iPrEx

:
PrEP for Men who have Sex with Men
Linda-Gail Bekker Desmond Tutu HIV Foundation IAS Vienna 2010

Today….
• • • • • • Why Prevention? Why PrEP? Why MSM? Why MSM in Africa? Where to from here? What else?

The War on HIV….
• 7400 new infections daily. • 5.5 Million in MLIC need ART • For every 2 on ART another 5 infected.

Why prevention must work…

Management of genital infections (STIs)

Microbicides Cervical Barriers Male circumcision

Condoms Behavioural Counselling and Testing

HIV PREVENTIO N

Chemoprophylaxis MTCTp Vaccines HSV-2 PEP Test +Treat Suppressive PrEP therapy

Reported Prevention Trials
Efficacy of intervention Type Positive Adverse Nil behavioural -* 7 µfinance 1 diaphragm 1 Vag microb -* 1* 11 PrEP 1 Male Circ 3 1 STI treat 1* 8 vaccine 1 -* 3 total 5 1 33
(Padian,et al:AIDS 2010)

Total 7 1 1 12 1 4 9 4 39

Male circumcision Not known to be helpful for men who have sex with men

Condoms Behavioral Counseling and Testing Intensive not better than standard

HIV PREVENTIO N

Chemoprophylaxis MTCTp PEP PrEP have unknown efficacy

Partial efficacy
PMTCT (HIVNET 012)

Circumcision (Orange F)

Vaccine (RV 144)

Prep

0%

100%

Low Utilization of Prevention Methods
Methods Utilization
• AIDS Education – Primary Schools 50% – Secondary Schools 48% • Maternal to Child Prevention 2-40% • Sex Workers Outreach 16% 4.3% • IDU Harm Reduction 11% • MSM Outreach

USAID, UNAIDS, UNICEF, Policy Project, June 2004

Why Chemoprophylaxis?
• Antiretroviral Drugs
– Inhibit HIV directly – Prevent mother to child transmission – Are already formulated and mass produced

• Chemoprophylaxis is a proven concept
– EG: Malaria, TB pneumonia, meningitis – Perioperative prophylaxis – A mainstay of prevention if no vaccine

Some Chemoprophylactic Agents
Therapy Year Indication Status
Zidovudine 1987 MTCTp licensed PEP used Lamivudine 1995 MTCTp used PEP used Nevirapine 1996 MTCTp efficacy shown Tenofovir 2001 PEP used Oral PrEP phase II/III Microbicide phase II/III MTCTp safety Emtricitabine 2003 PEP used Oral PrEP phase II/III Entry Inhibitors 1st in 2007 PrEP primates Microbicide primates Integrase Inhibitors 1st in 2007 TBD TBD

Trends in reduction of study results over time
1994 ACTG 076 1998 Bangkok AP/IP ZDV 1998 Abidjan AP/IP ZDV 1999 PETRA AZT/3TC 1999 2000 PHPT ZDV 2004: PHPT-2 ZDV + NVP HAART

2002 DITRAME +1 ZDV + NVP 2003: DITRAME +1.1 ZDV/3TC+ NVP

) % no s s m na T ( i i s r

HIVNET 012 sdNVP

PACTG USPHS AZT 076

Recommendations

80% declin e

PrEP: Back to the Basics
• HIV Infection is The Cause of AIDS
– Not Sex, Not Drugs – Antiretroviral Agents Target HIV Directly

• People Like Sex
– Pleasure, Intimacy, Company, Livelihood, Pregnancy – Prevention is utilized less if it alters sex

AVAC: Turning the page 2010

Post Exposure Prophylaxis

Why Pre-exposure?
• Pre-exposure dosing increases efficacy
– SHIV exposed nonhuman primates (Garcia Lerma 2008)

• People have difficulty recognizing exposure
– Denial (Schechter JAIDS 2004) – Substance use – Imperfect communication with partners

• For those at highest risk
– Pre- and post-exposure periods overlap

Data from Monkey Studies at CDC:
Prevention of Rectal SHIV Transmission by Chemoprophylaxis with ARVs

100

FTC/Tenofovir (subcut, n = 6)

% Uninfected animals

75
FTC/TDF (oral, n = 6) p = 0.0075, [HR = 7.8]

50

FTC (subcut, n = 6) p = 0.021, [HR = 3.9] TDF (oral, n = 4)* p = 0.3 Control (n = 18)

25

0 0 2 4 6 8 10 12 14 Number of rectal exposures

Courtesy of Laboratory Branch, DHAP, CDC See also, Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ‘04;

Why Tenofovir and/or Emtricitabine?
• • • • • • Protective in Animals Licensed for Human Use Excellent Safety Record Long Half Life (>48 hours) Enriched in Genital Fluids No interactions with tuberculosis treatment or hormonal contraception

HIV Reverse Transcriptase
Single stranded RNA

RNA-DNA double helix DNA Single stranded

Polymerase

Ribonuclease H

Nucleoside Reverse Transcriptase Inhibitor

Azido side chain

DNA RNA

Chain termination

FTC and TDF have Long Intracellular Half Life
Approved Approved Approved Approved Approved Approved as BID as QD or BIDas QD or BIDas QD or BIDas QD or BID as QD Approved as QD

50 45 40 35 30 25 20 15 10 5 0

**
>60

T1/2 (hours)

24 hours

*
12 hours

*

§

ZDV

d4T

ABC

3TC

ddI

TDF

FTC

Serum/Plasma half-life

Intracellular half-life

Data from Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64 unless otherwise noted *Anderson et al. AIDS 2003; 17(15):2159-2168. ‡Piliero et al. 43rd ICAAC, Chicago, 2003.

Drug Exposure in the Male Genital Tract
Percent of Blood Plasma Levels
Kashuba et al. CROI 13 Abstract 569 (Vourvahis), 13th CROI Abstracts 396 (Stekler), Abstract 618 (Katzenstein)

0

50%

100%

150%

200%

500%

600%

APV (20%) NVP (70%) ENF (ND) d4T (2%) EFV (3%) SQV (3%) RTV (3%) LPV (5%) NFV (5%) IDV (100%)

ABC (150%)

ZDV (200%)

TDF (500%)

3TC (600%)

NRTI

PI

NNRTI

FI

Preclinical Evaluation of Tenofovir (TDF) + Emtricitabine (FTC)
• Either FTC or TDF were protective
– 70% to 100% Effective

• Emtricitabine + Tenofovir
– The combination was 100% effective
• After repeated rectal exposures (14) • Given once prior to exposure, and once after

• Protection probably reflects
– High concentrations in genital tissues and fluids – Long intracellular half life – Activity in Macrophages

Tsai ‘95; Van Rompay ‘99 ‘00 ‘01 ‘04; Subbarao ’05; Heneine’06 ‘07 ‘08

Mitochondrion
christae

outer membrane

matrix ribosomes

DNA polymerase γ

Mitochondrial dysfunction with NRTI’s
Figure 1: Mitochondrial Energy substrate)

Oxidative Phosphorylation
2 Cytochrome C (Fe 3+) 2 Cytochrome C (Fe 2+)
rele gy ne r E as e

(OXPHOS)
NAD Ubiquinone + 2H Ubiquinone
gy er re se lea
Energy release

H 2O ½O2

Reduced energy substrate

En e

rg

NADH +H
y re le as e

En

ATP synthase

But...

ADP + Pi

ATP

Abnormal mitochondrial protein inefficient oxphos system anaerobic metabolism, lactate build-up

Mitochondrial DNA Depletion

DDI>DDC>D4T>AZT>Abacavir = 3TC = TDF Birkus, Hitchcock, Cihlar. Antimicrob Agents Chemother 2002

FTC/TDF Toxicity Concerns
• TDF
– Few Case Reports of Renal Failure – Headache, Dizziness, Cramps, Flatulence, – Small changes in bone density in HIV positive individuals

• FTC
– Skin or nail discoloration (0-8%; blacks>>Latinos>whites)

• Both
– HBV flare in those stopping – Lactic Acidosis
• All case reports involve other drugs as well (especially D4T or DDI) • Monitor anion gap and total CO2

2007

• Conducted between June 2004 and March 2006 • West Africa • Daily dose of 300 mg oral Tenofovir DF vs. placebo • All participants received testing, condoms, and counseling • Safety evaluated in N=936 including 428 person years

Findings From the West African PrEP Study
• Safety in seronegative individuals confirmed
– No increase in grade 1 renal abnormalities – No grade 2 or greater renal toxicity – No flares among 23 known to be HBsAg+

• A trend toward efficacy
– 8 seroconversions (2 TDF: 6 Placebo; P=0.34) – 2 seroconversions after 1 and 2 months of TDF • No specimens to Rule Out Pre-PREP infection • No bona fide case of PrEP failure yet documented

Peterson, Plos Clinical Trials, 2007

No TDF Resistance Detected in TDF PrEP Seroconverter
R Atchison, Resistance Workshop, Barbados 2007

iPrEx: PrEP Initiative / Iniciativa PrEx
Sponsored by NIH/NIAID/DAIDS
with co-funding by the

Bill and Melinda Gates Foundation
and drug donated by

Gilead Sciences

The PrEP Study: Safety, Efficacy, Behavior, and Biology
Gladstone Institute of Virology and Immunology

The Global PrEP Study: iPrEx

Why MSM?
• From 2002 to 2004
– The PrEP agenda did not include MSM

• MSM bear a major burden of the HIV epidemic
– Throughout the Americas – In at least some parts of Asia – Burden in Africa is increasingly appreciated

• Efficacy could be different after rectal exposure
– Higher efficiency of transmission – Possibly different tissue penetration of virus and drug

• PrEP is still the only efficacy study in MSM

Risk of Transmission
Type of contact Receptive anal intercourse Receptive vaginal intercourse Insertive anal intercourse Insertive vaginal intercourse Receptive oral intercourse Insertive oral intercourse Transmission Risk (per 10,000) 50 10 6.5 5 1 0.5

MSM in Sub-Saharan Africa
A neglected but significant population for prevention research.

Ungass reporting : 2008
35/52 African countries were unable to report any information relating to MSM indicators

HIV Incidence by modes of transmission
100 80 60 40 20 0
Percent new infections

(76,315)

(74,263)

(91,546)

(118,279)

(11,381)

(23,269) (N)

Kenya

Zambia

Uganda Mozambique Swaziland Lesotho
Clients of female sex workers Partners of clients of female sex workers Other Partners (Casual heterosexual sex) Injecting drug users

Casual heterosexual sex Men having sex with men Low risk heterosexual

Sources: Kevin De Cock, PEPFAR Implementers MEETING 2009 Draft results from Know your Epidemic project

The Challenge of Politics and Discrimination
•Homosexuality is outlawed in 38 African countries. •In 13 nations homosexuality is either legal or there are no laws pertaining to it. •Providing MSM focused services, or enrolling MSM into studies in these countries becomes a major challenge

Criminalization

Law

Public Opinion

Death 11 yr to life long imprisonment 1 to 10 yr imprisonment Imprisonment, unstated duration No specific law Protective legislation

Sources: Ottoman, LGBT 2009 Pew Global Attitudes Survey 2002

Senegal, 2005: 22%

Studies with HIV-testing & MSM, Egypt, 2000-2006 2006: 1%
Sudan, 2006: 9%

Kenya, 2006: 11%

OR 3.8 (95% CI 3-4) Baral et al, PlOS 2007

Studies with HIV-testing & MSM, 20002008
6%: Egypt Mauritania: 19% 8 - 9%: Sudan (2)

Senegal (2) : 22% Mali: 37% Cote D’Ivoire: 19% Ghana: 25% Nigeria (2): 13 – 14 % Namibia: 12% Botswana: 20%

11 - 25%: Kenya (2)

12%: Zanzibar 33%: Zambia

21%: Malawi

10 - 38%: South Africa (5)

A Smith, et al.Lancet 2009

HIV prevalence : Country (number of

Data from 4 sites in SADC
• Namibia
– The Rainbow Project (TRP)

• Botswana

– Botswana Network on Ethics, Law and HIV/AIDS (BONELA) – DTHF

• South Africa • Malawi
– Center for Development of People (CEDEP)

4 sites : Results
Characteristic Malawi Age HIV prevalence >30 yrs 25 21.4 35 Namibia Botswana RSA 24 12.4 31 26 19.7 46 26 26 36 (township)

Cape Town Township study
200 MSM in informal venues in Nyanga, Khayelitsha and Athlone and Mitchells Plain Oraquick HIV prevalence Short questionnaire

HIV Prevalence : CT township
40 35 30 25 20
%

MSM

15 10 5 0 15-19 20-29 30-39 40-49 50+

males females

AGE

Soweto men’s study: Results
• N=378 (including 15 seeds) • Soweto MSM population estimates: • 16.1% gay-identified • 33.6% bisexual-identified • 43.2% straight-identified • Crude sample HIV prevalence: 23.9% • Adjusted HIV prevalence estimates: 13.2% overall; 34.0% gay-identified

Context, IAVI-supported studies, Mombasa
Population: 1 million Multiple ethnic and religious groups Local economy reliant on sea port and international tourism MSM and MSM sex work reported in anthropology literature in 1960-80s Adult HIV prevalence (coast): 7.9%

Gill Shepherd, 1987

Kenya AIDS Indicator Survey, 2009

21% of new HIV infections attributed to ‘MSM & men in prison’

Kenya Mode of Transmission Model, 20

The iPrEx Study
• • • • Enrolled ~2500 High Risk MSM Daily Oral PREP Randomized 1:1 to FTC/TDF vs Placebo Followed on Drug for:
– – – – – – – HIV seroconversion Adverse Events (especially renal & liver) Metabolic Effects (Bone, Fat, Lipids) HBV Flares among HBsAg+ Risk Behavior & STIs Adherence If infected • Drug Resistance • Viral load • Immune responses & CD4 Count

Ethnicity
black coloured white

Location
60 50 40 30 20 10 0 township metro township metro

MSM Sensitivity Training For Health Workers
• 120 HIV Counselors, trainers, and coordinators trained between Jan – April 2010
– Partners include: city health services, metro district health services, and NGO’s providing HIV Counseling, testing, and support in the Western Cape

Adherence
• Measured by
– Quarterly Computer Assisted Survey Instrument (CASI) – Monthly Self Report to Counselor – Pill Count

• Improves After First On-Study Drug Visit • Individualized Counseling Strategies Used
– People Go From Pharmacy to Counseling

• Periodic Blinded Drug Levels

Timelines for PrEP Trials

PrEP Issues
• Risk Compensation • Costs • Drug Resistance

Protect or Disinhibit?
Jon Cohen, The New York Times Magazine, January 22, 2006

“…behavioral disinhibition: what if fear of HIV declined in people who took the drug, and they then skipped using condoms or increased their number of sex partners?”

What Do we see?

Reported Risk Behavior Declined With Open-Label Post-Exposure Prophylaxis and Counseling
Martin et al., AIDS 2004

Sexual Behavior during PREP Trial
Screening Number of partners (30 days) Number of new partners (30 days) Number of sex acts (7 days) Condom use (last act) 21 11 12 52% Follow-up 14 6 15 94%

Peterson, Plos Clinical Trials, 2007

Why No Risk Compensation?

Proposed Explanations For Declining Risk Behavior During PREP
• “…intense and consistent HIV/STI prevention services and messages were provided…” • “…taking a pill every day for HIV prevention may have served as a timely reminder of imminent HIV risk…” • Participants become members of a prevention community

Peterson, Plos Clinical Trials, 2007

Analyses of Cost Effectiveness
(Grant et al, Toronto 2006; Abbas et al, Plos One 2007, Paltiel CID 2009)

• PrEP Would be Cost Effective ONLY If:
– – – – – – Efficacy is High (>60%) AND Used By High Risk Groups (>2% incidence) AND Risk Compensation is Small AND Monitoring For Safety Is Manageable AND Drug Resistance is Not Common AND Price of Drug is Less Than Now (Paltiel CID 2009)

• Intermitant Dosing Lowers Drug Costs
– To 2/7ths or 3/7ths

Wild virus predominant, Effective ARV’s, ‘chance’ resistant virus ineffective, nonpathogenic crippled virus

Crippled but pathogenic virus

Rise of wild virus again, but large population of resistant virus

Good adherence, high drug pressure Wild type virus Resistant virus The evolution of HIV resistance Decreased drug pressure as resistance develops Stop all drugs time

Resistance and Adherence Concerns For PrEP
• Starting or Restarting PrEP
– during the RNA+/Ab- window – Expected to select resistance

• Non-adherence to the daily regimen
– Unclear effect on resistance – Depends on efficacy, drug levels, selection

• Fear of resistance drives a high bar
– People who miss doses may give up – People who miss doses when highly exposed may be told to give up (both sex and PrEP)

The Importance of adherence
• PrEP is a Behavioral Intervention
– Requires Adherence – Could Alter Risk Behavior

• Behavior is Complicated
– Especially Sexual Behavior – Numbers of partners, types of partners, practices with each partner

Questions Not Addressed In Current PrEP Research Program
• Dose Optimization
– Intermittent PrEP Studies Planned

• • • • • •

Long Term Safety Efficacy in Adolescents Treatability of PREP Failures Synergies and Antagonisms When to Start? When to Stop? How to Recruit? How to Counsel?

MTN 003/VOICE Global iPrEx in MSM CDC Thai IDU CDC US MSM Safety CDC Botswana Heterosexuals FHI FEMPREP Africa

PrEP Trial Portfolio
• All recommend daily dosing • Limited Cell Specimens
– iPrEx and CDC Studies – Every 6 months and SC at best – Not Expected to Identify a Surrogate Marker of Protection

• Dose Optimization Will Remain a Key Unanswered Question

PrEP Counseling for Intermittent Exposure

The Rationale For Intermittent Dosing

FTC and TDF have Long Intracellular Half Life
Approved as BID Approved as QD or BID Approved Approved Approved as QD or BID as QD or BID as QD or BID Approved as QD Approved as QD

50 45 40 35 30 25 20 15 10 5 0

**
>60

T1/2 (hours)

24 hours

*
12 hours

*

§

ZDV

d4T

ABC

3TC

ddI

TDF

FTC

Serum/Plasma half-life

Intracellular half-life

Data from Centers for Disease Control and Prevention. MMWR Recomm Rep. 2002;51(RR-7):1-64 unless otherwise noted *Anderson et al. AIDS 2003; 17(15):2159-2168. ‡Piliero et al. 43rd ICAAC, Chicago, 2003. ** Hawkins et al. 5th IWCPHT, Rome, 2004 § Wang et al. IAC, 2002, poster #4546.

Design
GROUP 1 (n =6) GROUP 2 (n = 6)

SHIV exposure

-22h

+2h

-3 days
GROUP 3 (n = 6)

+2h

-7 days

time

+2h

GROUP 4 (n = 6) GROUP 5 (n = 6)

-2h

+22h

*
+2h +26h

CONTROL S (n = 9)

Gerardo Garcia-Lerma et al

* Virus challenges every 2 weeks

Risk reduction with iPrEP with oral Truvada
% Uninfected macaques
-22h/+2h -3 days/+2h -7 days/+2h# Daily* +2h/+26h (PEP) -2h/+22h HR = 16.7, p = 0.006 HR = 15.4, p = 0.008 HR = 9.3, p = 0.003 HR = 9.9, p = 0.0 02 HR = 4, p = 0.03 HR = 4.1, p = 0.02

100 75 50 25 0 0 2 4 6 8 10 12 14

Untreated controls (n=32)
(9 real time and 23 historical)

Number of rectal exposures
Cox proportional hazard model # Interim results for the -7d/+2h arm; animals on follow-up after completing the 14 challenges

*

Garcia-Lerma at al., PLoS Med 2008

Absence of drug resistance in macaques failing iPrEP with oral Truvada (2 weekly doses)
Log10 RNA copies/ml
8 6 4 2 0 0 4 8 12 Weeks DK40 8 6 4 2 0 0 4 8 12 Weeks 16 20
wt

1800
wt

8 6 4 2 16 20 0 0 4

DM91

8 6

DM92X

wt

4 2

wt

8 12 Weeks DL6V

16

20

0

0

4

8 12 Weeks 35032
wt

16

20

Log10 RNA copies/ml

8 6 4 2 0 0 4

8
wt

6 4 2

8 12 Weeks

16

20

0

0

4

8 12 Weeks

16

20

Wild type

Not tested

Hypotheses and Aims
• Non-daily versus daily dosing may:
– – – – – – – Increase acceptance Increase adherence (to recommended usage) Decrease adverse events Increase tolerance Decrease costs Decrease the risk of drug resistance Be sufficient for protection

• Event-driven vs time-driven dosing
– May increase “agency” or “self-competence” – May increase anxiety

• Identify surrogate markers of protection
– Minimum protective concentration of drug – Hair vs intracellular PBMCs – FTC-TP vs TDF-DP

PrEP Counseling for Intermittent Exposure Overview
• Factorial Randomized Phase IIB • Randomized 3:1 to TDF/FTC vs Placebo • Randomized 1:1:1 to Open Usage Groups
– Daily – Time-Driven (3 times weekly) – Event-Driven (pre- and post-exposure)

Measurements
• • • • • • • • Adherence Usage Arm Switch at 12 weeks Sexual Behavior Drug Levels Adverse Events and Tolerance HIV Seroconversion Events Drug Resistance, VL, CD4 Costs (research and service)

Sample Size and Followup
• 2400 people
– 1200 MSM – 1200 Heterosexuals
• 800 women • 400 men

• Recruited over 72 weeks • Followed for at least 24 weeks

So-what if something works?
• In well designed and well run studies • With robust results • That show sufficient reduction in acquisition • To be deemed effective as well as efficacious • That can be rolled out to trial participants? What then?

Future for Prevention Research
• Before we have the “small pox equivalent” vaccine against HIV • Just as research money “flat lines” • the job just got harder and more costly…….

Since it got harder- we gotta get smarter….
• Principle 1: Trial participants must receive the best available (evidence based) standard of prevention. • Principle 2 : prevention in the future will be drawn from a menu-combo prevention already exists • Principle 3: this may be an opportunity to design more creative, broader clinical trials with innovative methods. • Principle 4: this behoves us to really know volunteer populations:
– – – – Accurate incidence estimations with modeling input Accurate risk measurements Accurate Adherence measurements Good idea of preference/acceptability/feasibility

Incidence

Adherence

(Padian)

The challenge is an opportunity
• Prevention research will need to move beyond the silos and cabales • Vaccine, Microbicide, T+T, behavioural, PrEP, Circumcision, etc should get into one room when trials are designed. • Social Scientists, epidemiologists, modelers, basic scientists, clinical trialists and clinicians need to be on the team. • We should consider a variety of innovative trials design methodologies that take into account the need to test more than one modality or combination.

PREP in Non-Human Primates
Garcia-Lerma et al

• Decreased plasma RNA level after seroconversion during PREP • Appears to persist after PREP stops • Immune correlates being sought

• SIVmac239 in macaque monkeys causes high viral load and simian AIDS in 1 year. • Tenofovir dosing from 1-28 days after exposure
– caused durable decreases in viral load. – Partial protection during viral rechallenge. – Some antiviral immune responses.

Exposed Seronegatives
Douglas Nixon and Ann Erickson with iPrEx team

• PrEP Participants start as exposed seronegatives:
– Anti-HIV immune responses were detected in 4/20 – An antiviral clone was derived in one – No viral RNA (<2 copies)

• iPrEx will test whether:
– PrEP increases the occurrence of immune responses without systemic infection – Whether such immune responses alter the course of infection

Other possibilities…
• PrEP in a vaccine trial may attract participants who make up a subpopulation with higher HIV incidence • On the other hand, PrEP may reduce viral load sufficiently for the immune response in a vaccinated individual to abort infection.

Thanks to
• • • • Bob Grant, Pedro and the iPrEx Team Ben, Andrew and Mens Division, DTHF Glenda Gray and Eduard Saunders Others whose slides and work we have described. • The thousands of volunteers who are currently involved in evaluating PrEP.

MSM in SSA represent a concentrated epidemic within a generalized epidemic. HIV rates are higher than HS background. They too, urgently need ways to protect themselves from HIV. Men CAN be reached and WILL volunteer. Authentic community engagement key.

Final word:
“I would never worship a homophobic God.”

Archbishop Emeritus Desmond Tutu

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