Over 1000 HIV-infected infants are born each day worldwide . Several studies [2–6] have shown that early initiation of combination antiretroviral therapy (ART) in HIV-infected infants, irrespective of clinical, immunological or virological condition, increases survival and reduces disease progression, and international guidelines have been changed accordingly [7,8]. Although high levels of viral replication occur in vertically HIV-infected infants, early initiation of ART can result in sustained viral suppression and maintain CD4 values at protective levels [4,9–11]. However, some studies have reported that rates of virological failure are higher in infants starting therapy than in older children and adults [12–15]. The efficacy, safety and tolerability of first-line ART regimens are, therefore, critical for HIV-infected infants who are likely to need lifelong treatment.
Two recent trials investigated the effectiveness of different first-line ART regimens in children, with contradictory results. In the PENPACT-1 [Paediatric European Network for Treatment of AIDS (PENTA) and Pediatric AIDS Clinical Trials Group/International Maternal Pediatric Adolescent AIDS Clinical Trials Group (PACTG/IMPAACT)] trial, 266 children from Europe, the USA and South America, aged 1 month to 18 years (26%, ≤3 years) were randomized to start protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART . At 4 years, more than 80% of children in both arms had viral load less than 400 copies/ml with no differences in CD4 cell responses; after 5 years, 71% were still taking their first-line regimen. There was no evidence (but low power) to suggest that this result was any different in children initiating ART at less than 3 years. Conversely, in the IMPAACT 1060 trial, conducted mainly in Africa, 288 children aged 2–36 months (median 20 months) and not exposed to nevirapine-based ART for the prevention of mother-to-child transmission (PMTCT) showed a significantly higher rate of treatment failure by 24 weeks in those starting nevirapine-based compared with lopinavir/ritonavir-based ART (40 vs. 19%. respectively) .
In studies including children who have received ART for PMTCT, exposure to single-dose nevirapine reduced subsequent response to NNRTI-based ART, unless a protease inhibitor-based ART regimen precedes simplification to an NNRTI-based regimen, as reported in the Nevirapine Resistance Study (NEVEREST) trial . An alternative ‘induction–maintenance’ approach of starting with a four-drug NNRTI-based regimen and reducing to three-drug ART later  has been reported to be promising in the UK and Irish Collaborative HIV Paediatric Study (CHIPS) cohort  and is under evaluation for long-term efficacy in PMTCT exposed and unexposed children in the Ugandan/Zimbabwe Anti-Retroviral Research for Watoto (ARROW) trial (www.arrowtrial.org).
Standard practice regarding ART management in HIV-infected infants has varied across Europe and over time. Using data from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC, 1996–2008), we investigated factors associated with 12-month virological and immunological response to first-line ART and predictors of switching and interrupting therapy up to 5 years from treatment initiation.
Data from nine observational cohort studies (five national or multicountry cohorts and four city-based cohorts; five birth cohorts and four prevalent cohorts) in 13 European countries were merged using a standardized format . Six cohorts with less than 25 infants each were combined into an ‘other’ category. HIV-infected infants born between 1996 and 2008 and who were ART-naive when they started therapy were included.
Definitions and statistical methods
ART during infancy was defined as the first time when at least three antiretroviral drugs were started within 2 weeks of each other and before 12 months of age, excluding ART for neonatal prophylaxis. Timing of ART initiation was categorized a priori as less than 3, 3–6 or 6–12 months of age . Baseline CD4 cell count and HIV-1 RNA viral load values were defined as the latest pretreatment measurements within 3 months before ART initiation. Virological and immunological responses were defined as viral load less than 400 copies/ml and mean change in CD4 Z-score at 12 months (±3 months) after ART initiation, respectively . CD4 Z-scores were used because of normal age-related changes in CD4 cell counts (and to a lesser extent CD4 percentages) during infancy .
Switching to second-line ART was defined as changing to at least three drugs simultaneously irrespective of reasons, or changing two drugs with documented treatment failure (virological, immunological and/or clinical) . Drug substitutions with undetectable viral load were likely related to toxicity or simplification, and were not included. Treatment interruption was defined as discontinuation of all medication for at least 14 days; our analyses focussed on interruptions with viral load less than 400 copies/ml because they are most relevant as potential future treatment strategies. Viral loads and CD4 cell count values at switch and treatment interruption were the latest measurements within 3 months before the event. We used virological and immunological measurements closest to 12 months after switching (±3 months).
The effects of potential predictors of virological and immunological responses to ART were analysed using logistic and linear regression, respectively. Competing risk methods separately estimated the cumulative incidence of switching and of treatment interruption with viral load les than 400 copies/ml and assessed potential predictors. Loss to follow-up, death and treatment interruption with detectable viral load more than 400 copies/ml (in analysis of treatment interruption with viral load <400 copies/ml only) were considered competing events .
A-priori confounders in analyses of treatment response included in multivariate models were age and calendar year at ART initiation, type of initial ART regimen and baseline CD4 Z-score (for CD4 response only). Other potential predictors considered were country, sex, ethnic group, baseline viral load, pretreatment AIDS diagnosis, maternal ART during pregnancy, neonatal prophylaxis and breastfeeding status; these factors remained in multivariable models if the corresponding P values in univariable and multivariable models were less than 0.10.
A-priori confounders in analyses of switching and of treatment interruption with viral load less than 400 copies/ml were type of initial ART regimen, age at ART initiation and country. Other potential predictors were sex, ethnic group, baseline viral load and CD4 Z-score, pretreatment AIDS diagnosis and most recent CD4 Z-score. Finally, calendar period of follow-up, having a viral load less than 400 copies/ml, and confirmed rebound of viral load (defined as two consecutive viral loads >400 copies/ml within 12 months after having suppressed <400 copies/ml) were also considered, all fitted as time-dependent covariates. Children enrolled in planned treatment interruption trials (namely PENTA 11, n = 8) were excluded in analyses of treatment interruption .
Missing data for covariates at ART initiation and for viral load at treatment interruption were imputed using chained equation methods with 20 imputations for regression analyses assessing potential predictors and for estimating cumulative incidence of treatment interruption with viral load less than 400 copies/ml . Statistical analyses were performed using Stata version 11 (Stata Corporation, College Station, Texas, USA).
A total of 437 infants born between 1996 and 2008 started ART before 12 months of age at a median of 3.7 [interquartile range (IQR) 2.1–5.8] months. Approximately 40% were from the UK/Ireland, 20% from Italy and 20% from France (Table 1). Half were female; half were black ethnic origin; and 34% had been exposed to maternal ART in pregnancy, of whom 29 (19%) were exposed to nevirapine (three as single-dose). Additionally, 28% received neonatal prophylaxis. One-third, in whom HIV was undiagnosed antenally, were breastfed. Thirty percent had an AIDS diagnosis, a median age of 3.6 (IQR 2.7–5.3) months prior to ART initiation. Twenty-six infants developed AIDS at median 40 days after ART initiation (IQR 14–189). The most common AIDS events were Pneumocystis jiroveci pneumonia (n = 81 before and n = 7 following ART initiation), cytomegalovirus infection (n = 52 and n = 7, respectively) and HIV encephalopathy (n = 33 and n = 10, respectively). Median duration of follow-up after starting ART was 5.9 (IQR 2.3–7.6) years, during which time 20 patients died and 32 were lost to follow-up (16 and 13 by 12 months, respectively). Median CD4 percentage and viral load at ART initiation were 29% and 5.7 log10 copies/ml, respectively (Table 1).
Seventy-six percent (331 of 437) infants started ART before 6 months of age (Table 1). Twenty-four percent (107 of 437) of ART regimens contained an NNRTI (mostly nevirapine) with two NRTIs, most commonly didanosine with stavudine (36%, eight of 22) in 1996–1999 and zidovudine with lamivudine (55%, 47 of 85) from 2000 onwards. Four-drug nevirapine-based regimens were more common in later years (3%, four of 121) of regimens in 1996–1999, and 18% (57 of 316) from 2000 onwards, almost all with three NRTIs [zidovudine, lamivudine and abacavir (98%, 60 of 61)]; most (58 of 61) were from UK/Ireland. Boosted protease inhibitor regimens were used only from 2001, increasing from 11% (21 of 180) of all regimens in 2000–2003 to 34% (46 of 136) in 2004–2008; the most common NRTI backbones being zidovudine with lamivudine (48%, 32 of 67) and lamivudine with abacavir (27%, 18 of 67). Use of unboosted protease inhibitor-based regimens, mainly nelfinavir (86%, 143 of 166 of all unboosted regimens), declined from 68% (82 of 121) in 1996–1999 to 17% (23 of 136) in 2004–2008.
Virological and immunological response to antiretroviral therapy
Table 2 shows factors associated with virological and immunological response 12 months after ART initiation. Viral load at 12 months was missing for 26% of children; these patients were more likely to be born in 2004–2008 (38 vs. 29% for those with an available viral load, P = 0.022) and reported from the Italian cohort (36 vs. 18%, P
= 0.002) and less likely to have been on a four-drug NNRTI regimen (9 vs. 16%, P = 0.011, as expected, given most missing data were from Italy). However, there were no differences by all other factors included in multivariable models.
Overall, 62% (199 of 322) of infants achieved virological suppression less than 400 copies/ml by 12 months after ART initiation. There was a trend toward improved viral suppression with calendar time from 53% for those initiating ART in 1996–1999 to 57% in 2000–2003 and 77% in 2004–2008 (adjusted P = 0.09, Table 2). Age at ART initiation was weakly associated with 12-month virological response, 6–12 month-old infants being more likely to suppress virus than less than 3-month olds [adjusted odds ratio (AOR) 1.98, 95% confidence interval (CI) 0.92–4.25, P = 0.06]. Infants on four-drug NNRTI regimens had significantly better viral load suppression (AOR 3.00, 95% CI 1.24–7.23) compared with three-drug NNRTI regimens, whereas boosted protease inhibitor regimens (AOR 1.39, 95% CI 0.62–3.13) were not statistically different from three-drug NNRTI regimens. In addition, the likelihood of achieving virological suppression declined with increasing baseline viral load (AOR 0.67 per log10 copies/ml, 95% CI 0.50–0.89, P = 0.01).
Half (47%, 203 of 437) all infants had baseline and 12-month CD4 cell count values available. As with viral load, infants with missing CD4 cell count values were also more likely to be reported from the Italian cohort (32 vs. 12%, P < 0.001) and less likely to be on four-drug NNRTI regimens (9 vs. 19%, P = 0.002). In addition, they were more likely to be white (44 vs. 21%, P < 0.001) and less likely to have had infant prophylaxis (21 vs. 36%, P < 0.001). However, there was no association between missing CD4 cell count and all other factors.
For infants with baseline and 12-month CD4 cell count values, median (IQR) changes in CD4 cell count, CD4 percentage and CD4 Z-score were 520 cells/μl (271–1340), 6% (−6 to 16%) and 0.92 (−0.14 to 2.34), respectively. Median CD4 Z-score increase was 2.29 in infants receiving four-drug NNRTI regimens compared with 0.65 in those receiving three-drug NNRTI regimens and 0.91 for boosted protease inhibitor regimens (overall adjusted P = 0.04) (Table 2). In addition, infants with lower baseline CD4 Z-scores had larger increases in CD4 cell count at 12 months than those with higher baseline values (P < 0.001), and infants whose mothers received ART in pregnancy had a smaller increase in CD4 Z-score at 12 months than those whose mothers did not receive ART (median Z-score increase 0.27 vs. 1.69, P = 0.02).
Switching to second-line antiretroviral therapy and treatment interruption
Eighteen percent (77 of 437) infants switched to second-line therapy. The cumulative incidence of switching by 2 and 5 years from ART initiation was 10.2% (95% CI 7.5–13.4%) and 16.7% (13.0–20.7%), respectively (Fig. 1). As expected, the main reported reason for switching was treatment failure (84%, 41 of 49 with information available). Three fifths (61%, 43 of 70) of these infants never achieved virological suppression (<400 copies/ml) by the time of switch and 31% (22 of 70) had a confirmed virological rebound before subsequently switching after a median interval of 8.9 (IQR 1.9–27.6) months from initial rebound. In the remaining five who had achieved virological suppression, treatment was switched without a confirmed virological rebound.
Those starting with either four-drug NNRTI or boosted protease inhibitor regimens were slower to switch [adjusted hazard ratio (HR) 0.41, 95% CI 0.15–1.14 and adjusted HR 0.26, 95% CI 0.06–1.19, respectively, P = 0.03] compared with other regimens (Table 3), although data were sparse. Risk of switching decreased considerably once a child had a viral load less than 400 copies/ml (HR 0.23, 95% CI 0.15–0.37, P < 0.001) and increased substantially once a child with viral load suppression had a confirmed virological rebound (HR 22.8, 95% CI 5.47–95.14, P < 0.001). However, among all children with a confirmed rebound while on first-line ART, only an estimated 10.7% (95% CI 5.8–17.2%) switched within 12 months of initial rebound.
Over half (56%, 13 of 23) of children switching from an NNRTI-based first-line regimen went on to a boosted protease inhibitor as second-line ART, and six to an unboosted protease inhibitor regimen. Two-fifths (42%, 19 of 45) of children switching from an unboosted protease inhibitor-based first-line regimen went on to a NNRTI-based second-line regimen, and 11 to a boosted protease inhibitor regimen with another protease inhibitor drug. Overall, only two of the 67 children initiating ART with a boosted protease inhibitor switched to second-line ART; one to an NNRTI-based and the other to a dual protease inhibitor second-line regimen. Half (53%, 31 of 58) of those switching to second-line ART achieved a viral load of less than 400 copies/ml within 12 months of switching.
Twenty-eight percent (121 of 429) of children had at least one treatment interruption lasting more than 14 days; 21 (17%) had two and four (3%) had three interruptions. Of those with a viral load available, 38% (36 of 94) had an interruption while viral load was suppressed, after a median 29 (IQR 16–54) months on ART; most (92%, 33 of 36) were on first-line therapy. The cumulative incidence of interruption with viral load of less than 400 copies/ml by 2 and 5 years was 5.3% (95% CI 3.2–8.0%) and 11.5% (95% CI 8.2–15.3%), respectively, (Fig. 1) and no factors predicted interruption, although data were sparse. Fifty-eight percent (21 of 36) restarted ART following their first interruption after an estimated median duration off therapy of 21.4 (IQR 3.7–68.6) months.
Children remaining on first-line antiretroviral therapy without treatment interruption
Two-thirds (65%, 278 of 429) of children had neither switched to second-line ART nor experienced any treatment interruption by last follow-up and, of these, 36% (100 of 278) had been treated for at least 5 years. At last follow-up, 81% (213 of 262 with measurement available) had viral load less than 400 copies/ml and median CD4 percentage was 36% (IQR 30–42%). The estimated probability of remaining on first-line ART without interruption was 79.3 (95% CI 75.1–83.1%) and 63.8% (95% CI 58.7–68.9%) by 2 and 5 years from ART initiation, respectively.
In our study, virological response in infants starting ART before 12 months of age showed improvement with calendar year of ART initiation, and virological and immunological responses were better in those starting with four-drug NNRTI-based regimens compared with three-drug NNRTI-based and boosted protease inhibitor regimens which were similar. The rate of switching to second-line ART was low, and almost 65% of children remained on first-line ART without treatment interruption after 5 years.
Our study has several limitations. We were unable to assess the influence of unmeasured confounders, and there is a risk of attrition and selection bias, particularly for data acquired from nonbirth cohorts. Clinicians’ preference in first-line treatment choice, influenced by patient presentation and adherence patterns, cannot be ruled out. However, there was no evidence of differences across countries (data not shown) or by pretreatment AIDS diagnosis. Missing data for viral load and CD4 cell count were higher for the Italian cohort, indicating that selection bias may be present, although multiple imputation techniques were employed to address this bias . Data on HIV resistance mutations were not available for most children and, thus, the impact of resistance could not be assessed.
Our findings demonstrate that across Europe, virological responses have improved over calendar time in infants starting ART early in life. Possible explanations include better regimen efficacy, better dosing and improved management, resulting in better caregiver adherence. Of note, in the Children with HIV Early Antiretroviral Therapy (CHER) trial, the proportion of children on lopinavir/ritonavir with viral load less than 400 copies/ml at 12 months was similar to that observed here for 2004–2008 (77%) [5,28]. Similarly, in the NEVEREST trial of young children less than 2 years of age starting on a protease inhibitor-based regimen, the proportion with viral load of less than 400 copies/ml at 9 months was 84% .
Firm evidence of better virological response to boosted protease inhibitor-based vs. NNRTI-based regimens is lacking in our study, after controlling for potential confounders. This is in agreement with the PENPACT-1 trial , but in contrast to the short-term IMPAACT 1060 trial findings . However, power to detect small differences was low in our study as relatively few infants started boosted protease inhibitor-based ART. African children in IMPAACT 1060 started ART according to clinical and immunological criteria and were more severely immunosuppressed (median CD4 percentage 15% overall vs. 29% in our study) and were assessed for a different study endpoint after only 24 weeks. PENPACT-1 included few infants and, like our study, included some started on early ART when asymptomatic with high CD4 cell count values; duration of follow-up in both PENPACT-1 and our study was considerably longer than in IMPAACT 1060.
Of interest, use of four-drug NNRTI-based regimens resulted in improved virological and immunological responses compared with other regimens. Given high viral loads in infancy and potential advantages of a protease inhibitor-sparing regimen in terms of tolerability, adherence, lack of interaction with other drugs, preservation of effective second-line options and cost, an NNRTI-based four-drug to three-drug induction–maintenance strategy could be valuable in infants not exposed to single-dose nevirapine for PMTCT. However, as infants initiating four-drug regimens in our study were mainly from UK/Ireland, potential biases in indication for treatment cannot be excluded; the results of the ARROW trial, which is evaluating this strategy, are awaited in 2012.
Immunological recovery was better in those initiating therapy with a lower CD4 Z-score at baseline, confirming good thymic activity in young children [20,30] and a possible ‘ceiling effect’ of CD4 response in infants, as noted elsewhere . In addition, the negative association with exposure to maternal ART prima facie suggests the possibility, supported by previous findings, that infants acquiring HIV despite maternal ART in pregnancy may have a worse prognosis and potentially suboptimal immunological response to treatment [31,32]. However, exposure to maternal ART was varied in our study, with infants being exposed to many different regimens, and we had insufficient data to fully evaluate this association.
Five years after starting ART, two-thirds of infants in our study were still on their first-line regimen without interruption, and a fifth had switched to second-line. Similarly, in the UK and Ireland paediatric cohort, 22% of children starting ART at a median age of 5 years switched to second-line after a median of 7 years . In our study, children starting ART on four-drug NNRTI-based or boosted protease inhibitor regimens switched to second-line ART more slowly, in line with evidence that these regimens maybe more durable, and result in a more sustained virological response and/or a higher genetic barrier to drug resistance [33,34].
Despite treatment interruption not being currently recommended in international paediatric guidelines, a quarter of infants interrupted treatment during follow-up. Sixty-two percent of interruptions occurred with detectable viral load, likely reflecting challenges encountered with tolerability, acceptability and adherence, which may be exacerbated in young children, with unclear impact on subsequent treatment response. Five-year results of the CHER trial comparing outcomes in infants randomized to planned interruption at 12 or 24 months of age after early ART vs. deferred ART are awaited later this year. In our study, children remained on first-line therapy longer than adults , even following the occurrence of viral load rebound. This is likely due to a more conservative approach to the clinical management of young children, especially in earlier years, and limited treatment options.
In conclusion, our findings suggest that outside trial settings, an effective treatment response can now be achieved in infants who start ART early in life, with the majority remaining on first-line ART after 5 years. However, issues around choice of first-line ART including potential treatment sequencing, feasibility and cost require careful consideration. Our findings are in line with evidence in the PENPACT-1 trial, suggesting similar responses to initial three-drug NNRTI-based and protease inhibitor-based regimens, but in addition suggest that a four-drug NNRTI-based initial regimen maybe superior. However, this approach needs further evidence from ongoing randomized trials, as do strategies of four-drug to three-drug NNRTI induction–maintenance and treatment interruption following early ART in infancy.
Writing Committee (ordered by project team first and in last place, followed by working group and finally all others alphabetically by name):
Ali Judd [Medical Research Council Clinical Trials Unit (MRC CTU), London, UK], Martina Penazzato (MRC CTU, London, UK and University of Padova, Italy), Claire Townsend (MRC CTU, London, UK)*, Trinh Duong (MRC CTU, London, UK)*, Hannah Castro (MRC CTU, London, UK); Tessa Goetghebuer (Hospital St Pierre, Brussels, Belgium), Josiane Warszawski (INSERM, Paris, France), Luisa Galli (University of Florence, Italy), Elena Chiappini (University of Florence, Italy); Maurizio de Martino (University of Florence, Italy), Luminita Ene (Victor Babes Hospital, Bucharest, Romania), Carlo Giaquinto (University of Padova, Italy), Christoph Königs (University of Frankfurt, Germany), Jerome LeChenadec (INSERM, Paris, France), Hermione Lyall (Imperial College Healthcare NHS Trust, London, UK), Antoni Noguera Julian (Hospital Sant Joan de Déu, Barcelona, Spain), Jose T. Ramos (Hospital Universitario de Getafe, Madrid, Spain), Pablo Rojo-Conejo (Hospital 12 de Octubre, Madrid, Spain), Christoph Rudin (Universität Basel, Switzerland), Claire Thorne (UCL Institute of Child Health, University College London (UCL), London, UK), Pat Tookey (UCL Institute of Child Health, UCL, London, UK), Gareth Tudor-Williams (Imperial College Healthcare NHS Trust, London, UK); and Di M. Gibb (MRC CTU, London, UK) (*these authors contributed equally).
Contributions: Ali Judd, Martina Penazzato, Hannah Castro and Di Gibb were responsible for the study concept and design. Claire Townsend, Trinh Duong and Hannah Castro were responsible for undertaking the analyses; Trinh Duong acts as guarantor for the analyses and has full access to the dataset. Ali Judd, Martina Penazzato, Claire Townsend, Trinh Duong and Di Gibb wrote the manuscript. Ali Judd, Di Gibb, Elena Chiappini, Maurizio de Martino, Luminita Ene, Luisa Galli, Tessa Goetghebuer, Jerome LeChenadec, Hermione Lyall, Antoni Noguera Julian, Jose T. Ramos, Pablo Rojo-Conejo, Christoph Rudin, Claire Thorne, Pat Tookey, Gareth Tudor-Williams and Josiane Warszawski provided data for the study. All members of the Writing Committee participated in discussions about the design of the study, the choice of statistical analyses, interpretation of the findings and critically reviewed the manuscript.
Contributing cohorts (listed alphabetically by cohort name): ANRS CO1 EPF/ANRS CO11 OBSERVATOIRE EPF, France (Josiane Warszawski, Jerome LeChenadec); Collaborative HIV Paediatric Study (CHIPS), UK and Ireland (Ali Judd, Di Gibb); CoRISPE-cat, Spain (Antoni Noguera-Julian); European Collaborative Study (ECS) (Claire Thorne); Italian Register (Luisa Galli, Elena Chiappini, Maurizio de Martino); Madrid Cohort, Spain (Jose T. Ramos, Pablo Rojo-Conejo); MoCHiV, Switzerland (Christoph Rudin); National Study of HIV in Pregnancy and Childhood (NSHPC), UK and Ireland (Pat Tookey); St Pierre Paediatric Cohort, Belgium (Tessa Goetghebuer); and Victor Babes Cohort, Romania (Luminita Ene).
The authors thank all the cohort data managers for providing their data, and Charlotte Duff, the EPPICC data manager, for merging the data and running quality checks.
This study was funded by the European Union Seventh Framework Programme (FP7/2007–2013) under EuroCoord grant agreement number 260694 and PENTA Foundation.
Conflicts of interest
The authors declare that they have no conflicts of interest.
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