Update and Guidance on PrEP for Clinicians

AIDS CLINICAL ROUNDS
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presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.

The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.

Introduction
 Antiretroviral medication for HIV prevention are an
attractive additional to existing interventions:
 Behavioral interventions
 HIV positive
 HIV negative

 HIV testing and counseling
 STD screening and treatment
 Partner notification
 IVDU reduction – methadone, needle exchange
 PMTC
 Male circumcision

Outline of Recent Advances
 Introduction

 Update on data on PrEP HIV negatives
 Efficacy in men and women
 Pharmacology
 Adverse events
 Future directions

 PrEP use guidance

Efficacy of ART for Reduced Transmission

Population/ Reduction in
Study Study Design
Outcomes Transmissions
5021 heterosexual
couples
Attia 2009 Meta-analysis 92%
Percent

461 transmissions
3381 heterosexual
African
Partners in couples
Prospective 92%
Prevention Observational
103 transmissions
1763 couples
Multisite
HPTN 052 People Living With HIV 96%
New Sexual infections/Year
RCT
(1,039,000-1,185,000) transmissions(~32,000)
28

Grant R, NEJMAIDS. 2006;20:1447-1450.
Marks G. 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.

Viral Suppression among HIV
infected in United States Smith PLoS 2012

Marks G. AIDS. 2006;20:1447-1450.

Awareness of HIV Serostatus:
Estimates of Transmission
1

~10%??
0.9 ~31%
0.8

0.7
Intervene ~36%
with ART
0.6 and PrEP
Aware (ART)

Aware (no ART)
0.5 ~44%
0.4
Unaware Intervene with
0.3 HIV testing ~54%
and PrEP
0.2
~25%
0.1

0
Status New infections
People Living New
With HIV Infections/Year
Marks G. AIDS. 2006;20:1447-1450. (~32,000)

Update on PrEP

PrEP Elf

Past and Current PrEP Trials
(July 2011)

Available at: www.avac.org.

Efficacy of Daily Oral FTC/TDF PrEP
Trial Pop. Efficacy 95% CI

iPrEx
2499 MSM 44% 15 to 63%
(completed)
Partners PrEP Men 83% 49 to 94%
(ongoing, placebo Women 62% 19 to 82%
Percent

arm stopped)
TDF2
Men 80% 25 to 97%
(stopped early due to
Women 49% -22 to 81%
large loss to FU)
FemPREP
6% - Not Significant - Only 26% had
(stopped early due to Women
detectable TDF
futility)
People Living With HIV TDF alone arm stopped due to futility,
New Sexual infections/Year
VOICE (ongoing) Women
(1,039,000-1,185,000) (~32,000)
continue TDF gel and TDF/FTC
Marks G. AIDS. 2006;20:1447-1450.
Celum 2012Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.

Important New PrEP Studies
Trial Population Study

Heterosexual
TDF/FTC daily vs. twice a week and one
HPTN 067 women and
PEP dose vs. event-driven
MSM
FNARAVHPIRE
MSM On demand coital TDF/FTC vs. placebo
Percent

G
TDF/FTC vs. placebo vs. no pill with
ATN 082 Young MSM
behavioral intervention
MVC vs. MVC/TDF vs. MVC/FTC vs.
HPTN 069 MSM
TDF/FTC

Poynten 2012

iPrEx Study Results:
Cumulative Probability of HIV Infection

Placebo
Cumulative Probability

(n=1248) P=0.005
of HIV Infection

Emtricitabine/
Tenofovir DF
(n=1251)

0 12 24 36 48 60 72 84 96 108 120 132
Weeks

Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

Partners PrEP
Partner PrEP Study
Modified Intention-to-Treat Analysis TDF FTC/TDF P
HIV incidence (per 100 PY) 0.74 Double-Blind
0.53 0.23
HIV protection (vs. placebo) 67% (44-81%)
Randomization 75% (55-87%)
p-value 1:1 <0.0001 <0.0001

0.04
Cumulative HIV Acquisition

TDF
0.03 FTC/TDF
Placebo

0.02

0.01

0
0 3 6 9 12 15 18 21 24 27 30 33 36
Months since start
Number at Risk
TDF 1573 1560 1546 1443 1292 1176 966 827 638 406 185 58 5
FTC/TDF 1567 1555 1544 1432 1303 1181 968 825 640 414 187 58 6
Placebo 1568 1557 1541 1431 1294 1164 970 829 637 405 203 62 6

Adapted from Baeten J. et al. IAS 2011; Rome. Oral #MOAX0106

Efficacy of Daily Oral FTC/TDF PrEP
Percent

People Living With HIV New Sexual infections/Year
(1,039,000-1,185,000) (~32,000)

Grant R, NEJMAIDS. 2006;20:1447-1450.
Marks G. 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.

Phamacology of PrEP
TDF dosing in HIV-uninfected individuals
 Oral dosing results in 20+ higher plasma levels compared to topical gel but
10 fold less local concentrations

 Oral TDF results in 100x greater TFV-DP in rectal tissue compared to
vaginal tissue. 20x greater in local CD4 cells. No diff. at 2 weeks.

 Oral TDF has a 49-64 hours terminal half life in plasma. 100-112 hours in
CD4 cells.

FTC dosing
 Oral FTC results in 10x greater FTC-TP in vaginal tissue compared to rectal
tissue.
 Oral FTC has a 8-10 hours terminal half life in plasma. 29-56 hours in
PBMCs.
Hendrix 2012

Adverse Events with PrEP
TDF/FTC
 Nausea, back pain, weight loss>5% (iPREX)

 1% drop in bone density (iPREX)

 Resistance
 iPREX had 2 on drug had M184V/I that was not detectable at 6 months
by ultrasensitive testing
 Partners in PrEP 1 M184V and 1 K65R

 Renal toxicity from TDF was not observed higher (2% vs. 1%, p=0.08) in
iPREX.

 Risk Compensation?


Sexual Behavior in PnP Celum IAS 2011

Marks G. AIDS. 2006;20:1447-1450.

Sexual Behavior in iPREX Liu IAS 2011

Marks G. AIDS. 2006;20:1447-1450.

Summary of PrEP
 TDF/FTC oral appears superior to topical
 TDF/FTC oral may be superior to TDF alone
 TDF/FTC oral is seems most effective among MSM
compared to heterosexual women
 This could be related to tissue penetration
 TDF/FTC is relatively safe for HIV-uninfected

 Tissue penetration and long half life may be the key
factor for future development of new PrEP


Marks G. AIDS. 2006;20:1447-1450.

Truvada Updated Monograph
INDICATIONS AND USAGE of TRUVADA
 TRUVADA is indicated in combination with other
antiretroviral agents for the treatment of HIV-1
infection in adults and pediatric patients 12 years of
age and older.
 TRUVADA is indicated in combination with safer sex
practices for pre- exposure prophylaxis (PrEP) to
reduce the risk of sexually acquired HIV-1 in adults at
high risk.


WARNINGS
 LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH
STEATOSIS, POST-TREATMENT ACUTE EXACERBATION OF
HEPATITIS B, and RISK OF DRUG RESISTANCE WITH USE OF
TRUVADA FOR PrEP IN UNDIAGNOSED HIV-1 INFECTION

 TRUVADA used for a PrEP indication must only be
prescribed to individuals confirmed to be HIV-negative
immediately prior to initial use and periodically during use. Drug-
resistant HIV-1 variants have been identified with the use of
TRUVADA for a PrEP indication following undetected acute HIV-1
infection. Do not initiate TRUVADA for a PrEP indication if signs
or symptoms of acute HIV infection are present unless negative
infection status is confirmed.


 Many HIV-1 tests, such as rapid tests, detect anti-HIV antibodies
and may not identify HIV-1 during the acute stage of infection.
 Prior to initiating PrEP indication, evaluate seronegative
individuals for current or recent signs or symptoms consistent
with acute viral infections (e.g., fever, fatigue, myalgia, skin rash,
etc.) and ask about potential exposure events (e.g., unprotected,
or condom broke during sex with an HIV-1 infected partner) that
may have occurred within the last month.

 If clinical symptoms consistent with acute viral infection are
present and recent (<1 month) exposures are suspected, delay
starting PrEP for at least one month and reconfirm HIV-1 status
or use a test approved by the FDA as an aid in the diagnosis of
HIV-1 infection, including acute or primary HIV-1 infection.


CONTRAINDICATIONS

 Do not use TRUVADA for pre-exposure prophylaxis in
individuals with unknown or positive HIV-1 status.
TRUVADA should be used in HIV-infected patients
only in combination with other antiretroviral agents.


WARNINGS AND PRECAUTIONS
New onset or worsening renal impairment: including ARF and Fanconi syndrome. Assess
creatinine clearance (CrCl) before initiating. Monitor CrCl and serum phosphorus in
patients at risk. Avoid with use of nephrotoxic drugs. Do not use TRUVADA for a PrEP
indication with creatinine clearance below 60 mL/min.

Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a
history of pathologic fracture or other risk factors for osteoporosis or bone loss.

Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a
comprehensive prevention strategy including other prevention measures; strictly adhere to
dosing schedule.

Management to reduce the risk of acquiring HIV-1 drug resistance:
 Prior to initiating for PrEP - if clinical symptoms consistent with acute viral infection are
present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one
month and reconfirm negative HIV-1 status or use a test approved by the FDA as an aid in
the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.

While using TRUVADA for PrEP - HIV-1 screening tests should be repeated at least every 3
months.

ADVERSE REACTIONS
 In HIV1 infected patients, the most common adverse
reactions (incidence greater than or equal to 10%) are
diarrhea, nausea, fatigue, headache, dizziness,
depression, insomnia, abnormal dreams, and rash.

 In HIV-1 uninfected individuals in PrEP trials, adverse
reactions that were reported by more than 2% of
TRUVADA subjects and more frequently than by
placebo subjects were headache, abdominal pain and
weight decreased.

 Comprehensive Management to Reduce the Risk of
Acquiring HIV-1
 Use TRUVADA for pre-exposure prophylaxis only as part of
a comprehensive prevention strategy that includes other
prevention measures, such as safer sex practices, because
TRUVADA is not always effective in preventing the
acquisition of HIV-1
 Counsel uninfected individuals about safer sex practices
that include consistent and correct use of condoms,
knowledge of their HIV-1 status and that of their
partner(s), and regular testing for other sexually
transmitted infections that can facilitate HIV-1
transmission (such as syphilis and gonorrhea).
 ␣ Inform uninfected individuals about and support their
efforts in reducing sexual risk behavior.

MORE

Marks G. AIDS. 2006;20:1447-1450.

CDC Interim Guidance for MSM
MMWR Jan 2011

Before initiating PrEP
Determine eligibility
Document negative HIV antibody test(s) immediately before starting
PrEP medication.
Test for acute HIV infection if patient has symptoms consistent with
acute HIV infection.
Confirm that patient is at substantial, ongoing, high risk for acquiring
HIV infection.
Confirm that calculated creatinine clearance is ≥60 mL per minute (via
Cockcroft-Gault formula).
Other recommended actions
Screen for hepatitis B infection; vaccinate against hepatitis B if
susceptible, or treat if active infection exists, regardless of decision about
prescribing PrEP.
Screen and treat as needed for STIs.


MMWR Jan 2011

Beginning PrEP medication regimen
 Prescribe 1 tablet of Truvada* (TDF [300 mg] plus FTC [200
mg]) daily.
 In general, prescribe no more than a 90-day supply,
renewable only after HIV testing confirms that patient
remains HIV-uninfected.
 If active hepatitis B infection is diagnosed, consider using
TDF/FTC for both treatment of active hepatitis B infection
and HIV prevention.
 Provide risk-reduction and PrEP medication adherence
counseling and condoms.


MMWR Jan 2011

Follow-up while PrEP medication is being taken
 Every 2--3 months, perform an HIV antibody test; document
negative result.
 Evaluate and support PrEP medication adherence at each follow-
up visit, more often if inconsistent adherence is identified.
 Every 2--3 months, assess risk behaviors and provide risk-
reduction counseling and condoms. Assess STI symptoms and, if
present, test and treat for STI as needed.
 Every 6 months, test for STI even if patient is asymptomatic, and
treat as needed.
 3 months after initiation, then yearly while on PrEP medication,
check blood urea nitrogen and serum creatinine.


MMWR Jan 2011

On discontinuing PrEP (at patient request, for
safety concerns, or if HIV infection is acquired)
 Perform HIV test(s) to confirm whether HIV infection
has occurred.
 If HIV positive, order and document results of
resistance testing and establish linkage to HIV care.
 If HIV negative, establish linkage to risk-reduction
support services as indicated.
 If active hepatitis B is diagnosed at initiation of PrEP,
consider appropriate medication for continued
treatment of hepatitis B.


CDC Interim Guidance-
Heterosexuals MMWR Aug 10 2012
Before initiating PrEP
 Determine eligibility
 Determine if women are planning to become pregnant, are
currently pregnant, or are breastfeeding.
 Confirm that patient is at ongoing, very high risk for acquiring
HIV infection.
 If any sexual partner is known to be HIV-infected, determine
whether receiving antiretroviral therapy; assist with linkage to
care if not in care or not receiving antiretroviral therapy.
Other recommended actions
 Disclose to women that safety for infants exposed during
pregnancy is not fully assessed but no harm has been reported.
 Do not prescribe PrEP to women who are breastfeeding.



Beginning PrEP medication regimen

 For women, ensure that pregnancy test is negative or,
if pregnant, that the patient has been informed about
use during pregnancy.



Follow-up while PrEP medication is being taken

 At each follow-up visit for women, conduct a
pregnancy test and document results; if pregnant,
discuss continued use of PrEP with patient and
prenatal-care provider.



 On discontinuing PrEP (at patient request, for
safety concerns, or if HIV infection is acquired

 Inform prenatal provider of PrEP use in early
pregnancy and coordinate care to maintain HIV
prevention during pregnancy and breastfeeding.


Some Possible PrEP Providers
• Implementation of PreP will be challenging due to the multiple needs of an
effective program
• Innovative programs that combine previously unlinked services may be needed

Access to High HIV Longitudinal Familiar
Seronegatives Incidence Care with ART
Percent

Testing Centers + +/- +/- -

STD Clinics + + - -

Community Clinics + +/- + -

Partners of
HIV Clinics ?* + +
HIV+ Patients

Prevention CBOs + + +/- -

People
Treatment CBOs Living With HIV
- - New Sexual infections/Year +
+/-
(1,039,000-1,185,000) (~32,000)
*Prevalence of HIV among seronegative partners of HIV+ pts is unknown

Grant R, etG. 51st ICAAC; Chicago, IL; September 17-20, 2011; Abst. H2-1007.
Marks al. AIDS. 2006;20:1447-1450.

Protocol Co-Chairs:
Sheldon Morris M.D., M.P.H.
David J. Moore, Ph.D.

PrEP Algorithm
1. Test for HIV at least
Identify individuals every 3 mo.
with substantial, 2. Offer STD screening as
ongoing risk for HIV needed every 6 mo.
acquisition 3. Provide ongoing risk
reduction
4. Check creatinine at
month 3 and then yearly
5. Preg. Test for women
every 3 months
1. Medical History
2. Elicit any acute HIV symptoms
3. Required lab testing:
Confirm HIV status
HBV status
1. Provide adherence
Creatinine clearance
counseling
Pregnancy test for women
2. Prescribe no more
4. Provide risk reduction counseling and
than 3 months
STD testing as needed

PrEP Study
Double-Blind
Randomization Truvada (n=200)
Multisite Study 1:1
(UCLA, USC, UCSD) Both receive comprehensive Minimum Follow-
High risk HIV-negative men who web based risk reduction Up 1 year
counseling, STD testing, HIV
have sex with men testing

(n=400)
Truvada + iTAB (n=200)

Intervention ousing texting Study Outcomes
reminders (iTAB) •HIV seroconversion
•Risk behavior and STIs
•Adherence (self report and FTC levels)
•Drug resistance

Drug resistance, HIV RNA level, immunologic response, and CD4 cell count assessed in people who
become HIV positive during the study.


Why Text Reminders Might Work

“ Well, I’m always aware of the
importance of taking my meds but
time gets lost and at the end of the
week or end of the month, you realize

”
you still have a lot of pills left!

iTAB Intervention

 Texting reminders developed and chosen by participant that
will be received daily
 If possible, participants use their own cell phone; otherwise
receive study phone
 All participant go through process of reminder generation

Inclusion Criteria

• Man or transgender M to F who has sex with men

• Age 18 years or older.

• Subjects must have substantial ongoing risk of acquisition of
HIV as evident by one or more of the following:
• Has at least one HIV infected sexual partner for ≥4 weeks (i.e.
serodiscordant couple).
• No condom use during anal intercourse with ≥3 male sex partners who
are HIV-positive or of unknown HIV status during the last 3 months
• No condom use during anal sex with ≥1 male partner and STI
diagnosis during the last 3 months

Conclusions
 PrEP works…Woohoo.

 Prescribing PrEP should be done with care:
 For those with substantial ongoing risk and no
medical contraindication (i.e. renal disease)
 CONFIRM HIV negative status
 Routine adherence counseling, HIV testing, STD
testing and risk reduction counseling

CCTG 595: TAPIR study
enrollment starting January 2013

Potential subjects can call AVRC:

619-543-3196

Update and Guidance on PrEP for Clinicians

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