1. 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

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
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

5. AIDS 24:621, 2010

6. 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

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)
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

8. 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??

10. “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

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
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

14. 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

15. COHERE Study
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

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
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.

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:

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