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.
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.
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Keywords:Copyright © 2013 Wolters Kluwer Health, Inc.
antiretroviral therapy; ART re-initiation; HIV-infected children; PTI; treatment interruption