9th Advanced HIV Course Aix-en-Provence 2011

Role of ARV as Prevention

Martin FisherBrighton and Sussex University Hospitals, UK

New HIV diagnoses (Adjusted) among MSM, UK, 2001-2010

Global HIV Epidemic

The number of new infections exceeds the number of new cases starting ART5 million untreated at <200; 10 million at <350

Clinical trial evidence for preventing sexual HIV transmission –2011

Efficacy

Study Effect size (CI)

Medical male circumcision (Orange Farm, Rakai, Kisumu)

54% (38; 66)

HIV Vaccine (Thailand)

31% (1; 51)

0% 10 20 30 40 50 60 70 80 90 100%

Modified from Slim Karim 6th Transmission Workshop, 2011

Clinical trial evidence for preventing sexual HIV transmission –2011

Efficacy

Study Effect size (CI)

Medical male circumcision (Orange Farm, Rakai, Kisumu)

54% (38; 66)

HIV Vaccine (Thailand)

31% (1; 51)

0% 10 20 30 40 50 60 70 80 90 100%

39% (6; 60)Tenofovir vaginal(SA)

Truvada oral MSMs(America’s, Thailand, SA)

44% (15; 63)

Treatment for prevention(Africa, Asia, America’s)

96% (73; 99)

Truvada oral for heterosexuals(Botswana TDF2)

63% (21; 48)

Tenofovir/truvada for discordant couples(Partners PrEP)

73% (49; 85)

Truvada for women(Kenya, SA, Tanzania)

0% (-69; 41)

Modified from Slim Karim 6th Transmission Workshop, 2011

Outline and Aims

Biological rationale for use of ART as prevention PEP, PrEP Microbicides Treatment as Prevention

Summarise latest key data on Prevention HPTN052, PrEP studies

Implications for global HIV prevention strategies Clinical implications

Four HIV-1 Prevention OpportunitiesFour HIV-1 Prevention Opportunities

YEARS

Treatment of HIVReduced Infectivity

INFECTED

YEARS

UNEXPOSED

Behavioral,Structural

CircumcisionCondoms

Cohen et al. JCI 2008; Cohen. IAS Journal online 2008

HOURS

VaccinesART PrEPMicrobicides

RX STDS

EXPOSED (precoital/coital)

72 HRS

VaccinesART PEP

EXPOSED (postcoital)

Cohen et al. JCI 2008; Cohen. IAS Journal online 2008

SemenSemenSI HIV (T-tropic)SI HIV (T-tropic)

NSI HIV (M-tropic)NSI HIV (M-tropic)

Lamina propriaLamina propriaDendritic cellDendritic cellCD4+CD4+CCR5+CCR5+DC-SIGN+DC-SIGN+

HIV-1 HIV-1 “swarm”“swarm”

T-cellT-cell

CD4CD4

CCR5CCR5DC-SIGNDC-SIGN

MigrationMigrationto lymphoid organsto lymphoid organs Transmitted HIV:Transmitted HIV:

99% R5, 82% 1 variant99% R5, 82% 1 variant Geijtenbeek TBH, et al. Cell 2000;100:587-597

Microbicides: Efficacy trials pre-ARV

Product Effect Confidence

interval

Interpretation at the time

N9 1.5 1.0 - 2.2 ?harm

Savvy 0.88

1.7

0.33 - 2.27

0.9 - 3.5

too few events

Carraguard 0.87 0.69 - 1.09 poor adherence

CS 1.61

0.8

0.86 - 3.01

0.3 - 1.8

?pH

?osmolality

0.5% PRO 2000

2% PRO 2000

0.7

1.05

1.21

0.5 - 1.08

0.82 - 1.34

0.88 - 1.68

reduced activity after coitus

Buffer Gel 1.1 0.75 - 1.62 lack of potency

Tenofovir 1% vaginal gel Tenofovir 1% vaginal gel protects - CAPRISA 004protects - CAPRISA 004

IAS 2010IAS 2010Science 2010Science 2010

10

ScienceJuly2011

More data on microbicides to come… Alternative agents: Delpivirine most

advanced Alternative methods of administration Acceptability to women Efficacy versus oral PrEP (VOICE)

10-5

10-4

10-3

10-2

10-1

101

102

103

104

105

106

107

108

Transmission

Vir

us

Co

nce

ntr

atio

n in

Ext

race

llula

r F

luid

or

Pla

sma

(c/m

l)

Time Postexposure (days)

0 5 10 15 20 30 3525 40 45 50 55 60 65 70

Set Point

Limit of detection for HIV RNA

Reservoir

Symptoms

Virus dissemination

Window of Opportunity? Established Infection

Transit

.

eclipse

100

HIV-1 Acquisition and Acute InfectionHIV-1 Acquisition and Acute Infection

Evidence: HCW case control study

16.1

5.2

5.1

6.4

0.2

0 5 10 15 20

Deep

Visible blood

Vessel

AIDS

AZT

OR

Cardo DM et al. N. Engl. J Med 1997; 337:1485

Significant exposure risk Negligible exposure risk

≤72 hours >72 hours since exposure

Source patientknown to be HIV+

Source patient of unknown HIV status

nPEP recommended

Case-by-casedetermination

nPEPnot recommended

Algorithm for nPEP UsageAlgorithm for nPEP Usage

Based upon British and USA Guidelines

Significant exposure risk Negligible exposure risk

≤72 hours >72 hours since exposure

Source patientknown to be HIV+

Source patient of unknown HIV status

nPEP recommended

Case-by-casedetermination

nPEPnot recommended

Algorithm for nPEP UsageAlgorithm for nPEP Usage

Based upon British and USA Guidelines

If “source” patient is on ART and undetectable?

Concerns with post-exposure prophylaxis Cost and cost-effectiveness Access issues (within 72 hours) Poor tolerability of existing regimens Multiple presentations

Patients ability to predict “risk” Failure to demonstrate benefit at population level

Praca Onze project in Brazil

How to alter recommendations if “source” individual is on ART and “undetectable…”

0 2 4 6 8 10 12 140

25

50

75

100

Number of Rectal Exposures

% U

nin

fect

ed A

nim

als

Controls (n = 18)

Injectable FTC (n = 6)

High-Dose Injectable Truvada (n = 6)

Oral Truvada (n = 6)

Oral TDF (n = 4)

PrEP in Macaques PrEP in Macaques

Garcia-Lerma et al. PLoS Med 2008

iPrEX Study

•44% reduction in HIV (95% CI: 15-63%) (p=0.005)•58%reduction (95% CI: 32-74%)(p=0.01) if reported URAI in 6m preceding enrolment

FEM-PREP – closed on 18 April 2011

Equal numbers of HIV seroconversions (28 each gp) Women from Kenya, South Africa and Tanzania, many of

whom were commercial sex workers Daily truvada (tenofovir + emtricitabine) 28 seroconversions in each group (estimated 95% CI for

HR: 0.59-1.69) Higher pregnancy rate in the women taking truvada Self-reported adherence ~ 95% overall

Antiretroviral Pre-Exposure Prophylaxis

for HIV-1 Prevention among Heterosexual African Men and Women:

The Partners PrEP Study

Jared Baeten & Connie Celumon behalf of

The Partners PrEP Study TeamIAS 2011

Partners PrEP Study

4758 HIV serodiscordant couples (HIV+ partner not yet medically eligible for ART)

TDF once daily Placebo once daily

Randomize HIV- partners (normal liver, renal, hematologic function)

1° endpoint: HIV infection in HIV- partnerCo- 1° endpoint: Safety

Follow couples for up to 36 months

FTC/TDF once daily

All receiving comprehensive HIV prevention services

Primary efficacy results

TDF FTC/TDF Placebo

Number of HIV infections 18 13 47

HIV incidence, per 100 person-years 0.74 0.53 1.92

HIV protection efficacy, vs placebo

62% 73%

95% CI (34-78%) (49-85%)

p-value 0.0003 <0.0001

Z-score, vs. H0=0.7 -2.17 -2.99

• Primary analysis: modified intention-to-treat (mITT)• excluding infections present at randomization (3 TDF, 3 FTC/TDF, 6 placebo)

ITT analysis results similar

Effect of TDF and FTC/TDF

statistically similar (p=0.18)

Subgroup analysis - gender

Efficacy 95% CI P-value Interaction p-value

TDF

Women

Men

68%

55%

29-85%

4-79%

p=0.01

p=0.04p=0.54

FTC/TDF

Women

Men

62%

83%

19-82%

49-94%

p=0.01

p=0.001p=0.24

• Both TDF and FTC/TDF significantly reduced HIV risk in both men and women

Women: 42 total infections: 8 TDF, 9 FTC/TDF, 25 placebo

Men: 36 infections: 10 TDF, 4 FTC/TDF, 22 placebo

Daily oral antiretroviral use for the prevention of HIV infection in

heterosexually active young adults in Botswana:

results from the TDF2 study

MC Thigpen, PM Kebaabetswe, DK Smith, TM Segolodi, FA Soud, K Chillag, LI Chirwa, M Kasonde,

R Mutanhaurwa, FL Henderson, S Pathak, R Gvetadze, CE Rose, LA Paxton for the TDF2 Study Team

27

28

29

TDF-2: Efficacy – Intention-to-Treat Analysis

Failure

0

0.0100

0.0200

0.0300

0.0400

0.0500

0.0600

0.0700

0.0800

0.0900

years

0.00000 1.00000 2.00000 3.00000

Time to Event Analysis of Seroconverter DataAnalysis using all 33 Seroconverters

TRT FTC/TDF Placebo

9 HIV-infected in TDF-FTC group and 24 HIV-infected in placebo group Overall protective efficacy 62.6% (95% CI 21.5 to 83.4, p=0.0133)

30

TDF-2: HIV Infection By Gender

Using 33 Seroconverters

TDF-FTC Placebo Efficacy 95% CI P-value

Female 7 14 49.4 -21.7, 80.8 0.107

Male 2 10 80.1 24.6, 96.9 0.026

Using 23 Seroconverters

TDF-FTC Placebo Efficacy 95% CI P-value

Female 3 13 75.5 23.8, 94.4 0.021

Male 1 6 82.4 -2.8, 99.1 0.065

31

Dumond et al. CROI 2008N=12

Maraviroc as PrEP?Maraviroc as PrEP?

Vaginal Tissue

Blood Plasma

N = 12 Protein-free IC90 = 0.5 ng/ml

Cervicovaginal Fluid

Why only 3 of 4 studies show a benefit? Multiple researchers working on:

Adherence Pharmacokinetics Sexual behaviour

Further studies still to report

Future PrEP Studies: ethical considerations Is it ethical to have a placebo?

ANRS Study: Coital PrEP in MSM UK: Immediate versus deferred PrEP

Will it be acceptable not to have a placebo? “pill parties”

Issues with implementing PrEP

Which drug(s)? maraviroc, raltegravir

How often? Daily, coitally?

Who to target? How often to monitor?

HIV test, toxicity screening Population impacts: condom displacement,

resistance

Proportion MSM in the community reporting having had an HIV test, London: 2000-2008

University College London/Health Protection Agency

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2000 2001 2002 2003 2004 2005 2008

% M

SM

re

pro

tin

g H

IV t

es

t

Year of survey

HIV test in last year

HIV test ever

Thai Study: no transmissions < 1049; Tovanabutra, JAIDS 2002

Meta-analysis: ART and viral load and transmission

Attia, AIDS, 2009

Partners in Prevention StudyDonnell, Lancet, 2010

92% reduction in HIV transmission with ART

Stable, healthy, serodiscordant couples, sexually activeCD4 count: 350 to 550 cells/mm3

Primary Transmission EndpointVirologically-linked transmission events

Primary Clinical EndpointWHO stage 4 clinical events, pulmonary tuberculosis, severe

bacterial infection and/or death

HPTN 052 Study Design

Immediate ART CD4 350-550

Delayed ART CD4 <250

Randomization

10,838 Individuals Screened

Immediate Arm886 Couples

Delayed Arm877 Couples

Major reasons for exclusion: 3058 HIV+ but CD4 count out of range 2565 HIV- but HIV+ partner ineligible 308 Seroconcordant couples 155 Ineligible due to sexual history

HPTN 052 Enrollment

1763 Couples(3526 Individuals)

Randomized

HPTN 052 Enrollment(Total Enrollment: 1763 couples)

U.S.

Brazil

South Africa

Botswana

Kenya

Thailand

IndiaAmericas

278

Africa954

Asia531Zimbabwe

Malawi

Total HIV-1 Transmission Events: 39

HPTN 052: HIV-1 Transmission

Immediate Arm

4

Delayed Arm

35

p < 0.0001

Total HIV-1 Transmission Events: 39

HPTN 052: HIV-1 Transmission

Linked Transmissions: 28

Unlinked or TBD Transmissions: 11

p < 0.001

Immediate Arm: 1

Delayed Arm: 27

• 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm3

• 23/28 (82%) transmissions in sub-Saharan Africa

• 18/28 (64%) transmissions from female to male partners

Granich et al Lancet 2009; 373:48-57

• 95% reduction in new HIV cases in 10 years

• HIV Incidence reduced from

15-20,000 to 1000 per million

• Prevalence decreases to less than 1% by 2050

Granich et al, Lancet 2009

• Annual testing by all >15 year old individuals• All HIV+ individuals started on ART immediately • 99% decrease in infectiousness• High adherence with ART• Low failure with first line ART

ART for Prevention: The WHO Model

1980 2000 2020 2040

Models of ART and transmission

San Francisco Katz, Am J Pub Health, 2002

Increase in risk behaviour in MSM will outweigh benefit of ART

Australia Clements, JAIDS, 2004 ART benefits outweighed by increased risk in MSM

South Africa Bertran, JAIDS, 2004 WHO guidelines: 12% reduction in incidence

US guidelines: 72%

Amsterdam Bezemer, AIDS, 2008 Benefits of ART outweighed by increased risk behaviour in MSM

British Columbia Lima, JID, 2008 67% reduction in incidence if 100% treated at CD4 <350

Australia Wilson, Lancet, 2008 ART rather than condoms may increase incidence 4 fold

WHO Granich, Lancet, 2009 Annual testing and universal ART could reduce prevalence of HIV to <1%

Impact may be different for MSM and heterosexuals?

The authors estimated that only about 19% of HIV infected individuals in the USA have an undetectable HIV-1 RNA level

The authors estimated that only about 19% of HIV infected individuals in the USA have an undetectable HIV-1 RNA level

Spectrum of Engagement in HIV Care - USA

Gardner E, McLees M, Steiner J, del Rio C, Burman W, Clin Infect Dis. (2011) 52 (6): 793-800

Might test-and-treat work differently in different contexts? Heterosexual epidemic

Lower partner change rate Less concurrency Most transmissions occur from established infection

Homosexual epidemic High rates of partner change More concurrency High rates of onward transmission from acute infection

Role of undiagnosed and primary HIV in onward transmissionUndiagnosed HIV: US: 54% of new infections come from 25% undiagnosed

Marks, AIDS 2006 Amsterdam: 90% from 24%

Bezemer, AIDS 2008 Brighton: 76% from 30%

Fisher, AIDS 2010

Primary HIV Infection: High viral load Infectivity increased ? 10-1000x PHI accounts for 10-50% of onward infections

Is the World ready yet for test-and-treat? Treating for public rather than individual health

Recruitment to START has been slow… Costs associated with this

£241million/year for the UK alone Ability to support infrastructure:

High testing rates High uptake of treatment rates Maintenance within treatment and care Virological monitoring

Controlling the epidemic_17Jul11

0

20

40

60

80

100

LCM

(n=590)

CDM

(n=617)

LCM

(n=109)

CDM (n=78)

<199 200-999 1000-9999 ≥10000

First-line ART Second-line ART

N.B. 149 values of <400 c/ml imputed as <199 c/ml

Pe

rce

nta

ge

0

20

40

60

80

100

LCM

(n=590)

CDM

(n=617)

LCM

(n=109)

CDM (n=78)

<199 200-999 1000-9999 ≥10000

First-line ART Second-line ART

N.B. 149 values of <400 c/ml imputed as <199 c/ml

Pe

rce

nta

ge

VL at 5y in DART, by monitoring strategy

C Kityo, D Dunn, R Kasirye et al CROI 2011

Clinical trial evidence for preventing sexual HIV transmission –2011

Efficacy

Study Effect size (CI)

Medical male circumcision (Orange Farm, Rakai, Kisumu)

54% (38; 66)

HIV Vaccine (Thailand)

31% (1; 51)

0% 10 20 30 40 50 60 70 80 90 100%

39% (6; 60)Tenofovir vaginal(SA)

Truvada oral MSMs(America’s, Thailand, SA)

44% (15; 63)

Treatment for prevention(Africa, Asia, America’s)

96% (73; 99)

Truvada oral for heterosexuals(Botswana TDF2)

63% (21; 48)

Tenofovir/truvada for discordant couples(Partners PrEP)

73% (49; 85)

Truvada for women(Kenya, SA, Tanzania)

0% (-69; 41)

Modified from Slim Karim 6th Transmission Workshop, 2011

Funding HIV with comprehensive prevention

The Economist, June 2011

Clinical Management

Serodiscordant couples Heterosexual: good data for reduced transmission MSM no data but plausible Early ART supported by all treatment guidelines

Seronegative persons with multiple partners Inform of PEP Inform of PrEP – if study available

Reinforce multifaceted approach to prevention

Increased testing, increased frequency of testing, and reducing undiagnosed infection central to any benefit of ART on transmission

Behavioural Intervention- Abstinence- Be Faithful

HIV Counselling and TestingCoates T, Lancet 2000

Male Condoms

Female Condoms

Treatment of STIs

Grosskurth H, Lancet 2000

Male circumcision

Auvert B, PloS Med 2005 Gray R, Lancet 2007 Bailey R, Lancet 2007

Microbicidesfor women

Abdool Karim Q, Science 2010

Treatment for prevention

Donnell D, Lancet 2010Cohen M, NEJM 2011

Behavioural positive prevention

Fisher J, JAIDS 2004

Grant R, NEJM 2010 (MSM)Baeten J , 2011 (Couples)Paxton L, 2011 (Heterosexuals)

Oral pre-exposure prophylaxis

Post Exposure prophylaxis (PEP)Scheckter M, 2002

Vaccines

Rerks-Ngarm S, NEJM 2009

COMBINATIONHIV

PREVENTION

Thanks

Sarah Fidler Sheen MacCormack Nicky Mackie Laura Waters