February 6, 2008

		The HVTN 502, or STEP, HIV Vaccine Study
1.		What is the STEP study?
		The STEP study, also known as the HVTN 502 or Merck V520-023 study, is a clinical trial to continue evaluating the safety and begin evaluating the efficacy of an investigational HIV vaccine. The vaccine was designed to induce HIV-specific cell-mediated immunity. This form of immunity involves a type of white blood cell called T cells, which suppress the multiplication of HIV and can kill HIV-infected cells. The trial was designed to determine if the vaccine could prevent HIV infection in HIV-negative individuals, reduce the amount of virus in those who do become HIV-infected during the study, or both.
2.		Who sponsored and conducted this trial?
		Merck & Co. Inc. (Whitehouse, NJ) and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), co-sponsored this investigational HIV vaccine trial. The study was conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN) and Merck, which also developed and supplied the candidate vaccine for the trial.
3.		When did the study begin?
		The STEP study began enrolling and vaccinating volunteers in December 2004.
4.		How many participants were involved, and where was the study being conducted?
		The trial, which was fully enrolled, involved 3,000 adult volunteers at sites around the world. The study site locations include: North America: Atlanta; Boston; Birmingham, AL; Chicago; Denver; Houston; Los Angeles; Miami; New York; Newark, NJ; Philadelphia; Rochester, NY; St. Louis; San Francisco; Seattle; Toronto; Montreal; and Vancouver, British Columbia South America: Iquitos and Lima, Peru; Rio de Janeiro and Sao Paulo, Brazil The Caribbean: Santo Domingo, Dominican Republic; Port-au-Prince, Haiti; Kingston, Jamaica; and San Juan, Puerto Rico Australia: Sydney
5.		What was the investigational vaccine being tested?
		The study was testing Merck’s candidate vaccine, the MRKAd5 HIV-1 gag/pol/nef trivalent vaccine, which is based on a weakened adenovirus (adenovirus type 5), a common virus that normally causes upper respiratory infections, such as the common cold, but that has been altered to render it unable to replicate. The vaccine is a mixture of three weakened adenoviruses that act as vectors, or carriers, for efficiently transporting into the body and presenting to the immune system three HIV proteins: gag, pol and nef.
6.		What was the design of the STEP study?
		The STEP study, or HVTN 502, was designed as a randomized, double-blind, placebo-controlled Phase IIb "test-of-concept" clinical trial. The trial enrolled HIV-negative volunteers between 18 and 45 years of age at high risk of HIV infection. After an initial HIV screening, confirmation of eligibility criteria and informed consent, participants were randomly assigned to receive three injections of either the study vaccine or a placebo vaccine. Neither the study investigators nor the trial participants know who received the study vaccine or placebo while the trial was underway. All participants continue to be closely followed to check their HIV status. Throughout the trial, all participants received HIV risk-reduction counseling and various supplies, such as condoms, and information to help them avoid HIV infection. Initially, the study only enrolled individuals with low pre-existing antibodies to adenovirus type 5 (Ad 5) based on earlier indications that the vaccine would have greatest potency for these persons; however, subsequent studies with the same vaccine lead to an amendment that opened participation to anyone who met the study’s inclusion criteria irrespective of pre-existing levels of adenovirus antibodies.
7.		What is a Data and Safety Monitoring Board, and how did it monitor this study?
		A Data and Safety Monitoring Board (DSMB) is an independent committee composed of clinical research experts, statisticians, ethicists and community representatives that provides additional oversight of a clinical study. The DSMB regularly reviews data while a clinical trial is in progress to ensure the safety of participants and that any benefits shown in the study are quickly made available to all participants. A DSMB may recommend that a trial, or part of a trial, be stopped if there are safety concerns or if the trial objectives have either been achieved or are unlikely to be achieved. A DSMB looks at analyses that are not available to the investigators or anyone else. Restricting certain information to the DSMB while the trial is ongoing helps to maintain the integrity of the study. The DSMB for the STEP study met at regular intervals throughout the course of the trial to review the study data. The DSMB meeting on September 18, 2007, was a planned interim meeting to review the potential efficacy of the vaccine based on a predetermined number of cases of HIV infection that had occurred during the study.
8.		What were the results of the September 18, 2007 DSMB review?
		On September 18, 2007, the DSMB reviewed the interim data obtained from the volunteers who had low antibody levels against adenovirus 5 at the time of enrollment. The DSMB recommended that the trial as originally designed should be discontinued because the trial would not meet its efficacy endpoints. Specifically, 24 cases of HIV infection were seen among the 741 volunteers who received at least one dose of the investigational vaccine, while 21 cases of HIV infection were seen in the 762 participants who received at least one dose of the placebo. In the subgroup of trial participants who had received at least two vaccinations and who were HIV-negative for at least the first 12 weeks of the trial, the DSMB found 19 cases of HIV infection among the 672 volunteers who received the investigational vaccine and 11 cases of HIV infection among the 691 participants who received the placebo. These latter differences were not statistically significant. As a result of the DSMB review, NIAID, Merck and the HVTN agreed to cease immunizations with the investigational vaccine and continue scheduled follow-up site visits with all volunteers until the data could be more thoroughly evaluated and a course of action developed.
9.		Has there been any additional analysis of the STEP data?
		On November 7, 2007, additional analyses of the STEP data were presented at an open scientific meeting in Seattle. These analyses suggested that those study participants who received the vaccine may get infected with HIV more easily if they are exposed to the virus. This trend was more evident among those volunteers with higher levels of pre-existing immunity (antibodies) to Ad5 because of prior natural exposure to that particular type of cold virus. The infections were mostly among men who have sex with men. Only one woman became infected with HIV during the trial, and only one heterosexual man acquired HIV. Therefore, there is little information about the effects of the vaccine in women or in heterosexual men. A multivariate analysis of the STEP data assessing the potential influence of certain confounding factors, such as baseline Ad5 levels, circumcision status, region, age and reported risk behavior, on the potential for developing HIV infection was presented at the February 2008 Conference on Retroviruses and Opportunistic Infections. That analysis confirmed that, overall, male study volunteers who received the vaccine were approximately 1.6 times more likely to develop HIV infection than those who received placebo, although the reason for this unexpected outcome remains unclear. The analysis also showed that when adjusting for confounding factors, the likelihood of acquiring HIV infection in male study participants who received the vaccine compared with those who received placebo varied by levels of pre-existing Ad5 immunity and by circumcision status. Among men who had pre-existing Ad5 immunity (Ad5 levels >18 units) and who were not circumcised, those who received vaccine were 4.2 times more likely to have acquired HIV infection than those who received placebo. This subgroup of vaccine recipients (uncircumcised men with pre-existing Ad5 immunity) had the greatest likelihood of developing HIV infection in comparison to the placebo group. The likelihood of developing HIV infection among those who received the vaccine in comparison to placebo was lower in all other subgroups than the subgroup of uncircumcised men with pre-existing Ad5 antibodies. Specifically, men who had higher levels of pre-existing Ad5 immunity and were circumcised, those who received vaccine were 1.4 times more likely to have acquired HIV infection than the placebo group. Among men who had low levels of pre-existing Ad5 immunity and who were not circumcised, those who received vaccine were 2.5 times more likely to have acquired HIV infection than those who received placebo. Among men who had low levels of pre-existing Ad5 immunity and who were circumcised, those who received vaccine were not more likely to acquire HIV infection than those who received placebo. Vaccine recipients were 0.6 times as likely to have acquired HIV infection as the placebo recipients. Regardless of circumcision status, the men who received the vaccine who also had pre-existing Ad5 antibodies were more likely to have developed HIV infection relative to the placebo group than those who had low levels of pre-existing Ad5 antibodies. Among those who received the vaccine and had pre-existing immunity to Ad5, those who were not circumcised were more likely to have developed HIV infection, relative to placebo, than those who were circumcised.
10.		What future analyses of the STEP data are planned?
		Additional analyses to determine why a greater number of HIV infections occurred among certain groups of STEP study participants is being explored in laboratory studies. An independent scientific committee is working with the HVTN, Merck and NIAID on this and is accepting proposals from the scientific community for suggestions on the most appropriate lab studies (see www.hvtn.org). Additional multivariate analyses will be conducted when data on herpes simplex virus type-2 infection, human leukocyte antigen typing and sexual network clustering become available.
11.		What is happening to the volunteers enrolled in the STEP trial?
		Although vaccinations have been discontinued in the STEP study, all participants (both those who remain HIV uninfected and those who are HIV-infected) are still being asked to return to their study sites for HIV risk-reduction counseling and protocol-related tests, so that investigators can fully evaluate the effects of the vaccine on HIV acquisition. Since November 13, 2007, the study participants have been told whether they received vaccine or placebo, and are also being told their level of pre-existing Ad5 antibodies. Volunteers are being counseled about the possibility that the investigational vaccine may have caused an increased susceptibility to acquiring HIV infection among those who received it, regardless of their Ad5 status. Throughout their participation in the study, volunteers have been counseled that prevention strategies to avoid HIV exposure are essential. That message continues to be reinforced during follow-up counseling. Volunteers who became HIV-infected during the trial are being referred for HIV evaluation and to the appropriate medical sources for treatment and care. Volunteers who became infected will also be offered continued immunological and virological follow-up for an extended period of time. Details concerning volunteer follow-up will be implemented as the data from HVTN 502 is more thoroughly evaluated.
The HVTN 503 (Phambili) HIV Vaccine Study
12.		What is the HVTN 503 or "Phambili" study?
		The HVTN 503 ("Phambili") study was designed to evaluate the safety and preliminary efficacy of the same Merck HIV candidate vaccine tested in the HVTN 502 STEP study, but it is being conducted in South Africa. In South Africa, the trial is known as Phambili, the Xhosa word for "moving forward." In light of the Sept. 18 DSMB review of HVTN 502, immunizations and enrollment in the HVTN 503 study were paused on Sept. 21, 2007.
13.		What is the current status of the HVTN 503 study?
		Since the September 21, 2007 announcement to discontinue the HVTN 502 (STEP) study and pause vaccinations and enrollment in the HVTN 503 (Phambili) study, the DSMB for the HVTN 503 study has reviewed data from the STEP study to determine its impact on the South African study. Based on its review, the DSMB concluded that there is no basis for anticipating more favorable results in the HVTN 503 study than the HVTN 502 trial and, therefore, recommended that vaccinations and enrollment in HVTN 503 be permanently suspended. The DSMB for the HVTN 503 study also recommended that all volunteers be told whether they received vaccine or placebo and be strongly encouraged to return to their study sites for HIV risk-reduction counseling, protocol-related tests and for counseling about the possibility that those who received the vaccine might have an increased susceptibility to acquiring HIV infections. The HVTN 503 oversight committee, which is comprised of senior representatives from NIAID, the HVTN and Merck, accepted these recommendations, and the South African clinical trial sites have been informed of these decisions.
14.		Did the vaccine used in both HVTN 502 and HVTN 503 cause HIV infection?
		No. The investigational vaccine used in both the HVTN 502 and HVTN 503 studies cannot cause HIV infection because it contains only synthetically produced snippets of viral material. There is no way for these snippets to reconstitute an intact virus. Researchers, however, are analyzing available data to better understand if there may be an increased susceptibility to acquiring HIV infection among those volunteers who received the vaccine.
15.		What will happen to the volunteers who were enrolled in the HVTN 503 trial?
		Volunteers who became infected with HIV during the study are being referred for HIV evaluation and to the appropriate medical sources for treatment and care. Additionally, volunteers who became HIV-infected will also be offered continued immunological and virological follow-up for an extended period. All study volunteers are being encouraged to return to their designated clinical sites for further HIV-risk reduction counseling and protocol-related tests. Throughout both the HVTN 503 and HVTN 502 studies, volunteers have been strongly counseled about prevention strategies for avoiding exposure to HIV. Volunteers will continue to be counseled on this essential need during follow-up.
16.		When did the HVTN 503 trial begin, and where in South Africa was it being conducted?
		The HVTN 503 study began enrolling and vaccinating participants in January 2007. Since that time, 801 individuals were enrolled and 55 were fully immunized. The study was being conducted at five sites in South Africa located in Soweto, Cape Town, Klerksdrop, Medunsa and Durban.
17.		Who was conducting the HVTN 503 trial?
		The trial was being conducted jointly by the South African AIDS Vaccine Initiative (SAAVI) and the NIAID-funded HIV Vaccine Trials Network (HVTN). The study was led by South African physician Glenda Gray, MBBCH, FCPaeds (SA), of the Perinatal HIV Research Unit, University of the Witwatersrand, based at the Chris Hani Baragwanath Hospital in Soweto. James Kublin, M.D., M.P.H., of Fred Hutchinson Cancer Research Center, Seattle, served as study co-chair.
18.		Who is supporting the HVTN 503 trial?
		HVTN 503 is supported by NIAID and in part by SAAVI. Merck supplied the candidate vaccine.
19.		What was the design of the HVTN 503 trial?
		The HVTN 503 trial design was very similar to the HVTN 502 trial. HVTN 503 was a randomized, placebo-controlled, double-blinded Phase IIb test-of-concept clinical trial. It was designed to further evaluate the safety of the vaccine and to obtain preliminary information on its efficacy. The trial was designed to enroll up to 3,000 HIV-negative, sexually active men and women at high risk for HIV infection recruited at five research sites located in areas of South Africa where there is a high prevalence of HIV infection. The study was designed to obtain more information about the safety of the vaccine and to determine if the vaccine could prevent HIV infection, reduce virus levels in those who became infected, or both, from the most common subtype of HIV (clade C) in South Africa. The test vaccine was based on HIV clade B, but data from other trials indicated that the vaccine could induce cross-clade immune responses. After an initial HIV screening, confirmation of eligibility criteria, and informed consent, participants were randomly assigned to receive either three doses of the study vaccine or placebo over the course of six months. Neither the trial participants nor the scientists knew who received the study vaccine and who received the placebo. After completing the series of vaccinations, participants were to be tested for HIV infection every six months for the remainder of the trial (the trial was originally scheduled to last four years). At each visit, all trial participants were counseled to reduce HIV risk behavior, were provided condoms, received access to care and treatment for sexually transmitted diseases, and were linked to prevention services. Additionally, male volunteers were also offered access to medical circumcision, which has been shown to reduce the risk of HIV transmission from women to men.
		View Statement

Media inquiries can be directed to the NIAID News and Public Information Branch at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

###

back to top