence in HIV-infected children. METHODS. Children born during 1986–1998 were followed until 2004 in the Perinatal AIDS Collaborative Transmission Study. We determined the pre–and post–highly active antiretroviral therapy (before and after January 1, 1997) incidence of bacteremia among HIV-infected children and characterized the CD4% temporal declines and mortality among patients with and those without incident bacteremias. RESULTS. Among 364 children, 68 had 118 documented bacteremias, 97 before and 21 after January 1, 1997. Streptococcus pneumoniae constituted 56 (58%) pre–and 13 (62%) post–highly active antiretroviral therapy cases. The incidence rate ratio of bacteremias comparing post–versus pre–highly active antiretroviral therapy was 0.3 overall and 0.2, 0.2, and 0.4 among children aged 0 to 24, 25 to 48, and 49 to 72 months, respectively. Kaplan-Meier analysis for time to first bacteremia in children born during the pre–highly active antiretroviral therapy compared with the post–highly active antiretroviral therapy era revealed that 69% and 94%, respectively, remained bacteremia free at a median follow-up of 6 years. The Cox proportional hazards model also showed a significant reduction of bacteremias in the post–highly active antiretroviral therapy era, even after controlling for gender and race. Among children <6 years of age, those who experienced bacteremia had faster temporal CD4% decline than those who never had bacteremia. Survival analysis revealed that HIV-infected children with bacteremia experienced higher overall mortality when controlling for gender, race, and clinic site. CONCLUSIONS. A significant decrease in bacteremia incidence and a prolongation in the time to first bacteremia incident were seen in the post–highly active antiretroviral therapy era. Children with a steeper decline of CD4 T cells were more likely to develop bacteremia. Children who experienced bacteremia had an associated higher mortality than their bacteremia-free counterparts.