Why, when, and how to use pre exposure prophylaxis for hiv acquisition. 2014

Why, When, and How to Use Pre-Exposure
Prophylaxis (PrEP) for HIV Acquisition:
Guidance for Midlevel Practitioners
Marcy S. Gelman, RN, MSN, MPH
Director of Operations and Clinical
Research
The Fenway Institute
Fenway Community Health
Boston, Massachusetts
Kevin M. O’Hara, PA
Assistant Professor of Medicine
Physician Associate Program
Yale School of Medicine
New Haven, Connecticut
This activity is supported by an independent educational grant
from Gilead Sciences.

Why, When, and How to Use Pre-Exposure Prophylaxis (PrEP) for HIV Acquisition
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Faculty
Marcy S. Gelman, RN,
MSN, MPH
Director of Operations and
Clinical Research
The Fenway Institute
Fenway Community Health
Boston, Massachusetts
Kevin M. O’Hara, PA
Assistant Professor of Medicine
Physician Associate Program
Yale School of Medicine
New Haven, Connecticut

Faculty Disclosures
Marcy S. Gelman, RN, MSN, MPH, has no significant
financial relationships to disclose.
Kevin M. O’Hara, PA, has disclosed that he has ownership
interest in AbbVie and Gilead Sciences.

Introduction to the Use of PrEP in
Clinical Practice

HIV/AIDS in the United States and
Worldwide
 Approximately 1.1 million people are living with HIV/AIDS in the
United States
– An estimated 1 in 6 (15.8%) of those people are undiagnosed
– Since the start of the epidemic, 636,000 people have died of AIDS
– An estimated 50,000 new HIV infections occur in the US every yr
 More than 35 million people are living with HIV/AIDS worldwide,
of whom 3.3 million are younger than 15 yrs of age
– In 2012, an estimated 2.3 million people were newly infected with
HIV
CDC. HIV Surveillance Report. 2013;18(no.5). CDC. HIV Surveillance Report, 2011; vol. 23.
UNAIDS Report On the Global AIDS Epidemic 2013.

The Need for HIV Prevention: Continued
HIV Risk in the US
 Estimated new HIV infections in the United States for the
most affected subpopulations, 2008-2011
2008 2009 2010 2011
70
60
50
40
30
CDC. HIV in the United States: 2013.
Yr
0
Diagnoses (%)
20
10
Male-to-male sexual contact
Heterosexual contact
IDU
Male-to-male sexual
contact and IDU
Other

HIV Prevention: Toolbox for Success
 Safer-sex counseling: understanding risk
 Condoms and lubricant
 Sterile syringes and avoiding sharing “works”
 HIV testing
 STI testing and treatment
 PEP (postexposure prophylaxis)
 PrEP (pre-exposure prophylaxis)

What Is PrEP?
 For PrEP, an HIV-uninfected individual takes antiretroviral
medication(s) before potential HIV exposure
 The idea of providing a medication as prophylaxis against
an infectious disease is well established, eg:
– Use of antimalarials before traveling to malarial zones
– Use of antibiotics prior to dental procedures
 Oral contraceptives are also used prophylactically to
prevent pregnancy

Antiretrovirals Used in HIV Prevention:
The Foundation for PrEP
 Prevention of mother-to-child transmission
– Antiretrovirals given to the mother during pregnancy, labor,
and delivery and to the infant postpartum[1]
– PMTCT has virtually eliminated perinatal HIV infection in the
US and other developed countries
 Postexposure prophylaxis
– Antiretrovirals given within hrs of a known or suspected HIV
exposure (eg, needle stick injury, rape)
– US public health guidance for PEP is available for both
occupational[2] and nonoccupational[3] exposure to HIV
1. DHHS. Perinatal Guidelines. 2014. 2. Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-892.
3. MMWR. 2005;54(RR-2):1-20.

Pre- vs Postexposure Prophylaxis
 After exposure to HIV,
infection may become
established
 Postexposure prophylaxis
(initiated soon after
exposure) reduces the
chance of infection
 Pre-exposure prophylaxis
begins treatment earlier
(before exposure), which
might increase the
prophylactic effect
HIV
infection
HIV
exposure
0 hr 36 hrs 72 hrs
1 mos 3 mos 5 mos
Postexposure
prophylaxis
Pre-exposure
prophylaxis

PrEP Trials Have Shown Efficacy in MSM,
Heterosexual Men and Women, and IDUs
Trial Population/Setting Intervention HIV Infections, n Reduction in
HIV Infection Rate,
PrEP Placebo % (95% CI)
iPrEX[1]
(N = 2499)
MSM, transgender women,
11 sites in US, South
America, Africa, Thailand
TDF/FTC 36 64 44 (15-63)
Partners
PrEP[2]
(N = 4747)
Serodiscordant couples
in Africa
TDF 17
52
67 (44-81)
TDF/FTC 13 75 (55-87)
TDF2[3]
(N = 1219)
Heterosexual males and
females in Botswana TDF/FTC 9 24 62 (21-83)
Thai IDU[4]
(N = 2413)
Volunteers from 17 drug
Thai treatment centers TDF 17 33 49 (10-72)
 2 additional trials of PrEP (FEM-PrEP[5] and VOICE[6]), both conducted among high-risk African
women, did not demonstrate protection against HIV; in both trials, PrEP adherence was very low
1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 2. Baeten JM, et al. N Engl J Med. 2012;367:399-
410. 3. Thigpen MC, et al. N Engl J Med. 2012;367:423-434. 4. Choopanya K, et al. Lancet. 2013;381:2083-
2090. 5. Van Damme L, et al. N Engl J Med. 2012;367:411-422. 6. Marrazzo J, et al. CROI 2013. Abstract
26LB.

PrEP Works, but Adherence Is Critical
Study Efficacy
Overall, %
Blood Samples With
TFV Detected, %
Efficacy By Blood
Detection of TFV, %
iPrEx[1] 44 51 92
iPrEx OLE[2] 49 71 NR
Partners
PrEP[3]
67 (TDF)
75 (TDF/FTC) 81 86 (TDF)
90 (TDF/FTC)
TDF2[4] 62 80 85
Thai IDU[5] 49 67 74
Fem-PrEP[6] No efficacy < 30 NR
VOICE[7] No efficacy < 30 NR
1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 2. Grant RM, et al. Lancet Infect Dis. 2014;
14:820-829. 3. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 4. Thigpen MC, et al. N Engl J Med.
2012;367:423-434. 5. Choopanya K, et al. Lancet. 2013;381:2083-2090. 6. Van Damme L, et al. N Engl
J Med. 2012;367:411-422. 7. Marrazzo J, et al. CROI 2013. Abstract 26LB.

PrEP in Clinical Practice: What Are the
Barriers to PrEP Uptake?
 Users
– Unaware of HIV risk,
PrEP availability, or how
to access it
– No or delayed access to
clinical preventive care
– Uninsured or unable to
pay
– Adherence challenges
– Concern about disclosure
and stigma
 Providers
– Unaware of intervention
– Uncertain how to deliver
the intervention
– Wary of complexity and
time involved
– Discomfort with
assessing candidacy
– Uncertain how to bill for
intervention

Risk Assessment and Shared
Decision Making

Provider–Patient Decision Making
 The role of the provider is to help the patient:
– Understand the likely outcomes of various options
– Think about what is personally important about the risks and
benefits of each option
– Participate in decisions
 These decisions are difficult because:
– There may be more than 1 choice
– Each choice has advantages and disadvantages
– There is no “correct” choice; what you choose depends on
what is important to you

CDC PrEP Guideline: For Which Patients
Is PrEP Recommended?
 PrEP is recommended as one prevention option for the following
adults at substantial risk of HIV acquisition
– Sexually active MSM
– Heterosexually active men and women
– Injection drug users
MSM Heterosexual Women and Men Injection Drug Users
Potential
indicators of
substantial
risk of
acquiring HIV
infection
 HIV-positive sexual
partner
 Recent bacterial STI
 High number of sex
partners
 History of inconsistent
or no condom use
 Commercial sex work
 HIV-positive sexual partner
 Recent bacterial STI
 High number of sex partners
 History of inconsistent or no
condom use
 Commercial sex work
 In high-prevalence area or
network
 HIV-positive injecting
partner
 Sharing injection
equipment
 Recent drug
treatment (but
currently injecting)
CDC. PrEP Guideline. 2014.

“Ironically, it may require
greater intimacy to discuss sex
than to engage in it”
The Hidden Epidemic
Institute of Medicine, 1997

Many Patients Want Clinicians to Ask
About Sexual Issues
 In a survey of adults, 85% expressed an interest in talking
to their providers about sexual issues; 71% thought their
provider would likely dismiss their concerns[1]
 In a survey of PCPs, 94% routinely asked patients about
smoking, whereas 49% asked about STIs, and 27% about
sexual orientation[2]
1. Marwick C. JAMA 1999;281:2173-2174. 2. CDC. MMWR Morb Mortal Wkly Rep. 1994;42:988-992.

How Do We Decide If a Patient May Be a
Candidate for PrEP?
 Are they at substantial risk of HIV infection?
 Are they able to adhere to a once-daily tablet regimen?
 What is their likely tolerance of possible adverse effects?
 Are they able to maintain follow-up appointments?
 Are there any economic issues or other concerns?

Pre-PrEP Counseling, Testing,
and Clinical Evaluation

CDC Guideline: Clinical Eligibility for PrEP
 The following are required before prescribing PrEP to
identify patients for whom PrEP would be harmful or may
present risks to health:
– Documented negative HIV test result
– No signs or symptoms of acute HIV infection
– Normal renal function; no use of contraindicated medications
– Documented HBV infection status and vaccination status

HIV Screening
 Exclude acute and chronic HIV infection[1,2]
– Consider variety of testing methods including 4th-generation
HIV Ag/Ab or HIV-1 RNA using nucleic acid–based tests
– At a minimum, document negative antibody test within the
wk before starting PrEP
– Do not accept patient-reported results
– Avoid use of oral rapid HIV testing due to lower sensitivity
1. CDC. PrEP Guideline. 2014.
2. Daar ES, et al. Curr Opin HIV AIDS. 2008;3:10-15.

Acute HIV Infection
 Patients who are candidates for PrEP are at substantial risk of
HIV infection
 Acute HIV infection should be suspected in patients with recent
HIV exposure[1]
– Signs and symptoms include fever, rash, pharyngitis,
lymphadenopathy, myalgia, headache, diarrhea, arthralgia[2]
 All PrEP candidates with a negative or indeterminate HIV
antibody test should be asked about symptoms of viral illness in
the previous month or on the day of evaluation
– Additional confirmatory testing is needed in patients reporting
recent signs or symptoms suggestive of acute HIV
1. CDC. PrEP Guideline. 2014.
2. Daar ES, et al. Curr Opin HIV AIDS. 2008;3:10-15.

Documenting
HIV Status
Blue = HIV-, eligible for PrEP
HIV immunoassay blood test
(rapid test if available)
Retest antibody in 1 mo;
defer PrEP decision
(pending confirmatory testing)
Retest VL; defer
PrEP decision
Green = HIV status unclear;
defer PrEP decision
Negative Indeterminate Positive Consider HIV+
VL < level of detection with signs/symptoms
on day of blood draw; retest in 1 mo;
defer PrEP decision
Signs/symptoms of acute HIV
infection anytime in previous 4 wks
No Yes
Option 1 Option 2 Option 3
Send blood for HIV
antibody/antigen assay*
Positive
Negative
HIV-HIV+
HIV-VL
> 50,000 copies/mL HIV+
VL < level of detection; no signs/
symptoms on day of blood draw HIV-Orange
= HIV+, not
eligible for PrEP
VL < 50,000 copies/mL
*Use only HIV antigen antibody tests that are approved by
FDA for diagnostic purposes
Send blood for HIV-1 RNA
assay

Additional Clinical and Laboratory
Evaluation
 Evaluate for comorbidities that may complicate PrEP use, such
as renal disease or hepatitis, and drug interactions
– Any person with an estimated CrCl of < 60 mL/min should not be
prescribed PrEP with TDF/FTC
– Document HBV and HCV status before PrEP use; vaccinate
patients who are HBV susceptible
– Comanage HBsAg+ with a hepatologist; monitor for HBV flares
 Optional assessments
– Patients with bone disease or significant risk factors for
osteoporosis should be referred for appropriate management
– Therapeutic drug monitoring
– Metabolic panel, urinalysis, STI, and pregnancy screening

Adverse Events
 Inform patients about AEs observed in HIV-uninfected
participants in PrEP trials[1]
– iPrEx: small but significant early nausea and weight loss[2]
 Potential bone and renal toxicity
– Known risk associated with TDF
 Potential for other serious AEs with long-term use
– However, TDF/FTC commonly used in HIV infection
 Potential for drug-resistant HIV infection
– Infrequent in clinical trials but must exclude HIV infection
1. CDC. PrEP Guideline. 2014. 2. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

CDC Guideline: Recommended PrEP
Regimen
 Fixed-dose TDF/FTC is the recommended PrEP regimen
for MSM, heterosexually active men and women, and IDU
who meet PrEP prescribing criteria
– Dosed as a single pill (300/200 mg) once daily
– This regimen is approved by the FDA for PrEP use
– Provide a prescription or refill for no more than 90 days
 TDF alone may be considered as an alternative for IDU
and heterosexually active men and women (but not MSM)
– Based on efficacy data from clinical trials
– This regimen is NOT approved by the FDA for PrEP use

Oral PrEP Reduces Incidence of HIV in
MSM, Even With Incomplete Adherence
 iPreX OLE: open-label extension
of iPrEX trial of daily TDF/FTC
oral PrEP in MSM and
transgender women (N = 1603)
 100% adherence was not
required to attain full benefit
from PrEP
– Benefit of 4-6 tablets/wk similar
to 7 tablets/wk
– 2-3 tablets/wk also associated
with significant risk reduction
 Higher levels of sexual risk taking
at baseline were associated with
greater adherence to PrEP
HIV Incidence and Drug Concentrations
5
4
3
2
1
7
Tablets/
Wk
Off PrEP
On PrEP
< 2 2-3
4-6 Tablets/Wk
Tablets/
Tablets/
Wk
Wk
0
0 LLOQ 350 500 700 1000 1250 1500
TFV-DP in fmol/punch
HIV Incidence per 100
Person-Yrs
Follow-up
Risk Reduction
95% Cl
26%
44%
-31 to 77%
12%
84%
21 to 99%
21%
100%
12%
100%
86 to 100% (combined)
1. Grant R, et al. IAC 2014. Abstract TUAC0105LB. 2. Grant R, et al. Lancet Infect Dis. 2014;14:820-829.

iPrEX OLE: HIV Infection Occurred During
Gaps in PrEP Use
1.0
0.8
0.6
0.4
0.2
0
72 60 48 36 24 12 0 12 24 36 48 60
Case Control
Control
Case
Wks Preinfection Wks Postinfection
Detected in Dried Blood Spots
Control, n: 380
1306
1647
1396
1489
1441
1338
768
386 266 171 44
Case, n:
8
22
22
24
24
26
28
7
Proportion With TFV-DP
First evidence of HIV infection
TFV-DP LLOQ
TFV-DP ≥ 350 fmol/punch
1. Grant R, et al. IAC 2014. Abstract TUAC0105LB. Reprinted with permission.
2. Grant R, et al. Lancet Infect Dis. 2014;[Epub ahead of print].

Key Components of Medication
Adherence Counseling
 Address adverse events[1]
 Identify barriers to adherence[1]
 Respond to missed doses with normalization and
nonjudgement, and emphasize importance of adherence[1]
 Patient self-reporting may not reflect actual adherence[2,3]
1. CDC. PrEP Guideline. 2014. 2. Van Der Straten A, et al. CROI 2014. Abstract 44. 3. Baxi SM, et al.
CROI 2014. Abstract 953.

CDC Guideline: Follow-up and Monitoring
Follow-up At Least Every 3 Mos After 3 Mos and at
Least Every 6 Mos
Thereafter
At Least Every
6 Mos
At Least Every
12 Mos
All patients  HIV test
 Medication adherence
counseling
 Behavioral risk
reduction support
 Adverse event
assessment
 STI symptom
assessment
 Assess renal
function
 Test for
bacterial STIs
 Evaluate need
to continue
PrEP
Women  Pregnancy test
(where appropriate)
HBsAg+  HBV DNA by quantitative assay*
*Every 6-12 mos.

Responding to Patient-Reported
Challenges
 Discuss management of common adverse events; most
will diminish within the first few wks of treatment[1]
 Patients may report feeling stigmatized by peers and
medical providers for their use of PrEP[2]
 Issues related to medication access should be addressed
promptly
1. CDC. PrEP Guideline. 2014. 2. Liu A, et al. PLoS Med. 2014;11:e1001613.

iPrEx[1] Partners PrEP[2]
50
30
10
0
Placebo
TDF/FTC
0 6 12 18 24 30
Follow-up Time (Mos)
40
20
3 9 15 21 27 33
Subjects Reporting
Unprotected Sex (%)
TDF
PrEP Trials Found Decreasing Risk
Behavior Over Time
100
80
60
0
0
Placebo
48 72 96 120 144
Wks Since Randomization
Subjects Reporting Unprotected
Receptive Anal Sex (%)
40
20
24
TDF/FTC
1. Grant RM, et al. N Engl J Med. 2010;363: 2587-2599.
2. Baeten JM, et al. N Engl J Med. 2012;367:399-410.

Pregnancy
 PrEP use at conception and during pregnancy by the
uninfected partner may offer an additional tool to reduce
the risk of sexual HIV acquisition[1]
 Data directly related to the safety of PrEP use for a
developing fetus are limited
 Potential risks and limited information should be discussed
 TDF and FTC are classified as FDA Pregnancy Category
B medications[2]
1. CDC. PrEP Guideline. 2014. 2. DHHS. HIV Perinatal Guideline. 2014.

Stopping PrEP
 Lack of guidance on when to stop PrEP in relationship to
exposures
 Reasons to stop PrEP:
– Evidence of HIV infection
– Pregnancy
– Adverse events
– Chronic nonadherence
– Patient choice
 If resuming PrEP after stopping, repeat standard pre-PrEP
evaluation

Conclusions
 PrEP is recommended as one prevention option for
sexually active MSM, heterosexual men and women, IDU
at substantial risk of HIV acquisition
 Adherence is a key factor in PrEP efficacy
 Before prescribing PrEP, acute and chronic HIV infection
must be excluded, and the patient assessed for
comorbidities that may present health risks
 The recommended PrEP regimen is fixed-dose TDF/FTC
 Patients prescribed PrEP should return for follow-up visits
at least every 3 mos

Resources for Healthcare Professionals
 CDC PrEP Guideline: Clinical Providers’ Supplement[1]
– Patient information sheets
– Patient/provider checklist
– MSM risk index screening tool
 Centers for Disease Control and Prevention[2]
– PrEP patient information sheets
1. http://www.cdc.gov/hiv/pdf/PrEPProviderSupplement2014.pdf. 2. http://www.cdc.gov/hiv/prep/.

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