Outcomes after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions
Bunupuradah, Torsaka,*; Duong, Trinhb,*; Compagnucci, Alexandrac; McMaster, Paddyd; Bernardi, Stefaniae; Kanjanavanit, Suparatf; Rampon, Osvaldag; Faye, Alberth; Saïdi, Yacinec; Riault, Yoannc; De Rossi, Anitag; Klein, Nigeli; Ananworanich, Jintanata,j,k,*; Gibb, Dianab,*; on behalf of the PENTA 11 Extension Study Group
aHIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok, Thailand
bMRC Clinical Trials Unit, UK
cINSERM SC10, France
dNorth Manchester General Hospital, UK
eOspedale Bambino Gesù, Rome, Italy
fNakornping Hospital, Chiang Mai, Thailand
gUniversity of Padova, Italy
hHôpital Robert Debré, Paris, France
iInstitute of Child Health, London, UK
jSEARCH, the Thai Red Cross AIDS Research Centre
kFaculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
*Torsak Bunupuradah, Trinh Duong, Jintanat Ananworanich, and Diana Gibb contributed equally to the writing of this article.
Correspondence to Torsak Bunupuradah, MD, HIV-NAT, The Thai Red Cross AIDS Research Center, 104 Ratchadamri Road, Pathumwan, Bangkok 10330, Thailand. Tel: +66 2 652 3040; fax: +66 2 252 5779; e-mail: email@example.com
Received 10 April, 2012
Revised 24 September, 2012
Accepted 30 October, 2012
Background: Excess risks for death/opportunistic disease in adults randomized to CD4-driven planned treatment interruption (PTI) in the Strategies for Management of Antiretroviral Therapy (SMART) trial remained after antiretroviral therapy (ART) re-initiation. Risks for children following PTI were evaluated in long-term follow-up of children in the PENTA 11 trial.
Methods: Children with HIV RNA below 50 copies/ml and CD4 at least 30% (2–6 years) or at least 500 cells/μl (7–15 years) were randomized to continuous ART (cART) or PTI in PENTA 11 (ISRCTN 36694210). After the end of the trial, all were recommended to resume ART. Data were collected annually and analysed up to the second year of visit.
Results: One hundred and one (51 cART, 50 PTI; median baseline age 9.2 years) children had median overall follow-up 4.6 (range 3.7–5.0) years. During 2-year post-trial period, there were no deaths or new Centers for Disease Control and Prevention (CDC) stage B/C events. Rate of clinical grade of at least two events was similar between PTI and cART [relative risk (RR) 1.03; 95% confidence interval (CI) 0.43, 2.50; P = 0.94]. At 2 years, difference in absolute CD4% between PTI and cART was −1.6% (−4.5%; 1.3%; P = 0.27), and proportions with HIV RNA below 50 copies/ml were 82 versus 86% (P = 0.57), respectively; no differences in growth or fasting lipids were observed. Key predictors of greater CD4% recovery after re-initiating ART were higher CD4% at baseline (P < 0.001) and longer time since ART re-initiation (P < 0.001). During overall follow-up, 4 (8%) PTI versus 5 (10%) CT children switched ART for failure (P = 0.75) and 9 (18%) versus 1 (2%) (P = 0.008) substituted ART for simplification.
Conclusions: No adverse clinical, immunological or virological consequences of PTI were observed 2 years after the end of PENTA 11 trial. Although ART interruption is not generally recommended, it may be an acceptable option for children, particularly when there is high risk of unplanned treatment interruptions.
Several randomized studies of CD4-guided planned treatment interruption (PTI) strategies in HIV-infected adults have been conducted [1–3] with goals to reduce long-term drug toxicity of antiretroviral therapy (ART) and preserve future ART options. However, greater risks of AIDS, deaths, and unexpectedly, serious non-AIDS events, were observed during CD4-guided PTI compared to continuous ART (cART) in the large randomized Strategies for Management of Antiretroviral Therapy (SMART) trial, making PTI a nonviable treatment strategy option for adults [1,4]. The excess risks for opportunistic disease and death remained after patients randomized to PTI resumed ART . Systemic inflammation induced by viraemia following PTI is postulated to be the underlying mechanism [6,7].
The Paediatric Eugropean Network for Treatment of AIDS (PENTA) 11 trial, the only paediatric randomized trial to date of PTI versus cART in children, did not find a greater risk of adverse clinical outcomes with PTI; however, its much smaller size compared to the SMART trial precluded making recommendations at this stage . As detailed in the main study, when the SMART results were released (March 2006), the Trial Steering Committee and Data Monitoring Committee endorsed continuation of PENTA 11 but with an amendment which increased the safety of the trial , and the trial continued to the end of the planned trial on 29 May 2008. Revised criterion to restart ART during the trial was a confirmed CD4% below 20% or interruption of ART for more than 48 weeks; any child needing to restart ART within 10 weeks of interruption would not interrupt ART again . At trial end, all children were recommended to re-initiate ART and were followed for possible long-term adverse consequences of PTI and further study of long-term detailed immunological  and neurodevelopmental  consequences of interruption in an extension phase. Here, we report on clinical, CD4 and virologic outcomes at 2 years following completion of the PENTA 11 main study, comparing between PTI and cART arms.
Study design and population
The PENTA 11 main trial (ISRCTN 36694210) has been previously described . In brief, HIV-infected children were eligible if they had been on any combination ART regimen containing three or more drugs which had been taken for at least 24 weeks; had confirmed HIV RNA below 50 copies/ml and had two most recent CD4% at least 30% (age 2–6 years) or at least 25% and CD4 cell count at least 500 cells/μl (age 7–15 years). Randomization was stratified by whether a child started combination ART before 3 months of age; and if not by age (< or ≥7 years) and by lowest recorded CD4% before starting ART (nadir CD4%, categorized as < or ≥15%). Children were followed until the last randomized child had completed 72 weeks of follow-up.
At trial end on 29 May 2008, children in the PTI arm were recommended to restart ART. Routine annual data (ART, AIDS events, weight and height, CD4, HIV RNA and lipid levels) were collected from the end of main trial with approvals from local ethics committees of all sites (for total 5 years). Further ethics and regulatory approvals were requested to take blood stores and perform annual neurocognitive function tests; consent from caregivers/young people and assent from children, as appropriate and according to national guidelines, were obtained for this. US sites did not participate in any long-term follow-up.
Analyses presented here were based on data collected up to end of second year following the end of the main trial among children participating in long-term follow-up. Weight, height, CD4, HIV RNA and other laboratory measurements at 1 and 2 years from trial end were defined as those taken nearest to but within ±3 months of these respective time points. Values at ART re-initiation following the most recent PTI were defined as the nearest measurements up to the ART restarting date which was taken within the preceding 3 months and while off therapy.
Comparison between the two randomized arms was according to intention-to-treat, adjusting for stratification factors in regression analyses. Rate of clinical events from end of the main trial up to last clinic visit was compared between arms using random-effects Poisson models, allowing more than one event(s) diagnosed per child. Virologic suppression below 50 copies/ml at 1 and 2 years was analysed using a modified Poisson regression approach (as recommended for binary outcomes which are common) . Absolute values of CD4 percentage and count, weight-for-age and height-for-age z-scores, and lipid levels at 1 and 2 years were analysed using linear regression, adjusted for baseline values. Based on two-sided significance level of 0.05, the power of the study to detect a difference in CD4 percentage of 5, 4, 3 and 2% between arms was 83, 65, 42 and 21%, respectively. For ART outcomes, proportions were compared using chi-squared or Fisher's exact tests. Analyses at 1 and 2 years were repeated excluding children in PTI arm who were off ART at the end of main trial and had not been back on treatment for at least 3 months at each respective time point.
On the basis of all CD4% measurements in the PTI arm after each child restarted ART following the most recent PTI, effects of the following factors on CD4 recovery were assessed: baseline characteristics, CD4% and HIV RNA at ART re-initiation, nadir CD4% (lowest recorded CD4% before starting combination ART), number of PTIs the child experienced and time since ART re-initiation. Longitudinal mixed models were fitted for absolute CD4% to account for repeated measures within the same child. Nonlinear effects of continuous covariates were assessed using cubic spline terms with knots at the 10th, 50th and 90th . All analyses were undertaken using Stata version 11 (Stata Corp., College Station, Texas, USA).
A total of 101 (51 cART, 50 PTI) of the 109 children in the main trial participated in long-term follow-up; all had year 1 and 95 had year 2 follow-ups (Fig. 1). Seventy-nine children were from Europe and 22 from Thailand. Of the remaining eight children not in long-term follow-up, four were from the US site, two were lost to follow-up, one withdrew consent during the main trial and one was transferred to adult care after the end of the main trial.
Among children participating in the long-term follow-up, median duration of follow-up from trial enrolment was 4.6 (range 3.7–5.0) years. Fifteen of the 50 children in the PTI arm had experienced a second PTI during the main trial, and none had a third PTI. Characteristics at PENTA 11 enrolment (pre-PTI) were similar between the two arms (Table 1). Almost half were male and the median baseline age was around 9 years. The majority initiated ART at a young age (median 2.0 years old), and had asymptomatic or mildly symptomatic HIV disease with median CD4% of 37% and CD4 cell count of 970 cells/μl. More cART children had HIV RNA less than 50 copies/ml at baseline (94 versus 86% in PTI).
Status at end of main trial
At the end of the main trial, one child in the cART arm was off ART. Forty-three (86%) of the 50 children in PTI were back on ART for a median duration 11.8 [interquartile range (IQR) 7.1–22.8] months since their last PTI. Among the remaining PTI children, six were still undergoing a PTI and one was off ART due to poor adherence. Compared to children in the cART arm, those in the PTI arm had lower CD4% (median 32 versus 36%; P < 0.001) and CD4 cell counts (792 versus 927 cells/μl; P = 0.06), and also were less likely to have viral load suppression below 50 copies/ml (60 versus 76%; P < 0.001) (Table 1). The cumulative ART exposures were 8.3 years in the cART arm and 7.0 years in the PTI arm.
Outcomes during the 2-year follow-up after the main trial
During the 2 years after trial end, no child died or had a new CDC stage B or C event. There were 21 clinical events diagnosed in 13 (25%) children in the cART arm and 20 events in 12 (24%) children in the PTI arm (all were grade 2 or above). The rates [95% confidence interval (CI)] of events per 100 child-years were 20.9 (13.6, 32.0) in the cART arm and 20.0 (12.9, 31.0) in the PTI arm (rate ratio comparing PTI versus CT of 1.03; 95% CI 0.43, 2.50; P = 0.94), with similar type of events presenting in the two arms. The most common events were infections/infestations (n = 7 total) and gastrointestinal disorders (n = 6). The other events were respiratory symptoms (n = 5), rash (n = 5), hyperlipidaemia (n = 5), anaemia/thrombocytopenia (n = 3) and others (n = 10). There were no differences in height-for-age and weight-for-age z-scores between arms at 1 and 2-year follow-up (Table 2). Mean CD4% was significantly lower in the PTI compared to the cART arms at 1 year from trial end (adjusted difference −3.5%; 95% CI −6.2%, −0.7%; P = 0.01), but there was no evidence of any difference by 2 years (−1.6% [−4.5%, 1.3%]; P = 0.27). Similar results were seen for CD4 cell count, with estimated difference at 2 years of −42 cells/μl (95% CI −149, 65 cells/μl; P = 0.44). The proportions with HIV RNA below 50 copies/ml were 77% (36/47) in the PTI arm versus 90% (44/49) in the cART arm at 1 year from the end of the main trial (P = 0.07); corresponding proportions at 2 years were 82% (37/45) versus 86% (37/43), respectively (P = 0.57). No differences in lipid levels between the two arms were seen at 1 or 2 years follow-up. When analyses at 1 and 2 years were repeated excluding children in PTI arm who were off ART at end of main trial and had not been back on treatment for at least 3 months at each respective time point, the overall conclusions remained the same. In addition, the estimated differences between arms for CD4%, CD4 cell count and proportion with HIV RNA below 50 copies/ml were less compared with original analyses, as expected. Figure 2 shows the trend in absolute CD4% (Fig. 2a) and CD4 cell count (Fig. 2b) and proportion of children with HIV RNA below 50 copies/ml (Fig. 2c) over time from the beginning of the main trial and also from after main trial end.
Among those with complete relevant ART follow-up data, none of the children in the cART arm (n = 46) were off ART at 2 years from trial end compared with 11% in PTI (5/47, three of whom had not restarted ART by this time following PTI, despite recommendation that all PTI children restart ART) (P = 0.06). During overall follow-up from baseline, the number (%) of children in the PTI versus cART arms who changed at least two antiretroviral drugs simultaneously for treatment failure was four (8%) versus five (10%) (P = 0.75), substituted at least three drugs simultaneously for toxicity was zero (0%) versus one (2%, for lipoatrophy) (P = 0.99) and substituted at least three drugs simultaneously for simplification (mainly to once-daily and fixed-dose combination of tenofovir/emtricitabine or abacavir/lamivudine) was nine (18%) versus one (2%) (P = 0.008), respectively. Six of the nine PTI children who substituted at least three drugs simultaneously for simplification did this when ART was resumed after PTI.
Predictors of greater CD4% recovery after restarting antiretroviral therapy
In multivariable analyses, independent predictors of higher absolute CD4% after restarting ART following the most recent PTI were higher baseline CD4% (P < 0.001), higher CD4% at ART re-initiation (P = 0.02) and longer duration of ART following re-initiation (P < 0.001) (Table 3). Of note, CD4% increased mainly within the first 2 years back on treatment with only a modest change thereafter (P < 0.001 for nonlinear trend). Also, the effect of CD4% at ART re-initiation on CD4 recovery was greatest soon after ART re-initiation and then decreased over time (P for interaction <0.001). Sex, ethnicity, baseline age, baseline CDC disease stage, baseline weight-for-age z-score, nadir CD4%, HIV RNA at ART re-initiation and number of PTIs did not predict long-term CD4 recovery.
At 2 years after the end of the PENTA 11 trial, children who underwent CD4-guided PTI achieved similar clinical, immunologic and virologic outcomes compared to those who were on cART. ART interruption is not generally recommended, but the results of this study indicate that, in contrast to adults, PTI may be an acceptable therapeutic option in children because of their superior ability for CD4 recovery. Of note, higher CD4% before PTI and at the time of ART re-initiation, and longer time since ART re-initiation, were independently associated with greater CD4% recovery.
Treatment interruptions are sometimes necessary in children who experience side-effects to ART [13,14]. However, most interruptions are unplanned and are largely due to treatment fatigue and poor adherence, which are unfortunately common in carers administering ART to children, and particularly among adolescents who are increasingly responsible for their own medication as they get older. The inevitable increase in ART resistance and diminishing therapeutic options  is an important health issue and is very demanding on resources. In the US Adolescent Master Protocol, 25% of 444 children aged 7–16 years had at least one unsupervised ART interruption of 3 months or more  and in some settings the frequency of unplanned treatment interruption may be greater. In the light of such high levels of unplanned interruptions, carefully planned interruptions of up to a year in duration could be preferable.
CD4-guided PTI in adults with chronic HIV infection in the SMART trial was associated with an increased risk for deaths, and increases in both AIDS and non-AIDS events, largely attributable to lower CD4 cell counts and higher HIV RNA in the PTI compared to the cART group [5,16]. Whereas re-initiation of ART resulted in a 38% decrease in the rate of opportunistic disease and deaths during 18 months of post-trial follow-up in SMART, there was ongoing excess risk with the hazard ratio for such clinical events in PTI versus cART arms of 1.4 (95% CI 1.0–2.0; P = 0.04). Whereas data are far fewer in children, this has not been described in association with treatment interruptions in children [8,13]. During the 2 years follow-up after trial end in PENTA 11, we did not observe an excess in deaths, serious AIDS/non-AIDS or clinical events grades at least 2 in the PTI arm, although the study clearly had much lower power compared with the SMART trial.
There are multiple differences between children in PENTA 11 and adults in SMART. Firstly children, unlike adults, are at low risk for cardiovascular, renal and liver complications due to their younger age and lower incidence of traditional risk factors such as hypertension, diabetes mellitus and tobacco smoking . Secondly, prior to ART re-initiation, none of the PENTA 11 children had experienced serious AIDS or non-AIDS events within the main trial; adults who experienced severe adverse events during the main SMART study had higher mortality rates in the ART re-initiation follow-up phase . Thirdly, PTI children in PENTA 11 achieved similar CD4% and CD4 cell count as those on cART within 2 years of trial end: 35% and 832 cells/μl in PTI versus 36% and 864 cells/μl in cART. In SMART, at 18 months after the end of the trial, CD4 cell count was still 152 cells/μl (95% CI −0.167 to −0.136; P < 0.001) lower in the PTI compared to the cART arms . Similarly, HIV RNA suppression rates after ART resumption were similar in both arms of PENTA 11 (82% in PTI versus 86% in cART at 2 years post-trial), whereas in SMART, lower virologic suppression was seen in PTI adults (73% in PTI versus 84% in cART; P < 0.001) . The highest risk of adverse events in SMART was observed in those with CD4 below 350 cells/μl and HIV RNA above 400 copies/ml ; of note, very few children in PENTA 11 ever had CD4 cell count falling below 350 cells/μl.
Several paediatric studies have shown varying rates of CD4 decline after treatment interruptions [13,14,18], but none have reported responses after ART was resumed. The rapid rise in CD4 after ART resumption in our PTI children was likely due to a combination of reduced CD4 cell death, along with a greater capacity for the thymus to repopulate the CD4+ T-cell pool in children, and particularly in the very young . This is in contrast to data from SMART and several adult trials showing a slow CD4 rise after ART re-initiation, with the majority failing to achieve pre-PTI CD4 cell counts [20–22]. In our study, higher baseline CD4 percentage as well as higher CD4 percentage at re-initiation were associated with greater CD4% recovery after ART re-initiation. Nadir CD4 percentage prior to ART did not have an independent effect once CD4 percentage at ART re-initiation was adjusted for (see footnote of Table 3); this suggests that the effect of nadir CD4 was mediated via CD4 percentage at ART re-initiation, given our previous finding that during PTI, CD4 nadir was an important determinant of the magnitude of CD4 decline and hence CD4 percentage at re-initiation . Importantly, duration of ART following re-initiation was also a strong predictor for CD4% recovery, with CD4 increase occurring mainly within the first 2 years back on ART (P < 0.001 for nonlinear trend; see Table 3). This may be due to the inherently higher thymic output in children and possibly because of additional supplementation of the thymic output in response to ART . This asymptotic pattern of CD4 cell recovery is in keeping with that seen following ART treatment of ART-naive children . Studies in ART-naive children have shown that high baseline CD4%, virologic suppression, young age and female sex are associated with favourable CD4 recovery [25,26].
In the SMART trial, biomarkers of immune activation, IL-6, high-sensitivity C-reactive protein and soluble CD14 were raised in the PTI arm, particularly during periods of interruptions compared to the cART arm, and they were associated with risks for mortality, opportunistic diseases and cardiovascular and renal events [6,7,27]. Data from PENTA 11 have shown evidence of immune activation during PTI  but as yet, no evidence for associated clinical events, likely also due to small numbers. Whilst PTI did not appear to irreversibly impair CD4 recovery in our study, immune activation during PTI and possibly after PTI could have the potential to increase the risk for premature non-AIDS events when children reach early adulthood, and thus warrants long-term monitoring. However, it is interesting that other potential consequences of PTI were also not evident. For example, growth, which is an important and often sensitive measure of successful treatment in children and youth, were comparable between PTI and cART arms, and more recently we have reported no difference between cART and PTI arms in neurodevelopmental test scores performed cross-sectionally in the PENTA 11 children after the end of the trial . Similarly, although a decline in total, low and high-density lipoprotein from baseline was seen in the first 12 weeks off ART among PTI children in the main trial , no differences in fasting lipids were observed between the two arms during long-term follow-up; in contrast, PTI was associated with increased low high-density lipoprotein levels in SMART .
Planned treatment interruption may have other consequences which may be advantageous. Children who experienced PTI were more likely to have their regimen simplified to once-daily and fixed-dose ART after restarting ART, suggesting that once time off ART has been experienced, there is an opportunity to request regimen simplification. The majority of carers (75%) and children (83%) in PENTA 11 also reported that PTI made life easier , and one could speculate that this might positively influence long-term adherence in a disease in which ART for life is much longer than in HIV acquired during adulthood. Others have also reported that simplification of ART by changing to a once-daily regimen enhanced treatment satisfaction, adherence and quality of life .
Our study has limitations including the small sample size and the lack of systematic sub-clinical evaluation for non-AIDS events such as cardiovascular complications. Our data may not be applicable to all children as we included mainly older children (median baseline age of 9 years old), the majority of whom maintained a relatively high CD4 level while on PTI. Younger children have a greater capability to regenerate CD4+ T cells, but also have a more rapid HIV disease progression in the absence of ART . Children who undergo unplanned PTI could be at greater risks for severe immunosuppression and HIV-related illnesses [13,18,31], although there was no evidence that children in the PTI arm adhered more poorly to ART after re-initiation . Detailed immunologic and neurocognitive investigations are being undertaken annually in PENTA 11, with follow-up to 5 years post-trial. We await results of the Botswana/Baylor Antiretroviral Assessment trial in Botswana which was similar in design to PENTA 11 and also in chronic HIV infection. Results from the recently presented South African Children with HIV Early Antiretroviral Therapy (CHER) trial  also provide evidence that ART could be interrupted following treatment started at age 6–12 weeks, near the time of seroconversion. Early limited ART for 1 or 2 years was associated with better clinical and mortality outcomes after 5 years, than deferred ART, and one-third of children on ART for 2 years were still off medication at trial end; of note, however, an early continuous arm was not included in this trial .
In conclusion, 2 years after end of PENTA 11, children who had CD4-guided PTI achieved similar immune recovery and viral suppression to those who were maintained on cART and clinical outcomes did not differ between the two arms. These data provide reassurance that no obvious long-term harm resulted from CD4-guided PTI. This contrasts with adults and may be due to children's greater potential for immune recovery. Further research is warranted to explore ART strategies such as PTI, to limit the unacceptably high rate of unstructured treatment interruptions, especially in older children and young people. Whilst considered by many to be unacceptable, judicious use of PTI may actually reduce the risks of developing ART resistance and the consequent limitation of future therapeutic options during childhood, and particularly during adolescent years.
We thank all the children, families and staff from the centres participating in the PENTA 11 (TICCH) Trial.
PENTA 11 (TICCH) Trial Committees
PENTA Steering Committee: J.-P. Aboulker, J. Ananworanich, A. Babiker, E. Belfrage, S. Bernardi, S. Blanche, A.-B. Bohlin, R. Bologna, K. Butler, G. Castelli-Gattinara, H. Castro, P. Clayden, A. Compagnucci, J.H. Darbyshire, M. Debré, A. Faye, R. de Groot, M. della Negra, A. di Biagio, D. Duicelescu, A. Faye, C. Giaquinto (chairperson), V. Giacomet, D.M. Gibb, I. Grosch-Wörner, M. Hainault, M. Lallemant, J. Levy, H. Lyall, M. Marczynska, M. Mardarescu, M.J. Mellado Peña, D. Nadal, T. Niehues, C. Peckham, J.T. Ramos Amador, L. Rosado, C. Rudin, H.J. Scherpbier, M. Sharland, M. Stevanovic, C. Thorne, P.A. Tovo, G. Tudor-Williams, N. Valerius, A.S. Walker, S. Welch, U. Wintergerst.
PENTA 11 Executive Committee: J.P. Aboulker, A. Babiker, D.M. Burger, A. Compagnucci, J.H. Darbyshire, M. Debré, C. Giaquinto, D.M. Gibb, H. Green, L. Harper, N. Klein, M. Lallemant, H. Lyall, L. Mofenson, J. Moye, D. Nadal, Y. Saïdi.
PENTA 11 Pharmacology Group: D.M. Burger, T.R. Cressey, E. Jacqz-Aigrain, S. Khoo, M. Regazzi, J.M. Tréluyer.
PENTA 11 Immunology/Virology Group: A. De Rossi, N. Klein, J. Moye, N. Ngo-Giang-Huong, M.A. Muñoz Fernandez, D. Pillay.
PENTA 11 Data Safety and Monitoring Committee: C. Hill (Chair until 2009), P. Lepage, A. Pozniak (Chair 2009 -), S. Vella, G. Chêne, T. Vesikari.
INSERM SC10, France: J.P. Aboulker, A. Compagnucci, G. Hadjou, S. Léonardo, Y. Riault, Y. Saïdi.
MRC Clinical Trials Unit, UK: A. Babiker, J. Bleier, L. Buck, H. Castro, J.H. Darbyshire, T. Duong, L. Farrelly, S. Forcat, D.M. Gibb, L. Harper, L. Harrison, J. Horton, D. Johnson, S. Moore, C. Taylor, A.S. Walker.
PHPT, Thailand: S. Chalermpantmetagul, T.R. Cressey, R. Peongjakta, W. Khamjakkaew, K. Than-in-at, S. Chailert, G. Jourdain, M. Lallemant, S. Le Coeur, N. Ngo-Giang-Huong.
Clinical sites (Pharmacists (P), Virologists/immunologists(L) Psychologists (PS))
France: Hôpital Femme-Mère-Enfant, Lyon/ Hôpital Edouard Herriot, Lyon: S. Corradini, D. Floret, P. Costanzo (PS) T.T. Le Thi (L); Hôpital de
l’Archet, Nice: F. Monpoux, S. Mellul (L), I. Caranta (PS); Hôpital Cochin Port-Royal, Paris: N. Boudjoudi, G. Firtion, M. Denon, E. Charlemaine (Ps), F. Picard (L); Hôpital Robert Debré, Paris: A. Faye, E. Hellier (Ps),C. Heuninck (PS), F. Damond (L); G. Alexandre (L); Hôpital Purpan, Toulouse: J. Tricoire, M. Antras, C. Lachendowier (PS), F. Nicot (L); Hôpital Saint-Vincent de Paul, Paris: A. Krivine (L); D. Rivaux.
Germany: Universitäts-kinderkliniken, Munich: U. Wintergerst, G. Notheis, G. Strotmann, S. Schlieben.
Italy: Università di Padova: C. Giaquinto, O. Rampon, V. Boscolo (PS), M. Zanchetta (L); Università di Genova: R. Rosso*, F. Ginocchio, C. Viscoli, A. di Biagio; Ospedale Bambino Gesù, Rome: G. Castelli-Gattinara, S. Bernardi, A. Martino, G. Pontrelli, S. Baldassar (PS), C. Concato (L); Ospedale S. Chiara, Trento: A. Mazza, V. Boscolo (PS), G. Rossetti (L).
Poland: Medical University of Warsaw/Regional Hospital of Infectious Diseases, Warsaw: M. Marczynska, S. Dobosz, A. Oldakowska, J. Popielska, M. Kaflik, J. Stanczak (L), G. Stanczack (L), T. Dyda (L), M. Kruk (PS).
Spain: Hospital Universitario 12 de Octubre, Madrid: M.I. González Tomé, P. Rojo Conejo, R. Delgado García (L), M.T. Fernandez Gonzalez, G. Medin (PS); Hospital Carlos III, Madrid: M. José Mellado Peña, P. Martín Fontelos, M., I. Garcia Mellado, A.F. Medina, B. Ascencion (L); Hospital Universitario de Getafe, Madrid: J.T. Ramos Amador, I. Garcia Bermejo (L); Hospital General Universitario Gregorio Marañón, Madrid: D., M.L. Navarro Gomez, J. Saavedra, C. Prieto (L), J.L. Jimenez (L), M.A. Muñoz-Fernandez (L), A. Garcia Torre (L); Hospital Infantíl La Paz, Madrid: M.I. de José Gómez, M.C. García Rodriguez; Hospital Materno-Infantil, Málaga: D. Moreno Pérez, E. Núñez Cuadros; Hospital Infantil La Fe, Valencia: F. Asensi-Botet, C. Otero Reigada, M.D. Pérez Tamarit, R. Vilalta (PS), J.M. Molina Moreno (L).
Switzerland: University Chidren's Hospital, Zurich: D. Nadal, Truninger Rainer (PS), National Laboratory for Retrovirus, Zurich: J. Schupbach, M. Rutishauser.
Thailand: HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok: T. Bunupuradah, J. Ananworanich, O. Butterworth, C. Phasomsap, W. Prasitsuebsai, T. Chuanjaroen, T. Jupimai, S. Ubolyam (L), P. Phanuphak, T. Puthanakit, C. Pancharoen; Nakornping Hospital, Chaing Mai: S. Kanjanavanit, T. Namwong, W. Punsakoon, S. Payakachat, D. Chutima, M. Raksasang, W. Punsakoon (PS), S. Payakachat (PS).
UK: Imperial College Hospital Healthcare Trust, London: H. Lyall, G. Tudor-Williams, C. Foster, D. Hamadache, S. Campbell, C. Newbould, C. Monrose, A. Abdulla, A. Walley, D. Melvin (PS), D. Patel (P), S. Kaye (L); Chelsea and Westminster Hospital, London: H. Lyall, P. Seery, D. Hamadache, A. Rankin (PS), A. Wildfire (L); Great Ormond Street Hospital for Children, London: V. Novelli, D.M. Gibb, N. Klein, D. Shingadia, K. Moshal, J. Flynn, M. Clapson, L. Farrelly, A. Allen, L. Spencer, C. Rackstraw, B. Ward, K. Parkes, M. Depala (P), M. Jacobsen (L), H. Poulsom (L), L. Barkley (PS), J. Miah (PS), D. Melvin (PS), P. Lurie (PS), C. Keane (PS); University Hospital of North Staffordshire, Stoke on Trent: P. McMaster, M. Phipps, J. Orendi, C. Farmer; Newham University Hospital: S. Liebeschuetz, O. Sodeinde, D. Shingadia, S. Wong, V. Bostock (PS); Birmingham Heartlands Hospital: S. Welch, Y. Heath, S. Scott, K. Gandhi (P); University Hospitals Coventry & Warwickshire NHS Trust University Hospital: P. Lewis, J. Daglish, K. Miles, L. Summerhill (PS); Royal Free and University College Medical School, London: D. Pillay (L); Derbyshire Childrens Hospital: B. Subramaniam.
USA: SUNY Upstate Medical University, Syracuse NY: L. Weiner, M. Famiglietti; Howard University Hospital, Washington DC: S. Rana, P. Yu, J. Roa; Children's Diagnostic & Treatment Center, Ft. Lauderdale, FL: A. Puga, A. Haerry.
The preliminary analysis of this study was presented as an oral presentation at the 3rd International Workshop on HIV Pediatrics, 15 – 16 July 2011, Rome, Italy.
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The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n.201057 (PENTA LABNET) and grant agreement n. 260694 (EUROCOORD).
Conflicts of interest
There are no conflicts of interest.
1. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided interruption of antiretroviral treatment
. N Engl J Med
2. Ananworanich J, Gayet-Ageron A, Le Braz M, Prasithsirikul W, Chetchotisakd P, Kiertiburanakul S, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial
3. Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, Kanga C, et al. CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in West Africa (Trivacan ANRS 1269 trial): a randomised trial
4. Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry K, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study
. AIDS (London, England)
5. El-Sadr WM, Grund B, Neuhaus J, Babiker A, Cohen CJ, Darbyshire J, et al. Risk for opportunistic disease and death after reinitiating continuous antiretroviral therapy in patients with HIV previously receiving episodic therapy: a randomized trial
. Annals Internal Med
6. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection
. PLoS Med
7. Rodger AJ, Fox Z, Lundgren JD, Kuller LH, Boesecke C, Gey D, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection
. J Infect Dis
8. Paediatric European Network for Treatment of AIDS. Response to planned treatment interruptions in HIV infection varies across childhood.AIDS
9. Sefe D, Klein N, Mosconi I, Ricci E, Castro, H (nee Green), Jacobsen M, et al.
, on behalf of the PENTA Steering Committee. Immunologic and viral dynamics among HIV-infected children after planned treatment interruption: a substudy of the Paediatric European Network for Treatment of AIDS (PENTA) 11 trial.17th Conference on Retroviruses and Opportunistic Infections
, San Francisco, 16–19 February 2010.
10. Ramos J, Melvin D, Medin G, Compagnucci A, Bleier J, Boscolo V, et al.
, on behalf of the PENTA Steering Committee. Neurocognitive and Quality of Life Outcomes in Children after Planned Treatment Interruptions: the randomized PENTA 11 trial.19th Conference on Retroviruses and Opportunistic Infections
, San Francisco, 5–8 March 2012.
11. Zou G. A modified Poisson regression approach to prospective studies with binary data
. Am J Epidemiol
12. Durrleman S, Simon R. Flexible regression models with cubic splines
. Stat Med
13. Siberry GK, Patel K, Van Dyke RB, Hazra R, Burchett SK, Spector SA, et al. CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption
. J Acquir Immune Defic Syndr
14. Fortuny C, Noguera-Julian A, Alsina L, Bellido R, Sanchez E, Munoz-Almagro C, et al. Impact of CD4 T cell count on the outcome of planned treatment interruptions in early-treated human immunodeficiency virus-infected children
. Pediatric Infect Dis J
15. Castro H, Judd A, Gibb DM, Butler K, Lodwick RK, van Sighem A, et al. Risk of triple-class virological failure in children with HIV: a retrospective cohort study
16. Lundgren JD, Babiker A, El-Sadr W, Emery S, Grund B, Neaton JD, et al. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ Cell counts and HIV RNA levels during follow-up
. J Infect Dis
17. Wald NJ, Simmonds M, Morris JK. Screening for future cardiovascular disease using age alone compared with multiple risk factors and age
. PloS One
18. Gibb DM, Duong T, Leclezio VA, Walker AS, Verweel G, Dunn DT. Immunologic changes during unplanned treatment interruptions of highly active antiretroviral therapy in children with human immunodeficiency virus type 1 infection
. Pediatric Infect Dis J
19. Gibb DM, Newberry A, Klein N, de Rossi A, Grosch-Woerner I, Babiker A. Immune repopulation after HAART in previously untreated HIV-1-infected children. Paediatric European Network for Treatment of AIDS (PENTA) Steering Committee
20. Chen RY, Westfall AO, Raper JL, Cloud GA, Chatham AK, Acosta EP, et al. Immunologic and virologic consequences of temporary antiretroviral treatment interruption in clinical practice
. AIDS Res Human Retroviruses
21. Ananworanich J, Siangphoe U, Hill A, Cardiello P, Apateerapong W, Hirschel B, et al. Highly active antiretroviral therapy (HAART) retreatment in patients on CD4-guided therapy achieved similar virologic suppression compared with patients on continuous HAART: the HIV Netherlands Australia Thailand Research Collaboration 001.4 study
. J Acquir Immune Defic Syndr
22. Boschi A, Tinelli C, Ortolani P, Arlotti M. Safety and factors predicting the duration of first and second treatment interruptions guided by CD4+ cell counts in patients with chronic HIV infection
. J Antimicrob Chemother
23. Weinberg A, Dickover R, Britto P, Hu C, Patterson-Bartlett J, Kraimer J, et al. Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy
. AIDS (London, England)
24. Lewis J, Walker AS, Castro H, De Rossi A, Gibb DM, Giaquinto C, et al. Age and CD4 count at initiation of antiretroviral therapy in HIV-infected children: effects on long-term T-cell reconstitution
. J Infect Dis
25. Puthanakit T, Kerr S, Ananworanich J, Bunupuradah T, Boonrak P, Sirisanthana V. Pattern and predictors of immunologic recovery in human immunodeficiency virus-infected children receiving nonnucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy
. Pediatric Infect Dis J
26. Renner L, Prin M, Li FY, Goka B, Northrup V, Paintsil E. Time to and predictors of CD4+ T-lymphocytes recovery in HIV-infected children initiating highly active antiretroviral therapy in Ghana
. AIDS Res Treat
27. Neuhaus J, Jacobs DR Jr, Baker JV, Calmy A, Duprez D, La Rosa A, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection
. J Infect Dis
28. Baker JV, Neuhaus J, Duprez D, Cooper DA, Hoy J, Kuller L, et al. Inflammation predicts changes in high-density lipoprotein particles and apolipoprotein A1 following initiation of antiretroviral therapy
. AIDS (London, England)
29. Harrison L, Hamadache D, Bunupuradah T, Mazza A, Ramos J T, Flynn J, et al.
, on behalf of the PENTA 11 Trial Steering Committee. Adherence to ART and acceptability of planned treatment interruptions (PTI) in the PENTA 11 trial (treatment interruption in children with chronic HIV-infection).
Poster number P 90. 1st International Workshop on HIV Pediatrics
, Cape Town, SA, 17–18 July 2009.
30. DeJesus E, Ruane P, McDonald C, Garcia F, Sharma S, Corales R, et al. Impact of switching virologically suppressed, HIV-1-infected patients from twice-daily fixed-dose zidovudine/lamivudine to once-daily fixed-dose tenofovir disoproxil fumarate/emtricitabine
. HIV Clin Trials
31. Saitoh A, Foca M, Viani RM, Heffernan-Vacca S, Vaida F, Lujan-Zilbermann J, et al. Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection
32. Cotton M, Violari A, Gibb D, Otwombe K, Josipovic D, Panchia R, et al.Early ART followed by Interruption Is Safe and Is Associated with Better Outcomes than Deferred ART in HIV+ Infants: Final Results from the 6-Year Randomized CHER Trial, South Africa.19th Conference on Retroviruses and Opportunistic Infections
, San Francisco, 5–8 March 2012.
antiretroviral therapy; ART re-initiation; HIV-infected children; PTI; treatment interruption
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