Immunizations Are Discontinued in Two HIV Vaccine Trials (9/24/2007)

An independent Data and Safety Monitoring Board (DSMB) met this week to review interim data from a large, international HIV vaccine clinical trial known as the STEP study - also referred to as the HVTN 502 or Merck V520-023 study. The clinical trial, which began enrolling volunteers in December 2004, is co-sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Inc., which also developed and supplied the candidate vaccine. Based on a review of interim data, the DSMB concluded that the vaccine cannot be shown in this trial to prevent HIV infection or affect the course of the disease in those who become infected with HIV as a result of their own behaviors that expose them to the virus. Therefore, Merck and NIAID instructed all study sites to cease administering the investigational vaccine but continue scheduled follow-up visits with all volunteers until the data can be more thoroughly evaluated and a course of action is developed.

The STEP study, which enrolled 3,000 participants, was conducted by the NIAID-funded HIV Vaccine Trials Network (HVTN) and Merck. Volunteers were enrolled at sites in Australia, Brazil, Canada, the Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico and the United States. The Phase IIb "test-of-concept" study was designed to test Merck's candidate HIV vaccine, the MRKAd5 trivalent vaccine, which aimed to stimulate production of immune system T cells that can kill HIV-infected cells. The goal of the study was to determine if the vaccine could prevent HIV infection, reduce the amount of HIV in those who do become infected, or both.

Based on its first evaluation of interim efficacy data, the DSMB found 24 cases of HIV infection among the 741 volunteers who received at least one dose of the investigational vaccine compared with 21 cases of HIV infection among the 762 volunteers who were vaccinated with placebo. In volunteers who received at least two vaccinations, the DSMB found 19 cases of HIV infection among the 672 volunteers who received the investigational vaccine and 11 instances of HIV infection among the 691 volunteers who received the placebo. The trial partners will fully evaluate the trial data, provide additional instructions to the STEP trial sites, and provide a detailed scientific analysis of the study results in the near future.

The same Merck candidate HIV vaccine is also being tested in South Africa by the HVTN and the South African AIDS Vaccine Initiative in a separate NIAID-sponsored clinical trial known as HVTN 503 or the "Phambili" study. This study was initiated in February 2007 and has enrolled 799 individuals. Immunizations and enrollment in the Phambili study have now been paused. This allows the independent DSMB that oversees the Phambili trial to review all available HVTN 503 and STEP interim findings to determine next steps. In contrast to the STEP study where the interim analysis was almost exclusively based on results in volunteers who were men who have sex with men, the Phambili study has primarily enrolled heterosexuals at high risk for HIV.

The study investigators at each site for both the STEP (HVTN 502/ Merck V520-023) and Phambili (HVTN 503) vaccine trials have been informed of the decision to cease immunizations and are contacting study volunteers to inform them of the developments.

For additional information about the HVTN 502 and HVTN 503 trials, see niaid.nih.gov/news/QA/step_qa.htm.

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 is 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 through their own behaviors or circumstances, or both.
2. Who is sponsoring and conducting 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-sponsor this investigational HIV vaccine trial. The study is being 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 are involved and where is the study being conducted?
The trial, which is fully enrolled, has 3,000 adult volunteers at sites around the world. The study site locations include:
• North America: 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; 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. 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 genes: gag, pol and nef.
6. What is the design of the HVTN 502 study?
The STEP study, or HVTN 502, is 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 and 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 an injection of either the study vaccine or a placebo vaccine. Neither the study investigators nor the trial participants know who receives the study vaccine or placebo until the trial is completed. All participants are closely followed to check the HIV status of the volunteers during regular study visits.

All participants received HIV risk-reduction counseling and various supplies, such as condoms, and information to help them avoid HIV infection throughout the trial. Volunteers who become HIV-infected during the trial are referred for HIV evaluation as well as medical care and treatment. Additionally, those volunteers who become infected are also offered continued immunological and virological follow-up assessment for an extended period of time.

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; based on accumulating information from other clinical trials with the same vaccine, a later amendment to the trial opened participation to anyone irrespective of pre-existing levels of adenovirus antibodies.
7. What is the Data and Safety Monitoring Board, and how does it monitor this study?
The 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 the 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.

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 meeting to review the potential effectiveness 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 most recent 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 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 differences were not statistically significant.

On the viral level endpoint, the HIV RNA levels approximately 8 to 12 weeks post-infection were not statistically significant between the vaccine and the placebo groups. 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 can be more thoroughly evaluated and a cause of action developed.
9. What will happen to the volunteers enrolled in the HVTN 502 trial?
Volunteers who became HIV-infected during the trial were 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. Once the data from HVTN 502 is more thoroughly evaluated, a more detailed follow-up plan will be implemented.

The HVTN 503 HIV Vaccine Study

10. What is the HVTN 503 or "Phambili" study?
The HVTN 503 ("Phambili") study is 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. It is the largest HIV vaccine trial in Africa to date. In South Africa, the trial is known as Phambili, the Xhosa word for "moving forward." In light of the DSMB review of HVTN 502, immunizations and enrollment in the HVTN 503 study have been paused.
11. When did the HVTN 503 trial begin, and where is South Africa is it being conducted?
The HVTN 503 study began enrolling and vaccinating participants in January 2007. Since that time, 799 individuals have been enrolled and 55 have been fully immunized. The study is being conducted at five sites in South Africa located in Soweto, Cape Town, Klerksdrop, Pretoria and Durban.
12. Who is conducting the HVTN 503 trial?
The trial is being conducted jointly by the South African AIDS Vaccine Initiative (SAAVI) and the NIAID-funded HIV Vaccine Trials Network (HVTN).

The study is led by 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, serves as study co-chair.
13. Who is supporting the HVTN 503 trial?
HVTN 503 is supported by NIAID and in part by SAAVI. Merck supplied the candidate vaccine.
14. What is the design of the HVTN 503 trial?
The HVTN 503 trial design is very similar to the HVTN 502 trial. HVTN 503 is a randomized, placebo-controlled, double-blinded Phase IIb clinical trial. It is designed to further evaluate the safety of the vaccine and to obtain preliminary information on its efficacy. The trial is 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. After an initial HIV screening, confirmation of eligibility criteria, and informed consent, participants are 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 will know who receives the study vaccine and who receives the placebo until the trial is completed.

After completing the series of vaccinations, participants will be tested for HIV infection every six months for the remainder of the trial (the trial is originally scheduled to last four years). All trial participants will be counseled to reduce HIV risk behavior at each visit, be given condoms, receive access to care and treatment for sexually transmitted diseases, and be linked to prevention services. In addition because recent findings indicate that medical circumcision can reduce the risk of HIV transmission from women to men, access to medical circumcision will also be provided to men in the trial who desire it. Despite all these measures, it is expected that some trial participants will become infected with HIV from engaging in risky sexual behavior. Individuals who become infected with HIV during the trial will be followed for at least an additional 18 months after their diagnosis and will be referred to an appropriate health care provider for access to medical care, treatment and counseling.
15. What are the objectives of the HVTN 503 trial?
The primary objectives of this trial are to obtain more information about the safety of the vaccine, and to learn if the study vaccine can decrease the risk of acquiring HIV infection or lower the amount of HIV in the blood early on if a person becomes infected with HIV. In addition, the trial is investigating whether a vaccine based on one HIV subtype, or clade, might be effective in regions where another subtype is predominant. In this case, the test vaccine, based on clade B HIV, is being tested in South Africa, where clade C virus is predominant. The rationale for testing this clade B vaccine in South Africa is that data from other trials indicate that this vaccine can induce cross-clade immunogenicity in the majority of volunteers. Immune responses in the first several hundred volunteers will be assessed to ensure the vaccine induces promising immune responses in this population against the clade C virus before proceeding to full enrollment.
16. What factors might affect whether or not the HVTN 503 trial continues?
Because HVTN 502 is currently studying the same vaccine as HVTN 503, data generated from HVTN 502 may affect the course of the HVTN 503 trial. Data from HVTN 502 will be shared with the NIAID DSMB to help guide and determine the direction of HVTN 503.
17. If this candidate vaccine is already being studied in HVTN 502, why is this study (HVTN 503) being conducted?
The South African study is likely to provide important new data on how the test vaccine might work in a predominantly heterosexual HIV epidemic. Most participants in HVTN 502 were men who have sex with men (MSM) and the conclusions reached recently by the HVTN 502 DSMB were almost exclusively based on infections in MSM. In contrast, HVTN 503 is designed to enroll equivalent numbers of heterosexual men and women to enable researchers to evaluate the vaccine's performance by gender.

Note: This story has been adapted from a news release issued by NIH

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