October 28, 2008

BULLETIN

DSMB Finds Ritonavir-boosted Lopinavir Superior to Nevirapine in HIV-positive Women Who Previously Took Single-dose Nevirapine

A recent interim review of a large clinical study comparing anti-HIV treatment regimens that contain either nevirapine (NVP) or ritonavir-boosted lopinavir (LPV/RTV) has found LPV/RTV to be significantly more effective than NVP in HIV-infected women who previously took single-dose NVP to avoid transmitting HIV to their newborns. The study leadership has advised that women who were previously exposed to NVP and were taking NVP as part of the study protocol should consult with their clinicians about how to proceed with HIV treatment. As part of the study, these women may choose to switch from NVP to LPV/RTV or to other anti-HIV drugs, or may stay on NVP. The study team will continue to follow these women until the planned end of the study in June 2009.

The study, called Optimal Combination Therapy after Nevirapine Exposure (OCTANE), is a Phase III clinical trial that enrolled 745 women at 10 sites in seven African countries. The AIDS Clinical Trials Group is carrying out the study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The purpose of OCTANE is twofold: to evaluate which of two anti-HIV treatments is more effective for women who previously took single-dose NVP to prevent the transmission of HIV from mother to infant at birth; and to evaluate whether taking single-dose NVP to prevent mother-to-child transmission subsequently compromises the effectiveness of NVP as a component of therapy for HIV-infected mothers. It is important to answer these questions because NVP, an inexpensive and accessible drug, is widely used in resource-constrained settings for both treating HIV and preventing mother-to-child transmission of the virus.

OCTANE has two components, called Trial 1 and Trial 2. The 243 women in Trial 1 had taken single-dose NVP before the study began, while the 502 women in Trial 2 have never taken NVP. The participants in each trial were randomly assigned to receive either one of two drug combinations for treating HIV: either NVP + emtricitabine/tenofovir (FTC/TDF) or LPV/RTV + FTC/TDF. Thus, the study has four arms:

Trial 1 Arm A: NVP + FTC/TDF
Trial 1 Arm B: LPV/RTV + FTC/TDF
Trial 2 Arm A: NVP + FTC/TDF
Trial 2 Arm B: LPV/RTV + FTC/TDF

On October 6, 2008, an independent data and safety monitoring board (DSMB) evaluated the interim study data and made several important findings about Trial 1.

First, the DSMB found LPV/RTV to be significantly more effective than NVP in Trial 1, and was associated with fewer side effects than NVP. Among 29 women (24 percent) who received NVP + FTC/TDF, either the drug combination failed to suppress HIV levels or the women died compared to the 8 women (7 percent) who received LPV/RTV + FTC/TDF who did not experience HIV suppression or died. The investigators defined viral suppression as a tenfold decrease in HIV RNA after 12 weeks of treatment or the presence of fewer than 400 copies of HIV RNA per milliliter of blood at or after 24 weeks of treatment.

Second, the DSMB found that among women in Trial 1 who began the study with evidence of NVP-resistant HIV, those who received NVP + FTC/TDF were more likely to have higher HIV levels or die than those who received LPV/RTV + FTC/TDF. Five of the 13 women (38 percent) treated with NVP + FTC/TDF who began the study with NVP-resistant HIV either had unsuppressed HIV levels or died, while all of the 12 women treated with LPV/RTV + FTC/TDF who began with NVP-resistant HIV are alive and maintained HIV suppression.

Third, the DSMB found that the negative effect of previous exposure to NVP appears to decrease with time and the more time elapsed between taking single-dose NVP and starting treatment, the smaller the difference in efficacy between NVP and LPV/RTV. For example, among women who took single-dose nevirapine 6 to 11 months before beginning the study, 37 percent of those treated with NVP + FTC/TDF have been unable to suppress HIV levels with the medication or have died, compared with 3 percent of those treated with LPV/RTV + FTC/TDF. Yet among women who took single-dose nevirapine at least 2 years before the study, 8 percent of those treated with NVP + FTC/TDF have not experienced HIV suppression or have died, compared with 10 percent of women treated with LPV/RTV + FTC/TDF.

The DSMB recommended that these findings about Trial 1 be shared with the study participants and investigators. As there are no safety concerns with Trial 2, the DSMB advised that it continue as planned. NIAID concurred with these recommendations.

The study investigators are notifying all participants of the findings of the DSMB. Treatment with LPV/RTV is available to the women in Trial 1 who have been receiving NVP, should they choose to change therapy. Trial 2 will continue as planned to determine how the two treatment options compare for women who have not previously taken NVP.

The World Health Organization develops international guidelines for the treatment of women with HIV infection (http://www.who.int/hiv/topics/treatment/en/index.html) while the U.S. Department of Health and Human Services develops HIV treatment guidelines for women in the United States (http://aidsinfo.nih.gov/Guidelines/Default.aspx?MenuItem=Guidelines).

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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