Peter E. Vink

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.

Vitamin A deficiency and maternal-infant transmission of HIV in two metropolitan areas in the United States

Objective: To determine whether vitamin A deficiency is associated with maternal-infant HIV transmission among HIV-infected pregnant women in two United States cities. Methods: Third trimester serum vitamin A levels were evaluated using high-performance liquid chromatography in 133 HIV-infected women who delivered livebirths during May 1986 to May 1994 and whose infants had known HIV infection status. Results: Sixteen per cent (seven out of 44) of the transmitting mothers and 6% (five out of 89) of the non-transmitting mothers had severe vitamin A deficiency (<0.70 μmol/l; P = 0.05). Maternal-infant transmission was also associated with prematurity <37 weeks gestation (P = 0.02), and Cesarean section delivery P = 0.04), CD4 percentage (p= 0.03) and marginally associated with duration of membrane rupture of ≥4 h (P= 0.06) by univariate analysis. In a multivariate logistic regression model, severe vitamin A deficiency (adjusted odds ratio (AOR), 5.05; 95% confidence interval (CI), 1.20-21.24), Cesarean section delivery (AOR, 3.75; 95% CI, 1.10-12.87), and prematurity (AOR, 2.25; 95%, CI, 1.22-4.13) were asscociated with transmission after adjusting for CD4+ percentage, and duration of membrane rupture. Conclusion: Increased risk of maternal-infant transmission was associated with severe vitamin A deficiency among non-breastfeeding women in these cohorts from the United States.

Comparison of the safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide vaccine in human immunodeficiency virus and non-human immunodeficiency virus-infected children

OBJECTIVE To compare the safety and immunogenicity of a 5-valent pneumococcal conjugate vaccine to a licensed 23-valent polysaccharide pneumococcal vaccine in HIV-infected and non-HIV-infected children > or = 2 years old. METHODS Thirty HIV-infected and 30 non-HIV-infected children > or = 2 years old were randomized to receive either a 5-valent pneumococcal conjugate vaccine (PCV) or a 23-valent pneumococcal polysaccharide vaccine (PPV) intramuscularly. Children who received PCV initially were given PPV after 6 weeks. Sera were obtained before and at 6 and 12 weeks after the first vaccination to determine IgG pneumococcal antibody titers by enzyme-linked immunosorbent assay to the 5 serotypes represented in the PCV. RESULTS Both vaccines were well-tolerated with no significant differences in the rates of fever (0 to 14%) or local reactions (0 to 40%) noted between PCV and PPV recipients. Pre-first vaccination geometric mean antibody titers (combined PCV and PPV recipients) to 3 of the 5 pneumococcal types tested were significantly lower in HIV-infected than in non-HIV-infected children (in microgram/ml: type 6B, 0.179 vs. 0.565; type 14, 0.026 vs. 0.060; type 23F, 0.025 vs. 0.119, respectively; P < 0.05). Fewer > or = 4-fold titer rises were observed in HIV vs. non-HIV-infected children whether they received PCV initially (60% vs. 79%, P < 0.05) or PPV (31% vs. 59%, P < 0.05). Also PCV elicited more > or = 4-fold titer rises compared with PPV in HIV-infected (60% vs. 31%, P < 0.05) and non-HIV-infected (79% vs. 59%, P < 0.05) children. No consistent antibody-boosting effect was noted in subjects who received PPV after PCV. CONCLUSIONS We conclude that antibody responses to natural infection, PCV and particularly PPV are poorer in HIV-infected than in non-HIV-infected children. PCV is as safe as and more immunogenic than the currently licensed PPV among HIV-infected and non-HIV-infected children.

Respiratory syncytial virus illnesses in human immunodeficiency virus- and noninfected children.

Respiratory syncytial virus (RSV) lower respiratory tract and febrile upper respiratory tract illnesses were prospectively assessed in cohorts of 83 infants born to human immunodeficiency virus (HIV)- and of 48 infants born to non-HIV-infected mothers. Of the infants born to HIV-infected mothers, 18 were themselves infected with HIV, 26 were indeterminant and 39 were free from HIV. Ten RSV illnesses occurred in 8 HIV-infected, 2 illnesses in 2 indeterminant and 17 illnesses occurred in 17 non-HIV-infected children. RSV shedding was prolonged in HIV class P2- vs. non-HIV-infected children, at medians of 30 days (range, 1 to 199 days) and 6 days (range, 1 to 21 days), respectively (P = 0.02). Ribavirin and intravenous immunoglobulin failed to eradicate RSV from one child who shed virus for 199 days. Wheezing occurred in 1 of 4 vs. 9 of 10 episodes of lower respiratory tract illness in HIV-infected and non-HIV-infected children, respectively (P = 0.04). No differences were noted in duration of illness, temperature, respiratory rate or oxygen saturation between HIV- and non-HIV-infected children. Infection control and public health concerns regarding prolonged shedding of RSV in HIV-infected children must be recognized.

Invasive pneumococcal disease among infected and uninfected children of mothers with human immunodeficiency virus infection

OBJECTIVE To describe the incidence and clinical presentation of invasive pneumococcal disease in a cohort of children infected with human immunodeficiency virus (HIV) who were prospectively followed from birth, in comparison with uninfected children born to HIV-infected mothers and control children. DESIGN Prospective follow-up of a cohort recruited at birth and born to mothers with known HIV status. The person-years analysis method used the occurrence of invasive pneumococcal disease as the end point. SETTING Hospital-based clinic specializing in care of HIV-at-risk and HIV-infected children in Baltimore, Md. PARTICIPANTS Forty-one vertically HIV-infected children, 128 uninfected children born to HIV-infected mothers, and 71 control children born to mothers with negative findings for HIV but with HIV risk factors. RESULTS Among HIV-infected children, 10 episodes of invasive pneumococcal disease occurred during the first 36 months of life compared with 4 episodes among uninfected children and 1 episode among control subjects. The relative risk for HIV-infected children versus the combined uninfected and control groups was 12.6 with a 95% confidence interval (5.4, 28.8) and a p value for difference between groups of < 0.001. The incidence rate per 100 child-years of observation during the first 36 months of life was 11.3 for HIV-infected, 1.1 for uninfected, and 0.5 for control children. Clinical and laboratory variables were not useful in identifying HIV-infected children at risk for pneumococcal disease. CONCLUSION Practical strategies to prevent pneumococcal disease among HIV-infected children need to be developed.

Thymic Dysfunction and Time of Infection Predict Mortality in Human Immunodeficiency Virus-Infected Infants

The effect of human immunodeficiency virus (HIV)-induced thymic dysfunction (TD) on mortality was studied in 265 infected infants in the CDC Perinatal AIDS Collaborative Transmission Study. TD was defined as both CD4 and CD8 T cell counts below the 5th percentile of joint distribution for uninfected infants within 6 months of life. The 40 HIV-infected infants with TD (15%) had a significantly greater mortality than did the 225 children without TD (44% vs. 9% within 2 years). Infants with TD infected in utero had higher mortality than did those infected intrapartum (70% vs. 37% within 2 years), while no significant difference was noted between infants without TD with either mode of transmission. The TD profile was independent of plasma virus load. Virus-induced TD by particular HIV strains and the time of transmission are likely to explain the variation in pathogenesis and patterns of disease progression and suggest the need for early aggressive therapies for HIV-infected infants with TD.

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.

Antiretroviral Resistance Mutations among Pregnant Human Immunodeficiency Virus Type 1–Infected Women and Their Newborns in the United States: Vertical Transmission and Clades

To assess the impact of antiretroviral resistance on perinatal transmission prevention efforts, human immunodeficiency virus type 1 (HIV-1) genotypic resistance testing was done for 220 HIV-1-infected, zidovudine (AZT)-exposed pregnant women and 24 of their infected infants. The women were prospectively enrolled in 4 US cities in 1991-1997. Phylogenetic and sequencing analyses revealed 5 women with non-clade B infections traced to western African origins. AZT-associated mutations were detected in 17.3% of pregnant women, whereas genotypic resistance to nonnucleoside reverse-transcriptase inhibitors and protease inhibitors was infrequent. No significant association was detected between perinatal transmission and the presence of either AZT or nucleoside reverse-transcriptase inhibitor resistance-associated mutations. AZT resistance mutations were detected in 2 (8.3%) neonatal samples, but the mutation pattern was not identical to the mothers. Although no effect of viral resistance on mother-infant transmission was demonstrated, the advent of more-potent drug classes and the potential for the rapid emergence of resistance warrant prospective surveillance.

Antibody titers eight months after three doses of a five-valent pneumococcal conjugate vaccine in HIV and non-HIV-infected children less than two years of age.

The objective of this study was to examine vaccine type-specific antibody titers eight months after a five-valent pneumococcal conjugate vaccine (PCV) in human immunodeficiency virus (HIV) and non-HIV-infected children under two years of age. Sixteen HIV-infected and 14 non-HIV-infected children under two years of age, and of similar age, race and sex distribution, received three doses (separated by two months each) of a five-valent oligosaccharide PCV (types 6B, 14, 18C, 19F, and 23F separately coupled to diphtheria CRM197). An additional 11 non-HIV-infected children, of similar demographic distribution to the PCV groups, received three doses of saline placebo. sera were collected just prior to, and at one and eight months after the three study drug doses. Serum vaccine type-specific pneumococcal IgG antibodies were measured by enzyme-linked immunoabsorbant assay (ELISA). There was an impressive rise in antibody titers pre- to one month post-third PCV in both the HIV (58-970-fold) and non-HIV-infected (19-553-fold) children. There was a rapid and similar drop in antibody titers eight months after the PCV series for both HIV (range 69-87% drop) and non-HIV-infected (range 57-79% drop) subjects respectively. However, 46% of the antibody titers from HIV-infected children and 62% of the titers from non-HIV-infected children were still > 1.0 microgram ml-1 compared to placebo recipients for whom only 5% of the titers were > 1.0 microgram ml-1 (p < 0.05). At the eight month post-PCV series blood draw, there were no significant differences in the GMTs, the percent drop in titers, or proportion of titers > 1.0 microgram ml-1 between the five HIV-infected children who had advanced (CDC class: N3, A3, B2-3, C1-3) compared to the 11 children with mild (CDC class: N1-2, A1-2, B1) HIV disease at the time of their first PCV dose. Eight months after the PCV series, the proportion of titers (combined all five serotypes) > 1.0 microgram ml-1 was slightly, but significantly, lower for HIV-infected subjects (46%) compared to non-HIV-infected subjects (62%) (p < 0.05). These data are helpful in describing the kinetics of antibody responses to pneumococcal conjugate vaccines in both HIV and non-HIV-infected young children.

Disease Progression and Early Viral Dynamics in Human Immunodeficiency Virus-Infected Children Exposed to Zidovudine during Prenatal and Perinatal Periods

Zidovudine (Zdv) is widely used to reduce maternal-infant human immunodeficiency virus transmission (HIV), but its consequences for disease progression among children infected despite Zdv exposure remain unknown. In a multicenter observational cohort study of 325 HIV-infected children born during 1986-1997, clinical progression was compared among infected children exposed or unexposed to Zdv during prenatal and perinatal periods. Zdv exposure was associated with 1.8-fold (95% confidence interval, 1.02-3.11) increased risk of progressing to AIDS or death after adjusting for year of birth, maternal CD4 cell count, maternal AIDS diagnosis, and subsequent antiretroviral therapy of the child. Mean log(10) viral copies at 7-12 weeks were higher among Zdv-exposed children (P=.004). No infected child treated early with multidrug therapy progressed to AIDS or died by 1 year, regardless of early Zdv exposure. More rapid disease progression was observed among infected children exposed during pregnancy or birth to Zdv if effective multidrug therapy was not initiated.