Современное лечение ВИЧ : АРТ как профилактика.Contemporary Management of HIV. Antiretroviral Therapy As Prevention.2016

Contemporary Management of HIV:
Antiretroviral Therapy
As Prevention
This program is supported by an independent educational grant from
ViiV Healthcare
Jointly provided by Albert Einstein College of Medicine, Montefiore Medical Center,
Annenberg Center for Health Sciences at Eisenhower, and Clinical Care Options, LLC

Slide credit: clinicaloptions.com
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Program Director and Core Faculty
Program Chair
Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of
Medicine at UCLA
Los Angeles, California
Kenneth Mayer, MD
Infectious Disease Attending
and Director of HIV Prevention
Research
Beth Israel Deaconess Medical
Center
Professor of Medicine
Harvard Medical School
Medical Research Director
Fenway Community Health
Boston, Massachusetts

Faculty Disclosure Information
Eric S. Daar, MD, has disclosed that he has received
consulting fees from AbbVie, Bristol-Myers Squibb, Gilead
Sciences, Janssen, Merck, Teva, and ViiV and funds for
research support from Bristol-Myers Squibb, Gilead
Sciences, Merck, and ViiV.
Kenneth Mayer, MD, has disclosed that he has received
scientific advisory meeting fees from Merck and funds for
research support from Gilead Sciences and ViiV.

Peer Review Disclosure
Barry S. Zingman, MD
Medical Director, AIDS Center
Clinical Director, Infectious Diseases, Moses Division
Professor of Clinical Medicine, Albert Einstein College of
Medicine
Montefiore Medical Center
The University Hospital for Albert Einstein College of
Medicine
Barry S. Zingman, MD, has no real or apparent conflicts of
interest to report.

Case 1:
MSM at High Risk for
HIV Infection

Case 1: Single HIV-Uninfected Gay Man at
Risk for HIV Infection
 The pt is a 35-yr-old single HIV-uninfected gay man
 He meets partners online and in clubs
 He does not like using condoms, so tries to avoid anal
sex with new partners
 He has condomless anal sex 1-2 times per mo, when
he has consumed too much alcohol or used
methamphetamine

Is this pt a candidate for PrEP?
A. Yes
B. No
C. Unsure
 35-yr-old HIV-uninfected gay man
 Reports occasional condomless anal sex
 Reports regular alcohol and methamphetamine use
 Recent treatment for syphilis

CDC: Recommended Indications for PrEP
in MSM
 Adult man
– Without acute or established HIV infection
– Any male sex partners in past 6 mos
– Not in a monogamous partnership with a recently tested,
HIV-negative man
 AND at least 1 of the following:
– Any anal sex without condoms (receptive or insertive) in past
6 mos
– Any STI diagnosed or reported in past 6 mos
– Is in an ongoing sexual relationship with an HIV-positive
male partner
CDC. PrEP Guidelines. 2014. Slide credit: clinicaloptions.com

What if . . . the pt was 16 yrs of age? Is
this pt a candidate for PrEP?
A. Yes
B. No
C. Unsure
 HIV-uninfected gay man

in Adolescent Minors
 Be aware of local laws and regulations concerning
consent, confidentiality, parental disclosure, and
reporting[1]
 Limited data in PrEP in pts younger than 18 yrs of
age, including bone and other toxicities[1]
 ATN 110 suggests that PrEP uptake can be high and
PrEP can be well tolerated in young MSM aged 18-24
yrs[2]
1. CDC. PrEP Guidelines. 2014.
2. Hosek S. et al. IAS 2015. Abstract TUAC0204LB. Slide credit: clinicaloptions.com

The Case for PrEP
 In the US, less than 20% of HIV-infected persons are
undiagnosed[1]
– Approximately 60% of younger HIV-infected persons (13-29 yrs of
age) are undiagnosed[2]
 Contemporary HIV prevention should include safer sex
counseling, STD diagnosis and treatment, referral for behavioral
health support, and consideration of PrEP
– Behavioral intervention alone may not be highly effective for long-
term behavioral change and reduction in HIV incidence[3]
– Many pts have mental health and substance abuse considerations
– Condom use can reduce the risk of HIV infection[4]
– Pts may feel that barrier protection impedes sexual pleasure

Clinical Trial Evidence for Oral and
Topical TDF-Based Prevention
Mayer KH, et al. Curr Opin HIV AIDS. 2015;10:226-232.
Modified from AVAC Report. 2013.
Serodiscordant
couples
MSM
Heterosexual
men and women
Heterosexual
women
People who
inject drugs
Partners PrEP—daily oral TDF/FTC
(Discordant couples—Kenya, Uganda)
Partners PrEP—daily oral tenofovir
(Discordant couples—Kenya, Uganda)
iPrEx—daily oral TDF/FTC
(MSM—North and South America, Thailand, South Africa)
PROUD—daily TDF/FTC
(MSM—UK)
IPERGAY—intermittent TDF/FTC
(MSM—France, Canada)
TDF2—daily TDF/FTC
(Heterosexual men and women—Botswana)
Bangkok TDF study—daily oral TDF
(IDUs—Thailand)
CAPRISA 004—“BAT-24” dosing vaginal TDF gel
(Women—South Africa)
FACTS 001—“BAT 24” dosing vaginal TDF gel
(Women—South Africa)
MTN 003/VOICE—daily vaginal dosing tenofovir gel
(Women—South Africa, Uganda, Zimbabwe)
FEM-PrEP—daily oral TDF/FTC
(Women—Kenya, South Africa, Tanzania)
MTN 003/VOICE—daily oral TDF/FTC
MTN 003/VOICE—daily oral tenofovir
75% (55-87)
67% (44-81)
44% (15-63)
86% (58-96) (90% CI)
86% (40-98)
62% (22-84)
39% (6-60)
0% (-1 to 2)
15% (-21 to 40)
6% (-52 to 41)
-4% (-49 to 27)
-49% (-129 to 3)
49% (10-72)
-130 0 100-60 -40 -20 20 40 60 80
Effectiveness
(%)

Effectiveness and Adherence in Trials of
Oral and Topical TDF-Based Prevention
AVAC Report. 2013.
Effectiveness and Adherence in Trials of
Oral and Topical TDF-Based Prevention
100
80
60
40
20
0
-20
-40
-60
Effectiveness(%)
Percentage of Participants’ Samples That Had Detectable Drug Levels
(Calculations based on analyses involving a subset of total trial participants)
10 20 30 40 50 60 70 80 90
CAPRISA 004 (tenofovir
gel, BAT-24 dosing)
iPrEx
TDF2
Partners PrEP (TDF)
Partners PrEP (TDV/FTC)
FEM-PrEP
VOICE (TDF)
VOICE (TDF/FTC)
VOICE (tenofovir gel,
daily dosing)
 Higher adherence associated with greater protection

PrEP Is Well Tolerated; Discontinuations
due to Adverse Events Are Rare
 No difference in proportion of participants reporting any AE (RR: 1.01; 95% CI: 0.99-1.03,
P = .27) or any grade 3/4 AE in PrEP vs placebo arms
 Several studies noted subclinical declines in renal functioning and BMD among PrEP users
WHO. Guideline on when to start antiretroviral therapy
and on pre-exposure prophylaxis for HIV.
Study Name Subgroup
Within Study
Comparison Statistics for each study Risk Ratio and 95% CI
BKK TDF Study
CDC Safety Study
FEM-PrEP
IAVI Kenya Study
IAVI Uganda Study
Ipergay
iPrEx
Partners PrEP-Main
Project PrEPare
TDF2
VOICE
Men and women
MSM
Women
MSM and FSW
Men and women
MSM
MSM and TG
Men and women
MSM
Men and women
Women-all PrEP
Daily PrEP vs PBO
Daily PrEP vs PBO
Daily PrEP vs PBO
Multiple PrEP dosing
Multiple PrEP
Intermittent PrEP
Daily PrEP vs PBO
Daily PrEP vs PBO
Daily PrEP vs PBO
Daily PrEP vs PBO
Daily PrEP vs PBO
Risk
Ratio
0.979
1.357
1.446
4.592
0.170
1.226
0.919
1.077
2.850
0.652
0.925
1.016
Lower
Limit
0.797
0.890
0.855
0.257
0.007
0.622
0.747
0.954
0.324
0.370
0.746
0.916
Upper
Limit
1.203
2.069
2.445
81.944
4.025
2.420
1.129
1.215
25.069
1.150
1.147
1.127
Z-Value
-0.202
1.420
1.376
1.037
-1.097
0.589
-0.806
1.194
0.944
-1.477
-0.713
0.305
P Value
.840
.155
.169
.300
.272
.556
.420
.233
.345
.140
.476
.760
Favors PrEP Favors Placebo
0.01 0.1 1 10 100

iPrEX: Daily Oral TDF/FTC PrEP for MSM
 Double-blinded, randomized trial of
oral TDF/FTC QD PrEP vs PBO for
HIV-negative MSM/TGW at high
risk for HIV infection (N = 2499)
 Relative reduction in cumulative
risk of HIV infection: 44% with
TDF/FTC vs PBO (P = .005)[1]
 All pts given counseling; no
differences between arms in sexual
practices, decrease in high-risk
behavior, STIs, self-reported pill
use[1]
– No evidence of risk compensation[2]
 More nausea with TDF/FTC during
Wks 1 to 4 (P < .001)[1]
 No resistance in 48 on-study HIV
infections in TDF/FTC arm; FTC
resistance in pts initiating PrEP
during acute HIV infection waned
on d/c[3]
1. Grant RM, et al. N Engl J Med. 2010;363:2587-2599.
2. Marcus JL, et al. PLoS One. 2013;8:e81997.
3. Liegler T, et al. J Infect Dis. 2014;210:1217-1227.
Kaplan-Meier Estimates of Time to HIV
Infection (Modified ITT Population)[1]
Wks
CumulativeProbability
ofHIVInfection
0.10
0.08
0.06
0.04
0.02
0
1320 12 24 36 48 60 72 84 96108120
Placebo
FTC-TDF

iPrEX OLE: PrEP Reduces Incidence of
HIV Even With Incomplete Adherence
 Open-label extension of
iPrEX trial; N = 1603 (75%
receiving PrEP)
 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
associated with greater
adherence to PrEP
Grant R, et al. IAC 2014. Abstract TUAC0105LB.
Grant R, et al. Lancet Infect Dis. 2014;14:820-829.
HIV Incidence and Drug Concentrations
5
4
3
2
1
0
150012501000700500350LLOQ0
Off PrEP
On PrEP
TFV-DP in fmol/punch
7
Tablets
/Wk
4-6 Tablets/Wk< 2
Tablets/
Wk
2-3
Tablets/
Wk
HIVIncidenceper100Person-Yrs

iPrEX: Bone Mineral Density Substudy
 iPrEX substudy:
dual-energy x-ray
absorptiometry assessment
(N = 498)
 Small net decrease in spine
and total hip BMD with
TDF/FTC vs PBO at Wk 24
(-0.91% and -0.61%,
respectively; P = .001 for
both)
 No difference in fracture
rate between groups
(P = .62)
Mulligan K, et al. Clin Infect Dis. 2015;61:572-580.
Mean Net Treatment Difference in BMD
Change, Placebo – TDF/FTC (95% CI)
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
Spine (L1-L4)
Treatment
Difference(%)
24 48 72 96
P value .001 .064 .004 .111
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
Total Hip
Treatment
Difference(%)
24 48 72 96
P value .001 <.001 .176 .246
Wk
Wk

 Data compared for TFV-DP < or ≥ 16 fmol/M viable PBMC, concentration
associated with 90% reduction in HIV infection risk in MSM/TGW
Slide credit: clinicaloptions.comGrant R, et al. CROI 2016. Abstract 48LB.
*P < .001; †
P < .05
ChangeinBMDFrom
iPrExEnrollment(%)
SpineHip
BL Wk 24 D/c 6-Mos Post
d/c
OLE
Enroll
BL Wk 24 D/c 6-Mos Post
d/c
OLE
Enroll
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
3.0
2.0
1.0
0
-1.0
-2.0
-3.0
3.0
2.0
1.0
0
-1.0
-2.0
-3.0
Age < 25 Yrs
Placebo
Wk 24 TFV-DP < 16
Wk 24 TFV-DP ≥ 16
Age ≥ 25 Yrs
Age < 25 Yrs
Age ≥ 25 Yrs
*
*
* †
*
*
iPrEx BMD Substudy: BMD Recovery After
Discontinuation of TDF/FTC PrEP

Cumulative TFV/FTC Exposure During
PrEP Assoc. With Decline in Renal Fxn
Change in eGFR From BL vs
Concentration of TFV or FTC in Hair[1]
Lowest Second Third Highest
Quartile of Hair Drug Concentrations
~ 2 doses/wk
~ 4 doses/wk
~ 7 doses/wk
%ChangeinMeaneGFRFrom
Baseline(95%CI)
-8
-6
-4
-2
0
TFV
FTC
Trend
P Value
.008
.006
1. Gandhi M, et al. CROI 2016. Abstract 866.
2. Liu AY, et al. CROI 2016. Abstract 867. Slide credit: clinicaloptions.com
 Higher TFV exposure
associated with greater
eGFR decreases in 2 studies
– iPrEx OLE[1]
(n = 220): hair
sampling for exposure
– US Demo Project[2]
(n =
557): dried blood spot
sampling for exposure
 In both studies, eGFR
decrease to < 70 mL/min
more frequent among those
with BL eGFR < 90 mL/min
and older persons (older
than 40-45 yrs)

PROUD: Immediate vs Deferred PrEP in
High-Risk MSM in “Real World” Trial
 Randomized, open-label trial of
daily oral TDF/FTC PrEP in
uninfected MSM at high risk for
HIV infection in England
– PrEP: immediate vs deferred
for 12 mos
 Fewer new HIV infections with
immediate vs deferred PrEP (3
vs 20)
– Number needed to treat to
prevent 1 infection: 13
 PEP used by 32% in deferred
arm
 Risk behaviors similar between
arms
McCormack S, et al. Lancet 2015;[Epub ahead of print]
HIV Incidence
HIVIncidence/100PY
9.0
(6.1-12.7)
86%
reduction
(90% CI: 64%
to 96%:
P = .0001)
Deferred
(n = 269)
Immediate
(n = 275)
1.2
(0.4-2.9)
10
9
8
7
6
5
4
3
2
1
0

Case Report: Multiclass Resistant HIV
Infection Despite High Adherence to PrEP
 43-yr-old MSM acquired multiclass resistant HIV-1 infection following
24 mos of oral once-daily TDF/FTC PrEP
 Pharmacy records, blood concentration analyses, and clinical history
support recent and long-term adherence to PrEP
 PrEP failure likely result of exposure to PrEP-resistant, multiclass
resistant HIV-1 strain
Knox DC, et al. CROI 2016. Abstract 169aLB.
Drug Class
Mutations Detected on Day 7
Following p24-Positive Test
Estimated Fold-Change in IC50 or
Change in Response (Drug)
NRTI 41L, 67G, 69D, 70R, 184V, 215E
1.9x (ABC), 61x (3TC), 38x (FTC), 1.3x
(TDF)
NNRTI 181C 43x (NVP)
PI 10I No relevant change
INSTI 51Y, 92Q
Reduced (RAL), resistant (EVG),
reduced (DTG)

PrEP Demonstration: High Adherence in
STD/Community-Based Clinics
 Prospective, open-label study of
48 wks of daily oral TDF/FTC
PrEP for MSM/TGW (N = 557)
– 3 US STD or community-based
clinics in San Francisco, Miami,
and Washington, DC
 Of pts with at least 2 DBS tested
(n = 272), 62.5% had protective
TFV levels (consistent with ≥ 4
doses/wk) at all visits
– 3% had TFV levels consistent
with < 2 doses/wk
 PrEP dispensation interrupted in
15%: most commonly due to AE
concerns or low perceived risk
 Overall STI incidence remained
stable during follow-up (90/100
PY)
Liu AY, et al. JAMA Intern Med. 2016;176:75-84.
100
80
60
40
20
0
Engagement,%ofParticipants
San Francisco, California
4
(n = 109)
12
(n = 114)
24
(n = 121)
36
(n = 121)
48
(n = 124)
Level of engagement
No visit BLQ < 2 doses/wk 2-3 doses/wk 4-7 doses/wk

PrEP Use and HIV/STI Incidence in a
Clinical Practice Setting
 Analysis of PrEP use and HIV/STI incidence in PrEP users in
large healthcare system (Kaiser Permanente San Francisco)
from 2012 to 2015
– 1045 referrals for PrEP; 801 individuals with ≥ 1 intake visit
– 657 initiated PrEP (82%*); mean duration of use 7.2 mos
 Key results (PrEP initators):
– No HIV diagnoses (388 PY follow-up)
– After 12 months, 50% diagnosed with any STI
– 33% rectal STI; 33% chlamydia; 28% gonorrhea
– After 6 mos PrEP, self-reported condom use was decreased in
41% of individuals
Volk JE, et al. Clin Infect Dis. 2015;61:1601-1603. Slide credit: clinicaloptions.com
*Of persons with ≥ 1 intake visit.

STI Screening and Incidence During PrEP
 Analysis of STI occurrence in pts in SPARK, a PrEP demonstration project at
a NY health care center[1]
– Pts screened for STIs every 3 mos while receiving PrEP; also visited clinic if
experienced symptoms
– CDC PrEP guidelines suggest STI screening every 6 mos[2]
1. Golub S, et al. CROI 2016. Abstract 869.
2. CDC. PrEP Guidelines. 2014. Slide credit: clinicaloptions.com
Time Point N STI Diagnosis,
n (%)
Diagnosed by Routine
Screening, n (% STIs)
Repeat STIs,
n (% STIs)
6 mos before PrEP 280 35 (13) NA NA
PrEP prescription 280 31 (11) 31 (100) 8 (26)
3-mo follow-up 225 30 (13) 23 (77) 10 (33)
6-mo follow-up 196 41 (21) 34 (83) 20 (48)
9-mo follow-up 169 25 (15) 17 (68) 21 (84)
12-mo follow-up 128 17 (13) 13 (77) 13 (77)
 At all time points, majority of pts (> 71%) had rectal STIs

IPERGAY: On-Demand Oral PrEP in High-
Risk MSM
 Randomized double-blind trial of event-driven oral TDF/FTC (n = 199)
vs PBO (n = 201) (both with prevention services) in France
– 2 tablets 2-24 hrs before sex, 1 tablet 24 hrs after first event-driven dose,
1 tablet 48 hrs after first dose
 Adherence:
– In self-reports, 43% took tablets correctly; 29% took tablets but
suboptimally
– Median 15 pills/mo in both groups
– TFV detected in plasma of 82% of pts in PrEP group (n = 113)
 Safety of on-demand PrEP was similar to PBO except for increased
GI AEs and creatinine elevations with TDF/FTC
 Limitations: early termination led to small N and short follow-up period;
sexually active group (averaging 2 sex acts per week), so efficacy of
event-driven dosing when sex is infrequent is not clear
Molina JM, et al. N Engl J Med. 2015;373:2237-2246. Slide credit: clinicaloptions.com

0.20
0.16
0.12
0.08
0.04
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
IPERGAY: Efficacy
 86% reduction in risk seen in PrEP arm (95% CI: 40%
to 98%; P = .002)
*Event-driven PrEP strategy not FDA approved.
2 infections;
incidence 0.91/100 PY
14 infections;
incidence 6.6/100 PY
201
199
141
141
74
82
55
58
41
43
Pts at Risk, n
Placebo
TDF/FTC
Placebo
TDF/FTC
P = .002
ProbabilityofHIV
Infection
Kaplan-Meier Estimate of Time to
HIV Infection
Molina JM, et al. N Engl J Med. 2015;373:2237-2246. Slide credit: clinicaloptions.com

HPTN 067/ADAPT: PrEP Strategies
 International, randomized, open-label phase II trial; results
reported from Harlem (N = 179), Bangkok (N = 178), and Cape
Town (N = 179) cohorts
Mannheimer S, et al. IAS 2015. Abstract MOAC0305LB. Holtz TH, et al.
IAS 2015. Abstract MOAC0306LB. Bekker L, et al. CROI 2015. Abstract
978LB.
Daily PrEP
1 dose daily
Time-Driven PrEP*
1 dose twice weekly +
1 dose after sex
HIV-negative
MSM, TGW
(Bangkok and
Harlem*), and
women
(Cape Town)
at risk for HIV
infection
Event-Driven PrEP*
1 dose before and
1 dose after sex
Lead-in period
of directly
observed
therapy
Final
study
visit
TDF/FTC PrEP given at standard dose.
*Participants instructed to take no more than 2 doses/day or 7 doses/wk.
Wk 34Wk 30Wk 0 Wk 6

0
66
47*†
52*
100
80
60
40
20
CompleteCoverage(%)
Daily
Time driven
Event driven
85 84
74‡
75
56
52
HPTN 067/ADAPT: Coverage of Sex Acts
According to PrEP Strategy
Mannheimer S, et al. IAS 2015. Abstract MOAC0305LB. Holtz TH, et
al. IAS 2015. Abstract MOAC0306LB. Bekker L, et al. CROI 2015.
Abstract 978LB.
*P = .001 vs daily. †
P = .47 vs event driven. ‡
P = .02 vs daily arm, P = .04 vs time-driven arm. §
P < .001
comparing 3 arms. Complete coverage: taking ≥ 1 PrEP dose within 4 days before sex and ≥ 1 dose
within 24 hrs after sex.
Harlem Bangkok Cape Town§

On-Demand PrEP: Points for Discussion
 Risk if pt not adherent (poor coverage)?
 Risk if pt infrequently having sex?
 Does median monthly number of pills in IPERGAY
translate to “on demand”?
 Do pharmacokinetics affect whether results can be
extrapolate to women? To be discussed in the next
case

CDC: Risk Behavior Risk Assessment for
MSM
 In the past 6 mos:
– Have you had sex with men, women, or both?
– If men or both sexes: How many men have you had sex with?
– How many times did you have receptive anal sex (ie, you were the
bottom) with a man who was not wearing a condom?
– How many of your male sex partners were HIV positive?
– If any positive: With these HIV-positive male partners, how many
times did you have insertive anal sex (ie, you were the top) without
you wearing a condom?
– Have you used methamphetamines (such as crystal or speed)?

CDC Guidance on PrEP for HIV
Prevention: Candidates
CDC. PrEP Guidelines. 2014.
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
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)
Clinically
eligible
 Documented negative HIV test result; no signs/symptoms of acute HIV
infection
 Creatinine clearance ≥ 60 mL/min; no contraindicated medications
 Documented hepatitis B virus infection and vaccination status

Prevention: Approaches
MSM
Heterosexual Women
and Men
Injection
Drug Users
Prescription
 TDF/FTC (300/200 mg) QD; daily, continuing, oral dose, ≤ 90-day
supply
 TDF alone can be considered as an alternative regimen in IDUs and
heterosexually active adults
 Other ARVs, coitally timed PrEP, or other noncontinuous daily use is not
recommended
Other
services
 Follow-up visits at least every 3 mos to provide HIV test, adherence
counseling, behavioral risk reduction support, AE assessment, STI
symptom assessment
 At 3 mos and every 6 mos thereafter, assess renal function
 Every 6 mos, test for bacterial STIs
 Do oral/rectal STI
testing
 Assess pregnancy intent
 Pregnancy test every 3
mos
 Access to clean
needles/syringes
and drug
treatment services

Lessons From Case 1
 TDF/FTC PrEP can play an important role in HIV
prevention
 Adherence is essential to efficacy
 Optimizing PrEP entails regular follow-up visits,
including periodic STD screening, monitoring of renal
function, and risk reduction counseling and
assessment of behavioral health needs
 35-yr-old HIV-uninfected gay man

Case 2:
Heterosexual HIV-Discordant
Couple

Case 2: Heterosexual HIV-Discordant
Couple
 Male partner is HIV-infected; his female partner of 5
yrs is HIV-uninfected
 Male 39 yrs of age, CD4+ cell count 750 cells/mm3
,
HIV-1 RNA 55,000 copies/mL, treatment naive,
otherwise healthy
 Female partner 32 yrs of age, healthy
 They have used condoms previously but are now
planning to start a family and would like your advice
on future strategies to minimize transmission to the
female partner and the infant

What would you recommend in terms of
ART, independent of fertility goals?
A. ART for the HIV-infected partner
B. PrEP for the HIV-uninfected partner
C. Both ART and PrEP immediately
D. Both ART and PrEP only if/when infected partner’s
CD4+ cell count reaches < 350 cells/mm3
E. Unsure
 HIV-serodiscordant couple
 Male 39 yrs, HIV-infected, CD4+ count 750 cells/mm3
, treatment naive, healthy
 Female 32 yrs, not infected with HIV, healthy
 Planning to start a family

What would you recommend in terms of
family planning?
A. ART and PrEP for appropriate partners prior to
attempted conception
B. Sperm donation
C. Adoption
D. Assisted reproduction (eg, sperm washing, assisted
insemination)
E. Unsure

HPTN 052: ART for Prevention of HIV
Transmission in Serodiscordant Couples
 International, randomized, controlled trial
Stable, healthy, sexually
active, HIV-discordant
couples with CD4+ cell
count 350-550 cells/mm3
(N = 1763 couples)
Early ART Arm
Initiate ART immediately
(n = 886 couples)
Delayed ART Arm
Initiate ART at CD4+ cell count
≤ 250 cells/mm3
or at development of
AIDS-defining illness
(n = 877 couples)
Cohen MS, et al. IAS 2015. Abstract MOAC0101LB. Slide credit: clinicaloptions.com

HPTN 052: Key Results
 N = 46 linked HIV transmissions to
HIV-negative partner observed[1]
– Overall 93% reduction in risk of
transmission with early therapy
 N = 8 linked partner infections
diagnosed after index partner
started ART[1]
– Recently initiated ART (n = 4)
– Virologic failure (n = 4)
 No linked HIV transmissions where
index partner suppressed on ART[1]
 Rate of unlinked infections similar
between arms: 0.32/100 PY early
ART vs 0.29/100 PY delayed ART[1]
1. Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.
2. Sabin D, et al. IAS 2015. Abstract TUPEB285.
Linked HIV Transmission
LinkedPartnerInfections(n)
2011-2014
43
Overall 2005-2011
3
36
1
7
2
Delayed ART
Early ART
 For pts in early ART group who
experienced tx failure (n = 85), resistance
increased from 8.2% at BL to 35.3% at
failure; higher BL HIV RNA levels were
associated with new resistance at ART
failure (P = .005)[2]
50
40
30
20
10
0

START: 57% Reduced Risk of Serious
Events or Death With Immediate ART
 TEMPRANO: immediate ART + 6 mos IPT reduced risk of severe illness vs deferred
ART + no IPT in African pts with CD4+ > 500 cells/mm3[3]
 Composite primary endpoint:
any serious AIDS-related or
non-AIDS–related event
 HR for primary endpoint
(imm/def): 0.43 (95% CI: 0.30-
0.62; P < .001)[1,2]
– 68% of primary endpoints
events occurred in pts with
CD4+ cell counts
> 500 cells/mm3
10
8
6
4
2
0
CumulativePercent
WithEvent
0 6 12 18 24 30 36 42 48 54 60
Mos
1. INSIGHT START Group. N Engl J Med. 2015;373:195-807.
2. Lundgren J, et al. IAS 2015. Abstract MOSY0302.
3. TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015;373:808-822.
2.5
5.3
Immediate ART
Deferred ART
 HIV-positive, ART-naive adults with CD4+ cell count > 500 cells/mm3
(N = 4685)
randomized to ART initiated immediately following randomization or ART deferred until
CD4+ cell count ≤ 350 cells/mm3
, AIDS, or event requiring ART

Partners PrEP: PrEP in Serodiscordant
Heterosexual Couples
 Multisite, randomized, double-blind, placebo-
controlled trial
HIV-discordant couples
with HIV+ partner not
receiving ART
(N = 4747 couples)
TDF QD
(n = 1584 couples)
TDF/FTC QD
(n = 1579 couples)
Baeten JM, et al. N Engl J Med. 2012;367:399-410.
Placebo
(n = 1584 couples)
All couples received standard HIV treatment and prevention services, including risk reduction counseling,
free condoms and condom counseling, contraception counseling and provision, screening and treatment
for STIs, counseling and referral for other HIV prevention interventions (eg, male circumcision)
Up to 36 mos of
follow-up

Partners PrEP: Efficacy and Resistance
Results
 Both PrEP arms significantly reduced
HIV acquisition risk; similar efficacy in
men and women[1]
– TDF levels correlated with HIV
protection
 No differences in serious AEs,
creatinine abnormalities across arms
 No evidence of risk compensation
 Ultradeep sequencing in 121 HIV
seroconverters (25 TDF/FTC, 38 TDF,
58 placebo)[2]
– Overall resistance: 7.4% (9/121)
– In 26 pts, drug levels suggested PrEP
use during or after HIV acquisition; in
5/26, resistance detected
 Residual transmission risk within 6 mos of
ART initiation by HIV+ partner comparable
to pre-ART risk in placebo pts[3]
1. Baeten JM, et al. N Engl J Med. 2012;367:399-410.
2. Lehman DA, et al. J Infect Dis. 2015;211:1211-1218.
3. Mujugira A, et al. CROI 2015. Abstract 989.
HIV Incidence[1]
HIVIncidence(per100PY)
1.99
0.65
67%
reduction
(P < .001)
0.50
75%
reduction
(P < .001)
Placebo TDF TDF/FTC
2
1.5
1
0.5
0

Partners PrEP: Efficacy in Women at High
Risk of HIV Acquisition
 No differences
in pregnancy
incidence, birth
outcomes,
infant growth
across
treatment arms;
although PrEP
discontinued if
pregnancy
detected[2]
1. Murnane PM, et al. AIDS. 2013;27:2155-2160.
2. Mugo NR, et al. JAMA. 2014;312:362-371.
*Composite risk score
includes age of the
uninfected partner, number
of children, circumcision
status of male HIV-
uninfected partner,
married/cohabiting,
unprotected sex, and HIV-
infected partner viral load.
HIV-1
Incidence
PrEP Efficacy
Subgroups
(Women)[1] Group n Events IR % (95% CI)
P
Value
All women
PBO 619 28 2.8
TDF 595 8 0.8 71 (37-87) .002
TDF/FTC 566 9 1.0 66 (28-84) .005
Partner plasma
HIV-1 RNA
> 50,000 c/mL
PBO 154 13 5.4
TDF 144 2 0.9 84 (29-96) .02
TDF/FTC 146 4 1.7 72 (13-91) .03
Younger than
30 yrs of age
PBO 194 17 6.1
TDF 202 4 1.3 77 (29-92) .01
TDF/FTC 188 5 1.8 72 (25-90) .01
Composite risk
score > 5*
PBO 165 16 6.6
TDF 140 4 1.9 69 (7-90) .04
TDF/FTC 140 5 2.4 64 (1-87) .05

Partners Demonstration Project: PrEP +
ART in High-Risk Serodiscordant Couples
 Oral daily TDF/FTC PrEP for HIV-
uninfected partner in
serodiscordant African couples
continued 6 mos beyond initiation
of ART for infected partner
 Interim analysis
– > 95% of HIV-negative partners
using PrEP
– 80% of HIV-positive partners have
initiated ART; of these, > 90% with
suppression
 96% reduction in expected infections
– IRR, expected vs observed: 0.04
(95% CI: 0.01-0.19; P < .0001)
 In pts with seroconversion, no TFV
detectable in plasma at time of
seroconversion
– HIV-positive partner in 1 couple not on
ART (high CD4+ count)
– Other couple dissolved and HIV-
negative partner in new relationship
Baeten J, et al. CROI 2015. Abstract 24.
HIV Incidence, Actual vs Expected
Group Infected, n
Incidence/100 PY
(95% CI)
Expected 39.7 5.2 (3.7-6.9)
Actual 2 0.2 (0-0.9)

After 6 months on ART, the HIV-infected male has
undetectable HIV-1 RNA. The couple asks if the HIV-
uninfected woman can stop PrEP before they attempt to
conceive. What do you recommend?
A. Continue PrEP for the uninfected partner because of
concerns about risk of transmission
B. Discontinue PrEP because of the low risk of transmission
C. Unsure

PARTNER: Risk of HIV Transmission With
Condomless Sex on Suppressive ART
 Observational study of rate
of HIV transmission in
heterosexual and MSM
serodiscordant couples
(N = 767 couples)
– HIV+ partner on suppressive
ART
– Condoms not used
 No linked transmissions
recorded in any couple during
study period
 Uncertainty over risk remains,
particularly regarding receptive
anal sex with ejaculation
Rodger A, et al. CROI 2014. Abstract 153LB.
0 20 40 60 80 100
Risk Behaviors, %
Vaginal sex with ejaculation
Vaginal sex
Receptive anal sex
Receptive anal sex with
ejaculation
Only insertive anal sex
MSM
HT♀
HT♂
0 1 2 3 4
Rate of Within-Couple Transmission Events
per 100 CYFU, % (95% CI)
HT♀ Vaginal sex with ejaculation
(CYFU = 192)
HT♂ Vaginal sex (CYFU = 272)
Receptive anal sex with
ejaculation (CYFU = 93)
Receptive anal sex without
ejaculation (CYFU = 157)
Insertive anal sex (CYFU = 262)
MSM
Estimated rate 95% CI

Opposites Attract Study: HIV Transmission
in Male Serodiscordant Couples
 Observational study of HIV transmission in serodiscordant MSM in
Australia, Brazil, Thailand: interim analysis[1]
– On ART, 84% (of whom 83% had HIV-1 RNA < 200 c/mL);
nonmonogamous relationship, 43%[1]
;any condomless anal intercourse
(CLAI) with outside partners in previous 3 mos: 17%[2]
 No linked HIV transmission in ~ 6000 acts of CLAI
1. Grulich A, et al. CROI 2015. Abstract 1019LB.
2. Bavinton BR, et al. AIDS 2015. Abstract TUAC0306.
Type of CLAI Reported
by HIV-Negative Partner
Linked HIV
Transmissions, n
CYFU
CLAI
Acts, N
IR per 100 CYFU
(95% CI)
Overall 0 149.96 5905 0 (0-2.46)
Any CLAI 0 90.83 5905 0 (0-4.06)
Insertive CLAI 0 77.87 3569 0 (0-4.74)
Receptive CLAI 0 57.08 2337 0 (0-6.46)
Any CLAI when
HIV-1 RNA < 200 c/mL
0 88.59 5656 0 (0-4.16)
Any CLAI when
HIV-1 RNA > 200 c/mL
0 2.00 237 0 (0-184.31)

Family Planning for HIV-Discordant
Couples
 No reason to adopt, unless desired, given multiple other
safe options and long life expectancy if HIV-infected
partner is treatment adherent[1]
 ART decreases HIV transmission risk by > 90%[2]
but may
take up to 6 mos[3]
to achieve HIV-1 RNA suppression
 PrEP is highly effective if used consistently by the HIV-
uninfected partner
 Assisted reproduction can decrease HIV transmission risk
– Expensive, may not be necessary if ART and PrEP are used
1. DHHS. HIV Perinatal Guideline. 2014.
2. Cohen et al. N Engl J Med. 2011;365:493-505.
3. DHHS Guidelines. November 2015. Slide credit: clinicaloptions.com

CDC: Time to Achieving Protection on
PrEP
 Time from initiation of daily TDF/FTC to maximal protection
against HIV infection is unknown
 No scientific consensus on what intracellular concentrations are
protective for either drug or the protective contribution of each
drug in specific body tissues
 TDF and FTC PK vary by tissue
 Preliminary PK data on lead-time to achieve maximal
intracellular TFV-DP concentrations with daily TDF dosing:
– Blood: ~ 20 days
– Rectal tissue: ~ 7 days
– Cervicovaginal tissues: 20 days
– Penile tissues: no data

PrEP in 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. Slide credit: clinicaloptions.com

MSM
Heterosexual Women and
Men
Injection Drug
Users
Potential
indicators of
substantial
risk of
acquiring
HIV
infection
partner
STI
partners
 History of
inconsistent or no
condom use
 Commercial sex
work
partners
no condom use
network
 HIV-positive
injecting partner
equipment
 Recent drug
treatment (but
Clinically
eligible
infection
 Normal renal function; no contraindicated medications

Prevention: Approaches
MSM
Men
Injection Drug
Users
Prescription
 TDF/FTC (300/200 mg) QD; daily, continuing, oral dose, ≤ 90-day
supply
 TDF alone can be considered as an alternative regimen in IDUs and
heterosexually active adults
 Other ARVs, coitally timed PrEP, or other noncontinuous daily use is not
recommended
Other
services
 Follow-up visits at least every 3 mos to provide HIV test, adherence
counseling, behavioral risk reduction support, AE assessment, STI
symptom assessment
 At 3 mos and every 6 mos thereafter, assess renal function
 Every 6 mos, test for bacterial STIs
 Do oral/rectal STI
testing
 Assess pregnancy intent
 Pregnancy test every 3
mos
 Access to clean
needles/syringes
and drug
treatment services

Lessons From Case 2
 Early initiation of ART is beneficial to HIV-infected people and will make them
less infectious to sexual partners
– Optimal virologic suppression may take up to 6 mos and requires ongoing
adherence
 Use of PrEP by the uninfected partner may help reduce the risk of HIV
transmission
 PrEP could be stopped once HIV-infected partner is stably virologically
suppressed
– Transmissions can occur outside relationship; PrEP may still be indicated
 PrEP may also be indicated if the HIV-uninfected partner is not monogamous

Case 3:
Woman With Substance Use
at Risk for HIV Infection

Case 3: HIV-Uninfected Woman With
Substance Use at Risk for HIV Infection
 28-yr-old woman with history of opiate use
 Progressed from occasional to daily heroin use
 Primary sexual partner is male; HIV status unknown
 Condom infrequently used
 Occasionally exchanges sex for drugs with male
partners of unknown HIV status
 Presents to ER after needle sharing with an individual
she believes is infected with HIV
 Rapid HIV test in ER is HIV antibody negative

Discussion Questions
 What screening would you perform?
 How would you manage her heroin use?
 Would you start PrEP or PEP?
 28-yr-old woman, current heroin use
 Male primary sexual partner and additional partners of unknown HIV status
 Recent needle sharing with individual who she believes is HIV-infected
 HIV antibody negative on rapid HIV test

Case 3: Recommended Steps
 Confirm HIV status; if any risk for acute infection, order
HIV-1 RNA test
 Screen for bacterial STDs and offer PEP—the sooner the
better
 Screen renal function, and evaluate for history of HBV
infection or vaccination
 Refer to substance use program, consider DOT with
buprenorphine and naloxone or methadone
 Refer to behavioral health program to address mental
health and relationship dynamics
Mayer KH, et al. J Acquir Immune Defic Syndr. 2012;59:354-359.NY
nPEP Guideline. 2014. DHHS HRSA Guideline. Integrating
Buprenorphine Therapy Into HIV Primary Care Settings. 2012.

CDC Guidelines: PEP for Adults With
Non-Occupational HIV Exposure
nPEP Recommendation
Preferred
regimens
TDF/FTC + RAL or DTG
Alternative
regimen
TDF/FTC + DRV + RTV
PEP duration 28 days
Timing
First dose should be given be given as soon as
possible after exposure;
PEP not recommended > 72 hours after exposure
Counseling
Pts should receive counseling regarding the regimen
(potential adverse events, the need for adherence and
future risk reduction)
CDC nPEP Guideline. 2016. Slide credit: clinicaloptions.com

Expanded nPEP With Raltegravir Is Well
Tolerated but BID Dosing a Challenge
Outcomes, % RAL + TDF/FTC
(n = 100)
AZT/3TC + Third Drug
(n = 119)
AEs
 Diarrhea 21 59*
 Fatigue 14 49*
 Nausea/vomiting 27 59*
 Abdominal pain/bloating 16 3*
Completion rates
 As prescribed 57 39*
 Modified or stopped 28 14*
 Lost to follow-up 15 47*
Mayer KH, et al. J Acquir Immune Defic Syndr. 2012;59:354-359.
*P <.01. RAL + TDF/FTC as reference group.
For completion rates for TDF/FTC, n = 44.

PEP to PrEP Transition
 PEP is a response to an acute exposure
 Some pts who present for PEP may be at recurrent
risk for HIV
 When monitoring PEP, ascertain if the pt would
benefit from PrEP
 It is important to confirm if the pt is HIV infected prior
to transitioning from PEP to PrEP
 PEP entails taking up to 3 medications daily for 28
days; PrEP entails 1 pill/day while risk persists
– Counseling about the importance of adherence is
indicated
Jain S, et al. Clin Infect Dis. 2015;60(suppl 3):S200-S204.
NY nPEP Guideline. 2014. Slide credit: clinicaloptions.com

Would you counsel a transition from PEP
to PrEP for the case pt?
A. Yes
B. No
C. Unsure

Penetration of Tenofovir in Mucosal
Tissues
 Exposure to TFV, TFV-DP, FTC, FTC-TP varied widely in
different mucosal tissues
 Women may need to be more adherent to PrEP than MSM
Patterson KB, et al. Sci Transl Med. 2011;3:112re4.
Concentrations of TFV (A) and TFV-DP (B) in Rectal, Vaginal, and
Cervical Tissues After a Single Dose of TDF/FTC
Rectal tissue
Vaginal tissue
Cervical tissue
10000
1000
100
10
1
0.1
TFVConcentration(ng/g)
141 2 3 4 5 6 7 8 9 10 11 12 13
Days After Single
TDF/FTC dose
Rectal tissue
Vaginal tissue
Cervical tissue
106
105
104
103
102
101
TFV-DPConcentration
(fmol/g)
141 2 3 4 5 6 7 8 9 10 11 12 13
Days After Single
TDF/FTC Dose
A B

in IDU
 Adult without acute or established HIV infection
 Any injection of drugs not prescribed by a clinician in
past 6 mos
 AND at least 1 of the following:
– Any sharing of injection or drug preparation equipment
in past 6 mos
– Been in a methadone, buprenorphine, or buprenorphine
and naloxone treatment program in
past 6 mos
– Risk of sexual acquisition

Bangkok Tenofovir Study: PrEP Efficacy
in IDUs
 HIV-negative adults aged 20-60 yrs reporting IDU in previous yr
randomized to PrEP with TDF QD (n = 1204) or PBO (n = 1209); pts
could choose DOT or monthly visits
Choopanya K, et al. Lancet. 2013;381:2083-2090.
Kaplan-Meier Estimates of Time to HIV
Infection in Modified ITT Population
Tenofovir
Placebo
10
8
6
4
2
0
CumulativeProbability
ofHIVInfection(%)
0 12 24 36 48 60 72 84
Mos Since Randomization
 Risk of infection significantly
decreased with TDF PrEP
(48.9%; P = .01)
 For pts who became infected
and met adherence criteria
(took study drug > 71% of days
with < 2 consecutive days off
study drug, n = 17), TDF PrEP
reduced risk of infection 55.9%
(-18.8% to 86.0%; P = 0.11)
– In pts with detectable TDF:
73.5% (16.6% to 94.0%;
P = .03)

MSM
Men
Injection Drug
Users
Potential
indicators of
substantial
risk of
acquiring
HIV
infection
partner
STI
partners
 History of
inconsistent or no
condom use
 Commercial sex
work
partners
no condom use
network
 HIV-positive
injecting partner
equipment
 Recent drug
treatment (but
Clinically
eligible
infection
 Normal renal function; no contraindicated medications

Lessons from Case 3
 For some individuals presenting with acute exposures
necessitating PEP, consideration of transition to PrEP
may be appropriate, if risks are expected to be
recurrent
 Differences in TDF penetration into mucosal tissues
may mean that greater adherence to PrEP is needed
to ensure efficacy in women

Practical Considerations for PrEP

Decrease in
HIV transmission
Decrease in
HIV transmission
Maintain viral
suppression
Maintain viral
suppression
TreatTreat
Enroll in careEnroll in care
HIV negativeHIV negative
TestTest
Interventions to Increase TestingInterventions to Increase Testing
Positive
prevention
Positive
prevention
Linkage to careLinkage to care
Adherence
to ART
Adherence
to ART
ART
initiation
ART
initiation
Risk assessment
PrEP, adherence
counseling
Risk assessment
PrEP, adherence
counseling
HIV positiveHIV positive
Address concomitant concerns:
depression, substance use, relationship
dynamics, structural/social issues
Address concomitant concerns:
depression, substance use, relationship
dynamics, structural/social issues
PrEP Alone Is Not Sufficient
Slide credit: clinicaloptions.comClinicalTrials.gov. NCT01152918.

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
– Pt choice
 If resuming PrEP after stopping, repeat standard pre-PrEP
evaluation
CDC. PrEP Guideline. 2014. Slide credit: clinicaloptions.com

How Many PrEP Users Could There Be in
the US?
 Analysis of data derived from national probability
surveys
 Substantial risk for acquiring HIV consistent with PrEP
indications observed in:
– 24.7% of sexually active MSM (n = 492,000; 95% CI:
212,000-772,000)
– 18.5% of PWID (n = 115,000; 95% CI: 45,000-185,000)
– 0.4% of heterosexually active adults (n = 624,000; 95%
CI: 404,000-846,000)
Smith DK, et al. MMWR Morb Mortal Wkly Rep. 2015;64:1291-1295. Slide credit: clinicaloptions.com

What do you consider the greatest barrier
to prescribing PrEP?
A. Time constraints
B. Insurance concerns
C. Lack of pt request
D. Limited number of high-risk pts
E. Lack of training/knowledge in prescribing PrEP
F. Something else

New England Prescribers Perceived
Numerous Barriers to Prescribing PrEP
Krakower DS, et al. PLoS One. 2015;10:e0132398.
Clinician Perceived Barriers to Prescribing PrEP (N = 155)
Numbers within bars represent the percentage of participants selecting each response category.
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Time constraints (eg, to discuss PrEP,
counseling/monitoring)
Concerns about whether insurers will
cover the cost of PrEP
Lack of pt request for PrEP
Limited number of high-risk, HIV-uninfected pts
Clinicians not aware of guidance from
normative bodies (eg, CDC)
Clinicians not trained to prescribe PrEP
Clinicians not aware of PrEPNot a barrier
Minor barrier
Moderate barrier
Major barrier
22 38 31 9
10 26 31 32
7 22 45 26
27 33 25 15
19 22 33 25
14 22 30 35
23 27 31 20

Providers Who Defer ART Also Cautious
About PrEP
 Emerging Infections Network: national survey of ID MDs,
September 2014 (N = 573)
 86.5% said they recommend ART initiation at diagnosis,
independent of CD4+ count, but 66% would defer ART in
active substance users with CD4+ count > 500 cells/mm3
 59% had discussed PrEP with their HIV-positive pts
 31.8% had prescribed PrEP at least once
 Providers who would defer early ART initiation were less
likely to have prescribed PrEP
 Acceptance of both practices growing, TasP > PrEP
Krakower DS, et al. Clin Infect Dis. 2015;[Epub ahead of print]. Slide credit: clinicaloptions.com

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