Risk of early febrile seizure with perinatal exposure to nucleoside analogues.

The frequency of seizures was studied in a prospective cohort of French children born to HIV-1-infected mothers. The analysis was restricted to the 4426 uninfected children, whether or not exposed to antiretrovirals. 81 convulsions were reported up to the age of 18 months, and 30 children fulfilled the criteria for simple febrile seizures. The risk of first febrile seizure was higher for children perinatally exposed to antiretrovirals than for those not exposed (log-rank test: p=0.0198). A similar trend was noted for other non-neonatal seizures (p=0.0537) but not for neonatal seizures.

Reproductive behaviour of HIV-infected women living in France, according to geographical origin.

Pregnancy rates were compared before and after HIV diagnosis according to geographical origin (sub-Saharan Africa versus Europe) among 533 HIV-infected women followed in the French SEROCO/SEROGEST cohorts between 1988 and 1996. Among European women, the incidence of deliveries and terminations decreased, respectively, by nearly twofold and fourfold after HIV diagnosis. Conversely, the pregnancy incidence increased among African women with fewer than two children. This study should help refine the reproductive counselling and management of HIV-infected women in France.

Zidovudine genotypic resistance in HIV-1-infected newborns in the French perinatal cohort.

A retrospective study was set up to investigate the frequency of zidovudine (ZDV)-resistant HIV-1 in infected newborns after ZDV prophylaxis in the French Perinatal Cohort study. Nucleotide sequence analysis was carried out from 34 infants' isolates and 18 maternal plasma samples. Mutations related to ZDV resistance were found in the HIV-1 reverse transcriptase in 7 of 34 children (20%). Evidence of mother-child transmission of ZDV-resistant HIV-1 was found in 4 cases. Phylogenetic analysis showed that 14 of 34 HIV-1 isolates from the infants belonged to non-B subtypes. The presence of ZDV resistance-encoding mutations in the newborn isolates was associated with a longer total duration of exposure to ZDV. In a context of a wide HIV-1 variability, ZDV resistance can be one of the factors contributing to mother-child transmission.

Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1.

CONTEXT: Zidovudine reduces maternal-infant transmission of human immunodeficiency virus 1 (HIV-1) infection by two thirds. Combination antiretroviral therapies are potentially more effective prevention. OBJECTIVES: To assess the safety of perinatal lamivudine-zidovudine therapy, especially in children, and its effects on viral load, acquisition of drug resistance, and maternal-infant transmission of HIV-1 in a nonbreastfeeding population. DESIGN AND SETTING: The Agence Nationale de Recherches sur le SIDA (ANRS) 075 Study, an open-label, nonrandomized intervention trial conducted in the context of an ongoing observational cohort study in 48 sites in France. PATIENTS: A total of 445 HIV-1-infected pregnant women were enrolled as the study cohort from February 1997 to September 1998; controls consisted of 899 pregnant women who had received zidovudine monotherapy in May 1994 to February 1997 as standard care. INTERVENTION: The study cohort received lamivudine in addition to the standard Pediatric AIDS Clinical Trial Group 076 Study zidovudine prophylaxis regimen. Lamivudine was initiated in women at 32 weeks' gestation through delivery at 150 mg twice per day orally; children received lamivudine, 2 mg/kg twice per day for 6 weeks. MAIN OUTCOME MEASURES: HIV-1 infection status and tolerance of therapy in children through age 18 months; maternal plasma HIV-1 RNA levels through 6 weeks after delivery. RESULTS: The transmission rate in the study group was 1.6% (7/437; 95% confidence interval [CI], 0.7%-3.3%). In a multivariable analysis, transmission in the study group was 5-fold lower than in controls. In the study group, maternal plasma HIV-1 RNA level was less than 500 copies/mL at delivery in 74%; the median decrease was 1.24 (range, -1.63 to 3.40) log(10) copies/mL. The M184V lamivudine resistance mutation was detected at 6 weeks after delivery in specimens from 52 of 132 women. The most frequent serious adverse events in children were neutropenia and anemia, requiring blood transfusion in 9 children and premature treatment discontinuation in 19. Two uninfected children died at age 1 year from neurologic complications related to mitochondrial dysfunction. CONCLUSIONS: Lamivudine-zidovudine may be effective in preventing maternal-infant HIV transmission. However, severe adverse effects and emergence of resistance to lamivudine occurred. Thus, the role of this combination therapy in this setting is as yet unclear, and further research involving a variety of strategies is needed to definitively ascertain its utility for preventing maternal-infant HIV transmission.

Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml.

In a collaboration of 7 European and United States prospective studies, 44 cases of vertical human immunodeficiency virus type 1 (HIV-1) transmission were identified among 1202 women with RNA virus loads <1000 copies/mL at delivery or at the measurement closest to delivery. For mothers receiving antiretroviral treatment during pregnancy or at the time of delivery (or both), there was a 1.0% transmission rate (8 of 834; 95% confidence interval [CI], 0.4%-1.9%), compared with 9.8% (36 of 368; 95% CI, 7.0%-13.4%) for untreated mothers (risk ratio, 0.10; 95% CI, 0.05-0.21). In multivariate analysis adjusting for study, transmission was lower with antiretroviral treatment (odds ratio [OR], 0.10; P<.001), cesarean section (OR, 0.30; P=.022), greater birth weight (P=.003), and higher CD4 cell count (P=.039). In 12 of 44 cases, multiple RNA measurements were obtained during pregnancy or at the time of delivery or within 4 months after giving birth; in 10 of the 12 cases, the geometric mean virus load was >500 copies/mL. Perinatal HIV-1 transmission occurs in only 1% of treated women with RNA virus loads <1000 copies/mL and may be almost eliminated with antiretroviral prophylaxis accompanied by suppression of maternal viremia.

Pregnancy and progression to AIDS: results of the French prospective cohorts. SEROGEST and SEROCO Study Groups.

OBJECTIVE: To investigate whether pregnancy accelerates HIV-1 disease progression. METHOD: In two large French SEROCO and SEROGEST prospective cohorts of HIV infected patients, the progression to AIDS in 365 women with a known date of HIV-1 seroconversion was examined by comparing those who delivered after HIV infection (n = 241) with those who did not become pregnant while HIV-infected (n = 124). RESULTS: The crude relative risk of developing AIDS associated with pregnancy was 0.7 [95% confidence interval (CI), 0.4-1.2]. Adjustment for age at seroconversion, the CD4+ cell percentage at entry, and the method used to date seroconversion did not modify the results (adjusted relative risk, 0.7; 95% CI 0.4-1.2). CONCLUSIONS: No deleterious effect of pregnancy on progression from seroconversion to AIDS was found. This result has important implications for the counselling of HIV-infected women of child-bearing age.

HIV-1-related encephalopathy in infants compared with children and adults. French Pediatric HIV Infection Study and the SEROCO Group.

OBJECTIVE: To characterize the specificities of HIV-1-related encephalopathy in children. METHODS: Comparison of patients from the French Perinatal Cohort of children born to HIV-1-infected mothers and followed from birth with the French SEROCO Cohort of adults with a known date of infection. Our study examines 1) the characteristics of encephalopathy with onset before 1 year, after 1 year, and in adults, and 2) the maternal and birth characteristics of infants who developed AIDS before 1 year and went on to develop either encephalopathy or opportunistic infection. RESULTS: The incidence of encephalopathy was higher in children than in adults during the first year (9.9% versus 0.3%) and intermediate during the second year (4.2% versus 0%) after infection but was similar thereafter (less than 1% per year in each group). The resulting cumulative incidence at 7 years postinfection reached 16% in children and 5% in adults. Encephalopathy that developed before 1 year 1) was more frequently an isolated symptom of AIDS, 2) was associated with a reduction of intrauterine brain growth, 3) was associated with a very low level of HIV-1 RNA in CSF, 4) occurred at a higher level of immunocompetence after taking into account the decrease in CD4 lymphocytes with age, and 5) was not prevented by zidovudine treatment during gestation. CONCLUSIONS: Early encephalopathy in infants has a different pathophysiologic mechanism than that occurring in children, which in turn shows similarities with that observed in adults. Early encephalopathy is probably related to the occurrence of pathologic events during late fetal life.

Frequent detection of HIV-1 in the gastric aspirates of neonates born to HIV-infected mothers.

OBJECTIVE: To evaluate the frequency and correlates of oral route exposure of infants born to HIV-1-infected women. METHODS: A multicenter study was performed within the prospective French Perinatal Cohort Study of mother-to-child HIV transmission. Oropharyngeal and gastric aspirates from 122 neonates were studied by reverse transcriptase (RT) polymerase chain reaction (PCR) for the presence of HIV-1, as well as for standard microbiology (Gram staining and culture). RESULTS: Aspirates from 101 neonates were analyzed by RT-PCR; 28% of these were positive for HIV RNA. Another 21 aspirates could not be tested because of PCR inhibition. The median concentration of HIV RNA in the positive aspirates was 126 copies/ml (range: 8-1270). Detection of HIV-1 in the aspirate was significantly related to high maternal plasma-viral load, presence of blood in the aspirate, positive Gram stain or culture, episiotomy or perineal lesions, and sexually transmitted infections during the pregnancy. Most of the mothers received zidovudine prophylaxis during pregnancy and delivery. Among the six infants who were infected with HIV, three had positive aspirates. Of the three assumed to have acquired the infection intrapartum, only one had an HIV RNA-positive aspirate. CONCLUSION: Exposure of the fetus to HIV via the oral route occurs frequently, even in the presence of zidovudine prophylaxis, and is likely to be one of the mechanisms of intrapartum transmission, but not the only one.

Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.

BACKGROUND: Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth. METHODS: We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues. FINDINGS: Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient. INTERPRETATION: Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.

CCR5 delta32 deletion and reduced risk of toxoplasmosis in persons infected with human immunodeficiency virus type 1. The SEROCO-HEMOCO-SEROGEST Study Groups.

This study attempted to determine whether the CCR5 Delta32 deletion affected progression to certain first AIDS-defining illnesses in human immunodeficiency virus type 1-infected patients enrolled in the French SEROCO/HEMOCO/SEROGEST cohorts. Toxoplasmosis onset as a first AIDS-defining illness was significantly delayed in 253 heterozygous patients, compared with 1404 wild type patients. The relative risk of toxoplasmosis associated with heterozygosity was 0. 39 (95% confidence interval, 0.16-0.96) after adjustment for age, CD4 cell count, and primary specific prophylaxis. A nonsignificant protective trend was observed with regard to the onset of mycobacterial, cytomegalovirus, and herpesvirus diseases, but these events were less frequent than toxoplasmosis. Progression to other conditions (e.g., wasting, non-Hodgkin's lymphoma, Kaposi's sarcoma) was similar in the 2 groups as was the frequency of toxoplasmosis as a subsequent AIDS-defining illness. As chemokines are involved in numerous infectious processes, the Delta32 deletion could delay progression to certain opportunistic infections such as toxoplasmosis.

Timing of human immunodeficiency virus type 1 (HIV-1) transmission from mother to child: bayesian estimation using a mixture.

The timing of mother-to-child HIV transmission is not directly observable but influences the infected child's viral and immune status in the neonatal period. A hierarchical model was developed in a Bayesian framework to 'back-calculate' the timing of HIV-1 transmission from mother to child from the virological and immunological kinetics in the infected infant. Joint evolution of viral markers and immune response was modelled as a continuous time Markov process. The modelling of the period from infection to birth was based on a mixture of three distributions taking into account the various mother-to-child transmission pathways: In utero (early or late in gestation) and intrapartum (during the delivery process), integrating the fact that transmission is a continuum during the pregnancy. Gibbs sampling was used to estimate the marginal posterior distributions of the transition intensities between stages of HIV infection and those of the individual times from infection to birth. We applied our model to data on 135 perinatally HIV-1-infected children included in the French Prospective Study on Pediatric HIV infection. The model suggested that transmission occurred late in utero during the last month of pregnancy and that the day of delivery was a particularly critical time in HIV-1 transmission from mother to child. The paper ends with a discussion of model assumptions and a comparison with results obtained using a non-parametric method.

CCR2B-64I chemokine receptor allele and mother-to-child HIV-1 transmission or disease progression in children. French pediatric HIV infection study group.

The beneficial role of a variant of the chemokine receptor CCR2B (CCR2B-641) in the evolution of HIV-1 infection in adults is still controversial. Furthermore, no studies have been performed in HIV-1-infected children. A multicenter and prospective study of 745 infants born to HIV-1-seropositive mothers was performed. The CCR2B-641 allele was studied in 525 non-African children among whom 523 had been previously genotyped for the CCR5delta32 allele and 220 African children. Of the 745 total, 376 children were infected and 369 were uninfected. In the complete population studied, the children homozygous for the CCR2B-64I allele and the heterozygous children were found distributed equally in the infected (respectively, 1.6% and 21%) and uninfected (respectively, 1.9% and 26.3%) groups (p < .22). Among 376 infected children, the incidence of stage C symptoms (U.S. Centers for Disease Control and Prevention [CDC] classification) or the progression of severe immune deficiency (CD4 <15%, CDC stage 3) was not significantly different in heterozygous infected children or children homozygous for the normal allele (p < .17 and p < .75, respectively). The same lack of protective effect was obtained when a separate analysis was performed in the non-African and African HIV-1-infected children.

Early HIV-specific cytotoxic T lymphocytes and disease progression in children born to HIV-infected mothers.

The activities of HIV-specific cytotoxic T lymphocytes (CTLs) were evaluated in 10 HIV-infected children, born to infected mothers who did not receive AZT during pregnancy. CTL activities were present as early as 4 months of age. The five children that progressed to AIDS before 1 year of age had reduced in vivo and in vitro CTL activities, when compared with children who remained AIDS free after 1 year of age. The latter children had weak in vivo activated CTL responses but strong memory CTLs. No relation was found between viral load, lymphocyte populations, and CTL responses between birth and 6 months of age. Between 7 and 12 months old, children with broader in vitro activated CTLs had higher absolute numbers of CD4+ and CD8+ T lymphocytes and lower plasma viral load. These data support a beneficial role of CTLs in pediatric HIV infection.

Impact of heterozygosity for the chemokine receptor CCR5 32-bp-deleted allele on plasma virus load and CD4 T lymphocytes in perinatally human immunodeficiency virus-infected children at 8 years of age.

The CCR5 gene encodes one of the major human immunodeficiency virus type 1 (HIV-1) coreceptors. A 32-bp deletion in this gene (delta ccr5) is associated with relative resistance to disease progression in heterozygous HIV-1-infected persons. The effect of this mutation on virologic and immunologic parameters was determined in a cohort of 45 perinatally HIV-1-infected children prospectively followed after 5 years of age. At a median age of 8.3 years, heterozygous children had significantly lower virus load than homozygous children (median, 3.3 vs. 4.1 log copies/mL, P < .009) and higher percentages of CD4 T cells (median, 26% vs. 17%, P < .07). However, there was no discernible influence of the CCR5 genotype on the percentages of CD8 T cells (P < .27) or on HIV-specific cytotoxic T lymphocyte activities (P < .65). There was a trend for lower rates of progression to AIDS (CDC stage C) in heterozygous children. These data confirm a major role for the CCR5 coreceptor in HIV-1 pathogenesis in children.

Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort.

CONTEXT: It is unclear whether elective cesarean delivery may have a protective effect against the transmission of human immunodeficiency virus 1 (HIV-1). OBJECTIVE: To investigate whether mode of delivery has an impact on perinatal HIV-1 transmission in the presence of zidovudine prophylaxis. DESIGN: A prospective cohort study. SETTING: The 85 perinatal centers in the French Perinatal Cohort, from 1985 to 1996. PATIENTS: A total of 2834 singleton children born to mothers with HIV-1 infection. MAIN OUTCOME MEASURE: Human immunodeficiency virus 1 infection of the infant. RESULTS: No zidovudine was used in 1917 pregnancies and zidovudine prophylaxis was used in 902 pregnancies. Cesarean deliveries were performed in 10.9% on an emergent basis and in 8.3% electively, prior to labor or membrane rupture. In 1917 mothers who did not receive zidovudine, of 1877 with information on mode of delivery, 17.2% transmitted HIV-1 to their child. Risk factors statistically significantly associated with transmission were maternal p24 antigenemia, cervicovaginal infections during pregnancy, amniotic fluid color, and rupture of membranes 4 hours or more before delivery. Mode of delivery was not related to transmission. In 902 mothers receiving zidovudine, transmission was 6.4% in 872 with information on mode of delivery, and elective cesarean delivery (n = 133) was associated with a lower transmission rate than emergent cesarean or vaginal delivery (0.8%, 11.4%, and 6.6%, respectively; P=.002). In a multivariate analysis of all mother-child pairs, including obstetrical risk factors, maternal p24 antigenemia, and zidovudine prophylaxis, interaction between mode of delivery and zidovudine prophylaxis was significant (P=.007). In the multivariate analysis of pregnancies with zidovudine prophylaxis, factors related to transmission rate were maternal p24 antigenemia, amniotic fluid color, and mode of delivery. Adjusted odds ratios (95% confidence intervals) were 1.6 (0.7-3.6) for emergent cesarean delivery and 0.2 (0.0-0.9) for elective cesarean delivery (P = .04) in comparison with vaginal delivery. CONCLUSIONS: We observed an interaction between zidovudine prophylaxis and elective cesarean delivery in decreasing transmission of HIV-1 from mother to child. This observation may have clinical implications for prevention.

CCR5 chemokine receptor variant in HIV-1 mother-to-child transmission and disease progression in children. French Pediatric HIV Infection Study Group.

CONTEXT: Studies suggest that adults with the CCR5delta32 deletion are less likely to become infected with the human immunodeficiency virus (HIV) and to develop HIV-related disease progression, but the effect of the mutation in children is not known. OBJECTIVE: To study the effect of the CCR5 chemokine receptor mutant allele on mother-to-child transmission of HIV type 1 (HIV-1) and subsequent disease progression in infected children. DESIGN: Multicenter, prospective study of infants born to mothers seropositive for HIV-1. SETTING: A total of 52 medical centers participating in the French Pediatric HIV Cohort studies. PARTICIPANTS: The CCR5delta32 deletion was studied in 512 non-African children, born between 1983 and 1996 to HIV-1-infected mothers. Among them, 276 children were infected and 236 were not. MAIN OUTCOME MEASURES: HIV-1 infection status and, in infected children followed up since birth, incidence of category B and C disease events and severe immunosuppression as defined in the new pediatric Centers for Disease Control and Prevention (CDC) classification, according to CCR5 genotype. RESULTS: The 32-base pair deleted allele was detected at a frequency of 0.05. Only 1 infant, not infected by HIV-1, was homozygous for the delta32 deletion. The 49 heterozygous children (9.6% of the total; 95% confidence interval [CI], 7.1-12.2) were equally distributed into the infected (9.8%) and uninfected (9.3%) groups. The incidence of stage C symptoms in heterozygous infected children was 9% at 36 months vs 28% in children homozygous for the normal allele (P<.004). The proportion of children at 8 years old with no stage B or C symptoms was 49% for heterozygous children and 11% for children homozygous for the normal allele (P<.003). The progression of severe immune deficiency (CD4 <15%, CDC stage 3) was also significantly different between the 2 groups (P<.001). CONCLUSIONS: Heterozygosity for the CCR5delta32 deletion does not protect children from infection by the maternal virus but substantially reduces the progression of the disease in HIV-1-infected children.