Transcript Pre-Exposure Prophylaxis Education

Mountain West AIDS Education and Training Center
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
This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice
related to any specific patient.
Disclosures and Disclaimers
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
Key HIV PrEP Trials Using Oral Tenofovir (TDF) or Tenofovir-Emtricitabine (TDF-FTC)
Study
Study Population
Study Randomization
HIV Incidence Impact
IPrEx
2499 MSM and
transgender women
Daily oral TDF-FTC or placebo
TDF-FTC: 44% 
4147 heterosexual HIV
discordant couples
Daily oral TDF, TDF-FTC, or
placebo
TDF: 67% 
TDF-FTC: 75% 
1219 heterosexual men
and women
Daily oral TDF-FTC or placebo
TDF-FTC: 63% 
2120 women
Daily oral TDF-FTC or placebo
TDF-FTC: no protection
(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
2413 injection drug
users
Randomized to daily oral TDF
or placebo
TDF: 49% 
400 MSM
Randomized to “on-demand”
TDF-FTC or placebo
TDF-FTC: 86% 
545 MSM and
transgender women
Randomized to daily oral TDFFTC immediately or delayed
Immediate TDF-FTC:
86% 
(Brazil, Ecuador, South
Africa, Thailand, US)
Partners PrEP Study
(Kenya, Uganda)
TDF2 Study
(Botswana)
FEM-PrEP
(Kenya, South Africa,
Tanzania)
VOICE
(Thailand)
IPERGAY
(France, Quebec)
PROUD
(United Kingdon)
The Relationship Between Adherence and Efficacy
Efficacy in randomized
% of blood samples
comparison
with tenofovir detected
80
70
TDF2
Efficacy (risk reduction)
Partners
PrEP
60
50
40 TDF
Bangkok
iPrEx
30
20
FEM-PrEP
75%
81%
62%
79%
49%
67%
44%
51%
6%
26%
-
29%
10
VOICE
0
0
10
Baeten et al N Engl J Med 2012
Grant et al N Engl J Med 2010
Choopanya et al Lancet 2013
20
30
40
50
60
% blood specimens with TDF detected
Van Damme et al N Engl J Med 2012
Thigpen et al N Engl J Med 2012
Marrazzo et al CROI 2013 #26LB
70
80
90
The Relationship Between Adherence and Efficacy
Lessons from iPrEx
Detectable Drug Levels in Patients on Tenofovir-Emtricitabine
A. Intracellular Emtricitabine Levels
9%
B. Intracellular Tenofovir-DF Levels
52%
6%
Adjusted RR reduction (any detectable level) = 95%
Source: Grant RM, et al. N Engl J Med. 2010;363:2587-99.
50%
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; 819-829.
PrEP Side Effects and Safety
“Startup Syndrome”
• 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
Renal Safety
• 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
Bone Effects
• In trials, TDF-FTC associated with small change (~1%) in bone
density, though generally stabilized or improved
• No increase in fractures seen
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.
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.
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.
Partners PrEP
Proportion of HIV – participants
with any unprotected sex (%)
iPrEx
50
40
30
20
10
0
0
3
6
9
12
15
18
21
24
27
30
Follow-up time (Month)
TDF
FTC/TDF
Placebo
PrEP and sexual behavior in the “real world”
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
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
60%
50%
30%
40%
Z
E
R
O
30%
20%
25%
20%
15%
10%
10%
5%
0%
Any
CT
GC
Volk et al. Clin Infect Dis 2015
TP
HIV
0%
Rectal GC Rectal CT Urethral Urethral
GC
CT
McCormack et al. Lancet 2016
Syphilis
450
4500
400
4000
350
3500
300
3000
250
2500
200
2000
150
1500
100
1000
50
500
0
0
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Incidence per 100,000
Syphilis cases/year
Syphilis in King County
non-MSM
HIV- MSM
HIV+ MSM
Incidence (HIV+ MSM)
Incidence (HIV- MSM)
Drug resistance in PrEP Trials
Infected at Entry
Study
iPrEx
Partners PrEP
TDF2
FEM-PrEP
VOICE
Total
%
(95% CI)
•
•
•
•
Incident Infection
Study Drug
Resist/Tot
2/2
Placebo
Resist/Tot
1/8
Study Drug
Resist/Tot
0/48
Placebo
Resist/Tot
0/83
1/3
0/6
0/13
0/52
1/1
0/1
2/9
6/16
37.5%
0/2
0/1
0/1
1/18
5%
(1 to 26%)
0/9
4/33
1/61
5/164
3%
(1 to 7%)
0/24
1/35
0/60
1/254
0.3%
(.06 to 2%)
(18 to 61%)
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
www.cdc.gov/hiv/pdf/prepguidelines2014.pdf
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.
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.
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.
Who Should Get PrEP?
(Results from iPrEx)
Buchbinder et al., Lancet ID 2014
Who Should Get PrEP?
(Results from iPrEx)
Buchbinder et al., Lancet ID 2014
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.
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
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.
20
15
Slide courtesy of Bernie Branson
10
5
0
Days before WB positive
Modified from Masciotra et al, J Clin Virol 2011; Owen et al, J Clin Micro 2008
Vironostka (+) 2
Unigold (-2)
OraQuick (-1)
WB positive
COMPLETE HIV-1/2 (-5)
HIV-1/2 STAT-PAK (-5)
Multi-Spot (-7)
Reveal G3 (-6)
INSTI (-9)
GS 1/2+O (-12)
Determine Combo (-15)
25
Architect Combo (-20)
Bio-Rad Combo (-19)
APTIMA (-26)
Sequence of test positivity relative to WB
166 specimens, 17 Seroconverters
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 falsenegative tests, particularly with oral fluid tests.
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.
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.
Monitoring Adherence to PrEP
Lessons from iPrEx
• 510 subjects with plasma levels drawn at wk 24
Self-report
CASI
Pharmacy data
100%
55%
43%
65%
90-99%
22%
29%
22%
50-89%
13%
18%
10%
<50%
2%
2%
3%
Missing/unknown
7%
9%
• Among subjects reporting 100% adherence
- 51% had any drug detected
- 35% had levels consistent w regular dosing
Source: Amico et al., JAIDS. 2014: 66(5); 530-537.
Adherence and Efficacy in Open-label Projects
The Demo Project (SF, Miami, DC)
100%
Protective TFV-DP in
DBS
90%
Rating scale: very
good/excellent
80%
70%
Medication Possession
Ratio (mean)
Percent
60%
•
50%
•
40%
•
30%
•
20%
10%
0%
4
12
24
Visit week
Source: Liu et al., JAMA Intern Med, 2016
36
48
2 infections (incidence
0.43/100py)
63% had protective
DBS levels at all visits
3% always had DBS
levels <2 doses/week
PrEP dispensation
interrupted in 15%:
most commonly due to
side effect concerns or
low perceived risk
How to Monitor Adherence to PrEP
1) Does your patient show up to appointments?
2) Did your patient pick up their prescriptions?
3) 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)
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/email
- 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.
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.
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.
Summary of Recommended Laboratory Evaluation
Baseline and Routine Monitoring for Patients taking PrEP
Recommended Laboratory Testing and Frequency for Patients Taking PrEP
Laboratory test
HIV screening
assay
Baseline
Every 3
months
✔
✔
HBV antibody panel
and HCV antibody
✔
Serum creatinine
✔
General STI screen
✔
Pregnancy test for
women
✔
At least every
6 months
Notes
Consider need for
HIV RNA PCR
Offer HBV
vaccination if not
immune
✔
Avoid PrEP if
CrCl <60 mL/min
✔
Include oral/rectal
screen for MSM if risk
✔
Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.
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.
Asymptomatic STIs among persons on PrEP
Proportion of infections for which treatment would have been
delayed with q6 month screening
100%
20.4
90%
80%
34.3
35.3
40
70%
60%
50%
79.6
40%
30%
65.7
64.7
60
20%
10%
0%
Gonorrhea n=181
Chlamydia n=210
Detected
Cohen et al, CROI 2016
Syphilis n=54
Delayed
Total n=445
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.
Paying for PrEP
Project Inform: www.projectinform.org
ICD-10 codes to consider using for PrEP prescribing
Visit and HIV/STD testing
Z20
Z20.6
Z72.5
Z72.51
Z72.52
Z72.53
Z11
Z11.3
Z11.4
Contact with and (suspected) exposure to HIV
High risk behavior (main category not billable)
High risk heterosexual behavior
High risk homosexual behavior
High risk bisexual behavior
Encounter for screening infectious and parasitic diseases (not billable)
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
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.
“Highly active HIV prevention”
HIV Testing
&
Serosorting?
Needle
Condoms
Exchange
Vaccines
PrEP as part of the larger puzzle
Mental
health
Drug
treatment
PrEP
Relationships
Housing
Conception
How can I learn more?
General Information
www.cdc.gov/hiv/basics/prep.html
www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf
www.facebook.com/groups/PrEPFacts
www.prepfacts.org
UCSF Clinician Consultation Center
1-855-HIV-PrEP (1-855-448-7737), M-F 11-6 EST
How to Pay for PrEP
- Gilead’s Medication Assistance Program
http://www.gilead.com/responsibility/us-patient-access/us%20advancing%20access
- Washington PrEP DAP (also has list of PrEP providers by county)
www.doh.wa.gov/YouandYourFamily/IllnessandDisease/HIVAIDS/HIVCareClientServices/PrEPDAP
Conclusions
• PrEP is safe, easy to prescribe, covered by insurance and drugassistance 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/email me if you have any questions about PrEP.
Questions?
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.
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
Intermittent or “On-Demand” PrEP for High-Risk MSM
IPERGAY: Results
Number of HIV Infections
25
P = 0.002
20
15
14
⇓ 86%
10
5
2
0
Placebo
Tenofovir-Emtricitabine
Due to high effectiveness of PrEP, participants unrandomized and all offered PrEP
Source: Molina JM, et al. CROI. 2015; Abstract 23LB.
How far in advance do MSM “plan” for sex?
N=1013
Volk et al, JAIDS, 2012