UW Researchers Play Key Role in Trials to
Prevent Spread of HIVThomas R. Fleming
Steven G. SelfThe human immunodeficiency virus (HIV) pandemic continues to grow by recent World Health Organization (WHO) estimates, more than 20 million persons have been infected - more than 4.5 million have developed AIDS. An estimated 6,000 new infections occur each day. WHO predicts that by 2000, 30 to 40 million persons will have been infected.
For more than a decade, extensive efforts have been made to develop effective treatment for HIV/AIDS patients. Until recently, antitretroviral therapies provided only short-term benefits. Unfortunately, viral resistance typically developed within one year and resulted in increased viral loads, declining concentrations of immune cells, and higher risk of symptomatic AIDS events. For these immune-suppressed patients, useful interventions have been found to offer prophylaxis for symptomatic disease. Even if the new treatment regimens that include protease inhibitors prove to eradicate HIV in some persons, they are expensive, toxic, and often incompatible with other drugs.
Despite therapeutic advances, it is unrealistic to expect curative treatment for this disease in the foreseeable future. As with other major life-threatening conditions, prevention research appears to provide the greatest hope for achieving major public health benefits. To address this challenge, a broad-based, integrated approach involving basic science and empiric research is required to develop and evaluate interventions to prevent the spread of HIV.
In 1993, the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID) established the HIV Network for Prevention Trials (HIVNET). The primary mission of HIVNET is to conduct domestic and international multicenter clinical trials to evaluate the safety and efficacy of promising interventions to prevent sexual, perinatal, and parenteral transmission of HIV. The University of Washington School of Public Health and Community Medicine has a significant role in this effort.
HIVNET's Structure and Research Agenda
Domestic SettingThe demographics of the HIV pandemic have greatly influenced the configuration of HIVNET and its research agenda. In the United States, more than one million persons have been infected with HIV More than half have developed AIDS. Of U.S. adults and adolescents with AIDS in 1995, 81% were male with more than 90% infected through homosexual contact or injection of illicit drugs. Among women, about two-thirds were infected through drug injection or heterosexual contact with an injecting drug user (IDU), and nearly one-third through heterosexual contact. In 1995, 54% of men and women reported with AIDS were African-American or Hispanic.
Across the United States, eight sites, including one at the University of Washington, were awarded contracts by HIVNET to recruit participants to vaccine preparedness cohorts. These cohorts of participants at high risk for HIV infection (at least 2% annual risk) are predominantly from the risk groups of men having sex with men or from IDUs, and have significant components of ethnic/racial minorities. In turn, these participants will also be eligible for clinical trials of vaccines, rectal microbicides, and behavioral interventions.
International Setting
The dynamics of the HIV pandemic are strikingly different in many other countries. In many populations in sub-Saharan Africa, where 11 million persons are living with HIV, and in South and Southeast Asia, where three million adults are infected and where HIV is spreading fastest, annual incidence rates are well over 10%. The Caribbean and Latin America have also been hard hit by the pandemic. Unlike in the United States, the spread of HIV among adults in these countries is predominantly through heterosexual contact.
In turn, with the prevalence of HIV exceeding 20% among women of reproductive age in many of these populations, 1.5 million children have been infected perinatally HIVNET has awarded contracts to nine international sites: Kenya, Malawi, Senegal, Uganda, Zimbabwe, India, Thailand, Brazil, and Haiti (Figure 1). In these countries the need for preventive health care is great and high incidence rates, ranging from 4% to greater than 12%, permit efficient trial designs. The participants will engage in international trials evaluating vaccines, vaginal microbicides, and behavioral and perinatal interventions.
School of Public Health and Community Medicine faculty collaborate with investigators from Kenya in conducting research efforts at that site. The principal investigator at the Kenya site is Joan Kreiss, while Harold Martin provides field site epidemiological leadership.
HIVNET Prime Contractors
In addition to the eight domestic and nine international field sites, HIVNET has four prime contractors. Two on the East Coast are responsible for recruitment and for administrative and scientific supervision of domestic and international field sites. A contractor in California is responsible for the development, standardization, and evaluation of laboratory assays from HIVNET trials. The Fred Hutchinson Cancer Research Center and the University of Washington are collaborating as contractors for the Statistical and Clinical Coordinating Center (SC), which provides statistical collaboration in the design, data management, and general conduct, analysis, and reporting of HIVNET studies. Epidemiologist Cathy Critchlow and biostatisticians Thomas Fleming, Patrick Heagerty, Barbara Richardson, and Steven Self participate in this work.
Figure 1:HIVNET primary contractors (top row of boxes) and domestic and international study centers.
HIVNET's Accomplishments and Future
The responsibilities for development of the science direction within HIVNET, clinical trial concept plans, and corresponding study protocols essentially are handled by four Scientific Direction Working Groups organized around areas of HIV vaccines, prevention of perinatal transmission, topical microbicides and STD treatments, and behavioral interventions.HIV Vaccines
An effective HIV vaccine may have the greatest potential for helping to control the HIV pandemic. HIVNET is prepared to evaluate promising vaccines. In the United States, HIVNET has enrolled 4,892 participants (gay men, injection drug users, and women at heterosexual risk) who are at high risk of HIV infection. Evaluation of these subjects is providing valuable insights about incidence rates, cofactors; for transmission to guide development of behavioral interventions, participant willingness to join a randomized vaccine trial, and efficient methods to rapidly recruit and retain subjects. With similar scientific goals, the nine international HIVNET sites have studied more than 8,000 subjects in cohorts of female commercial sex workers, gay men, patients at sexually transmitted disease (STD) clinics, long-distance truck drivers, factory workers, and pregnant women.
One promising vaccine concept is receiving preliminary testing of immunogenicity and safety if results are favorable, HIVNET could proceed with a randomized controlled trial of efficacy of this HIV vaccine in the United States in 1998. In addition to U.S. studies, the HIVNET has been assessing the safety and immunogenicity of a vaccine in Uganda.
Prevention of Perinatal Transmission
Perinatal transmission is an important source of HIV disease in developing countries. In a U.S. trial, antiretroviral therapy administered prior to and at delivery substantially reduced transmission of HIV from mother to infant. However, cost and limited access to prenatal care preclude implementation of this approach in developing countries. A priority is to identify effective antiretroviral therapies that can be administered over a shorter course (e.g., at delivery) and at reduced cost.
A recently completed clinical study of the safety of nevirapine in infected pregnant women and their newborns in Uganda showed no unexpected safety concerns, so HIVNET will proceed with a placebo-controlled trial in Uganda to evaluate nevirapine and zidovudine (AZT) in preventing perinatal transmission. The HIVNET will consider evaluating other promising antiretroviral drugs, such as protease inhibitors, in prevention trials as soon as initial U.S. safety studies are completed.
Topical Microbicide and STD Treatment
The development of female-controlled methods to protect against sexual transmission is a high priority of HIVNET. The Kenya and Malawi sites are conducting a controlled clinical trial of a nonoxynol-9 (N-9) vaginal microbicide gel for preventing sexual transmission among commercial sex workers and postpartum women. HIVNET also will conduct a series of preclinical trials to establish the safety and acceptability of new topical microbicide products. A recently completed domestic trial examining the safety and acceptability of an acid-buffering gel identified no safety concerns in U.S. participants, so the trial will be extended to the HIVNET sites in Thailand, India, Malawi, and Zimbabwe. The goal of HIVNET will be to complete early clinical testing and move new products into efficacy trials in the next few years.
Microbicides also may be a promising strategy for preventing rectal transmission of HIV Microbicide products such as N-9 have been used extensively by gay men, but their safety and efficacy in rectal use has not been established. HIVNET has completed a clinical study examining the safety of gel containing N-9. Further trials could be proposed for the cohort of U.S. gay men during the next few years.
Behavioral Interventions
Behavioral interventions to promote condom use, STD treatment, and reduction in numbers of sex partners may reduce HIV transmission. However, to date, these interventions have not been evaluated systematically in randomized controlled trials with HIV infection as the primary endpoint. Providing such an evaluation will be a priority of the HIVNET.
In Zimbabwe, a randomized trial is evaluating peer counseling to prevent sexual transmission in factory workers. A clinical study of condom promotion for prevention of heterosexual transmission among stable couples discordant for HIV infection will be conducted in India, Thailand, and Uganda. The domestic HIVNET sites, in conjunction with National Institute of Mental Health investigators, are planning a randomized trial to evaluate an individualized behavioral counseling intervention for gay men to reduce HIV and other STD transmission. HIVNET also is planning a pilot study of postexposure chemoprophylaxis (PEP) following sexual exposure, with possible expansion to an efficacy trial of PEP to be initiated in 1998.
The HIVNET provides a valuable research infrastructure, encompassing a cooperative network of domestic and international sites. This infrastructure is well-suited for developing and conducting multicenter clinical trials of promising HIV prevention strategies. The multicenter feature of HIVNET makes it uniquely capable of conducting large randomized trials using HIV incidence as the primary outcome measure, which is the ultimate step in obtaining a reliable evaluation of any prevention intervention.
Authors
Thomas R. Fleming, Ph.D., is professor and chair of the Department of Biostatistics, UW School of Public Health and Community Medicine; director of the Biostatistics/Epidemiology Core, Center for AIDS Research at the University of Washington; member of the Fred Hutchinson Cancer Research Center; and co-director of the HIVNET Statistical and Clinical Coordinating Center.
Steven G. Self, Ph.D., is head of the Program in Biostatistics at the Fred Hutchinson Cancer Research Center; professor of biostatistics at the UW School of Public Health and Community Medicine; and co-director of the HIVNET Statistical and Clinical Coordinating Center.
Return to the Table of Contents
Created: 3/3/98 Updated: 7/15/99
