Randomized clinical trial of immediate versus deferred antiretroviral therapy initiation in children

Thanyawee Puthanakit, MD

A new study from HIV-NAT has found that HIV-infected children ages 1 to 12 years are equally likely to survive with mild to moderate symptoms of HIV disease whether they start treatment immediately upon diagnosis or delay treatment until their immune systems weaken severely. However, those HIV-infected children whose treatment is deferred grow at a slightly slower rate and have poorer immune health than those who begin therapy right away.

These findings, which come from the first randomized clinical trial to examine the best time to start treatment for HIV infection in children ages 1 to 12 years, was presented by Thanyawee Puthanakit, M.D., at the 3rd International Workshop on HIV Pediatrics in Rome in July 2011. This clinical trial called PREDICT took place in Thailand and Cambodia from March 2006 to May 2011.

For instance, it could be advantageous to postpone HIV therapy for younger children if they are likely to spit out part or all of a dose, which limits the ability to treat them and increases their risk of developing drug resistance. Deferring treatment also delays the child’s exposure to the toxicities of AIDS drugs that potentially could affect their development and that they likely will have to take for the rest of their lives. Financially and logistically, it may be beneficial to delay treatment until a child is old enough to take AIDS drugs in a pill form rather than a liquid, which is available for fewer drugs and is more difficult and expensive to obtain in resource-limited settings.

The PREDICT study team enrolled 300 HIV-infected children ages 1 to 12 years who had never been treated for their infection, had moderately weak immune systems and were experiencing mild to moderate symptoms of HIV disease. Half of the children were randomly assigned to begin taking a three-drug regimen upon enrollment, and half were assigned to defer treatment until either their immune systems severely weakened or they developed AIDS. The study team followed each child for two years and 40 weeks, primarily observing how many kids survived without developing AIDS.

At the end of the observation period, three children in the immediate treatment group and two in the deferred treatment group had developed AIDS, and one child with AIDS in the immediate treatment group had died. The difference in AIDS-free survival between the groups was not statistically significant, preventing the study investigators from concluding whether one treatment strategy was more beneficial than the other. Given that 98 percent of children in one group and 99 percent in the other survived free of AIDS, it would take a much larger study with thousands of children to identify the more beneficial strategy, according to the investigators.

The PREDICT study also measured the growth and immune health of study participants and the presence of drug-resistant HIV. The children in the deferred treatment group were significantly shorter for their age and had weaker immune systems than the children in the immediate treatment group. Meanwhile, children in the immediate treatment group were more likely to develop drug-resistant HIV, requiring them to switch to a different set of drugs and limiting their future treatment options. Preliminary results from a sub-study that examined the participants’ neurodevelopment found no significant difference between the two groups.

The PREDICT study was conducted by the Thai Red Cross, the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT) and the Cambodian National Center for HIV/AIDS, Dermatology and STDs (NCHADS). Leading the study were Kiat Ruxrungtham, M.D., M.P.H., deputy director of HIV-NAT; and Saphonn Vonthanak, M.D, Ph.D., deputy director of NCHADS.

The World Health Organization’s HIV treatment guidelines for children allow a delay in starting treatment for children ages 2 years and older who have mild or no symptoms and moderately healthy immune systems. The PREDICT study findings support these guidelines but suggest that it may be safe to let the child’s immune system grow weaker before starting treatment.