NIAID Topical Microbicide Research Developing New Tools to Protect Women from HIV/AIDS and Other STDsDate: March 1, 2000
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)
HIV/AIDS, chlamydial infection, gonorrhea and other sexually transmitted diseases (STDs) are among the most common infectious diseases reported to the Centers for Disease Control and Prevention (CDC). STDs are caused by a variety of contagious microbes that infect more than 15 million people in the United States each year. At current rates, at least one person in four will contract an STD at some point in his or her life. Scientists now believe that people who have STDs are at an increased risk of contracting HIV/AIDS. HIV infection alone represents a considerable portion of the STD problem in this country and abroad. As many as 900,000 Americans are believed to be infected with HIV, and more than 5 million new HIV infections occurred worldwide during 1999.
Avoiding HIV/STD infections often is more problematic for women than for men. Condoms provide good protection against HIV infection and other STDs when used correctly and consistently during sexual intercourse. But condom use ultimately requires the consent and cooperation of the male partner, and women cannot always successfully negotiate their use. Abstinence, the only fail-safe measure against HIV/STD infection, is not always an option for women, since non-consensual sex is an all-too-common reality. Just as oral contraceptives dramatically enhanced the ability of women to avoid unwanted pregnancy, effective female-controlled strategies are urgently needed to enhance the ability of women to avoid HIV and other STDs. Although antibiotics are available to treat STD infections, microbes are becoming resistant to these drugs, forcing researchers to develop newer, stronger antibiotics to fight the infection. In some cases, drugs can help control symptoms but cannot eliminate the microbe from the body, such as in herpes virus and HIV infections.
Women bear the brunt of the HIV/STD burden. Worldwide, HIV infections are increasing most rapidly among women, who contract the virus primarily through sex with an infected male partner. Between 1985 and 1996, AIDS cases among women in the United States increased threefold, and AIDS is now the fourth leading cause of death among women ages 25 to 44 in this country.
Women are also biologically more susceptible than men to certain STD pathogens, and they experience more asymptomatic STD infections. These "silent" infections often go untreated, and consequently, women suffer more frequent and more severe STD complications. For example, pelvic inflammatory disease (PID) affects more than 1 million women in the United States each year, and cervical cancer caused by infection with human papillomavirus kills more than 4,000 women annually in this country.
STD infections also commonly cause problems during pregnancy and delivery. Some STDs can spread into the uterus and fallopian tubes, causing pelvic inflammatory disease, which can result in infertility or ectopic (tubal) pregnancy. Between one-quarter and one-half of acutely infected pregnant women give birth to low-weight or premature infants. And approximately one- to two-thirds of infants of acutely infected mothers become infected with STD pathogens while in the womb or during childbirth.
To meet the reproductive health needs of women, researchers increasingly have focused on the development of virus- and bacteria-killing gels, foams, creams or films, known collectively as topical microbicides, that women can apply intravaginally before having sex. These products work by killing the STD pathogen upon entering the body or by creating a barrier to the pathogen, blocking its ability to enter or bind with cells. These products could give women greater control over their risk for exposure to sexually transmitted pathogens. Ideally, microbicides should be unnoticeable, so they can be used without a male partner's knowledge, if necessary; fast-acting against HIV and a broad range of other STD pathogens; inexpensive; and safe for use at least one to two times daily. In addition, microbicides with and without contraceptive properties should be formulated so women's reproductive decisions do not affect their risk for HIV/STD infection. Although microbicides are intended for use by women, effective products will prevent infection in both partners.
The development of safe, effective, female-controlled topical microbicides is a central focus of NIAID's HIV/STD research programs. These programs span basic science through discovery and preclinical development to clinical trials. NIAID funding for topical microbicide research has increased significantly in recent years, from $12.2 million in 1996 to an estimated $20.5 million in 2000. The Institute's research program reflects five goals that are necessary for developing safe and effective topical microbicides:
1. Define the molecular basis and chronology of the early steps in the infectious process.
2. Define vaginal and cervical ecology and the natural defense mechanisms of the female reproductive tract.
3. Evaluate candidate topical microbicides through laboratory and preclinical testing strategies.
4. Establish the safety and effectiveness of promising compounds in controlled clinical trials.
5. Develop effective behavioral interventions to ensure the acceptance and appropriate use of topical microbicides.
Central to NIAID's research efforts are Topical Microbicide Program Projects at six U.S. institutions. These multi-year projects address a variety of basic and clinical research questions.
1. At the University of California, Los Angeles, for example, scientists are investigating protegrins, naturally occurring protein fragments with antibiotic properties. In laboratory experiments, researchers assess the activity of various protegrin formulations against HIV and pathogens causing gonorrhea, chlamydial infection, syphilis, genital herpes, and trichomoniasis.
2. A research team at the University of Cincinnati's Children's Hospital Medical Center studies the microbicidal potential of over-the-counter spermicides as well as newly developed products. They also are exploring the disease-causing mechanisms of herpes simplex virus, chlamydia bacteria, and HIV, to gain a better understanding of the properties that microbicides must possess to prevent infection with these pathogens.
3. At Pennsylvania State University's Hershey Medical Center, NIAID-supported scientists are developing a system to predict the safety and effectiveness of microbicides in clinical trials. They have developed an animal model in which human tissue has been grafted onto mice. Ultimately, the scientists will use the model to determine if experimental topical microbicides can destroy STD pathogens without harming the vaginal tissue.
4. Scientists at the University of Pittsburgh are evaluating a number of synthetic and naturally occurring microbicides in laboratory studies. Researchers recently discovered a correlation between lactobacilli, a type of bacteria that can occur naturally in the vagina, and protection from gonorrhea, bacterial vaginosis, and HIV infection. Lactobacilli produce hydrogen peroxide and other microbe-killing compounds. Based on this finding, scientists developed a lactobacillus vaginal suppository that enables these "good bacteria" to grow in the vagina.
5. At Johns Hopkins University, scientists are studying how STD pathogens enter and infect cells, and how the body organizes and deploys antibodies to fight off infection. Products containing antibodies that would block the entry points of STD pathogens are being investigated as potential elements in microbicide candidates.
6. Researchers at Emory University are examining porphyrin compounds that have been shown in previous studies to have antibacterial properties. In addition to antibacterial compounds, scientists are also studying antiviral compounds that might destroy viruses such as the herpes simplex viruses and HIV. In one project, an antiviral compound will be tested in a mucosal primate model for activity against SIV (simian immunodeficiency virus, the primate equivalent of HIV disease in humans). Throughout the course of these studies, researchers will identify and test potential drug candidates in vivo for use in topical microbicides.
The HIV Network for Prevention Trials (HIVNET) was established in 1993 by NIAID's Division of AIDS. HIVNET is a multicenter, collaborative research network that evaluates the safety and effectiveness of promising interventions to prevent the transmission of HIV. NIAID is sponsoring clinical trials of new microbicidal products through several HIVNET sites.
Scientists have recently evaluated the safety and tolerability of an acid-buffering gel, called BufferGel. The gel is designed to help maintain the vagina's normal acidity, thereby disrupting the transmission of acid-sensitive pathogens, such as HIV, that thrive in a more alkaline environment. Researchers conducted the trial in two parts, first in the United States, and then in India, Thailand, Zimbabwe and Malawi, and found that BufferGel was non-toxic and well-tolerated.
In another study, NIAID is evaluating a topical antiviral microbicide called PRO2000. This antiviral compound has been designed to protect cells from infection with HIV by blocking the ability of the virus to bind and fuse with uninfected cells. Test tube studies have shown PRO2000 to be effective in preventing HIV and other STD infections, including genital herpes and chlamydial infection. Study investigators are currently analyzing the safety and acceptability of this product in a Phase 1 clinical trial at four sites in the United States and South Africa.
NIAID also sponsors clinical studies of over-the-counter spermicides containing nonoxynol-9 (N-9). A study of women sex workers in Cameroon recently showed that a contraceptive film containing N-9 had no effect on transmission of HIV/AIDS, gonorrhea or chlamydia infection when provided as part of an overall HIV/STD prevention program.
Another study of N-9 is being conducted through a Phase 3 clinical trial at two sites in Malawi and one in Zimbabwe. The purpose of this study is to investigate whether a vaginal gel containing N-9 can prevent sexual transmission of HIV between heterosexual partners. Researchers project an enrollment of 4,440 HIV-negative women in the study who will receive either the N-9 gel, called Conceptrol, or a placebo. All prospective study participants will receive behavioral counseling prior to enrollment about the importance of consistent and correct condom use.
STD COOPERATIVE RESEARCH PROGRAM
The Sexually Transmitted Diseases Cooperative Research Program is designed to provide multidisciplinary approaches to STD research. The program encourages investigators to work together by bridging basic biomedical, clinical, behavioral and epidemiological research, promoting productive collaborations, and facilitating the development of intervention-oriented research.
The STD Cooperative Research Program currently funds studies at universities in Alabama, Indiana, Maryland, Massachusetts, North Carolina, Pennsylvania and Washington. For example, at the University of Pittsburgh, scientists have developed a suppository that restores normal vaginal bacteria, lactobacilli, to women. These bacteria prevent some infections by secreting hydrogen peroxide, a microbe-killing compound. Phase 2 safety studies have shown the suppository to be safe and tolerable. Scientists plan to conduct a Phase 3 clinical trial to determine the effect of the suppository on bacterial vaginosis.
NIAID, a component of the National Institutes of Health (NIH), supports research on AIDS, tuberculosis and other infectious diseases as well as allergies and immunology. NIH is an agency of the U.S. Department of Health and Human Services.
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