PEDIATRICS Vol. 108 No. 1 July 2001, pp. 116-122

Fluctuations in Symptoms in Human Immunodeficiency Virus-Infected Children: The First 10 Years of Life

The European Collaborative Study^{a, b}

	ABSTRACT

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Objective.  To describe patterns of clinical and immunologic progression in children who are vertically infected with the human immunodeficiency virus.

Methods.  Children who were born to mothers who were infected with the human immunodeficiency virus in 11 European centers were enrolled at birth in a prospective study and followed according to a standard protocol. At each visit, a clinical and immunologic class was allocated according to guidelines of the Centers for Disease Control and Prevention (CDC). Progression to serious disease and death was assessed, allowing for available and actual antiretroviral therapy (ART). CDC class at each visit was assessed cross-sectionally.

Results.  More than 15% of infected children will have progressed to category C or death by age 1 year and nearly 50% by 10 years. Just under 20% of children will have evidence of severe immunodeficiency by age 1 and 75% by 10 years. In general, immune status poorly reflected clinical condition. Children who were born after 1994, when the recommendation of earlier initiation of more active therapy was introduced, were significantly less likely to progress than those who were born when treatment was not widely available or was largely confined to zidovudine monotherapy. Estimated progression to CDC class C or death initially was faster in untreated than in treated children, but by 10 years estimated cumulative progression was similar in both groups. Treatment started before class C disease was associated with significantly slower progression. Cross-sectional analysis showed that children largely are symptom-free throughout their lives. After 4 years of age, fewer than 25% of infected children had symptoms at any one time, irrespective of ART received.

Conclusion.  Vertically infected children are without serious symptoms or signs for most of the time. The prognosis has improved with more widespread availability and use of combination ART. These findings have implications for health, education, and other support-service provision.  Key words:  HIV infection, clinical patterns, disease progression, antiretroviral therapy, survival, Europe.

In a primarily untreated population, ~20% of children who are vertically infected with the human immunodeficiency virus (HIV) progress rapidly to acquired immunodeficiency syndrome (AIDS) or death in the first year of life.¹ Progression of disease is slower thereafter, and by 6 years of age, an estimated 40% of infected children will have progressed to AIDS or death.^1-3 In 1994, the Centers for Disease Control and Prevention (CDC) published a revised classification scheme for pediatric HIV infection,⁴ which has been used in analyses of cohort studies and in surveillance registers.^1,2,5 However, existing information on the natural history of vertically acquired HIV infection in children focuses on cumulative proportions of infected children being diagnosed with serious disease (CDC class C) or death, and little is known about the pattern of disease during the first 10 years of life. From both a parental and a service-needs point of view, it is important to know what happens with infected children over time and whether children who receive a diagnosis of having a severe illness subsequently improve and remain well for prolonged periods.

In a previous analysis that combined data from 2 European cohort studies¹ in which zidovudine (ZDV) was the only treatment received by only a minority of children, progression to immunodeficiency occurred early. By 1 year of age, half of the infected children already were in the moderate immunologic suppression category.⁴ By 6 years of age, an estimated 99% of infected children would have progressed to moderate immune suppression, three quarters of whom would have progressed to severe immune suppression. As with clinical status, there also is a lack of information on fluctuations in immune status over time in treated and untreated children.

Although antiretroviral therapy (ART) to delay progression of disease now generally is initiated early in the course of the disease, there remains wide variation between and within countries.^6,7 The description of the disease pattern in vertically infected children thus has become complicated by the widespread and rapidly changing use and the variation in time of initiation of therapy. To achieve a composite and comprehensive picture of the pattern of clinical disease in children who live with HIV infection, we analyzed data collected prospectively on infected children since 1986 in 11 European centers.^1,3 We describe fluctuations in clinical and immunologic manifestations in children who either were never treated, or before and after they received antiretroviral treatment. We also investigate the effect of changing treatment policy over time.

	METHODS

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All children who were born to women who were known to be infected with HIV at the time of delivery were followed according to a standard protocol, with detailed clinical and laboratory information collected regularly in 11 pediatric centers in 7 European countries.^1,3 Children were seen at birth; 3 and 6 weeks; 3, 4.5, and 6 months; and then at 3-month intervals until 24 months of age. Subsequently, infected children were seen at least twice a year, and clinical and laboratory information and the current treatment were recorded on standard forms. Parental consent was obtained before enrollment in the European Collaborative Study (ECS), and the study was approved by the local ethics committees.

The analysis presented here is based on children who were known to be infected with HIV according to the CDC definition of pediatric HIV infection.⁴ For the purpose of the study, a CDC class was allocated at each visit on the basis of information regarding current clinical symptoms and signs⁴ to enable reclassification with changing clinical status. Clinical manifestations were grouped into 4 categories: N (asymptomatic), A (mildly symptomatic), B (moderately severe symptoms, including lymphoid interstitial pneumonitis [LIP]), and C (severe symptoms). Children who died with HIV-related disease were classified as category D.

Infected children were also allocated to a CDC immunologic class at each visit.⁴ Normal (category 1), moderate (2), and severe (3) immune suppression was assessed by CD4 cell counts or percentages appropriate for age at the time of assessment.

Statistical Analysis

Kaplan-Meier product-limit analysis was performed of age at progression to each of the CDC categories A (or worse), B (or worse), C (or death), and D. Children were censored at the age when last seen. Children who died from non-HIV-related causes were censored at death. Life-table analysis also was performed for progression to immunologic categories 2 and 3. Immunologic and clinical categories were cross-tabulated to assess agreement between the 2 classification systems.

Children were considered in 3 separate cohorts that were defined a priori according to treatment policy at the time of birth. Cohort 1 (1985-1988), no recommendation for treatment; cohort 2 (1989-1994), treatment policy restricted to monotherapy for symptomatic children; and cohort 3 (1995-1999), initiation of combination therapies recommended at an early stage. Progression to serious disease and actual treatment received were assessed for each of these 3 cohorts separately.

Not taking into account vertical transmission prophylaxis, children were identified as ever or never having received ART, and progression to CDC categories A, B, C, and D was examined separately for the 2 groups. Time-dependent Cox regression analysis was used to assess the separate effects of ART, Pneumocystis carinii pneumonia (PCP) prophylaxis, and intravenous immunoglobulin (IVIG).⁸ Similar analysis was performed to assess the effect of ART on the risk of progression to severe immunodeficiency (category 3). Progression to category C for children who received prophylactic ZDV in the first weeks of life⁹ was compared, with the use of the log rank test, with disease progression in those who had not received prophylaxis.¹⁰

Cross-sectional analysis was performed with the use of the CDC classification, allocated on the basis of symptoms or signs present at each visit. At 6-month intervals from birth, the numbers of children in each of the CDC classes at that time were ascertained. The intermittence of HIV-related symptoms also was assessed through a look-back exercise for children in follow-up at 5 years of age, providing an example of the clinical and immunologic history of children up to that age.

Analyses were conducted with the use of SAS (Version 6.12; SAS Institute, Inc, Cary, NC) and STATA (STATA Version 6.0; College Station, TX) statistical procedures.

	RESULTS

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Between 1984 and 1999, 170 infected children were born to 170 mothers. The likely mode of HIV acquisition in the mothers was intravenous drug use (93 women), an intravenous drug-using partner (21), heterosexual transmission (36), blood transfusion (4), or unknown (16). The median number of visits was 15 (range: 1-68). Median length of follow-up was 5.8 years, with a maximum of 15 years. Fifteen children are no longer followed up by ECS clinicians: 4 moved and are now under the care of other clinicians, 8 were living in socially disadvantaged circumstances and their mothers did not return for additional visits, and for 3 the reasons for loss of contact were unclear. The age at which these 15 children were last seen ranged from 5 months to 9 years, and the number of recorded visits ranged from 3 to 26.

Overall Disease Progression in Infected Children

Clinical Status Forty-five children (26%) died of AIDS, and 2 died of non-HIV-related causes. Including 4 children with LIP (category B), 70 children (41%) progressed to AIDS. More than 15% of infected children will have progressed to category C or death by 1 year of age, rising annually thereafter by 7% to just under 40% by 5 years and then by 2% to just under 50% by 10 years (Fig 1).

View larger version (16K): [in this window] [in a new window]   Fig. 1.   Estimated progression to CDC clinical categories for all children using Kaplan-Meier life-table analysis.

Immunologic Status Overall, progression to moderate or severe immunodeficiency was common and rapid. By 1 year of age, an estimated 50% of children would have progressed to category 2, >90% by 5 years. After 1 year of follow-up, just >20% of infected children will have evidence of severe immunodeficiency (category 3), rising to >50% by 5 years and to approximately 75% by 10 years of age. Immunologic status generally poorly reflected clinical condition.

Progression to Serious Disease by Calendar Period of Birth

The 21 children who were born after 1994 (when treatment policy was to initiate combination therapy at an early stage) were significantly less likely to progress than those who were born at a time when treatment was not widely recommended (N = 47) or recommended for symptomatic children only with the use of monotherapy or combination therapy with 2 nucleoside reverse transcriptase inhibitors (N = 101; Fig 2). For example, by 1 year of age, >25% of the children in cohort 1 would have progressed to category C compared with 15% in cohort 2 and only 5% in cohort 3 (log rank ² = 9.10; P = .011).

View larger version (11K): [in this window] [in a new window]   Fig. 2.   Estimated progression to serious disease (CDC stage C) or death by calendar period of birth using Kaplan-Meier life-table analysis.

The distinction by birth cohorts on the basis of treatment policy only partially reflected actual treatment received; 53% (25 of 47) of children born into cohort 1, 75% (76 of 101) of children born in cohort 2, and 62% (13 of 21) of children born in cohort 3 actually received ART. However, 80% of children in cohort 1, 75% (57 of 76) in cohort 2, and 54% (7 of 13) in cohort 3 were started on treatment only after they had progressed to serious disease.

Progression in Untreated Children

Of the 170 infected children, 55 never received ART, only 8 of whom were born at a time when early initiation of combination therapy was the recommended policy (22 were born in the pretreatment era and 25 when monotherapy was recommended for symptomatic children). Ten (18%) untreated children remained asymptomatic when last seen between the ages of 1.5 months and 7.6 years (median: 4.5 years). Forty-five children (82%) received a diagnosis of being category A or having more severe HIV-related symptoms or signs (Table 1); in all but 2 children, this occurred in the first year of life. Overall, 20 (36%) of the 55 children who did not receive treatment died. Progression was rapid, and nearly one third of untreated children would have progressed to serious disease or death by 1 year of age.

Progression in ART-Treated Children

Children were classified as treated, with progression before or after initiation of treatment. At start of treatment, 81 (70%) of 115 treated children received monotherapy (usually ZDV), 33 (29%) received combination therapy without protease inhibitor (PI), and only 1 received combination therapy with PI. The median age by clinical stage at initiation of treatment was 2.5 years for treated children who had category C symptoms, 4 years for those in category B, 7 years for those with mild symptoms, and 6 years for the asymptomatic children. The healthier the child at treatment initiation, the longer they lived: 90% of the children who were asymptomatic at treatment initiation were still alive 5 years later compared with only 25% of the children with clinical category C symptoms at treatment. Reflecting changing clinical practice over time, treatment was modified in many children, and at the last visit included in this analysis, 28 (24%) children were receiving monotherapy, 67 (58%) were receiving combination without PI, and 20 (17%) were receiving combination therapy with PI.

Immunologic information was available for 82 of the 115 ever-treated children at start of treatment: 25 had no evidence of immune suppression (18 N1, 2 A1, 4 B1, and 1 C1), 26 had moderate immune suppression (20 N2, 2 A2, 3 B2, and 1 C2), and 31 had severe immune deficiency (17 N3, 4 A3, 7 B3, and 3 C3).

In total, 27 (23%) treated children died during follow-up, including 2 who died of non-HIV-related causes (Table 1). Of the 88 ever-treated children who were alive at the last visit, most were asymptomatic (78%), only 7 (8%) had category A symptoms, and the remaining 12 (14%) had clinical category B symptoms. Seven treated children remained asymptomatic throughout their follow-up of between 3 months and 10.5 years (median: 3.6 years).

Comparison of Progression in ART-Treated and Untreated Children

The estimated progression to category C and to death initially was more rapid in the untreated children (Table 1), which almost certainly reflects treatment opportunity: these children were enrolled in the early years of the study and died before having had the chance to be treated. By 10 years of follow-up, the estimated cumulative progression to category C is more similar in the 2 groups (61% vs 43%), although the overall patterns were significantly different (log rank ² = 4.41; P = .036).

Progression by Treatment

The immediate risk of progression to category C in children after initiation of ART, PCP prophylaxis, and IVIG separately were investigated by time-dependent Cox regression analysis. In this analysis, any child who had progressed to category C before having received treatment was regarded as untreated. At any time, children who received ART or PCP prophylaxis were less likely to progress to category C than those who did not receive it (relative risk: 0.58 and 0.63; P = .037 and .071, respectively). Most children who started ART before progression to category C disease were started on combination therapy. Of the 115 children who received ART, 76 also received PCP prophylaxis; thus, it is difficult to distinguish independent effects of these treatments. There was no evidence of a difference in progression to category C between children did or did not receive IVIG (relative risk: 1.02; P = .923).

Risk of progressing to severe immunodeficiency (immunologic category 3) was 64% higher when receiving ART (risk ratio: 1.64; 95% confidence interval: 0.96-2.82) with borderline significance (P = .070).

ZDV Vertical Transmission Prophylaxis

A total of 157 (92%) infected children had not received ZDV as prophylaxis for vertical transmission. Nearly 20% of these children would have progressed to category C or death in the first year of life compared with 0% of the children who received prophylaxis. Disease progression patterns were distinct with borderline significance (log rank test ² = 2.84; P = .092). However, these results should be interpreted in the light of the more widespread use of ART therapy for infected children after 1995. Of the 13 children who received prophylaxis with ZDV, 11 (85%) also subsequently were treated with ART; 91% (10 of 11) were treated with combination therapy.

Presence of HIV-Related Symptoms at 6-Month Age Intervals

At each 6-month visit, most infected children were without serious symptoms or signs (Fig 3). For each of the points before 3 years of life, just more than half of children were asymptomatic, and after 4 years of age, fewer than one quarter of the children had symptoms at any one time. This picture is very similar for both ART-treated and untreated children (data not shown). Infected children who died contribute most of their information in the first 4 years of life; after that age, the picture largely relates to the experience of survivors. However, restricting the analysis to 45 children who died with AIDS showed a similar pattern to that of the overall cohort, with approximately half of the visits reflecting an absence of clinical symptoms, but when there were symptoms, they were likely to be serious.

View larger version (35K): [in this window] [in a new window]   Fig. 3.   CDC clinical status for all infected children assessed cross-sectionally at 6-month visits.

Clinical Status 5-Year Look-Back

Seventy-six children who were still alive and in follow-up at or beyond age 5 were included in the 5-year look-back analysis (Fig 4). Of the 944 previous visits of the 58 children with no or only minor symptoms at 5 years, 14 had been category C visits. However, the 1 child who had category C symptoms at age 5 primarily had been symptom-free up to that age. The 1 previous visit for category C symptoms was, in fact, the 6- month visit before the 5-year visit when the child had esophageal candida. Conventional cumulative progression of disease thus does not predict clinical status at subsequent visits.

View larger version (73K): [in this window] [in a new window]   Fig. 4.   Children alive and in follow-up at 5 years of age: CDC clinical status at current and previous visits.

Of these 76 children, 64 had been treated with ART and 12 were untreated. Of the treated children, 46 (72%) were asymptomatic at 5 years of age and had been asymptomatic most (521) of the previous 740 visits, too. One treated child received the diagnosis of having a C-defining illness at the 5-year visit. The 12 never-treated children all were asymptomatic at the last visit closest to 5 years of age, and none of them had ever had a C-defining illness.

With the exception of the 1 child in category C at the 5-year visit, children in clinical category N were most likely to be on combination therapy: 19% (11 of 58) in category N compared with 9% (1 of 11) and none in category B. The immunologic look-back of 5-year-olds gave a similar impression as the clinical exercise.

	DISCUSSION

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An estimated 15% of infected children will progress to serious disease or die before age 1, but both infected children who had ever and never been treated with ART are well most of the time. Overall, progression of disease is less rapid between the ages of 1 and 5 years and slow between 5 and 10 years. Fewer than 10% of infected children will remain asymptomatic throughout the first 5 years of life. The current analysis extends to 10 years of age and elaborates on the previous one on combined data from the ECS and the French cohort studies,¹ which showed similar rates of disease progression in the first 5 years of life. All 19 children who progressed to moderate disease (class B) because of LIP were born before 1993, and the diagnosis of LIP now is made less frequently. Ten of these 19 died, 3 within days of first diagnosis of LIP, suggesting that the disease may well have been misdiagnosed.

With the more widespread use of ART to delay disease progression in children, it is no longer appropriate to talk in terms of the natural history of vertically acquired pediatric HIV infection. Therefore, we described patterns of disease in both treated and untreated children and grouped children into 3 cohorts according to therapeutic policy recommendations. There is variation in treatment decisions between centers, likely influenced by the experience of the local clinician,⁶ and treatment policy changes over time. Our results show that a subset of vertically infected children can do well, even without early initiation of treatment, provided that they survive beyond infancy. Fifty-five infected children who were followed up to 13 years of age were never treated with ART. This group consisted of a few children who were less likely to progress and thus less likely to be put on ART and a larger group of 22 children who were born in the early years of the study when treatment was recommended only for seriously ill children who progressed so rapidly that treatment could not be initiated in time. Treatment decisions also may be influenced by clinical status, and when treatment was initiated in children before they progressed to serious disease, the risk of further progression was decreased. Treatment decisions also are likely to be influenced by policy and general recommendations. For example, in our cohort, children who were born before 1989 were less likely to be treated early and more likely to be started on monotherapy than those who were born after 1994. Children who were born at a time when combination treatment was becoming more widespread and recommended to be initiated at an early stage were considerably less likely to progress to serious disease than those who were born in the early years of the study when few therapy options were available and when therapy was confined to those with serious disease. This confirms the recent findings from the Italian pediatric register, which suggested that overall survival of vertically infected children improved with the introduction of combination ART.¹¹

Immune status did not reflect clinical stage at any age, and progression of disease is difficult to predict by immune status.¹² Immune status assessed by absolute values at each age probably reflects poorly the ongoing virological activity, and divergence from age-related values and centiles may be more clinically relevant. There is no evidence for the existence of a subgroup of infected children who are always severely symptomatic.

In our cohort, progression of disease slowed after the first year of life, and this brings up the issue of when to stop PCP or bacterial infection prophylaxis. Children who received PCP prophylaxis (most commonly trimethoprim-sulfamethoxazole) were less likely to progress to a C-defining illness than those who were not on prophylaxis, but most of these children also were receiving ART. There was no evidence of any beneficial effect of IVIG.¹³ The small number of infected children who had been exposed to ZVD prophylaxis to reduce the risk of vertical transmission in their first weeks of life were less likely to progress to serious disease than those who were not exposed. However, this may partly reflect the increasing experience in the management of pediatric infection in recent years. The relatively small numbers and nature of the study make it difficult to draw reliable conclusions. In the Italian pediatric register,¹⁴ children who were exposed to ZVD in utero were more likely to progress quickly than children who were not exposed, but this analysis also included children who were born to women who received ZVD for clinical indications rather than as vertical transmission prophylaxis.

The approach taken in this analysis is broader than that used by others^1,5,15,16 in that a CDC category was allocated at each visit and children were allowed to move to a less serious category as their clinical or immunologic status improved. We thus were able to show that at each 6-month visit, the majority of infected children, whether treated or not, are asymptomatic. This was true also for children who died during the study period. Fluctuations in clinical symptoms mainly were associated with intermittent serious infections, whereas children who received a diagnosis of encephalopathy remained seriously ill or died. These findings have implications for health and education service provision for these children. Adherence to therapy requires not only cooperation from the child and his or her parents but also sustained support from a multidisciplinary team of professionals. In recent years, the emphasis in the care of these children increasingly has included psychosocial support as well as clinical care.

Our findings indicate a generally better-than-appreciated clinical picture for children with vertically acquired HIV infection and may have implications for populations in resource-poor settings. Infants who survive an initial episode of serious opportunistic disease are subsequently likely to become asymptomatic or to have only mild symptoms for prolonged periods, even without aggressive ART.

	STUDY PARTICIPANTS

The European Collaborative Study includes the following individuals: Dr C. Giaquinto, Dr E. Ruga, and A. De Rossi (Universita degli Studi di Padova, Italy); Dr I. Grosch-Wörner, Dr K. Seel, and Dr A. Schäfer (Charite Virchow-Klinikum, Berlin, Germany); Dr J. Mok (Royal Hospital for Sick Children, Edinburgh); Dr F. Johnstone (Department of Obstetrics, University of Edinburgh, UK); Dr M. C. Garcia-Rodriguez, Dr. I. Bates, Dr I. de José, Dr F. Hawkins, Dr C. Ladrón de Guevara, Dr J. M. Peña, Dr J. Gonzalez Garcia, and Dr J. R. Arribas Lopez (Hospital Infantil La Paz, Madrid); Prof F. Asensi-Botet, Dr M. C. Otero, Dr. D. Pérez-Tamarit, Dr. S. Ridaura, Dr. P. Gregori, and Dr. R. de la Torre (Hospital La Fe, Valencia, Spain); Dr. H. Scherpbier, M. Kreyenbroek, and Dr K. Boer (Academisch Medisch Centrum, Amsterdam, The Netherlands); Dr A. B. Bohlin, Dr E. Belfrage, and Dr B. Christensson (Huddinge, Karolinska, and Lund University Hospitals, Sweden); Dr P. Barlow, Dr. M. Hainaut, Dr A. Peltier, and Dr S. Wibaut (Hospital St. Pierre, Brussels, Belgium); Dr A. Ferrazin, and Prof D. Bassetti (Department of Infectious Diseases, University of Genoa, Italy); Dr A. De Maria (Department of Internal Medicine, University of Genoa, Italy); Dr C. Gotta (Department of Obstetrics and Gynecology-Neonatology Unit, University of Genoa, Italy); Dr A. Mûr, Dr A. Payà, Dr M. Viñolas, Dr M. A. López-Vilchez, Dr P. Martinez-Gómez, and Dr R. Carreras (Hospital del Mar, Universidad Autonoma, Barcelona, Spain); and Dr N. H. Valerius (Hvidovre Hospital, Denmark).

	ACKNOWLEDGMENTS

We thank K. Bennett and Dr Simona Fiore (London); Prof L. Chieco-Bianchi, Prof F. Zacchello, Dr R. D'Elia, Dr A. M. Laverda, Dr S. Cozzani, Dr C. Cattelan, Dr A. Mazza, Prof B. Grella, Dr A. R. Del Mistro, Dr V. Giacomet, Dr O. Rampon, and S. Oletto (Padua); Dr Cornelia Feiterna and Dr R. Weigel (Berlin); Dr S. Burns, Dr N. Hallam, Dr P. L. Yap, and Dr J. Whitelaw (Edinburgh); Dr B. Sancho and Dr G. Fontan-Casanego (Madrid); Dr F. Asensi, Dr M. C. Otero, Dr A. Perez Tamarit, Dr A. Gonzalez Molina, Dr M. Gobernado, Dr J. L. Lopez, and Dr J. Cordoba (Valencia); Dr G. Mulder, Mevr T. Kosten, Mevr M. C. A. van Leeuwen, and the participants of the Dutch collaborative study of HIV-infected women and their children (Amsterdam); Dr L. Navér, Dr G. Lidin-Janson, Dr R. Ljung, Dr P. Bolme, and Dr U. Ewald (Sweden); Dr G. Di Siena, Dr E. Pontali, Prof M. F. Pantarotto, G. Mantero, and Dr P. Dignetti (Genoa); and Dr A. Hottard, Dr M. Poncin, Dr S. Sprecher, Dr B. Lejeune, Dr G. Zississ, and Prof N. Clumeck (Brussels).

	FOOTNOTES

^a The European Collaborative Study is a concerted action of the European Commission (Biomed II PL 97 2005). The Medical Research Council (UK) provided support to the coordinating center. Collaborating centers were supported by grants from the Ministero della Sanita-Istituto Superiore di Sanita, Progetto AIDS (Padua, Genoa); the Medical Research Council (UK), the AIDS Virus Education Research Trust, and the Scottish Office Home and Health Department (Edinburgh); Praeventiefonds No. 28-1704 (Amsterdam); Bundesminister fur Gesundheit (Berlin); Fonds Houtman, Office de la Naissance et de L'Enfance, and Communaute Francaise de Belgique (Brussels); and the Research Foundations of Karolinska Institutet (Stockholm).

^b See "Acknowledgments" for members of the European Collaborative Study.

This article was prepared by Linsay Gray, MSc; Marie-Louise Newell, PhD; Claire Thorne, PhD; and Catherine Peckham, MD, from the Institute of Child Health, University College, London, United Kingdom; and Jack Levy, MD, from the Department of Pediatric Infectious Diseases, Hospital St Pierre, Brussels, Belgium.

Received for publication Sep 15, 2000; accepted Nov 2, 2000.

Reprint requests to (M.L.N.) Department of Pediatric Epidemiology and Biostatistics, Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK. E-mail: m.newell{at}ich.ucl.ac.uk

	ABBREVIATIONS

HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; CDC, Centers for Disease Control and Prevention; ZDV, zidovudine; ART, antiretroviral therapy; ECS, European Collaborative Study; LIP, lymphoid interstitial pneumonitis; PCP, Pneumocystis carinii pneumonia; IVIG, intravenous immunoglobulin; PI, protease inhibitor.

	REFERENCES

Top Abstract Methods Results Discussion References

1. French Pediatric HIV Infection Study Group, European Collaborative Study Morbidity and mortality in European children vertically infected by HIV-1. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14:442-450 [Medline]
2. Diaz C, Hanson C, Cooper ER, Disease progression in a cohort of infants with vertically acquired HIV infection observed from birth: the women and infants transmission study (WITS). J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18:221-228 [Medline]
3. European Collaborative Study Natural history of vertically acquired human immunodeficiency virus-1 infection. Pediatrics 1994; 94:815-819 [Abstract/Free Full Text]
4. Centers For Disease Control. 1994 Revised classification system for human immunodeficiency virus infection in children less than 13 years of age. MMWR Morb Mortal Wkly Rep. 1994;43(RR12):1-10
5. Barnhart HX, Caldwell MB, Thomas P, Natural history of human immunodeficiency virus disease in perinatally infected children: an analysis from the Pediatric Spectrum of Disease Project. Pediatrics 1996; 97:710-716 [Abstract/Free Full Text]
6. Bernardi S, Thorne C, Newell ML, Giaquinto C, Tovo P-A, Rossi P Variable use of therapeutic interventions for HIV-infected children in Europe. Eur J Pediatr 2000; 159:170-175 [CrossRef][Medline]
7. Funk M, Linde R, Braner HJ, Groeschel B, Kornheuber B, Kreuz W Genotypic and phenotypic resistance under zidovudine and lamivudine therapy in HIV-infected children. Eur J Pediatr 1999; 158:86-87 [CrossRef][Medline]
8. Cox DR, Oakes D. Analysis of Survival Data. London, England: Chapman and Hall; 1984
9. Connor EM, Sperling RS, Gelber R, Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331:1173-1180 [Abstract/Free Full Text]
10. Miller RGJ. Survival Analysis. New York, NY: John Wiley; 1981
11. de Martino M, Tovo P-A, Balducci M, Reduction in mortality with availability of antiretroviral therapy for children with perinatal HIV-1 infection. JAMA 2000; 284:190-197 [Abstract/Free Full Text]
12. European Collaborative Study Group CD4 T cell count as predictor of Pneumocystis carinii pneumonia in children born to mothers infected with HIV. Br Med J 1994; 308:437-440 [Abstract/Free Full Text]
13. Mofenson LM, Moye J, Bethel J, Hirschhorn R, Jordan C, Nugent R Prophylactic intravenous immunoglobulin in HIV-infected children with CD4+ counts of 0.20 X 10 9/L or more. JAMA 1992; 268:483-488 [Abstract]
14. The Italian Register for HIV Infection in Children Rapid disease progression in HIV-1 perinatally infected children born to mothers receiving zidovudine monotherapy during pregnancy. AIDS 1999; 13:927-933 [CrossRef][Medline]
15. Italian Register for HIV Infection in Children Features of children perinatally infected with HIV-1 surviving longer than 5 years. Lancet 1994; 343:191-195 [CrossRef][Medline]
16. Abrams EJ, Weedon J, Steketee RW, Association of Human Immunodeficiency Virus (HIV) Load Early in Life with Disease Progression among HIV-infected infants. J Infect Dis 1998; 178:101-108 [Medline]