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Background Children with HIV will be on antiretroviral therapy (ART) longer than adults, and therefore the durability of first-line ART and timing of switch to second-line are key questions. We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) first-line ART and viral load switch criteria in children. Methods In a randomised open-label factorial trial, we compared effectiveness of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America. Random assignment was by computer-generated sequentially numbered lists stratified by age, region, and by exposure to perinatal ART. Primary outcome was change in viral load between baseline and 4 years. Analysis was by intention to treat, which we defined as all patients that started treatment. This study is registered with ISRCTN, number ISRCTN73318385. Findings Between Sept 25, 2002, and Sept 7, 2005, 266 children (median age 6.5 years; IQR 2.8-12.9) were randomly assigned treatment regimens: 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL (PI-low), 65 protease inhibitor and switch at 30,000 copies per mL (PI-higher), 68 NNRTI and switch at 1000 copies per mL (NNRTI-low), and 67 NNRTI and switch at 30,000 copies per mL (NNRTI-higher). Median follow-up was 5.0 years (IQR 4.2-6.0) and 188 (71%) children were on first-line ART at trial end. At 4 years, mean reductions in viral load were -3.16 log(10) copies per mL for protease inhibitors versus -3.31 log(10) copies per mL for NNRTIs (difference -0.15 log(10) copies per mL, 95% CI -0.41 to 0.11; p=0.26), and -3.26 log(10) copies per mL for switching at the low versus -3.20 log(10) copies per mL for switching at the higher threshold (difference 0.06 log(10) copies per mL, 95% CI -0.20 to 0.32; p=0.56). Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group. NNRTI resistance was selected early, and about 10% more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group. Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events; both were balanced across randomised groups. Interpretation Good long-term outcomes were achieved with all treatments strategies. Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited, because the risk of selecting for NRTI and protease-inhibitor resistance is low. Funding Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group (PACTG/IMPAACT).

One of TEDDY objectives is to “to identify unmet therapeutic needs for the development and use of medicinal products in male/female children” and it is compliant with the new provisions established by the Paediatric Regulation. Thus TEDDY set up 12 Therapeutic Experts Groups (TEGs) to identify the needs in some therapeutic areas of paediatric interest. Starting from the Assessment Documents released by EMEA-PEG and later on by EMEA-PDCO, a total of 14 therapeutic areas were analysed. TEDDY experts have identified 442 products that need to be specifically developed for children by either extending the current authorised indication or developing new indications. Moreover, the study shows that a total of 1480 studies (i.e. PK, dosage, efficacy, safety or long term safety) should be conducted in order to develop more drugs for children. In the light of these results, it is reasonable to question if all these studies are absolutely necessary and consequently if there are enough children to be enrolled in the trials for the same therapeutic area. It is imperative to adopt a procedure of selecting which drugs need to be developed for each therapeutic area in order to avoid repetitive and unnecessary trials in children.

In line with European initiatives, TEDDY set up a new database, the European Paediatric Medicines Database, with the aim of creating a harmonised, integrated and reliable pan-European source of information. The data stored in the Database were the basis for examining the ‘state of the art’ of paediatric medicines licensed by the European Medicines Agency between October 1995 and December 2007. The results of the study show that 33% of medicinal products approved by the European Medicines Agency are intended for the paediatric population, and that this percentage has remained more or less constant in the 12 years of activity of the Agency. This trend is expected to increase rapidly in the future as a result of the adoption of the Paediatric Regulation. Nevertheless, it is essential that information on medicinal products for paediatric use are made publicly accessible and data should be verified and controllable. The European Medicines Agency has recently made public many information on medicines authorised in EU through the EudraPharm database. The TEDDY European Paediatric Medicines Database grants access also to information related to paediatric medicines, some of which are not available elsewhere. We deem this aspect a useful service to end users and a valid support to Regulatory Authorities.

For years the lack of studies specifically designed to investigate pharmacological and toxicological aspects in the paediatric population has forced children to use many approved drugs without a proper information on dosage, efficacy and safety and on the basis of data extrapolated from adults studies. In Europe, the Directive EC/2001/20 on Good Clinical Practice, was the first to take into consideration the need of performing clinical trials in children in compliance with the current GCP requirements. Moreover, the Note for Guidance ICH Topic E11 gives recommendations on clinical trials’ characteristics. Our study found that under the EMEA centralised procedure, 60 drugs were licensed for use in children in the period 1995-2005. These data show an increasing trend in the percentage of EMEA approved medicines for children compared with previously reported figures. Moreover, few clinical studies were performed in compliance with the paediatric age groups as defined by the ICH/E11 guideline. This is of particular concern especially when the adolescent age group is considered, since adolescents are frequently recruited together with adults. The new Paediatric Regulation, in force from January 2007, is expected to dramatically change this situation. © 2009 Network of Centres for Study of Pharmaceutical Law.

Eight of 13 children pre- or perinatally infected with the HIV virus subsequently developed neurological symptoms. Three children also had other nonspecific symptoms (fever, lymphadenopathy, diarrhoea, hepatosplenomegaly, failure to thrive and mucocutaneous thrush). Five children developed illnesses associated with AIDS (opportunistic infections, cachexia and lymphocytic interstitial pneumonia). The neurological abnormalities predominantly affected motor functions, only later also involving sensory ones. Motor, cognitive and language development was impaired in all eight children. A loss of developmental milestones occurred in three children with HIV encephalopathy: they have since died. In all the children the HIV infection caused symptoms within the first year, progressing more quickly in the three with encephalopathy. There were no discernible risk factors to account for the difference in the course of the disease.

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.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.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 and5 years of age, respectively, compared with5 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 ( chi2 = 0.824; P = .82).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.

Introduction Treatment options for children with HIV-1 are limited. We aimed to compare activity and safety of three dualnucleoside analogue reverse-transcriptase inhibitor (NRTI) regimens with or without a protease inhibitor in previously untreated children with HIV-1. Methods In our multicentre trial, we randomly assigned 36 children to zidovudine and lamivudine, 45 to zidovudine and abacavir, and 47 to lamivudine and abacavir. Children who were symptomfree (n=55) were also randomly assigned to receive nelfinavir or placebo. Children with more advanced disease received open-label nelfinavir (73). Primary endpoints were change in plasma HIV-1 RNA at 24 and 48 weeks for the NRTI comparison and occurrence of serious adverse events for both randomised comparisons. Analyses were by intention to treat. Findings Children had a median CD4 percentage of 22% (IQR 15–29) and a mean HIV-1 RNA concentration of 5·0 log copies/mL (SD 0·8). One child was lost to follow-up and one died of sepsis. At 48 weeks, in the zidovudine/lamivudine, zidovudine/abacavir, and lamivudine/abacavir groups, mean HIV-1 RNA had decreased by 1·71, 2·19, and 2·63 log copies/mL, respectively (estimated in absence of nelfinavir) (p=0·02 after adjustment for baseline factors). One child had a hypersensitivity reaction to abacavir; and three with possible reactions stopped abacavir. There were 24 serious adverse events—six in the symptom-free children (all on nelfinavir), but none were attributed to nelfinavir. Interpretation Regimens containing abacavir were more effective than zidovudine/lamivudine. Such regimens could be combined with protease inhibitors and non-nucleoside reverse transcriptase inhibitors for safe and effective treatment of previously untreated children with HIV-1.

To estimate prevalence of body fat redistribution and dyslipidaemia in HIV-infected children and to assess associated risk factors, ultimately to inform the definition of lipodystrophy in children.Cross-sectional observational study.During a 2-3 month period, 477 HIV-infected children agedor= 3 years (median 9.78; range, 3-18) in 30 paediatric HIV clinics were assessed at their first visit. Sociodemographic, clinical and immunological data were recorded and the presence or absence of clinical signs of fat redistribution (peripheral lipoatrophy and central lipohypertrophy) determined according to an agreed protocol. Laboratory indicators of lipid/glucose metabolism were recorded for all children in 18 centres.Prevalence was 26.0% [95% confidence interval (CI), 22.1-30.2] for any fat redistribution, 8.81% (95% CI, 6.42-11.7) for central lipohypertrophy, 7.55% (95% CI, 5.34-10.3) for peripheral lipoatrophy and 9.64% (95% CI, 7.15-12.7) for the combined subtype (more than one sign of each). Independent predictors of fat redistribution included Centers for Disease Control and Prevention class C disease, female gender, ever used versus never use of protease inhibitors and of stavudine. Increasing time since initiation of antiretroviral therapy was associated with increased severity of fat redistribution. In the metabolic assessment subgroup, 27% (95% CI, 21.6-32.7) of children had hypercholesterolaemia and 21% (95% CI, 16.4-26.6) hypertriglyceridaemia; however, significantly more children had fat redistribution in this subgroup than overall (31%).Approximately a quarter of children and adolescents could be taken to have signs of lipodystrophy, with clinical presentation and risk factors similar to those described in adults.

Hintergrund: Viele Studien uber den Kaiserschnitt und die Rate der vertikalen Transmission von HIV-1 (TR) haben sehr unterschiedliche Ergebnisse erbracht, wenn nicht gleichzeitig AZT in der Schwangerschaft gegeben wurde.

Die Autoren haben einen von amerikanischen Experten fur die USA erarbeiteten Konsens ausfuhrlich diskutiert und eigene Empfehlungen entwickelt, die den verantwortlichen Fachgesellschaften zur Begutachtung vorgelegt wurden. Nach diesem Konsens wird eine antiretrovirale Therapie primar entsprechend der Anzahl der HIV-Kopien im Plasma eingeleitet, sekundar entsprechend immunologischen und klinischen Kriterien. Zusatzlich mussen altersspezifische Grenzwerte fur den Einsatz der Therapie berucksichtigt werden. Kriterien fur die Effektivitat der Therapie werden definiert und fur den Fall des Scheiterns der Behandlung Alternativen aufgezeigt. Zahlreiche Medikamenteninteraktionen mussen bei der Durchfuhrung einer antiretroviralen Therapie berucksichtigt werden. Schlieslich wird aus padiatrischer Sicht eine Empfehlung zur Reduktion der vertikalen Transmission gegeben.

In children born to immunocompetent women, congenital toxoplasmosis almost always results from primary infection during pregnancy. However, reactivation of latent toxoplasmosis during pregnancy could occur in HIV-infected pregnant women, particularly in those who are severely immunocompromised, and result in maternal-fetal transmission of the parasite. This mode of infection has been described in case reports but the risk of transmission is unknown. Findings on toxoplasmosis are presented from the European Collaborative Study, a prospective study of children born to women known to be HIV-infected at the time of delivery. In 1058 children followed for a mean duration of 35 months, only one child developed clinical toxoplasmosis. This child was HIV-infected, severely immunocompromised, and acquired toxop]asmosis postnatally. Congenital infection was excluded serologically in a subgroup of 167 children, of whom an estimated 71 had been at risk of infection. These clinical and serological findings indicate a low general risk of maternal-fetal transmission of Toxoplasma infection in HIV-infected women. It is not possible to draw conclusions about the risk of transmission for severely immunocompromised HIV-infected women because most women in the study were asymptomatic.

We examined 48 placentas of human immunodeficiency virus (HIV)-exposed pregnancies morphologically for HIV-specific changes and immunohistologically for the presence of HIV antigen and RNA. Findings were correlated to infectious states of the children and maternal risk factors. Few HIV antigen-positive Hofbauer cells and HIV RNA positive syncytiotrophoblast and Hofbauer cells were detected. HIV-positive cells in the placenta did not correlate with intrauterine infection and maternal immunologic parameters. Light microscopically, we found two changes: immaturity of the terminal villi and allantois vasculopathy. These changes, however, are not HIV specific. Our results show that vertical HIV transmission cannot be diagnosed by morphological examination of the placenta.

BACKGROUND: Risk factors for mother-to-child transmission of hepatitis C virus (HCV) are poorly quantified. METHODS: We conducted a European multicenter prospective study of HCV-infected pregnant women and their infants. Children with > or =2 positive HCV RNA polymerase chain reaction test results and/or anti-HCV antibodies after 18 months of age were considered to be infected. RESULTS: The overall HCV vertical transmission rate was 6.2% (95% confidence interval [CI], 5.0%-7.5%; 91/1479). Girls were twice as likely to be infected as boys (adjusted odds ratio [OR], 2.07 [95% CI, 1.23-3.48]; P=.006). There was no protective effect of elective cesarean section (CS) delivery on HCV vertical transmission (adjusted OR, 1.46 [95% CI, 0.86-2.48]; P=.16). HCV/human immunodeficiency virus-coinfected women more frequently transmitted HCV than did women with HCV infection only, although the difference was not statistically significant (adjusted OR, 1.82 [95% CI, 0.94-3.52]; P=.08). Maternal history of injection drug use, prematurity, and breast-feeding were not significantly associated with transmission. Transmission occurred more frequently from viremic women, but it also occurred from a few nonviremic women. CONCLUSIONS: Our results strongly suggest that women should neither be offered an elective CS nor be discouraged from breast-feeding on the basis of HCV infection alone. The sex association is an intriguing finding that probably reflects biological differences in susceptibility or response to infection.

Objective To investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. Interventions Elective caesarean section before labour, usually at 36-38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen). Results Of 179 mother-infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0-4.7] and 12.6% (6.4-19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6-8 weeks. Conclusion A much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.

CMV infection is common in pediatric HIV-1 infected patients. We present a case report, to our knowledge the first pediatric patient, in which Addison-disease due to CMV was suspected during lifetime. We want to point out the importance of routine clinical and laboratory follow up once a HIV-1 infected child is shown to be infected with CMV.

As a result of preventive measures during pregnancy and improved antiretroviral combination treatment, the problem area of HIV infection in childhood has undergone a change in recent years. Thanks to intensive cooperation between obstetricians and pediatricians, mother-to-child transmission of HIV in Germany has been decreased to less than 2%. Improvements in the diagnosis of HIV infection in childhood, infected children have been identified very early, and started on antiretroviral treatment, and prophylactic measures initiated. In the case of life-long anti-HIV treatment beginning in childhood, the same problems as those seen in adults must be expected (development of resistance, adherence, adverse effects).

Inwieweit der Patient einer verschriebenen Medikation nachkommt, wird durch eine Reihe von Faktoren beeinflutst. Aus der Behandlung verschiedener akuter and chronischer Erkrankungen des Kindesalters ist bekannt, das Arzt-Patientenverhaltnis, Charakteristika der medikamentosen Behandlung and Eigenschaften des Patienten die Adharenz, im folgenden immer auf die Medikamenteneinnahme bezogen, in unterschiedlicher Weise verandern. Abweichend von der Erwachsenenmedzin werden in der Padiatrie Adharenzbestimmende Faktoren durch das Alter des Kindes and die Vermittlung der Eltern modifiziert. Durch die Anwendung einer Vielzahl von Mefsmethoden fur die Adharenz (z. B. Selbsteinschatzung durch Interview oder Fragebogen, Auswertung uber die Anzahl ausgestellter Rezepte, Einschatzung durch medizinisches Personal, Medikamentenspiegel-messungen) liegen die Angaben zum Grad der Adharenz weft auseinander.

The objective of this study was to compare polymerase chain reaction (PCR) fingerprinting with other molecular typing methods as an epidemiologic tool to investigate the transmission of Candida strains between HIV-positive mothers and their children. Forty-nine yeast strains (including Candida albicans, Candida glabrata, Rhodotorula rubra, Candida tropicalis, Candida famata, Candida dubliniensis, Saccharomyces cerevisiae) from 30 individuals (15 children and 15 HIV-infected mothers or accompanying person) were isolated. Colonization/infection with yeast was observed in 80% of all individuals in the oral cavity, and in 33% from hand cultures, respectively. Thirteen out of 15 children (86%) and 12 out of 15 adults (80%) were colonized/infected with yeasts. Candida dubliniensis strains were found in four HIV-infected women but not in children. The results with an arbitrarily primed (AP)-PCR mediated genotyping assay using phage M13 core sequence were compared with the hybridization patterns using the species-specific DNA probe CARE-2 for the C. albicans isolates. Typing of non-C. albicans strains was done using AP-PCR in comparison with pulsed-field gel electrophoresis (PFGE). Twenty-six C. albicans strains gave two different genotypes by AP-PCR but 16 genotypes by CARE-2 hybridization. The CARE-2 probe appeared to have a higher discriminatory power compared with the primer 'M13'-mediated AP-PCR in typing C. albicans isolates.

Neben der Ubertragung der HIV-Infektion durch infektioses Blut oder Blutprodukte oder sexuellen Kontakt stellt die vertikale HIV-Transmission den haufigsten Infektionsmodus der kindlichen HIV-Infektion dar. Bei der vertikalen Transmission handelt es sich meist um eine pra- bzw. perinatale Infektion, wesentlich seltener ist eine postpartale Ubertragung durch das Stillen.

In a prospective study 15 consecutive children and 12 HIV-infected mothers were examined according to their colonization with Candida species in the oral cavity and on the hands. From 39 samples a total of 49 Candida isolates could be recovered (26 C. albicans, 4 C. glabrata, 9 Rhodotorula rubra, 4 C. dubliniensis, 3 C. tropicalis, 2 C. famata, 1 S. cerevisiae). Antifungal susceptibility testing revealed fluconazole MICs from 0.09 microgram/ml to 100 micrograms/ml. Genotyping was done with an AP-PCR technique using the primer "M13" and "(GACA)4". From the mycologic culture identical yeast isolates were found in 10 families. However, with PCR typing identical findings were seen only in 5 families. A C. albicans isolate resistant to fluconazole in vitro was found in a child and the mother of the same family. It could be summarized that yeast strains are transmitted between HIV infected mothers and their children. With PCR typing diversity among yeast isolates could be demonstrated even between members of the same family.

Within a prospective study of the course of HIV-infection in women, 80 HIV-infected women without AIDS were delivered of 80 children between 1985 and September 1992. The median of the age of gestation was 38 weeks. Until 1988 Caesarean section was chosen as mode of delivery (45 women). Later when the mode of delivery appeared to have no influence on the frequency of maternofetal HIV transmission, vaginal delivery was preferred (35 women). None of the infants was breastfed. Three infants --delivered vaginally--died within the first 6 months of life before their infection status could be determined. Seventy-seven children could be observed for 18 months or longer regularly every three months. 10 of the 77 children were found to be HIV- infected by serological, virological and clinical criteria. Taking into account the mode of delivery, of 32 children who were delivered vaginally or by emergency Caesarean section 8 were found to be HIV-infected. None of 26 children delivered by elective Caesarean section after an uneventful pregnancy is infected. In 19 women Caesarean section was performed within 2 hours after onset of labour or after episodes of preterm labour which required hospital admission for treatment. Two children of these women are infected. No differences of CD4+ cell counts and p24 antigenaemia could be determined between the mothers of the three groups. The risk of fetal HIV infection was increased by preterm labour (p0.01) and the mode of delivery (p0.01). A correlation between loss of CD4 cells in the mother and increased risk of infection for the child is seen in children born spontaneously or delivered by emergency Caesarean section (p0.001). No correlation was found between the length of labour at delivery, the time of the rupture of membranes before birth as well as of the parity and the risk of fetal infection in that group. These findings point to labour as an important factor which increases the risk of maternofetal transmission of HIV. The onset of labour is accompanied by dramatic immunological alterations as a sudden increase of chemotactics and inflammatory cytokines at the maternofetal interface. The accumulation and stimulation of maternal immune cells will--if these cells are carriers of HIV--result in production and release of infectious HIV. This virus may accumulate in the maternofetal interface or gain access to the amniotic cavity. Since amniotic fluid is swallowed by the fetus, the largest potential port of entry for HIV in the fetus are the fetal lungs and the gastrointestinal tract. For the prevention of maternofetal transmission of HIV delivery before onset of labour or alternatively the protection of the fetus during parturition by means of potent antiviral compounds can be considered.

Eight of 13 children pre- or perinatally infected with the HIV virus subsequently developed neurological symptoms. Three children also had other nonspecific symptoms (fever, lymphadenopathy, diarrhoea, hepatosplenomegaly, failure to thrive and mucocutaneous thrush). Five children developed illnesses associated with AIDS (opportunistic infections, cachexia and lymphocytic interstitial pneumonia). The neurological abnormalities predominantly affected motor functions, only later also involving sensory ones. Motor, cognitive and language development was impaired in all eight children. A loss of developmental milestones occurred in three children with HIV encephalopathy: they have since died. In all the children the HIV infection caused symptoms within the first year, progressing more quickly in the three with encephalopathy. There were no discernible risk factors to account for the difference in the course of the disease.

Treatment of secondary infections in HIV infected children represents a problem of increasing importance in several children's hospitals. As it is unlikely that the AIDS-problem will be solved by itself within the next years it seems reasonable to summarize our current knowledge about opportunistic infections in order to establish standards for therapy. We will mainly focus on microorganisms endemic in Germany.

Infection with the human immunodeficiency virus (HIV) induces a polyclonal B-cell activation. Despite elevated serum immunoglobulin levels, a significant deterioration of the antigen specific humoral immune response exists in most cases. We studied the influence of HIV infection on the serum levels of IgG subclasses in children. We investigated 76 children (aged 15 months to 18 years) with HIV-1-infection. Most children (88%) showed elevated serum immunoglobulin levels. IgA (87%) and IgM (74%) were more often above normal levels for age than IgG (60%). IgG subclass serum levels were significantly altered. The increase in total IgG was mainly due to a marked augmentation of the IgG1 fraction. In most cases IgG3 was simultaneously elevated. Ten children (13%) had very low IgG4 levels (less than 0.03 g/l). Out of 61 patients older than 2 years 8 (13%) had a profound IgG2 deficiency with normal or elevated total IgG. Four of them also had low IgG4 levels (less than 0.03 g/l). A correlation between IgG2 deficiency and HIV infection according to the Centres for Disease Control classification for acquired immunodeficiency syndrome could not be demonstrated (three patients with symptomatic and five with asymptomatic infection).

The determination of an HIV infection in children of infected mothers has been a problem for years. Despite the development of new diagnostic methods, this problem has not been simplified. On the contrary, contradictions between the clinical courses and the laboratory results become ever more obvious and complicate the assessment of HIV exposed child's infection status. It is therefore necessary to monitor all HIV-exposed children through longitudinal examinations in order to verify or exclude HIV infection.

The spectrum of opportunistic infections seen in HIV disease in children resembles that in adults. Most striking, however, is the role of bacterial infections in pediatric AIDS. Although defective humoral immunity seems to play a significant role in predisposing to bacterial infections, there is no direct correlation between the risk for bacterial infections and poor B cell mitogenic responses or hypergammaglobulinemia (Rubinstein 85), suggesting additional predisposing factors.

Case histories of two infants with malignant melanoma are presented. Both tumors had developed from a congenital mole to advanced disease with lymph node metastasis at time of diagnosis, findings which are commonly correlated with poor outcome. Initially, both patients were surgically treated. From the experience with few described cases of melanoma in childhood and with a large number of adult patients, neither chemotherapy and conventional BCG immunotherapy nor irradiation seem to be an effective treatment and are accompanied by many adverse side effects. Therefore in one patient therapy was limited to surgery alone. In the other child it was followed by treatment with high-dose recombinant alpha-2-interferon (1 Mill. i.u./Kg X d) plus an H2-receptor antagonist. Unexpectedly this girl developed neurological side effects, characterized by spastic paraparesis, indicating damage to the first motoneuron. All symptoms completely resolved after discontinuation of drugs within three months. Both children have been in complete remission for 18+ and 32+ months, respectively.

Both resolved and still open questions are discussed. The natural course of HIV infection from the time at which a child becomes symptomatic is known. The incidence rate of HI-virus transmission to the child remains uncertain. Likewise the time of transmission and its cofactors as well as data about the incubation and latency periods remain open questions. The greatest problem thus, is the early and reliable definition of HIV infection. Initial results from prospective HIV-perinatal studies are presented, showing that a transmission rate between 20% and 40% is to be reckoned with.

As part of a project within the European Community research activities on acquired immunodeficiency syndrome (AIDS), infants born to human-immunodeficiency-virus-seropositive mothers are being followed up from birth. By October, 1986, 71 infants from Padua, Berlin, and Edinburgh had been followed up to a median age of 6 months (range 1-15 months). Symptoms of AIDS or AIDS-related complex (ARC) had developed in 5, 3 of whom had died. The median age at antibody loss was during the 10th month. An estimated 75% will have lost maternal antibody by 12 months, but loss of antibody did not exclude infection confirmed by virus culture. Numbers were too small to draw conclusions about the risk of AIDS/ARC and mode of delivery or breast-feeding. The study suggested that the risk of AIDS/ARC is higher in infants born to mothers who have AIDS symptoms during pregnancy.

Primare Lymphome des Zentralnervensystems (ZNS) sind seltene Erkrankungen. Haufig findet sich in ihrer Umgebung eine ausgepragte Gliaproliferation, die zur Fehldiagnose «Astrozytom» fuhren kann. Ein 15jahriger Patient wurde wegen eines vermeintlichen Astrozytoms Grad 2 extern mit 40 Gy im Bereich der hinteren Schadelgrube und des Hirnstammes bestrahlt. Ein Tumorrezidiv 5 Monate nach Radiatio fuhrte nach erneuter Biopsie zu einer Revision der Eingangsdiagnose i.S. eines hochmalignen Non-Hodgkin-Lymphoms (NHL) vom B-Zell-Typ (zentroblastisches Lymphom). Nach zyklischer Polychemotherapie, unter anderem mit hochdosiertem Methotrexat und Cytosin-Arabinosid, kam es zur kompletten Remission. Der Patient ist bisher 18 Monate nach Ende der Therapie krankheitsfrei. Eine nochmalige Strahlentherapie erfolgte nicht.

In 23 children with mild iron-deficiency anemia, 22 children with latent iron-deficiency, and in 46 healthy controls the3H-thymidine incorporation in blood lymphocytes after stimulation with phytohemagglutinin, concanavalin A, pokeweed mitogen, and serum against thymocytic cells was measured. In 11 of the children with iron-deficiency anemia, in 13 of the children with latent iron-deficiency, and in 20 controls the lymphotoxin secretion after phytohemagglutinin stimulation was also performed. All patients studied were without intercurrent infections and were well nourished.

The results of the first screening in pregnant women for HIV antibodies published in the literature were obtained at the Charlottenburg Gynecological Clinic of the Free University of Berlin, and are communicated here. They indicate that in future it will be questionable whether AIDS should be looked for only among risk groups, as is currently the case in many obstetric centers. Tests for HIV were positive in 0.5% of 1295 pregnant women who did not belong to a risk group (heroin addicts, prostitutes, transfusion recipients); the findings were confirmed with the more specific Western Blot. Consequently, therefore, it is recommended that HIV screening should be included among the basic antenatal care examinations, the patient having been thoroughly informed. In order that the patient be aware of the reality of the risk, she should, if possible, be informed in early pregnancy: the family physician therefore has a special obligation to fulfil. The fact that increasing numbers of infected women do not belong to risk groups is a further argument in favor of HIV screening. Moreover, AIDS has become the most common infection with serious consequences for mother and child. Patients in whom the test for HIV antibodies is positive also require appropriate counseling and care. Finally, the need to protect both patients and staff against infection during birth must not be neglected.

The cyclic chemotherapy scheme OS I/75 was tried in 6 patients with newly diagnosed osteosarcoma and in 3 patients with secondary metastases. The treatment consists of high dose methotrexate, followed by citrovorum-factor rescue, doxorubicine (Adriblastin) and cyclophosphamide (Endoxan). All 6 primary patients are in a continuous remission of 6+ to 21+ months (median 12+ months). The length of remission in the patients with metastases is 5.5+ and 8+ months. The haematological side effects led to an average prolongation of the cycle by 11 days in a planned cycle duration of 42 days. However, they were readily manageable. Among the other side effects two cases of Adriblastin myocardiopathy are remarkable which became apparent after methotrexate and ifosfamide. In order to improve possibilities for treatment regional centralisation of patient care and interdisciplinary and supraregional cooperation of treatment centres are necessary. A prospective treatment programme has been developed for the Federal Republic of Germany and Austria.

Both resolved and still open questions are discussed. The natural course of HIV infection from the time at which a child becomes symptomatic is known. The incidence rate of HI-virus transmission to the child remains uncertain. Likewise the time of transmission and its cofactors as well as data about the incubation and latency periods remain open questions. The greatest problem thus, is the early and reliable definition of HIV infection. Initial results from prospective HIV-perinatal studies are presented, showing that a transmission rate between 20% and 40% is to be reckoned with.

The cooperative study COALL-80 is derived from the BFM-78-study. The aim of the study is a reduction of the initial therapy-morbidity and -mortality without loss of efficacy by omitting asparaginase from the four drug-induction regimen and interposing it between induction- and CNS-therapy phase. The expected two years disease free survival rate of a pilot study will be 82%. This finding is hitherto comparable with the BFM-study results.

Blood cells proliferated and differentiated in vitro should be classified according to the classical hematologic nomenclature only after unequivocal identification by classical hematologic techniques. This has been done by Maxinow [6] and others at the beginning of this century, more than 50 years ago, when they established their in vitro methods of bone marrow in semisolid media. In contrast, modern experimental hematologists sometimes use the nearly 100 years old classification of human blood cells which is rather uncritical to characterize blood cells grown in vitro.

Das humane Immundefizienzvirus HIV (= LAV/HTLV III, ARV, AAV) wird heute als den Lentiviren sehr eng verwandt angesehen. Lentiviren stellen eine Untergruppe der Retroviren dar, ihr Name leitet sich von dem langsamen Krankheitsverlauf ihrer Infektionen ab (lentus = langsam). Typisch fur diese Erregergruppe sind Viruspersistenz bei gleichzeitiger Antikorperbildung, bedingt durch haufige Mutationen des Virus (Sonigo et al. 1985; Petursson et al. 1976; Haase 1986), und langsam sich entwickelnde Erkrankungen des Immunsystems und anderer Teile des hamopoetischen Systems sowie progrediente neurologische Storungen. Typisch ist auch eine sehr hohe Letalitat bei Infektionen mit dieser Virusgruppe.

From 1971 through 1979 145 newly diagnosed patients with ALL have been treated within a series of consecutive studies. Study I corresponds to branch A of the 1972 DAL study. In the following studies the induction therapy has been escalated stepwise with the continuation therapy remaining mostly unchanged. Thereby the disease free survival rates increased from 75 to 94% after one year and from 32 to 60% after 4 years respectively. CNS-relapse mainly occurred during the second year of treatment. Their incidence rose from 5% to more than 10% in connection with a change in the radiation portal. Since another correction of the portals with special consideration of the paramedian lower border of the skull base no more CNS-relapses have been observed until now. The actual cooperative ALL-study follows a modified BFM-protocol with postponed asparaginase in hoping to achieve reduced initial morbidity and at least equal good survival times.