1. HIV Preexposure Prophylaxis (PrEP) 2019
Roy M. Gulick, MD, MPH
Chief, Division of Infectious Diseases
Rochelle Belfer Professor in Medicine
Weill Cornell Medicine
New York City, New York

2. Financial Relationships With Commercial Entities
Dr Gulick has no relevant financial affiliations to disclose. (Updated 08/14/19)

3. Learning Objectives
After attending this presentation, learners will be able to:
Discuss the current data to support the use of HIV PrEP
Discuss investigational agents for HIV PrEP

4. New HIV Infections: Global
↓16% since 2010
UNAIDS:

5. New HIV Diagnoses, NYC, 2017 Poverty Gender Age Borough
In NYC, for the last few years, HIV case numbers have been decreasing annually.
This bar chart highlights groups disproportionately affected: Balcks and Hispanics, Men, esp MSM, and those with inclomes below the fed pov line.
Side note:
In ,718 cases were reported 48 diagnoses among transgender women & 1 among transgender men
Identified as transgender by self-report, diagnosing provider or medical chart review. Transgender women were assigned male sex at birth and currently identify as female. Transgender men were assigned female sex at birth and currently identify as male.
Poverty
(area based)
Gender
Age
Borough
Transmission Risk
Source: NYC DOHMH, Bureau of HIV Surveillance Data

6. Governor Cuomo’s Plan to End AIDS in New York -- 2014
1. Diagnose HIV and link to care
2. Link, retain and treat to achieve virologic suppression
3. Provide PrEP for high-risk people to keep them HIV negative
October 2014

7. Federal Plan to End AIDS by 2030
February 2019

8. Oral PrEP Studies (1) Study (reference) Study population Design
Results: ↓HIV Infection
IPREX
Grant NEJM 2010;363:2587
2499 gay men
TDF/FTC vs. placebo
TDF/FTC: 45%
(92% if tenofovir detected)
Partners PREP
Baeten NEJM 2012;367:399
4758 discordant Kenya and Uganda couples
TDF vs. TDF/FTC vs. placebo
TDF: 67%
TDF/FTC: 75%
(86-90% if tenofovir detected)
CDC – TDF-2
Thigpen NEJM 2012;367:423
1200 Botswana adults (45% women)
TDF/FTC: 63%
(84% if tenofovir detected)

9. PrEP Approvals
In July 2012, U.S. FDA approves TDF/FTC for pre-exposure prophylaxis (PrEP) in combination with safer sex practices to reduce the risk of sexually acquired HIV-infection in adults at high risk.
Additional approvals followed including: Australia, Canada, France, India, Israel, Kenya, Peru, South Africa

10. Oral PrEP Studies (2) Study (reference) Study population Design
Results: Reduction in HIV Infection
FEM-PREP
Van Damme
NEJM
2012;367:411
2120 women in Kenya, South Africa, Tanzania
TDF/FTC vs. placebo
TDF/FTC: 6%
VOICE
Marrazzo
2015;372:509
5029 women in South Africa, Uganda, Zimbabwe
1% TDF gel vs. placebo gel;
oral TDF vs. TDF/FTC vs. placebo
0% -- no study drugs effective
(adherence <40%)
(adherence < 30%)

11. Oral PrEP Studies (3) Study (reference) Study population Design
Results: Reduction in HIV Infection
iPERGAY
Molina
NEJM 2015;373:2237
414 MSM in France and Canada
TDF/FTC vs. placebo (event-driven)
TDF/FTC: 86%
PROUD
McCormack
Lancet 2016;387:53
545 men in England
TDF/FTC vs. placebo

12. Oral TDF/FTC PrEP Trials: Effectiveness Improves With Adherence
100
iPrEx Efficacy 44% Adherence 51%
Partners PrEP Efficacy 75% Adherence 81%
TDF2 Efficacy 62% Adherence 80%
VOICE/FEM-PrEP Efficacy 0%/6% Adherence 29%/≤ 37%
PROUD Efficacy 86% Adherence ~100% 80 60 40 20
100
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
References
1. Marrazzo JM, et al. N Engl J Med. 2015;372:
2. Van Damme L, et al. N Engl J Med. 2012;367:
3. Grant RM, et al. N Engl J Med. 2010;363:
4. Thigpen MC, et al. N Engl J Med. 2012;367:
5. Baeten JM, et al. N Engl J Med. 2012;367:
6. McCormack S, et al. Lancet. 2016;387:53-60.
Overall, these randomized clinical trials of PrEP using TDF/emtricitabine have shown that HIV incidence decreases with patient adherence. The y axis depicts the effectiveness of HIV protection in each trial while the x axis documents each trial’s adherence level. Adherence was based on pill counts or the detection of study drug in plasma.
A very clear and strong linear relationship exists where greater adherence across the study population tracks with greater HIV protection. This emphasizes how important it is to be adherent to PrEP. The TDF2, Partners PrEP, and PROUD studies all demonstrated very high degrees of HIV protection in populations that took PrEP consistently.
Slide 12 of 40
Adherence (%)†

13. Oral PrEP Studies (4) Study (reference) Study population Design
Results: Reduction in HIV Infection
Thai IDU
Choopanya Lancet 2013;381:2083
2413 Thai injection drug users
TDF vs. placebo
TDF: 49%
(70% if TFV detected)

14. WHO Evaluation of PrEP Data 2015
Efficacy: Effective across groups, genders
Adherence: Heterogeneous
Side effects: no more common than placebo (subclinical renal/bone issues)
Drug resistance: low (0.1%) risk
Risk compensation: did not increase
Cost: could be cost-effective/cost-saving
Logistics: significant concerns

15. PrEP Safety: Meta Analysis 13 randomized trials of PrEP vs
PrEP Safety: Meta Analysis 13 randomized trials of PrEP vs. placebo (or no treatment) (N=15,678)
all grade
creatinine ↑:
PrEP 336 vs.
control 178
(p=0.04)
grade 3-4
Pilkington J Virus Erad 2018;4:

16. Genotypic Drug Resistance (DR) to TDF or FTC in PrEP Studies
Overall risk of FTC or TFV resistance is 5/9222 (0.05%)
Fonner AIDS 2016;30:

17. Case Reports: HIV Infection with High Adherence to PrEP (N=6)
3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; MSM, men who have sex with men; NVP, nevirapine; PrEP, pre-exposure prophylaxis; RAL, raltegravir; TDF, tenofovir disoproxil fumarate.
However, as illustrated by this case reported at CROI 2016, PrEP is never going to necessarily be 100% effective. This was a MSM from Toronto, Canada. His clinician had a strong index of suspicion when the patient reported substantial risks for HIV and came in with some atypical symptoms. So, the clinician ordered an acute HIV infection assessment, did an RNA testing, and at the same time saved blood to test for TDF/FTC and found that the patient, indeed, was highly adherent to the study medication.
When the RNA test came back positive, the clinician ordered resistance testing, which suggested a high level of resistance, including resistance to some of the drugs that are not contained in a PrEP regimen of TDF/FTC. For example, the patient had resistance to integrase strand inhibitors and nonnucleoside reverse transcriptase agents and protease inhibitors, suggesting that this is a case of a patient having a highly resistant strain of HIV and transmitting it despite PrEP. So, this is a case in point that makes us say that we cannot guarantee PrEP being 100% effective, but it's certainly highly effective. So, if individuals really want maximal protection, there's still a rationale for using condoms. The other rationale for using condoms even in the setting of using PrEP is to avoid other sexually transmitted infections, because PrEP only protects against HIV.
Gibas Drugs 2019;79:

18. PrEP and STIs Systematic Review and Meta-Analysis 8 studies with 4388 participants
Traeger CID 2018;67:

19. U.S. CDC HIV PrEP Guidelines (2017)
“Recommended for substantial risk of HIV Infection”

20. CDC HIV PrEP Guidelines (2017)
Rule out acute HIV infection
Assess baseline renal function
Prescribe 3 months of TDF/FTC
Follow-up visits every 3 months for:
HIV testing
Adherence and risk reduction counseling
Side effect assessment
Sexually transmitted infection symptom assessment and routine testing (chlamydia, gonorrhea, syphilis); treat if necessary
Assess renal function every 6 months

21. U.S. Preventive Services Task Force (UPSTF)
Recommendation Summary
Population
Recommendation
Grade
Persons at high risk of HIV acquisition
The USPSTF recommends that clinicians offer PrEP with effective ART to persons who are at high risk of HIV acquisition. A
JAMA 2019;321:
Federal Rule: Private Insurance and Medicare must offer A or B services without a co-pay.

22. ARS Question 1: Have you prescribed oral daily TDF/FTC for PrEP?
Yes No
I’m not a prescriber

23. In 2017  120,000 PrEP users
In 2019  270,000 PrEP users

25. Mera IAS 2017 #WEPEC0919

26. PrEP Initiations by Country 2018
> 25,000
10,000-25,000
5,000-10,000
1,500-5,000
500-1,500
< 500
No Data
PrEP Available (No Data)
>300,000 PrEP starts globally >200,000 in the US
Source: AVAC Global PrEP Initiation Tracker 2018

27. Intermittent PrEP (I-PrEP)
IPREX Follow-Up: Modeling Pharmacokinetics in Men Who Have Sex With Men (MSM)
Using data from a separate PK study:
7 doses/week: 99% risk reduction
4 doses/week: 97% risk reduction
2 doses/week: 76% risk reduction
Anderson Sci Transl Med 2012;4:151ra125.

28. ARS Question 2: Have you recommended “on-demand” TDF/FTC for PrEP?
Yes No
I’m not a prescriber

29. Event-Driven PrEP: Status
FDA label of TDF/FTC specifies once-daily
Recommended by IAS-USA, BHIVA, EACS (2018) and WHO (2019)

30. Prevenir INTERIM REPORT
Open-label, prospective, cohort study in Paris
Cohort population: HIV- high-risk adults, inconsistent condom use, GFR >50, HBsAg negative if using on-demand (N=3057)
Rx: Choose TDF/FTC daily or on-demand dosing (and can switch); f/u every 3 months
Goal: Show 15% ↓ in new HIV infections in Paris
Results (HIV modified ITT analysis):
2 seroconversions, both off PrEP
X 7-10 weeks
3 PrEP discontiunations due to GI sx
Conclusion: High efficacy of daily and on-demand PrEP
Molina IAS 2019 #TUAC0202

31. Rates of Detectable TFV/TFV-metabolite detection in Female Mucosal Tissues – Single Dose Study
TAF 25mg
TDF 300mg
100%
37%
Rectal Tissue
DETECTABLE CONCENTRATIONS OF TFV AND TFV-DP IN FEMALE MUCOSAL TISSUES AFTER SINGLE DOSE
Cottrell J Antimicrob Chemother 2017;72:

32. ARS Question 3: Have you prescribed oral daily TAF/FTC for PrEP?
Yes No
I’m (still) not a prescriber

33. Newer PrEP Agents study drug mechanism dosing route dosing PrEP stage
TAF
NRTI
oral
daily
phase 3
completed
cabotegravir
integrase inhibitor
injectable, subcutaneous
once every other month
studies
monoclonal antibodies
CD4 or gp120 attachment inhibitors
Injectable subcutaneous
pilot studies; phase 2b/3
AMP studies

34. Rates of Detectable TFV/TFV-metabolite detection in Female Mucosal Tissues – Single Dose Study
TAF 25mg
TDF 300mg
100%
37%
Rectal Tissue
DETECTABLE CONCENTRATIONS OF TFV AND TFV-DP IN FEMALE MUCOSAL TISSUES AFTER SINGLE DOSE
Cottrell J Antimicrob Chemother 2017;72:

35. DISCOVER: TDF vs. TAF for PrEP
Double-blind, non-inferiority PrEP study
Study population: MSM and TGW (N=5387)
median 34 yo, 84% W, 24% L, 16% non-white, 74 TGW
Study rx: daily oral TDF vs. TAF
Results:
22 incident infections
5 at first visit
15 with ↓ drug levels
2 with adeq. drug levels
>57% with STI
Improved bone, renal markers with TAF
Conclusion: TAF non-inferior to TDF for PrEP
Hare CROI 2019 #104

36. DISCOVER: TAF/FTC vs. TDF/FTC
Subanalyses:
No difference in
number of condomless RAI partners
rectal GC/chlamydia
self-reported adherence, pill counts
TFV-DP levels by dried blood spots: HIV cases << controls
Published data: TAF achieves EC90 within 4 hrs, TDF takes 3 days
Conclusions: TAF “potentially more efficacious”
FDA Advisory Committee (8/7/19): TAF/FTC PrEP approval vote: men: for ♂; women: 10-8 against
Spinner IAS 2019 #TUAC0403LB

37. HPTN 083: PrEP with TDF/FTC oral vs. cabotegravir (CAB) intramuscular
Study population: Adult MSM and transgender women at high-risk for HIV acquisition (N=4500)
Study regimen: TDF/FTC daily oral vs. CAB every 2 month injections
double-blind, double-dummy design
Design: non-inferiority, efficacy study
4358 (97%) enrolled globally (as of 9/10/19)!

38. Islatravir (ISL, formerly MK-8591) Implant
Matthews IAS #TUAC0401LB

39. Impact: Big Cities
All in context of high levels of testing & ART
San Francisco: 50+% ↓ in new HIV infections in the past decade
SFDPH Annual Report 2017
Sydney: 32% ↓ (25% ↓ in 2 years)
Grulich Lancet HIV 2018;5:e629-e637
London: 42% ↓
Nwokolo Lancet HIV 2017;4:e482-e483
New York: 37% ↓ 20112017
NYC HIV Surveillance Report 2017

40. New York State AIDS Institute

41. Acknowledgments Cornell HIV Clinical Trials Unit (CCTU)
Division of Infectious Diseases
Weill Cornell Medicine
AIDS Clinical Trials Group (ACTG)
Division of AIDS, NIAID, NIH
The patient volunteers!
Demetre Daskalakis, Raphy Landovitz, Ken Mayer for slides

42. Question-and-Answer