1. Jeanne M. Marrazzo, MD, MPH University of Washington
A Shot in the Arm for HIV Prevention? Opportunities and Challenges in 2016
Jeanne M. Marrazzo, MD, MPH
Professor of Medicine
University of Washington
Seattle, Washington
FORMATTED: 11/17/15
New Orleans, Louisiana: December 15-17, 2015

2. After attending this presentation, participants will be able to:
Learning Objectives
After attending this presentation, participants will be able to:
Discuss the approach to transitioning from PrEP to PEP
Define contraindications to initiating antiretroviral PrEP
Discuss accurate counseling messages for men who elect to use TDF-FTC as PrEP

3. Discussion HIV incidence: two snapshots & a case
Slide 4 of 34
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?

4. One third of new HIV infections globally occur in young African women
Slide 5 of 34
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

5. Slide 6 of 34
Diagnoses of HIV Infection among Adults and Adolescents, by Transmission Category, 2009–2013 — United States and 6 Dependent Areas
Accounts for 81% of transmissions among men; increase highest in y.o.
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.
This slide presents the distribution of diagnoses of HIV infection among adults and adolescents diagnosed from 2009 through 2013, by transmission category, for the United States and 6 dependent areas.
The percentage of adults and adolescents with diagnosed HIV infection attributed to male-to-male sexual contact increased from 58% in 2009 to 65% in The percentages of diagnosed HIV infections attributed to injection drug use, male-to-male sexual contact and injection drug use, and heterosexual contact remained relatively stable (less than a 5% increase or decrease) from 2009 through A very small percentage of diagnosed infections each year were attributed to other transmission categories.
Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data are estimates. Estimated numbers resulted from statistical adjustment that accounted for reporting delays and missing transmission category, but not for incomplete reporting.
Heterosexual contact is with a person known to have, or to be at high risk for, HIV infection.
Other transmission categories include hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or not identified.

6. Rene P, 20 yo man, referred by partner “who had syphilis”
Slide 7 of 34
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

7. Rene P, 21 yo man, referred by a partner “who had syphilis”
Slide 9 of 34
Rene P, 21 yo man, referred by a partner “who had syphilis”
What do you do?

8. Rene P, 21 yo man, referred by partner “who had syphilis”
Slide 10 of 34
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)
PLEASE FORMAT AS ARS

9. Emphasized biobehavioral nature of the interventions needed
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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

10. Antiretroviral Prevention: A Timeline
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Antiretroviral Prevention: A Timeline
1995
PMPA effective
in macaque
2006
HPTN-059
Phase 2
2010
CAPRISA 004
Phase 2B
2015
FACTS 001
2013
MTN-003
VOICE
2011
Partners
PrEP
2015
iPerGay
2010
iPrEX
2005
HPTN-050
Phase 1
2007
TDF
PrEP
Study
2011
HPTN-052
2015
PROUD
The efficacy of pre- and postexposure treatment with the antiviral compound (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA) was tested against simian immunodeficiency virus (SIV) in macaques as a model for human immunodeficiency virus (HIV). PMPA was administered subcutaneously once daily beginning either 48 hours before, 4 hours after, or 24 hours after virus inoculation. Treatment continued for 4 weeks and the virologic, immunologic, and clinical status of the macaques was monitored for up to 56 weeks. PMPA prevented SIV infection in all macaques without toxicity, whereas all control macaques became infected. These results suggest a potential role for PMPA prophylaxis against early HIV infection in cases of known exposure.
Science
2011
FEM-PrEP
2011
TDF2 10 10

11. Efficacy of Biomedical Interventions to Prevent HIV Acquisition: Evidence from Selected Randomized Clinical Trials
Why important to review the evidence: because PrEP efficacy and safety in the real world depend critically on this understanding.
Modified from Ambitious Treatment Targets: Writing the Final Chapter of the AIDS Epidemic, UNAIDS, 2014

12. Key Components of These Trials
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HPTN 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

13. Key Components of These Trials
Slide 17 of 34
HPTN 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

14. Adherence & PrEP Efficacy
Slide 18 of 34
% of blood samples with TFV detected
HIV protection efficacy in randomized comparison
Partners PrEP
FTC/TDF arm
81%
75%
TDF2
79%
62%
iPrEx
51%
44%
FEM-PrEP
26% NS
VOICE
28%
Clear dose-response relationship
between evidence of PrEP use & efficacy
Baeten et al N Engl J Med 2012
Grant et al N Engl J Med 2010
Van Damme et al N Engl J Med 2012
Thigpen et al N Engl J Med 2012
Slide modified from J. Baeten

15. Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples
Slide 19 of 34
Oral PrEP + ART as Prevention in High-Risk Serodiscordant Couples
96% reduction in expected infections
IRR, expected vs observed: 0.04 (95% CI: ; 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
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
HIV Incidence, Actual vs Expected
Group
Infected, n
Incidence/100 PY (95% CI)
Expected
39.7
5.2 ( )
Actual 2
0.2 (0-0.9)
ART, antiretroviral therapy; FTC, emtricitabine; IRR, incident rate ratio; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir DF; TFV, tenofovir.
Baeten J, et al. CROI Abstract 24. Reproduced with permission.

16. Slide 20 of 34
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

17. Slide 22 of 34
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)
HIV Incidence
Group
Infected, n
Incidence/100 PY (90% CI)
Immediate 3
1.3 ( )
Deferred 19
8.9 ( )
DMSB interrupted trial; recommended that all participants be offered PrEP
Lancet 2015

18. 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

19. Patterns of Pill Use on the Basis of Clinic Visits
Figure 2 Patterns of Pill Use on the Basis of Clinic Visits during the Study Period. Shown are the number of doses of TDF-FTC (Panel A) and placebo (Panel B) that were taken during the 32-month study period (M1 through M32). Six categories of pill use per month were defined at each visit: no pill use or missing data, 1 to 4 pills, 5 to 11 pills, 12 to 18 pills, 19 to 25 pills, and 26 to 30 pills. Each colored bar represents a single patient; the length of follow-up varies according to the time of enrollment.
Molina J-M et al. N Engl J Med 2015;373:

20. Probability of HIV-1 Infection
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
Figure 3 Kaplan–Meier Estimates of the Probability of HIV-1 Infection. The cumulative probability of HIV-1 acquisition is shown for the two study groups in the modified intention-to-treat analysis. The inset shows the same data on an enlarged y axis.
Molina J-M et al. N Engl J Med 2015;373:

21. Clinical Infect Dis, Sept 2015
Slide 24 of 34
Clinical Infect Dis, Sept 2015
(95% CI 58-71)

22. PrEP in the “Real” World
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The Good News:
No new HIV infections in over 600 PrEP initiators at Kaiser Permanente San Francisco
No new HIV infections despite self-reported decreases in condom use – PrEP works
Limitations of KP data:
No control group
Fewer condoms ≠ more HIV risk ?
“PrEP-sorting”
Undetectable viral loads
Nuanced decisions about condoms
Volk et al. CID 2015;
Image courtesy J Volk

23. PrEP and STIs in >600 MSM Kaiser Permanente San Francisco
Slide 26 of 34
Expected HIV incidence with this STI incidence: 8.9%
(95% CI 58-71)
Volk et al. CID Slide courtesy J. Volk

24. PrEP Demo Project (NIAID), n=557
Slide 27 of 34
Cohen 2015, ISSTDR
HIV incidence = cases / 100 py (95% CI )
STI incidence (90 cases/100 py) stable across quarterly intervals (P> 0.1)
50.9% of participants had at least one STI during follow-up
As expected, >75% of GC and >85% of CT infections were asymptomatic

25. Syphilis rates among MSM: timeline
Slide 28 of 34
Syphilis rates among MSM: timeline
Syphilis rates among MSM will soon be similar to those in the early 1980s
Peterman, 2015, Expert Rev Anti Infect Ther

26. A Vicious Cycle: STDs predict future HIV Risk
Slide 29 of 34
A Vicious Cycle: STDs predict future HIV Risk
Rectal GC
or CT
1 in 15 MSM were diagnosed with HIV within 1 year.*
Primary or
Secondary
Syphilis
1 in 18 MSM were diagnosed with HIV within 1 year.**
No rectal STD or syphilis infection
NOTE: This slide has limitations because they are not exact comparisons.
P&S Syphilis analysis uses case based surveillance data matching to get the hazard ratio and the annual incidence on the slide. The incidence for all men in the syphilis group was 1/20 within the year. As such, there is no data on syphilis negatives – this makes it a pretend cohort rather than a real cohort.
Rectal GC/CT and the no STD category uses an STD clinic cohort that was then matched to HIV case registry data. It seems like a much more valid cohort analysis to me, since we have information on STD-negatives to compare it to. I used incidence among those negative for rectal infection and no syphilis in the past 2 years to get the 1/53 figure.
The population for all of these groups was HIV-negative MSM, which is implied but not explicit on this slide.
1 in 53 MSM were diagnosed with HIV within 1 year.*
*STD Clinic Patients, New York City. Pathela, CID 2013:57;
**Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61

27. Vaginal Rings for HIV Prevention
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Vaginal Rings for HIV Prevention
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

28. Slide 31 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