Early Combination Anitretroviral Therapy of Vertical HIV Infection - First Report on Viral Kinetics and Control of Viral Replication in Children

A report by Jules Levin, Executive Director of NATAP (April 16, 1998)

Dr Katherine Luzuriaga reported important preliminary findings from pediatric protocol ACTG 356. In that protocol a number of different potent combinations are used early in vertical infection. In this report she presented data on viral kinetics and control of viral replication following the initiation of the first regimen to be examined which is AZT/3TC/nevirapine.

To date 16 infants and children have entered the trial. The children were stratified by age into two cohorts. Cohort 1 consisted of infants ranging in age from 15 days to 3 months. Five of the infants had prior treatment experience with AZT ranging from 15 days to 10 weeks. The median baseline HIV RNA for this group was 5.9 log (about 795,000 copies/ml) and the range was from 4.81 log to 6.82 log (64,500 to 6.6 million copies/ml). The CD4 % at baseline ranged from 15 to 47% with a median of 34%.

In cohort two there were 9 infants and children ranging in age from 3 months to 2 years. None of these children had prior antiretroviral therapy. Their baseline HIV RNA ranged from 4.75 log to 6.67 log (about 56,000 to 4.67 million copies/ml) with a median of 5.89 log (776,000 copies/ml). Their baseline CD4 % ranged from 14% to 48% with a median of 35%.

Overall in both cohorts, a minimum of a 2 log reduction in plasma HIV RNA was sustained for 12 weeks or longer in 11/16 (69%) of children; but, 6/9 in cohort 2 had sustained viral load <400 copies/ml at week 12 or longer while 2 had done so in cohort 1. Virus turnover or decay was slower in the younger children (cohort 1).

Table. Virological Responses in Cohort 1

A reduction in plasma HIV RNA of at least 2 log was observed early on for all children in this cohort of younger children ranging from 15 days to 3 months of age. This reduction was sustained in 5 infants. In 3 infants HIV RNA fell to below the limit of detection of the Roche Amplicor Assay which is 400 copies/ml by 12 weeks. In two other infants there was an early reduction of 2 log below baseline but that reduction was not sustained to 12 weeks.

Table. Virological Response in Cohort 2

This table summarizes the response in the older age cohort for children from 4 months to 2 years of age. Of the 9 children in this cohort, 6 have had a durable reduction in plasma HIV RNA ranging from 2.5 log to over 4 log below baseline. All 6 have reached the limits of detection of the Roche Amplicor Assay (<400 copies/ml), and sustained that in over 12 weeks of follow-up. Three children had an initial reduction in HIV RNA of between 2 to 2.5 log. These reductions were not sustained out to 12 weeks or longer.

Viral Kinetics and Control of Replication

An important part of this study was to use these regimens to calculate the kinetics of viral replication in infants and children which to date has not been done as it has been in adults. To do this, samples were taken frequently in the first week: 6 samples in the first week, again at week 2, week 4, and then monthly after that. As has been observed in adults, a rapid reduction of plasma HIV RNA levels was observed over the first week of therapy followed by a slower second phase decay, in children who sustain there viral load reduction. The halflife of the virus was 0.57 days in the older children of cohort 2 (> 3 months of age). This means about half of the virus turns over every 12 hours. In the younger children of cohort 1 (<3 months) the half-life was 1.1 days. This means half the virus turns over about every 24 hours.

Control of viral replication occurred less rapidly in the younger group than in the older children in this study. Virus in the the younger children took longer to decline and longer to clear. The investigators are uncertain why this occurs. Some of the potential reasons could be:

• there could be a difference in pharmacokinetics between the younger and older age groups; there could be a difference in treatment effect due to lower drug blood levels in the younger children
• there could be differences between the groups in their immune systems; possibly, the older children have developed more of an immune system which could contribute to the viral control
• the distribution of the virus could be different between the two age groups

 

You may be questioning the difference in %<400 copies/ml between cohort 1 and 2. Dr Luzuriage said the younger children clear the virus more slowly so it could take them longer to reach undetectable, but she expects them to get there. Preliminary information about the children at 24 weeks was obtained subsequent to the Retrovirus Conference meeting. At 24 weeks, 5 of the children in cohort 1 (<3 months) achieved viral load reductions from baseline of 2.2 to 3.3 log. In cohort 2, 6/9 have sustained viral load reductions <400 copies/ml at 24 weeks.

Studies similar to this one are starting and they will address many of the same questions. In ACTG 345, a similar age group of children are receiving ritonavir+AZT/3TC. The initial data is starting to be analyzed now. Dr Luzuriaga said it will be interesting to see if the kinetics and viral load data are replicated from the study data reported in this report. The Pediatric AIDS Foundation is conducting a study of children aged 1 month to 3 months receiving 1592+AZT/3TC. Two additional ACTG studies will explore these following two regimens: 1592+AZT/3TC+nevirapine, this study has enrolled and is ongoing; d4T+3TC+nevirapine+nelfinavir is about to begin.

Dr Luzuriaga’s clinical approach is to aim for eradication and to begin treatment starting immediately after birth. She and others believe the best chance for eradication is to start treatment early in the hopes of preventing the virus from establishing itself in the child’s body. She said, "young children they’ve treated very early and very hard who’ve achieved control of viral replication very early on haven’t been ill, they’re growing, and they’re thriving". She has not yet observed the side effects, such as fat redistribution, in young children that we’ve observed in adults. She has observed one 13 year old hemophiliac boy with these side effects. But, as a group, children have been exposed to protease inhibitors for a shorter period of time than adults. (See the NATAP report on fat redistribution on this website).