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US Military HIV Vaccine Research Group Response
 
 
  RV 144 Update
October 10, 2009
http://www.hivresearch.org
 
On September 24, the results of a prime-boost HIV vaccine clinical trial involving more than 16,000 adult volunteers in Thailand were announced by the trial collaborators. According to the results, the trial demonstrated that the vaccine regimen was safe and lowered the rate of HIV infection by 31.2 percent compared to placebo.
 
While this is a modest level of efficacy, it represents a major step forward for HIV vaccine research, providing the first evidence that development of a safe and effective preventive HIV vaccine is possible.
 
The initial results announced on September 24 were based on a modified intent to treat (mITT) population (Intent to Treat less 7 individuals who were already HIV infected on the first day of vaccination), and focused on the most biologically and clinically relevant findings. The mITT analysis includes everyone who entered the study, and is considered the more stringent and unbiased analysis for clinical trials such as this "proof-of-concept" study.
 
The trial collaborators, which include the U.S. Army, the Thai Ministry of Public Health, the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, sanofi pasteur, and Global Solutions for Infectious Diseases, are committed to releasing the detailed trial information in appropriate scientific forums when the pre-publication embargo is lifted. Complete analyses of multiple data subgroups including ITT and per protocol (PP), their definitions and results, will be presented later this month at the AIDS Vaccine Conference on October 20 in Paris, France. A manuscript is also under review at a leading peer-reviewed journal.
 
Data from this study will have important implications for the design of future HIV vaccines and how they are tested and should accelerate research efforts toward a more effective vaccine; however, additional research is needed to better understand how this vaccine regimen reduced the risk of HIV infection.
 
Frequently Asked Questions
 
What data were included in the initial results?

 
The initial results announced on September 24 were based on a modified intent to treat (mITT) population (ITT less 7 individuals who were already HIV infected on the first day of vaccination), and focused on the most biologically and clinically relevant of the many relevant results. The mITT analysis includes all 125 uninfected individuals who entered the study and subsequently became infected, and is considered the more stringent and unbiased analysis for clinical trials such as this one (proof-of-concept).
 
The study, including its size, was designed based on ITT analysis. ITT was also used by the Data Safety and Monitoring Board to determine efficacy at the interim analysis in 2007.
 
Complete analyses of multiple data subgroups including ITT and per protocol (PP), their definitions and results, are under review in standard scientific channels and will be presented at the AIDS Vaccine Conference in October and are also under review at a leading peer-reviewed journal.
 
Why didn't you announce results in a scientific forum?
 
On September 24 the results of the prime-boost HIV vaccine trial conducted in Thailand were announced by the trial collaborators in Thailand and in the United States through an international teleconference.
 
The Thai Ministry of Public Health and other trial collaborators wished to inform the volunteers and Thai citizens of the results as soon as possible, instead of waiting for a scientific conference or publication. The results would have been announced on the same day, and in the same manner regardless of the trial outcome. This reflects our commitment to the volunteers who participated in this trial.
 
Why did you not announce results based on the other analysis?
 
The multiple statistical analyses are all consistent with the same conclusion: that the vaccine was modestly effective at preventing HIV. However, explaining the differences between them is complex and the appropriate venue for this technical discussion of statistics is at an open scientific conference and in the scientific publication now under review at a major journal.
 
What is the difference between ITT and PP?
 
The intent-to-treat (ITT) analysis includes everyone who entered the study, and is considered the more stringent and unbiased analysis for clinical trials such as this "proof-of-concept" study. Per protocol analyses are critical for studies leading to U.S. product licensure, which this study was not designed to be.
 
ITT is considered a stronger test of what we would see if the vaccines were given to a general population in the "real world" outside of a study, where some individuals might miss or be late for their vaccinations. Accordingly, the ITT analysis includes everyone who entered the study. Since we do not know whether all of the vaccinations were important for protection, this is the best and most unbiased approach.
 
The per-protocol (PP) analysis excludes anyone who became HIV infected before all four vaccine visits and includes only those who completed all protocol vaccinations on time. That is very important since it would exclude those who were potentially protected after receiving just a part of the vaccine regimen of six shots. The PP analysis excluded nearly one-third of the trial endpoints - only 86 of the 125 infected individuals in the study were included in the PP analysis - which substantially reduces the study power.
 
The result based on the PP analysis is viewed to be consistent with the ITT analysis that was presented, even though the PP vaccine efficacy estimate was slightly lower and did not reach statistical significance due to the lower number of volunteers included in the PP analysis.
 
 
 
 
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