The clinical benefit of antiretroviral therapy in infants is established. In this cohort collaboration, we compare immunological and virological response to treatment started before or after 3 months of age. Early initiation provides a better short-term response, although evolution after 12 months of age is similar in both group

Dollfus, Catherine

Galli, Luisa

Goetghebuer, Tessa

Haelterman, Edwige

Judd, Ali

Keiser, Olivia

Le Chenadec, Jerome

Levy, Jack

Ramos, Jose Tomas

Thorne, Claire

Warszawski, Josiane

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H I V / A I D S B R I E F R E P O R TShort- and Long-termImmunological and VirologicalOutcome in HIV-Infected InfantsAccording to the Age atAntiretroviral Treatment InitiationTessa Goetghebuer,1 Jerome Le Chenadec,2 Edwige Haelterman,1Luisa Galli,3 Catherine Dollfus,4 Claire Thorne,5 Ali Judd,6 Olivia Keiser,7,8Jose Tomas Ramos,9 Jack Levy,1 Josiane Warszawski,2,10 and the EuropeanInfant Collaboration Groupa1Pediatric Department, CHU St Pierre, Brussels, Belgium; 2Inserm, U822, LeKremlin-Biceˆtre, France; 3Italian Register, Department of Paediatrics, University ofFlorence, Italy; 4P-HP, Hoˆpital Trousseau, Service d'He´matologie et d'oncologiepe´diatrique, Paris, France; 5MRC Centre of Epidemiology for Child Health, Institute ofChild Health, University College London, 6Collaborative HIV Paediatric Study, MRCClinical Trials Unit, London, United Kingdom; 7Data Center of the Swiss HIV CohortStudy, Lausanne, and 8Institute of Social and Preventive Medicine, University of Bern,Switzerland; 9Pediatric Department, Hospital Universitario de Getafe, Madrid, Spain;and 10Universite´ Paris-Sud, Faculte´ de Me´decine Paris-Sud, U822, Le Kremlin-Biceˆtre,FranceThe clinical benefit of antiretroviral therapy in infants isestablished. In this cohort collaboration, we compare im-munological and virological response to treatment startedbefore or after 3 months of age. Early initiation provides abetter short-termresponse, althoughevolutionafter 12monthsof age is similar in both groups.In the absence of combination antiretroviral therapy (cART),approximately 20% of vertically infected children born indeveloped countries progress to AIDS in the first year of life [1].Since cART became available, early initiation of antiretroviraltherapy (ART) in infants has been questioned, and policieshave varied across Europe. The prevention of disease pro-gression when treatment is started before the age of 3 monthswas clearly demonstrated in the South African Children withHIV Early Antiretroviral Therapy randomized trial [2] and in theEuropean Infant Collaboration (EIC) [3]. All guidelines havebeen updated to recommend early ART in infants infected withhuman immunodeficiency virus (HIV).Vertical infection is associated with rapid viral multiplicationduring the first weeks of life and high viral load (VL) over the first2 years of life. At birth, the CD4 percentage is high and decreasesto reach a plateau around the age of 1 year [4]. CD4 T-celldepletion associated with HIV infection is correlated with clinicalprogression [1]. The level of plasma HIV RNA has a poorerprognostic significance than CD4 percentage.Although the clinical benefits of early treatment are recog-nized, early initiation of cART does not prevent establishment ofa reservoir of latently infected cells. It was suggested that earlyintervention during primary infection leads to better long-termvirological suppression (VS) and preserved immune systemfunction [5]. Indeed, when cART is started early in infancywith persistent control of HIV replication, children may becomeseronegative after the loss of maternal antibodies [5, 6]. Our aim,within the EIC group, was to determine if virological andimmunological responses to treatment differ according to theage at which cART is started during first 12 months of life.METHODSStudy PopulationEIC study methods have been described previously [3]. For thepresent analysis, infants were excluded if they received mono-therapy or dual therapy (n 5 38), developed AIDS before cARTwas initiated (n 5 7), or did not begin treatment before the ageof 12 months (n 5 26). The final sample size was 139 infants.A subsequent data merger collected virological and immunolog-ical data to the end of 2008.VariablesDemographics, pregnancy data, details of prophylaxis andtreatment, and CD4 and VL measurements available since birthwere collected. We defined cART as any regimen that included atleast 3 antiretroviral drugs. Infants were classified into 3 groups:those starting cART at#3 months of age (0–91 days) (the early-treatment group), those starting at ages 3–6 months, and thosestarting at ages 6–12 months; the latter 2 groups were consideredthe deferred-treatment group.Baseline VL and CD4 percentages were measured before3 months of age in both groups. This corresponded to thepretreatment values in the early treatment group, which weremeasured at a median age 37 days (interquartile range [IQR],12–54 days) for VL and 39 days (IQR, 17–56 days) for CD4Received 19 July 2011; accepted 15 November 2011; electronically published 23 December2011.aThe European Infant Collaboration Group is described in the Acknowledgments.Correspondence: Tessa Goetghebuer, MD, Pediatric Department, CHU St Pierre, 322 rueHaute, 1000 Brussels, Belgium (tessa_goetghebuer@stpierre-bru.be).Clinical Infectious Diseases 2012;54(6):878–81 The Author 2011. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/cir950878 d CID 2012:54 (15 March) d HIV/AIDSpercentage. In the deferred treatment group, baseline valueswere selected at the age closest to the median ages before age3 months. Outcomes were VL and CD4 percentage at 6, 12, 18, 24,and 48 months of age. As the threshold for viral detection variedalong the study period, VS was defined as VL ,500 copies/mL.Statistical AnalysisEvolution of CD4 percentage and log10 VL from baseline to48 months was described separately for the 3 groups, usingsmoother techniques [7]. We added the reference curve of CD4percentage by age established among HIV-exposed, uninfected(HEU) children included in the national French Perinatal Cohort(N 5 11 851) and the European Collaborative Study (ECS)(N 5 1028) [8]. CD4 z scores generated from these populationsas reference were compared with zero at 6, 12, and 24 months inearly- and deferred-treatment groups.The time from treatment initiation to first VS was estimatedin each group by the Kaplan-Meier method, censored at lastfollow-up using the log-rank test for significance. A hazard ratiofor the associations with early versus deferred treatment wasestimated using the Cox model.Levels of quantitative CD4 percentage and log10 VL, and pro-portion of VL ,500 copies/mL at baseline and measured at6 months (61.5 month) and 12, 18, 24, and 48 months(63 months) were compared in the 2 groups. The v2 test, Fisherexact test, or Monte Carlo method was used for categorical data,and the Student t test, analysis of variance, Mann-Whitney U test,and Kruskal-Wallis test were used for continuous data.The analysis was intent-to-treat, using SAS (version 9.1; SASInstitute, Cary, North Carolina) and R software (Foundation forStatistical Computing).RESULTSBaseline characteristics of the 139 infants were evenly distributedbetween the 3 treatment groups including cohort of origin, yearof birth, geographical origin of the mother, mode of delivery,antenatal and postnatal ART prophylaxis, maternal VL nearestdelivery, gestational age, sex, and baseline infant CD4 cell countand VL (Supplementary Table 1).Immunological ResponseThe CD4 percentage diminished less markedly over the first yearof life in the early-treatment group compared with the deferred-treatment groups (Figure 1a). However, CD4 percentages wereconsistently lower in all groups of HIV-infected infants comparedwith HEU infants, and median CD4 z score values remainedsignificantly lower in both early- and deferred-treatment groups atthe ages of 6, 12, and 24months (Supplementary Table 2).Mediannadir CD4 cell count and CD4 percentages were significantlyhigher in the early-treatment group until the age of 6 months, butnot thereafter.Virological ResponseA lower peak VL was observed in the early-treatment groupinfants compared with the 2 other groups (Figure 1b). Kaplan-Meier survival analysis showed that time from treatment initi-ation to first VS was significantly shorter in the early-treatmentgroup (crude hazard ratio [HR], 1.8 [95% confidence interval{CI}, 1.2–2.7]; P 5 .003; HR adjusted for baseline VL andcohort 5 1.7 [95% CI; 1.0–2.9]; P 5 .05) (Figure 1c).Although similar at baseline, the zenith VL and median VL at6 months were significantly lower in the early-treatment group,compared with the deferred-treatment group. Moreover, in theearly-treatment group, the zenith VL was significantly correlatedwith the starting age for cART (r 5 0.48, P , .001). There wasa trend to lower VL between 12 and 48 months in the early-treatment group compared with the deferred-treatment group.DISCUSSIONThe prognosis of HIV-infected children has improved consid-erably since the introduction of cART in 1996 [9]. The EIC hasdemonstrated that, in routine clinical practice in industrializedcountries, the risk of AIDS/death was 5 times lower in infantsstarting ART before 3 months of age compared with those whosetreatment was deferred, and the difference was significant untilthe age of 60 months [3]. Several reports previously demon-strated that early initiation of treatment and low-baseline VLwere significant predictors of long-term VS [10–12]. In thisarticle, we report that early initiation of cART was associatedwith a lower VL peak despite similar baseline VL. Moreover, weshowed that the virological response was more rapid whencART was started before 3 months of age. There was a significantcorrelation between the age at treatment initiation and thezenith VL in this latter group, suggesting that the sooner thetreatment is started, the better the virological control. Thisobservation is important, because VL peak may be correlatedwith the establishment of a reservoir of latently infected cells.Regarding the immunological response to treatment, weobserved that the decrease of CD4 cell count was less pronouncedand the CD4 percentages were higher in the early-treament groupuntil 12 months of age than in the deferred-treatment group.However, the CD4 percentages remained significantly lower in allgroups of HIV-infected infants than in HEU controls up to theage of 2 years.In this report, the better immunological and virologicalevolution observed in the early-treatment group compared withthe deferred-treatment group was no longer detectable by age12 months, possibly because of lack of power due to sample size.However, it is possible that the functional competences of CD4cells are influenced by early initiation of therapy and maymaintain an impact on the clinical outcome after the age of12 months.HIV/AIDS d CID 2012:54 (15 March) d 879To limit potential selection and information biases, thestudy included HIV-infected infants prospectively followedfrom birth to exclude the few long-term nonprogressorchildren diagnosed later. We analyzed only infants who re-ceived cART as first treatment before AIDS developed toevaluate response to cART in asymptomatic children. TheAGE (MONTHS)CD4 PERCENTAGE8463422163010203040506070 Treatment <3months Treatment 3−6 months Treatment 6−12 months HEU childrenAGE (MONTHS)LOG OF RNA VIRAL LOAD846342216301234567 Treatment <3 months Treatment 3−6 months Treatment 6−12 monthsBTIME FROM TREATMENT INITIATION (YEARS) Treatment <3 months Treatment 3−6 months Treatment 6−12 months0 2 4 6 8 10 120102030405060708090100 %CAFigure 1. Comparison of immunological and virological evolution according to age at treatment initiation. A, Evolution of CD4 percentage in humanimmunodeficiency virus (HIV)–infected infants according to age at treatment initiation and in HIV-exposed uninfected infants (HEU). B, Evolution of viralload (VL) from birth in different groups according to age at treatment initiation. C, Kaplan-Meier survival analysis: time to attaining undetectableVL (VL ,500 copies/mL) from the time of treatment initiation according to age at treatment initiation.880 d CID 2012:54 (15 March) d HIV/AIDS2 groups did not differ significantly for the type of first cARTregimen used.In conclusion, this analysis of the EIC study indicatesthat cART initiated before the age of 3 months, in addition tothe strong and durable impact on the clinical outcome pre-viously described, results in more rapid control of earlyvirological replication and preservation of CD4 lymphocytesup to age 12 months compared with deferred treatment. Afterthe age of 12 months, immunovirological outcomes did notdiffer significantly between the groups. Because early initia-tion of treatment in HIV vertically infected infants is nowrecommended in all guidelines, efforts should be made toestablish the diagnosis of infection as soon as possible afterbirth.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases online(http://www.oxfordjournals.org/our_journals/cid/). Supplementary materialsconsist of data provided by the author that are published to benefit the reader.The posted materials are not copyedited. The contents of all supplementarydata are the sole responsibility of the authors. Questions or messages regardingerrors should be addressed to the author.NotesAcknowledgments. We are indebted to the infants included in thisstudy and to their parents, and to all physicians who participated incollecting clinical data. We thank Dr A. Marchant for his critical review ofthe manuscript.EIC group: Albert Faye, AP-HP, Hoˆpital Robert Debre´, Service depe´diatrie ge´ne´rale, Paris, France; Stephane Blanche, AP-HP, HoˆpitalNecker, Service d’immunologie pe´diatrique, Paris, France; Clara Gabiano,Italian Register, Department of Paediatrics, University of Turin, Italy; DianaGibb, Hannah Castro, Trinh Duong, Collaborative HIV Paediatric Study,MRC Clinical Trials Unit, London; Carlo Giaquinto, Martina Penazzato,Department of Pediatrics, University of Padova, Italy; MagdalenaMarczynska, Infectious Disease Hospital, Medical University Warsaw,Poland; Luminita Ene, Hospital for Infectious Diseases ‘‘Dr Victor Babes,’’Bucharest, Romania; Marc Hainaut, Paediatric Department, CHU St Pierre,Brussels, Belgium; Henriette Scherpbier, Emma Children’s Hospital,Academic Medical Center, Amsterdam, Netherlands; Uwe Wintergerst,University Children’s Hospital, Munich, Germany; Ve´ronique Schmitz,Hoˆpital La Citadelle, Lie`ge, Belgium; Be´ne´dicte Brichard, Hoˆpital St Luc,Brussels, Belgium; Gwenda Verweel, Erasmus MC Sophia Children’sHospital, Rotterdam, Netherlands; Pat Tookey, National Study of HIV inPregnancy and Childhood, MRC Centre of Epidemiology for Child Health,Institute of Child Health, UCL, London.Financial support. This work was supported by the Paediatric EuropeanNetwork for the Treatment of AIDS (PENTA), which has previously receivedfunding from the European Union Sixth Framework Programme (grantagreement PENTA/ECS 018865); the European Union Seventh FrameworkProgramme (FP7/2007–2013) under EuroCoord grant agreement 260694;the French National Agency for AIDS and Hepatitis Research; and theSmiles Foundation, Belgium.Potential conflicts of interest. All authors: No conflicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConflicts of Interest. Conflicts that the editors consider relevant to thecontent of the manuscript have been disclosed.References1. Gray L, Newell ML, Thorne C, Peckham C, Levy J. Fluctuations insymptoms in human immunodeficiency virus-infected children: thefirst 10 years of life. Pediatrics 2001; 108:116–22.2. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy andmortality among HIV-infected infants. N Engl J Med 2008; 359:2233–44.3. 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Short- and Long-term Immunological and Virological Outcome in HIV-Infected Infants According to the Age at Antiretroviral Treatment Initiation

Short- and Long-term Immunological and Virological Outcome in HIV-Infected Infants According to the Age at Antiretroviral Treatment Initiation

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