Ghislaine Firtion

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.

A prospective study of infants born to women seropositive for human immunodeficiency virus type 1.

Assessment of the risks of transmission of infection with human immunodeficiency virus type 1 (HIV-1) from mother to newborn is difficult, partly because of the persistence for up to a year of maternal antibodies transmitted passively to the infant. To determine the frequency of perinatal transmission of HIV infection, we studied from birth 308 infants born to seropositive women, 62 percent of whom were intravenous drug abusers. Of 117 infants evaluated 18 months after birth, 32 (27 percent) were seropositive for HIV or had died of the acquired immunodeficiency syndrome (AIDS) (n = 6); of the 32, only 2 remained asymptomatic. Another 76 infants (65 percent) were seronegative and free of symptoms, whereas 9 (8 percent) were seronegative but had symptoms suggestive of HIV-1 infection. The infants infected with HIV-1 did not differ from the others at birth with respect to weight, height, head circumference, or rate of malformations, but as compared with newborns who were seronegative at 18 months, their serum IgM levels were higher (78 +/- 81 mg per deciliter vs. 38 +/- 39 mg per deciliter; P less than 0.03) and their CD4 lymphocyte counts were lower (2054 +/- 1221 per cubic millimeter vs. 2901 +/- 1195 per cubic millimeter; P less than 0.006). Neither maternal risk factors nor the route of delivery was a predictor of seropositivity at 18 months; however, 5 of the 6 infants who were breast-fed became seropositive, as compared with 25 of 99 who were not (P less than 0.01). We conclude that approximately one third of the infants born to seropositive mothers will have evidence of HIV-1 infection or of AIDS by the age of 18 months, and that about one fifth of this group will have died.

Relation of the course of HIV infection in children to the severity of the disease in their mothers at delivery

Background Among infants with maternally transmitted human immunodeficiency virus (HIV) infection, there are two patterns of disease progression. In about a fifth of these infants there is a rapid progression to profound immunodeficiency, whereas in the majority the disease progresses much more slowly. Methods We studied the clinical and biologic characteristics of the mothers of infants infected with HIV type 1 (HIV-1) in the French Prospective Multicenter Cohort. Infection in the children was confirmed by serologic tests at the age of 18 months or by death from the acquired immunodeficiency syndrome at an earlier age. Only the 162 infected infants who could be followed for at least 18 months or until death were included in the analysis. Results The risk of opportunistic infections or encephalopathy in the first 18 months was 50 percent in the infants of mothers with class IV disease, according to the Centers for Disease Control and Prevention classification, and 14 percent in the infants of mothers with...

Early versus Deferred Antiretroviral Multidrug Therapy in Infants Infected with HIV Type 1

BACKGROUND The clinical impact of early antiretroviral multidrug therapy on the risk of early-onset severe human immunodeficiency virus (HIV) disease has not been evaluated on a large scale. METHODS We evaluated the risk of early-onset events associated with acquired immunodeficiency syndrome (AIDS), particularly the risk of encephalopathy, among infants in the French Perinatal Cohort, according to whether antiretroviral multidrug therapy was initiated before or after the age of 6 months. RESULTS Of 83 HIV-infected infants born in 1996 (when HAART became available) or later, 40 received early treatment on or before the age of 6 months, and 43 received deferred multidrug therapy after the age of 6 months. In the group that received early multidrug therapy, no child developed an opportunistic infection or an encephalopathy during the first 24 months of life. In the deferred multidrug therapy group, 6 infants presented with a total of 7 AIDS-associated events (P=.01), 3 of which were encephalopathies (P=.08). The small number of events prevented the identification of clinical and biological markers that accurately predict progression of early-onset severe HIV disease. CONCLUSION In this observational study, infants who received multidrug therapy before 6 months of age did not have the early-onset severe form of childhood HIV disease. Further studies are needed to find accurate early markers of disease progression in this age group.

Maternal-Fetal Transfer and Amniotic Fluid Accumulation of Nucleoside Analogue Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pregnant Women

ABSTRACT This study was performed to investigate placental transfer of nucleoside analogue reverse transcriptase inhibitors (NRTIs) and their concentrations in amniotic fluid when given to human immunodeficiency virus (HIV)-infected pregnant women. A total of 100 HIV type 1-infected mothers receiving antiretroviral therapy, including one or more NRTIs, for clinical indications at the time of delivery were enrolled. Maternal blood samples and amniotic fluid were obtained during delivery or cesarean section, and paired cord blood samples were obtained by venipuncture immediately after delivery. Drug concentrations were measured by using high-performance liquid chromatography. A significant relationship between concentrations in maternal and cord plasma samples was found for zidovudine, lamivudine, stavudine, and didanosine. The ratio between the concentrations in cord and maternal plasma samples (R) was high for zidovudine (R = 1.22), its glucuronide metabolite (3′-azido-3′-deoxythymidine-β-d-glucuronide) (R = 1.01), stavudine (R = 1.32), lamivudine (R = 0.93), and abacavir (R = 1.03) and was low for didanosine (R = 0.38). The ratio between the concentrations in amniotic fluid and cord plasma samples was high for zidovudine (R = 2.24), its glucuronide metabolite (R = 2.83), stavudine (R = 4.87), and lamivudine (R = 3.99) and was lower for didanosine (R = 1.14). These findings indicate that most NRTIs cross the placenta by simple diffusion and are concentrated in the amniotic fluid, probably through fetal urinary excretion. The efficacy or toxicity of NRTIs may vary according to placental transfer.

Maternal Factors Associated with Perinatal Hiv-1 Transmission: The French Cohort Study

A nationwide, longitudinal study of infants born to human immunodeficiency virus-seropositive mothers has been under way in France since 1986. After 7 years of follow-up observations, we will update our assessment of the transmission rate in France and analyze, on a larger number of mother-infant pairs, the influence of maternal factors. Among the 848 pairs included in this analysis, the transmission rate was 20.2 +/- 2.7%. The transmission rate has remained stable with time and was not influenced by the mode of delivery, the mode of maternal infection, or the mothers ethnic origin. It was twice as high among the breast-fed infants as among the bottle-fed infants (40 vs. 19%, p < 0.04). Two factors were identified in a multivariate analysis (that did not include lymphocyte subset counts and the mode of feeding) as being associated with an increased risk of maternofetal transmission: p24 antigenemia (odds ratio = 3.1, confidence interval, = 1.5-6.2; p < 0.003) and elevated maternal age (p < 0.05). In the subgroup of 277 women whose absolute CD4+ lymphocyte counts at the time of delivery were available, the risk of transmission increased gradually from 15% of counts of > 600 CD4+ cells to 43% at counts of < 200. The risk of transmission was also related to the percentage of CD8+ cells, but each of the two factors seemed to play an independent role: the risk was lowest (12%) when the CD4+ cell count was > 500 and the proportion of CD8+ cells was < or = 40%, and was highest (50%) for values < 200 and > 40%.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Early multitherapy including a protease inhibitor for human immunodeficiency virus type 1-infected infants.

Background. To assess tolerance and efficacy of early multitherapy including a protease inhibitor for infants perinatally infected with HIV. Methods. Observational study of tolerance and clinical and immunovirologic evolution in HIV-infected infants treated before the age of 1 year in the French Perinatal Study. Results. Thirty-one infants were included. The median age was 3.7 months at initiation of multitherapy. Clinical stage was C (n = 8), B (n = 5) or A/N (n = 18). The median HIV RNA viral load was 5.8 log copies/ml, and the median CD4 cell percentage was 29%. Median follow-up of treatment was 27 months. Of 31 infants 15 experienced mild to moderate adverse events. No infant had clinical or immunologic progression. The median change in viral load was −2.7 log copies/ml after 3 months, −2.0 log after 12 months and −1.7 log after 24 months of treatment. The proportion of infants with a viral load below 500 copies/ml decreased from 53% at 6 months to 18% at 24 months of treatment. The virologic response was not correlated with viral load at baseline. However, the slope of the viral load decrease during the first month of treatment was predictive of the virologic response at 3 and 6 months. Fourteen infants with a viral load of >500 copies/ml after 6 months of treatment displayed viruses with antiretroviral resistance mutations in reverse transcriptase and/or protease genes. Conclusions. Despite the absence of clinical or immunologic progression, the high frequency of virologic failure associated with genotypic resistance reveals the difficulties associated with implementing antiretroviral multitherapy in infants. Suboptimal doses of protease inhibitor could be a factor contributing to treatment failure.

Population analysis of weight-, age-, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years

ABSTRACT The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

Increased incidence of necrotizing enterocolitis in premature infants born to HIV-positive mothers.

Objective:To examine if being born to an HIV-positive mother may increase the risk of necrotizing enterocolitis in premature infants. Design:Case–control study. Setting:Neonatal unit of a level 3 perinatal centre. Methods:Over a period of 8.5 years, all cases of necrotizing enterocolitis occurring in premature infants admitted to the neonatal unit were identified. For each case, two controls were retrospectively chosen that matched for postmenstrual age at birth, intrauterine growth and year of birth. Perinatal characteristics were studied in all infants. Main results:There were 79 cases of necrotizing enterocolitis, which were compared with 158 controls. Using multivariate analysis, multiple pregnancy [odds ratio (OR), 2.29; 95% confidence interval (CI), 1.23–4.25; P = 0.009], abnormal umbilical artery velocity (OR, 2.21; 95% CI, 1.08–4.54; P = 0.030), abnormal fetal heart rate (OR, 2.14; 95% CI, 1.05–4.36; P = 0.036) and HIV-positive mother (OR, 6.63; 95% CI, 1.26–34.8; P = 0.025) were significantly more frequent in fetuses who subsequently developed necrotizing enterocolitis. Conclusions:This preliminary report suggests an association, not previously reported, between maternal HIV-positive status and an increased risk of necrotizing enterocolitis in premature infants. Despite the limitations of this study, we suggest that premature newborn infants of HIV-positive mothers should be monitored very carefully for a possible increased risk of necrotizing enterocolitis.