Antiretroviral Therapy Interruption Safe for HIV-Positive Infants

Jim Kling

March 09, 2012

March 9, 2012 (Seattle, Washington) — Limited antiretroviral therapy (ART) in the first 1 or 2 years of life followed by interruption appears to be safe and leads to better outcomes, according to a study presented here at the 19th Conference on Retroviruses and Opportunistic Infections.

For infants who were on ART for a longer period before interruption (96 vs 40 weeks), the treatment interruption was longer and the outcomes slightly better.

Interim results from the Children With HIV Early Antiretroviral Therapy (CHER) study show that ART should be prescribed to HIV-positive infants, although it has potential lifelong complications. This suggests a need for innovative regimens, said presenter Mark Cotton, PhD, from the Department of Paediatrics and Child Health at Stellenbosch University in Tygerberg, South Africa.

In CHER, HIV-positive infants were assigned to 1 of 3 treatment groups: deferred ART with lopinavir/ritonavir plus zidovudine plus lamivudine (deferred group); immediate ART with interruption after 40 weeks (40-week group); and immediate ART with interruption after 96 weeks (96-week group).

ART was initiated or restarted according to World Health Organization criteria (CD4 count <25% or <20% after infancy) or in response to a Centers for Disease Control and Prevention (CDC) clinical severity of B or C.

In CHER, 377 infants younger than 12 weeks of age (median age, 7.4 weeks) were enrolled from 2005 to 2007. Of these, 341 infants (91%) completed follow-up.

In the deferred group, median time to starting ART was 20 weeks; median time to restarting ART was 33 weeks in the 40-week group and 70 weeks in the 96-week group.

In the deferred group, 39 of 125 patients (31%) reached the primary end point — time to failure of first-line ART or death — as did 31 of 126 patients (25%) in the 40-week group and 25 of 126 (20%) in the 96-week group.

Deaths occurred in 22 patients (18%) in the deferred group, 11 patients (9%) in the 40-week group, and 9 patients (7%) in the 96-week groups. Compared with the deferred group, the 40-week group had a hazard ratio (HR) of reaching a primary end point of 0.73 (95% confidence interval [CI], 0.46 to 1.17; P = .19); for the 96-week group, HR was 0.58 (95% CI, 0.35 to 0.96; P = .03).

Seven children switched to second-line ART (3 in the deferred group, 3 in the 40-week group, 1 in the 96-week group).

In the deferred group, there were 66 events with a CDC clinical severity of B or C in 52 children; in the 40-week group, there were 39 events in 34 children, and in the 96-week group, there were 31 events in 28 children.

Compared with the deferred group, HR for first clinical event in the 40-week group was 0.5 (95% CI, 0.3 to 0.8; P = .005), and in the 96-week group was 0.4 (95% CI, 0.3 to 0.7; P = .0003).

Differences in clinical events in the deferred, 40-week, and 96-week groups were mainly the result of failure to thrive (14 vs 14 vs 10) and encephalopathy (9 vs 5 vs 2). There were 181 grade 3/4 adverse events in the 40-week group (75 children) and 157 in the 96-week group (71 children).

From June 2007 to February 2008, 34 more children with a CD4 count above 25% were randomized to the 40-week and 96-week groups (for a total of 143 infants per group). At the end of follow-up, 30 of 143 (21%) infants in the 40-week group and 46 of 143 (32%) infants in the 96-week group remained off ART.

In the 40-week group, 34 of 143 reached the primary end point of failure of first-line ART or death, as did 29 of 143 in the 96-week group (HR, 0.84; 95% CI, 0.51 to 1.38; P = .49).

There were 11 deaths in the 40-week group (9 in patients on primary ART, 1 during ART interruption, 1 after ART restart) and 12 in the 96-week group (10, 2, and 0, respectively).

Dr. Cotton said the results suggest that ART interruption is safe, but the results from another trial presented at the meeting are less promising. In that study, HIV-positive infants underwent a planned treatment interruption after at least 24 months of ART; a high percentage met the restart criteria within 3 months.

According to Dr. Cotton, who presented the work, the difference in success might be that the team identified patients early. "We think at that stage we were probably dealing with an intact immune system. Our patients were different. It illustrates the complexity of treating infants."

"We've been waiting for these results," Alexandra Compagnucci, MD, medical trial coordinator INSERV HIV Clinical Trials Unit in Paris, France, who moderated the session at which the research was presented, told Medscape Medical News. "Longer follow-up is needed, to see when they will restart the patient and how the CD4 counts recover."

Challenges remain, including adherence, resistance, and particularly lack of formulations designed for children. "We want to spare them from long-term complications [of ART], because these children are growing," Dr. Compagnucci added.

Dr. Cotton and Dr. Compagnucci have disclosed no relevant financial relationships.

19th Conference on Retroviruses and Opportunistic Infections (CROI): Late-breaking abstracts 27 and 28. Presented March 6, 2012.


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