A pilot study of three treatment strategies for HIV-positive infants
Polly Clayden, HIV i-Base
In a late breaker presentation, Andrew Prendergast from the University of Oxford, described findings from a paediatric study conducted in KwaZulu Natal, by investigators from South Africa, UK and the US.
This was a prospective, feasibility, randomised study to pilot three treatment strategies for young HIV-positive infants.
Infants born to HIV-positive mothers were tested by polymerase chain reaction (PCR) on days 1 and 28. HIV-positive infants were randomised to: Arm A: standard of care ie deferred, continuous ART, started when CD4 percentage was </=20%; Arm B: immediate ART for 12 months; or C) immediate ART with as many as 3 structured treatment interruptions (STIs)ART stopped at viral load <50 copies/mL and restarted at viral load >5000 copies/mL.
Infants in arms B and C restarted ART once CD4 </=20% if <18 months old, or </=15% if >18 months old.
Infants in this study received AZT+3TC+NVP+NFV as first line treatment in this study. Four drug ART was used until infants achieved viral load <50 copies/mm3, the NVP was stopped and three drug ART was continued (ie children undergoing STIs were not stopping and starting NVP every few weeks). Viral load and CD4 percentage were checked monthly, and weekly during STIs. Infants with virologic failure switched to 2nd line treatment and had no further STIs.
The investigators reported that, of 740 infants screened, 75 were found to be HIV-infected at 28 days. 12 were ineligible for the study and 63 were randomised to Arms A (n=20), B (n=22), and C (n=21).
In Arm A, 17/20 (85%) infants reached CD4 </=20% by 12 months and started continuous ART. 16 infants had 12-month ART, started on median day 30, and 15 stopped ART at 12 months. In Arm B, 2 infants withdrew, 4 died and one received continuous ART.In Arm C, all 21 infants started ART (median day 34) and underwent 0 (n=4), 1 (n=5), 2 (n=3), or 3 (n= 8) viral load driven STIs. These were for a median of 19 days and there was no increase in duration with successive STIs.
In Arms A and B (where continuous treatment ws started), 94% of the infants achieved an undetectable viral load (<50 copies/mL within 12 months.
Although there was no significant difference at interim DSMB analysis, by 2 years of age, 12/20 infants in Arm C required second-line ART compared to 4/16 in Arm B and 3/17 in Arm A (p=0.03 for virological failure only, p=0.05 for all cause switches).
After immediate ART, 23 infants (15 in Arm B and 8 in Arm C) stopped ART as planned; 10/23 (43%) reached starting treatment criteria within 12 months compared to 17/20 (85%) in Arm A (p=0.01).
The investigators noted that rapid progressors have a lower CD4 percentage at birth compared to slower progressors (p=0.008) and the infants time off treatment correlated with CD4 percentage at birth (p=0.0003).
Dr Prendergast explained that with mounting evidence that early treatment of HIV-positive infants is beneficial and lifelong treatment may not be feasible, novel strategies are needed.
He concluded from this study STIs in acute infection are problematic and there was no evidence of improved virologic control. He suggested:
- Early, short-term ART, may be a feasible approach.
- Treatment might be stopped at 1 or 2 years; more evidence needed for such an approach.
- CD4 percentage at diagnosis may enable identification of infants where interruption may be most feasible
- Time off therapy would reduce cost, toxicity and resistance
Other larger studies (especially CHER, also conducted in South Africa) are looking at similar short term ART strategies in infants. Although the interim results from CHER made the advantages of immediate vs deferred treatment pretty clear and are influencing guideline changes, identifying and treating infants on any scale is no small matter.
We know we are like a stuck record on this one, but once again we would argue for better maternal healthcare and avoiding paediatric HIV infection in the first place.
Prendergast A, Chonco F, Tudor-Williams G et al. Randomised, controlled trial of 3 approaches to management of HIV-infected infants. 15th CROI, February 2008, Boston, USA. Oral abstract 77LB.