Background. Considerable uncertainty remains as to whether early initiation of antiretroviral therapy ( ART) in children with vertically acquired human immunodeficiency virus (HIV) infection increases the benefit in terms of immunological response.Methods. The association between immunological outcome and early initiation of and/or more-potent ART was investigated, using age-standardized z scores for CD4 cell counts ( hereafter, "CD4 z scores"), in 131 HIV-infected children enrolled in the European Collaborative Study, a birth cohort study.Results. Median age at initiation of the most-potent ART was 4 years ( range, 0.1-15.5 years). Initiation of treatment after 5 months of age resulted in nonsignificantly lower CD4 z scores 6 months after initiation. Time to a 20% increase in CD4 z score was associated with age at initiation of the most-potent ART ( adjusted hazard ratios [AHRs], 0.37 [P < .01] and 0.43 [P = .05] for 5 months-5 years of age and > 5 years of age, respectively, compared with < 5 months of age), ethnicity ( AHR, 0.48 [P = .01], for black vs. white), and highly active ART (HAART) with or without prior ART ( AHRs, 3.16 [P < .01] and 3.95 [P < .001], vs. mono or dual ART, respectively). The risk of subsequent deterioration of CD4 z score was similar for children who initiated ART in different age groups (chi(2) = 0.824; P = .82).Conclusions. We confirm the effectiveness of HAART with respect to the recovery of CD4 cell count and suggest a benefit of initiating ART before the age of 5 months. Age at initiation of the most-potent ART was not associated with the likelihood of sustaining the recovery of CD4 cell count.

community level will save lives and prevent wastage of valuable resources. Increasing levels of resistance to cheap, first-line antimalarials means that many poor countries must promote new, more expensive treatment in the form of Artemisinin-based Combination Therapies (ACTs). Due to the resultant rising costs, it is no longer feasible to treat all fevers as malaria; the current high levels of misdiagnosis are unsustainable. The need, therefore, for improved diagnostic tools that can be used at community level has never been greater.

Objective To examine how the subsequent childbearing of HIV-infected mothers enrolled in the European Collaborative Study (ECS) has changed over time and identify factors predictive of further childbearing.Design Prospective cohort study.Setting Centres in nine European countries included in the ECS, enrolled between end 1986 and November 2003.Population HIV-infected women (3911): 3693 with only one and 218 with subsequent live births.Methods Univariable and multivariable logistic regression analyses to obtain odds ratios (OR) and 95% confidence intervals (CI). Kaplan-Meier (KM) analyses to estimate cumulative proportions of women having a subsequent live birth.Main outcome measures Subsequent live birth.Results In multivariable analysis adjusting for time period, ethnicity, maternal age and parity, black women were more likely [adjusted odds ratio (AOR) 2.45; 95% CI, 1.75-3.43], and women > 30 years less likely (AOR 0.54, 0.37-0.80), to have a subsequent live birth. Time to subsequent live birth significantly shortened over time, with an estimated 2% of women having a subsequent live birth within 24 months of enrolment pre-1989 versus 14% in 2000-2003 (P < 0.001). Estimated time to subsequent live birth was shorter for black than for white women (P < 0.001).Conclusions The likelihood of subsequent live births substantially increased after 1995 and birth intervals were shorter in women on HAART and among black women. Numbers are currently too small to address the issue of advantages and disadvantages in the management of subsequent deliveries.

Objective: Currently used reference values for immunologic markers in children are largely derived from cross-sectional data from historic, small sample size studies in predominantly white children. There is a lack of reliable age-related standards for immunologic markers, such as CD4+ cell counts, in particular in black children whose values according to recent reports may differ from those in white children. Standards are essential for diagnosing and monitoring childhood diseases such as pediatric human immunodeficiency virus (HIV) infection. Design: Prospective cohort study with data on 1781 uninfected children born to HIV-infected mothers in the European Collaborative Study. Methods: Age-related standards (centiles) for immunologic markers (CD4+ and CD8+ cell counts and total lymphocyte counts) up to 5 years in black and up to 10 years in white children were constructed using Generalized Additive Models for Location, Scale and Shape method, which allows for variability and skewness of the data. The optimal model was chosen according to the Akaike Information Criterion. Results: Patterns and values of total lymphocyte, CD4+ and CD8+ cell counts varied with age, especially in the first 3 years of life, but less so thereafter. Values of all 3 immunologic markers were substantially and significantly lower in black than in white children of the same age. Conclusions: We present age-related standards separately for black and white children to aid clinicians in the monitoring of childhood diseases. These standards may also contribute to the decision on an accurate cutoff for CD4+ cell counts for initiating treatment of HIV-infected children.

Background: Antiretroviral drugs (ARV) as prophylaxis to prevent mother-to-child transmission of HIV results in decreased haematological parameters during and shortly after exposure, with recent data suggesting a more prolonged inhibition of haematopoiesis until at least 18 months. Design: Data on 156 HIV-infected and 1533 uninfected children in the European Collaborative Study followed from birth until at least 8 years of age. Methods: Smoothers and splines were used to elucidate patterns over age; linear mixed effects allowed for repeated measurements. Covariates included the child's HIV-1 infection status, prematurity, gender, race, drug withdrawal symptoms at birth and ARV exposure; effects on neutrophil count were quantified in regression analyses using z-scores (SD from mean) of neutrophil counts obtained after modelling untransformed values using the LMS method. For HIV-infected children, progression to AIDS and ARV therapy were also included. Results: After approximately 4 months of age, neutrophil counts were consistently and substantially lower in HIV-infected children than in uninfected children; in both groups, black children had significantly lower counts than white children across the whole age range. In uninfected children, male gender and ARV exposure were associated with reduced neutrophil count until at least 8 years of age. In HIV-infected children, advanced disease and ARV treatment were significantly associated with neutrophil count. Conclusion: A considerably longer effect of exposure to ARV was shown in uninfected children than previously thought and significant associations were shown between race and gender and neutrophil count, as previously observed for lymphocyte counts. The clinical relevance of these reduced levels of neutrophils requires further investigation.

Concerns have been raised over possible adverse effects of prophylactic antiretroviral therapy (ART) on the fetus and newborn. We analyzed data relating to uninfected children enrolled in the European Collaborative Study and investigated the association between ART exposure, perinatal problems, and major adverse health events later in life. Median length of follow-up was 2.2 (0-15.9) years. Of the 2414 uninfected children, 687 (28%) were exposed to ART in all three periods (antenatal, intrapartum, and neonatal). Of the 1008 infants exposed to ART at any time, 906 (90%) were exposed antenatally, 840 (83%) neonatally, and 750 (74%) both antenatally and neonatally. ART exposure was not significantly associated with pattern or prevalence of congenital abnormalities or low birth weight. In multivariate analysis, prematurity was associated with exposure to combination therapy without a protease inhibitor (PI) (OR = 2.66; 95% CI: 1.52-4.67) and with a PI (OR = 4.14; 95% CI: 2.36-7.23). ART exposure was associated with anemia in early life ( <.001). There was no evidence of an association with clinical manifestations suggestive of mitochondrial abnormalities. The absence of serious adverse events in this large cohort of uninfected children exposed to prophylactic ART in the short to medium term is reassuring.

A traction device is provided that includes a harness coupled to a suspension assembly for suspending the harness at a predetermined height. The harness includes a neck support placed behind a user's neck and a chin rest connected to the neck support on which the user's chin rests. Hand grips extending from the chin or forehead rest allow a user to manually grasp the chin rest and support a portion of their weight as the remainder of their weight is supported by the cervical spine through the traction device. Approximately six to eight repetitions of the method, each performed for ten to twenty seconds, result in nourishment, repair, and regeneration of avascular tissues in the disks, ligaments, cartilage, and improved cervical and lumbar lordotic curves.

Objective: To estimate RNA viral load patterns over age in vertically infected children that account for between- and within-individual variation, treatment and assay cut-off detection level. To investigate possible sex-based differences.Design: A total of 118 infected children with 894 RNA viral load measurements enrolled in the European Collaborative Study were prospectively followed from birth for up to 15 years.Methods: Fractional polynomial and mixed effects models with censored data to assess the non-linear pattern of viral load over age, allowing for repeated measures.Results: The RNA viral load peaked at approximately 3 months of age, and gradually declined thereafter. The sex by age interaction was significant (chi(2) = 19.7, P < 0.001); viral load peaked higher for girls than boys, but after 4 years the RNA load was consistently 0.25-0.5 log(10) lower for girls than boys. The effects of sex and treatment on viral load vary over age (chi(2) = 6.31, P = 0.043). Sex differences in RNA viral load relating to measurement without treatment were more pronounced than those under treatment. Disease progression was more rapid for girls than for boys up to the age of 4 years, and less rapid thereafter; the overall difference was not statistically significant.Conclusion: Differences in RNA viral load over age between untreated boys and girls may have implications for policies for the initiation of antiretroviral therapy, but do not seem to translate into differences in progression to serious disease, The findings would suggest underlying biological explanations, which need further investigation. (C) 2002 Lippincott Williams Wilkins.

SUMMARY Prevention of perinatal transmission of the human immunodeficency virus is a major goal in the manage- ment of pregnant women infected with HIV. Effectiveness of zidovudine as a preventive agent has been pro- bably one of the most important advances in this regard. Later evidence has shown the benefit of employing combination antiretroviral therapy in reducing the transmission as well as in improving maternal control. Elective cesarean section reduces vertical transmission of HIV but its benefit is less clear when viral load is very low. If possible, HIV-infected women should avoid breastfeeding. This article reviews the main features of vertical transmission and points out several others which remain unclear. The article also provides some comments on the obstetrical and perinatal set of data obtained from a sample of 120 pregnant infected women at our hospital.

ObjectiveTo describe changes over a 15-year period in characteristics and management of HIV-infected pregnant women in Europe. DesignProspective study. MethodsAnalysis of prospective data on 2876 pregnant HIV-infected women and their 3076 infants. Factors examined included maternal socio-demographic, immunological and virological characteristics, antiretroviral therapy and pregnancy outcome. ResultsAmong women enrolled, the proportion with heterosexual acquisition of infection has increased significantly from 59% (201/342) in 1985–1987 to 69% (327/471) after 1997 while the proportion acquiring HIV through injecting drug use has declined. Overall median CD4 cell count was 440 × 106/l and 41% of women had undetectable viral load at delivery. In 1995 28% (72/256) of mother–child pairs received the full 076 regimen to reduce risk of vertical transmission, rising significantly to 89% (116/130) by 1999. Use of triple therapy started in pregnancy has increased significantly from < 1% (1/153) in 1997 to 44% (47/107) in 1999. Exposure to antiretroviral therapy was not associated with prevalence or pattern of congenital abnormalities (P = 0.88) but was associated with reversible anaemia in the infant (P < 0.002). The elective cesarean section rate has increased from 10% in 1992 to 71% in 1999/2000. The vertical transmission rate declined from 15.5% by 1994 to 2.6% after 1998. In multivariate analysis, adjusting for maternal CD4 cell count, risk of vertical transmission was reduced by 66% (95% confidence interval, 37–82%) with the full 076 regimen and by 60% (95% confidence interval, 33–73%) with elective cesarean section delivery. ConclusionsChanges in treatment of adult HIV disease have affected the management of infected pregnant women. Despite therapeutic and surgical interventions, vertical transmission still occurs.

Objective: To test the a priori hypothesis that longer duration of ruptured membranes is associated with increased risk of vertical transmission of HIV.Design: The relationship between duration of ruptured membranes and vertical transmission of HIV was evaluated in an individual patient data meta-analysis.Methods: Eligible studies were prospective cohort studies including at least 100 mother-child pairs, from regions where HIV-infected women are counselled not to breastfeed. Analyses were restricted to vaginal deliveries and non-elective Cesarean sections; elective Cesarean section deliveries (those performed before onset of labour and before rupture of membranes) were excluded.Results: The primary analysis included 4721 deliveries with duration of ruptured membranes less than or equal to 24 h. After adjusting for other factors known to be associated with vertical transmission using logistic regression analysis to assess the strength of the relationship, the risk of vertical HIV transmission increased approximately 2% with an increase of 1 h in the duration of ruptured membranes [adjusted odds ratio, 1.02; 95% confidence interval, 1.01-1.04; for each 1 h increment]. There were no significant interactions of duration of ruptured membranes with study cohort or with any of the covariates, except maternal AIDS. Among women diagnosed with AIDS, the estimated probability of transmission increased from 8% to 31% with duration of ruptured membranes of 2 h and 24 h respectively (P < 0.01).Conclusions: These results support the importance of duration of ruptured membranes as a risk factor for vertical transmission of HIV and suggest that a diagnosis of AIDS in the mother at the time of delivery may potentiate the effect of duration of ruptured membranes. (C) 2001 Lippincott Williams & Wilkins.

ObjectiveTo assess the association between type and timing of initiation of antiretroviral therapy in pregnancy and duration of pregnancy. DesignProspective study. MethodsData on 3920 mother–child pairs were examined (3015 mother–child pairs from the European Collaborative Study and 905 from the Swiss Mother + Child HIV Cohort Study). Factors examined included gestational age, antiretroviral therapy during pregnancy, maternal CD4 count, viral load, illicit drug use (IDU) and mode of delivery. Deliveries at less than 37 weeks were defined as premature. ResultsThe prematurity rate was 17% and median gestational age 39 weeks. Twenty-three per cent (896 of 3920) of women received antiretroviral therapy during pregnancy: 64% (573 of 896) zidovudine monotherapy, 24% (215) combination therapy without protease inhibitors (PI) and 12% (108) combination therapy with PI. In multivariate analysis, adjusted for maternal CD4 count and IDU, odds ratio (OR) of prematurity was 2.60 [95% confidence interval (CI), 1.43–4.75] and 1.82 (95% CI, 1.13–2.92) for infants exposed to combination therapy with and without a PI, respectively, compared to no treatment. Exposure to monotherapy was not associated with prematurity, but severe immunosuppression and IDU in pregnancy were. Women on combination therapy from before pregnancy were twice as likely to deliver prematurely as those starting therapy in the third trimester (OR, 2.17; 95% CI, 1.03–4.58). ConclusionsPregnancy issues should be discussed when making decisions about initiation of combination antiretroviral therapy for HIV-infected women. Elective caesarean section to reduce vertical transmission at 36 weeks rather than 38 weeks may be advisable in women on combination therapy with PI.

Objective: Prophylactic zidovudine during pregnancy and labour reduces maternal viral load and, with neonatal therapy, has been shown to reduce vertical transmission. However, zidovudine may have additional effects. Advanced HIV disease is associated with premature delivery, which in turn results in increased vertical transmission. Data from the European Collaborative Study (ECS) were analysed to investigate whether zidovudine could be associated with decreased prematurity risk and/or with a reduced frequency of low birthweight.Methods: HIV-infected pregnant women enrolled in the ECS were followed prospectively according to a standard protocol. Gestational age was assessed by ultrasound, prematurity was defined as delivery before 37 weeks and the cut-off for low birthweight was 2500 g. We calculated odds ratios (OR) to estimate the effect of zidovudine on the risk of premature or low birthweight delivery.Results: In 2299 mothers, zidovudine taken to reduce the risk of vertical transmission decreased the odds of premature delivery by a quarter (OR = 0.76, 95% confidence interval (CI) 0.53-1.09), and the odds of low birthweight by nearly half (OR = 0.55, 95% CI 0.39-0.79). Allowing for CD4 count and mode of delivery did not greatly alter these OR values. A multivariate analysis suggested that prophylactic zidovudine and prematurity were independently associated with risk of transmission.Conclusion: Our findings suggest an additional health benefit of zidovudine. Even ii most vertical transmission occurs around the time of delivery, therapy earlier in pregnancy could have an indirect effect on transmission rates through delaying delivery. This hypothesis needs to be confirmed or refuted by more appropriate studies.

Children of HIV-infected women are likely to be profoundly affected by their mothers' infection, regardless of their own infection status and their number will increase with the spread of infection among women in Europe. This article describes the family circumstances and social care of 1,123 children born to HIV-infected women enrolled in the European Collaborative Study and followed prospectively from birth. Most mothers were white, married or cohabiting, asymptomatic and had a history of drug use, with 45% currently using injecting drugs at the time of enrolment. Seventy percent of children were cared for by their mothers and/or fathers consistently in their first four years of life, but by age eight an estimated 60% will have lived away from their parents (i.e. with foster or adoptive parents, other relatives or in an institution). Whether or not a child was infected did not influence the likelihood of living in alternative care. Maternal injecting drug use, single parenthood and health status were the major reasons necessitating alternative care. The type of alternative care varied according to maternal characteristics, child's age and geographic location. The mothers of 98 children had died and average age at maternal death was four years.

Objective: To examine immunological markers in HIV-infected pregnant women. Design: Women enrolled in the European Collaborative Study and the Swiss HIV Pregnancy Cohort were followed throughout pregnancy according to similar clinical and immunological protocols. Information was recorded at various times during pregnancy and, in some centres, also 6 weeks and 6 months post-partum. Method: Locally-weighted linear regression analysis was used to investigate changes in markers of cellular and humoral immune function during pregnancy and immediately post-partum, taking into account the serial measurement data structure. Women who received zidovudine during pregnancy were excluded. Results: Four hundred and thirty-eight women had two or more measurements during pregnancy or within 6 months of delivery. Twenty-four per cent (106) of the women reported injecting drugs during pregnancy. Mean CD4 and CD8 cell counts declined to a low level 6 months before delivery, increased gradually until delivery and rose sharply to a peak level 3 months post-partum. In contrast, CD4 and CD8 percentages were stable during pregnancy, and increased slightly thereafter. The same pattern was evident for transmitting women, those delivered by Cesarean section, and women who injected drugs during pregnancy, and there was no evidence for an association with immunosuppression. Total immunoglobulin (Ig) G levels declined gradually throughout pregnancy until delivery, and increased in the 6 month post-partum period. Total IgM and IgA levels remained stable throughout pregnancy. Conclusions: These findings suggest that pregnancy does not accelerate HIV progression, but in view of the intrinsic variability in serial CD4 counts, caution should be exercised when assessing changes in immunological markers in individual pregnant women.