A recent scheduled interim data and safety review of a clinical study comparing anti-HIV treatment regimens in young children who acquired HIV during birth or breastfeeding has found a lopinavir (LPV/r)-based regimen more effective than a nevirapine (NVP)-based regimen in children who were not previously exposed to NVP. Consequently, the study team has unblinded the data and has advised the parents and guardians of the children to consult with their healthcare providers about the best antiretroviral regimen for their children. The team will continue to conduct follow-up visits with the children as planned.
This finding has potential clinical and financial implications, say the study leaders, because LPV/r currently is more expensive and less accessible than NVP. In resource-limited settings, NVP-based antiretroviral treatment regimens are widely used for HIV-infected children without previous exposure to a single dose of NVP, which is designed to prevent HIV transmission from mother to child. A change to LPV/r-based regimens for these children would incur significant additional costs for groups funding HIV care.
At the time of the interim review, this Phase II clinical trial, known as IMPAACT P1060, had enrolled 452 children ages 2 to 35 months in seven countries: India, Malawi, South Africa, Tanzania, Uganda, Zambia and Zimbabwe. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group has been conducting the study since November 2006 with funds from the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, both part of the National Institutes of Health.
The trial involved two groups of HIV-infected children: 164 who had received single-dose NVP at birth to try to prevent HIV transmission from mother to child (cohort 1) and 287 who had not (cohort 2). The children in each cohort were randomly selected to receive one of two anti-HIV drug regimens: either the NVP-based regimen of NVP + lamivudine (3TC) + zidovudine (AZT), or the LPV/r-based regimen of LPV/r + 3TC+ AZT.
The purpose of the study was to determine which of these treatment regimens is more effective for HIV-infected children. In 2009, an interim review of the study data showed that the LVP/r-based regimen was more effective than the NVP-based regimen in children previously exposed to single-dose nevirapine. As a consequence, cohort 1 was closed to accrual in 2009 and the initial findings published in the Oct. 14, 2010 issue of the New England Journal of Medicine. Now the study has determined that the LPV/r-based treatment regimen also is more effective than the NVP-based regimen in children who lack previous exposure to single-dose NVP.
On October 27, 2010, an independent data and safety monitoring board (DSMB) evaluated the study data for cohort 2 and noted two important findings. First, 40.1 percent of the children taking the NVP-based regimen either had failed to adequately suppress HIV to undetectable levels or had stopped taking their treatment regimen for any reason, including death, by their 24th week in the study. In contrast, only 18.6 percent of the children taking the LPV/r-based regimen had reached either of these outcomes after 24 weeks in the study.
Second, 28.6 percent of the children in cohort 2 taking the NVP-based regimen either had failed to adequately suppress the virus to undetectable levels or did not survive, while only 12.3 percent of the children in that cohort taking the LPV/r-based regimen either had failed to adequately suppress the virus to undetectable levels or did not survive.
The strength of these data led the DSMB to recommend that the investigators unblind the results and share them as soon as possible with the scientific community, study investigators and the parents and guardians of the participating children. The DSMB also recommended that the clinical care providers at each study site evaluate the children in cohort 2, decide with their parents and guardians on the best course of treatment, and continue following these children as planned. NIAID and the IMPAACT study team concurred with these recommendations.
The study investigators are notifying the parents and guardians of all participants, as well as the institutional review boards and national ethics committees involved with IMPAACT P1060, about the recommendations of the DSMB.
The clear advantage of an LPV/r-based regimen in cohort 2 of this study marks a departure from the results of studies in adults and older children who lack prior exposure to NVP. The reason for this advantage in infants remains unclear, but the study team is reviewing the data in greater detail to attempt to determine potential explanations.
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