Antiretroviral Chemoprophylaxis:

What have we learned so far?

Kenneth H. Mayer, MDMarch 26th, 2011

Search for A Cure

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HIV Prevention:HIV Prevention:Current TargetsCurrent TargetsHIV Prevention:HIV Prevention:Current TargetsCurrent Targets

Condom and HIV testing promotionIndividual interventionsCouples interventions

Community-based interventionsStructural interventions

Condom and HIV testing promotionIndividual interventionsCouples interventions

Community-based interventionsStructural interventions

Barrier protectionBlood screening

IDU harm reductionAntiretroviral therapy

(PMTCT, treatinfected partners)

STI treatment

Barrier protectionBlood screening

IDU harm reductionAntiretroviral therapy

(PMTCT, treatinfected partners)

STI treatment

Alter BehaviorAlter Behavior

Barrier protectionInfection control

CircumcisionPEP, PrEP

Topical microbicidesVaccines

STI treatment

Barrier protectionInfection control

CircumcisionPEP, PrEP

Topical microbicidesVaccines

STI treatment

Decrease HostDecrease HostSusceptibilitySusceptibility

Decrease SourceDecrease Sourceof Infectionof Infection

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Why Antiretroviral AgentsWhy Antiretroviral Agentsfor HIV Prevention?for HIV Prevention?

Why Antiretroviral AgentsWhy Antiretroviral Agentsfor HIV Prevention?for HIV Prevention?

• Animal dataAnimal data- Multiple drugs have decreased HIV transmission as Multiple drugs have decreased HIV transmission as

PEP or PrEPPEP or PrEP

• Human dataHuman data- PMTCTPMTCT- Occupational PEP after percutaneous exposuresOccupational PEP after percutaneous exposures

- Non-occupational PEP experience (no RCT)- Non-occupational PEP experience (no RCT)

• Tolerability of newer antiretroviral agentsTolerability of newer antiretroviral agents• Increased affordabilityIncreased affordability• Challenges with other approaches (eg, vaccine)Challenges with other approaches (eg, vaccine)Connor EM, et al. N Engl J Med. 1994;331:1173-1180.Cardo DM, et al. N Engl J Med. 1997;337:1485-1490.Grant RM, et al. Clin Infect Dis. 2010;50(suppl 3):S96-S101.Venkatesh KK, et al. Future Virol. 2010;5:405-415.

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01/05

Per-Act Risk for HIV Acquisition Exposure Route Risk per 10,000 exposures

Blood transfusion 9,000

Needle-sharing injection drug use 67

Receptive anal intercourse 50

Percutaneous needle stick 30

Receptive penile-vaginal intercourse 10

Insertive anal intercourse 6.5

Insertive penile-vaginal intercourse 10

Receptive oral intercourse 1

Insertive oral intercourse 0.5

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Not all ART may be equal for Prevention:Not all ART may be equal for Prevention:Ratio of Genital:Blood Plasma LevelsRatio of Genital:Blood Plasma Levels

Not all ART may be equal for Prevention:Not all ART may be equal for Prevention:Ratio of Genital:Blood Plasma LevelsRatio of Genital:Blood Plasma Levels

Nicol MR, et al. Clin Pharmacol Ther. 2010;88:598-609.

Women Men

Gen

ital

Tra

ct:B

loo

d P

lasm

a A

UC

Ratio of 1.0: genital tract AUC=blood plasma AUC.Genital tract exposure within 2 and 1 hour of dosing for women and men, respectively.

NRTI NNRTI PI EntryInhibitor

INSTI

6.0

5.0

4.0

3.0

2.0

1.0

0.5

0

ddIABCd4T

TDFTDF

ZDVZDV

FTCFTC3TC3TC

ETVETV

NVPNVP

EFVEFV

APVRTVATV

LPVSQV

DRVDRVIDVIDV

MRVMRV

RALRALG

enit

al T

ract

:Blo

od

Pla

sma

AU

C

NRTI NNRTI PI EntryInhibitor

INSTI

6.0

5.0

4.0

3.0

2.0

1.0

0.5

0d4T

TDFTDF

ZDVZDV

3TC3TCFTCFTC

NVPNVP

EFVEFVAPV, ATV,LPVDRV,SQV, RTV

IDVIDV

MRVMRV

RALRAL

ABCABC

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PEP: GuidelinesPEP: GuidelinesPEP: GuidelinesPEP: Guidelines

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PEP vs. PrEPPEP vs. PrEPPEP vs. PrEPPEP vs. PrEP

• PEP has been associated with decreased PEP has been associated with decreased subsequent risk when coupled with counseling, subsequent risk when coupled with counseling, but not as a stand alonebut not as a stand alone (Roland, CID, 39:82-89, 2005)(Roland, CID, 39:82-89, 2005)

• MSM in Brazilian study who took AZT/3TC PEP MSM in Brazilian study who took AZT/3TC PEP were less likely to become HIV-infected were less likely to become HIV-infected (Schechter, JAIDS, 5:519-525, 2004)(Schechter, JAIDS, 5:519-525, 2004)

• But, most of those infected assumed their But, most of those infected assumed their partner was not HIV-infectedpartner was not HIV-infected

• So, “teachable moment” makes the case for PEPSo, “teachable moment” makes the case for PEP• Inability to assess risk in real time, esp. for those Inability to assess risk in real time, esp. for those

who are frequently risky make the case for PrEPwho are frequently risky make the case for PrEP

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PEP: Fenway ExperiencePEP: Fenway ExperiencePEP: Fenway ExperiencePEP: Fenway ExperienceFenway Health 1997-2007Fenway Health 1997-2007• 558 PEP cases (368 not part of clinical trial, 190 part of 2 558 PEP cases (368 not part of clinical trial, 190 part of 2

tenofovir-based Phase IV PEP trial)tenofovir-based Phase IV PEP trial)• Most common regimens: TDF/FTC, AZT/3TC, AZT/3TC or Most common regimens: TDF/FTC, AZT/3TC, AZT/3TC or

TDF/FTC + PI, TDF/FTC + RALTDF/FTC + PI, TDF/FTC + RAL• TDF/FTCTDF/FTC

- most common regimen usedmost common regimen used- most often completed overall regimen (73%)most often completed overall regimen (73%)

• 4 total infections – all had documented adherence problems 4 total infections – all had documented adherence problems and/or ongoing sexual risk taking before and after PEP and/or ongoing sexual risk taking before and after PEP administrationadministration

Mayer et al, JAIDS, 47:494-99, 2008

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PEP: GuidelinesPEP: GuidelinesPEP: GuidelinesPEP: GuidelinesDrug ChoiceDrug Choice• 2 drugs or 3? Increased tolerability vs. Extra protection2 drugs or 3? Increased tolerability vs. Extra protection• Early OPEP studies confirm monotherapy is very Early OPEP studies confirm monotherapy is very

successful, so key is to pick regimen that will contain at successful, so key is to pick regimen that will contain at least one active drug and maintain adherence for 28 day least one active drug and maintain adherence for 28 day coursecourse

• Once-a-day regimen is more likely to maintain adherenceOnce-a-day regimen is more likely to maintain adherence• Newer drugs are associated with increased tolerability and Newer drugs are associated with increased tolerability and

completion ratescompletion rates• Must consider prevalence of drug resistance in addition to Must consider prevalence of drug resistance in addition to

source patient datasource patient data

Bassett IV, et al. CID. 2004;39:395-401.Mayer KH, et al. AJPH. 2010;100:1867-1876

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15

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Genotypic Resistance

HIV Status at Enrollment

Infected Uninfected

PlaceboN=8

FTC/TDFN=2

PlaceboN=83

FTC/TDFN=48

65R 0 (0%) 0 (0%) 0 (0%) 0 (0%)

70E 0 (0%) 0 (0%) 0 (0%) 0 (0%)

184I 0 (0%) 1 (50%) 0 (0%) 0 (0%)

184V 1 (13%) 1 (50%) 0 (0%) 0 (0%)

TDF Resistance 0 (0%) 0 (0%) 0 (0%) 0 (0%)

FTC Resistance 1 (13%) 2 (100%) 0 (0%) 0 (0%)

Drug Resistance

Grant et al, CROI 2010

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Topical TDF or FTC/TDF Gel:Topical TDF or FTC/TDF Gel:Complete Protection From SHIV ExposuresComplete Protection From SHIV Exposures

Topical TDF or FTC/TDF Gel:Topical TDF or FTC/TDF Gel:Complete Protection From SHIV ExposuresComplete Protection From SHIV Exposures

Protection From SHIV

Un

infe

cted

(%

)

1% TDF (n=6)

Challenges

0 2 4 6 8 10 12 14 16 18 20

• Twice-weekly repeat Twice-weekly repeat vaginal SHIV challenge vaginal SHIV challenge macaque model (n=23)macaque model (n=23)- Total of 20 challengesTotal of 20 challenges

• Topical gel Topical gel (matrix + (matrix + preservative)preservative)- 1% tenofovir DF1% tenofovir DF

- 5% emtricitabine/ 1% 5% emtricitabine/ 1% tenofovir DFtenofovir DF

• DosingDosing- 3 mL applied 30 minutes before 3 mL applied 30 minutes before

vaginal challenge with R5 virus vaginal challenge with R5 virus inoculum (10 TCIDinoculum (10 TCID5050))Parikh UM, et al. J Virol. 2009;83:10358-10365.

5% FTC/1% TDF (n=6)

Placebo Gel(n=9)No Gel

(n=2)

SHIV: simian (SIV)-human (HIV) hybrid.

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CAPRISA 004 Results:CAPRISA 004 Results:HIV IncidenceHIV Incidence

CAPRISA 004 Results:CAPRISA 004 Results:HIV IncidenceHIV Incidence

Abdool Karim Q, et al. Science. 2010;329:1168-1174.

HIV

Inci

den

ce R

ate

(%)

12 30

10.5%

5.2%

9.1%

5.6%

Follow-Up (months)

50%(P=0.007)

39%(P=0.017)

Overall

Placebo

Tenofovir DF gel

HIV

Inci

den

ce R

ate

(%)

>80%

9.3%

4.2%

10.0%

8.6%54%(P=0.025)

38%(P=0.34)

By Adherence

Placebo

Tenofovir DF gel

6.3% 6.2%

28%(P=0.30)

50%-80% <50%Adherence Level (months)

Investigation:Ongoing PrEP efficacy studies

Location Sponsor/Funder

Population N PrEP Agent Status

Thailand Bangkok Tenofovir

Study

CDC IDU 2400 TDF Fully enrolledResults 2012

Kenya, Uganda Partners PrEP Study

UW / BMGF

HIV discordant couples

4758 TDF, FTC/TDF Fully enrolledResults 2012

Kenya, South Africa , Tanzania, Zimbabwe FEM-PrEP

FHI / USAID & BMGF

Women 3900 FTC/TDF 49% enrolled Results 2013

South Africa, Uganda, Zimbabwe VOICE / MTN 003

MTN / NIH Women 5000 TDF, FTC/TDF,Vaginal tenofovir gel

(daily)

65% enrolled Results 2013

• Safety, efficacy, resistance & costs of TDF & FTC-TDF will inform choice of drugs for PrEP roll-out

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Peri-Exposure Prophylaxis inPeri-Exposure Prophylaxis inMacaques With Oral FTC/TDFMacaques With Oral FTC/TDFPeri-Exposure Prophylaxis inPeri-Exposure Prophylaxis inMacaques With Oral FTC/TDFMacaques With Oral FTC/TDF

Protection From SHIV

Un

infe

cted

(%

)

Rectal Exposures (number)

0 2 4 6 8 10 12 14

• Macaque model of rectal Macaque model of rectal transmission of HIVtransmission of HIV

- Rectal exposure with R5 virus inoculum (10 TCID50)

• 2 doses of FTC/TDF2 doses of FTC/TDF

- Before SHIV exposure (-)Before SHIV exposure (-)

- After SHIV exposure (+)After SHIV exposure (+)

• Extended window of Extended window of protectionprotection

- Associated with extended Associated with extended long intracellular long intracellular persistence of drugpersistence of drug

• No drug resistance in No drug resistance in macaques failing PrEPmacaques failing PrEP

Garcia-Lerma JG, et al. Sci Transl Med. 2010;2:14ra4.

FTC/TDFDosing HR

-22h/+2h-3d/+2h

-7d/+2h

-2h/+22h

16.715.4

9.4

4.1

UntreatedControls

PValue

.006

.008

.003

.02

What about intermittant PrEP?What about intermittant PrEP? What about intermittant PrEP?What about intermittant PrEP?

• IAVIIAVI studies in East Africa: MSM and FSW, studies in East Africa: MSM and FSW, small size, but many missed post-coital dosessmall size, but many missed post-coital doses

• HPTN 066: HPTN 066: dose proportionality study of dose proportionality study of weekly TDF/FTC, twice weekly, and double weekly TDF/FTC, twice weekly, and double dose twice weekly. Sampling all relevant dose twice weekly. Sampling all relevant tissues. tissues.

• HPTN 067: HPTN 067: 180 MSM in Bangkok and 180 180 MSM in Bangkok and 180 high risk women in Capetown, to compare high risk women in Capetown, to compare adherence to coitally dependent vs. fixed adherence to coitally dependent vs. fixed intermittant PrEP.intermittant PrEP.

Human studies of intermittent PrEP

• IAVI E001/E002: Daily, twice weekly & post-coital dosing of FTC/TDF (Mutua, IAS 2010)

– Adherence measured by MEMS

– Highest adherence: daily dosing & among discordant couples

– Post-coital dosing significantly lower than twice weekly dosing

Dosing strategy HIV discordant couples, Uganda (N=72)

High risk women & MSM, Kenya (N=72)

Daily dosing, adjusted rate 96-97% 82-92%

Fixed twice weekly dosing 91% 55%

Post-coital dosing 45% 26%

What about rectal gel?What about rectal gel?What about rectal gel?What about rectal gel?Tenofovir protects monkeys after rectal Tenofovir protects monkeys after rectal challengechallengeVaginal tenofovir gel used rectally was not Vaginal tenofovir gel used rectally was not optimal in LA/Pittsburgh studyoptimal in LA/Pittsburgh studyNew formulation will be studied in MTN New formulation will be studied in MTN 007: Pittsburgh, Boston, Birmingham007: Pittsburgh, Boston, BirminghamNew formulation will also be studied in New formulation will also be studied in younger MSM (Project Gel): Pittsburgh, younger MSM (Project Gel): Pittsburgh, Boston, San JuanBoston, San JuanMTN 017: To assess rectal efficacyMTN 017: To assess rectal efficacy

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New AntiretroviralNew AntiretroviralTopical MicrobicidesTopical Microbicides

New AntiretroviralNew AntiretroviralTopical MicrobicidesTopical Microbicides

Gel with applicator Vaginal ring (sustained delivery)

Ideal: long acting, safe, effective, low cost and user-friendly

Maximize choice & optimize effectiveness

Potential for combination ARVs to increase effectiveness

Potential to combine ring or injections with contraception

PrEP Delivery Platforms: Long-acting topical & systemic delivery

Vaginal film Injectable (long-acting)

Pill

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PREP: GuidelinesPREP: GuidelinesPREP: GuidelinesPREP: Guidelines

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Decrease inDecrease inHIV TransmissionHIV Transmission

Maintain ViralMaintain ViralSuppressionSuppression

TreatTreat

Enroll in CareEnroll in Care

Address concomitant concerns, Address concomitant concerns, e.g. depression, substance use, e.g. depression, substance use,

relationship dynamicsrelationship dynamics

Combination Antiretroviral PreventionCombination Antiretroviral PreventionCombination Antiretroviral PreventionCombination Antiretroviral Prevention

HIV NegativeHIV Negative

TestTest

Interventions to Increase Testing Interventions to Increase Testing

PositivePositivePreventionPrevention

LinkageLinkageTo CareTo Care

Adherence Adherence to ARTto ART

ART ART InitiationInitiation

Modified from www.hptn.org.

Risk Assessment Risk Assessment PrEP, AdherencePrEP, Adherence

CounselingCounseling

HIV PositiveHIV Positive

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Optimizing ART for PreventionOptimizing ART for PreventionOptimizing ART for PreventionOptimizing ART for Prevention• Block other steps in the HIV life cycle?Block other steps in the HIV life cycle?

- Develop drugs just for prevention (Maraviroc)?Develop drugs just for prevention (Maraviroc)?

• New co-formulations; Generic PrEP?New co-formulations; Generic PrEP?• Topical versus oral (VOICE and beyond): role of Topical versus oral (VOICE and beyond): role of

culture, belief systems, as well as lifestylesculture, belief systems, as well as lifestyles• Optimal drug delivery system (ring; depot?)Optimal drug delivery system (ring; depot?)• Who are the priority populations?Who are the priority populations?• How to best train providers? Which providers?How to best train providers? Which providers?• Interaction with other prevention modalitiesInteraction with other prevention modalities• Optimal utilization and effectiveness may require Optimal utilization and effectiveness may require

multiple modalities: one size will not fit allmultiple modalities: one size will not fit all

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Many thanksMany thanksMarcy Gelman Steve Boswell Marcy Gelman Steve Boswell

Chris Chianese Janet DargonChris Chianese Janet DargonLori Panther Jim MaynardLori Panther Jim MaynardRodney Vanderwarker Jackie WhiteRodney Vanderwarker Jackie WhiteMatthew Mimiaga Doug KrakowerMatthew Mimiaga Doug KrakowerVanessa Marquez Jo TrufantVanessa Marquez Jo TrufantCoco Alisung Bill O’BrienCoco Alisung Bill O’BrienRalph Miele Danny TuRalph Miele Danny TuAmy Pechukas Bill O’BrienAmy Pechukas Bill O’BrienJesse Ripton Ronn BillJesse Ripton Ronn BillBob Grant Craig HendrixBob Grant Craig HendrixSusan Buchbinder Connie CelumSusan Buchbinder Connie Celum The Participants IRB and CAB The Participants IRB and CAB NIH, BMGF, GileadNIH, BMGF, Gilead