October 20, 2009

Final Results: “Modest Benefit” Seen in Thai Vaccine Study

Researchers conclude that a preventive HIV vaccine conferred modest benefit in a Thai clinical trial, according to final results published today, October 20, in The New England Journal of Medicine (NEJM). Amid ongoing debate regarding the true significance of the trial’s findings, the study authors offered two important considerations for future exploration—that this particular vaccine strategy’s effectiveness might dwindle over time, while its efficacy might be more pronounced in people facing a lower risk for HIV infection in the first place.  

The debate among activists and researchers surrounding the effectiveness of the tested vaccine strategy—four doses of Sanofi Pasteur’s ALVAC plus two doses of VaxGen’s AIDSVAX, compared with placebo—stems from the conflicting results of two statistical analyses of the study data. Both analyses are included in the NEJM paper but have already been reported in preliminary form.

A modified intent-to-treat (ITT) analysis of the study included all 16,402 people enrolled in the study (with the exception of seven who tested positive for HIV before receiving the vaccines), regardless of whether or not they received all six vaccine doses exactly as recommended by the study protocol. In this analysis, 51 of the 8,197 given the vaccine and 74 of the 8,198 given the placebo tested positive for HIV after three years of follow-up. This translated into a 31.2 percent lower risk of infection for the vaccine group. The difference in the modified ITT analysis was statistically significant, meaning that it was too large to have occurred by chance.

A per-protocol analysis of the study included only 12,452 volunteers who received their vaccine or placebo injections exactly as prescribed and were followed for the length of the study. This analysis documented 36 infections in the vaccine group and 50 infections in the placebo group. This difference translated into a 26.2 percent lower risk of infection in the vaccine group. However, unlike the modified ITT analysis, the difference between the two groups in the per-protocol analysis was not statistically significant. In other words, it could have been due to chance.   

In the full ITT analysis—which included all people enrolled in the study, including those who tested positive for HIV before being vaccinated—there was a 26.4 percent lower risk of infection in the vaccine group. But here, too, the difference between both groups was not statistically significant.

In all three analyses, the researchers reported, those who received the vaccine and became infected with HIV did not have lower viral loads or higher CD4 counts, compared with those who received placebo and became infected with HIV. These findings speak, rather negatively, to a long-held assumption that a vaccine capable of sparking the immune system to prevent HIV infection would also help control HIV replication if infection did occur.

“Taken together,” the researchers conclude, “these data are consistent with a modest protective effect of vaccine in this study. However, there was no significant difference in the HIV-1 viral load or the postinfection CD4+ count between the two study groups.”

The authors also highlight two “intriguing considerations” for future study, given that the Thai clinical trial itself yielded too few HIV infections, in either group, to allow for any serious sub-study analyses.

First, the reduction in the risk of HIV infection among those at low- and medium risk of HIV infection was 40.4 and 47.6 percent in the modified ITT analysis, compared with a 3.7 percent reduction among high-risk individuals. “Perhaps the requirements for protection against transmission in low-risk heterosexual persons are considerably different or less stringent,” Raphael Dolin, MD, of Beth Israel Deaconess Medical Center in Boston, wrote in an accompanying editorial.

The researchers also noted that the vaccine seemed to confer protection against HIV for up to one year but then seemed to dwindle. But again, too few infections occurred in the study to allow for a sound statistical analysis.

While [these results] will not likely have any immediate public health benefit,” said Colonel Nelson Michael, director of the U.S. Military HIV Research Program and an RV 144 study investigator, “we are hopeful that the findings will guide additional studies and accelerate research efforts toward a more effective vaccine.”

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