Eric S. Rosenberg, M.D.

1. Eric S. Rosenberg, M.D. Associate Professor of Medicine Massachusetts General Hospital Harvard Medical School erosenberg1@partners.org

2. 47 year old male • Present to MGH ED with an 8 day history of : Fever to 102.5 Headache Photophobia Myalgias and arthralgias Nausea and vomiting 3rd visit to health care system

3. 47 year old male Additional history: MSM Recent unprotected sex with an HIV infected partner PMH: prior hx of syphilis Exam: Fever Cervical lymphadenopathy Rash (started on torso spread to limbs and scalp)

5. 47 year old male Diagnostics: Test for EBV, CMV, influenza were negative HIV ELISA Positive Western Blot negative (no bands) HIV RNA > 750,000 copies/ml 1:100 dilution 47,000,000 copies/ml CD4 count = 432 cells

6. Diagnosis Acute HIV infection

7. Framing the QuestionMGH-NCSU collaboration Should this individual be treated with antiretroviral therapy??

8. Acute HIV infectionGoals • To discuss the advantages and disadvantages of treating individuals with acute HIV • To review the early biological events of acute HIV infection • To review the immunologic rationale for treatment during acute infection and possible treatment interruption

9. Should individuals with Acute HIV-1 infection be treated with antiretroviral therapy? ? ? ? ? ? Kassutto et al, CID 2006

10. Understanding the terminology and variables that can be measured Viral Load = Speed of the train CD4 count = Distance from cliff Antiviral therapy = Brakes HIV infection J. Coffin, XI International Conf. on AIDS, Vancouver, 1996

11. CTL 6-12 months The Dynamics of Acute HIV Infection Interquartile ranges Rapid Progression 59, 987 HIV Viral Load HIV Ab 28, 240 11,843 Slow Progression 2-8 weeks Lyles et al, 2000

12. Since the level of HIV in the blood predicts progression, What factors influence viral replication?

13. Host genetic factors Viral factors Host immune responses

14. Soluble factors CTL New virus assembly 2-3 Days Cellular Immune Responses

15. If CTL are present, why is the immune response not more effective in HIV infection?

16. HIV-Specific T Helper Cells are impaired in all stages of disease 1. Activation 2. Clonal expansion Class II TCR CD4 3. Cytokine secretion Antigen Presenting Cell CD4+ Th Cell

17. Critical relationship between CD4 and CD8

18. What happens to HIV-specific T helper cells? The acute infection hypothesis Hypothesis (pathogenesis): • HIV-specific T helper cell (CD4) responses are impaired during acute infection Hypothesis (opportunity): • Treatment with ARV during acute infection will protect these responses from being lost

19. CD4 cells Activation & Expansion Infection Impairment Class II TCR CD4

20. CD4 cells Activation & Expansion Antiretroviral therapy Class II TCR CD4

21. Kassuttoet al, CID 2006

22. Spontaneously control virus 1000 100 Stimulation index 10 1 control chronic acute acute LTNP No Rx Rx Rosenberg et al, Science 1997

23. Observation • Immune damage occurs in the earliest stages of acute HIV infection, but there appears to be a “window of opportunity” to reverse this damage with treatment

24. Can treatment be initiated during acute HIV infection and then discontinued?

25. Lessons from Berlin Lisziewicz et al, NEJM 340 (21), 1999

26. Augment HIV-specific immunitySTI Hypothesis RX RX RX RX CTL Th Magnitude Viral Load Time

27. Can therapy be discontinued? • Will HIV-1-specific immune responses generated and maintained during acute infection be enough to control viremia? • If virus returns once therapy is discontinued, can this “snap-shot” of autologous virus further boost the immune system?

28. Structured treatment interruption • Several patterns have emerged • Failure • Transient control of viremia with sudden loss of containment • Control (durability?) Rosenberg et al, Nature 2000Kaufmann et al, PLoS Med 2004

29. Is the “possibility” of STI enough reason to treat individuals during acute HIV infection? Enough question exists regarding the use of STI as a management strategy that the most relevant question in 2008 is whether or not to treat during acute infection

30. Conclusions • It is not known whether treatment during acute infection is the correct thing to do • STI may have a role in management of individuals treated during acute infection but optimal approach not known. • Robust mathematical and statistical modeling (NCSU-MGH) to inform the design of the first randomized trial of treatment versus no treatment during acute HIV.