Treatment of HIV Stops Transmission: Where DO We Go From Here 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

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

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

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

AIDS 24:621, 2010

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

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) 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 TISSUE CERVICOVAGINAL FLUID SEMEN CCR5 Receptor Antagonists Integrase Inhibitors Nonnucleoside RT Inhibitors Nucleoside(tide) Protease

HPTN 052 Enrollment Cohen et al NEJM, July 2011 U.S. Thailand Americas Brazil South Africa Botswana Kenya Thailand India Americas 278 Africa 954 Asia 531 Zimbabwe Malawi WE NEED A MAP WITH n by site OR A LIST OF SITE and N??

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

The Economist, June 2011

Risk Comparison of Serodiscordant Couples Anglemeyer et al. JAMA 2013

HPTN 052: Primary Endpoints Grinsztejn et al Lancet ID (in press) Number of subjects experiencing >1 event Delayed Immediate Tuberculosis 34 (4%) 17 (2%) Serious bacterial infection 13 (1%) 20 (2%) WHO Stage 4 event 19 (2%) 9 (1%) Oesophageal candidiasis 2 Cervical carcinoma Cryptococcosis 1 HIV-related encephalopathy Herpes simplex, chronic 8 Kaposi’s sarcoma CNS Lymphoma Pneumocystis pneumonia Septicemia HIV Wasting Bacterial pneumonia Also I would remind the audience that we kind of redefined “AIDS defining” to include all TB (not just extra-pulmonary) and serous bateial infection

HIV-1 RNA and CD4 Over Time (ITT) Grinstejn et al. Lancet ID (in press) Immediate CD4 (cells/mm3) Delayed Proportion <400 copies/ml This slide shows the viral load and CD4 cell count trajectories in the two groups. These data are presented as intent to treat and thus provide estimates of population level CD4 and VL in the setting of each of the treatment strategies and contain information from all participants including those on the delayed arm who initiated therapy. The upper panel shows the mean CD4 cell counts over time. In the immediate arm, mean CD4 cell count increased from 449  cells/mm3 at enrollment to 678 at 2 years. While in the delayed arm, mean follow-up CD4 count decreased from 449  cells/mm3 at enrollment to 406 at 2 years. The magnitude of the decline is blunted, no doubt, as those individuals with the fastest declines would initiate ART. In the lower panel, proportion with HIV RNA levels<400 copies/ml are shown. In the immediate arm there is a rapid and profound drop in plasma HIV RNA with 90% of subjects reaching an HIV RNA of < 400 copies in the first year. In the delayed group mean HIV RNA level remains stable over time with larger variance as the number of subjects with observed values declines.The proportion of subjects with HIV RNA viral load <400 increases from 5% at enrollment to 20% at 2 years. Again, this represents an increase in those initiating ART over time. . Immediate Delayed

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

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

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”

Higher employment at CD4≥500 Thurminathy, Health Affairs ,2012 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 In multivariable regression analysis with CD4 categories and controls for age and sex, we found that HIV+, no ART adults with CD4≥500 worked 5.8 more days/month than those with CD4<200. This difference was statistically significant, with a p-value<0.05. We found no significant diff. between other CD4 categories and CD4<200. We also found that those with CD4≥500 worked 2.2 more hours/day than those with CD4<200 – in other words, 40 percent more than the 5.5 hours worked per day by those with CD4<200. Takeaway: those with CD4≥500 worked nearly 1 week more than those with CD4<200, and moreover, their employment level was statistically indistinguishable from those of HIV-uninfected peers.

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

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

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