May 6, 2009

A recent, scheduled interim data and safety review of a clinical study comparing anti-HIV treatment regimens based on either nevirapine (NVP) or ritonavir-boosted lopinavir (LPV/r) has found the LPV/r-based regimen to be more effective than the NVP-based regimen in HIV-infected children who received a single dose of NVP at birth. Consequently, the study team has stopped enrolling children who received single-dose NVP at birth. In addition, the team has advised the parents and guardians of children who received single-dose NVP at birth and have been taking the NVP-based treatment regimen as part of the study to consult with their providers about the best regimen for their children. The team will continue to follow these children as planned. Meanwhile, the study will continue to compare the effectiveness of NVP-based treatment regimens versus LPV/r-based regimens in HIV-infected children who did not receive single-dose NVP at birth. 

At the time of the interim review, this Phase II clinical trial, known as P1060, had enrolled 286 children ages 6 to 35 months at nine sites in six countries: India, Malawi, South Africa, Uganda, Zambia and Zimbabwe. The International Maternal Pediatric Adolescent AIDS Clinical Trial Group (IMPAACT) is carrying out the study 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 NIH.

The purpose of the study is to determine which of two treatment regimens is more effective for HIV-infected children and whether an HIV-infected baby’s exposure to single-dose NVP at birth reduces the effectiveness of NVP-based antiretroviral therapy for the child later. These questions are important because NVP, an inexpensive and accessible drug, is widely used in resource-constrained settings both to prevent the transmission of HIV from an infected mother to her child at the time of birth and to treat HIV infection. Although single-dose NVP often protects newborns from acquiring HIV during birth, breakthrough infections do occur, and these infants need to begin antiretroviral therapy as soon as they are identified as HIV-infected.

Previous research has raised concerns that anti-HIV treatment regimens containing NVP are likely to be less effective than other drug regimens for HIV-infected women who have recently taken single-dose NVP to avoid transmitting the virus to their newborns, as well as for their infants who become infected with HIV. The reduced effectiveness of NVP-based multi-drug therapy for these women was confirmed in a recently completed, NIAID-funded study. To determine the effectiveness of NVP therapy in infants exposed to NVP at the time of birth, a team of IMPAACT investigators led by Paul E. Palumbo, M.D., of the Dartmouth-Hitchcock Medical Center, and Avy Violari, F.C.Paed., of the University of the Witwatersrand, has been studying HIV-infected children, 153 of whom had received single-dose NVP at birth (cohort I) and 133 of whom had not (cohort II). The children in each cohort were randomly selected to receive one of two anti-HIV drug regimens:

• Nevirapine arm: NVP + lamivudine + zidovudine
• Lopinavir arm: LPV/r + lamivudine + zidovudine

On April 20, an independent data and safety monitoring board (DSMB) evaluated the interim study data for P1060 and noted two important findings about cohort I. First, by their 24th week in the study, 40 percent of the NVP-exposed children in the nevirapine arm had either failed to adequately suppress HIV to undetectable levels or stopped taking their treatment regimen. In contrast, after 24 weeks in the study, only 22 percent of the NVP-exposed children in the lopinavir arm had reached either of these outcomes.

Second, when considering control of HIV replication alone, 24 percent of the children in the nevirapine arm had failed to adequately suppress the virus to undetectable levels, while only 7 percent of the children in the lopinavir arm had failed to adequately suppress the virus to undetectable levels.

These data show a clear trend in favor of the LPV/r-based regimen for children who previously received single-dose NVP.  The strength of the trend and its consistency with the findings of the similar study of NVP in women led the DSMB to recommend that the investigators stop enrolling NVP-exposed children in P1060. The DSMB also advised the investigators to unblind these results and share them with the scientific community as soon as possible. Finally, the DSMB recommended that the clinical care providers at each study site evaluate the children already in cohort I, decide with their parents and guardians on the best course of treatment, and continue following these children as planned. NIAID concurred with these recommendations.

The study investigators are notifying the parents and guardians of all participants, institutional review boards and national ethics committees involved with P1060 about the findings of the DSMB. The data to date do not necessitate any change in the conduct of the study for the children who have not received NVP at birth, so enrollment in cohort II will continue as planned.

These findings provide clear evidence in support of the current World Health Organization recommendation that HIV-infected infants who have received NVP at birth should be started on an LPV/r-based treatment regimen whenever possible.

Media inquiries can be directed to the NIAID Office of Communications at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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