Natural History of Vertically Acquired Human Immunodeficiency Virus-1 Infection

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Natural

History

of Vertically

Acquired

Human

Immunodeficiency

PEDIATRICS Vol. 94 No. 6 December 1994 815

Virus-i

Infection

The European Collaborative Study

ABSTRACT. Objective. To describe the natural

his-tory of vertically acquired human immunodeficiency

virus (HIV) infection.

Design. This was a prospective follow-up study.

Setting. Ten centers of the European Collaborative

Study participated.

Subjects. One hundred twenty-four HIV-infected

children were born to women known to be infected at or

before the time of delivery since 1986.

Main outcome measures. Deaths, acquired

immuno-deficiency syndrome (AIDS), and HIV-related symptoms

and signs were assessed.

Results. In this cohort, treatment before the onset of

AIDS was not universaL Less than 10% of children were

treated with Zidovudine or intravenous gamma globulin before 6 months of age, with a steady increase to about 40% after 3 years of life. An estimated 23% (95% confidence

interval 15% to 31%) of infected children develop AIDS

before the age of 1 year, and nearly 40% (27% to 50%) by 4 years. Ten percent (5% to 16%) die before age 1 year and

28% (16% to 41%) before age 5 years. Twenty-four months

after the AIDS diagnosis, an estimated 48% (36% to 70%) of

the children are still alive. Although after the age of 1 year

immunologic abnormalities became increasingly common,

the proportion of infected children with significant

HIV-related symptoms or signs dedined.

Conclusion. The progression of disease in this cohort

of vertically infected children was not as fast as

previ-ously suggested, even though treatment was not

wide-spread. Although infected children have a high risk of

developing some manifestation of HIV infection early in

life, serious HIV-related symptoms became less frequent

with increasing age. This has important implications for

health planning and care provision. Pediatrics 199494:

815-819; natural history, vertical transmission, pediatric

HIV.

ABBREVIATIONS. I-IIV, human imnnmodeficiency virus; AIDS, acquired immunodeficiency syndrome; ECS, European Collabora-five Study; LIP, lymphoid interstitial pneumonitis; CI, confidence interval; AZT, Zidovudme; IVGG, intravenous gamma globulin; TMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis

ca-rinhi pneumonia.

The natural history of vertically acquired human

immunodeficiency virus (HIV) infection has not yet

* A complete list of names of those who collaborated in this study can be

found at the end of this article. This article was prepared by Marie-Louise Newell, Catherine Peckham, David Dunn, Tony Ades (coordinating centre), and Carlo Giaquinto.

Received for publication Jan 27, 1994; accepted Mar 29, 1994.

Reprint requests to (M.-L.N.) Department of Epidemiology, institute of

Child Health, 30 Guilford Street, London WC1N IEH, United Kingdom.

PEDIATRICS (ISSN 0031 4005). Copyright 0 1994 by the American

Acad-emy of Pediatrics.

been elucidated fully,’3 and the longer term

progno-sis for infected children is not known. Acquired

im-munodeficiency syndrome (AIDS) registers can

pro-vide information on the frequency and outcome of

specific AIDS-defining conditions, but they do not

describe the natural history for all infected children

born to HIV-seropositive mothers.4’6

The age at onset of AIDS is often described as

bimodal; some infected children develop AIDS very

early in the first year of life, whereas others survive

for several years without developing MDS.2’7 Much

of the evidence to support this is based on data from

AIDS registries. To date, prospective studies have

demonstrated only the early peak.

Although nearly 90% of HIV-infected children in

the European Collaborative Study (ECS)3 showed

some manifestation of HIV infection by the age of I

year, not all of these children were symptomatic

continuously; many improved during the second

and third years of life. Uttle is known about the

fluctuation of symptoms over time. This paper

de-scribes the natural history of WV infection in a

Eu-ropean cohort of children born to women known to

be HIV-infected at or before the time of delivery.

METhODS

The ES was set up in late 1986 to estimate the rate of vertical transmission of H1V and to clarify the natural history of vertically acquired Hl\’ infection.3”0 Infected women are identified before or at the time of delivery and their infants are followed from birth according to a standard dinical and laboratory protocol. Children are examined at 3-month intervals up to age 24 months, and every

6 months thereafter. Ten European centers are involved in the natural-history component of the ECS (Padua, Berlin, Edinburgh, Madrid, Valencia, Amsterdam, Stockholm, Genoa, Brussels, and Barcelona).

Infection is defined as the persistence of WV-I antibodies be-yond the age of 18 months, detection of AIDS, or the isolation of virus or p24-antigen on two or more occasions. The Centers for Disease Control definition of AIDS” applies, with the exclusion of mild asymptomatic lymphoid interstitial pneumomtis (UP). Fail-are to thrive is reported separately. In describing the natural history, the centers defined the children as symptomatic at an examination if they had AIDS, oral Candida, parotitis, LIP, or a

serious bacterial infection; HIV-related signs were defined as any

two of generalized lymphadenopathy, hepatomegaly, or

spleno-megaly. Calculation of the rate of vertical transmission was based

on 610 children who were born more than 18 months before the

date of analysis”#{176};the natural-history analysis induded all chil-dren who were known to be infected.

Survival curves were calculated by the Kaplan-Meier method, and 95% confidence intervals (CIa) were calculated with Green-wood’s formula.’2 To determine the prevalence of symptoms or signs at given ages, we considered a child to be symptomatic if he or she met the definition at any visit in the 3-month interval. North American reference data were used to derive standard deviation scores for weight, controlling for age and sex.

at Viet Nam:AAP Sponsored on September 1, 2020 www.aappublications.org/news

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RESULTS

By August 1993, 990 children from 10 European

centers had been enrolled in the natural-history arm

of the ECS, and 124 were known to be infected. The

rate of vertical transmission was 15.1 % (95% CI:

12.2% to 17.9%).

Treatment

The description of the natural history must be

considered in the context of treatment received by

these children. In this cohort, treatment before the

onset of AIDS was not universal. More than 90% of

infected children without AIDS and about 80% of

children with AIDS did not receive any treatment

before 6 months of age. Figure 1 shows the

percent-ages of children who had received treatment within

6-month age intervals, according to whether the

child had or had not been diagnosed with AIDS. The

number of infected children receiving Zidovudine

(AZT) treatment increased to over 40% after age 3

years. A similar number of children were given

in-travenous gamma globulin (IVGG) therapy to

pre-vent bacterial infections. Prophylaxis with

hi-methoprim-sulfamethoxazole (TMP-SMX) was not

widespread, either before or after AIDS diagnosis,

although increasing numbers of children are now

receiving it. Both AZT and IVGG treatments were

more common after AIDS diagnosis; about half the

children over I year of age were treated with AZT

and/or IVGG, of whom 50% received both. In two

children with AIDS, AZT treatment was

discontin-ued, in one because of severe adverse effects and in

the other because of lack of response. The latter child

is now on DDi (the only child in the ECS receiving

DDi). Combined therapy with AZT and TMP-SMX

or with IVGG and TMP-SMX was rare.

Time to AIDS Onset and HIV-Related Deaths

Of the 124 infected children, 37 (30%) have been

diagnosed with AIDS or have died with serious

HIV-related symptoms. Life table analysis shows that an

estimated 23% (95% CI: 15% to 31%) of infected

.,

0 12 24 36

Fig 1. Percentages of children before and after AIDS diagnosis treated with AZT, IVGG, or TMX-SMP, by age. Solid lines, chil-dren with AIDS; dashed lines, children before AIDS onset; squares, TMP-SMX; triangles, AZT; drcles, IVGG treatment.

children will develop AIDS before the age of I year,

and 39% (27% to 50%) by 4 years.

Of the 27 children with AIDS diagnosed in the first

year of life, 13 (48%) had Pneumocystis carinhi

pneu-monia (PCP) (Table). Three children, all with

HIV-related symptoms and signs, died unexpectedly at an

early age, and postmortem was refused. It was not

possible to exclude PCP in these three children, or in

the two children presenting with serious recurrent

bacterial infections at an early age and who died.

Children who developed AIDS in the first year of

life could not be distinguished from the remaining

infected children in terms of mode of delivery, birth

weight, gestational age, breast-feeding, or maternal

clinical or immunologic status.

There have been 22 HIV-related deaths, including

19 children with AIDS and the three children with

HP/-related symptoms mentioned above (Table). An

estimated 48% (95% CI 36% to 70%) of children are

still alive 24 months after their AIDS diagnosis.

Based on life table analysis, an estimated 10% (5% to

16%) of infected children die before age I year, and

28% (16% to 41%) before age 5 years (Fig 2).

Prevalence of HIV-Related Signs and Symptoms

Most children developed some HIV-related

symp-toms or signs, but these episodes tended to be

inter-mittent. Although HIV-related signs such as

lymph-adenopathy were common, many children were

asymptomatic (according to the definition) for long

periods, even after AIDS had been diagnosed. In

addition to the life table estimates of survival and

progression to AIDS, Fig 2 shows the proportions of

children with HIV-related symptoms or signs in the

preceding 3 months, both before and after AIDS

diagnosis. For example, at age 6 months, about 8% of

infected children had died; about 10% had been

di-agnosed with AIDS but were still alive, all of whom

were symptomatic; 82% had not developed AIDS

(39% with and 43% without symptoms or signs).

Both before and after AIDS diagnosis, symptoms and

signs were most frequent in the first 18 months of

life. Subsequently, most children, even those

previ-ously diagnosed with AIDS, did not meet the study

definition of symptoms or signs.

Indeed, of the 15 children with AIDS who were

still alive when last seen, only four met the definition

of symptomatic (Table). One recently had been

diag-nosed with AIDS, another had symptomatic LIP, the

third had encephalopathy, cardiomyopathy, and a

nonspecific pneumonia, and the fourth had herpes

zoster and oral Candida. None of these four children

had been hospitalized for these symptoms.

Figure 2 also shows the proportions of the 87

in-fected non-AIDS children who had HIV-related

symptoms or signs during the first 4 years of life.

In the first year, HIV-related symptoms and signs

-‘ were relatively common, even in combination. Oral

48 Candida occurred in 30% of infected children

pre-AIDS in the first year of life, but was rare thereafter.

However, even in the first year, it rarely persisted for

more than I month. Although approximately 70% of

these children had either lymphadenopathy,

hepato-megaly, or splenomegaly at one or more visits

(3)

AIDS Indicator With Age (mo)

TABLE. Acquired Immunodeficiency Syndrome (AIDS) Indicator Disease and Status at Last Visit for 34 Children With AIDS and Three

Children Who Died With Human Immunodeficiency Virus (HIV)-Related Disease*

Status 15 3 64 38 53 4 4 7 5 38 14 6 42 3 6 6 38 8 22 58 19 33 17 44 52 34 71 67 44 45 61 18 27 78 6 4 4

* Abbreviations: PCP, Pnt’unzocysfis carinii pneumonia; CMV, cytomegalovirus; FYI’, failure to thrive; tb, tuberculosis; CNS, central

nervous system; bact inf, bacterial infection; SUD, sudden unexpected death; LIP, lymphoid interstitial pneumonitis; MAI, Mycobacteriurn

aVilun infection; RSV, respiratory syncytial virus infection.

0 12 24 36

ARTICLES 817 PCP (2) PCP (3) PCP (3) PCP (3) PCP (3) PCp (4) PCP (4) pCP (5)

pCp + encephalopathy (5)

PCP (5)

PCP (6)

pCP (probable) (6) PCP (22)

CMV (3)

CMV (3)

CMV + encephalopathy (5)

Bact inf (3)

Bact inf (3) Bact inf (5) Bact inf (9) Bact mi + LIP (10)

Bact inf (13) Encephalopathy (11) Encephalopathy (11) LIP (5) LIP (31) LIP (42) Cryptosporidium (17) Cryptosporidium (18) Cryptosporidium (34) Cryptosporidium (42) Esophageal Candida (2) Esophageal Candida + tb (27) Esophageal Candida (74)

HIV-related deaths

Age Last Seen or Age at Death,

mo

Alive, minor signs Dead, PCP - CMV Alive, asymptomatic Dead, FIT, probable tb Alive, asymptomatic Dead, PCP Dead, PCP Alive, asymptomatic Dead, PCP

Dead, encephalopathy, hemorrhage

Alive, pneumonia, encephalopathy, cardiomyopathy

Dead, PCP

Alive, herpes zoster, oral Candida

Dead, disseminated CMV Dead, encephalopathy, PCP, CMV

Dead, CMV, CNS lymphoma

Alive, minor signs

Dead, FIT + encephalopathy

SUD

Alive, minor signs

Dead, encephalopathy, PCP Dead, encephalopathy + diarrhea Dead, renal + cardiac failure, FIT

Alive, LIP, encephalopathy

Dead, disseminated MAI, encephalopathy, Kiebsiella

pneumonia Alive, asymptomatic

Alive, asymptomatic

Alive, asymptomatic

Dead, pneumonia, encephalopathy Dead, renal failure, CMV

Alive, asymptomatic

Dead, septic shock, FIT, developmental delay Alive

Alive, asymptomatic Dead, oral Candida, SUD

Dead, interstitial pneumonia, pulmonary hemorrhage

Dead, RSV pneumonia

:g

J)

Age(months)

Fig 2. The natural history of vertically acquired HIV infection based on 124 infected children.

ing the first year of life, combinations were less

fre-quent. The HIV-related signs were more common

than HIV-related symptoms, and after the first 18

months of life less than 10% of these children were

symptomatic (as defined).

Failure to Thrive

Severe failure to thrive was not a common initial

presentation in this cohort. Seventeen of the 124

(14%) infected children showed signs of severe

fail-ure to thrive, defined as a standard deviation score

below -3 (there is approximately a 1:1000 chance that

a normal child would fall below this) on two or more

consecutive occasions. Fourteen of the 17 had other

AIDS-defining symptoms. Life table analysis

esti-mates that by 6 months of age, 5% of infected

chil-dren have severe failure to thrive, and 14% by 1 year

of age, with utile increase thereafter.

48 Immunologic Status

There was no consistent pattern in CD4 cell counts

with progression of disease. Evidence of

immuno-logic impairment as measured by CD4 count was

more common than clinical manifestations of HIV

infection. An estimated 17% (95% CI: 10% to 25%) of

infected children who had not yet developed AIDS

had ever had a CD4 count below the third

percen-til&3 by 6 months of age, about 34% (24% to 44%) by

age 1 year, and 54% (43% to 65%) by age 3 years.

(4)

Although the CD4 count of infected children with

AIDS tended to be low, there was no clear

associa-tion between CD4 cell count and onset of disease or

death, or between CD4 levels before and after AIDS.

Some children who developed PCP showed a rapid

decline in CD4 count at the time of the PCP attack,

although the absolute CD4 count had no prognostic

value.

DISCUSSION

The rate of vertical transmission in the ECS was

15% (95% CI: 12% to 18%), not significantly different

from the rates quoted in the other two European

prospective studies.’4”5 Results from the ECS cohort

suggest that about one quarter of infected children

develop AIDS in the first year of life and about 40%

by age 4 years. This is a faster rate of progression

than is seen in adults’6 but is similar to estimates

derived using indirect methods.6’9 Although it is

of-ten assumed that early onset of AIDS indicates

intra-uterine transmission,4”7 there is little evidence to

support this. Unlike in the French study,18 the ECS

children who developed AIDS in the first year of life

could not be distinguished from those infected

chil-dren who did not, in terms of mode of delivery, birth

weight, gestational age, perinatal findings,

breast-feeding, and maternal clinical and immunologic

characteristics. In this study, not enough suitable

samples were collected at birth to investigate

whether positive virologic tests in the newborn

pe-nod are associated with progression of HIV disease.

Although infected children were lighter at birth than

uninfected children, this difference could be

explained by the maternal immunologic status.’9

In the ECS cohort, infant mortality among infected

children was an estimated 10%, and mortality before

5 years was an estimated 28%. This is similar to the

mortality rates reported in the Italian multicenter

register#{176} and the Swiss perinatal study,’4 but lower

than that reported by others.4Th Differences in

mor-tality rates may reflect in part the health care

avail-able. Furthermore, in populations in which

back-ground infections are prevalent, mortality is high in

all children born to infected mothers, regardless of

the infant’s infection status.24 In Kigali, Rwanda,

mortality at 24 months of age was 19% (14% to 25%)

in children born to HIV-positive mothers. The

au-thors commented that this lower than expected

mor-tality is probably related to the regular follow-up and

improved medical care provided to all children in

the study.

Treatment with AZT, IVGG, or TMP-SMX was not

widespread in the ECS cohort, although the number

of children being treated has increased over the past

2 years, in accordance with available guidelines.26 It

will be important to compare this cohort with others

in which the majority of children have received AZT

or PCP prophylaxis to see how this therapy could

influence the natural history in a population of

HIV-infected children born to seropositive mothers and

followed from birth.27 It is now apparent that

untreated infected children can survive for a

consid-erable length of time with only minor HIV-related

signs. Indeed, in a study in Kigali, Rwanda,

perina-tally infected children surviving beyond 5 years of

age often presented with only moderate signs and

symptoms. Further follow-up of the ECS cohort

will help describe the natural history and prognosis

of vertically acquired HIV infection in older children.

Despite the large number of mother/child pairs

enrolled in the ECS and the 15% transmission rate,

the number of children with AIDS was too small to

investigate associations between AIDS indicator

dis-ease and survival. This information is better obtained

from studies following symptomatic children or

from AIDS registries.5’9 It has been reported that the

risk of dying is higher for children who are

diag-nosed with AIDS early, and in those who develop

PCP. For example, in the New York State AIDS

reg-ister, age at diagnosis and clinical presentation were

significant and independent predictors of survival.5

There is conflicting evidence on the length of time

to AIDS in vertically infected children as compared

with children infected through blood transfusions

early in life. In a study based on the Centers for

Disease Control AIDS register, the estimated

incuba-tion time was longer for pediatric transfusion AIDS

cases (median 3.5 years) than for vertically infected

AIDS cases (median 1.75 years).#{176} After AIDS

diag-nosis, the median survival was similar in both

groups (13.7 versus 14.3 months), though LIP was

more common in the vertically infected group and

encephalopathy in the transfused group. However,

other studies have found no differences in incubation

time by mode of acquisition of infection.3’ Rapid

onset of HIV-related disease has been reported in

children infected by transfusion at birth,32 with

cm-ical ifiness developing in one child as early as 4

months.

The ECS data provide a unique opportunity to

describe the pattern of development of symptoms

and signs before and after AIDS is diagnosed.

Al-though infected children have a high risk of

devel-oping some manifestations of HIV infection early in

life, many are free of serious HIV-related symptoms

at a later age, even though treatment with

anti-ret-roviral drugs, IVGG, or PCP prophylaxis was not

widespread. In this cohort, CD4 count was not

clearly associated with progression of disease,

con-trary to the findings from the Italian multicenter

register.’9’ Despite the finding that many children

have had a CD4 count below the third percentile, less

than 10% of infected children showed some

HIV-related symptoms before AIDS onset after the first

year of life, and fewer than 50% of children met the

definition of symptomatic after their AIDS diagnosis.

This has important implications for health planning

and care provision.

COLLABORATORS

We performed this study in collaboration with the following: Dr A. De Rossi, Prof L. Chieco-Bianchi, and Prof F. Zacchello (Universita degli Studi di Padova, Italy); Dr I. Grosch-W#{246}rner, Dr R. Bunikowski, and Dr M. Langhof (Universit#{228}tsklinikum Rudolf Virchow, Berlin, Germany); Dr J.Mok (City Hospital, Edinburgh, United Kingdom); Dr F. Omenaca Teres and Dr M. C. Garcia-Rodriguez (Hospital Infantil La Paz, Madrid, Spain); Dr C. A. Canosa, Dr F. Asensi, Dr M. C. Otero, and Dr A. Perez Tamarit (Hospital La Fe, Valencia, Spain); Dr H. Scherpbier (Academisch

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ARTICLES 819

Medisch Centrum, Amsterdam, The Netherlands); Dr A. B. Bohlin, Dr E. Belfrage, Dr A. Ehrnst, and Dr M. Forsgren (Hud-dinge and Danderyd Hospitals and Central Microbiological Lab-oratory, Stockholm, Sweden); Dr A. Ferrazin, Dr A. De Maria, and Dr C. Gotta (Hospital San Martino, Genova, Italy); Dr J.Levy and Dr A. Alimenti (Hospital St. Pierre, Brussels, Belgium); and Dr A. Mur, Dr H. Yazbeck, and Dr J. Llorens (Hospital del Mar, Laboratorio Referencia de Catalu#{241}a,Barcelona, Spain).

ACKNOWLEDGMENTS

This study is a concerted action of the European Commission.

The Medical Research Council (UK) provides support to the co-ordinating center. Collaborating Centers were supported by grants from the Ministero della Sanita-Istituto Superiore di Samta, progetto AIDS 1989-1992 (Padua, Genoa); the Medical Research Council (UK); the AIDS Virus Education Research Trust,

the Scottish Office Home and Health Department (Edinburgh);

Praeventiefonds number 28-1704 (Amsterdam); Bundesminister fur Gesundheit (Berlin); and Fonds de la Recherche Scientifique Medicale (Brussels).

We would like to acknowledge the help we have had from Ms

J.Caffis (London). We thank Dr R D’Elia, Dr A. M. Laverda, Dr E.

Ruga, Dr S. Cozzani, Dr A. Giacomelli, Dr A. Pagliaro, Dr A.

Condini, Dr C. Cattelan, Dr A. Mazza, Prof B. Grella, Dr A. R. Del Mistro, and Dr A. Amadori (Padua); Dr A. Schafer, Dr M. Mielke,

Prof B. Stuck, and Dr J.Woweries (Berlin); Dr R. Hague, Dr F. D. Johnstone, Dr P. L. Yap, Dr S. Burns, Dr J. Peutherer, Dr J.

Whitelaw, Mrs F. Mitchell, and Mrs C. Lockhart (Edinburgh); Dr

G. Fontan-Casanego, Dr R. Martinez-Capico, Dr M. D. Jose, Srta M. L. Gonzalez, and Srta M. L. Prieto (Madrid); Dr A. Gonzalez Molina, Dr M. Gobernado, Dr J.L. Lopez, and Dr M. Sanchez (Valencia); Dr M. Roos, Dr G. Mulder-Kampinga, Dr K. Boer, Mevr. M. C. A. van Leeuwen, and the participants of the Dutch collaborative study of HIV-infected women and their children (Amsterdam); Dr G. Lidin-Jansson, Dr R. Ljung, and Dr B. Chris-tensson (Sweden); Dr F. Melica, Dr C. Cirillo, Dr G. Barigione, M. Bellomo, and F. Caocci (Genoa); Dr S. Sprecher and Prof N. Clumeck (Brussels); and Dr E. Gimenez, Dr C. Sierra, Dr M.

Vinolas, and Dr M. A. Lopez (Barcelona).

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