AIDS - Treatment

Anti-HIV Drugs The diagram above shows (1) the virus entering the cell, (2-3) conversion of viral RNA to DNA using the enzyme reverse transcriptase and incorporation of the viral genome into the DNA of the host cell, (4) viral proteins cleaved by protease for assembly of new viral particles, (5) new virus particles budding from the surface of the host cell. It also shows the steps in the viral life cycle that are interrupted by (A) reverse transcriptase inhibitors and (B) protease inhibitors.

AIDS Deaths in the United States from January 1986 to June 1998 Estimates Adjusted for Reporting Delays Data Reported to CDC through December 31, 1998 The increased use of potent combinations of anti-HIV drugs has led to a significant decline in AIDS deaths in the United States in the past 2 years.

Background

HIV/AIDS, chlamydial infection, gonorrhea and other sexually transmitted diseases (STDs) are among the most common diseases reported to the Centers for Disease Control and Prevention (CDC). More than 14 million people in the United States get STDs each year and, at current rates, at least one person in four will contract an STD at some point in his or her life. HIV infection 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 3 million new HIV infections occurred worldwide during 1996.

Women bear the brunt of the HIV/STD burden. Worldwide, HIV infections are increasing most rapidly among women, who contract the virus primarily through heterosexual contact. Between 1985 and 1995, AIDS cases among women in the United States increased nearly three-fold, and AIDS is now the third leading cause of death among women ages 25 to 44 in this country and the leading cause of death among black women in this age group.

Women are also biologically more susceptible to certain STD pathogens than men, 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. Low birth weight or premature birth may complicate between one-quarter and one-half of pregnancies in acutely infected women. Approximately one- to two-thirds of infants of acutely infected mothers become infected with STD pathogens in utero or during childbirth.

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.

Topical Microbicides

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 that women can apply intravaginally before having sex. Known collectively as topical microbicides, 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 should be formulated both with and without contraceptive properties, so women’s reproductive decisions do not affect their risk for HIV/STD infection.

NIAID Research

The development of safe, effective, female-controlled topical microbicides is a central focus of NIAID’s HIV/STD research program. NIAID funding for topical microbicide research has more than doubled in recent years, increasing from $5.3 million in 1994 to $12.2 million in 1996. The Institute's research program reflects five goals that are necessary for developing safe and effective topical microbicides:

• Define the molecular basis and chronology of the early steps in the infectious process.

• Define vaginal and cervical ecology and the natural defense mechanisms of the female reproductive tract.

• Evaluate candidate topical microbicides through laboratory and pre-clinical testing strategies.

• Establish the safety and effectiveness of promising compounds in controlled clinical trials.

• Develop effective behavioral interventions to ensure the acceptance and use of topical microbicides.

Central to NIAID’s research efforts are Topical Microbicide Program Projects at four U.S. institutions. These multi-year projects address a variety of basic and clinical research questions. 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.

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.

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 vaginal 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.

Scientists at the University of Pittsburgh are evaluating a number of synthetic and naturally occurring microbicides in laboratory and clinical 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. Clinical trials are under way to determine whether use of these suppositories can reduce women’s risk of gonorrhea and bacterial vaginosis.

HIVNET Studies

In addition, NIAID is sponsoring a clinical trial of another new microbicidal product at Memorial Hospital in Providence, Rhode Island, one of NIAID’s HIV Network for Prevention Trials (HIVNET) sites. Researchers are evaluating the safety of an acid-buffer gel, a compound designed to maintain the vagina’s mild acidity. Scientists believe this acidic environment is hostile for HIV and other sexually transmitted organisms.

Semen is very alkaline and raises the pH in the vagina to levels that are more hospitable to HIV and other sexually transmitted pathogens. Scientists hypothesize that the acid-buffer gel should counteract the alkalinity of semen and keep the vaginal pH low enough to kill pathogenic microbes. Depending on the results of this study, further studies are planned for sites in Asia and 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 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 investigation in Kenya is testing whether a vaginal gel containing N-9 affects the transmission of HIV or other microbes.

Barriers to HIV/AIDS Treatment and Treatment Adherence Among African-American Adults with Disadvantaged Educations