Jeanne M. Marrazzo, MD, MPHProfessor of Medicine

University of WashingtonSeattle, Washington

A Shot in the Arm for HIV Prevention? Opportunities and Challenges in 2016

FORMATTED: 11/17/15

New Orleans, Louisiana: December 15-17, 2015

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Learning Objectives

After attending this presentation, participants will be able to: Discuss the approach to transitioning from PrEP to PEPDefine contraindications to initiating antiretroviral PrEPDiscuss accurate counseling messages for men who elect

to use TDF-FTC as PrEP

Discussion HIV incidence: two snapshots & a case

MSM in U.S. Young women in sub-Saharan Africa

Understanding the evidence for new prevention options & implementation Pre-exposure prophylaxis with antiretrovirals

(PrEP) Multipurpose prevention

Unintended consequences?

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One third of new HIV infections globally occur in young African women

• In context of ART scale up with 40% of HIV+ persons on ART & 6 million medical male circumcisions performed by end of 2013

• Need to implement effective primary prevention strategies

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Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category,

2009–2013 — United States and 6 Dependent Areas

Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting.

a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection. b Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or not

identified.

Accounts for 81% of transmissions among men;

increase highest in 25-34 y.o.

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Rene P, 20 yo man, referred by partner “who had syphilis”

Considers himself healthy, no symptoms HIV Ag-Ab test negative last week Last syphilis serology negative 3 months ago Two episodes of rectal gonorrhea last year Moved to U.S. from Mexico last year Sometimes uses meth on weekends 6 partners in last 3 months, some anonymous.

Last unprotected sex 12 h ago

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Rene P, 21 yo man, referred by a partner “who had syphilis”

What do you do?

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Rene P, 21 yo man, referred by partner “who had syphilis”

Send confirmatory syphilis test (EIA, TPPA) before treating for syphilis

Treat him with BZN PCN 2.4 x 10-6 mu IM weekly for three weeks

Check plasma HIV viral load Offer him TDF-FTC as PrEP and see him in 3

months Treat now for sexual PEP (TDF/FTC/raltegravir)

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HIV Prevention in Clinical Care Settings: 2014

Recommendations of the International Antiviral

Society-USA Panel:

Emphasized biobehavioral nature of the interventions

needed

Marrazzo JM, Holtgrave DR, del Rio C et al, JAMA 2014

Free web access to the paper at jama.com

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Antiretroviral Prevention: A Timeline

1995PMPA

effectivein macaque

2005HPTN-050

Phase 1

2006HPTN-059Phase 2

2010CAPRISA 004

Phase 2B

2010iPrEX

2011FEM-PrEP

2011HPTN-052

2011TDF2

2015PROUD

2013MTN-003VOICE

2007TDFPrEPStudy

2015FACTS

001

2015iPerGay

2011Partners

PrEP

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Efficacy of Biomedical Interventions to Prevent HIV Acquisition: Evidence from Selected Randomized Clinical Trials

Modified from Ambitious Treatment Targets: Writing the Final Chapter of the AIDS Epidemic, UNAIDS, 2014

Key Components of These TrialsHPTN 052 Partners

PrEP iPrEX VOICE & FEM-PrEP CAPRISA 004

Standard prevention “package”* ✔ ✔ ✔ ✔ ✔

Intensive adherence counseling ✔ ✔ ✔ ✔ ✔

Enrolled both members of discordant couples ✔ ✔

Study product use timed with likely HIV exposure ✔

Real-time biological marker of product adherence ✔* Condoms, counseling, STI management

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Key Components of These TrialsHPTN 052 Partners

PrEP iPrEX VOICE & FEM-PrEP CAPRISA 004

Standard prevention “package”* ✔ ✔ ✔ ✔ ✔

Intensive adherence counseling ✔ ✔ ✔ ✔ ✔

Enrolled both members of discordant couples ✔ ✔

Study product use timed with likely HIV exposure ✔

Real-time biological marker of product adherence ✔* Condoms, counseling, STI management

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Adherence & PrEP Efficacy

% of blood samples with TFV detected

HIV protection efficacy in randomized comparison

Partners PrEPFTC/TDF arm 81% 75%

TDF2 79% 62%

iPrEx 51% 44%

FEM-PrEP 26% NS

VOICE 28% NS

Clear dose-response relationship between evidence of PrEP use & efficacyBaeten et al N Engl J Med 2012

Grant et al N Engl J Med 2010Van Damme et al N Engl J Med 2012Thigpen et al N Engl J Med 2012 Slide modified from J. Baeten

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Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples

• Partners Demonstration Project in Africa– Oral daily TDF/FTC PrEP for HIV-uninfected

partner in serodiscordant couple continued 6 mos beyond initiation of ART for infected partner

– High-risk couples defined as younger age, fewer children, uncircumcised HIV-negative male, cohabitating, unprotected sex in past mo, high HIV-1 RNA in HIV-positive partner

• Interim analysis– > 95% of HIV-negative partners using PrEP– 80% of HIV-positive partners have initiated

ART; of these, > 90% with suppression

96% reduction in expected infections‒ IRR, expected vs observed: 0.04 (95% CI: 0.01-0.19; P

< .0001)

In pts with seroconversion, no TFV detectable in plasma at time of seroconversion

– HIV-positive partner in 1 couple not on ART (high CD4+ count)

– Other couple dissolved and HIV-negative partner in new relationship

Baeten J, et al. CROI 2015. Abstract 24. Reproduced with permission.

HIV Incidence, Actual vs Expected

Group Infected, n Incidence/100 PY (95% CI)

Expected 39.7 5.2 (3.7-6.9)

Actual 2 0.2 (0-0.9)

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PrEP Safety• Rates of death, serious adverse events, and laboratory abnormalities

(including renal dysfunction) very low• Not significantly different between those on PrEP and placebo

• PrEP well tolerated• Adverse effects occurred in minority of subjects• GI adverse effects (e.g., nausea) more common in those receiving PrEP

than placebo (< 10%, primarily during the first month only)• PrEP safe during pregnancy (Mugo JAMA 2014)• No reduction in contraceptive efficacy (Murnane AIDS 2014)• Rare acquired resistance (about 3%); 12 infections averted for each

case of resistance

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Randomized, open-label trial of daily oral TDF/FTC PrEP in HIV- MSM in 13 clinics in London

– Immediate (n = 267) vs

– Deferred for 12 mos (n = 256)

Primary endpoint: HIV infection in 12 mos

86% reduction in risk seen over 60 wks with immediate PrEP (90% CI: 58% to 96%, P = .0002)

– Number needed to treat to prevent 1 infection: 13 (90% CI: 9-25)

DMSB interrupted trial; recommended that all participants be offered PrEP

HIV Incidence

Group Infected, n Incidence/100 PY (90% CI)

Immediate 3 1.3 (0.4-3.0)

Deferred 19 8.9 (6.0-12.7)

Lancet 2015

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NEJM 14 Dec 2015

Randomized double-blind trial of event-driven oral TDF/FTC* (n = 199) vs placebo (n = 201) (both with prevention services) in France– 2 tablets taken 2-24 hrs before sex– 1 tablet 24 hrs after sex – 1 tablet 48 hrs after first event-driven dose

Primary endpoint: HIV seroconversion

Patterns of Pill Use on the Basis of Clinic Visits

Molina J-M et al. N Engl J Med 2015;373:2237-2246

Probability of HIV-1 Infection

Molina J-M et al. N Engl J Med 2015;373:2237-2246

86% reduction in risk in PrEP arm (95% CI: 40% to 99%, P = .002)

• Number needed to treat for 1 yr to prevent 1 infection: 18

• Median of 16 pills taken per mo in each arm

Clinical Infect Dis, Sept 2015

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The Good News: No new HIV infections

in over 600 PrEP initiators at Kaiser Permanente San Francisco

Volk et al. CID 2015; Image courtesy J Volk

PrEP in the “Real” WorldSlide 25 of 34

PrEP and STIs in >600 MSMKaiser Permanente San Francisco

Any S

TI

Rectal

STI

Chlamyd

ia

Gonorr

hea

Syph

ilis HIV0%

20%

40%

60% 50%33% 33% 28%

5.5%0%

STI Incidence After 12 Months of PrEP Use

Volk et al. CID 2015 Slide courtesy J. Volk

Expected HIV incidence with this STI

incidence: 8.9%

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HIV incidence = 0.43 cases / 100 py (95% CI 0.05-1.54)STI incidence (90 cases/100 py) stable across quarterly intervals (P> 0.1)50.9% of participants had at least one STI during follow-upAs expected, >75% of GC and >85% of CT infections were asymptomatic

Screening 12 24 36 4805

1015202530

GC, CT or SyphilisRectal GC or CTPharyngeal GC or CT

Visit Week

% P

ositi

vePrEP Demo Project (NIAID), n=557

Cohen 2015, ISSTDR

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Syphilis rates among MSM: timeline

Peterman, 2015, Expert Rev Anti Infect Ther

Syphilis rates among MSM will soon be similar to those in the early 1980s

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A Vicious Cycle: STDs predict future HIV Risk

1 in 15 MSM were diagnosed with HIV within 1 year.*

1 in 53 MSM were diagnosed with HIV within 1 year.*

Rectal GC or CT

1 in 18 MSM were diagnosed with HIV within 1 year.**

Primary orSecondarySyphilisNo rectal STD or syphilis infection

*STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61

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Goal: reliable, long-lasting, woman-initiated method to protect against HIV acquisition

ASPIRE (MTN-020) studied dapivirine, with complementary studies: IPM 027 (efficacy & safety) >25 completed phase I/II studies Results anticipated early 2016

Vaginal Rings for HIV PreventionSlide 30 of 34

Thoughts & Next Steps PrEP works, when taken consistently, and is the most

effective tool for preventing sexual HIV transmission we have so far Only one ARV (TFV) available; data for women still limited

Critically dependent results coming up: Intravaginal dapivirine ring HPTN studies of long-acting ARV (cabotegravir, rilpivirine) Rectal microbicide development

Combination product development Antiretroviral + hormonal contraceptive

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