Initial results from PENTA 11 trial of planned treatment interruption
Polly Clayden, HIV i-Base
Di Gibb presented findings from the PENTA 11 trial on behalf of the Paediatric European network for treatment of AIDS (PENTA).
PENTA 11 was a phase II randomised trial of antiretroviral treatment (ART) strategies, comparing CD4-guided planned treatment interruption (PTI) to continuous therapy (CT) in children with viral load <50 copies/mL, and CD4% ≥30% (2-6 years) or CD4% ≥25% and CD4 ≥500 cells/mm3 (7-15 years). In the PTI arm, ART was stopped and restarted if a child had a confirmed CD4% <20% (7 years) or CD4% <20% or CD4 <350 cells/mm3 (≥7 years).
After a DSMB review following the SMART results, the protocol was amended so that no interuption lasted longer than 48 weeks and further PTIs were only undertaken in children who spent >10 weeks off ART during their first PTI and had been back on ART for at least 24 weeks.
The trial was powered on equivalence; 2-sided with a 15% margin. The primary end-point was CD4% <15% (and/or CD4 <200 cells/mm3 >/=7 years), new CDC C diagnosis or death. Minimum follow up was 72 weeks.
Professor Gibb reported that from 2004 to 2006, 109 children were randomised to CT (n=53) or PTI (n=56): 45% children were boys; their median age was 9.3 (range 2-16) years; 35% white, 31% black; 26% CDC stage C, median time on ART 5.7 (IQR: 3-9) years. Their median baseline CD4% was 37% (IQR: 33-41), CD4 966 (IQR: 793-1258) cells/mm3; prior to ART nadir (at age 3 years) CD4% 18% (IQR: 10-27) and CD4 627 (IQR: 320-1050) cells/mm3.
After a median of 130 (IQR: 80-144) weeks (one child lost to follow up), the investigators found that 4% of the study period was spent off ART by children in the CT arm vs 48% in the PTI arm.
During the first PTI, 9 children restarted treatment in <10 weeks; 21 (38%) children restarted ART <48 weeks (14 failing CD4, 7 non-protocol reasons); 32 (57%) restarted at or after 48 weeks and three remained off ART. 16 children had a 2nd PTI.
Professor Gibb reported no child died or had a CDC C event.CD4 primary end points occured in 1 (2%) CT vs 4 (7%) PTI (difference 5% [95% CI -2%, 13%], p=0.2). 98.4% of total time in CT vs. 95.9% in PTI was spent with CD4 >350 cells/mm3.
The mean change in CD4 count from baseline to 72 weeks was -106 vs. -240 cells/mm3 in CT vs. PTI (difference -134 cells/mm3, 95% CI -237, -31, p = 0.01). Differences between the two groups are difficult to interpret as some children in the PTI arm were off ART at 72 weeks. In an exploratory analysis, the mean CD4 change 0-72 weeks was -124 cells/mm3 in 27 PTI children who had all been back on ART for >/=24 weeks; this is closer to the -106 value observed in CT children.
The CD4 fall of 106 cells in the CT arm is unlikely to be due to the natural fall in CD4 experienced by children throughout childhood, as childrens’ CD4 counts normalise to those of adults by the age of 6 and the median age of the cohort was 9.3 years.
When the investigators looked at CD4 z-score change in the PTI arm from 0-24 weeks (1st PTI) after restarting, they reported that age adjusted CD4 recovery was significantly better in young children (mean, SE): -0.1 (0.3), -0.9, -1.3 for ages 2-6 (n=4), 7-10 (n=20) and 11+ (n=13) years, respectively, p = 0.02. Thus children <6 years almost fully recovered their CD4 values within 24 weeks, but older children did not.
At 72 weeks, 94%/85% vs. 81%/58% children had VL <400/<50 copies/mL in CT vs PTI (p = 0.05/0.003). Of the 28 PTI children back on ART for ≥24 weeks, 89%/68% had VL <400/<50 copies/mL, there was no evidence of more resistance in the PTI arm using standard genotype tests: 10 (5 CT and 5 PTI) of 13 children with 2 consecutive measurements >100 copies/mL on treatment had resistance; of these, 4 CT and 2 PTI had 4 or more mutations.
Although adverse events were more frequent in the PTI arm, these were mostly predictable (more lymphadenopathy, consistent with new onset viraemia).
With respect to both CD4 recovery and viral load suppression after PTI, Professor Gibb noted that because some children were off ART at 72 weeks, results so far are difficult to interpret and longer follow-up is essential, and is ongoing. The investigators concluded, “Longer-term assessment of all children after restarting ART will be required to fully assess risks and benefits of PTI in this population”.
In the meantime, paediatricians have advised all children on PTI to be restarted on ART. These results do provide reassurance that ongoing interruption trials should continue in both chronically infected children (BANA trial in Botswana) and following primary infection (CHER trial in South Africa). Results of adherence/acceptability and immunology/virology studies alongside PENTA 11 are now being analysed.
The PENTA group does not currently support treatment interuptions in children outside of a research study and has recommended that children in this study now restart ART. The same questions raised by the SMART study that now need to be answered in children include:
- Whether children re-suppress viral load.
- Whether higher sensitivity resistance tests show development of resistance.
- Whether CD4 recovery similarly lags behind that of baseline levels, even 18 months after reintroduction of treatment, and
- What is the long-term implications of ongoing viral replication and importance of ongoing immune activation? (See the study from Pontrelli et al below).
Gibb DM, Compagnucci A, Green H et al. Treatment interruption in children with chronic HIV-infection: the results of the paediatric European network for treatment of AIDS (PENTA) 11 trial. 9th International Congress on Drug Therapy in HIV Infection, 9-13 November 2008, Glasgow. Abstract O222.