Long-Term Clinical, Virological and Immunological Outcomes Following Planned Treatment Interruption in HIV-Infected Children

R Freguja; A Bamford; M Zanchetta; P Del Bianco; C Giaquinto; L Harper; A Dalzini; TR Cressey; A Compagnucci; Y Saidi; Y Riault; D Ford; D Gibb; N Klein; A De Rossi


HIV Medicine. 2021;22(3):172-184. 

In This Article

Abstract and Introduction


Objectives: Planned treatment interruption (PTI) of antiretroviral therapy (ART) in adults is associated with adverse outcomes. The PENTA 11 trial randomized HIV-infected children to continuous ART (CT) vs. CD4-driven PTIs. We report 5 years' follow-up after the end of main trial.

Methods: Post-trial, all children resumed ART. Clinical, immunological, virological and treatment data were collected annually. A sub-study investigated more detailed immunophenotype. CT and PTI arms were compared using intention-to-treat. Laboratory parameters were compared using linear regression, adjusting for baseline values; mixed models were used to include all data over time.

Results: In all, 101 children (51 CT, 50 PTI) contributed a median of 7.6 years, including 5.1 years of post-trial follow-up. Post-trial, there were no deaths, one pulmonary tuberculosis and no other CDC stage B/C events. At 5 years post-trial, 90% of children in the CT vs. 82% in the PTI arm had HIV RNA < 50 copies/mL (P = 0.26). A persistent increase in CD8 cells was observed in the PTI arm. The sub-study (54 children) suggested that both naïve and memory populations contributed to higher CD8 cells following PTI. Mean CD4/CD8 ratios at 5 years post-trial were 1.22 and 1.08 in CT and PTI arms, respectively [difference (CT – PTI) = −0.15; 95% CI: −0.34–0.05), P = 0.14]. The sub-study also suggested that during the trial and at early timepoints after the end of the trial, reduction in CD4 in the PTI arm was mainly from loss of CD4 memory cells.

Conclusions: Children tolerated PTI with few long-term clinical, virological or immunological consequences.


Studies of planned treatment interruption (PTI) of antiretroviral therapy (ART) have aimed to reduce ART exposure, toxicity and development of resistance.[1–3] Results in adult studies demonstrated poor immunological and virological outcomes and higher rates of opportunistic infections, non-AIDS events and mortality.[4–7] The Paediatric European Network for Treatment of AIDS (PENTA) 11 trial was a randomized phase II trial investigating clinical and immunological responses to PTIs in HIV-1-infected children aged 2–15 years, 26% CDC category C disease.[8] Children were randomized to continuous therapy (CT) or PTI until a predefined CD4 cut-off was reached, a CDC B/C clinical event occurred or 48 weeks of PTI were completed. In the PTI arm, after 24 weeks back on continuous ART, children whose CD4 had recovered were eligible for a second PTI.

Results from the main trial showed that in the PTI arm, there were no significant increases in clinical adverse outcomes. HIV-1 plasma viraemia increased rapidly. After an initial decline following ART interruption, CD4 cell counts remained stable up to 48 weeks off ART in most children, and naïve and memory cell proportions remained constant.[8,9] This contrasts with adults in whom an initial rapid CD4 decrease was followed by a steady lower rate of decline.[3] In PENTA 11, younger age and higher nadir CD4 were associated with better recovery following PTI.[8] PTI was associated with increases in CD4 cells expressing Ki67 and human leucocyte antigen-DR and increased cell-associated HIV-1 DNA.[9]

After the main trial, children were restarted ART and were followed up long-term. We have previously reported outcomes at 2 years after the end of main trial.[10] Here we describe 5-year outcomes.