Treatment of HIV Stops Transmission : Where DO We Go From Here? Cohen et al Lancet, Nov. 2013 Myron...

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