QUESTIONS AND ANSWERS
HVTN 502 and HVTN 503 HIV Vaccine Clinical Trials
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 (the vaccine itself cannot cause HIV infection because it contains only synthetically produced snippets of viral material), 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), cosponsored 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, had 3,000 adult volunteers at sites around the world. The study site locations include
North America: Atlanta, Boston; Birmingham, AL; Chicago; Decatur, GA; Denver; Houston; Los Angeles; Miami; New York; Newark, NJ; Philadelphia; Rochester, NY; St. Louis; San Francisco; Seattle; Toronto; Montreal; and Vancouver, British Columbia; and San Juan, Puerto Rico
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
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 (type 5 adenovirus), 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 is the design of the STEP study?
The STEP study 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 who met certain medical and non-medical criteria. 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 knew who received the study vaccine or placebo while the trial was under way. All participants continue to be closely followed to check their HIV status.
All participants received HIV risk-reduction counseling and various supplies, such as condoms, and information to help them avoid HIV infection throughout the trial. Initially, the study only enrolled individuals with low pre-existing antibodies to type 5 adenovirus 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 does 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. What is happening to the volunteers enrolled in the HVTN 502 trial?
Volunteers in the HVTN 502 study are being encouraged 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, including whether there is any increased susceptibility to acquisition of HIV infection among those who received the vaccine. 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.
Discussions are under way to define the details of the continued follow-up of the volunteers, including when the volunteers will be told whether they received the vaccine or placebo.
Volunteers who became HIV-infected during the trial ar