Primary HIV-1 Infection Pathogenesis, Diagnosis, and Treatment Summary of Evidence

1. Primary HIV-1 Infection Pathogenesis, Diagnosis, and Treatment Summary of Evidence Martin Markowitz M.D. Clinical Director and Staff Investigator Aaron Diamond AIDS Research Center Aaron Diamond Professor at the Rockefeller University

2. Topics • Detection of acute HIV-1 infection • Point of care tests to diagnose acute HIV-1 • Treatment of acute HIV-1 infection • Benefits of early therapy • Results of randomized clinical trials • Reservoir size • GALT and CD4 depletion and immune reconstitution

3. Staging of Acute and Early HIV-1 Infection Modified from Cohen et al NEJM 2011; 364:20 p 1943-54

4. HIV Testing Assays and Window Periods Branson and Steckler J. Inf. Dis. 2012; 205:521-524

5. CDC AHI Study Patel et al, J. Clin Virol 2012 54:42-47

6. Lack of sensitivity of Combo RT Ag Rosenberg et al J. Inf. Dis. 2012; 205:p528-534

7. Conclusions:1 • Improvements in technology do allow for earlier diagnosis • “the window is closing, but still remains open” • However, point of care tests have not performed well in field testing to date • Supports continued use of nucleic acid amplification testing in conjunction with serologic testing • Studies support cost effectiveness

8. Treatment of Acute HIV-1 Infection • Potential benefits: • Beneficial effect on laboratory markers and disease progression • Decrease severity of acute disease • Alter initial viral set point, which can affect disease progression rates • Reduce rate of viral mutation as a result of suppression of viral replication • Reduce risk for viral transmission • Potential risks: • Drug toxicities • Development of ART drug resistance • Need for continuous therapy and strict adherence • Adverse effect on quality of life DHHS Guidelines, 2012

9. Results of randomized clinical trials in acute and early HIV-1 infection

10. Arguments for early and continuously suppressive therapy • Maintained suppression maintains reduced risk of transmission • Sparing of immune system • HIV-1 specific immune responses • Integrity of the GALT • Maintains lower levels of viral reservoirs • Levels of proviral DNA measured in CD4+ T cells

11. Early establishment of the latently infected CD4+ T cell reservoir Ananworanich et al. PLOS One 2012: 7(3);e33948

12. Reservoir size during acute infection predicts size after 24 weeks of therapy Ananworanich et al. 5th Intl. Workshop on HIV Persistence 2011

13. Levels of HIV-1 DNA in CD4+ T cells: Effect of Early Therapy Buzon et al 5th Intl. Wkshp on HIV Persistence 2011

14. Levels of HIV-1 DNA in CD4+ T cells: Effects of Early Therapy Buzon et al 5th Intl. Wkshp on HIV Persistence 2011

15. Infectious HIV-1 in resting CD4+ T cells after 96-weeks of suppressive cART P=0.81 Markowitz et al 5th Intl. Wkshp on HIV Persistence 2011

16. Persistent depletion of % CD4+ T cells in patients followed cross-sectionally for up to 7 years * * ** ** Mehandru et al PLOS Medicine 2006

17. Rapid loss of mucosal CD4+ T cells during acute infection Ananworanich et al. PLOS One 2012: 7(3);e33948

18. Immune reconstitution in mucosal CD4+CCR5+ T cells in GALT Ananworanich et al. PLOS One 2012: 7(3);e33948

19. Immune reconstitution in GALT Markowitz et al 5th Intl. Wkshp on HIV Persistence 2011

20. Conclusions 2 • Randomized clinical trials confirm virologic and immunologic benefits of early therapy • Long term benefit yet to be demonstrated • Very early treatment • Limits size of viral reservoirs • May protect or allow for reconstitution of GI-tract associated lymphoid tissue • sCD14 levels, a marker of microbial translocation, remain comparable to HIV-uninfected individuals • Result in normalization of markers of immune activation • Relative benefits of more intensive therapy during acute infection have yet to be shown in the setting of acute and early infection