Phase IIB HIV Vaccine Trials & viral load endpoints: looking for efficacy Glenda Gray

1. Phase IIB HIV Vaccine Trials & viral load endpoints: looking for efficacy Glenda Gray Perinatal HIV Research UnitUniversity of the WitwatersrandChris Hani Baragwanath HospitalJohannesburg, South Africa

2. Scope Rational for a phase IIB TOC vaccine trial vs Phase III HIV vaccine trial Viral load endpoints in a phase IIB TOC HVTN 503 phase IIB trial

3. A preventive vaccine should • Mimic the effects of natural exposure to microbes • Provide long lasting protection against infection • Serve as a free standing prevention method • Presently • There is a lack of knowledge of the quality and quantity of immune responses required for protection against HIV or the development of disease

4. Features of a Phase IIB “Test of Concept” HIV Vaccine Trial • Provide a rapid preliminary assessment of whether a vaccine concept is sufficiently promising to warrant advancement to a pivotal phase III trial (intended to inform the “stop-go” decisions) • Be a randomised double blind placebo controlled trial in an at risk population • Directly evaluate efficacy using selected endpoints that augment immunogenicity • Virological and Immunological follow up participants that become infected on the trial will provide valuable information on the effect of vaccine on disease progression

5. Potential Differences between a phase IIB-TOC and phase III pivotal trial design WHO/UNAIDS/IAVI International Expert Group, AIDS, 2007

6. Phase IIB-TOC and Phase III pivotal trials WHO/UNAIDS/IAVI International Expert Group, AIDS, 2007

7. Phase II Screening Test of Concept Trials (STOC) • Novel approach to gather preliminary efficacy data in a short period of time in fewer trial participants • STOC: 30 incident HIV infections to detect a 1 log reduction of viral load which would require a 4% HIV incidence and 500 subjects with 18 months post-vaccination follow up Wayne Koff, IAVI: 2007

8. HIV-1 Virologic and Immunologic Progression and Initiation of ART among HIV-1 infected subjects in a trial of the efficacy of rgp120 Vaccine Gilbert PB, JID, 2005

9. CTL-based vaccines

10. Role of CTL/CMI based HIV vaccines: • A vaccine that may induce a strong T-cell mediated immune response in the absence of broadly neutralizing antibodies that may prove beneficial even if infection is not completely prevented • Vaccine-induced T-cell responses may blunt initial viraemia and prevent the early and massive destruction of memory CD4+T cells that help control infection and prolong disease-free survival • Such a vaccine may impact on secondary transmission of HIV if the vaccine helps control viral replication

11. Evaluating CTL-based vaccines • Vaccine efficacy-susceptibility (VEs): reduction in risk of acquiring HIV infection • Vaccine efficacy-disease progression (VEp):Need to demonstrate that the initial reduction in viral load set-point results in a clinical benefit • Vaccine efficacy-disease progression (VEp):Need to demonstrate the durability of T-cell mediated control of infection • Vaccine efficacy-infectiousness (VEi):Need to demonstrate that vaccination reduced the spread of HIV in the community

12. Johnston M, Fauci A. N Engl J Med 2007;356:2073-2081 • Vaccine efficacy-disease progression (VEp): • Reduce peak viremia • VL set-point • CD4+ count • Durability of VL reduction • Time to initiate ART

13. Course of HIV Infection in Unvaccinated Persons and the Hypothetical Course of Infection in Vaccinated Persons Johnston M, Fauci A. N Engl J Med 2007;356:2073-2081

14. Viral Load as a measure of efficacy may be affected by • Gender • Age • Sub-type • Region • HLA (HLA*B5701 allele) • Route of infection

15. Impact of Early HIV RNA and T-lymphocyte Dynamics during Primary HIV-1 infection and the Subsequent Course of HIV-1 RNA levels and CD4+T-Lymphocytes in the first year of HIV-1 infection Kaufmann GR, JAIDS, 1999

16. Review of early natural history of HIV infection by region, sub-type, gender in cohort studies

17. Disease Progression in Sero-Convertors: predictors of undetectable viremia without ART (France). Madec Y, Clin Infect Dis, 2005 NOTE.     Data are median (range),unless otherwise indicated. a In multivariatelogistic regression, adjusted forthe 6 variables.b   26 years(33rd percentile) vs. >26years.c For each 100 cells/mm3.d   3.76log10 copies/mL (33rd percentile)vs. >3.76 log10 copies/mL.e Dataavailable for 31 subjectswith undetectable viremia and343 subjects with detectableviremia.f   2.61 log10 copies/mL (33rdpercentile) vs. >2.61 log10copies/mL.g Data available for 35subjects with undetectable viremiaand 369 subjects withdetectable viremia during follow-up.

18. FACTORS ASSOCIATED WITH SPONTANEOUS CONTROL OF VIRAL LOAD AND CD4 CELL COUNT PROGRESSION AMONG-1 HIV SERO-CONVERTORS (CASCADE COLLABORATION) Median duration of undetectable viremia was 11,2 months MADEC Y, AIDS, 2005

19. Viral Load and CD4 Count following HIV-1 sero-conversion (sub-type B): impact of gender and region

20. Viral Load and CD4: post sero-conversion in Asia: Impact of Region Cascade: Median Age to AIDS was 11 years Lancet 2000

21. Disease Progression in Sero-Convertors in Africa

22. HAZARD RATIOS FOR PROGRESSION TO AIDS IN MEN AND WOMEN Sterling TR, NEJM, 2001

23. Gender, Age and Route of Infection Touloumi G, AIDS, 2004: Cascade Collaboration

24. Age and Sex Touloumi G, AIDS, 2004: Cascade Collaboration

27. Primary Safety The MRKAd5 HIV-1 gag/pol/nef vaccine will be safe and well tolerated in 18 to 35-year old HIV-1 seronegative adults. Co-Primary Efficacy Infection endpoint Subjects who receive the vaccine will have a lower likelihood of acquiring HIV-1 infection than those who receive placebo AND/OR Viral load endpoint Among subjects who become HIV-1 infected, those who receive the vaccine will have a smaller average viral load set-point at ~ 3 months post seroconversion than those who receive placebo Ensure sufficient power for efficacy analysis in subgroup with baseline Ad5 titers < 200 HVTN 503 – Primary Hypotheses

28. Will CMI responses elicited by the vaccine Prevent persistent HIV infection and/or Control HIV viral replication if infection does occur What is the impact of pre-existing Ad5 titer on immunogenicity What is the role of clade in vaccine protection? That is, will a clade B-based vaccine designed to elicit cellular immunity demonstrate efficacy in non- Clade B regions? It is likely not feasible to develop a different vaccine targeted against each HIV-1 clade. Our ability as a scientific community to provide tailor-made vaccine for specific regions and ensure specificity is not realistic. Key questions addressed by the HVTN 503 phase IIB TOC trial

29. A Test-of-Concept South African Study Address efficacy Merck Ad 5 trivalent vaccine in a Subtype C region Predominantly heterosexual populations The key question addressed by the RSA Study Will the efficacy of the vaccine be influenced by HIV-1 subtype South Africa has studied non-Clade C vaccines (IAVI, HVTN) Other questions addressed by the RSA Study Markedly enhance the information on efficacy in women Refine the assessment of the impact of pre-existing Ad5 titers More than double the number of endpoints to enhance the evaluation of correlates of protection. HVTN 503 phase IIB TOC

30. Conclusion • Results from properly designed phase IIb TOC trials will help with the decision to move ahead with a pivotal trial or go back to the drawing board • Phase IIB TOC will provide further data on viral dynamics in early infection. • Phase IIB TOC trials will further elucidate the interaction between virus and the immune system that will inform vaccine design and development

31. Acknowledgments: HVTN Core: Larry Corey Ann Duerr Niles Eaton HVTN 503 Investigators: Jim Kublin Linda Gail Bekker Gavin Churchyard Koleka Mlisani Mophashane Nchabeleng NIAID: Peggy Johnston Jorge Flores Alan Fix PHRU: Guy de Bruyn James McIntyre Eftyhia Vardas