As the AIDS epidemic nears the end of its second decade, public health experts are sharpening strategies for fighting this deadly disease. They are honing new technologies to prevent infection, including vaccines, drugs and microbicides. Meanwhile, recent findings on how HIV behaves soon after infection may point to improved prevention strategies.
"Family planning managers need to emphasize condoms and continue to build on other proven prevention efforts," says Dr. Willard Cates Jr., FHI senior vice-president of biomedical affairs. In addition to promoting condom use, these proven interventions include preventing other sexually transmitted diseases (STDs), since the presence of other STDs enhances HIV transmission, and counseling clients to reduce the number of sex partners.
Currently, such efforts are often blanketed across populations, an expensive approach. New research suggests that focusing on recently infected people, during the first weeks or months after they acquire HIV, could be an important consideration in prevention strategies.
This early infection period may be the biggest contributor to HIV transmission, says Dr. James S. Koopman, a professor of epidemiology at the University of Michigan. Viral levels are high, AIDS has not yet weakened its new victims, and these recent carriers are likely to be having sex with other high-risk partners. These conditions can lead to an explosion of new infections.1
If people identify their infections early and help public health officials trace their recent sex partners, it can point to infection "hot spots." Then transmission can be curtailed by urging people within these groups to reduce high-risk behavior.
However, doubts remain about how important the early infection period is for HIV transmission through sex. While HIV levels in the blood are clearly higher soon after exposure, viral levels in vaginal or seminal fluids may not be unusually high. Data have not yet clearly shown that people with HIV are more infectious during this period, researchers say.
In spite of these caveats, focusing on the early infection period may still be worthwhile. "Even if it turns out that people are equally infectious over time, it is still in our best interest to catch them early," says Dr. Margaret A. Chesney, co-director of the Center for AIDS Prevention Studies at the University of California at San Francisco (UCSF). "Then we can help them change their behavior so they do not infect others. We can frame being safe and not transmitting the virus as a way of caring for others."
Condoms for life?
Tailoring messages to prevent transmission during the early infection period may also encourage more people to practice safer sex. FHI's Dr. Cates and other experts suggest emphasizing condom use with non-primary sex partners and during the first three months of a new relationship. Reinforcing messages can be given later.2
"When individuals hear 'Wear condoms for life,' they say 'Not me. I cannot even think of that,'" Dr. Cates says. "But if you say 'Wear condoms for a short period, then get tested,' they may build a habit that continues."
Dr. Cates cautions that such a theoretical approach has not yet been rigorously tested. Moreover, it may result in adverse consequences, such as giving people a false sense of security, he says. However, he says, new ways to encourage increased condom use should be tried and evaluated.
Another approach to prevention offers people at risk of infection a series of choices to fit their own circumstances. The New York State Department of Health suggests these options (in order of preference) for women at risk of HIV: use a latex male condom or female condom with spermicide; use a latex male condom or female condom without spermicide; use a diaphragm with spermicide; or, as a last resort, use a spermicide alone.3
Whatever the message, counseling for HIV-positive people must be culturally sensitive and protect individual rights, says Dr. Chesney of UCSF. "Once they have been notified they are HIV-positive, people need to be assisted in deciding how to disclose this to others and how to access care," she says.
Early treatment
In addition to improving ways to prevent transmission, research is seeking better treatment for those who do become infected. Scientists once thought that HIV entered the body and, soon after, became dormant until AIDS developed years later. Recent research shows that the virus follows a different pattern of invasion. First, HIV infects immune system cells, which carry it to the lymph nodes. There, viruses establish base camps, churning out billions of copies of themselves daily.
Eventually, the immune system fights back. It produces antibodies and uses other defenses to bring viral levels down to an equilibrium, or "set point." The higher the viral load at this point, the faster the disease will progress. Thus, if drug treatment can be offered early, it should lower the set point and prolong life.
The main obstacle to treating HIV-positive people soon after infection is that many do not know they carry the virus. This lack of knowledge is due to viral biology, available testing methods for infection and other conditions.
Because HIV often exists in the body for a long time without symptoms, infection may not become apparent until diseases associated with AIDS develop. In the meantime, HIV-infected people pass the virus to their sex partners unintentionally.
In addition, most HIV tests detect antibodies, not viruses. These tests may not register positive for up to six months after a person becomes infected.
HIV testing is not available in many parts of the world. Even in countries where HIV tests are free and anonymous, some people who fear they may have been infected will choose not to be tested. They may make the choice because of the stigma associated with AIDS, or because the disease has no cure and treatment is expensive but not always very effective.
New advances may help to dismantle these roadblocks. Recently, researchers have noticed that many people exposed to HIV suffer an acute illness similar to mononucleosis within two to six weeks after infection.4 Rashes on the upper part of the body, ulcers in the mouth or on the genitals, gastrointestinal distress, or even some AIDS-related disorders can develop, making early diagnosis possible.
Other scientists are working on tests that could accurately identify people with early HIV infections sooner, says Dr. Robert Janssen, acting director of the HIV/AIDS prevention-surveillance and epidemiology division of the U.S. Centers for Disease Control and Prevention (CDC). These new tests may be easier to use in the developing world.
Also, new treatment regimens may make early HIV testing less discouraging. For example, combination therapy uses two or more drugs to strike the virus at different points in its life cycle, reducing HIV to very low levels in the body while also making it more difficult for the virus to develop drug resistance. Such treatment may prolong life and reduce infectiousness, a crucial step in slowing the epidemic. In developing countries, however, this expensive therapy is not expected to become widely available.
Microbicides
While early intervention may slow the AIDS epidemic within specific populations, vaccines, microbicides and other drugs are being added to the arsenal for HIV prevention in individuals. Most are years away from becoming widely available, but anti-viral compounds already offer hope to pregnant HIV-infected women (see article, page 29).
Currently, the most promising approach uses zidovudine (AZT) in a prescribed regimen to help pregnant women prevent HIV transmission to their developing fetuses. Researchers have also tried washing women's birth canals with the microbicide chlorhexidine during labor, but the treatment did not lower HIV transmission rates, except in women whose membranes ruptured more than four hours before delivery.5
Despite the disappointment with chlorhexidine in the perinatal trial, other microbicides are being explored for HIV prevention. They would be appealing because women would have better control over initiating their own protection, whereas male condoms require a man's cooperation.
Microbicides can theoretically prevent HIV infection by killing or inactivating the virus, by preventing its entry into tissues, or by preventing viral replication.6 While many microbicides are being tested, new ones probably will not be available on the market for at least five years, says Christiana Coggins, a staff associate at the New York-based Population Council.
Currently, the main candidate microbicide is N-9, a spermicide that potentially prevents gonorrhea and chlamydia. Four U.S. Food and Drug Administration (FDA) advisory committees recently voted that the agency should consider calling for label changes to reflect the spermicide's effectiveness against these sexually transmitted diseases (STDs). It is not clear whether N-9 prevents HIV transmission directly, but concurrent STD infections increase transmission of the virus, so preventing them could reduce its transmission.
FHI researcher Ron Roddy is examining whether N-9 blocks HIV transmission directly in a study of 1,300 commercial sex workers in Cameroon. Half of the women were given vaginal contraceptive film containing N-9, while the other half were given placebo film. Both groups received condoms and were followed for at least one year. Their rates of HIV infection will be compared, and the results should be available this year. Other trials are being done with Advantage-24, an N-9 gel that coats the vagina and cervix and theoretically works for 24 hours.
One concern about N-9 is that it is a detergent. When used frequently, it causes vaginal irritation that could facilitate HIV transmission. The N-9 studies include vaginal exams to see whether such irritation occurs.
Non-detergent microbicides might also prevent HIV transmission. In the United States, the National Institutes of Health is testing compounds that buffer vaginal pH. Future tests may expand to India, Thailand, Zimbabwe and Malawi.
The vagina usually has an acidic pH of between 4 and 5, which inactivates or retards viral and bacterial activity. When semen is present, however, the pH increases to a neutral 7, a state much more amenable for microbes. The acid-buffering microbicides lower the pH even in the presence of semen. This shift may block HIV transmission.
While many microbicide candidates are also spermicides, the Population Council is testing compounds, including sulfated polymers, that allow sperm to survive. "These would be useful for women whose partners are HIV-positive and who want to conceive," says Coggins of the Population Council. "They would also be suitable for women who are in a part of the world where it is not culturally acceptable to contracept."
Vaccines
Several vaccines are in different stages of testing for HIV prevention. Some of the trials will be conducted within the HIV Network for Prevention Trials (HIVNET), a system of clinical trial sites to evaluate promising HIV prevention interventions, including vaccines. FHI manages the international arm of HIVNET.
Developing a vaccine is particularly challenging for several reasons, says Dr. José Esparza, vaccine development advisor for the Joint United Nations Programme on HIV/AIDS (UNAIDS). First, researchers do not yet know which immune system weapons protect best against HIV. Second, the virus consists of many strains, and scientists are uncertain whether a vaccine made against one will work against another. Third, research results from animal studies may not correspond with how a vaccine would perform among humans.
Most of the vaccines being tested are made against strains found in the United States and Europe. "We have to increase our efforts in developing countries," Dr. Esparza says. "There is a sense of urgency."
One of the most promising vaccine strategies, known as ALVAC-HIV/gp-120, establishes two lines of defense against the virus, says Dr. Zeda Rosenberg, a senior scientist for adult prevention research in the AIDS division of the National Institute of Allergy and Infectious Diseases. The first line is vaccination with canarypox virus, which enters human cells but does not reproduce well there. The virus contains HIV genes whose protein products prime the immune system to fight HIV-infected cells. The second line of defense is a vaccination with gp-120, an inactive portion of HIV's protein coat. It causes the immune system to produce antibodies aimed at identifying and attacking HIV.
Plans are underway in Uganda to test the ALVAC-HIV canarypox vaccine alone. Researchers from Case-Western Reserve University in the United States hope to see if a vaccine made from subtype B of HIV (the predominant strain in the U.S. and Europe) will stimulate an immune response among populations primarily exposed to subtypes A and C (the dominant strains in Africa).
Other vaccines under development contain gp-120 or other viral coat proteins alone, or DNA from HIV. These vaccines are in phase I or phase II trials to study their safety and ability to induce virus-specific immune responses. However, none has moved to large-scale clinical trials. Candidate vaccines made with whole, inactivated HIV or with altered, live HIV are being tested in animals.
Preventing HIV transmission completely is the goal of vaccine development, but some researchers have suggested that a vaccine decreasing viral infectiousness would be just as useful, on a population-wide scale. For the vaccinated individual, this approach might also delay or prevent onset of AIDS even if the person becomes infected with HIV.
"If you have a vaccine that causes an immune response early [thus reducing viral levels], that will stop transmission," says Koopman of the University of Michigan. "Vaccines can stop the epidemic. Even if they do not prevent an individual from getting infected, they may prevent him or her from infecting others."
-- Carol Lynn Blaney
Carol Lynn Blaney, a former Network staff writer, is a science writer based in San Jose, CA.
References
- Koopman JS, Jacquez JA, Welch GW, et al. The role of early HIV infection in the spread of HIV through populations. Unpublished paper. University of Michigan, 1996.
- Cates WC, Jr., Chesney MA, Cohen MS. Primary HIV infection: A new public health emergency? Unpublished paper. Family Health International, 1996.
- Cleary J. Female Condom: Efficacy, Acceptability and Relationship to the Women's Hierarchy of Risk Reduction. Albany, NY: NY State Department of Health, 1994.
- Jolles S, Kinloch de Loes S, Johnson MA, et al. Primary HIV-1 infection: A new medical emergency? BMJ 1996;312:1243-44.
- Biggar RJ, Miotti PG, Taha TE, et al. Perinatal intervention trial in Africa: Effect of a birth canal cleansing intervention to prevent HIV transmission. Lancet 1996;347:1647-50.
- Elias CJ, Coggins C. Female-controlled methods to prevent sexual transmission of HIV. AIDS 1996;10(suppl. 3):S43-S51.
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