HIV-1 RNA and drug resistance
In the PTI group, HIV-1 RNA increased rapidly in the first weeks off ART; 100 and 98% of children had HIV-1 RNA of at least 50 and at least 400 copies/ml at 12 weeks, respectively, compared with 10 and 2%, respectively, in the continuous therapy group. Suppression of viral load to less than 50 copies/ml following the first PTI was achieved for 77% (38/49) of children by 24 weeks back on ART, 96% (47/49) were less than 400 copies/ml. Of the 11 children with viral load of at least 50 copies/ml, nine subsequently attained viral load suppression of less than 50 copies/ml.
In the PTI group, among 68 samples tested for resistance at a median [interquartile range (IQR)] of 4 (2–5) weeks after interruption and 30 samples at 4 (3–5) weeks after restarting ART, 30 (31%) samples had at least one major resistance mutation. All except one mutation appeared to be associated with previous rather than current ART regimens; the exception was a child who developed a new K103N mutation after stopping efavirenz during a second PTI (HIV-1 RNA at the time of assay 10 691 copies/ml); plasma concentrations of efavirenz were still detectable 2 weeks after stopping efavirenz during the first PTI. The protocol was subsequently amended to recommend that efavirenz should be replaced with lopinavir/ritonavir for 4 weeks before interrupting all drugs.
While on ART, 19 (17%) children (10 continuous therapy and nine PTI) had confirmed HIV-1 RNA of more than 100 copies/ml. Two (one continuous therapy and one PTI) children had HIV-1 RNA between at least 400 copies/ml and less than 1000 copies/ml and five (two continuous therapy and three PTI) had at least 1000 copies/ml. Resistance test results were available for 13 children; six (three continuous therapy and three PTI) children had nonamplifiable (n = 3) or missing (n = 3) samples. Ten (five continuous therapy and five PTI) children had at least one major resistance mutation; the median (range) number of mutations was five (2–8) in the continuous therapy and three (2–4) in the PTI group (P = 0.1). In the continuous therapy group, four children had multiple thymidine analogue mutations [all had previous mono/dual-nucleoside reverse transcriptase inhibitor (NRTI) therapy] as well as mutations associated with individual drugs in their current regimen. In the PTI group, three children had new resistance mutations associated with drugs in the regimen they restarted after their first PTI, which had not been present on a sample tested after interruption. At the last follow-up, two of these 10 children (one continuous therapy and one PTI) had HIV-1 RNA of less than 50 copies/ml.
There were no significant differences between groups in the number of laboratory grade 2 (86%) or 3 (14%) events (continuous therapy: 23 events in 11 (21%) children and PTI: 34 events in 15 (27%) children; rate ratio 1.4, 95% CI 0.7–3.1, P = 0.3). Total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol (nonfasting) decreased from baseline by mean (SE) −37 (5) mg/dl, −17 (7) mg/dl and −14 (2) mg/dl, respectively, in the first 12 weeks off ART among children on PTI, although the change in the total/HDL ratio was small [+0.2 (0.3)]. Platelets also decreased by mean (SE) −60 (10) 109/l. No significant changes were observed in haemoglobin, white blood cell or neutrophil values.
HIV-infected children acquire HIV when the immune system is developing and start ART early compared with adults. Therefore, they may respond differently to PTIs. Here, we observed no major disadvantages of PTIs guided by CD4%/cell count thresholds; however, there was a significant excess of reported minor clinical events in the PTI group. Events, such as lymphadenopathy and mild skin complaints, may well have been related to immune activation with HIV viraemia after stopping ART; of note, there was no evidence of an increase in any infections in the PTI group. The only grade 3 ART-related adverse event report of headache could have been related to restarting ART with efavirenz after a PTI. Even if not serious, the occurrence of minor clinical symptoms in the PTI group after stopping ART may have been problematic for children and families, and questionnaires completed during the trial on acceptability of PTI versus continuous therapy are currently being analysed. Because the allocation to treatment strategy was not masked, reporting bias among both families and paediatricians could have contributed to the excess reporting of minor clinical events. Children on PTIs were also reviewed in clinic more often than children on continuous therapy, increasing the opportunity for reporting events, particularly in the initial weeks of PTI. Lack of blinding could also have contributed to a lower threshold for admitting children to hospital in the PTI group; the number of short-term admissions was greater among PTI children, although total admission days were very similar in both the groups.
Despite relatively advanced disease before starting combination ART, nearly 60% of children in the PTI group only restarted ART because they reached the predefined 48 weeks off ART. In addition, in the PTI group, only 4% of follow-up time was spent with a CD4 cell count of less than 350 cells/μl. This compares with 32% of time in the interruption arm in the adult SMART trial, which had lower CD4 cell count thresholds for starting and stopping ART . As the average age of children at entry into the PENTA 11 trial was around 9 years and 90% were more than 5 years of age, CD4 cell counts would have similar predictive value for disease progression as young adults for most children , suggesting that any clinical risks, not observed due to small numbers in this trial, would likely be lower than in the SMART trial.
All four children in the PTI group who reached a CD4%/cell count outcome did so within 12 weeks after stopping ART, as did two-thirds of all children who reached CD4%/cell count threshold values to restart ART. As also reported in PTI studies in adults, we observed a rapid initial decline in CD4%, which was predicted by nadir CD4% before starting combination ART [18–20]. Nadir CD4% and cell z score were also a predictor of CD4% and cell z score recovery respectively following interruption, as was age, with children of less than 7 years of age and with good nadir CD4% and cell z score able to recover CD4% and CD4 cell z score values within 24 weeks of restarting ART. CD4 cell count declines naturally with age in HIV-uninfected children , and the dynamics of CD4 cell count response to ART in HIV-infected children varies considerably with age ; interpretation of results is, therefore, complex and requires adjustment for age, as failure to return to preinterruption CD4 cell count values might be expected as a consequence of older age alone. Only 11 children in the PENTA 11 trial were less than 5 years old, and therefore, although encouraging, our findings in young children remain exploratory. As it is now recommended that all infants start ART as soon as they are diagnosed with HIV, a focus for future research should be the role of PTIs in younger children starting early ART; CD4 cell count and% predict disease progression most poorly in this age group [22,23], and maintaining long-term ART is also most difficult.
The high proportion of children with suppressed viral load after 24 weeks back on ART in the PTI group precludes investigation of predictors of re-suppression of viral load. There was no evidence of more drug resistance in the PTI group than in the continuous therapy group; if anything, there was a tendency towards a higher number of mutations in the continuous therapy group. One child in the PTI group developed a new mutation to efavirenz, which prompted recommendation of ‘protease inhibitor replacement’ (as is currently recommended in adult guidelines) rather than ‘staggered stop’ strategy for children on efavirenz.
Only small (mainly observational) studies have so far reported on treatment interruptions in the management of HIV-infected children , including one small, randomized, pilot trial  of 30 children in whom no AIDS events or deaths were reported in either the interruption (guided by viral load rather than CD4%/cell count) or continuous ART arm. Two large interruption trials in children are ongoing in Africa: the South African Children with HIV Early antiRetroviral therapy trial (CHER) is addressing the question of early limited ART (starting ART before 12 weeks of age and stopping at first or second birthday) in around 400 infants. The Bana trial in Botswana (600 children with chronic HIV infection) has a similar design to the PENTA 11 trial, but lower CD4% thresholds for stopping (25%) and restarting (15%) ART in the PTI arm. The results from the PENTA 11 trial provide reassurance for continuation of these trials (at the recent IDMC meetings, continuation was recommended for both trials; A Violari and M. Kline, personal communication). Five-year follow-up of all children in the PENTA 11 trial, who were recommended to take ART continuously at the end of the main follow-up of the trial, is ongoing, and along with the results of CHER and Bana trials, should help to determine the extent of CD4% and cell count recovery after longer periods back on ART after PTI, and whether this occurs across all ages in childhood or only in the youngest children. Of note, at 18 months after re-initiation of ART in adults (median age 43 years) in the SMART trial, mean CD4 cell counts were still statistically significantly lower (152 cells/μl lower, 95% CI 136–167, P < 0.001) in those initially randomized to CD4-guided PTI compared with those on continuous therapy .
The overall aim of paediatric HIV management is to ensure that children reach adulthood not only with no adverse clinical outcomes, optimal growth, good cognitive development and intact immune systems but also with minimal HIV drug resistance and toxicity. Results of the PENTA 11 trial so far provide useful information for paediatricians and families about children who may undergo unplanned interruptions of ART for a variety of reasons but cannot be used to advocate PTIs at the moment. The balance of risks and benefits of HIV and lifelong ART is clearly different in vertically HIV-infected children starting ART early compared with adults. The long-term consequences of PTIs in the PENTA 11 trial as well as the results from the ongoing African trials will hopefully clarify whether PTIs have a future role in paediatric HIV management.
We thank all the children, families and staff from the centres participating in the PENTA 11 (TICCH) trial.
PENTA is a coordinated action of the European Commission, supported by the sixth framework contract number LSHP-CT-2006-018865 and fifth framework program contract number QLK2-2000-00150. The PENTA 11 trial was sponsored by the PENTA Foundation in Europe and Thailand, and by the National Institute of Child Health and Human Development in the USA. The trial was coordinated by four trials centres: the Medical Research Council (MRC) Clinical Trials Unit, London (with support from the MRC); INSERM SC10, Paris (supported by Agènce Nationale de Recherche sur le Sida); Program for HIV Preventions and Treatment, Chiang Mai, Thailand (with support from the PENTA Foundation and Institut de Recherche pour le Developpement – URI 174); and Westat, Maryland, USA (supported by the National Institute of Child Health and Human Development). UK clinical sites were supported by a grant from the MRC, whereas those in Italy by a grant from the Istituto Superiore di Sanità – Progetto Terapia Antivirale 2004, 2005.
Writing committee: D.M. Gibb, H. Castro (nee Green), A. Compagnucci, N. Klein, M. Lallemant, H. Lyall, D. Nadal, J. Ananworanich, A. Babiker, T. Bunupuradah, J.H. Darbyshire, A. De Rossi, M.I. Gonzalez Tomé, L. Harper, S. Kanjavanit, M. Marczynska, L. Mofenson, F. Monpoux, J. Moye, M.A. Muñoz-Fernández, N. Ngo-Giang-Huong, T. Niehues, Y. Saidi, A.S. Walker, U. Wintergerst and C. Giaquinto.
PENTA Steering Committee: J.-P. Aboulker, A. Babiker, S. Blanche, A.-B. Bohlin, K. Butler, G. Castelli-Gattinara, P. Clayden, A. Compagnucci, J.H. Darbyshire, M. Debré, A. Faye, R. de Groot, M. della Negra, D. Duicelescu, C. Giaquinto (chairperson), D.M. Gibb, I. Grosch-Wörner, M. Lallemant, J. Levy, H. Lyall, M. Marczynska, 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, P.A. Tovo, G. Tudor-Williams, N. Valerius, A.S. Walker and U. Wintergerst.
PENTA 11 trial Executive Committee: J.P. Aboulker, A. Babiker, D.M. Burger, A. Compagnucci, J.H. Darbyshire, M. Debré, C. Giaquinto, D.M. Gibb, H. Castro (nee Green), L. Harper, N. Klein, M. Lallemant, H. Lyall, L. Mofenson, J. Moye, D. Nadal and Y. Saïdi.
PENTA 11 trial Pharmacology Group: D.M. Burger, T.R. Cressey, E. Jacqz-Aigrain, S. Khoo and J.M. Tréluyer.
PENTA 11 trial Immunology/Virology Group: A. De Rossi, N. Klein, J. Moye, N. Ngo-Giang-Huong, M.A. Muñoz Fernandez and D. Pillay.
PENTA 11 trial Data Safety and Monitoring Committee: C. Hill (Chair), P. Lepage, A. Pozniak and S. Vella.
Trials centres: INSERM SC10, France – J.P. Aboulker, A. Compagnucci, V. Eliette, G. Hadjou, S. Léonardo, C. Pitrou, Y. Riault, Y. Saïdi; MRC Clinical Trials Unit, UK – A. Babiker, L. Buck, J.H. Darbyshire, L. Farrelly, S. Forcat, D.M. Gibb, H. Castro (nee Green), L. Harper, L. Harrison, J. Horton, D. Johnson, C. Taylor, A.S. Walker; Program for HIV Preventions and Treatment (PHPT), Thailand – S. Chalermpantmetagul, T.R. Cressey, R. Peongjakta, S. Chailert, F. Fregonese, G. Jourdain, M. Lallemant, N. Ngo-Giang-Huong. Westat/NICHD, USA – D. Butler, C. Carlton, D. Collins, G. Kao, L. Mofenson, J. Moye, S. Van Buskirk, S. Watson.
Clinical sites [pharmacists (P), virologists/immunologists (L)]: France: Hôpital Femme-Mère-Enfant, Lyon – S. Corradini, D. Floret, T.T. Le Thi (L); Hôpital de l'Archet, Nice – F. Monpoux, J. Cottalorda, J.C. Lefebvre, S. Mellul; Hôpital Cochin Port-Royal, Paris – N. Boudjoudi, G. Firtion, M. Denon, F. Picard (L); Hôpital Robert Debré, Paris – A. Faye, D. Beniken (L), F. Damond (L); G. Alexandre (L); Hôpital Purpan, Toulouse – J. Tricoire, F. Nicot (L); Hôpital Saint-Vincent de Paul, Paris – A. Krivine (L); D. Rivaux; Hôpital Necker, Paris – ML Chaix. Germany: Universitäts-kinderkliniken, Munich – U. Wintergerst, G. Notheis, G. Strotmann, S. Schlieben. Italy: Università di Padova – C. Giaquinto, O. Rampon, M. Zanchetta; Università di Genova – R. Rosso, F. Ginocchio, C. Viscoli; Ospedale Bambino Gesù, Rome – G. Castelli-Gattinara, S. Bernardi, A. Martino, G. Pontrelli, C. Concato (L); Ospedale S. Chiara, Trento – A. Mazza, 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, G. Stanczack, T. Dyda. Spain: Hospital Universitario 12 de Octubre, Madrid: M.I. González Tomé, R. Delgado García, M.T. Fernandez Gonzalez; Hospital Carlos III, Madrid – M. José Mellado Peña, P. Martín-Fontelos, R. Piñeiro Pérez, M. Penin, I. Garcia Mellado, A.F. Medina, B. Ascencion (L); Hospital Universitario de Getafe, Madrid – J.T. Ramos Amador, I. Garcia Bermejo (L), J.A. Garcia Vela (L), I. Martin Rubio (L); Hospital General Universitario Gregorio Marañón, Madrid – D. Gurbindo, M.L. Navarro Gomez, 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, A. Pérez, M.D. Pérez Tamarit, M. Gobernado Serrano (L), A. Gonzales Molina (L). Switzerland: University Chidren's Hospital, Zurich – C. Kalhert, D. Nadal, M. Dobrovoljac, C. Berger, G. Nobile, S. Reinhard (L); National Laboratory for Retrovirus, Zurich – J. Schupbach. Thailand: HIV-NAT, the Thai Red Cross AIDS Research Centre, Bangkok – T. Bunupuradah, J. Ananworanich, O. Butterworth, C. Phasomsap, T. Jupimai, S. Ubolyam (L), P. Phanuphak, T. Puthanakit, C. Pancharoen; Nakornping Hospital – S. Kanjanavanit, T. Namwong, D. Chutima (P), M. Raksasang (L). UK: Imperial College Hospital Healthcare Trust, London – H. Lyall, G. Tudor-Williams, C. Foster, D. Hamadache, S. Campbell, C. Newbould, C. Monrose, D. Patel (P), S. Kaye (L); Chelsea and Westminster Hospital, London – H. Lyall, P. Seery, D. Hamadache, 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, M. Depala (P), M. Jacobsen (L); University Hospital of North Staffordshire, Stoke on Trent – P. McMaster, M. Phipps, J. Orendi, C. Farmer; Newham University Hospital, London – S. Liebeschuetz, O. Sodeinde, D. Shingadia, S. Wong; Birmingham Heartlands Hospital, Birmingham – S. Welch, Y. Heath, S. Scott, K. Gandhi (P); University Hospitals Coventry and Warwickshire National Health Service (NHS) Trust University Hospital – P. Lewis, J. Daglish; Royal Free and University College Medical School, London – D. Pillay (L). USA: SUNY Upstate Medical University, Syracuse, New York – L. Weiner, M. Famiglietti; Howard University Hospital, Washington, District of Columbia – S. Rana, P. Yu, J. Roa; Children's Diagnostic and Treatment Center, Ft. Lauderdale, Florida – A. Puga, A. Haerry, A. Inman.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; clinical trial; paediatrics; randomized; treatment interruption