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Date: Monday, May 6, 1996 FOR IMMEDIATE RELEASE Contact: Robert Bock (301) 496-5133
A recent study has found that rhesus monkeys given the hormone progesterone are more likely to become infected after vaginal exposure to simian immune deficiency virus (SIV) than are monkeys that have not been given the hormone. The finding was reported today at a clinical research meeting in Washington, DC. Rhesus monkey infection with SIV is an experimental model for human infection with the human immunodeficiency virus (HIV), which causes AIDS. The finding raises the possibility that contraceptives containing progestins may cause vaginal changes that might increase the risk of infection for women exposed to HIV. However, the study's authors caution that it is still too early to know whether the results of this animal study will hold true for human beings, and additional studies need to be undertaken.
"This is only an animal study, and while the study is important, its primary value is to determine the direction of future research," said Dr. Duane Alexander, Director of the National Institute of Child Health and Human Development, the agency which funded the study. This finding does not change any U.S. Public Health Service Recommendations, which make clear that only sexual abstinence or use of a latex condom, consistently and correctly, can protect against AIDS transmission. The U.S. Food and Drug Administration already requires that non-barrier contraceptives must include labeling stating that they do not provide protection against HIV infection.
Dr. David Satcher, the Director of the Centers for Disease Control and Prevention, stressed that any woman who wishes to control fertility and has found a suitable contraceptive method should continue it. But he emphasized that only abstinence or latex condoms can prevent sexual transmission of HIV.
"Under any circumstances, a woman who is sexually active should take precautions to protect against HIV infection," Dr. Satcher said. "Abstinence from sexual activity is the safest strategy. For individuals who choose to be sexually active, using latex condoms consistently and correctly during each act of intercourse is a highly effective prevention strategy."
The authors of the study have submitted the paper for early publication. The finding was presented today at the annual meeting of the American Society for Clinical Investigation and the American Federation for Clinical Research, in Washington, DC, by the principal investigator Dr. Preston Marx, a researcher at the Aaron Diamond AIDS Research Center, and a professor at the New York University School of Medicine.
Progesterone is naturally produced in the ovaries and other organs. Synthetic forms of the hormone are the active ingredients in such long-acting contraceptive preparations as Depo-Provera and Norplant . Synthetic progestins are also an ingredient in oral contraceptives, although the study reported today involved implanted progesterone pellets, not oral ingestion.
Synthetic progestins generally have pharmacologic effects similar to those of progesterone, but they differ chemically from the natural form of the hormone. Moreover, blood levels of progestins that result from administration of the various forms of hormonal contraception differ significantly from the levels of progesterone in the blood of the monkeys during the study.
It is not known how these differences might have affected the results of the study or their relevance to women who use long-acting or other hormonal contraceptives.
The study was conducted because of concern that hormonal contraceptives might influence the risk of infection among women exposed to HIV. Overall, the human evidence to date is inconclusive. Unpublished preliminary CDC studies in Thailand have not shown a significantly increased infection rate in women using hormonal contraceptives, compared to those not using any method of contraception. The monkey model offered a way to study the question of HIV transmission in a carefully controlled manner that would be impossible to do in human subjects.
For the current study, twenty-eight monkeys were divided into two groups, with 18 in the progesterone-treated group and 10 in the placebo group. An identical dose of SIV was administered into the vagina in both groups. Monkeys implanted with progesterone pellets under the skin on their backs prior to SIV exposure had a high rate of infection when vaginally inoculated with SIV, i.e., 14 out of 18 were infected, compared to 1 in 10 in the placebo group.
The study authors said that a possible reason for the enhanced infectivity for the progesterone-treated animals was that the vaginal epithelium--the protective lining of the vagina--was significantly thinner in the progesterone group than in the placebo group. These are the first data to indicate that treatment with a large dose of progesterone results in increased rates of infection with SIV.
The SIV-monkey model has provided insight into transmission of HIV, but the researchers stressed that while an animal model can provide useful information, the result is not immediately transferable to humans.
Some epidemiologic studies are under way and others are being designed to determine if there is an increased risk of sexual transmission of HIV in women who use hormonal contraception. Other NIH-funded research is under way to develop topical microbicides for vaginal use to prevent the spread of AIDS and other sexually transmitted diseases.
"We are moving as quickly as possible to follow up on these research findings," Dr. Alexander said. "We need to understand the transmission mechanism that is apparently at work in these cases, and we need to determine whether it may be applicable to humans."
As part of this effort, the NICHD, together with NIAID and the Office of AIDS Research, are convening a research planning workshop on June 6 at the NIH. At this workshop, leading research scientists will review the current status of epidemiologic studies on this topic and develop specific plans for the studies to be initiated.
The research was conducted at the Aaron Diamond AIDS Research Center in New York City, and New York University Medical Center's Laboratory for Experimental Medicine and Surgery in Primates in Tuxedo, NY. Partial funding for the study was provided by the Contraceptive Research and Development (CONRAD) Program of the Eastern Virginia Medical School, under a cooperative agreement with the United States Agency for International Development, which in turn receives funds for AIDS research from an interagency agreement with the National Institute of Child Health and Human Development, one of the National Institutes of Health (NIH).
Additional funding was provided by the National Institute of Allergy and Infectious Diseases and the National Center for Research Resources, both part of the NIH.
Authors of the study were Preston A. Marx, Alexander I. Spira, Agegnehu Gettie, Peter J. Dailey, Ronald S. Veazey, Andrew A. Lackner, C. James Mahoney, Christopher J. Miller, Lee E. Claypool, David D. Ho and Nancy J. Alexander.
Questions and Answers: Animal Study on Progesterone and SIV
Q: What were the results of this study?
A: The study found that monkeys implanted with long-acting pellets of progesterone are more likely to become infected after vaginal exposure to simian immune deficiency virus (SIV) than are monkeys that have not been given progesterone.
Q: What is progesterone?
A: Progesterone is the naturally occurring form of a class of steroids known as progestins. Progesterone is primarily produced in the ovaries.
Q: Is progesterone contained in birth control pills?
A: No, synthetic progestins are used in these preparations.
Q: What is the relationship of progesterone to the steroids used in contraception?
A: Progesterone is the naturally occurring form of a class of hormones known as progestins. The pharmacological effects of synthetic progestins differ somewhat from progesterone. Thus we must be very careful in translating the data observed in the present study to what may happen to women using the various steroidal contraceptives. Moreover, not only does progesterone differ from the synthetic progestins, but the progestins differ among themselves.
Q: The authors indicate that the vaginal epithelium of progesterone treated monkeys was thinner than that of placebo-treated animals. What is known about this phenomenon from studies in monkeys and women?
A: A number of studies in monkeys indicate that the vaginal epithelium of animals undergoes changes in thickness during various phases of the menstrual cycle. It is thickest prior to ovulation and thins out prior to menses. In animals treated with progesterone and synthetic progestins, thinning of the epithelium has been reported. A similar effect is noted in women, however. the situation is more complex. In women, menstrual cycle changes in the vaginal epithelium have been observed and are similar to what has been reported in monkeys. During pregnancy, thinning of the vaginal epithelium has been observed after the first trimester. Thinning is also observed during lactation. While vaginal thinning in this animal study was associated with increased infection rates of SIV, it may not be the only mechanism or even the most critical mechanism for infection. Other possible co-factors are changes in the immune system or changes in cervical mucus.
Q: What kind of research is planned to determine possible progestin effects of the vaginal epithelium of women and HIV infection?
A: Studies are under way to evaluate the thickness of the vaginal epithelium of women with normal menstrual cycles and women using various hormonal regimens. This will provide information on changes that may occur in the vaginal epithelium as part of the normal menstrual cycle and on any changes that may occur with use of various types of hormonal contraception. These studies are expected to be completed in a year. Even more definite information will be available from epidemiologic studies of large populations of women, following those who are using various hormonal contraceptives and observing rates of infection with HIV. Some of these studies are under way; others are in the planning phase. These are inevitably long term studies taking several years to complete.
Q: How do the progesterone levels of the treated monkeys compare with the levels of progestins used in injectable or implantable contraceptive methods?
An exact comparison cannot be made. Progesterone, the natural hormone, differs structurally from the synthetic progestins used in contraceptive preparations. Synthetic progestins generally have pharmacologic effects similar to those of progesterone. However, it is not known whether the use of the synthetic compounds in the study would have produced the same results as did using progesterone. Similarly, because synthetic progestins differ in strength from progesterone, blood levels of these drugs cannot be directly compared to blood levels of progesterone. To be an effective long acting contraceptive, Depo Provera is given in a large dose which creates high initial levels of the drug for a few days after injection but then declines sharply. With the implant Norplant , blood levels of the drug are much lower, and decline slowly over time. In contrast, the progesterone implants provided steady levels of blood progesterone for about 30 days, before the animals received new implants. It is not known how these differences could have affected the results of the study or their relevance to women on long-acting contraceptives.
Q: Do we know whether the rate of infection with SIV differs according to the stage of the menstrual cycle?
A: Studies comparing infection rates at various times of the menstrual cycle are under way. Preliminary data in monkeys suggest that vaginal exposure to SIV in the second half of the menstrual cycle (after ovulation) results in higher virus levels in the blood.
Q: Do the results of this study apply to women?
A: The SIV-macaque system is an excellent animal model for the study of the AIDS virus. However, the results of even the best animal studies cannot be immediately applied to humans. The results of the current study merely provide basic information that points to the need for further studies.
Q: Should women on implantable or injectable forms of progestin-based contraceptives or taking oral contraceptives containing a progestin discontinue the method, based on the current finding?
A: Any woman who wishes to control fertility and has found a suitable contraceptive method should continue it. However, contraceptives other than latex condoms, while effective at controlling fertility, cannot prevent the of HIV. Any woman at risk for the AIDS virus or any other sexually transmitted disease should take proper precautions. Besides abstinence, the only effective way to help prevent transmission of HIV or any other sexually transmitted disease is with a latex condom.
Q: Should women be afraid that their contraceptive is making them more susceptible to AIDS transmission?
A: We do not know if any contraceptive makes a woman more vulnerable to AIDS. However, any risk of AIDS is very serious and any indication of a contraceptive increasing that risk raises concern. Most women are not at risk for AIDS, but any woman who is sexually active outside of a relationship with a monogamous, uninfected partner or who is uncertain if her partner is monogamous, needs to take precautions and the use of a latex condom correctly and consistently in such cases is advised. Non-barrier contraceptives are designed to prevent pregnancy; they are not designed to protect against sexually transmitted diseases, including AIDS. The labeling for such contraceptives clearly states that they do not protect against sexually transmitted diseases.
Q: How many women are on long-acting, progestin-based contraceptives?
A: Approximately 1 ? to 2 million women in the United States are currently using Depo-Provera and over 30 million women world-wide have used this contraceptive since it was made available in the late 1960s. More than 1 million women are on Norplant in the United States; 4 million women world-wide use this preparation.
Q: How many women have AIDS in the United States?
A: As of 1995, the Centers for Disease Control and Prevention receivedreports of 75, 191 cases of AIDS among adult and adolescent women (age 13 and older). AIDS is increasing faster in women than it is in men. In 1985, women accounted for 7 percent of all AIDS cases in 1985, but jumped to 18 percent of cases in 1994. Heterosexual contact is the most rapidly increasing category for women.
Q: Should women using progestin-based contraceptives take special precautions?
A: All women who are at risk for sexually transmitted diseases are warned to take precautions. Only latex condoms can protect against sexually transmitted diseases and HIV infection. Regardless of the contraceptive method used, this advice is important. Before discontinuing an acceptable and useful contraceptive, there are also serious consequences related to pregnancy that need to be considered.
Q: What are you doing about these study results?
A: We have reviewed the study results with the principal investigator, Dr. Marx, together with experts in reproductive biology and AIDS to consider the implications of the research. These discussions have included scientists who are expert in animal models and gynecologists to compare the animal model to that of the human. Other completed and on-going studies relevant to this issue have been reviewed. Meetings have been held with officials of other government agencies, and officials of outside organizations have been informed of the results. The authors of the study worked with us to submit the paper rapidly for publication and for presentation at the American Society for Clinical Investigation and the American Federation for Clinical Research on May 6, 1996, in Washington, DC. To consider future research needs in light of these findings, the NICHD, together with NIAID and the Office of AIDS Research, are convening a research planning workshop on June 6 at the NIH. At this workshop, leading research scientists will review the current status of epidemiologic studies on this topic and develop specific plans for the studies to be initiated.