The following interview was conducted via email on Tuesday, October 30.
Dr. Karen Mark is clinical director of the University of Washington/Fred Hutchinson Cancer Research Center HIV Vaccine Trials Unit.
We asked Dr. Mark to give us some background on the vaccine trial.
We often hear the term "double-blind" in stories about the virus trial. What does that mean?
Karen E. Mark, MD, MPH: In a "double-blind" study such as the STEP study, half of the study volunteers receive the actual vaccine and the other half are given a placebo—a safe, but fake, injection—instead of the actual vaccine. The decision regarding who gets what is made at random (like the toss of a coin) and neither the study volunteers nor the clinicians seeing them know who receives what. This is done to reduce bias. For example, if study participants knew whether they got vaccine or placebo, they might be more likely to engage in riskier sexual practices (for example less condom use) if they got the vaccine and thought it might protect them against getting HIV. If this occurred during the study, then it might look as though the vaccine increased people’s risk of acquiring HIV, whereas it really might not have affected their risk except by changing their behavior.
Note: The analysis of the study data that led to the September announcement that administration of the virus would be halted was done by an independent group called the Drug Safety Monitoring Board (DSMB).
Did researchers looking only at the blinded data begin to see disturbing trends even before the DSMB analysis?
In a blinded study such as the STEP study, while the study is ongoing the data are only examined during scheduled meetings of the DSMB. The DSMB is an independent safety monitoring board, separate from the study investigators. The DSMB examines the study data at scheduled times during the study to monitor the data for safety concerns and to see if the study should be stopped early, either because of safety concerns or because the study objectives have been met early. During previous meetings of the DSMB, no safety concerns arose and the data indicated that the study should proceed as planned. However, when the data were examined for the DSMB meeting in September, it was clear that vaccinations should be stopped early because the vaccine was not effective. The decision to stop vaccinations was made not because of safety concerns but because the vaccine had been shown to be ineffective.
Why was it necessary to get such a large and geographically diverse population of study volunteers for STEP? Is that part of the nature of a vaccine study?
To find out whether a vaccine is effective at preventing HIV infection or lessening the severity of HIV among those who become infected through sexual or other exposure to HIV requires a large population of study volunteers. Geographic diversity is important in HIV vaccine studies because different strains of HIV are present in different areas of the world, and the goal is to find an HIV vaccine which will protect people against all strains of HIV.
Have you contacted all local STEP study participants about the cancellation?
First I'd like to clarify that the STEP study has not been cancelled. It is still continuing. What has changed is that no more participants will receive this vaccine. The decision to stop vaccinations in the STEP study does not affect the Seattle site since all of our 119 participants had already received all 3 doses of the vaccine. In fact, 93% of participants in the STEP study worldwide had received all 3 doses.
That having been said, we have been very proactive about notifying all of our participants about all new information regarding the STEP study. We mailed all of our STEP study participants a letter after the September 21st announcement. This letter explained that a review of preliminary data from the study indicated that the vaccine did not prevent HIV infection or affect the course of the disease in those who became infected through sexual or other exposure to HIV. The vaccine itself cannot cause HIV infection.
The letter also explained that vaccinations in the study were being stopped, but that follow-up of all study participants is continuing, and emphasized the importance of participants protecting themselves from acquiring HIV.
What are you telling them about those hints from the African study that the vaccine, under some rare conditions, might increase susceptibility to HIV?
Preliminary analyses of the STEP study data indicate that a somewhat larger number of people in the vaccine group acquired HIV through sexual or other exposure to an HIV infected person, compared with the number of people in the placebo group who acquired HIV. This difference was not statistically significant. We don't know whether or not this means that the vaccine group is at increased risk, or if this is due to chance. We also don't know if this increased risk, if present, would apply to everyone who got the vaccine or just some people. For example, there were very few women who became HIV infected in this study, so we don't know whether these findings apply to them. Because of the possibility of increased risk, we felt it best to remind everyone in the trial that this possibility exists. Even if this is a real effect from the vaccine, we don't know how long this effect may last. The vaccine itself did not infect anyone with HIV.
Since the information regarding the potential of the vaccine to increase susceptibility to HIV became available last week, we have mailed another letter to all of our participants in Seattle regarding this possibility and again emphasizing the importance of all participants protecting themselves from acquiring HIV. In addition, we have been attempting to contact all participants personally (via phone, email, or in person as they prefer) to answer any questions that they might have. We are very committed to the health and well-being of each and every one of our study volunteers and want to make sure that we have done everything possible to educate them and help them protect themselves from acquiring HIV.
Have you lost contact with anyone who volunteered for the study?
A very few participants had dropped out of the study due to life circumstances changing (moving, etc). We have attempted to contact all of these participants as well using their last known contact information.
If a study volunteer hasn't heard from you, what should they do?
If they have any questions, they can call us at (206) 667-2300, or call their study clinician directly. Follow-up of all STEP study participants is still continuing, so they should continue to come in for their regularly scheduled study appointments. Participants receive regular HIV testing and counseling about ways to reduce their risk of acquiring HIV during these visits.
What has been the reaction among local volunteers to the news?
Local volunteers have been understandably disappointed that the preliminary data show that the vaccine does not work, but they understood that this was a possibility from the start and have been supportive. Most are very altruistic and want to know if they can participate in other HIV vaccine studies. We have emphasized that continuing their follow-up in the STEP study is the most important thing that they can do now to help us find a safe and effective HIV vaccine as soon as possible. There is still a tremendous amount to be learned from participants in this study that will help guide future HIV vaccine development.
How have local staff of HVTN reacted to the news?
Everyone involved in this study-investigators, local study staff, study volunteers, community members, etc-has been disappointed that the preliminary data show that the vaccine does not work. We are doing this work because we want to find a safe and effective vaccine to prevent HIV infection as soon as possible.
However, we also recognize that we have learned a tremendous amount from the STEP study. The study was designed to figure out whether the vaccine worked or not as quickly and efficiently as possible. Unfortunately, we found that it didn't work, but we found this out as quickly as possible and can now move on to learn more about why it may not have worked. This information will be used to develop hopefully better HIV vaccines in the future.
We are eternally grateful to all of our study volunteers who make this work possible. Because of them, we hope to one day develop a safe and effective vaccine to prevent HIV.
Where does HVTU -- Seattle go from here?
We are continuing to follow all Seattle STEP study participants, and hope to learn a lot more from this study. In addition, we have studies of other vaccines both ongoing and planned.
Do you have other studies under way?
We have several other vaccine studies on-going, including one for which we are currently looking for study volunteers, and at least 2 more studies scheduled to start in early 2008. Anyone interested in obtaining more information about volunteering for a HIV vaccine study can give us a call at 206-667-2300, or email us at info@seattlevaccines.org.
