1. Treatment of HIV Stops Transmission : Where DO We Go From Here? Cohen et al Lancet, Nov. 2013 Myron S. Cohen, MD Yergan-Bate Professor Medicine, Microbiology and Epidemiology Director, Institute for Global Health & Infectious Diseases

2. BACK TO BASICS How HIV Became Pandemic Ro = bDC When Ro >1 epidemic is sustained b = Efficiency of transmission D = Duration of infectiousness C = Number of people (partners) exposed Anderson and May, 1966

3. Viral Load Predicts Heterosexual Transmission Source: Quinn et al. (2000). N Engl J Med, 342, 13, 921–929.

4. Four Prevention Opportunities Cohen et al. Lancet, 2013 YEARS Treatment Of HIV Reduced Infectivity YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital) INFECTED

5. AIDS 24:621, 2010

6. Four Prevention Opportunities Cohen et al. Lancet, 2013 YEARS Treatment Of HIV Reduced Infectivity YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital) INFECTED

7. Antiretroviral Exposure at Mucosal Surfaces Rectal Tissue, CVF, Semen Exposure Relative to Blood MRV (4) MRV (0.6) MRV (27) RAL (2) RAL (150) ETR (8) TFV (46) DRV (2.7) RTV (13) ETR (1.3) EVF (0.6) DLV (0.2) ETR (0.15) EFV (0.03) FTC/ 3TC (4) ZDV (2) DDI (0.21) ABC (0.08) D4T (0.05) 3TC (6) TFV (5) D4T (3.5) ZDV (2) FTC (2.6) APV (0.5) RTV (0.3) ATV (0.18) LPV (0.08) SQV (ND) IDV (2) IDV (1) APV (0.2) SQV & RTV (0.03) LPV/NFV (0.05) DRV (0.17) RAL (1) NVP (0.8) NVP (0.7) TFV (1) ABC (1.5) RECTAL TISSUECERVICOVAGINAL FLUIDSEMEN CCR5 Receptor Antagonists Integrase Inhibitors Nonnucleoside RT Inhibitors Nucleoside(tide) RT Inhibitors Protease Inhibitors

8. HPTN 052 Enrollment Cohen et al NEJM, July 2011 U.S. Brazil South Africa Botswana Kenya Thailand India Americas 278 Africa 954 Asia 531 Zimbabwe Malawi

10. Bruce Alberts, editor of Science “The results have galvanized efforts to end the world’s AIDS epidemic in a way that would have been inconceivable even a year ago”

11. The Economist, June 2011

12. Risk Comparison of Serodiscordant Couples Anglemeyer et al. JAMA 2013

13. HPTN 052: Primary Endpoints Grinsztejn et al Lancet ID (in press) Number of subjects experiencing >1 event DelayedImmediate Tuberculosis 34 (4%)17 (2%) Serious bacterial infection 13 (1%)20 (2%) WHO Stage 4 event 19 (2%)9 (1%) Oesophageal candidiasis 22 Cervical carcinoma 20 Cryptococcosis 01 HIV-related encephalopathy 10 Herpes simplex, chronic 82 Kaposi’s sarcoma 11 CNS Lymphoma 10 Pneumocystis pneumonia 10 Septicemia 01 HIV Wasting 20 Bacterial pneumonia 12

14. Immediate Delayed HIV-1 RNA and CD4 Over Time (ITT) Grinstejn et al. Lancet ID (in press)

15. COHERE Study 1998-2010 A. Mocroft, et al., Oxford Journal, August 2013 Relationship between current CD4 and AIDS-defining illness with a CD4 count ≥500 cells/μL: relationship with current viral load and antiretroviral treatment All patientsARV naive First 6 mo cART VL < 400VL > 400

16. EVERYONE Should Start ART IAS-USA DHHS Guidelines HIV replication has negative consequences Earlier ART prolongs survival ART blocks HIV transmission BUT… arguments for delay in ART include Anticipated detection of novel “harm” (?) Ongoing search for visible “benefit” (?) START and TEMPERANO studies (?) Distracting focus on logistical challenges

18. HPTN 052 Cost Effectiveness Walensky et al. NEJM, 2013 HPTN 052 results for India, South Africa used Treatment/Prevention benefits both considered i) In South Africa, over the short term, early ART is “cost-saving” ii) Over time ART in INDIA and South Africa proves “very cost effective”

19. Higher employment at CD4≥500 Compared to CD4<200, CD4≥500 associated with –5.8 more days/month –2.2 more hours/day (40% more than ref. mean of 5.5) Linear regression model with age, age-squared, and sex included as controls ** p<0.05, * p<0.10 Reference group has CD4<200 Those with CD4≥500 worked nearly 1 week/month more than those with CD4<200, and as much as HIV- uninfected adults Thurminathy, Health Affairs,2012

20. Who SHOULD We Treat? Couples (WHO Guidelines) CD4 Count>500 (WHO) Pregnant women (WHO) WHO estimates 26,000,00 people

21. Fig. 1a: Time series of maps showing the evolution of the proportion of the HIV-infected adults (≥15 years of age) receiving ART across the demographic surveillance area (2005 to 2008, left to right, top row; 2009 to 2011, left to right, bottom row). F Tanser et al. Science 2013;339:966-971

23. Antiretroviral Treatment Prevents HIV Axiom: viral suppression stops HIV spread Axiom: immediate ART improves health 30 years of “mixed messages” are a problem A NEW message will improve adherence Immediate, universal ART is the best strategy available for the HIV pandemic