HIVNET 012: Questions and Answers

1. What was the purpose of study HIVNET 012?
   HIVNET 012 compared two different short-course regimens of antiviral drugs administered late in pregnancy and in the first day of the baby's life to determine their safety and efficacy in preventing transmission of HIV from HIV-infected mothers to their infants.

   The two drugs compared in this study were nevirapine and zidovudine (also known as ZDV or AZT). Nevirapine is a non-nucleoside reverse transcriptase inhibitor that has many attractive features. In addition to being a safe and potent antiviral drug, nevirapine remains active in the body for a long time and is rapidly absorbed and transferred to the fetus in the womb. For these reasons, researchers hypothesized that a single dose of nevirapine given to the mother and to the infant might provide enough protection to the baby to prevent HIV transmission during labor.

2. How was the study designed?
   HIVNET 012 was a randomized, controlled trial of oral nevirapine versus oral zidovudine administered to pregnant, HIV-infected women during labor, and to their infants during the first week of life. The study measured the number of new HIV infections in the infants.

   Women were randomly assigned to receive either:

   1. Nevirapine:
      Mother: one 200 mg dose at the onset of labor
      Infant: one 2 mg/kg dose within 72 hours after birth
      OR
   2. Zidovudine:
      Mother: one 600 mg dose at the onset of labor, followed by 300 mg doses every 3 hours during labor
      Infant: 4 mg/kg twice daily for the first week of life.

   Note: HIVNET 012 was originally designed as a double-blind, placebo-controlled study in 1500 women and their newborns in Uganda. After the announcement of the results of the CDC-sponsored Thai zidovudine trial in February 1998, the placebo arm in HIVNET 012 was discontinued. The study was redesigned to compare nevirapine to zidovudine.

3. What are the preliminary results of HIVNET 012?
   A single 200 mg dose of oral nevirapine administered at the onset of labor to an HIV- infected woman, as well as a single dose of oral nevirapine to her infant within 72 hours of birth, significantly reduced the risk of maternal-infant transmission of HIV when compared with a short course regimen of zidovudine.

   At 6-8 weeks of age, 11.9 percent of infants in the nevirapine group were HIV-infected compared to 21.3 percent of infants in the zidovudine group. At 14-16 weeks of age, 13.1 percent of infants in the nevirapine group were infected compared with 25.1 percent of infants in the zidovudine group.

   This study did not compare the effectiveness of nevirapine or zidovudine to placebo reducing mother to infant transmission. However, if the short-course zidovudine reg-imen is more effective than placebo, the benefit of the nevirapine regimen over placebo would be even greater than its benefit over zidovudine.

4. What agency is sponsoring the trial?
   The trial is sponsored by the HIV Prevention Trials Network (HIVNET) of the National Institute of Allergy and Infectious Diseases (NIAID) the U.S. Governments' lead agency for AIDS research. HIVNET conducts domestic and international multicenter studies to evaluate the safety and efficacy of promising drugs or other methods that may prevent HIV infection.

   HIVNET-supported researchers from Makerere University in Kampala, Uganda, and Johns Hopkins University in Baltimore conducted the study. Glaxo-Wellcome and Boehringer-Ingelheim Pharmaceuticals provided the drugs used in the study.

5. When and where was the study conducted?
   Women were enrolled in the study between November 1997 and April 1999. The study was conducted at Mulago Hospital, the teaching hospital affiliated with Makerere University in Kampala, the capital city of Uganda. Over 21,000 women deliver at this hospital annually and nearly 16 percent of those women are HIV infected.

   Mothers and children will continue to be followed until 18 months of age to determine the long-term impact of the treatment in preventing maternal-infant transmission of HIV.

6. Who is participating in the study?
   The study enrolled 645 mothers and their infants from areas in and around Kampala, Uganda. This preliminary analysis looked at data from 618 mothers (308 receiving zidovudine and 310 receiving nevirapine) and 618 infants. At enrollment, all women were HIV-infected, had reached 36 weeks in their pregnancy and had received no antiviral treatment during the pregnancy. The average age of mothers was 24 years. The average maternal CD4 cell count was 448 cells per microliter of blood and the average maternal plasma HIV RNA level (often called "viral load") was 26,943 copies per microliter of blood.
7. Why is this study being done in Uganda?
   HIVNET 012 was developed in partnership with Ugandan investigators and with the support of the Ugandan government to address Uganda's need for safe, effective and affordable regimens to prevent maternal-infant HIV transmission. An estimated 30 percent of women are infected with HIV in many urban areas in sub-Saharan Africa. About 25-35 percent of infected women transmit the virus to their infants.

   The long-course zidovudine regimen used in AIDS Clinical Trial Group protocol 076 (ACTG 076), now the standard of care for HIV-infected pregnant women in the United States, is unaffordable in many developing countries, where annual per capita spending on health is often less than $10. The cost of the drugs alone for the 076 regimen is 80 times that amount. Successful implementation of the 076 regimen also requires that women receive prenatal care early in their pregnancy. Recently studied shorter courses of zidovudine plus the drug lamivudine (3TC) have lowered the cost of treatment, but all are still substantially more expensive than the cost of the nevirapine regimen used in this study.

8. What other studies have addressed mother-to-child transmission of HIV?
   Recent studies have shown that short regimens of zidovudine can be effective in reducing maternal-infant HIV transmission. In 1998, a randomized trial in Thailand using a regimen of four weeks of zidovudine given to the mother in late pregnancy and delivery (no zidovudine to the infant) showed a 50 percent reduction in transmission in children who were followed to six months of age. When the same regimen was used in a breastfeeding population in Ivory Coast, the reduction was 37 percent at three months of age. In early 1999, results from the UNAIDS-sponsored PETRA study in South Africa, Uganda, and Tanzania were announced. This study compared three different regimens of zidovudine plus lamivudine (3TC) with placebo. When the drugs were given to women during the last four weeks of pregnancy and to mother and infant for one week after birth there was a 50 percent reduction in transmission at six weeks after birth. In women who received the combination at the onset of labor, and to the mother and infant for one week the transmission rate was slightly lower (40 percent). There was no efficacy when the drugs were given only to the mother.

   A recent study in Ivory Coast and Burkina Faso, sponsored by France's ANRS using zidovudine before, during labor, and after birth, showed a 38 percent reduction of transmission at six months of age.

9. Was the HIV transmission rate in the group receiving zidovudine higher than rates observed in zidovudine arms from other studies?
   It is higher than some studies, but not all. Since there was no direct comparison with other previously studied regimens, it is impossible to know whether these data are different from other mother-to-infant prevention studies using zidovudine. However, the zidovudine regimen used in HIVNET 012 is shorter than any other previously studied, and women in this study had more advanced disease in previous studies.

   Results in the zidovudine arm in the 012 study are consistent with a modest reduction in transmission observed in some other studies. When transmission risk in Ugandan infants on the placebo arm in the PETRA trial or in breastfed Kenyan infants in the Nuadi-Kreiss trial is compared to the zidovudine arm in this study, the transmission rates are comparable.

   In addition, data from the 49 infants randomized to the placebo arm before the study was redesigned suggest that there is a small benefit in the zidovudine arm compared to placebo.

10. Did the mothers or infants develop any side-effects from the drugs?
    Participants in both the zidovudine and the nevirapine arms reported infrequent and mild side-effects. Mild skin rashes were observed in nine infants receiving nevirapine and in nine infants receiving zidovudine. Anemia was also equally distributed among infants (three nevirapine recipients and five zidovudine recipients). Long-term follow-up of all HIVNET 012 infants remains a high priority so that researchers can determine any long-term toxicities in the nevirapine and zidovudine groups.
11. What are the advantages of nevirapine in preventing mother-to-child transmission of HIV?
    The advantages of nevirapine, as used in the HIVNET 012 trial, are its simplicity, low cost, and potential for widespread use. Compared with other antiviral regimens, the nevirapine regimen achieves a similar reduction of transmission with only a single dose to the mother and a single dose to the baby. The nevirapine regimen alone currently costs about $4. Many other factors, however, such counseling and testing, contribute to the overall cost of any intervention to prevent mother-to-child HIV transmission. Using U.S. retail prices, this regimen is nearly 70 times cheaper than even a short course of zidovudine and 200 times cheaper than the long-course zidovudine used in the U.S.

    Another practical advantage is that nevirapine can be stored in hot climates.

12. How much did the study cost?
    To date, the study has cost approximately $2 million.
13. What are the international implications of this study?
    This study makes a significant step toward addressing the cost barriers that prevent most developing countries from adopting regimens to decrease mother-to-child transmission of HIV. It does not address other limiting factors, such as costs of HIV counseling and testing that will need to be considered to achieve widespread use of this regimen. However, if nevirapine continues to be shown to be safe, it could potentially be given to all women in labor in high HIV-prevalence areas, without HIV counseling and testing or could be used in conjunction with a rapid HIV test.
14. What are the implications of this study for other ongoing or planned clinical trials studying prevention of mother-to-child transmission of HIV?
    The urgency of developing interventions to prevent mother-to-child transmission of HIV in the developing world mandates evaluation of different regimens that can be adapted to various settings. The results of the nevirapine study will be carefully evaluated. A one-dose nevirapine regimen is being considered for some ongoing and planned studies.
15. Do these results have implications for the recommended antiviral drug treatments in the United States and other industrialized countries?
    In 1998, the U.S. Public Health Service recommended that HIV-infected women be offered antiviral therapies that are standard for HIV-infected adults. For many women, these consist of combination antiviral regimens that include zidovudine. The HIVNET 012 findings do not address whether nevirapine would give additional benefit beyond the standard HIV treatment and obstetrical practices used in the United States. An ongoing study being conducted in the United States and Europe (Pediatric ACTG 316) is evaluating whether adding nevirapine to standard of care regimens will provide added benefit in preventing maternal-infant HIV transmission.
16. Does nevirapine prevent or lower transmission of HIV by breastfeeding?
    Breastfeeding of infants is universal in developing countries. The ability of the nevirapine regimen to decrease HIV transmission during pregnancy and labor may be partially offset by an increase in post-natal transmission through breastfeeding. Particularly in settings with high HIV prevalence in women, possible HIV transmission to the infant must be balanced with the known benefits of breastfeeding (nutritional excellence, reduced infant morbidity and mortality). No intervention as yet has been shown to prevent transmission through breast milk other than alternative feeding practices. Most studies indicate that the risk of HIV infection through breastfeeding is highest in the first few months of life. A study in Kenya of mothers who breast fed versus bottle fed showed that breastfeeding raised the risk of HIV transmission by about two-thirds during the first six weeks of life. Based on those data and the HIVNET 012 data, the HIVNET 012 team is planning a study to evaluate the impact of additional doses of nevirapine to breastfeeding infants.

Prepared by:
Office of Communications and Public Liaison
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892-2520

U.S. Department of Health and Human Services
http://www.niaid.nih.gov

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