29 March 2002

Clinical Trials Show HIV Drug Nevirapine to be Safe

The U.S. National Institute of Allergy and Infectious Diseases (NIAID) reports that clinical studies conducted in the United States and several other countries have shown nevirapine to be a safe, effective and affordable drug to prevent mother-to-child transmission of the human immunodeficiency virus (HIV) that causes AIDS.

The following terms are used in the fact sheet:

UNAIDS: The Joint United Nations Program on HIV/AIDS

Following is the text of the NIAID fact sheet:

National Institute of Allergy and Infectious Diseases

March 2002

Fact Sheet

Overview

In the late 1990s, powerful new medicines became available in some parts of the world to effectively treat HIV infection in adults and children. Known as antiretroviral drugs, they have dramatically improved health and quality of life for many people with HIV. But, the drugs are difficult to take, require regular medical supervision, may have serious side effects, and are expensive. Because the need still exists for safe, effective, and inexpensive anti-HIV drugs that can be given in a variety of medical settings, NIAID supports studies in the United States and abroad to evaluate the safety and effectiveness of HIV treatments in all affected populations. NIAID supports research and development of therapies for HIV disease, including associated opportunistic infections and other complications of AIDS in adults, infants, children and adolescents. The drug nevirapine (NVP) is being studied for its ability to block transmission of HIV from a mother to her newborn infant in settings where prenatal care and antiretroviral drugs are not typically available.

About Nevirapine

Nevirapine inhibits HIV replication by blocking the action of the viral enzyme reverse transcriptase. Because the drug is rapidly absorbed and remains in the body for several hours, taking the drug just twice a day can produce high enough levels in the blood to stop HIV replication. The U.S. Food and Drug Administration (FDA) approved nevirapine in 1996 for use in combination with other antiretrovirals to treat HIV in adults. In 1998, FDA approved nevirapine as part of a combination therapy to treat HIV in infants and children 2 months of age and older.

Nevirapine for Prevention of Mother-to-Child Transmission of HIV

NIAID funded the nevirapine study known as HIVNET 012 in partnership with Ugandan investigators and with the support of the Ugandan government to address that country's need for safe, effective and affordable regimens to prevent mother-to-child transmission (MTCT) of HIV. An estimated 30 percent of women are infected with HIV in many urban areas in sub-Saharan Africa. About 25 to 35 percent of women with HIV transmit the virus to their infants, and UNAIDS estimates that 6,000 infants are born with HIV infection every day in sub-Saharan Africa. Because NVP has been shown to be a safe, potent and long-lasting antiretroviral drug, which is transferred to a fetus in the womb, researchers hypothesized that a single dose of nevirapine given to the mother during labor and to the newborn baby might prevent HIV transmission during labor and delivery. Nevirapine can also be stored safely in hot climates.

Results from several clinical studies support the use of NVP to reduce the risk of MTCT. Preliminary studies done first in the United States (ACTG 250) and later in Uganda (HIVNET 006) demonstrated that a single dose given to pregnant women during labor and a single dose given to their newborns was a well-tolerated regimen that produced drug levels in the infants that were expected to inhibit virus growth. Later, HIVNET 012 compared the single NVP dose given to mothers and their newborns to zidovudine (AZT) given to women during labor along with daily doses of AZT given to their infants for the first week of life. After about 15 weeks, infants who received NVP were nearly 50 percent less likely to become infected with HIV compared to infants who received the short course of AZT. Both regimens were well tolerated; adverse side effects were few for both drugs. Those results were reported in the medical journal Lancet in September 1999.

A similar study (PACTG 316) was conducted in the United States, Europe, Brazil and the Bahamas in HIV-infected pregnant women who were already receiving other antiretroviral drugs. Women in that study received either NVP or a placebo. Although the amount of HIV transmission among participants was too low to determine NVP's effectiveness at blocking MTCT, the drug was well tolerated. Side effects were rare and about the same in people who received the drug or a placebo.

The South African Intrapartum Nevirapine Trial (SAINT) also reported that NVP safety is similar to that seen in earlier studies. The SAINT study has found a reduction in MTCT similar to those of HIVNET 012.

Use of Nevirapine for Treatment and Prevention of HIV Infection in the United States

In the United States, NVP is widely used in combination with other antiretroviral drugs to treat HIV infection in adults, adolescents and children as young as 2 months of age. Most pregnant women in the United States receive prenatal care. Pregnant women who have HIV usually take AZT after the first trimester, alone or in combination with other antiretroviral drugs. Their newborn infants usually receive AZT for six weeks. If a pregnant woman is not known to be HIV positive until late in pregnancy or during labor, the U.S. Public Health Service Task Force recommends NVP as a treatment option for the mother and her newborn to block MTCT.

The Boehringer Ingelheim Application to FDA

Nevirapine is manufactured by Boehringer Ingelheim Pharmaceuticals, Inc. The company donates the drug to clinical studies around the world, including HIVNET 012. When a 1999 data safety and monitoring board review of HIVNET 012 showed a nearly 50 percent reduction in MTCT in participants who received NVP compared to those who received AZT, the company chose to seek an expanded FDA licensure of the drug for use in preventing MTCT. As part of the routine data evaluation required for such licensure, NIAID and the company began a review of how the study was conducted as well as its scientific results. In a limited initial review, no evidence has been found that the conclusions of HIVNET 012 are incorrect or that study participants were placed at increased risk of harm. However, some aspects of how the study data were collected and documented may not conform to FDA regulatory requirements. A comprehensive examination has begun to determine the conformance of the data collection processes to those requirements. Because the comprehensive review could not be completed within an established timeline, the company notified the FDA of its decision to withdraw the application for prevention of MTCT at this time. That decision has not altered the current FDA-approved uses of nevirapine or the recommendations of the U.S. Public Health Service Task Force.

The drug-treatment phase of the HIVNET 012 trial was completed in 1999, and study investigators continue to follow the mothers and their infants to determine the long-term effectiveness of the single nevirapine dose. The U.S. National Institutes of Health (NIH) and other federal agencies continue to support studies of the use of NVP to prevent MTCT of HIV. New studies are being prepared for implementation.

Standards for Clinical Trials in Foreign Countries

Standards for the study in Uganda were the same as those for studies in the United States. All clinical trials supported by the U.S. government, including international trials, are required to establish an institutional review board (IRB), which works in collaboration with the IRB at the U.S. co-investigator's institution. The FDA requires the same level of safety and efficacy data from international trials as it does for U.S. trials before it will approve a drug for use.

Prevention of MTCT in Uganda

HIVNET 012 was designed for settings in Uganda because the long-course AZT regimen used in the United States is both unaffordable and impractical in such regions where a woman's first prenatal medical visit is usually just before delivery. It is important to study a drug's effectiveness directly in the setting in which it will be used because cultural norms, locally common infections, or nutritional status may affect either the course of HIV infection or responses to drugs. Participation in clinical trials is particularly important in the development and evaluation of new or improved interventions that are appropriate, affordable and sustainable in the Ugandan setting. Ugandans and other international research partners should continue to make decisions about participation in studies they believe are important for advancing the health of their people.

Public Health Importance of Nevirapine

Reduction of MTCT by a safe and effective regimen that is both easy to use and affordable represents a major public health advance for regions in which most people do not have access to expensive antiretroviral drugs or continuous medical care. The simple dosage schedule and low cost of nevirapine may make it suitable for use in a variety of countries and health care settings. NIH supports the use of single-dose nevirapine as a component of MTCT prevention programs. NIAID believes there is no reason for programs implementing the life-saving, NVP regimen to change their practices. Studies will continue to evaluate implementation of this regimen in resource-poor settings, where effective preventive regimens are urgently needed.

Results from Uganda and other countries conducting large nevirapine studies demonstrate that the drug is well tolerated and achieves a dramatic reduction of MTCT. Future studies will emphasize evaluation of operational issues to learn how to effectively deliver the drug to larger populations, and how to manage monitoring and follow-up of large numbers of patients in the clinical and public health settings.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

Prepared by: Office of Communications and Public Liaison, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD. NIH is part of the U.S. Department of Health and Human Services.

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