HIV/AIDS • CID 2007:45 (15 September) • 785
H I V / A I D S M A J O R A R T I C L E
Long-Term Nonprogression of HIV Infection in
Children: Evaluation of the ANRS Prospective French
Josiane Warszawski,1,2,3,4Je ´ro ˆme Lechenadec,1Albert Faye,5Catherine Dollfus,6Ghislaine Firtion,7
Laurence Meyer,1,2,3Danielle Douard,11Fabrice Monpoux,12Joe ¨lle Tricoire,13Yassine Benmebarek,1
Christine Rouzioux,8,10and Ste ´phane Blanche9,10
1Institut National de la Sante ´ et de la Recherche Medicale U822,2Universite ´ Paris-Sud, and3Assistance Publique–Ho ˆpitaux de Paris (AP-HP) Ho ˆpital
Bice ˆtre, Service de Sante ´ Publique, Le Kremlin-Bice ˆtre,4Institut National d’Etude Demographique,5AP-HP Ho ˆpital Robert Debre ´ Service de Pe ´diatrie
Ge ´ne ´rale,6AP-HP Ho ˆpital Trousseau Service d’He ´matologie et de Cance ´rologie,7AP-HP Ho ˆpital Cochin-Saint Vincent de Paul Services de Me ´decine
Ne ´onatale et d’Obste ´trique,8Laboratoire de Virologie and
Me ´decine Rene ´ Descartes, Equipe d’Accueil EA 3620, Universite ´ Paris V, Paris,11Ho ˆpital des Enfants Service de Pe ´diatrie, Bordeaux,12Ho ˆpital de
l’Archet Service d’He ´matologie et de Cance ´rologie Pe ´diatrique, Nice, and13Ho ˆpital Purpan Service de Pe ´diatrie, Toulouse, France
9Unite ´ d’Immunologie He ´matologie, AP-HP Ho ˆpital Necker Enfants-Malades, and10Faculte ´ de
perinatal period remain asymptomatic for very long periods in the absence of antiretroviral treatment, as is the
case for some adults. Our objective was to estimate the proportion of children who developed neither symptoms
nor major immunological perturbations to the age of ?10 years in a prospective cohort of infected children who
had been observed since birth.
The ongoing prospective French Pediatric Cohort includes 568 HIV-1–infected children. Here, we
report the follow-up data for all 348 HIV-1–infected children who were born before 1 January 1994. Children
with long-term nonprogression of infection (LTNPs) were defined as HIV-1–infected children who had been
observed for at least 10 years, never received antiretroviral treatment other than zidovudine monotherapy, never
developed symptoms of Centers for Disease Control and Prevention clinical category C or B, and had a CD4+cell
percentage of !25% no more than once during follow-up. Other definitions were compared.
The Kaplan-Meier estimate of long-term nonprogression was 2.4% (95% confidence interval, 1.1%–
4.6%) at 10 years of age, and 7 children were classified as LTNPs. The Kaplan-Meier estimates decreased slightly
with age, to 1.8% at 12 years of age and 1.4% at 14 years of age. Plasma HIV-1 replication rates were low (!1000
copies RNA/mL) for 2 of the 7 LTNPs at the age of 10 years (0.6% of the total denominator). None of the routinely
measured maternal or perinatal markers were significantly linked to long-term nonprogression, with the exception
of the mother’s Centers for Disease Control and Prevention clinical category at the time of delivery.
Approximately 2% of children who were infected during the perinatal period displayed no
immunological or clinical progression by the age of 10 years. This figure is close to that reported for adults in
studies that have used similar definitions.
Some children who are infected with human immunodeficiency virus type 1 (HIV-1) during the
Little is known about the long-term evolution of HIV-
1 infection in children who are infected during the
perinatal period. The early and severeformofinfection,
in which opportunistic infections and/or encephalop-
Received 6 February 2007; accepted 11 May 2007; electronically published 14
Reprints or correspondence: Dr. Ste ´phane Blanche, Unite ´ d’Immunologie et
d’He ´matologie Pe ´diatriques, Ho ˆpital Necker Enfants-Malades, 149 rue de Se `vres
75015 Paris, France (email@example.com).
Clinical Infectious Diseases2007;45:785–94
? 2007 by the Infectious Diseases Society of America. All rights reserved.
athy occur in the first 2 years of life, affects only 10%–
15% of HIV-1–infected children, with progression be-
ing much slower in most children . Recent studies
have reported immunological or genetic analyses of
children who did not have clinical or immunological
progression at ?8 years of age [2–6]. The only pub-
lished estimate of the frequency of this phenomenon
comes from a prospective cohort study, which revealed
that 10 of 137 children who were infected during the
perinatal period did not have progression by 8 years of
age, as determined on the basis of an exclusively im-
munological definition of nonprogression . Various
definitions have been used for “long-term nonpro-
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786 • CID 2007:45 (15 September) • HIV/AIDS
gression/nonprogressor” (LTNP) in studies of adults, resulting
in 1%–25% of HIV-1–infected persons being classified as
LTNPs after 8–10 years of infection [7–9]. These definitions
are based mostly on quantitative immunological criteria in pa-
tients who have not received treatment, and in some studies,
the definition has involved clinical criteria (i.e., the absence of
AIDS-defining symptoms or even the absence of anysymptoms
linked to HIV-1 infection). Some studies also distinguish a
subgroup of LTNPs who havepersistentlylowHIV-1loads.
The particularly slow progression of HIV-1 infection in these
patients may be associated, at least in part, witha geneticprofile
in the host that limits viral replication and/or affects the quality
of the specific anti–HIV-1 immune response (reviewed in [11,
12]. In the vast majority of cases, the replicative capacities of
the virus do not appear to be modified [13, 14]. However, it
remains unclear whether LTNPs are a particular subgroup of
patients who experience no adverse effects of HIV-1 infection
or are simply persons at the tail end of the survival curve.
Definitions applied to adults need to be adapted to the spec-
ificities of pediatric care before they can be used for children.
CD4+cell counts, expressed as absolute cell counts, are higher
in infants than in older children and, in fact, decrease over the
first few years of life . In addition, children may develop
opportunistic infections at higher CD4+cell counts, compared
with adults, as confirmed by a recent meta-analysis. CD4+cell
percentages are a better marker than absolute CD4+cellcounts,
which vary more with age in children .
Our objective was to estimate the proportion of LTNPs in
the French Pediatric HIV-1 Cohort (EPF), one of the largest
and oldest incident cohorts of children who were infected with
HIV-1 at birth. We used a definition of LTNP derived from
definitions generally used for adults: continual maintenance of
a high CD4+cell percentage and an absence of HIV-1–related
symptoms, without receipt of antiretroviral treatment, at the
age of 10 years. We assessed various CD4+cell percentage
thresholds and various definitions of HIV-1–relatedsymptoms.
We then studied perinatal characteristics associated with LTNP.
PATIENTS AND METHODS
data concerning HIV-1–infected pregnant women and their
children in 90 health carecentersthroughoutFrancesince1986.
Informed consent was obtained from all mothers during preg-
nancy or at delivery. The cohort study was approved, in ac-
cordance with French law, by the Cochin Hospital Institutional
Review Board and the French computer database watchdog
commission (Commission Nationale de l’Informatique et des
As previously reported , HIV-1–uninfectedchildrenwere
observed in accordance with recommended standards of care,
including clinical and biological examination at birth; at ages
The ongoing EPF study has prospectively collected
1, 3, and 6 months; and then every 6 months until they were
24 months of age. HIV-1–infected children were observeduntil
adulthood. No specific recommendations for HIV-1 treatment
or obstetrical care were made for women and children enrolled
in the cohort, although investigators were encouraged tofollow
French national guidelines, as regularly published and updated
Among the 12,325 children born to
HIV-1–infected mothers included in the EPF cohort up to 15
December 2006, a total of 568 were infected with HIV-1. All
348 HIV-1–infected children born before 1 January 1994 were
included in this analysis: these persons were old enough tohave
undergone at least 12 years of follow-up and did not receive
perinatal prophylaxis for mother-to-child transmissionof HIV-
1 (such prophylaxis was not yet available at that time). HIV-1
infection in children was defined on the basis of 2 positive
HIV-1 PCR results or 2 positive culture results before the age
of 18 months, positive results of a serologic test after the age
of 18 months, or AIDS-related death before the age of 18
months in the absence of viral isolation (especially for children
born before PCR testing wasavailable).Follow-upwascensored
at the French legal age for adulthood (i.e., 18 years) for all
Definitions of LTNP.
We initially defined LTNPs as HIV-
1–infected children who had been observed for at least10years,
who had never received antiretroviral treatment (other than
of Centers for Disease Control and Prevention (CDC) clinical
category C or B, and for whom the CD4+cell percentage was
!25% no more than once throughout the follow-up period
before they reached 10 years of age. This threshold fortheCD4+
cell percentage corresponds with the highest of the 3 immu-
nological categories of the 1994 CDC classification for HIV-1–
infected children, defined as “no evidence of immunosuppres-
sion” . Zidovudine monotherapy alone was allowed, be-
cause it has no long-term immunological and clinical efficacy,
either in adults or children [19, 20]. In accordance with the
inclusion period criteria, no child had received perinatal an-
tiretroviral prophylaxis. We then considered less restrictiveclin-
ical and immunological definitions (i.e., use of only AIDS-
defining events [CDC category C] as a marker of clinical
progression and use of a CD4+cell percentage thresholdof15%
rather than 25%).
We also examined the effect of considering only nontreated
children (with zidovudine monotherapy again excluded) or of
allowing children who had received dual–nucleoside analogue
therapy. In the latter instance, only children treated with
HAART were excluded from the definition of LTNP, with
HAART defined as the combination of ?3 antiretroviraldrugs.
The studied maternal characteristics were age at the time of
delivery; geographic origin, as classified in 3 categories (sub-
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794 • CID 2007:45 (15 September) • HIV/AIDS
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