October 23, 2007
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.
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.
The STEP study began enrolling and vaccinating volunteers in December 2004.
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.
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.
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.
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.
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 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) 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 September 18 DSMB review of HVTN 502, immunizations and enrollment in the HVTN 503 study were paused on September 21, 2007.
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 in 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 counseling about the possibility that those who received the vaccine might have an increased susceptibility to acquiring HIV infection.
The HVTN 503 oversight committee, which comprises senior representatives from NIAID, the HVTN and Merck, accepted these recommendations, and the South African clinical trial sites have been informed of these decisions.
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.
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.
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.
The trial was 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.
HVTN 503 is supported by NIAID and in part by SAAVI. Merck supplied the candidate vaccine.
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.