ALVAC-HIV Vaccine Fails to Halt Disease Progression in Patients Undergoing Antiretroviral Treatment Interruption

A study published in the July 11, 2008 issue of AIDS adds to the recent string of disappointing results from HIV vaccine studies.

In this analysis, researchers with the international ORVACS Study Group evaluated the immunogenicity and clinical efficacy of 2 immunization strategies using the ALVAC-HIV (vCP1452) recombinant canarypox vaccine in HIV positive patients on antiretroviral therapy.

Unlike the adenovirus candidate being tested in the discontinued STEP trial, which was a preventive vaccine intended to stop initial HIV infection, ALVAC-HIV is a therapeutic vaccine designed to slow or halt disease progression in people who are already infected.

This present study was a randomized, double-blind, placebo-controlled, Phase II trial that included 65 patients with chronic HIV infection who were receiving antiretroviral therapy at baseline. All had a CD4 T-cell count above 350 cells/mm3, a CD4 nadir (lowest-ever level) below 400 cells/ mm3, and HIV viral load less than 400 copies/mL.

Participants were equally randomized to receive either 4 injections at weeks 0, 4, 8, 20; 3 injections at weeks 4, 8, 20; or placebo. The underwent antiretroviral treatment interruption, resuming therapy when CD4 count fell below 250 cells/mm3 or decreased by 50% from baseline, or when HIV viral load rose to more than 50,000 copies/mL.

The primary endpoint was vaccine immunogenicity at week 24 as measured by enzyme-linked immunospot interferon-gamma against the HIV-gag-reverse transcriptase-nef sequences in the vaccine. Secondary endpoints included time to treatment resumption and viral load following treatment interruption at week 24.

Results

• Changes from baseline in HIV-specific T-cells in the group receiving 4 vaccine injections were significantly greater than those in the placebo arm group of patients receiving placebo (+480 vs +8 spot-forming cells; P = 0.014).

• Changes were similar, however, in the 4-injection vaccine group compared with the 3-injection arm (+480 vs +322 spot-forming cells; P = non-significant).

• Week 36 HIV viral load after treatment interruption was higher in the 4-injection vaccine arm (4.71 log10 copies/mL; P = 0.023) and the 3-injection arm (4.82 log10 copies/mL; P = 0.009) compared with the placebo arm (4.40 log10 copies/mL).

• 74% of patients in the 4-injection vaccine arm, 55% in the 3-injection vaccine arm, and 23% in the placebo arm reached treatment resumption criteria by week 48 (P = 0.013).

• By 96 weeks, the corresponding percentages were 90%, 71%, and 59%.

• 2 independent factors influenced time to treatment resumption:

• Immunization with the vaccine (P = 0.048 for 3 injections; P = 0.003 for 4 injections).

• CD4 cell nadir (P = 0.002).

In conclusion, the study authors wrote, "Significant immunogenicity was induced by vCP1452; however, this strategy was independently associated with a shorter time to resume therapy and higher viral rebound."

Discussion

This study showed that the vCP1452 canarypox vaccine administered to chronic HIV patients on combination antiretroviral therapy induced significant T-cell response. Overall, the study authors wrote in their discussion, vCP1452-induced immunogenicity remained weak, "far below the levels usually observed in 'long-term nonprogressors'." Unfortunately, this vaccine-induced immunity was associated with reduced control of viral replication.

"The most striking result from our study," they continued, is the poor viral control after treatment interruption and the shorter time to resumption of combination antiretroviral therapy in patients who were vaccinated.

They observed that their study results differed from those of prior studies in chronically infected HIV patients, which "had shown some benefit during treatment interruption after immunization with a canarypox HIV vaccine used either alone or in combination with other immunostimulants."

Fortunately, the immunization regimens used in this study were safe, as there were no significant treatment-related adverse effects, no major reductions in CD4 cell counts, or increased frequency of AIDS-related or unrelated events during treatment interruption.

"Once reinstituted," wrote the authors, "combination ART was effective with rapid control of the virus and increases in CD4 cell counts. Our treatment interruption was brief, which we believe enhanced the safety aspects of this trial."

They emphasized that future studies involving treatment interruption should minimize time off therapy if viral load rebounds. "We believe that treatment interruptions should not even be considered in future trials unless immunogenicity is significantly improved," they stated.

According to the authors, "this placebo-controlled study conducted in chronically infected patients suggests that the immunogenicity conferred by the vCP1452 candidate vaccine alone is associated with higher virus production following treatment interruption, independent of the CD4 nadir."

Finally, they stated, "Further studies are required to better define the appropriate balance between the levels of generated immune responses by T-cell-based vaccines and its effect on controlling viral replication in the absence of antiretroviral therapy."

7/29/08

Reference
B Autran, RL Murphy, D Costagliola, and others (ORVACS Study Group). Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic immunization with the ALVAC-HIV vaccine (vCP1452). AIDS 22(11): 1313-1322. July 11, 2008. (Abstract)