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Additional ALVAC/AIDSVAX HIV Vaccine Data Show Only Modest Benefit with Minimal Statistical Significance

A closer look at complete data from an HIV vaccine trial in Thailand indicates that the results are less impressive than suggested when partial results were announced last month. The ALVAC/AIDSVAX vaccine combination showed a moderate protective effect according to one type of analysis, investigators said at the AIDS Vaccine 2009 conference this week in Paris, but the full analysis indicates that the results could have been due to chance.

Investigators with the U.S. Military HIV Research Program (MHRP) announced in late September that a Phase 3 trial of more than 16,000 participants in Thailand found that an ALVAC-HIV primer vaccine followed by an AIDSVAX B/E booster reduced the risk of HIV infection by about 30%. The findings were widely hailed in the media as being the first evidence that a vaccine could prevent HIV in humans, after years of disappointing results.

In the RV144 trial -- the largest HIV vaccine study ever conducted in humans -- 16,402 initially HIV negative men and women aged 18-30 years were randomly assigned on a 1-to-1 basis to receive either the vaccine combination (4 doses of ALVAC followed by 2 doses of AIDSVAX) or placebo injections. Both genetically engineered vaccines carry genes from HIV strains prevalent in Southeast Asia.

Injections were administered within a 6-month period and participants were then followed for an additional 3 years, receiving HIV testing and prevention counseling every 6 months. The researchers looked at whether participants became HIV infected, and whether those who did seroconvert had lower viral loads.

Results were reported at the Paris conference and published the same day in the October 20, 2009 advance online edition of the New England Journal of Medicine.

Results

• In an intention-to-treat analysis of all 16,402 participants, there was a trend toward prevention of HIV infection among vaccine recipients, with an efficacy of 26.4%:
  • 56 vaccine vs 76 placebo recipients infected;
  • 95% confidence interval (CI): -4.0 to 47.9; very wide, indicating considerable uncertainty;
  • P = 0.08; a value < 0.05 is generally used as a cut off for statistical significance.
• In a modified intention-to-treat analysis involving 16,395 participants, excluding 7 people who were determined to have been already HIV-infected at study entry, the vaccine efficacy was 31.2% -- the figure reported in September:
  • 74 vaccine vs 51 placebo recipients infected;
  • 95% CI: 1.1 to 51.2;
  • P = 0.04, just reaching statistical significance.
• In a per-protocol or "as treated" analysis involving 12,452 participants who received all vaccine doses as scheduled, the vaccine efficacy was 26.2%:
  • 36 vaccine vs 50 placebo recipients infected;
  • 95% CI: -13.3 to 51.9.
  • P = 0.16, no longer close to borderline significance.
• The vaccine appeared to provide the greatest protective effect during the first year (about a 60% decrease in infection risk).
• Heterosexual participants at low or medium risk for infection appeared to derive more benefit from the vaccine than high-risk participants such as men who have sex with men, injection drug users, or sex workers (about a 40% risk reduction for low-risk, 47% for medium-risk, and 4% for high-risk recipients).
• Vaccination did not affect viral load levels or CD4 cell counts in participants who became infected.
• The vaccine combination was generally well-tolerated, with no serious safety concerns identified.

"This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk," the investigators concluded. "Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research."

"This is the first evidence that a prime-boost HIV vaccine regimen may prevent infection and represents a significant step forward for vaccine research," Colonel Nelson Michael, Director of the U.S. Military HIV Research Program, said in a press statement. "While it will not likely have any immediate public health benefit, we are hopeful that the findings will guide additional studies and accelerate research efforts toward a more effective vaccine."

The initial presentation of the modified intention-to-treat result -- the only one to reach statistical significance -- ahead of the others garnered considerable criticism after the less impressive data was revealed in Science magazine's Science Insider blog earlier this month.

While a complete intention-to-treat analysis is generally considered the most rigorous, Colonel Michael argued that the modified analysis was appropriate for this trial. "Given that you cannot protect someone from an infection that they already have acquired, the modified intent-to-treat analysis excluded these individuals," he said, noting that all 3 types of analysis were planned, not ad hoc. Full results were not released in September due to policies about "embargoes" on findings prior to publication or presentation at a conference.

"The trial raises more questions than it answers," Alan Bernstein of the Global HIV Vaccine Enterprise, one of the sponsors of the Paris conference, told Bloomberg news. "The initial protective effect after the first year looked like it was 60 percent and it dropped off with time. The most important thing with vaccines is memory."

"Perhaps the requirements for protection against transmission in low-risk, heterosexual persons are considerably different or less stringent than those in high-risk subjects," wrote Raphael Dolin of Beth Israel Deaconess Medical Center in an editorial accompanying the New England Journal of Medicine report.

The ambiguity of the RV144 findings -- and a preliminary announcement that many regarded as overly hyped -- have deepened the debate about the ethics and cost-effectiveness of pursuing HIV vaccine research of this type. The purported protective effect of the ALVAC/AIDSVAX combination was particularly unexpected, since both component vaccines have shown no benefit when used alone.

The researchers plan to conduct more in-depth studies of blood samples from a smaller subset of vaccine recipients in an attempt to learn more about the "correlates of protection," or differences in immune cell activity and other biological markers in vaccinated individuals.

"The establishment of such correlates is the central question in HIV vaccine development and will have a profound effect on the designs of vaccines and clinical trials to assess their efficacy," Dolin wrote in his editorial. "Given the lack of detection of conventional immune responses in earlier studies of these vaccine components, as well as the divergence between the vaccine's effect on the infection and the effect on viral load, the correlates of protection may, indeed, reflect new concepts of host response. This should be the focus of intense research using the most current research techniques. Ultimately, it is the results of such studies that will most likely determine the significance of this clinical trial to the field of HIV vaccine development."

"This is a weak signal, but a signal that has enough relevance that we need to
pursue it," said National Institute of Allergy and Infectious Diseases director Anthony Fauci.

10/23/09

References

S Rerks-Ngarm, P Pitisuttithum, S Nitayaphan, and others.
Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. New England Journal of Medicine. October 20, 2009 (Epub ahead of print). Free full text.

R Dolin. HIV Vaccine Trial Results -- An Opening for Further Research. New England Journal of Medicine. October 20, 2009 (Epub ahead of print). Free full text.

Other Sources

U.S. Military HIV Research Program. Detailed Results from RV 144 HIV Vaccine Trial Published Today in The New England Journal of Medicine and Presented at the AIDS Vaccine 2009 Conference Provide Insight for Future Research. Press release. October 20, 2009.

S Bennett and MF Cortez. AIDS Vaccine's Benefit May Wane After First Year. Bloomberg.com. October 20, 2009.

J Cohen. Unrevealed Analysis Weakens Claim of AIDS Vaccine "Success." Science Insider. October 5, 2009.