National Institutes of Health, National Institute for Allergy and Infectious Disease - March, 1998

To this end, NIAID established the HIV Network for Prevention Trials (HIVNET) in 1993 to conduct trials of promising HIV prevention strategies in both the United States and abroad.

HIVNET is a cooperative group of investigators who primarily evaluate the safety and efficacy of interventions to prevent the sexual, perinatal and parenteral transmission of HIV. HIVNET's main area of emphasis is vaccines but it also encompasses other interventions: topical microbicides, sexually transmitted disease (STD) treatment, prophylaxis to prevent mother-to-infant transmission and behavioral risk-reduction strategies. To accomplish its main mission, HIVNET supports randomized, controlled clinical trials that use HIV seroincidence as the primary endpoint. HIVNET also conducts a range of other studies, such as baseline seroincidence surveys, that lead to or support prevention efficacy trials.

HIVNET has five components:

• A domestic master contract was awarded in October 1993 to Abt Associates of Cambridge, Mass. Abt subsequently awarded subcontracts to several clinical sites in the United States to evaluate candidate interventions. Currently, there are 11 main U.S. sites and 19 field sites throughout the country.

• An international master contract was awarded in October 1993 to Family Health International (FHI) of Research Triangle Park, N.C. FHI subsequently awarded subcontracts to field sites to conduct intervention trials in populations outside the United States. Currently, there are 13 international field sites in 11 countries.

• A statistical and data coordinating center provides statistical and data management support for the domestic and international trials. In March 1994, NIAID awarded this contract jointly to the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle.

• A central laboratory contract provides laboratory support for specialized testing of populations in the domestic and international trials. In March 1994, NIAID awarded this contract to Public Health Enterprises of Los Angeles, Calif., with the California State Health Laboratory in Berkeley as a subcontractor.

• A specimen repository serves the domestic and international trials. NIAID renewed this contract with Biomedical Research, Inc., of Rockville, Md., in June 1994.

HIVNET studies often engage collaborators at other institutes within the National Institutes of Health and at the Centers for Disease Control and Prevention, the U.S. Army and various national and international health organizations.

To foster trust and mutual understanding of clinical trial issues, and to ensure that the studies respect cultural and ethnic differences among participants, HIVNET has involved community members in all phases of the research process.

Highlights of HIVNET Accomplishments and Future Plans

Vaccine Preparedness Study

The original eight domestic HIVNET sites completed a multicenter Vaccine Preparedness Study (VPS) in April 1997. The VPS was a prospective cohort study designed to recruit and retain volunteers, and estimate HIV-1 incidence over time while conducting risk reduction counseling. In addition to determining the seroincidence in this cohort, the investigators collected data on willingness to participate in a future vaccine trial.

A total of 4,892 participants at high risk for HIV infection (3,257 men who have sex with men, 770 male injection drug users, 354 female injection drug users (IDUs), and 511 women at high risk of HIV infection through sexual contact) were enrolled. Overall, 88 percent of the participants were still in the study after 18 months of follow-up, and seroincidence in that cohort was 1.36 percent. However, HIV-1 seroincidence rates varied significantly by risk category and willingness to participate in a vaccine trial. For example, rates varied from 0.38 percent in male IDUs, to 2.44 percent in women with multiple high-risk sexual behaviors. The study showed that those participants who were definitely willing to enroll in an HIV vaccine trial had the highest seroincidence rate. This study has shown that men who have sex with men and women at heterosexual/injection risk can be rapidly recruited, enrolled and followed under conditions comparable to a preventive HIV vaccine trial. The data from this study will be very important for planning future vaccine efficacy trials.

With the recent addition of more domestic sites, a new VPS study opened in February 1998 to recruit new volunteers from eight main sites. The study will recruit a total of 2,800 participants: 600 men who have sex with men, 525 male IDUs, 225 female IDUs and 1,450 women at high risk for HIV infection through sexual contact.

In addition, recruitment of new IDU cohorts in Philadelphia and New York began in August 1997. Each site will recruit 500 IDUs with eligibility targeted specifically to male IDUs with a higher than average HIV-1 seroincidence.

International Cohort Studies

Activities from 1994 to 1997 in nine HIVNET international sites (five in Africa, two in Asia and two in the Americas) included both international cohort studies and several intervention studies. Overall, the sites recruited and followed more than 15,000 people at high risk for HIV infection (female sex workers, STD clinic patients, truck drivers, factory workers, gay men and pregnant women). The cumulative HIV seroincidence at these sites ranged from less than 1 percent to greater than 12 percent, with follow-up retention rates ranging from 70 to 97 percent. HIV strains isolated from participants in the diverse cohorts represent all the major HIV subtypes.

Data from this international cohort provide a basis for designing future intervention research. The 13 international field sites are currently designing multicenter vaccine and non-vaccine HIV intervention trials.

Vaccine Research

One promising vaccine concept, the ALVAC vCP205/gp120 combination, has undergone expanded testing in HIVNET. A Phase II trial in the United States to assess the safety and immunogenicity of the ALVAC vCP205/gp120 combination -- which HIVNET is conducting in collaboration with the AIDS Vaccine Evaluation Group -- is now under way. A series of trials of other vaccine candidates are in various stages of planning.

In addition to U.S. studies, HIVNET has designed a Phase I study in African populations to assess the safety and immunogenicity of the ALVAC vCP205 vaccine alone, scheduled to begin in the first half of 1998 at the Uganda site. Data from this study will be used to develop an appropriate ALVAC HIV vaccine for East African countries. Phase I/II vaccine trials in other international HIVNET sites are being designed.

HIVNET also is providing supplemental support for community involvement and education for vaccine research in Thailand. This includes an ongoing HIV gp120 vaccine trial sponsored by the Walter Reed Army Institute of Research.

Perinatal Interventions

An efficacy study in the Malawi site, which was jointly funded by the National Cancer Institute, evaluated the effect of chlorohexidine wash of the birth canal to prevent perinatal transmission of HIV. Although chlorohexidine had no effect on virus transmission, it produced a significant drop in the rate of neonatal sepsis.

In November 1996, the Uganda site began a Phase I study of the safety of nevirapine in seropositive pregnant women and their newborns. Key findings included: 1) a single dose of nevirapine was well-tolerated by mothers and infants; 2) a significant reduction in maternal virus was evident seven days after a single dose of nevirapine was administered; and 3) a single dose for infants at 72 hours maintained nevirapine levels at 17 to 75 times the mean inhibitory concentration (MIC) at seven days post-birth.

Based on these encouraging findings, in November 1997, the Uganda site began a Phase III trial to evaluate the efficacy of short-course nevirapine or zidovudine (AZT) compared with placebo in preventing perinatal transmission. On Feb. 18, 1998, the Centers for Disease Control and Prevention announced that a short course of oral AZT given to HIV-infected pregnant women in Thailand who did not breastfeed cut the rate of perinatal HIV transmission in half. The NIH decided that the placebo arms of their ongoing or planned perinatal trials would be dropped or replaced with the short-course AZT regimen. Therefore, enrollment in the Phase III HIVNET study in Uganda was immediately stopped. The protocol team has requested approval to continue open-label enrollment in either the AZT or nevirapine arms of the trial until the study can be redesigned with an appropriate control arm.

The HIVNET Perinatal Working Group is reviewing additional proposals to evaluate other perinatal interventions.

Topical Microbicides

In January 1996, the Kenya site successfully completed a Phase II safety study of low-dose (52.5 mg) nonoxynol-9 (N-9) vaginal microbicide gel. Following this success, the site began a Phase III efficacy trial of this product in July 1996 to determine if it can prevent sexual transmission of HIV among commercial sex workers.

In March 1997, results from a Phase III trial in Kenya of a 70mg N-9 film showed that, in the presence of high levels of condom use and treatment of STDs, this N-9 formulation did not prevent HIV infection. After careful consideration by the HIVNET Scientific Steering Group and review of the recruitment, product use and follow-up data, the trial has been stopped. HIVNET is currently designing a new Phase III trial to be conducted in two to three countries using a 100mg N-9 gel. This study will begin recruitment in the summer of 1998.

To further clinical development of novel topical microbicide products for vaginal use, HIVNET has planned a series of Phase I/II trials to establish the safety and acceptability of new products in different populations. In August 1997, the Rhode Island site completed a Phase I study of an acid buffer gel. The product was found to be both safe and acceptable by the U.S. study participants. The trial has been expanded to HIVNET sites in Thailand, India, Malawi and Zimbabwe, which have begun recruiting women for this study.

A new Phase I domestic study is being planned in the HIVNET of another microbicide, PMPA gel. The purpose of the study is to assess both the systemic and mucosal toxicity when the product is used vaginally. The study will enroll up to 70 women. Pending FDA review of the IND application, accrual is expected to begin in April 1998.

In the summer of 1997, the Seattle site completed a Phase I safety study of an N-9 containing gel for rectal use. The data are currently being analyzed.

Phase I studies of other microbicide products are expected to be implemented in the first half of 1998.

Behavioral Interventions

A new study of a behavioral intervention for men who have sex with men began in the fall of 1997 in six domestic HIVNET sites. The purpose of this study is to assess the efficacy of an individually delivered, multi-session behavioral intervention vs. standard risk reduction counseling to prevent acquisition of HIV. A total of 3,930 men are being recruited for this study.

Another study planned for five domestic HIVNET sites is a Phase II, randomized clinical trial to assess the effectiveness of a post-exposure prophylaxis (PEP) intervention to prevent acquisition of HIV among men who have sex with men. A total of 750 men will be recruited for this study, which is expected to open by the summer of 1998.

The Zimbabwe site completed a randomized community study of peer counseling to prevent sexual transmission of HIV in factory workers. Factories that implemented a peer education program showed a decrease of nearly 33 percent in new HIV infections compared with those factories where standard counseling was provided.

Three international HIVNET sites (India, Thailand and Uganda) are completing pre-implementation activities related to a condom promotion trial. The trial will enroll committed heterosexual couples in which one partner is infected and the other is not. The trial is expected to get under way by late spring 1998.

Domestic HIVNET Field Sites:

• Bronx Lebanon Hospital, N.Y.
  Principal Investigator: Jerome Ernst, M.D.

• Denver Department of Public Health, Colo.
  Principal Investigator: Frank Judson, M.D.

• Fenway Community Health Center, Boston, Mass.
  Principal Investigator: Kenneth Mayer, M.D.
  Field Subsites: Miriam Hospital, Providence, R.I., Memorial Hospital, Pawtucket, R.I.

• Health Research Association, Los Angeles, Calif.
  Principal Investigator: Peter Kerndt, M.D.
  Field Subsites: Drew University, Oasis Clinic, King-Drew Medical Center, Minority AIDS Project, Los Angeles Gay and Lesbian Center

• Howard Brown Health Center, Chicago, Ill.
  Principal Investigator: David McKirnan, Ph.D.
  Field Subsite: University of Illinois, Chicago

• Johns Hopkins University, Baltimore, Md.
  Principal Investigator: Alice Tang, Ph.D.

• New York Blood Center, New York City
  Co-Principal Investigators: Cladd E. Stevens, M.D., Beryl A. Kobin, Ph.D.
  Field Subsites: Bronx Clinic, Union Square Clinic

• New York University, New York City
  Principal Investigator: Michael Marmor, Ph.D.
  Field Subsites: Beth Israel Medical Center, Bellevue Health Center

• San Francisco AIDS Office/Public Health Foundation Enterprises, Inc., Calif.
  Principal Investigator: Susan Buchbinder, M.D.

• University of Pennsylvania, Philadelphia
  Co-Principal Investigators: George Woody, M.D., David Metzger, Ph.D.

• University of Washington, Seattle
  Principal Investigator: Connie Celum, M.D.

International HIVNET Field Sites:

• Case Western Reserve University, Cleveland, Ohio/Makerere University, Kampala, Uganda
  Principal Investigator: Jerrold Ellner, M.D.
  Co-Investigator: Roy Mugerwa, M.B.Ch.B., M.Med.

• Center for Epidemiological Research in South Africa, Durban
  Principal Investigator: Salim Abdool Karim, M.D.

• Chris Hani Baragwanath Hospital, Perinatal HIV Research Unit,
  Johannesburg, South Africa
  Principal Investigator: James McIntyre, M.D.

• Cornell University Medical College, New York, N.Y./Groupe Haitien d’Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO), Port-au-Prince, Haiti
  Principal Investigator: Jean W. Pape, M.D.
  Co-Investigator: Warren Johnson, M.D.

• Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Md./Malawi College of Medicine, Blantyre, Malawi
  Principal Investigator: Taha E.T. Taha, M.D., Ph.D.
  Co-Investigators: George Liomba, M.D., Newton Kumwenda, Ph.D., Robert Broadhead, M.D.

• Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Md./Research Institute for Health Sciences, Chaing Mai, Thailand
  Principal Investigator: Kenrad Nelson, M.D.
  Co-Investigators: Chirasak Khamboonruang, M.D., Chawalit Natpratan, M.D.

• Johns Hopkins University, School of Medicine, Baltimore, Md./Makerere University, Kampala, Uganda
  Principal Investigator: Brooks Jackson, M.D.
  Co-Investigator: Francis Mmiro, M.D., Ch.B.

• Johns Hopkins University, School of Medicine, Baltimore, Md./National AIDS Research Institute, Pune, India
  Principal Investigator: Robert Bollinger, M.D., M.P.H.
  Co-Investigator: Deepak Gadkari, Ph.D.

• Stanford University, School of Medicine, Palo Alto, Calif./University of Zimbabwe Medical School, Harare, Zimbabwe
  Principal Investigator: Julie Parsonnet, M.D.
  Co-Investigator: Jacob Mafunda, M.D.

• University of Alabama at Birmingham, School of Public Health/University Teaching Hospital, Lusaka, Zambia
  Principal Investigator: Susan Allen, M.D., M.P.H., D.T.M.&H.
  Co-Investigator: Luo Chewe, M.D.

• University of Maryland, Institute of Human Virology, Baltimore, Md./Medical Research Foundation of Trinidad and Tobago, Port of Spain, Trinidad
  Principal Investigator: Farley R. Cleghorn, M.D., M.P.H.
  Co-Investigator: Courtenay Barthalomew, M.D.

• University of Pittsburgh, Department of Epidemiology, Pa./Federal University of Rio de Janeiro, Brazil
  Principal Investigator: Lee H. Harrison, M.D.
  Co-Investigator: Mauro Shecter, M.D.

• University of Washington, Seattle, Wash./University of Nairobi, Nairobi, Kenya
  Principal Investigator: Joan Kreiss, M.D., M.S.P.H.
  Co-Investigator: J. O. Ndinya-Achola, M.B.C.h.B.

NIAID, a component of the National Institutes of Health, supports research on AIDS, malaria, tuberculosis and other infectious diseases, as well as allergies and immunology.

Prepared by:

Office of Communications
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, MD 20892

Public Health Service
U.S. Department of Health and Human Services
March1998

DT 980301
DOCN: NIAID98_FACT_SHEET_HIVPREV

Source: National Institute of Allergy and Infectious Disease (NIAID). NIAID, a component of the National Institutes of Health (NIH), supports research on AIDS, tuberculosis, malaria 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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