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Treatment of HIV Stops Transmission:
Where DO We Go From Here? Cohen et al Lancet , Nov. 2013
Myron S. Cohen, MD
Yergan-Bate ProfessorMedicine, Microbiology and Epidemiology
Director, Institute for Global Health & Infectious Diseases
BACK TO BASICSHow 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
Treatment Of HIVReduced Infectivity
YEARS
UNEXPOSED
Behavioral,Structural
StructuralCircumcisio
nCondoms
HOURS
VaccinesART PrEP
Microbicides
EXPOSED (precoital/coital)
72h
VaccinesART PEP
EXPOSED (postcoital)
INFECTED
AIDS 24:621, 2010
Four Prevention Opportunities Cohen et al. Lancet, 2013
YEARS
Treatment Of HIVReduced Infectivity
YEARS
UNEXPOSED
Behavioral,Structural
StructuralCircumcisio
nCondoms
HOURS
VaccinesART PrEP
Microbicides
EXPOSED (precoital/coital)
72h
VaccinesART PEP
EXPOSED (postcoital)
INFECTED
Antiretroviral Exposure at Mucosal Surfaces Rectal Tissue, CVF, Semen Exposure Relative to Blood
CCR5 RA INSTI NNRTI NRTI PI
Ma
trix
:Blo
od
Pla
sma
Ra
tio
0.01
0.1
1
10
100
1000
ARV Class
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 TISSUE CERVICOVAGINAL FLUID SEMEN
CCR5Receptor
Antagonists
IntegraseInhibitors
NonnucleosideRT Inhibitors
Nucleoside(tide)RT Inhibitors
ProteaseInhibitors
HPTN 052 Enrollment Cohen et al NEJM, July 2011
U.S.
Brazil
South Africa
Botswana
Kenya
Thailand
IndiaAmericas
278
Africa954
Asia531Zimbabwe
Malawi
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”
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 2
Cervical carcinoma 2 0
Cryptococcosis 0 1
HIV-related encephalopathy 1 0
Herpes simplex, chronic 8 2
Kaposi’s sarcoma 1 1
CNS Lymphoma 1 0
Pneumocystis pneumonia 1 0
Septicemia 0 1
HIV Wasting 2 0
Bacterial pneumonia 1 2
ImmediateDelayed
HIV-1 RNA and CD4 Over Time (ITT) Grinstejn et al. Lancet ID (in press)
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 patients ARV naive First 6 mo cART VL < 400 VL > 400
EVERYONE Should Start ARTIAS-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
• 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
Regression model coefficients(1) (2)
Outcome:Days worked in the
past monthHours worked on usual day in past
CD4<200 Reference ReferenceCD4 200-349 2.7 1.8CD4 350-499 4.8 0.9CD4 ≥500 5.8** 2.2*Observations 107 107
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
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