V ALVAC HIV and AIDSVAX B/E Prime Boost HIV 1 Preventive Vaccine Regimen Final Results of the Phase III Community based Trial in Thailand Supachai Rerks Ngarm, Punnee Pittisutthithum, Sorachai Nitayaphan, Jaranit Kaewkungwal, Joseph Chiu, Merlin Robb, Robert Paris, Arthur Brown, Elizabeth Adams, Sanjay Gurunathan, Donald Francis, Chirasak Khamboonruang, Prasert Thongcharoen, Nelson L. Michael, Prayura Kunasol, Jerome Kim for the MOPH TAVEG Collaboration 0 Primary data to be published online by the New England Journal of Medicine 20 October 2009 at 1050 CET.
V RV 1
RV Trial Objectives and Design Demographics Results 2
Primary Trial Objectives To determine whether immunizationwith ALVAC HIV (vcp1521) boosted by AIDSVAX B/E gp120 B/E protects Thai volunteers from HIV infection. To determine effect of immunizationon viralloadafter load after intercurrent infection. Secondary To determine effect of immunization on CD4 cell count after inter current infection. To confirm the safety of this vaccine combination. To evaluate whether participation is associated with behavior change increasing risk of HIV infection. 3
Acquisition Endpoint Co primary Endpoints ~50% reduction in the relative risk of infection ViralLoadEndpoint orearlyviremia 0.4 log HIV RNA reduction 4
ALVAC HIV (vcp1521) Study Vaccines Recombinant canarypox vector vaccine genetically engineered to express HIV 1 gp120 (subtype E: 92TH023) linked to the transmembrane anchoring portion of gp41 (subtype B: LAI), and HIV 1 gag and protease (subtype B: LAI). AIDSVAX B/E Bivalent HIV gp120 envelope glycoprotein gy vaccine containing a subtype E envelope from the HIV 1 strain CM244 and a subtype B envelope from the HIV 1 strain MN. 5
Design Community based, randomized, double blind, placebocontrolled trial (vaccine: placebo 1:1) Volunteers: HIV negative, 18 30 years of age Excluded: chronic disease, pregnancy or breastfeeding 6 month period of study vaccinations HIV testing every 6 months for 3 years post vaccination 6
Vaccination and Follow up Schedule HIV test, risk assessment and counseling 0.5 1 2 3 (time inyears) 6 month vaccination schedule 3 years of follow up (every 6 mo.) ALVAC HIV (vcp1521) priming at week 0, 4, 12, 24 AIDSVAX B/E gp120 boosting at week 12, 24 7
Important Milestones 24 September 2003 Screening began 20 October 2003 First vaccination 30 December 2005 Enrollment completed 31 July 2006 Vaccination completed July 2007 Spring 2009 June 2009 DSMB Interim Analysis (based on mitt statistical plan) Communication Plan finalized Commitment to ensuring that the Thai people would be the first to learn the outcome irrespective of the final result Study Follow up Complete 8
RV Trial Objectives and Design Demographics Results 9
From Screening to Vaccination Up to 45 days 7 Baseline HIV PCR Positive 26,676 Initial Screen 26,548 HIV Test 17,350 Clinic Screen 16,402 Randomized 16,395 Infection Free 128 Not Referred 418 HIV seropositive 8,780 Discontinued 948 Ineligible 422 TB/Other Disease 341 Female Reproductive 66 Unavailable for 3.5 years 119 Other 8,197 Vaccine 8,198 Placebo 10
Definition of Analytical Methods 7 Baseline HIV PCR Positive 16,402 Randomized Intent to Treat (ITT) 16,395 Infection Free 8,197 Vaccine 8,198 Placebo Modified dintent to Treat t t t (mitt) 6,176 All doses on schedule 6,366 All doses on schedule Per Protocol (PP) 11
Baseline Demographics Gender Age 70 60 50 5033 5031 3164 3167 40 40 % Vaccine % 30 30 Placebo 20 20 70 Vaccine 60 50 3633 3708 2297 2267 2246 2244 Placebo 10 0 Male Female 10 0 18 20 21 25 26 30 12
Baseline Demographics Marital Status % 70 Vaccine 60 Placebo 50 4110 4169 3353 3338 40 30 20 10 734 691 0 Single Married Other 13 Other: Widowed, Separated, Divorced
Definition of Risk Behavior High Risk: Self assessment as high risk OR self report of one or more high risk behavior(s) () in the previous six months Needle sharing Occupation entertainment t t STI symptoms Occupation CSW Sex with HIV positive partner Jail drug injection No condom use during highrisk encounters Multiple sex partners 14
Baseline Demographics Sexual Partner Frequency Vaccine Placebo n (%) n (%) 0 Sex Partners 1864 (22.7) 1801 (22.0) 1 Sex Partner 5428 (66.2) 5495 (67.0) >1 Sex Partners 619 (7.6) 620 (7.6) No Answer 280 (3.4) 273 (3.3) Missing Value 6 (0.1) 9 (0.1) Other Risk Behaviors (from a list of 8 criteria) Same gender partner 184 (2.2%) 182 (2.2%) Needle sharing 68 (0.8%) 65 (0.8%) 15
Low Risk Definition of Risk Behavior Self assessment as low risk AND self report of no high risk behavior in the previous six months Medium Risk Neither low risk nor high risk (as defined above) 16
Risk Behavior Baseline Demographics 70 60 Vaccine Placebo 50 3865 3924 40 % 30 2369 2292 1963 1982 20 10 0 17 Low Medium High
RV Trial Objectives and Design Demographics Results 18
Safety and Reactogenicity 80 Vaccine 70 60 50 5625 5685 Placebo % 40 30 20 1175 1219 10 0 309 295 Any AE Any SAE Any Tx related The vaccine regimen was safe and well tolerated. 19
Acquisition Endpoint: Modified Intent to Treat (mitt) Probability of HIV- -1 Infection n (%) 20 1.0.96 0.9 0.8 07 0.7.64 0.6 0.5 0.4 0.3.38 0.2.15 0.1.41.84.58.68 Placebo Vaccine 00 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 YEARS Placebo Vaccine Vaccine infections: 51 Placebo infections: 74 p = 0.0404 Efficacy: 31.2% 95% CI (OBF): 1.1, 51.2
Acquisition Endpoint: Per Protocol (PP) 1.0 Probabil lity of HIV- -1 Infection n (%) 21 0.9 0.8 07 0.7 0.6 0.5 0.4 0.3 0.2 0.1.49.25.36.70.52.08 Placebo Vaccine.80.59 00 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 YEARS Placebo Vaccine Vaccine infections: 36 Placebo infections: 50 p = 016 0.16 Efficacy: 26.2% 95% CI: 13.3, 51.9
Early Viremia Endpoint 6 Vaccine Placebo 6 5 5 Log 10 Viral Load X X 4 4 3 3 2 Mean Viral Load 2 1 Vaccine recipients: 4.3 log 10 Placebo recipients: 4.2 log 10 p = NS VACCINE PLACEBO 1 Dx 3 wks 6 wks Average 22
Conclusions 1. The observed vaccine efficacy in the mitt analysis was 31.2% [p = 0.04, 95% CI (OBF) 1.1, 52.1]. 2. PP and mitt results were qualitatively consistent. 3. There is no difference in early viremia between vaccine and placebo recipients. 4. The vaccine regimen is safe and well tolerated. 5. Self reported behavioral risk was the same in vaccine and placebo groups. 23
Acknowledgements RV volunteers and community members AFRIMS US and Thai Component Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH Faculty of Tropical Medicine, Mahidol University Global Solutions for Infectious Diseases Henry M. Jackson Foundation for the Advancement of Military Medicine Ministry of Public Health, Thailand sanofi pasteur U.S. Military HIV Research Program, Walter Reed Army Institute of Research; U.S. Army Medical Research and Materiel Command 24