1. Pre-exposure Prophylaxis for HIV Prevention
What’s New in Medicine Conference
Joanne Stekler, MD MPH
Associate Professor, UW Department of Medicine
September 9, 2016

2. Disclosures and Disclaimers

3. Topics To Be Covered Efficacy, medication adherence, and side effects
Sexual behavior and STIs in persons on PrEP
Drug resistance and PrEP
Implementing the guidelines: prescribing and monitoring
Paying for PrEP and insurance billing

4. Key HIV PrEP Trials Using Oral Tenofovir (TDF) or Tenofovir-Emtricitabine (TDF-FTC)
Study
Study Population
Study Randomization
HIV Incidence Impact
IPrEx (Brazil, Ecuador, South Africa, Thailand, US)
2499 MSM and transgender women
Daily oral TDF-FTC or placebo
TDF-FTC: 44% 
Partners PrEP Study (Kenya, Uganda)
4147 heterosexual HIV discordant couples
Daily oral TDF, TDF-FTC, or placebo
TDF: 67%  TDF-FTC: 75% 
TDF2 Study (Botswana)
1219 heterosexual men and women
TDF-FTC: 63% 
FEM-PrEP
(Kenya, South Africa, Tanzania)
2120 women
TDF-FTC: no protection
VOICE (South Africa, Uganda, Zimbabwe)
5029 women
Randomized to daily oral TDF, TDF-FTC, oral placebo, TDF vaginal gel, or gel placebo
TDF: no protection TDF-FTC: no protection TDF gel: no protection
Bangkok TDF Study (Thailand)
2413 injection drug users
Randomized to daily oral TDF or placebo
TDF: 49% 
IPERGAY (France, Quebec)
400 MSM
Randomized to “on-demand” TDF-FTC or placebo
TDF-FTC: 86% 
PROUD (United Kingdon)
545 MSM and transgender women
Randomized to daily oral TDF-FTC immediately or delayed
Immediate TDF-FTC: 86% 

5. The Relationship Between Adherence and Efficacy
Efficacy in randomized comparison
% of blood samples with tenofovir detected
Partners PrEP
75%
81%
TDF2
62%
79%
Bangkok TDF
49%
67%
iPrEx
44%
51%
FEM-PrEP 6%
26%
VOICE -
29%
Baeten et al N Engl J Med 2012 Van Damme et al N Engl J Med 2012 Grant et al N Engl J Med 2010 Thigpen et al N Engl J Med 2012 Choopanya et al Lancet 2013 Marrazzo et al CROI 2013 #26LB

6. The Relationship Between Adherence and Efficacy Lessons from iPrEx
Detectable Drug Levels in Patients on Tenofovir-Emtricitabine
A. Intracellular Emtricitabine Levels
B. Intracellular Tenofovir-DF Levels 9%
52% 6%
50%
Adjusted RR reduction (any detectable level) = 95%
Source: Grant RM, et al. N Engl J Med. 2010;363:

7. Adherence and Efficacy in Open-label Projects iPrEx OLE (open label extension)
Overall adherence 71%
Estimated adherence
(TDF in DBS)
Incidence
Not detected
4.7/100 person-years
<2 tab/week
2.3/100 person-years
2-3 tab/week
0.6/100 person-years
4-7 tab/week
0/100 person-years
Source: Grant et al, Lancet. 2014: 14;

8. PrEP Side Effects and Safety
In trials, nausea more common with TDF-FTC than placebo
Nausea, headache, or fatigue may occur in first 2-4 weeks
Generally resolves; OTC or PRN meds may help
“Startup Syndrome”
In trials, changes in renal function not more frequent with TDF-FTC than placebo, though follow-up limited
Monitoring at least every 6 months recommended
Renal Safety
In trials, TDF-FTC associated with small change (~1%) in bone density, though generally stabilized or improved
No increase in fractures seen
Bone Effects
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

10. Behavioral disinhibition
Risk compensation could negate prevention benefits of PrEP.
BUT
Careful of our own morality/judgement (PrEP stigma)
Important to remember:
Birth control has not led to increased sexual risk.
Needle exchange has not led to increased IDU.
HPV vaccine has not led to earlier sexual debut.
We prescribe lipid-lowering agents to reduce MI risk for people who continue to eat French fries.

11. PrEP and sexual behavior in RCTs
In RCTs, condomless sex was less common over time.
BUT subjects did not know if they were on PrEP or placebo.
iPrEx
Partners PrEP 50 40 30
Proportion of HIV – participants with any unprotected sex (%) 20 10 3 6 9 12 15 18 21 24 27 30
Follow-up time (Month)
TDF
FTC/TDF
Placebo

12. PrEP and sexual behavior in the “real world”

13. Behavior change and STIs in the Demo Project (San Francisco, Miami, Washington D.C.)
Liu et al. JAMA Intern Med. 2016;176(1):75-84

14. STIs among PrEP users and persons at risk for HIV
Kaiser-Permanente, CA,
12-month cumulative %
N=657
PROUD Study, UK
12 months prior to enrollment
N=544
Volk et al. Clin Infect Dis McCormack et al. Lancet 2016

15. Syphilis in King County

16. Drug resistance in PrEP Trials
Infected at Entry
Incident Infection
Study Drug
Placebo
Study
Resist/Tot
iPrEx
2/2
1/8
0/48
0/83
Partners PrEP
1/3
0/6
0/13
0/52
TDF2
1/1
0/2
0/9
0/24
FEM-PrEP
0/1
4/33
1/35
VOICE
2/9
1/61
0/60
Total %
(95% CI)
6/16
37.5%
(18 to 61%)
1/18 5%
(1 to 26%)
5/164 3%
(1 to 7%)
1/254
0.3%
(.06 to 2%)
9 excess DR infections: 11 active, 2 placebo
92 infections averted by FTC/TDF PrEP = (254+18)-(164+16)
8 (92/9) infections averted per DR infection overall
Excluding acute infections when PrEP was started:
22 (90/4) infections averted per DR infection.
IAS: Grant, oral abstract TUAC0104

17.
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

18. Summary of Clinical Eligibility for HIV PrEP
Considered to be at “substantial risk” of HIV infection
Documented negative HIV test before prescribing PrEP
No symptoms of acute HIV infection
Normal renal function (>60 mL/min)
Documented hepatitis B viral immune status
Able to adhere to a daily medication
Able to adhere to follow-up visits (at least every 3 months)
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

19. Who Should Be Considered for PrEP
Who Should Be Considered for PrEP? Individuals with “Substantial Risk” of Acquiring HIV
Indications for PrEP use by men-who-have-sex-with-men (MSM)
Adult man
Without acute or established HIV infection
Any male sex partners in past 6 months
Not in a monogamous partnership with an HIV-negative man
AND at least one of the following
Any anal sex without condoms in past 6 months
Any STI diagnosed or reported in past 6 months
In an ongoing sexual relationship with an HIV-positive male partner
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

20. Who Should Get PrEP? (Results from iPrEx)
Buchbinder et al., Lancet ID 2014

21. Who Should Get PrEP? (Results from iPrEx)
Buchbinder et al., Lancet ID 2014

22. Summary of Clinical Eligibility for HIV PrEP
Considered to be at “substantial risk” of HIV infection
Documented negative HIV test before prescribing PrEP
No symptoms of acute HIV infection
Normal renal function (>60 mL/min)
Documented hepatitis B viral immune status
Able to adhere to a daily medication
Able to adhere to follow-up visits (at least every 3 months)
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

23. Symptoms of acute HIV infection
Approximately 50-90% of individuals have ≥1 symptoms ~2 weeks after Infection
Fever
Fatigue
Sore throat
Muscle/joint aches
Night sweats
Headaches
Diarrhea
Rash

24. Recommended HIV Screening Prior to PrEP Initiation
At a minimum, document a negative screening test within 1 week before initiating (or reinitiating) PrEP
(A) Blood (serum) lab-based testing, or
(B) Rapid, point-of-care, fingerstick blood testing*
If negative or indeterminate screening result in a patient with recent signs and symptoms of acute HIV
(A) Repeat screening test in 1 month and defer PrEP decision, or
(B) Send HIV RNA PCR (preferred)
*Per the guidelines, oral rapid tests should not be used to screen for HIV infection when considering PrEP because they can be less sensitive than blood tests
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

25. Sequence of test positivity relative to WB 166 specimens, 17 Seroconverters
Architect Combo (-20)
Bio-Rad Combo (-19)
Determine Combo (-15)
Reveal G3 (-6)
COMPLETE HIV-1/2 (-5)
GS 1/2+O (-12)
HIV-1/2 STAT-PAK (-5)
Vironostka (+) 2
APTIMA (-26)
INSTI (-9)
Multi-Spot (-7)
OraQuick (-1)
Unigold (-2)
WB positive 25 20 15 10 5
Days before WB positive
Modified from Masciotra et al, J Clin Virol 2011; Owen et al, J Clin Micro 2008 Slide courtesy of Bernie Branson

26. (starting PrEP during AHI → resistance)
HIV testing in PrEP
· When starting PrEP, use the test with shortest window period available. Do not use oral fluid tests.
(starting PrEP during AHI → resistance)
· Do not ask people to remain abstinent/use condom while waiting out the window period.
· Screen for symptoms of AHI
If symptoms and recent exposure → delay PrEP start
*Almost all* symptomatic AHI will test pos on lab 4th gen
But…. There is a 2nd window period….
· PrEP may lead to delayed seroconversion and false-negative tests, particularly with oral fluid tests.

27. Summary of Clinical Eligibility for HIV PrEP
Considered to be at “substantial risk” of HIV infection
Documented negative HIV test before prescribing PrEP
No symptoms of acute HIV infection
Normal renal function (>60 mL/min)
Documented hepatitis B viral immune status
Able to adhere to a daily medication
Able to adhere to follow-up visits (at least every 3 months)
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

28. Recommended Follow-Up Counseling and Services
Recommended Follow-Up Counseling and Services for Patients Taking PrEP
Follow-up services
Every 3 months
Adherence counseling ✔
Behavioral risk reduction support and condoms
Assessment for side effects
Assessment for STI symptoms and symptoms of acute HIV
For women, discuss pregnancy intent and contraceptive options
Access to clean needles/syringes and drug treatment services
Provide a refill of daily TDF/FTC for no more than 90 days
Abbreviations: STI = sexually transmitted infection; TDF/FTC = tenofovir/emtricitabine
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

29. Monitoring Adherence to PrEP Lessons from iPrEx
510 subjects with plasma levels drawn at wk 24
Among subjects reporting 100% adherence
51% had any drug detected
35% had levels consistent w regular dosing
Self-report
CASI
Pharmacy data
100%
55%
43%
65%
90-99%
22%
29%
50-89%
13%
18%
10%
<50% 2% 3%
Missing/unknown 7% 9%
Source: Amico et al., JAIDS. 2014: 66(5);

30. Adherence and Efficacy in Open-label Projects The Demo Project (SF, Miami, DC)
Source: Liu et al., JAMA Intern Med, 2016

31. How to Monitor Adherence to PrEP
Does your patient show up to appointments?
Did your patient pick up their prescriptions?
Single best questions
- How many pills missed in the last month?
- How many pills missed in the last week?
- How good has your adherence been over the last month? (very poor, poor, fair, good, very good, excellent)

32. How to Promote Adherence to PrEP
At baseline
Provide education about PrEP
Importance of adherence, side effects
Help to establish a dosing routine
What to do about missed doses
Discuss reminder systems and tools
Medisets, alarms (clocks, phones, smartwatches), apps, text messaging/
Address financial, substance abuse, mental health needs
Facilitate social support
During follow-up
Assess adherence and identify barriers to adherence
Assess and help manage side-effects
Normalize missed doses
Reinforce success
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

33. Summary of Clinical Eligibility for HIV PrEP
Considered to be at “substantial risk” of HIV infection
Documented negative HIV test before prescribing PrEP
No symptoms of acute HIV infection
Normal renal function (>60 mL/min)
Documented hepatitis B viral immune status
Able to adhere to a daily medication
Able to adhere to follow-up visits (at least every 3 months)
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

34. Recommended Follow-Up Counseling and Services
Recommended Follow-Up Counseling and Services for Patients Taking PrEP
Follow-up services
Every 3 months
Adherence counseling ✔
Behavioral risk reduction support and condoms
Assessment for side effects
Assessment for STI symptoms and symptoms of acute HIV
For women, discuss pregnancy intent and contraceptive options
Access to clean needles/syringes and drug treatment services
Provide a refill of daily TDF/FTC for no more than 90 days
Abbreviations: STI = sexually transmitted infection; TDF/FTC = tenofovir/emtricitabine
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

35. Summary of Recommended Laboratory Evaluation Baseline and Routine Monitoring for Patients taking PrEP
Recommended Laboratory Testing and Frequency for Patients Taking PrEP
Laboratory test
Baseline
Every 3 months
At least every 6 months
Notes
HIV screening assay ✔
Consider need for HIV RNA PCR
HBV antibody panel and HCV antibody
Offer HBV vaccination if not immune
Serum creatinine
Avoid PrEP if CrCl <60 mL/min
General STI screen
Include oral/rectal screen for MSM if risk
Pregnancy test for women
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

36. Recommended Follow-Up Counseling and Services
Recommended Follow-Up Counseling and Services for Patients Taking PrEP
Follow-up services
Every 3 months
Adherence counseling ✔
Behavioral risk reduction support and condoms
Assessment for side effects
Assessment for STI symptoms and symptoms of acute HIV
For women, discuss pregnancy intent and contraceptive options
Access to clean needles/syringes and drug treatment services
Provide a refill of daily TDF/FTC for no more than 90 days
Abbreviations: STI = sexually transmitted infection; TDF/FTC = tenofovir/emtricitabine
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

37. Asymptomatic STIs among persons on PrEP
Cohen et al, CROI 2016

38. Summary of Clinical Eligibility for HIV PrEP
Considered to be at “substantial risk” of HIV infection
Documented negative HIV test before prescribing PrEP
No symptoms of acute HIV infection
Normal renal function (>60 mL/min)
Documented hepatitis B viral immune status
Able to adhere to a daily medication
Able to adhere to follow-up visits (at least every 3 months)
Insurance coverage or other ability to pay for PrEP
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

39. Paying for PrEP
Project Inform:

40. Thank you.

41. ICD-10 codes to consider using for PrEP prescribing
Visit and HIV/STD testing
Z20
Z20.6
Contact with and (suspected) exposure to HIV
Z72.5
High risk behavior (main category not billable)
Z72.51
Z72.52
Z72.53
High risk heterosexual behavior
High risk homosexual behavior
High risk bisexual behavior
Z11
Encounter for screening infectious and parasitic diseases (not billable)
Z11.3
Z11.4
Encounter for screening for infectious with a predominantly sexual mode of transmission
Encounter for screening for HIV
Laboratory monitoring
Z51.81
Encounter for therapeutic drug level monitoring
Z79.899
Other long-term (current) use of drug/prophylactic therapy
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014

42. What is wanted = prevention options.
PrEP in the future
Pill
Gel
Vaginal film
Vaginal ring
Injectable
Tenofovir-containing pills are not feasible for everyone. There is an encouraging pipeline of new PrEP prevention products that will deliver additional options.
However, we would be naïve to imagine that any one of these will work or be workable for every person.
What is wanted = prevention options. 42

43. “Highly active HIV prevention”
HIV Testing
&
Serosorting?
Needle
Exchange
Condoms
HIV and STI
Vaccines
Treatment
PEP & PrEP

44. PrEP as part of the larger puzzle
Mental health
Drug treatment
PrEP
Relationships
Housing
Conception

45. How can I learn more? General Information
UCSF Clinician Consultation Center
1-855-HIV-PrEP ( ), M-F 11-6 EST
How to Pay for PrEP
- Gilead’s Medication Assistance Program
- Washington PrEP DAP (also has list of PrEP providers by county)

46. Conclusions
PrEP is safe, easy to prescribe, covered by insurance and drug-assistance programs, and an important part of HIV prevention and End AIDS Washington.
PrEP is intended for people who, for whatever reason, cannot/will not/do not use condoms. PrEP decreases that person’s risk for HIV acquisition (i.e. harm reduction).
Frequent STI screenings are important in high-risk populations, whether or not persons are on PrEP.
There are many resources for you to learn more. Do not hesitate to call/ me if you have any questions about PrEP.

47. Questions?

48. Intermittent or “On-Demand” PrEP for High-Risk MSM IPERGAY: Background
Study Features
N = 400 high-risk men-who-have-sex-with-men (MSM)
Setting: France and Canada
Condomless anal sex with ≥2 partners in prior 6 months
eGFR >60 mL/min
All received risk-reduction counseling, condoms, and HAV and HBV vaccines if needed, as well as information about PEP
Randomized to one of two arms
Source: Molina JM, et al. CROI. 2015; Abstract 23LB.

49. Intermittent or “On-Demand” Preexposure Prophylaxis IPERGAY Event-Driven Strategy
HIV Exposure Event
Time
2 tabs 2-24 hours before sex (or 1 pill if most recent dose taken between 1-6 days prior)
1 tab 24 and 48 hours after the last pre-sex dose

50. Intermittent or “On-Demand” PrEP for High-Risk MSM IPERGAY: Results
⇓ 86%
Additional data that could be added:
Median follow-up was 8.8 months (IQR: 4.3 to 20.5).
The average number of sexual partners participants had had in the previous two months was eight. Seventy per cent had had condomless anal sex in the previous two months.
The two participants in the Truvada arm who acquired HIV did not become infected until late in the study – one 16 and one 21 months after entering the study. Principal investigator Jean-Michel Molina said that the two had pretty certainly stopped taking PrEP by that time – they had even been returning unused pill bottles to the clinic.
During the study, 35% of participants were diagnosed with a sexually transmitted infection including 20% with gonorrhoea and 10% with syphilis; Jean-Michel Molina reported two in a hundred participants acquired hepatitis C, equating to six infections.
Pts used a median of 14 pills/month (IQR: 8-20).
Reference:
Molina J-M et al. On Demand PrEP With Oral TDF-FTC in MSM: Results of the ANRS Ipergay Trial Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, USA, abstract 23LB, 2015.
Due to high effectiveness of PrEP, participants unrandomized and all offered PrEP
Source: Molina JM, et al. CROI. 2015; Abstract 23LB.

51. How far in advance do MSM “plan” for sex?
N=1013 Volk et al, JAIDS, 2012