A New Options for HIV Prevention.The Role of Antiretrovirals

New Options for HIV Prevention:
The Role of Antiretrovirals
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Strengthening HIV Prevention in Primary Care
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Program Director and Core Faculty
Jeanne Marrazzo, MD, MPH
Professor of Medicine
Division of Infectious Diseases
University of Washington
Medical Director
Seattle STD/HIV Prevention Training
Center
Seattle, Washington
Jared M. Baeten, MD, PhD
Associate Professor, Departments of
Global Health and Medicine
Seattle, Washington
Kenneth Mayer, MD
Infectious Disease Attending and
Director of HIV Prevention Research
Beth Israel Deaconess Medical Center
Visiting Professor of Medicine
Harvard Medical School
Medical Research Director
Fenway Community Health
Boston, Massachusetts

Other Faculty Who Contributed to This
Program
Laura H. Bachmann, MD, MPH
Associate Professor
Department of Medicine
Wake Forest University Health
Sciences
Winston-Salem, North Carolina
Susan Buchbinder, MD
Associate Clinical Professor
Departments of Medicine,
Epidemiology and Biostatistics
Director, HIV Research Section
San Francisco Department of
Public Health
San Francisco, California
Connie Celum, MD, MPH
Professor, Department of Global
Health and Medicine
Seattle, Washington
Khalil Ghanem, MD, PhD
Associate Professor of Medicine
Johns Hopkins University
School of Medicine
Baltimore, Maryland

Program
Katherine Hsu, MD, MPH
Associate Professor
Department of Pediatrics
Boston University School of Medicine
Medical Director
Division of STD Prevention and
HIV Surveillance
Massachusetts Department of
Public Health
Boston, Massachusetts
Raphael J. Landovitz, MD, MSc
Associate Professor of Medicine
University of California, Los Angeles
Los Angeles, California
Albert Liu, MD, MPH
Assistant Clinical Professor
University of California, San Francisco
Director, HIV Prevention Intervention
Studies
HIV Research Section
San Francisco Department of
Public Health
San Francisco, California

Program
Anne Rompalo, MD, ScM
Professor of Medicine
Johns Hopkins School of Medicine
Baltimore, Maryland
Mark Thrun, MD
Associate Professor
University of Colorado
Director, HIV/STD Prevention and
Control
Denver Public Health
Denver, Colorado

Faculty Disclosures
Jared M. Baeten, MD, PhD; Susan Buchbinder, MD; Connie
Celum, MD, MPH; Khalil Ghanem, MD, PhD; Katherine Hsu,
MD, MPH; Albert Liu, MD, MPH; Jeanne Marrazzo, MD, MPH;
Anne Rompalo, MD, ScM; and Mark Thrun, MD, have no
significant financial relationships to disclose.
Laura H. Bachmann, MD, MPH, has disclosed that she has
received funds for research support from Cepheid
Raphael J. Landovitz, MD, MSc, has disclosed that he has
received funds for research support from Gilead Sciences,
GlaxoSmithKline, and ViiV.
Kenneth Mayer, MD, has disclosed that he has received funds for
research support from Bristol-Myers Squibb, Gilead Sciences, and
Merck.

The Need for HIV Prevention:
Continued HIV Risk in the US
 Estimated new HIV infections in the United States for the
most affected subpopulations, 2008-201
CDC. HIV in the United States: 2013.
Yr
2008 2009 2010 2011
0
30
40
50
60
70
Diagnoses(%)
20
10
Male-to-male sexual contact
Heterosexual contact
IDU
Male-to-male sexual
contact and IDU
Other

Treatment of HIV-Infected Persons
for Prevention of
HIV Transmission

ART for HIV Prevention: The Hypothesis
 The quantity of HIV in plasma
(and genital secretions) is the
prime determinant of whether
someone with HIV will transmit
the virus to a sexual partner[1]
 Initiation of ART results in early
and sustained reductions in
plasma and genital HIV levels
 Led to the hypothesis that ART
use would result in decreased
infectiousness
1. Quinn TC, et al. N Engl J Med. 2000;342:921-929.
35
30
25
20
15
10
5
0
TransmissionRateper100Person-Yrs
<
400
400-3499
3500-9999
10,000-49,000
≥
50,000
HIV-1 RNA (copies/mL)

Observational Studies: ART Decreases
Risk of Transmitting HIV
Anglemyer A, et al. Cochrane Database Syst Rev. 2013;4:CD009153.

HPTN 052: Immediate vs Delayed ART for
HIV Prevention in Serodiscordant Couples
 Primary efficacy endpoint: virologically linked HIV transmission
 Primary clinical endpoints: WHO stage IV events, pulmonary TB,
severe bacterial infection and/or death
 Couples received intensive counseling on risk reduction and use of
condoms
Cohen MS, et al. N Engl J Med. 2011;365:493-505.
Immediate ART
Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ART
Initiate ART at CD4+ cell count ≤ 250 cells/mm3
*
(n = 877 couples)
HIV-infected, sexually
active serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
*Based on 2 consecutive values ≤ 250 cells/mm3
.

HPTN 052: HIV Transmission Reduced by
96% in Serodiscordant Couples
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .0001)
Linked
Transmissions: 28
Unlinked or TBD
Transmissions: 11
P < .001
Immediate
Arm: 1
Delayed
Arm: 27
96% reduction in risk of HIV
transmission within the
partnership (95% CI: 73% to 99%)

HPTN 052: HIV Transmission Reduced by
96% in Serodiscordant Couples
Single transmission in patient in
immediate ART arm believed
to have occurred close to time
therapy began and prior to
suppression of genital tract HIV
Total HIV-1 Transmission Events: 39
(4 in immediate arm and
35 in delayed arm; P < .0001)
Linked
Transmissions: 28
Unlinked or TBD
Transmissions: 11
P < .001
Immediate
Arm: 1
Delayed
Arm: 27

Adherence and ART for HIV Prevention
 In HPTN 052, viral suppression was nearly universal in
those receiving ART, reflecting intensive strategies to
achieve nearly perfect adherence
– Adherence counselors with detailed checklists; patients
received extensive education about ART[1]
– Adherence assessed at Wk 2, monthly x 3, and then
quarterly
 Real-world adherence to ART is not as high as achieved in
HPTN 052
1. Cohen MS, et al. N Engl J Med. 2011;365:493-505. Supplementary appendix.

CDC: Breaks in the Continuum of Care in
HIV-Infected Patients in the US
 CDC study shows that only ~ 25% of US patients with HIV have
suppressed HIV-1 RNA
Hall HI, et al. JAMA Intern Med. 2013;17:1-7.
100
80
60
40
20
0
Diagnosed Linked
to Care
Retained
in Care
Prescribed
ART
Viral
Suppression
82
66
37
33
25
Patients(%)

2006 Recommendations From CDC:
Routine Opt-Out Testing for HIV
 Routine voluntary testing for
patients aged 13-64 yrs in
healthcare settings—not
based on patient risk
 Opt-out testing
 No separate consent for HIV
 Pretest counseling not
required
 Repeat HIV testing at least
annually for persons at high
risk
Branson BM, et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

DHHS Guidelines 2013: When to Start
 ART recommended for all HIV-infected patients in US
 Strength of recommendation varies depending on CD4+ count
– CD4+ < 350 (AI); CD4+ 350-500 (AII); CD4+ > 500 (BIII)
 Certain groups highlighted as priorities for therapy
– History of AIDS-defining illness
– Pregnancy
– HIV-associated nephropathy
– HBV coinfection (AII); HCV coinfection
– At risk of transmitting HIV to sexual partners
– Acute HIV infection
?
DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. February 2013.

Limitations of Current Data on ART for HIV
Prevention
 ART may mediate different degree of risk reduction when other
modes of transmission (eg, needles, anal intercourse) taken
into account
 Adherence to lifelong ART may be difficult when initiated in
asymptomatic individuals
 Observational studies of the effect of ART on transmission
among HIV serodiscordant couples have shown lower HIV risk
reduction, likely as a result of lower adherence to ART[1]
 28% of infections in HPTN 052 occurred from outside of study
partnerships, for which ART use by the HIV-infected partner
offered no protection[2]
1. Anglemyer A, et al. Cochrane Database Syst Rev. 2013;4:CD009153.
2. Cohen MS, et al. N Engl J Med. 2011;365:493-505.

Summary: ART as Prevention
 Initiation of effective ART results in a substantial decrease in
HIV infectiousness and transmission risk
 Adherence (with viral suppression) is key to preventive effects
of ART
 Prescribing guidelines now include risk of transmission as an
indication to initiate ART
– However, no formal indication for prevention of transmission exists
for any antiretroviral
 Providers should talk about prevention as part of ART’s benefits

Pre-Exposure Prophylaxis (PrEP)
for HIV-Uninfected Persons to
Reduce Risk of HIV Acquisition

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
– For example, taking medications for diseases such as
malaria before traveling to high-risk areas reduces risk of
infection establishing itself if exposure occurs

Pre- vs Postexposure Prophylaxis
HIV
infection
0 hr 36 hrs 72 hrs
HIV
1 mos 3 mos 5 mos
After exposure to
HIV, infection may
become established

Postexposure
prophylaxis
HIV
infection
0 hr 36 hrs 1 mos 3 mos 5 mos
Postexposure
prophylaxis—
initiated soon after
an exposure—reduces
the chance of infection
HIV
72 hrs

Pre-exposure
prophylaxis
HIV
infection
Pre-exposure
prophylaxis begins
treatment earlier—
before exposure—
which might increase
the prophylactic
effect
HIV
72 hrs

HIV HIV
Postexposure
prophylaxis
For persons with ongoing/
repeated HIV exposure,
intermittent postexposure
prophylaxis may not be sufficient
HIV
72 hrs

HIV HIV
Pre-exposure
prophylaxis
Pre-exposure prophylaxis
might protect against a period
of ongoing risk by having a
continuing level of medication
available
HIV
72 hrs

PrEP Clinical Trials
 Phase III clinical trials of PrEP tested daily oral TDF-based
tablets (alone or in combination with FTC)
 Factors that supported testing of TDF-based PrEP in
clinical trials
– Potency: rapid antiretroviral activity
– Safety: high tolerability, substantial treatment safety
experience
– Ease: once-daily dosing, few drug–drug interactions
– Preclinical/early clinical evidence: animal model data found
high efficacy of PrEP for HIV protection[1]
1. Garcia-Lerma JG, et al. Current Opin HIV AIDS. 2012;7:505-513.

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,
% (95% CI)
PrEP Placebo
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
treatment centers in
Thailand
TDF 17 33 49 (10-72)
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.

Adherence Is a Key Determinant of PrEP
Trial Outcomes
Study
Detection of TFV in Plasma, %
HIV Seroconverters HIV Uninfected
iPrEx[1]
51
Partners PrEP[2]
(TDF/FTC arm)
81
Thai IDU[3]
67
In the large iPrEx, Partners PrEP, and Thai IDU studies,
TFV was detected in blood samples of the majority of subjects who
remained HIV uninfected during the study
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. Choopanya K, et al. Lancet. 2013;381:2083-2090.

Trial Outcomes
Study
iPrEx[1]
9 51
Partners PrEP[2]
(TDF/FTC arm)
25 81
Thai IDU[3]
39 67
By contrast, TFV was detected in only a minority of subjects who
acquired HIV, arguing that adherence to taking the study
medication was related to remaining HIV uninfected

Trial Outcomes
Study
iPrEx[1]
9 51
Partners PrEP[2]
(TDF/FTC arm)
25 81
Thai IDU[3]
39 67
This difference in TFV detection translated into a
relative risk reduction of acquiring HIV:
iPrEx: 92% (95% CI: 40% to 99%; P < .001)
Partners PrEP TDF/FTC: 90% (95% CI: 56% to 98%; P = .002)
Thai IDU: 70% (95% CI: 2% to 91%; P = .04)

PrEP (Like ART) Works When Taken
2 additional trials of PrEP (FEM-PrEP and VOICE), both conducted
among high-risk African women, did not demonstrate protection against
HIV; in both trials, PrEP adherence was very low (< 30%)
Study Blood Samples With
TFV
Detected, %
HIV Protection Efficacy
in Randomized
Comparison,%
Partners PrEP[1]
81 75
TDF2[2]
80 62
iPrEx[3]
51 44
Thai IDU[4]
67 49
FEM-PrEP[5]
and VOICE[6]
< 30 No HIV protection
1. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 2. Thigpen MC, et al. N Engl J Med.
2012;367:423-434. 3. Grant RM, et al. N Engl J Med. 2010;363:2587-2599. 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.

Partners PrEP: Comparable Efficacy in
Heterosexual Men and Women
Arm Groups Efficacy, %
(95% CI)
P Value vs Placebo
TDF
Women
(n = 595)
Men
(n = 984)
71
(37-87)
63
(20-83)
.002
.01
TDF/FTC
Women
(n = 566)
Men
(n = 1010)
66
(28-84)
84
(54-94)
.005
< .001
Baeten JM, et al. N Engl J Med. 2012;367:399-410.

PrEP Safety
 Rates of death, serious adverse events, and laboratory
abnormalities (including renal dysfunction) low and not
significantly different between those receiving PrEP and those
receiving placebo
 PrEP was well tolerated
– Adverse events occurred in minority of subjects
– GI adverse events (eg, nausea) more common in those receiving
PrEP than placebo
– Occurred in < 10% and primarily during the first month only (PrEP
“start up” symptoms)
 PrEP associated with a small change (~ 1%) in bone mineral
density but without increased risk of fracture

iPrEx[1]
Partners PrEP[2]
50
30
10
0
0 6 12 18 24 30
Follow-up Time (Mos)
40
20
3 9 15 21 27 33
SubjectsReporting
UnprotectedSex(%)
TDF
FTC/TDF
Placebo
PrEP Trials Found Decreasing Risk
Behavior Over Time
100
80
0
0
Wks Since Randomization
48 72 96 120 144
SubjectsReportingUnprotected
ReceptiveAnalSex(%)
40
60
20
24
FTC/TDF
Placebo
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.

PrEP and HIV Drug Resistance
 Resistance rare (consistent with subjects who acquired
HIV not taking PrEP)
– Exception: those with undiagnosed (seronegative) acute HIV
infection at time PrEP was initiated
 Resistance mutations seen: K65R (TDF) or M184V/I
(FTC)
Liegler T, et al. CROI 2011. Abstract 97LB. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
Baeten JM, et al. N Engl J Med. 2012;367:399-410 (supplementary appendix). Thigpen MC, et al. N
Engl J Med. 2012;367:423-434 (supplementary appendix). Choopanya K, et al. Lancet. 2013;381:2083-2090.

FDA Approval of TDF/FTC Fixed-Dose
Combination for PrEP
 In July 2012, the FDA approved the fixed-dose combination
TDF/FTC as PrEP in combination with safer sex practices to
reduce the risk of sexually acquired HIV infection in adults at
high risk
 Must be used only by individuals who are confirmed to be HIV
negative
– Prior to prescribing the drug and at least every 3 mos during use
 Once-daily dosing (no evidence for any other prescribing
frequency)
 Manufacturer required to have training and education program
to assist prescribers in counseling individuals who are receiving
or considering TDF/FTC for PrEP
– Patient assistance available: 855.330.5479

Prescribing PrEP: CDC Interim Guidance
for MSM, Heterosexual Couples, IDUs
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. CDC. MMWR Morb Mortal Wkly Rep. 2012;61:586-
589. CDC. MMWR Morb Mortal Wkly Rep. 2013;62;463-465.
Component Recommendation
Risk
assessment
 PrEP indicated for those at high HIV risk
Eligibility  HIV negative, adequate renal function
Dosing  1 FDC tablet, once daily
Follow-up  Testing for HIV every 3 mos
 Counseling on risk reduction and testing creatinine at 3 mos
and then annually
 Testing for STIs every 6 mos, even if asymptomatic
Discontinuation  PrEP not meant for lifelong administration but rather for
periods of highest risk

Limitations of Current Data
 Long-term adherence to PrEP and long-term health
effects of TDF/FTC in HIV-negative persons and HIV
seroconverters not known
 Adherence, risk behavior, and PrEP interest likely to be
different now that PrEP HIV protection benefits known
CDC. MMWR Morb Mortal Wkly Rep. 2011;60:65-68. Grant RM, et al. N Engl J Med. 2010;363:2587-
2599.

Summary: PrEP
 TDF/FTC is approved as PrEP in combination with safer
sex practices to reduce the risk of sexually acquired HIV
infection in adults at high risk (July 2012)
 Adherence appears to be key to PrEP efficacy
 Providers should be prepared to do risk assessment,
counseling, and prescribe PrEP for high-risk individuals

Talking About Treatment and PrEP
 A common belief is that antiretroviral medications are
awful; this delays treatment and is a prominent patient
concern for PrEP
 New messages from
providers are needed

Key Questions for ART as Prevention and
PrEP
 Cost
 Uptake
 Adherence
 Sexual behavior
 Impact
 Resistance

PrEP Works Together With Other HIV
Prevention Strategies
 Example from Partners PrEP Study: package of HIV prevention
services, including ongoing risk-reduction counseling, HIV testing,
ART, treatment of STIs, and other strategies plus PrEP synergize to
maximally reduce HIV risk
HIVIncidence
10% to 15%/yr
Serodiscordant
Couples Outside of
Clinical Trials[1]
Partners PrEP
Placebo Arm[2]
2%/yr
0.5%/yr
Partners PrEP
TDF/FTC Arm[2]
1. Quinn TC, et al. N Engl J Med. 2000;342:921-929. 2. Baeten JM, et al. N Engl J Med. 2012;367:399-410.

Putting This Together
2 incredibly powerful prevention strategies
HIV Prevention Effect With High Adherence
Antiretroviral
treatment for HIV
prevention
96%
(HPTN 052,
near-perfect adherence)
PrEP for HIV prevention
90% to 92%
(With high adherence as
measured by TFV levels in
iPrEx and Partners PrEP)

A New Options for HIV Prevention.The Role of Antiretrovirals

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