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

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. Topics. Detection of acute HIV-1 infection

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

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  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

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