The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians and researchers to provide the most current research, clinical practices, and trends in HIV and other infectious diseases. The slides from an AIDS Clinical Rounds presentation are intended for educational purposes of the audience and may not be used without the presenter's permission. The presentation provides an update on PrEP (pre-exposure prophylaxis) for HIV, including data on efficacy from recent studies, pharmacology, adverse events, and guidance for its use.

1. The UC San Diego AntiViral Research Center sponsors weekly
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.
AIDS CLINICAL ROUNDS

3. 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

4. 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

5. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
Efficacy of ART for Reduced Transmission
Grant R, NEJM 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.
Study Study Design
Population/
Outcomes
Reduction in
Transmissions
Attia 2009 Meta-analysis
5021 heterosexual
couples
461 transmissions
92%
Partners in
Prevention
African
Prospective
Observational
3381 heterosexual
couples
103 transmissions
92%
HPTN 052
Multisite
RCT
1763 couples
28 transmissions
96%

6. Viral Suppression among HIV
infected in United States Smith PLoS 2012
Marks G. AIDS. 2006;20:1447-1450.

7. 0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Status New infections
Aware (ART)
Aware (no ART)
Unaware
Awareness of HIV Serostatus:
Estimates of Transmission
~31%
~36%
~54%
~44%
Marks G. AIDS. 2006;20:1447-1450.
~25%
~10%??
New
Infections/Year
(~32,000)
People Living
With HIV
Intervene
with ART
and PrEP
Intervene with
HIV testing
and PrEP

8. Update on PrEP
PrEP Elf

9. Past and Current PrEP Trials
(July 2011)
Available at: www.avac.org.

10. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
Efficacy of Daily Oral FTC/TDF PrEP
Celum 2012Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.
Trial Pop. Efficacy 95% CI
iPrEx
(completed)
2499 MSM 44% 15 to 63%
Partners PrEP
(ongoing, placebo
arm stopped)
Men
Women
83%
62%
49 to 94%
19 to 82%
TDF2
(stopped early due to
large loss to FU)
Men
Women
80%
49%
25 to 97%
-22 to 81%
FemPREP
(stopped early due to
futility)
Women
6% - Not Significant - Only 26% had
detectable TDF
VOICE (ongoing) Women
TDF alone arm stopped due to futility,
continue TDF gel and TDF/FTC

11. Poynten 2012
Percent Important New PrEP Studies
Trial Population Study
HPTN 067
Heterosexual
women and
MSM
TDF/FTC daily vs. twice a week and one
PEP dose vs. event-driven
FNARAVHPIRE
G
MSM On demand coital TDF/FTC vs. placebo
ATN 082 Young MSM
TDF/FTC vs. placebo vs. no pill with
behavioral intervention
HPTN 069 MSM
MVC vs. MVC/TDF vs. MVC/FTC vs.
TDF/FTC

12. iPrEx Study Results:
Cumulative Probability of HIV Infection
0 12 24 36 48 60 72 84 96 108 120 132
Weeks
Placebo
(n=1248)
Emtricitabine/
Tenofovir DF
(n=1251)
P=0.005
CumulativeProbability
ofHIVInfection
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

13. Partner PrEP Study
Double-Blind
Randomization
1:1
Adapted from Baeten J. et al. IAS 2011; Rome. Oral #MOAX0106
Modified Intention-to-Treat Analysis TDF FTC/TDF P
HIV incidence (per 100 PY) 0.74 0.53 0.23
HIV protection (vs. placebo)
p-value
67% (44-81%)
<0.0001
75% (55-87%)
<0.0001
Partners PrEP
0.03
0.02
0.01
0
CumulativeHIVAcquisition
Months since start
TDF
FTC/TDF
Placebo
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
0 3 6 12 159 18 21 24 27 30 33 360 3 6 12 159 18 21 24 27 30 33 36
0.04

14. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
Efficacy of Daily Oral FTC/TDF PrEP
Grant R, NEJM 2010; Grant R, IAS 2011 (Rome); Baeten J, IAS 2011 (Rome); Thigpen M, IAS 2011 (Rome); FHI Press Release April 18, 2011.

15. 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

16. 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?
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

17. Sexual Behavior in PnP Celum IAS 2011
Marks G. AIDS. 2006;20:1447-1450.

18. Sexual Behavior in iPREX Liu IAS 2011
Marks G. AIDS. 2006;20:1447-1450.

19. 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
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

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

21. 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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

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

23. Truvada Updated Monograph
 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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

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

25. Truvada Updated MonographWARNINGS 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.

26. Truvada Updated Monograph
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.

27. Truvada Updated Monograph
 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.

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

29. 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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

30. CDC Interim Guidance for MSM
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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

31. CDC Interim Guidance for MSM
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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

32. CDC Interim Guidance for MSM
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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

33. 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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

34. CDC Interim Guidance-
Heterosexuals MMWR Aug 10 2012
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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

35. CDC Interim Guidance-
Heterosexuals MMWR Aug 10 2012
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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

36. CDC Interim Guidance-
Heterosexuals MMWR Aug 10 2012
 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.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.

37. People Living With HIV
(1,039,000-1,185,000)
New Sexual infections/Year
(~32,000)
Percent
Marks G. AIDS. 2006;20:1447-1450.
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
Grant R, et al. 51st ICAAC; Chicago, IL; September 17-20, 2011; Abst. H2-1007.
*Prevalence of HIV among seronegative partners of HIV+ pts is unknown
Access to
Seronegatives
High HIV
Incidence
Longitudinal
Care
Familiar
with ART
Testing Centers + +/- +/- -
STD Clinics + + - -
Community Clinics + +/- + -
HIV Clinics
Partners of
HIV+ Patients
?* + +
Prevention CBOs + + +/- -
Treatment CBOs - - +/- +

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

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

40. PrEP Study
Double-Blind
Multisite Study
(UCLA, USC, UCSD)
High risk HIV-negative men who
have sex with men
(n=400)
Randomization
1:1
Truvada (n=200)
Study Outcomes
•HIV seroconversion
•Risk behavior and STIs
•Adherence (self report and FTC levels)
•Drug resistance
Both receive comprehensive
web based risk reduction
counseling, STD testing, HIV
testing
Drug resistance, HIV RNA level, immunologic response, and CD4 cell count assessed in people who
become HIV positive during the study.
Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Minimum Follow-
Up 1 year
Truvada + iTAB (n=200)
Intervention ousing texting
reminders (iTAB)

41. 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!
”
“

42. 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

43. • 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
Inclusion Criteria

44. 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

45. CCTG 595: TAPIR study
enrollment starting January 2013
Potential subjects can call AVRC:
619-543-3196

46. Questions