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A Phase II Randomized, Partially Blinded Trial of Antiretroviral Therapy, HIV-specific Immunizations, and IL-2 Cycles to Promote Efficient Control of Viral Replication (ACTG A5024)
J Michael Kilby*1, R Wang2, D Mildvan3, M Fischl4, J Santana-Bagur5, C Pilcher6, A Zolopa7, J Lawrence8, R Pollard9, R Bosch2, R Bucy1, R Mitsuyasu10, and The ACTG A5024 Protocol Team
1Univ of Alabama at Birmingham, USA; 2Harvard Univ, Boston, MA, USA; 3Beth Israel Deaconess Med Ctr, Boston, MA, USA; 4Univ of Miami, FL, USA; 5Univ of Puerto Rico, San Juan; 6Univ of North Carolina at Chapel Hill, USA; 7Stanford Univ, CA, USA; 8Univ of California, San Francisco, USA; 9Univ of California, Davis, USA; and 10Univ of California, Los Angeles, USA
Background: The degree of viremia in the absence of ART is an in
vivo measure of each host’s ability to control HIV replication. We
hypothesized that effectiveness of HIV therapeutic immunization following
different immune-based adjunctive strategies can be measured by comparing the
amount of viral rebound during an analytical therapy interruption (ATI).
Methods: Subjects with viral load of < 50 and CD4 ≥350
while receiving stable ART were
randomized to 4 arms to continue the same ART
± blinded canarypox HIV-specific immunogen (ALVAC vCP1452 or placebo; weeks 0, 8,
16, 24, and 48) or open-label interleukin-2 (Ill-2) cycles (4.5 MIU subcutaneously
twice a day x 5 days for 8 weeks, synchronized with ALVAC/placebo injections)
for a year: A) ALVAC placebo; B) ALVAC;
C) IL-2 + ALVAC placebo; D) IL-2 + ALVAC. Subjects with a viral load of < 50
and CD4 ≥350 after 48 weeks were eligible to interrupt ART. Primary endpoint
was intent-to-treat analysis of rebound (viral load at weeks 11 to 12 after ART interruption or the last measurement before ART resumption and closest to week 12). A 1-sided
Wilcoxon rank-sum was used to compare each experimental arm (B, C, or D) to
controls (A). Subjects were then allowed to remain off or resume ART.
Results: We enrolled 81 subjects (from 19 sites) with
well-balanced characteristics (median baseline CD4 609, all had a viral load of
< 50); > 90% completed at least 40 weeks but only 52 (64%) underwent the
ATI phase. Viral load during ATI was lower in subjects vaccinated with ALVAC
vCP1452 (B) compared to placebo (A), whether by intent-to-treat (median 4.26 vs
5.57 log10; p = 0.011) or
observed (3.97 vs 4.38 log10; p
= 0.053) analysis. Among subjects who received IL-2, there was no significant
difference in the viral load endpoint, whether they received placebo (C) or
vaccine (D), compared to the placebo alone arm (A). Discontinuation (whether
due to loss of follow-up, subject preference, or intolerability) were more
common in subjects receiving IL-2. Grade 3/4 adverse events (e.g., rash, fever,
malaise) never occurred (0%) in arms A and B, but did occur in 6 of 20 (30%) in
C, and 14 of 19 (74%) in D. Although adjunctive therapy with IL-2 resulted in
more adverse events, these subjects experienced greater increases in CD4 T
cells (A = +87; B = +49; C = +311; D = +331 cells).
Conclusions: This exploratory protocol suggests an HIV-specific
immunogen may enhance host immune control as measured by plasma viral load
after ART withdrawal. Although IL-2 boosts absolute numbers of CD4 cells, this
agent does not appear to augment effectiveness of the HIV-specific antigen
immunization.
Keywords: immune-based therapy; vaccination; interleukin-2
