Christian Kind

International multicentre pooled analysis of late postnatal mother-to-child transmission of HIV-1 infection

BACKGROUND An understanding of the risk and timing of mother-to-child transmission of HIV-1 in the postnatal period is important for the development of public-health strategies. We aimed to estimate the rate and timing of late postnatal transmission of HIV-1. METHODS We did an international multicentre pooled analysis of individual data from prospective cohort studies of children followed-up from birth born to HIV-1-infected mothers. We enrolled all uninfected children confirmed by HIV-1-DNA PCR, HIV-1 serology, or both. Late postnatal transmission was taken to have occurred if a child later became infected. We calculated duration of follow-up for non-infected children from the time of negative diagnosis to the date of the last laboratory follow-up, or for infected children to the mid-point between the date of last negative and first positive results. We stratified the analysis for breastfeeding. FINDINGS Less than 5% of the 2807 children in four studies from industrialised countries (USA, Switzerland, France, and Europe) were breastfed and no HIV-1 infection was diagnosed. By contrast, late postnatal transmission occurred in 49 (5%) of 902 children in four cohorts from developing countries, in which breastfeeding was the norm (Rwanda [Butare and Kigali], Ivory Coast, Kenya), with an overall estimated risk of 3.2 per 100 child-years of breastfeeding follow-up (95% CI 3.1-3.8), with similar estimates in individual studies (p=0.10). Exact information on timing of infection and duration of breastfeeding was available for 20 of the 49 children with late postnatal transmission. We took transmission to have occurred midway between last negative and first positive HIV-1 tests. If breastfeeding had stopped at age 4 months transmission would have occurred in no infants, and in three if it had stopped at 6 months. INTERPRETATION Risk of late postnatal transmission is consistently shown to be substantial for breastfed children born to HIV-1-positive mothers. This risk should be balanced against the effect of early weaning on infant mortality and morbidity and maternal fertility.

Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects

Background:Therapies containing two reverse transcriptase inhibitors (RTI) with or without protease inhibitors are used with increasing frequency in pregnant HIV-infected women. Objective:To assess the safety of antiretroviral therapy in pregnant women and their newborns. Methods:All clinical events and laboratory abnormalities in pregnant women on RTI with or without protease inhibitors and in their newborns were collected through an observational study. Results:A total of 37 HIV-infected pregnant women have given birth to 30 children (by 30 April 1998). All received RTI, which were combined with protease inhibitors in 16 cases. Twelve women became pregnant while on treatment. Drugs used were as follows: zidovudine (n = 33), lamivudine (n = 33), stavudine (n = 4), indinavir (n = 9), ritonavir (n = 4), nelfinavir (n = 2) and saquinavir (n = 2). Adverse events during pregnancy were anaemia (n = 15), elevation of transaminases (n = 4), nausea/vomiting (n = 4), glucose intolerance (n = 2), nephrolithiasis (n = 2), diarrhoea (n = 2), hypertension (n = 1), insulin-requiring diabetes (n = 1). Adverse events in neonates were prematurity (n = 10), anaemia (n = 8), cutaneous angioma (n = 2), cryptorchidism (n = 2), transient hepatitis (n = 1). Non-life-threatening intracerebral haemorrhage occurred in a premature baby (33 weeks gestation) exposed during fetal life to zidovudine-lamivudine-indinavir, and in a term baby exposed to stavudine-lamivudine-indinavir. Extrahepatic biliary atresia occurred in one newborn exposed to zidovudine-lamivudine-indinavir. Maternal viral load was below 400 copies/ml in 18 out of 30 patients who delivered. One case of mother-to-child HIV transmission was identified. Conclusions:In HIV-infected pregnant women treated with two RTI with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies. In newborns, frequent prematurity, one case of biliary malformation and one intracerebral haemorrhage in a term baby are of concern. These observations do not preclude combination therapies during pregnancy but emphasize the necessity to maintain updated registers on their safety.

Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. Swiss Neonatal HIV Study Group.

Objective: To study the effect of elective Cesarean section and zidovudine prophylaxis on vertical HIV transmission. Design: Prospective study. Setting: Obstetric and paediatric clinics in Switzerland. Participants: Children of mothers with HIV infection identified before or at delivery. Interventions: Routine use of elective Cesarean section for HIV-infected parturients by some Swiss centres since 1985. National recommendation for zidovudine prophylaxis in mid-1994. Main outcome measure: HIV infection status of children. Results: In a cohort of 494 children born at least 6 months before the analysis date, 67 out of 414 children with known infection status were found to be infected, giving an overall transmission rate of 16.2% [95% confidence interval (CI), 13.0–18.5]. Elective Cesarean section with intact membranes and without previous labour was associated with a lower transmission rate of 6% [odds ratio (OR), 0.29; 95% CI, 0.12–0.70; P = 0.006 versus other delivery modes]. Transmission rate was intermediate after spontaneous delivery or non-elective Cesarean section (18%), and higher after obstetric interventions (27%; test for trend, P < 0.001). Since mid-1994, 78% of all women with registered pregnancies have received some form of zidovudine prophylaxis. Transmission rate was reduced from 17 to 7% after any zidovudine exposure (OR, 0.4; 95% CI, 0.11–1.41). Combined use of elective Cesarean section and zidovudine resulted in a 0% transmission rate (none out of 31), compared with 8% (seven out of 86) after elective Cesarean section without zidovudine, 17% (four out of 24) after zidovudine alone, and 20% (55 out of 271) after no intervention. Conclusions: Elective Cesarean section and zidovudine prophylaxis appear to have an additive effect in the prevention of vertical HIV transmission.

Prevalence of Enteroaggregative Escherichia coli among Children with and without Diarrhea in Switzerland

ABSTRACT In a prospective study between July 1999 and September 2000, stool specimens of children below the age of 16 years with (n = 187) and without (n = 137) diarrhea were tested for the presence of enterovirulent bacteria by standard culture methods and by PCR. Targets for the PCR were the plasmid pCVD432 for enteroaggregative Escherichia coli (EAEC), the verotoxin 1 and verotoxin 2 genes for enterohemorrhagic E. coli, ipaH for enteroinvasive E. coli (EIEC) and Shigella spp., genes coding for heat-stable and heat-labile toxins for enterotoxigenic E. coli (ETEC), and the eaeA gene for enteropathogenic E. coli. The following bacteria could be associated with diarrhea: Salmonella enterica (P = 0.001), Campylobacter spp. (P = 0.036), ETEC (P = 0.012), and EAEC (P = 0.006). The detection of EAEC, ETEC, and S. enterica was strongly associated with a history of recent travel outside of Switzerland. EAEC isolates were found in the specimens of 19 (10.2%) of 187 children with diarrhea and in those of 3 (2.2%) of 137 children without diarrhea (P = 0.006) and were the most frequently detected bacteria associated with diarrhea. Among the children below the age of 5 years, the specimens of 18 (11.9%) of 151 with diarrhea were positive for EAEC, while this agent was found in the specimens of 2 (2.2%) of 91 controls (P = 0.007). Enteropathogenic E. coli isolates were found in the specimens of 30 (16.4%) of the patients and in those of 15 (10.9%) of the controls, with similar frequencies in all age groups (P > 0.05). We conclude that EAEC bacteria are involved in a significant proportion of diarrhea cases among children. Children younger than 5 years of age are more often affected by EAEC than older children.

Perinatal care at the limit of viability between 22 and 26 completed weeks of gestation in Switzerland 2011 Revision of the Swiss recommendations

Perinatal care of pregnant women at high risk for preterm delivery and of preterm infants born at the limit of viability (22-26 completed weeks of gestation) requires a multidisciplinary approach by an experienced perinatal team. Limited precision in the determination of both gestational age and foetal weight, as well as biological variability may significantly affect the course of action chosen in individual cases. The decisions that must be taken with the pregnant women and on behalf of the preterm infant in this context are complex and have far-reaching consequences. When counselling pregnant women and their partners, neonatologists and obstetricians should provide them with comprehensive information in a sensitive and supportive way to build a basis of trust. The decisions are developed in a continuing dialogue between all parties involved (physicians, midwives, nursing staff and parents) with the principal aim to find solutions that are in the infants and pregnant womans best interest. Knowledge of current gestational age-specific mortality and morbidity rates and how they are modified by prenatally known prognostic factors (estimated foetal weight, sex, exposure or nonexposure to antenatal corticosteroids, single or multiple births) as well as the application of accepted ethical principles form the basis for responsible decision-making. Communication between all parties involved plays a central role. The members of the interdisciplinary working group suggest that the care of preterm infants with a gestational age between 22 0/7 and 23 6/7 weeks should generally be limited to palliative care. Obstetric interventions for foetal indications such as Caesarean section delivery are usually not indicated. In selected cases, for example, after 23 weeks of pregnancy have been completed and several of the above mentioned prenatally known prognostic factors are favourable or well informed parents insist on the initiation of life-sustaining therapies, active obstetric interventions for foetal indications and provisional intensive care of the neonate may be reasonable. In preterm infants with a gestational age between 24 0/7 and 24 6/7 weeks, it can be difficult to determine whether the burden of obstetric interventions and neonatal intensive care is justified given the limited chances of success of such a therapy. In such cases, the individual constellation of prenatally known factors which impact on prognosis can be helpful in the decision making process with the parents. In preterm infants with a gestational age between 25 0/7 and 25 6/7 weeks, foetal surveillance, obstetric interventions for foetal indications and neonatal intensive care measures are generally indicated. However, if several prenatally known prognostic factors are unfavourable and the parents agree, primary non-intervention and neonatal palliative care can be considered. All pregnant women with threatening preterm delivery or premature rupture of membranes at the limit of viability must be transferred to a perinatal centre with a level III neonatal intensive care unit no later than 23 0/7 weeks of gestation, unless emergency delivery is indicated. An experienced neonatology team should be involved in all deliveries that take place after 23 0/7 weeks of gestation to help to decide together with the parents if the initiation of intensive care measures appears to be appropriate or if preference should be given to palliative care (i.e., primary non-intervention). In doubtful situations, it can be reasonable to initiate intensive care and to admit the preterm infant to a neonatal intensive care unit (i.e., provisional intensive care). The infants clinical evolution and additional discussions with the parents will help to clarify whether the life-sustaining therapies should be continued or withdrawn. Life support is continued as long as there is reasonable hope for survival and the infants burden of intensive care is acceptable. If, on the other hand, the health care team and the parents have to recognise that in the light of a very poor prognosis the burden of the currently used therapies has become disproportionate, intensive care measures are no longer justified and other aspects of care (e.g., relief of pain and suffering) are the new priorities (i.e., redirection of care). If a decision is made to withhold or withdraw life-sustaining therapies, the health care team should focus on comfort care for the dying infant and support for the parents.

Hyperlipidemia in HIV-infected children treated with protease inhibitors: Relevance for cardiovascular diseases

&NA; Cases of severely hypercholesterolemic HIV‐infected children taking protease inhibitors (PIs) have been reported. Because high cholesterol levels (≥15 mmol/L), as seen in homozygous familial hypercholesterolemia (FH), may lead to heart disease in childhood, the authors performed a systematic retrospective survey of all plasma lipid levels recorded for children who had received ritonavir or nelfinavir between 1995 and 2001 in Switzerland. Administration of PIs was associated with a significant increase in plasma cholesterol levels, which was more pronounced for those given ritonavir (from 3.3 ± 0.7 mmol/L, n = 5 to 6.3 ± 2.8 mmol/L, n = 19 [mean ± SD]; p = .03) than for nelfinavir (from 3.0 ± 0.7 mmol/L, n = 11 to 4.9 ± 1.0 mmol/L, n = 30; p = < .001). Cholesterol levels exceeded 10.0 mmol/L in 3 of 49 (6%) PI‐treated children and culminated at 13.8 mmol/L. Plasma cholesterol levels in PI‐treated children were comparable with levels reported for heterozygous FH children but were all lower than in homozygous FH children. Because heterozygous FH patients usually develop heart disease in middle age, the authors conclude that the risk for heart disease in PI‐treated children is minimal. Long‐term monitoring of these children, however, will be necessary.

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples.

ObjectiveTo determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. MethodsIn a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. ResultsHIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31–41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery;P  = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9–16.8 days). This time was increased by 15% (95% CI, −11 to 48%;P  = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. ConclusionsThe outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

Codon 215 Mutations in Human Immunodeficiency Virus—Infected Pregnant Women

In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 demonstrated a two-thirds reduction of perinatal human immunodeficiency virus (HIV) type 1 transmission with zidovudine chemoprophylaxis. However, zidovudine alone does not fully suppress HIV replication, and chemoprophylaxis with zidovudine alone might select for zidovudine-resistant viral variants, decreasing the efficacy of zidovudine prophylaxis and affecting future responses to combined antiretroviral regimens. Sixty-two HIV-infected pregnant women consecutively enrolled in the ongoing Swiss HIV and Pregnancy Study were prospectively evaluated for the presence or development of zidovudine resistance by analysis of codon 215 of the reverse transcriptase gene. Six women (9.6%) harbored a codon T215Y/F mutation, which is associated with high-level resistance to zidovudine. Postnatal evaluation was completed in all children of mothers harboring the mutation. None was HIV-infected. The observed prevalence of codon 215 mutations of 9.6% raises important concerns regarding the future use of the PACTG 076 regimen.

Prevalence of nosocomial infections in Swiss children's hospitals

OBJECTIVE To acquire data on pediatric nosocomial infections (NIs), which are associated with substantial morbidity and mortality and for which data are scarce. DESIGN Prevalence survey and evaluation of a new comorbidity index. SETTING Seven Swiss pediatric hospitals. PATIENTS Those hospitalized for at least 24 hours in a medical, surgical, intensive care, or intermediate care ward. RESULTS Thirty-five NIs were observed among 520 patients (6.7%; range per hospital, 1.4% to 11.8%). Bacteremia was most frequent (2.5 per 100 patients), followed by urinary tract infection (1.3 per 100 patients) and surgical-site infection (1.1 per 100 patients; 3.2 per 100 patients undergoing surgery). The median duration until the onset of infection was 19 days. Independent risk factors for NI were age between 1 and 12 months, a comorbidity score of 2 or greater, and a urinary catheter. Among surgical patients, an American Society of Anesthesiologists (ASA) score of 2 or greater was associated with any type of NI (P = .03). Enterobacteriaceae were the most frequent cause of NI, followed by coagulase-negative staphylococci; viruses were rarely the cause. CONCLUSIONS This national prevalence survey yielded valuable information about the rate and risk factors of pediatric NI. A new comorbidity score showed promising performance. ASA score may be a predictor of NI. The season in which a prevalence survey is conducted must be considered, as this determines whether seasonal viral infections are observed. Periodic prevalence surveys are a simple and cost-effective method for assessing NI and comparing rates among pediatric hospitals.

Antiretroviral therapy during pregnancy and premature birth : analysis of Swiss data

There is an ongoing debate as to whether combined antiretroviral treatment (cART) during pregnancy is an independent risk factor for prematurity in HIV‐1‐infected women.