Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome
Paediatric European Network for Treatment of AIDS (PENTA)
See also p. 325
From *See Appendix for Writing Committee and PENTA Committees.
Requests for reprints to: Dr A. Faye, Hôpital Robert Debré, Service de Pédiatrie Générale, 48 Boulevard Serurier 75935 Paris Cedex 19, France.
Correspondence to Dr A. Compagnucci, INSERM SC 10, 16 Avenue P.V.Couturier, 94807 Villejuif, France.
Received: 29 January 2003; revised: 11 June 2003; accepted: 8 July 2003.
Objective: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age.
Design: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7).
Methods: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated.
Results: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9–4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2–6.8) and CD4% 33% (range, 11–66). Median follow-up was 96 weeks (range, 60–144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations.
Conclusions: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.
The use of highly active antiretroviral therapy (HAART) has dramatically reduced mortality and morbidity in HIV-infected adults and children [1–3]. Further, the use of antiretroviral therapy in pregnancy ensures that few children born to known HIV-infected women in developed countries are now themselves infected. However, there are currently no randomized trials examining when to start HAART in asymptomatic infants who are diagnosed very early in life.
Cohort data from the United States and Europe showed that 20–25% of untreated HIV-infected babies in the early 1990s progressed to AIDS or death during the first year of life, mostly as a result of Pneumocystis carinii pneumonia (PCP) . Further, very high HIV-1 RNA viral loads are observed following primary infection during infancy and are likely to reflect the immaturity of the immune system for bringing viral replication under control . These factors provide a rationale for immediate initiation of HAART in vertically HIV-1-infected infants with early diagnosis, which is supported by current paediatric guidelines on initiation of HAART in the United States .
In the small numbers of children studied to date, initiation of therapy around the time of birth dramatically restored the developing immune system . However, treatment of infants with HAART is complex, and high rates of virological failure have also been observed in infancy . Lack of appropriate age-specific pharmacokinetic data, immature drug metabolism , food restrictions and inadequate paediatric formulations need to be considered when treating infants.
In order to assess the impact of HAART started early in infancy, PENTA 7 is a prospective multicentre, non-randomized study of a triple combination therapy, stavudine, didanosine and nelfinavir, in vertically HIV-1-infected infants aged less than 3 months.
Children aged less than 12 weeks were eligible if they had evidence of definitive HIV-1 infection, defined as the presence of virus on culture in peripheral blood mononuclear cells, the presence of p24 antigen, or HIV-1 DNA/RNA detected by polymerase chain reaction (PCR) or equivalent technique on each of two consecutive samples taken on separate days. Inclusion up to 16 weeks of age was allowed for infants where diagnosis was delayed. Infected children exposed to in utero and/or perinatal antiretroviral therapy to prevent mother-to-child transmission were eligible, but resistance testing was required before enrolment if the infant had been exposed to any of the trial drugs. Infants were excluded if they had Centers for Disease Control and Prevention (CDC) stage C disease; severe hepatic or renal insufficiency; abnormalities leading to problems with intake and absorption of the drug; or haematological, hepatic, pancreatic or renal contraindications to receiving didanosine, stavudine or nelfinavir.
All primary caregivers gave written informed consent following receipt of detailed information about the study from clinical staff at each site. The protocol was approved by the ethics committee of each participating centre.
Trial design and treatment
PENTA 7 is a multicentre, phase I/II, open label, non-randomized study to assess the toxicity, tolerability and activity of stavudine, didanosine and nelfinavir in vertically HIV-1-infected infants. These drugs were chosen because, at the time, zidovudine, lamivudine and nevirapine were all commonly used to reduce mother-to-child transmission, so concerns about resistance supported the use of a stavudine plus didanosine backbone. Further, efavirenz and other protease inhibitors were not available in formulations suitable for infants, nor were there adequate pharmacokinetic data in infants. Nelfinavir was available as a powder or tablet (which could be crushed and mixed with milk). Infants initially received stavudine suspension (2 mg/kg daily in two divided doses), didanosine suspension (200 mg/m2 daily in two divided doses) and nelfinavir powder/crushed tablets (120 mg/kg daily in three divided doses). The daily dose of nelfinavir was increased to 150 mg/kg after pre-planned pharmacokinetic studies performed on the first four infants showed low area under the concentration–time curve (AUC) . In addition, subsequent infants received nelfinavir twice daily after data within the study showed similar AUC and troughs with dosing twice or three times a day.
Toxicity and tolerability were evaluated through reporting of adverse events, categorized according to the US National Cancer Institute toxicity table modified for children. Activity was measured by plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression. The emergence of resistance mutations was also investigated as a contributing factor to the efficacy of the HAART regimen.
Trial management and procedures
Infants were screened for eligibility once the HIV-1 diagnosis was confirmed (week −2). Trial drugs were prescribed at week 0. Clinical assessments were performed at week −2, 0, 2 and 4, then every 4 weeks to 36 weeks and every 6 weeks to 72 weeks. Laboratory assessments included full blood count, biochemistry (including lipase, triglycerides and glucose), plasma HIV-1 RNA levels and CD4 cell counts at weeks −2, 0, 4, 12 and then every 12 weeks. Lactate levels during the follow-up were included from June 2001 after the report of three fatal cases of lactic acidosis in pregnant women receiving stavudine with didanosine. Blood levels of nelfinavir and its active metabolite M8 were measured in stored plasma samples collected before dosing or, if not possible, at 1.5 or 3.5 h after dosing. The time of the last dose was accurately recorded. All samples taken between 0 and 1.5 h and beyond 10.5 h after dosing were considered as trough levels.
Serious adverse events were those following the International Committee on Harmonization of Adverse Event Reporting (ICH) definition and laboratory grade 3 and 4 adverse events.
Clinical disease was staged according to the 1994 CDC revised classification .
Plasma HIV-1 RNA was determined by reverse transcriptase PCR in real time in a central Laboratory (Covance-Geneva) using the Roche Standard Amplicor assay version 1.5 (Roche Molecular Systems, Branchburg, New Jersey, USA; lower limit of quantification, 400 copies/ml). All samples < 400 copies/ml were retested with the Roche Ultrasensitive assay version 1.5 (lower limit of quantification 50 copies/ml) and those > 750 000 copies/ml were retested using a dilution method. T cell lymphocyte subset analysis was performed locally at each site.
Virological failure was defined as HIV-1 RNA levels > 400 copies/ml on two successive occasions after 12 weeks of therapy (with the time to failure taken as the time to the first of the two measurements). Patients who did not reach < 400 copies/ml were considered as failing at 12 weeks of treatment. Resistance genotypic test was performed at baseline in all children and then, through follow-up, on samples available from children failing therapy. Viral RNA was isolated from plasma samples and amplification and sequencing of the genes for reverse transcriptase and protease were performed using the consensus technique of the Resistance Group of ANRS . Changes at codons linked to resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors were reported according to the International AIDS Society recommendations (http://www.iasusa.org) .
The PENTA 7 study was jointly coordinated by the Medical Research Council Clinical Trials Unit in the United Kingdom and INSERM SC10 in France under the auspices of PENTA (Paediatric European Network for Treatment of AIDS), according to the ICH Guidelines for Good Clinical Practice.
The Data and Safety Monitoring Committee met in March and December 2000 to review safety and efficacy data. In December 2000, the Committee recommended to stop enrolment of new infants but continue follow-up of the 20 infants already enrolled.
All analyses other than toxicity were performed for all enrolled children regardless of any changes to therapy. Toxicity analyses were performed for time on any of the trial drugs (didanosine, stavudine or nelfinavir) plus 30 days.
HIV-1 RNA levels were log10 transformed prior to analysis. Baseline values were those recorded nearest to, but before and within, 2 weeks of initiation of therapy. After baseline, the closest measurement to the nominal assessment week was used.
CD4 cell counts, height and weight were expressed as Z-scores with reference to healthy children who were not infected with HIV-1 . Changes in HIV-1 RNA, CD4 cells, height and weight Z-scores from baseline were assessed using the paired Wilcoxon signed-rank test. All reported P values are two sided.
Twenty infants were enrolled between August 1999 and December 2000 from 16 clinical centres in five countries: France (eight), Spain (five), Germany (three), Italy (three) and UK (one). The demographic and baseline characteristics are shown in Table 1. Four (20%) infants were premature (gestational ages 24, 29, 30 and 31 weeks). Their weights at birth were 0.65, 1.0, 1.83 and 2.10 kg, respectively, and their ages at treatment initiation were 2.6, 3.6, 3.4 and 4.0 months, respectively. Six infants started after 3 months of age (three because of delayed diagnosis, one because of prematurity and two because of a delay in drug supply).
The seven (35%) infants receiving only postnatal prophylaxis took zidovudine (five), zidovudine plus lamivudine (one) and zidovudine plus nevirapine (one). Eleven (55%) infants were exposed to antiretroviral drugs both in utero and perinatally: zidovudine (five), zidovudine plus lamivudine (one), zidovudine plus lamivudine plus nelfinavir (one), zidovudine plus lamivudine plus nevirapine (two), didanosine plus zalcitabine plus saquinavir (one), and stavudine plus lamivudine plus nevirapine (one).
The three infants with stage B diagnoses at baseline had septicaemia, cytomegalovirus infection before 1 month of age and failure to thrive, respectively.
Follow-up and treatment status
Median follow-up to 1 August 2002 was 96 weeks (range, 60–144). One infant died at week 60 (see below) and all others were followed up to at least week 72. Eleven (55%) infants were last seen alive still on the initial triple therapy. Four (20%) infants stopped all trial drugs – and did not start new therapy – because of viral load rebound (one, week 66), lack of viral load response (one, week 28) or parental request (two, week 72; HIV-1 RNA < 50 copies/ml). Four (20%) infants switched immediately or subsequently to other three or four-drug combination at week 32 (one) and week 60 (three) because of lack of viral load response.
Eight weeks after the change in recommended nelfinavir daily dose to 150 mg/kg in two divided doses, the mean prescribed nelfinavir daily dose was 155 mg/kg (range, 120–196) and remained stable subsequently.
Safety and tolerability
One infant died at week 60 from respiratory distress not related to HIV (obliterant bronchiolitis related to prematurity). The infant was born at 30 weeks of gestation, with treatment initiated 15 weeks after birth and with last recorded HIV-1 RNA < 50 copies/ml and CD4% 28%. Four serious adverse events were reported (two episodes of bronchiolitis in the infant who died, two hospitalisations for a central line placement and suspicion of arthritis, respectively) but none was considered related to any of the trial drugs. A total of 48 minor (clinical grade 1 and 2 and laboratory grade 2) adverse events were reported in 15 infants, the most common being neutropenia (10 in six infants; 30%), anaemia (seven in five infants; 25%), raised alkaline phosphatase (four in four infants; 20%), vomiting (five in four infants; 20%) and diarrhoea (three in three infants; 15%). Although 11 events (in seven infants; 35%) were considered to be related to at least one of the trial drugs, only three caused trial drug modification: rash/erythema interrupting didanosine and stavudine for 1 day and nelfinavir for 10 days; diarrhoea resulting in permanent discontinuation of didanosine and switch to lamivudine; and neutropenia, resulting in reduction of stavudine dosage.
Seven infants started with nelfinavir powder and switched after a median of 103 days (range, 8–283) to crushed tablets because of difficulties in administering powder reported in a self-administered questionnaire (data not shown).
Non-fasting triglycerides levels were determined in all infants during follow-up (range of number of concentrations, 5–20). All infants but one (95%) had at least one episode of grade 1 triglyceridaemia (defined as a value between 136 and 749 mg/dl). Post-baseline total cholesterol data were available for 12 infants (range of number of concentrations, 1–16). Nine (9/12) infants had at least one episode of grade 1 hypercholesterolaemia (defined as a value between 171 and 499 mg/dl). No infant had grade 2 or more cholesterol or triglycerides concentrations, and no infant developed clinical lipodystrophy.
In two infants, HIV disease progressed: from CDC stage A to B at week 8 in one caused by persistent fungal infection and recurrent diarrhoea, and from CDC stage N to A because of lymphadenopathy at week 20 in the other. No infant progressed to CDC stage C disease. Further, both weight and height adjusted for sex and age had increased significantly by week 72 (median changes from baseline were +0.53 and +1.41, respectively, at week 72; P ≤ 0.02; Table 2).
Although the increases in CD4% and CD4 cell Z-score were not significant (Table 2), all but two (with CD4% of 17 and 23) of the 19 infants alive at week 72 had CD4% > 25%, including both the infants with CD4% < 15% at baseline.
A rapid decrease in plasma HIV-1 RNA occurred after 4 weeks of therapy (median fall 2.06 log10 copies/ml); although this decrease was sustained beyond week 12, the decline did not continue further (Fig. 1). However, relatively few infants achieved suppression of plasma HIV-1 RNA to < 400 or < 50 copies/ml (Table 3). For example, at 48 weeks, 37% of infants with HIV-1 RNA measurements had values < 400 copies/ml and 21% < 50 copies/ml.
Excluding the infant who died with a last HIV-1 RNA < 50 copies/ml, 14 infants had virological failure by week 72, of whom six (30%) never achieved viral load < 400 copies/ml. In four infants, viral load decreased to < 400 copies/ml and then rebounded to > 400 copies/ml. Four infants only achieved viral load suppression to < 400 copies/ml after week 72, one without changing therapy. In the five infants with no rebound and remaining at < 400 copies/ml at week 72, the median time to reach < 400 copies/ml was 16 weeks (range, 4–36).
Although the power to detect genuine differences was low because of the small sample size, Cox proportional hazards regression model was used to investigate prognostic value of some baseline characteristics or early changes on the risk of virological failure by 72 weeks. There was no association between virological failure and gestational age, age at initiation of HAART, baseline HIV-1 RNA, baseline CD4%, time between stopping prophylaxis and starting HAART, or time between HIV evidence and starting HAART. However, log10 HIV-1 RNA value at week 4 was predictive of virological failure (hazard ratio, 2.37; confidence interval, 1.13–4.97; P = 0.022) although log10 HIV-1 RNA decline at week 4 was not a predictive factor (P = 0.22).
Nelfinavir and metabolite M8 trough levels were determined in 99 samples from 18 infants. The median number of samples per infant was five (range, 1–11). Only 30 samples (30%) had nelfinavir trough levels above the nelfinavir target value of 700 μg/l showing lower nelfinavir concentrations in these infants compared to older childen (21). Overall the median concentrations of nelfinavir and metabolite M8 were 337 μg/l (interquartile range, 63–975) and 204 μg/l (interquartile range, 57–505), respectively.
At baseline, two infants were infected with a resistant virus (one infant with virus mutations 41L, 103N, 210W, 215Y, M36I, conferring resistance to zidovudine, stavudine and non-nucleoside reverse transcriptase inhibitor drugs; one infant with virus mutation 215Y, conferring resistance to zidovudine and stavudine). At time of inclusion, these mutations were not considered as conferring resistance to stavudine and didanosine (changes in resistance algorithm interpretation) and, therefore, both children were included in the study. Of the remaining 18 infants with wild-type virus at baseline, six achieved plasma HIV-1 RNA < 400 copies/ml and maintained suppression throughout follow-up and seven did not select resistance mutations despite ongoing viral replication during follow-up. However, five (25%) infants did select resistance mutations (three to nelfinavir alone; one to stavudine, zidovudine and nelfinavir; one to didanosine). One of the infants with mutant virus at baseline had selected further mutations (41L, 67N, 70R, 215Y, 30N, 46I/l, 63P/A) at week 72, conferring resistance to stavudine, didanosine, zidovudine, nelfinavir and indinavir (Table 4). The phylogenetic analysis revealed that 11 children were infected with B subtype virus, four with CRF02, two with subtype A, one with subtype G, one with subtype C and one with subtype D. Five of the mutated viruses were subtype B strains; one was subtype C.
Few data on early treatment in infants are available. In PENTA 7, we have shown that early initiation of HAART with stavudine plus didadosine plus nelfinavir is feasible, well tolerated and results in improved immunological status and stable clinical status over a period of 72 weeks. However, the presence of incomplete viral suppression in 70% of the infants, associated with genotypic resistance mutations to antiretroviral drugs in six (30%), is much higher than observed in adults treated following primary infection; in the latter, viral loads < 20 copies/ml at week 24 and 72 of HAART have been reported in aproximately 45% and 73% of patients, respectively .
Short-term toxicity of the study drug combination was acceptable, with relatively few adverse events related to the treatment being reported, and all of these being minor and leading to treatment interruption in only three infants. Few data are available in children concerning lipodystrophy syndrome, lipid or glucose abnormalities, although these abnormalities were found in 33% of children in a recent study . We did not observe any significant metabolic or body shape abnormalities in PENTA 7; however, we should be cautious about the possibility of long-term onset of lipodystrophy and cardiovascular disease in these infants.
No child had any major clinical progression, in particular no HIV encephalopathy or PCP occurred, and all but one infant had improved or stable immune function. In particular, none of the five infants with presumed in utero transmission of HIV experienced any HIV symptoms or progression to AIDS. Moreover, three of these infants had viral load < 200 copies/ml at week 72 of treatment. However, the number of infants is too small to draw any conclusion concerning the clinical benefit of early treatment. Indeed, an exact 95% confidence interval for the observed zero rate of AIDS-defining diseases in the 20 infants ranged from 0% to 15%, which might be consistent with the natural history of HIV in infants in the absence of HAART, as under 10% of infants taking primary PCP prophylaxis experience a rapid pattern of disease progression .
Initial viral load response seems to be predictive of virological failure: the risk of virological failure is higher in infants with a high HIV-1 RNA viral load at 4 weeks. This is in accordance with previous reports in adults and children [17,18], suggesting that potent HAART regimens are required to achieve virological response among infants with very high HIV viral loads.
The relative lack of potency of the chosen combination, stavudine plus didadosine plus nelfinavir, may explain the high rate of virological failure in our study. Although viral load decreased by about 2 log10 copies/ml during the first weeks of treatment, this could be insufficient to achieve full suppression in infants with high viral load at baseline. The effects in infants of other triple regimens containing a protease inhibitor have recently been reported, with similar high rate of virological failure and resistance mutations, in particular in those on stavudine-containing regimens . Quadruple therapy could be more effective, although more complicated to administer and to adhere to. In a recent study, 21 severely symptomatic children who remained on zidovudine plus lamivudine plus abacavir plus nevirapine achieved viral suppression of HIV-1 RNA to < 400 copies/ml at week 48 (three children had to discontinue for toxicity) . A key difference in this study was that most infants had experienced severe symptoms, which may be a potent reason for improved adherence among caregivers.
Despite the increase in the daily dose of nelfinavir to 150 mg/kg in two divided doses, based on the subsequent pharmacokinetic studies performed on the PENTA 7 infants, more than two-thirds of nelfinavir trough measurements were below the target value of 700 μg/l. This could reflect problems related to drug intake, owing to poor adherence, or poor absorption, because of weaning or food restrictions. Low blood levels of the active metabolite of nelfinavir, M8, could also explain the high rate of virological failure. In spite of similar blood levels of nelfinavir, infants who failed had lower blood levels of M8 (data not shown). Pharmacokinetic studies of nelfinavir [20,21] have shown high interindividual variability of nelfinavir and M8 blood levels, as confirmed in our study. Monitoring levels of both nelfinavir and this metabolite could, therefore, be potentially important.
Whether or not to treat HIV-1-infected infants at the time of primary infection and, if so, for how long remains a crucial question. It is important to evaluate the optimal duration of treatment once adequate virological suppression is achieved and whether to switch to other strategies (vaccination, structured treatment interruptions). Stopping therapy relatively early in order to prevent selection of resistance mutations needs to be considered in those infants with incomplete virological response, particularly when poor adherence is suspected. Pharmacological studies (pharmacokinetics and therapeutic drug monitoring) must be undertaken when considering treatment of very young children with new antiretroviral drugs.
We thank all the children, families and staff from all the centres participating in the PENTA 7 Study.
Sponsorship: PENTA is a Concerted Action of the European Commission, supported by BIOMED 2 contract BMH4-CT96-0836. The Medical Research Council provides support to the MRC HIV Clinical Trials Unit and the Agence Nationale de Recherche sur le Sida (ANRS) provides support for INSERM SC10. These two trials centres jointly coordinate the PENTA studies. Italian collaborating centres were supported by a grant from the Istituto Superiore di Sanità – Progetto Terapia Antivirale – and those in Spain by a grant from Comunidad Autonoma de Madrid, Spain. Bristol-MyersSquibb provided didanosine and and stavudine, and Roche provided nelfinavir. Both pharmaceutical companies also contributed funding for the coordination of the PENTA 7 trial.
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Writing Committee: J.-P. Aboulker, A. Babiker, M. L. Chaix, A. Compagnucci, J. Darbyshire, M. Debré, A. Faye, C. Giaquinto, D. M. Gibb, L. Harper, Y. Saïdi and A. S. Walker.
PENTA committees and participants (alphabetical order): J.-P. Aboulker, A. Babiker, A. Compagnucci, J. Darbyshire, M. Debré, A. Faye, C. Giaquinto (chairperson), D. M. Gibb (Executive Committee for PENTA 7); J.-P. Aboulker, A. Babiker, S. Blanche, A. Britt-Bohlin, P. Clayden, K. Butler, G. Castelli-Gattinara, J. Darbyshire, M. Debré, A. Faye, C. Giaquinto (chairperson), D. M. Gibb, C. Griscelli, I. Grosch-Wörner, C. Kind, J. Levy, M. Mellado Pena, D. Nadal, C. Peckham, J. T. Ramos Amador, L. Rosado, C. Rudin, H. Scherpbier, M. Sharland, P. A. Tovo, G. Tudor-Williams, A. Volnay, U. Wintergerst, V. Wahn (PENTA Steering Committee); C. Hill (chairperson), P. Lepage, A. Pozniak, S. Vella, R. Withnall (PENTA-7 DSMC).
National Trials Centres: MRC Clinical Trials Unit, HIV Division, 222 Euston Rd, London NW1 2DA (A. Babiker, J. Darbyshire, D. M. Gibb, L. Harper, D. Johnson, P. Kelleher, L. McGee, Y. Sowunmi A. S. Walker); INSERM SC10, 16 avenue Paul Vaillant Couturier, 94807 Villejuif, France (J.-P. Aboulker, A. Compagnucci, M. Debré, V. Eliette, S. Girard, S. Leonardo, C. Moulinier, Y. Saïdi).
Participating centres (pediatricians/virologists/biochemists). France: Hôpital Robert Debré, Paris (A. Faye, F. Damond); Hôpital Necker Enfants Malades (S. Blanche, Ch. Rouzioux, M. L. Chaix); Hôpital Jeanne de Flandre, Lille (F. Mazingue, L. Bocket, P. Wattre); Centre Hospitalier Universitaire, Nantes (F. Mechinaud, V. Reliquet, A.-S. Poirier, V. Ferre); Hôpital Jean Verdier, Bondy (E. Lachassinne, J. Vaysse, M. Pontet); Hôpital Cochin-Port-Royal, Paris (G. Firtion, A. Krivine); Hôpital Louis Mourier, Colombes (C. Floch Tudal, S. Gaba). Germany: Virchow-Klinikum, Humboldt-Universität zu Berlin (I. Grosch-Wörner, R. Weigel, K. Seel, C. Feiterna-Sperling, C. Müller); Klinikum Augsburg (W. Schenk, M. Dmoch, B. Sauerteig); Universitäts-Kinderklinik, Munchen (G. Notheis). Italy: Università di Padova (C. Giaquinto, V. Giacomet, C. Manzardo, O. Rampon, R. D'Elia, A. de Rossi, M. Zanchetta); Università di Torino (C. Gabiano). Spain: Hospital La Paz (I. De José, F. Baquero); Hospital Materno Infantil 12 de Octubre, Madrid (J. Ruiz Contreras, J. T. Ramos Amador, R. Delgado); Hospital Son Dureta, Palma de Mallorca (L. Ciria Calavia, J. Dueñas Morales, N. Matamoros); Hospital General Gregorio Marañon, Madrid (M. D. Gurbindo, M. L. Navarro, M. A. Muñoz). United Kingdom: Royal Free Hospital, London (V. Van Someren, K. Moshal, A. Burke, J. Page). Cited Here...
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