Tuberculosis in HIV-infected children in Europe, Thailand and Brazil: Paediatric TB-HIV EuroCoord study

SETTING: Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil. OBJECTIVE: To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children. DESIGN: Observational study of TB diagnosed in HIV-infected children in 2011-2013. RESULTS: Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0-11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti-tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes. CONCLUSION: Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention

Tuberculosis in HIV-infected children in Europe, Thailand and Brazil: paediatric TB-HIV EuroCoord study.

SETTING: Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil. OBJECTIVE: To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children. DESIGN: Observational study of TB diagnosed in HIV-infected children in 2011-2013. RESULTS: Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0-11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti-tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes. CONCLUSION: Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention.

Stroke volume and cardiac output evaluation by electrical cardiometry: accuracy and reference nomograms in hemodynamically stable preterm neonates.

OBJECTIVE: To investigate the accuracy of electrical cardiometry (EC) to measure stroke volume (SV) and cardiac output (CO) and to provide gestational age (GA) and birth weight (BW)-based reference data for SV and CO in hemodynamically stable preterm neonates. STUDY DESIGN: Prospective observational blinded study. Paired measurements of SV and CO on stable preterm infants without any hemodynamic compromise were carried out using EC (SVEC) and echocardiography (SVECHO). RESULTS: Seventy-nine preterm neonates (mean GA: 31±3.2 weeks) were enrolled. A good correlation was found for SV (r=0.743; P<0.0001) and CO (r=0.7; P<0.0001) measured by EC and echocardiography. These correlations remained significant after adjusting for GA, patent ductus arteriosus and type of respiratory support (SV: St.ß=0.48, P<0.0001 and CO: St.ß=0.69, P<0.0001). Mean biases (and variabilities) were -1.1 (from 0.7 to -2.9) ml and -0.21 (from 0.15 to -0.55) l min(-1) for SV and CO, respectively. Local regression shows a tendency for EC to overestimate SV and CO especially at higher values (at about >2 ml and >0.4 l min(-1), respectively). Coefficient of variation of SV was 48.9% and 52%, for EC and echocardiography. SV and CO rose with increasing GA and BW following an exponential equation (R(2)>0.8). CONCLUSION: Measuring SV and CO with EC in hemodynamically stable preterm infants shows good correlation and variability similar to that of echocardiography. A trend to overestimation exists at highest values, but it is unlikely to be clinically significant. Reference GA and BW-based nomograms for SV and CO are provided.

HIV-1 drug resistance mutations in children after failure of first-line nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy.

OBJECTIVES: The aim of the study was to assess the prevalence, predictors and patterns of genotypic resistance mutations in children after failure of World Health Organization-recommended initial nonnucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimens. METHODS: We carried out a multicentre retrospective study of genotyping tests performed for all HIV-infected children at eight paediatric centres in Thailand who experienced failure of NNRTI therapy at a time when virological monitoring was not routinely available. RESULTS: One hundred and twenty children were included in the study. Their median age (interquartile range) was 9.1 (6.8-11.0) years, the median duration of their NNRTI regimens was 23.7 (15.7-32.6) months, their median CD4 percentage was 12% (4-20%), and their median plasma HIV RNA at the time of genotype testing was 4.8 (4.3-5.2) log(10) HIV-1 RNA copies/mL. The nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations found were as follows: 85% of the children had M184V/I, 23% had at least four thymidine analogue mutations, 12% had the Q151M complex, 5% had K65R, and 1% had the 69 insertion. Ninety-eight per cent of the children had at least one NNRTI resistance mutation, and 48% had etravirine mutation-weighted scores ≥4. CD4 percentage <15% prior to switching regimens [odds ratio (OR) 5.49; 95% confidence interval (CI) 2.02-14.93] and plasma HIV RNA>5 log(10) copies/mL (OR 2.46; 95% CI 1.04-5.82) were independent predictors of at least four thymidine analogue mutations, the Q151M complex or the 69 insertion. CONCLUSIONS: In settings without routine viral load monitoring, second-line antiretroviral therapy regimens should be designed assuming that clinical or immunological failure is associated with high rates of multi-NRTI resistance and NNRTI resistance, including resistance to etravirine.

[Air or oxygen for neonatal resuscitation in the delivery room?]. / Air ou oxygène pour le nouveau-né en salle de naissance?

Most of the contemporary guidelines on newborn resuscitation are based on experience but lack scientific evidence. The use of 100% oxygen is one of the more evident. Today, these practices are questioned, particularly for the resuscitation of moderately depressed full term or near term newborns. Results of recent meta-analysis of trials that compared ventilation with air versus pure oxygen at birth suggests current practices should be revisited. On the basis of these data, air can be the initial gas to use for these babies. Large scale trials, including preterm and cause and/or severity of initial asphyxia, must now be undertaken before the publication of new guidelines for these populations. Particularly severely asphyxiated infants might require supplemental oxygen with titration of oxygen delivery and continuous monitoring of oxygen saturation.

[HIV-1 transmission from mother to child and its prevention]. / Transmission du VIH-1 de la mère à l'enfant et sa prévention.

Mother-to-child transmission of HIV-1 can occur during pregnancy, labor/delivery, or breastfeeding. Without intervention HIV infection occurs in about 35% of infants born to HIV-infected women: 10% during pregnancy, 15% during labor/delivery, and 10% during breastfeeding. As early as 1994, the PACTG 076-ANRS 024 study documented the remarkable effectiveness of AZT in reducing mother-to-child HIV transmission from 26% to 8% in women who did not breastfeed. Since then, AZT or multiple antiretroviral therapies has been widely used in pregnant HIV-infected women in industrialized countries resulting in decline of the transmission rate to less than 3%. In developing countries where most perinatal transmissions occur, preventive treatment is more difficult to implement. Abbreviated treatment using AZT or nevirapine (NVP) in a single dose to the mother during delivery and to the newborn reduces perinatal transmission but to a lesser extent in comparison with standard treatment. Combination treatment using AZT + 3TC or AZT + NVP is more effective. Elective cesarean section has also been proposed but is not recommended in developing countries. To date the only alternative of proven efficacy for reducing transmission during breastfeeding is formula feeding, but this method may be hazardous if sanitary conditions are poor. Studies are currently under way to test the efficacy of antiretrovirals administered to the mother and/or infant in reducing HIV transmission during breastfeeding.

A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal HIV Prevention Trial (Thailand) Investigators.

BACKGROUND: The optimal duration of zidovudine administration to prevent perinatal transmission of human immunodeficiency virus type 1 (HIV-1) should be determined to facilitate its use in areas where resources are limited. METHODS: We conducted a randomized, double-blind equivalence trial of zidovudine starting in the mother at 28 weeks' gestation, with 6 weeks of treatment in the infant (the long-long regimen), which is similar to protocol 076; zidovudine starting at 35 weeks' gestation, with 3 days of treatment in the infant (the short-short regimen); a long-short regimen; and a short-long regimen. The mothers received zidovudine orally during labor. The infants were fed formula and were tested for HIV DNA at 1, 45, 120, and 180 days. After the first interim analysis, the short-short regimen was stopped. RESULTS: A total of 1437 women were enrolled. At the first interim analysis, the rates of HIV transmission were 4.1 percent for the long-long regimen and 10.5 percent for the short-short regimen (P=0.004). For the entire study period, the transmission rates were 6.5 percent (95 percent confidence interval, 4.1 to 8.9 percent) for the long-long regimen, 4.7 percent (95 percent confidence interval, 2.4 to 7.0 percent) for the long-short regimen, and 8.6 percent (95 percent confidence interval, 5.6 to 11.6 percent) for the short-long regimen. The rate of in utero transmission was significantly higher with the two regimens with shorter maternal treatment (5.1 percent) than with the two with longer maternal treatment (1.6 percent). CONCLUSIONS: The short-short zidovudine regimen is inferior to the long-long regimen and leads to a higher rate of perinatal HIV transmission. The long-short, short-long, and long-long regimens had equivalent efficacy. However, the higher rate of in utero transmission with the short-long regimen suggests that longer treatment of the infant cannot substitute for longer treatment of the mother.

The Riluzole Early Access Programme: descriptive analysis of 844 patients in France. ALS/Riluzole Study Group III.

Recent controlled trials in outpatients with amyotrophic lateral sclerosis (ALS) indicate that riluzole prolongs tracheostomy-free survival. After 12 months' treatment, riluzole 50 mg, 100 mg and 200 mg daily reduced the risk of death or tracheostomy (relative to placebo) by 24%, 34% and 31%, respectively (by 28%, 43% and 43%, respectively, after adjustment for known prognostic factors). This survival advantage (6-9 patients require treatment with riluzole to avoid 1 death/tracheostomy annually) compares favourably with that achieved therapeutically in breast cancer and coronary artery disease. Some 6000 ALS patients are currently receiving riluzole 50 mg twice daily within the Riluzole Early Access Program. In France, this programme is being implemented as an open-label multicentre trial to assess patients' functional status and quality of life. To date, 844 patients have been enrolled, and they will be followed up for 12 months on riluzole. Baseline demographic and clinical characteristics of this study population are presented here.

[Study methods of drugs in Alzheimer disease]. / Méthodes d'étude des médicaments dans la maladie de l'Alzheimer.

The availability of new drugs for Alzheimer's disease, with different pharmacological profiles, leads to a redefinition the relevant methodology for developing drugs in this indication, including the inclusion/exclusion criteria, the duration of the studies, and therefore, the relevant guidelines. This was the purpose of the Giens Round-table devoted to the new methodology for drug development in Alzheimer disease.

Characteristics associated with HIV-1 infection in pregnant women in Brazzaville, Congo.

Maternal human immunodeficiency virus type 1 (HIV-1) infection in sub-Saharan Africa is a major public health concern because of the high prevalence among women of childbearing age and the poor prognosis for perinatally infected children. Characteristics associated with HIV seroprevalence were studied in a population of 1,833 pregnant women seen in two large mother-child clinics in Brazzaville, Congo. The prevalence of HIV infection was 3.9% (95% confidence interval, 3.0-4.9%) and differed significantly according to the district of residence, marital status, duration of the relationship with the current partner, number of sexual partners in the year prior to pregnancy, number of living and dead children, and history of blood transfusion and/or hospitalization. Logistic regression analysis identified six significant factors independently associated with seropositivity; age, history of blood transfusion and/or hospitalization, district of residence, duration of the relationship, number of living children, and number of decreased children. However, the predictive value of the model was poor: while 80% of the truly positive women were correctly predicted positive by the model, 50% of the truly negative women were misclassified. Among pregnant women attending these clinics it is therefore difficult to identify a subgroup at risk toward which specific actions could be targeted.

Over-reporting of maladjustment by depressed subjects. Findings from retesting after recovery.

The extent to which patients' reports of maladjustment is influenced by depressive symptoms was estimated in 25 acute depressed patients responding to pharmacotherapy. Their social adjustment over the same four-month period immediately prior to hospitalization was assessed on two separate occasions: firstly when they were acutely depressed, and again a mean of 20 days later when clinically recovered. Significant differences between the two reports were found in mean score of maladjustment in four out of five fields of social adjustment (work, social/leisure life, family of origin, marriage, and sex). The reduction in depressive symptoms scores (of pessimism considered separately), correlated significantly with changes in the total maladjustment score. The reduction in pessimism scores correlated with changes in the scores for both work and social/leisure fields, and also accounted for 40% of the total variance in maladjustment score. These results indicate that impaired social adjustment as assessed during the height of the depressive illness arises in part from a symptom--related overreporting bias leading patients to make a harsh appraisal of themselves.

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder.

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54-59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

Polymerase chain reaction for studies of mother to child transmission of HIV1 in Africa.

The feasibility and implications of the use of the polymerase chain reaction (PCR) assay in studies of HIV1 mother to child transmission in Africa were investigated. Uncultured leukocyte blood cells (PBL) obtained in Brazzaville (Congo) from newborns and infants (mean age = 27 weeks) of infected mothers were tested. HIV1 DNA sequences were identified in the PBL of six of eight newborns and 14 of 23 babies born to HIV1-positive mothers. In addition two of four babies, who at birth had been seropositive and subsequently were seronegative, were HIV1 DNA positive by PCR. This study demonstrates directly, therefore, a high rate of HIV1 transmission in Africa; it also indicates that PCR should be used for such epidemiological studies.

Mother-child transmission of HIV-1 and infant survival in Brazzaville, Congo.

The aim of this study was to compare the probability of survival of infants born to anti-HIV-1-positive and anti-HIV-1-negative mothers. One thousand, eight hundred and thirty-three pregnant women, recruited sequentially in two mother-child clinics in Brazzaville, were screened for anti-HIV-1 (by enzyme-linked immunosorbent assay with confirmation by Western blot). Each seropositive mother (71 out of 1833, 3.9%) was matched for age, presumed date of delivery and place of residence with two seronegative mothers. Sixty-four babies born to anti-HIV-1-positive mothers and 130 control babies born to anti-HIV-1-negative mothers were followed up for 12-22 months (mean, 18 months). The probabilities of survival were estimated by the Kaplan-Meier method. At birth, the two groups of babies did not differ with regard to rate of stillbirths, gestational age, sex ratio and weight. Among babies born to seropositive mothers, the probability of survival was 0.87 (s.d. 0.04) at 3 months, 0.71 (s.d. 0.06) at 6 months, 0.68 (s.d. 0.06) at 9 months and 0.61 (s.d. 0.06) at 12.5 months. In the controls the probability of survival was 0.98 (s.d. 0.01) at 3 months and 0.97 (s.d. 0.02) at 12 months. The excess of mortality in the babies born to anti-HIV-1-positive mothers is highly significant (P less than 0.001). The deaths occurred more frequently and earlier than in similar cohort studies performed in developed countries.

[The unacceptability of pregnancy among schoolgirls in Brazzaville]. / La grossesse impossible chez les jeunes filles scolarisees a Brazzaville

PIP: Abortion in the Congo is discussed from the perspectives of the law, demography, actual experience, and ethics. The information presented is primarily from interviews with young women attending school in the capital, Brazzaville. (summary in ENG)^ieng