1. Contemporary Management of HIV: Antiretroviral Therapy as Prevention
This program is supported by an independent educational grant from ViiV Healthcare.

2. About These Slides
Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients
When using our slides, please retain the source attribution:
These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details
Slide credit: clinicaloptions.com
Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. Program Director and Core Faculty
Program Chair Joseph J. Eron, Jr., MD Professor of Medicine and Epidemiology University of North Carolina School of Medicine Director, AIDS Clinical Trials Unit University of North Carolina Chapel Hill, North Carolina
Core Faculty 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
Slidenotes may include transcripts from live presentations given by faculty other than those listed on this slide.

4. Faculty Disclosure Information
Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from AbbVie, Gilead Sciences, Janssen, and ViiV. Kenneth Mayer, MD, has disclosed that he has received funds for research support from Gilead Sciences and ViiV.
Slidenotes may include transcripts from live presentations given by faculty other than those listed on this slide.

5. Case 1: MSM at High Risk for HIV Infection
MSM, men who have sex with men.

6. Case 1: HIV-Uninfected Black MSM at Risk for HIV Infection
The pt is a 25-yr-old single HIV-uninfected black MSM
Several casual partners of unknown HIV status in the past 6 mos
Treated for syphilis 5 mos ago
He has condomless receptive anal sex “occasionally”
MSM, man who has sex with men.
Slide credit: clinicaloptions.com

7. 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 STD diagnosed or reported in past 6 mos
Is in an ongoing sexual relationship with an HIV-positive male partner
MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

8. CDC: Considerations for PrEP in Adolescent Minors
HIV screening should be part of care for all adolescents who are sexually active or with a history of injection drug use[1]
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]
Weigh these risks against possible benefit of PrEP in adolescents at risk for HIV
ATN 110 and 113 showed declining adherence in US MSM aged and [2,3]
Pluspills study showed adherence decreased over time with less frequent study visits for adolescents yrs of age in South Africa[4]
MSM, men who have sex with men; PrEP, pre-exposure prophylaxis.
1. CDC. PrEP Guidelines Hosek S. et al. IAS Abstract TUAC0204LB. 3. Hosek S, et al. AIDS Abstract TUAX0104LB. 4. Gill K, et al. IAS Abstract TUAC0207LB.
Slide credit: clinicaloptions.com

9. The Case for PrEP
In the US, 15% of HIV-infected persons are undiagnosed[1]
Approximately 60% of younger HIV-infected persons (13-29 yrs of age) are undiagnosed[2] and incidence is rising among MSM yrs of age[3]
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[4]
Many pts have mental health and substance abuse considerations
Condom use can reduce the risk of HIV infection[5]
Pts may feel that barrier protection impedes sexual pleasure
HIV diagnoses highest among black MSM[6] and rising among Hispanic/Latino MSM[7]
MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
References:
Singh S, et al. CROI Abstract 30.
Zanoni BC, et al. AIDS Patient Care STDS. 2014;28:
CDC. HIV among gay and bisexual men. February 2017.
Koblin B, et al. Lancet. 2004;364:41-50.
Davis KR, et al. Fam Plann Perspect. 1999;31:
CDC. HIV by racial/ethic groups. April 2015.
Gray KM, et al. MMWR Morb Mortal Wkly Rep. 2015;64:
Slide credit: clinicaloptions.com
References in slidenotes.

10. US TDF/FTC PrEP Use From 2012-2015
Analysis of TDF/FTC PrEP prescription data from in US retail pharmacies
PrEP initiation increased 738% from 2012 to 2015
Women comprised 44% of individuals starting PrEP in vs 17% in 2015
Mean age of those initiating PrEP in 2015: 36.2 yrs
Persons Initiating TDF/FTC PrEP, (N = 79,684)
16000
14000
12000
10000
Persons Initiating TDF/FTC PrEP
8000
6000
4000
2000
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate. Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
2012
2013
2014
2015 Yr
Slide credit: clinicaloptions.com
Mera R, et al. IAC Abstract TUAX0105LB.

11. Sex and Racial Disparities in US TDF/FTC PrEP Use Expansion From 2012 to 2016
Electronic pt-level data from 82% of US retail pharmacies with TDF/FTC dispensed for PrEP
January 2013 to March 2016
67,403 individuals initiated TDF/FTC PrEP
Quarter-by-quarter growth in utilization 770% overall
72% among women
1350% among men
In 2015 and Q1 2016, likelihood of initiating PrEP 3.4 and 4.2 times higher for white vs black or Latino women, respectively
Likelihood 8.1 and 6.6 times higher for white vs black or Latino men, respectively
FTC/TDF PrEP Start by Race/ Ethnicity Within Sex Subgroups, %
Women
Men
White 65 76
Black 17 9
Latino 15 11
Asian 3
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
Slide credit: clinicaloptions.com
Bush S, et al. Glasgow Abstract O314.

12. Select Daily Oral TDF/FTC PrEP Trials: Effectiveness Improves With Adherence
PROUD[6] Efficacy 86% Adherence ~100%
100
Partners PrEP[5] Efficacy 75% Adherence 81% 80 60
TDF2[4] Efficacy 62% Adherence 80%
Effectiveness (%)* 40
iPrEx[3] Efficacy 44% Adherence 51% 20
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
References
1. Marrazzo JM, et al. N Engl J Med. 2015;372:
2. Van Damme L, et al. N Engl J Med. 2012;367:
3. Grant RM, et al. N Engl J Med. 2010;363:
4. Thigpen MC, et al. N Engl J Med. 2012;367:
5. Baeten JM, et al. N Engl J Med. 2012;367:
6. McCormack S, et al. Lancet. 2016;387:53-60.
For training, please note populations:
VOICE/FEM-PrEP: Women
iPrEx and PROUD: MSM
Partners PrEP: Heterosexual discordant couples
TDF2: Men and women
VOICE/FEM-PrEP[1,2] Efficacy 0%/6% Adherence 29%/≤ 37% 20 40 60 80
100
Adherence (%)†
*Reduction in HIV incidence vs control. †Based on pill counts or the detection of study drug in plasma.
Slide credit: clinicaloptions.com
References in slidenotes.

13. 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[1]
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
In post-deferred phase (Yrs 2-4, in which all pts offered PrEP), similar rate of HIV infection in immediate group vs deferred phase; rate of infection in deferred group fell to infections/100 PY[2]
HIV Incidence
HIV Incidence/100 PY
9.0
( )
86% reduction
(90% CI: 64% to 96%; P = .0001)
Deferred (n = 269)
Immediate
(n = 275)
1.2
( ) 10 9 8 7 6 5 4 3 2 1
FTC, emtricitabine; MSM, men who have sex with men; PEP, postexposure prophylaxis; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir disoproxil fumarate.
For training, please note that in England PrEP is not approved
Additional key points:
After all pts could receive PrEP in the post-deferred phase (Yrs 2-4), HIV infection was significantly reduced in the deferred PrEP group.
Slide credit: clinicaloptions.com
1. McCormack S, et al. Lancet. 2016;387: White E, et al. IAS Abstract TUAC0101.

14. Is TDF/FTC PrEP Safe?
Meta-analysis of randomized, placebo-controlled PrEP studies demonstrated that the risk of any AE or grade 3/4 AEs is not statistically significantly increased for TDF-based PrEP vs placebo[1]
Bone safety: iPrEx bone mineral density substudy[2,3]
High-risk MSM/TGW who received TDF/FTC PO QD PrEP and had dual-energy x-ray absorptiometry assessment (N = 498)
Small net decrease in spine and total hip BMD with TDF/FTC vs placebo at Wk 24 (-0.91% and -0.61%, respectively; P = .001 for both)
No difference in fracture rate between groups (P = .62)
BMD lost from hip and spine during TDF/FTC use recovered within 6 mos of PrEP discontinuation
AE, adverse event; BMD, bone mineral density; FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TGW, transgender women.
1. Fonner VA, et al. AIDS. 2016;30: Mulligan K, et al. Clin Infect Dis. 2015;61: Grant R, et al. CROI Abstract 48LB.
Slide credit: clinicaloptions.com

15. Cumulative TFV/FTC Exposure During PrEP Associated With Decline in Renal Function
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 age (≥ 40 yrs)
iPrEx OLE: Change in Mean eGFR From BL* vs Concentration of TFV in Hair[1] -2
% Change in Mean eGFR From Baseline ( 1 SE) -4
BL, baseline; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; Fxn, function; OLE, open-label extension; PrEP, pre-exposure prophylaxis; TFV, tenofovir; SE, standard error. -6
Not Detected
< 2
2-3
4-6
≥ 7
Average Doses per Wk by TFV Levels in Hair
*Mean BL eGFR: 114 mL/min (range: ).
1. Gandhi M, et al. Lancet HIV. 2016;3:e521-e Liu AY, et al. CROI Abstract 867.
Slide credit: clinicaloptions.com

16. HIV Incidence and Drug Concentrations HIV Incidence per 100 Person-Yrs
iPrEX OLE: PrEP Reduces Incidence of HIV Even With Incomplete Adherence
OLE of iPrEX trial of MSM/TGW; N = 1603 (75% receiving PrEP)
Model suggests 100% adherence 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
HIV Incidence and Drug Concentrations 5 4 3 2 1
< 2 Tablets/Wk
2-3 Tablets/Wk
4-6 Tablets/Wk
7 Tablets/Wk
Off PrEP
HIV Incidence per 100 Person-Yrs
On PrEP
OLE, open-label extension; PrEP, pre-exposure prophylaxis; TFV-DP, tenofovir diphosphate; MSM, men who have sex with men; TGW, transgender women.
1500
1250
1000
700
500
350
LLOQ
TFV-DP in fmol/punch
Grant RM, et al. Lancet Infect Dis. 2014;14:
Grant RM, et al. IAC Abstract TUAC0105LB.
Slide credit: clinicaloptions.com

17. Case Reports: HIV Infection Despite High Adherence to PrEPPt
PrEP Adherence
Seroconversion
Likely Cause of PrEP Failure
43-yr-old MSM[1]
24 mos, supported by pharmacy records, blood concentration analyses, and clinical history
Acquired MDR HIV infection
Exposure to PrEP-resistant, multiclass-resistant HIV strain
MSM in his 20s[2]
Excellent by self-report, supported by blood and hair concentration analyses
Acquired MDR HIV infection after 2 instances of condomless insertive anal intercourse with 2 different partners within 11 wks before diagnosis
50-yr-old MSM[3]
Excellent by self report, supported by blood analyses
Acquired wild-type HIV infection after median condomless anal sex partners per day in each mo following PrEP initiation
Chronic rectal inflammation ± trauma
MDR, multidrug resistant; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
PrEP is not 100% effective, but is highly protective, so to optimize protection and decrease STDs, condoms can be helpful
1. Knox DC, et al. N Engl J Med 2017;376:
2. Grossman H, et al. HIVR4P Abstract OA03.06LB.
3. Hoornenborg E, et al. CROI Abstract 953.
Slide credit: clinicaloptions.com

18. PrEP Implementation: Challenges
Adherence
Risk decompensation and STDs
Resistance
When to stop PrEP
PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
Slide credit: clinicaloptions.com

19. 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), % 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 STD incidence remained stable during follow-up (90/100 PY)
Level of Engagement
No visit
BLQ
< 2 doses/wk
2-3 doses/wk
4-7 doses/wk
100 80 60
Engagement, % of Participants 40
AE, adverse event; BLQ, below level of quantification; DBS, dried blood spots; FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TGW, transgender women. 20
4 (n = 109)
12 (n = 114)
24 (n = 121)
36 (n = 121)
48 (n = 124)
San Francisco, California
Slide credit: clinicaloptions.com
Liu AY, et al. JAMA Intern Med. 2016;176:75-84.

20. STDs Will Occur for Persons Using PrEP
Analysis of HIV/STD incidence in PrEP users in large healthcare system (Kaiser Permanente San Francisco) from to 2015[1] 50
STDs in PrEP Initiators (N = 657) 50 40 33
12 Mos PrEP Use (%)
STD During 30 28 20 10 6
PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease; PY, patient-years.
Any STD
Chlamydia
Gonorrhea
Syphilis
HIV
PROUD: similar rates of any STD in 12 mos before starting PrEP (63%) vs during 12 mos of PrEP (57%)[2]
Among 220 MSM initiating PrEP at STD clinic in Seattle, WA, from Sept 2014 to June 2016[3]:
Decreased rate of condom use during receptive anal intercourse with HIV+ partners and increased rates of CT and GC diagnosis following PrEP initiation (vs pre-PrEP baseline)
1. Volk JE, et al. Clin Infect Dis. 2015;61: McCormack S, et al. Lancet. 2016;387: Montano MA, et al. CROI Abstract 979.
Slide credit: clinicaloptions.com

21. Diagnosed by Routine Screening, n (% STDs)
Should STD Screening With PrEP Be More Often Than CDC Suggestion of Every 6 Mos?
Analysis of STD in a PrEP demonstration project at a NY health care center[1]
Pts screened for STDs every 3 mos while receiving PrEP; also visited clinic if experienced symptoms
Time Point N
STD Diagnosis, n (%)
Diagnosed by Routine Screening, n (% STDs)
Repeat STDs, n (% STDs)
6 mos before PrEP
280
35 (13) NA
PrEP prescription
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)
CDC, Centers for Disease Control and Prevention; NY, New York; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
STDs were common at each time point, supporting screening every 3 mos in high-risk population
Slide credit: clinicaloptions.com
Golub S, et al. CROI Abstract 869. CDC. PrEP Guidelines

22. IPERGAY: On-Demand Oral PrEP in High-Risk MSM in France and Canada
Event-driven* oral TDF/FTC vs PBO (both with prevention services)[1]
Study N
Median Follow- up, Mos
Risk Reduction With PrEP, %
P Value
Randomized, double blind[1]
400
9.3 86
.002
Open-label extension[2]
362
18.4 97
Not reported
0.20
0.16
0.12
0.08
0.04 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
2 infections;
incidence 0.91/100 PY
14 infections;
incidence 6.6/100 PY
Placebo
TDF/FTC
P = .002
Probability of HIV Infection
Kaplan-Meier Estimate of Probability of HIV Infection
Safety of on-demand PrEP similar to PBO except for increased GI AEs and creatinine elevations with TDF/FTC [1,2]
Median 15 pills/mo in both groups[1]
Substudy of 269 pts using ≤ 15 pills/mo with reported PrEP use systematically/ often during intercourse:[3]
HIV incidence rate/100 PY, FTC/TDF vs placebo groups: 0 vs 9.3 (P = .013)
CI, confidence interval; FDA, US Food and Drug Administration; FTC, emtricitabine; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir disoproxil fumarate.
Additional key points:
In a substudy of participants who used lower numbers of pills per month but reliably used PrEP with intercourse, PrEP remained effective.
*Event-driven PrEP strategy not FDA approved.
1. Molina JM, et al. N Engl J Med. 2015;373: Molina JM, et al. IAC Abstract WEAC Antoni G, et al. IAS Abstract TUAC0102.
Slide credit: clinicaloptions.com

23. On-Demand PrEP: Points for Discussion
Risk if pt not adherent (poor coverage)?
Effective if pt infrequently having sex?
Does median monthly number of pills in IPERGAY translate to “on demand”?
Do pharmacokinetics affect whether results can be extrapolated to women? To be discussed in the next case
PrEP, pre-exposure prophylaxis.
Slide credit: clinicaloptions.com

24. CDC Guidance on PrEP for HIV Prevention: Candidates
MSM
Heterosexual Women and Men
Injection Drug Users
Potential indicators of substantial risk of acquiring HIV infection
HIV-positive sexual partner
Recent bacterial STD
High number of sex partners
History of inconsistent or no condom use
Commercial sex work
HIV-positive sexual partner
High number of sex partners
History of inconsistent or no condom use
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
CDC, Centers for Disease Control and Prevention; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

25. CDC Guidance on PrEP for HIV 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, STD symptom assessment
At 3 mos and every 6 mos thereafter, assess renal function
Every 6 mos, test for bacterial STDs
Do oral/rectal STD testing
Assess pregnancy intent
Pregnancy test every 3 mos
Access to clean needles/syringes and drug treatment services
AE, adverse events; ARVs, antiretrovirals; CDC, Centers for Disease Control and Prevention; FTC, emtricitabine; IDU, injection drug users; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; QD, daily; STD, sexually transmitted disease; TDF, tenofovir disoproxil fumarate.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

26. TAF/FTC for PrEP? TAF: TFV prodrug
TAF/FTC approved in combination with other ARVs for HIV treatment[1]; not currently approved for PrEP
DISCOVER: multicenter, double-blind, randomized phase III trial of TAF/FTC vs TDF/FTC as PrEP in MSM and transgender women who have sex with men[2]
Estimated completion in 2019/2020
Q4W, every 4 weeks.
Slide credit: clinicaloptions.com
1. TAF/FTC [package insert] ClinicalTrials.gov. NCT

27. 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
Consider testing for STD more frequently than every 6 mos in high-risk populations
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease; TDF, tenofovir disoproxil fumarate.
25-yr-old HIV-uninfected black MSM
Reports occasional condomless anal sex
Recent treatment for syphilis

28. Case 2: Heterosexual HIV-Discordant Couple

29. 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 5,000 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
Slide credit: clinicaloptions.com

30. Initiate ART immediately (n = 886 couples)
HPTN 052: ART for Prevention of HIV Transmission in Serodiscordant Couples
International, randomized, controlled trial
Early ART Arm
Initiate ART immediately (n = 886 couples)
Stable, healthy, sexually active, HIV-discordant couples with CD4+ cell count cells/mm3
(N = 1763 couples)
Delayed ART Arm
Initiate ART at CD4+ cell count ≤ 250 cells/mm3 or at development of AIDS-defining illness
(n = 877 couples)
ART, antiretroviral therapy.
Slide credit: clinicaloptions.com
Cohen MS, et al. N Engl J Med. 2016;375:

31. Linked HIV Transmission
HPTN 052: Key Results
N = 46 linked HIV transmissions to HIV- negative partner observed
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
Rate of unlinked infections similar between arms
Linked HIV Transmission
Linked Partner Infections (n)
Post-2011 43
Overall 3 36 1 7 2 50 40 30 20 10
Delayed ART
Early ART
BL, baseline; ART, antiretroviral therapy; PY, patient-years.
Slide credit: clinicaloptions.com
Cohen MS, et al. N Engl J Med. 2016;375:

32. 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+ cell count > 500 cells/mm3[1]
Composite primary endpoint: any serious AIDS-related or non-AIDS–related event
HR for primary endpoint (imm/def): 0.43 (95% CI: ; P < .001)[2,3]
68% of primary endpoints events occurred in pts with CD4+ cell counts > 500 cells/mm3
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
Immediate ART
Deferred ART 10 8 6
5.3
Cumulative Percent With Event 4
2.5
IPT, isoniazid preventive therapy. 2 6 12 18 24 30 36 42 48 54 60
Mos
1. TEMPRANO ANRS Study Group. N Engl J Med. 2015;373: INSIGHT START Group. N Engl J Med. 2015;373: Lundgren J, et al. IAS Abstract MOSY0302.
Slide credit: clinicaloptions.com

33. Partners PrEP: PrEP in Serodiscordant Heterosexual Couples
Multisite, randomized, double-blind, placebo-controlled trial
Up to 36 mos of follow-up
TDF QD
(n = 1584 couples)
HIV-discordant couples
from Kenya and Uganda with HIV+ partner not receiving ART
(N = 4747 couples)
TDF/FTC QD
(n = 1579 couples)
Placebo
(n = 1584 couples)
ART, antiretroviral therapy; FTC, emtricitabine; PrEP, pre-exposure prophylaxis; QD, daily; STD, sexually transmitted disease; TDF, tenofovir disoproxil fumarate.
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 STDs, counseling and referral for other HIV prevention interventions (eg, male circumcision)
Slide credit: clinicaloptions.com
Baeten JM, et al. N Engl J Med. 2012;367:

34. 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
Resistance detected in 7.4% (9/121) HIV seroconverters[2]
Transmission risk within 6 mos of ART initiation by HIV+ partner comparable to pre-ART risk in placebo pts[3]
HIV Incidence[1]
HIV Incidence (per 100 PY)
1.99
0.65
67%
reduction
(P < .001)
0.50
75%
Placebo
TDF
TDF/FTC 2
1.5 1
0.5
AEs, adverse events; ART, antiretroviral therapy; FTC, emtricitabine; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir disoproxil fumarate.
1. Baeten JM, et al. N Engl J Med. 2012;367: Lehman DA, et al. J Infect Dis. 2015;211: Mujugira A, et al. CROI Abstract 989.
Slide credit: clinicaloptions.com

35. Opposites Attract: PrEP in Serodiscordant MSM Couples
International, prospective cohort study assessing the incidence of linked HIV transmission in serodiscordant MSM couples when HIV-infected partner on ART and virologically suppressed
N = 343 couples; 591 CYFU; 16,889 acts of CLAI
For HIV-infected partner, HIV-1 RNA undetectable for 95% of CYFU; for uninfected partner, PrEP use for 19% of CYFU
No linked infections; 3 infections occurring during study contracted from outside partners
AE, adverse event; CLAI, condomless anal intercourse; CYFU, couple-years follow-up; FTC, emtricitabine; MSM, men who have sex with men; TDF, tenofovir disoproxil fumarate.
Key points:
No linked infections in serodiscordant MSM couples in almost 17,000 acts of CLAI
Slide credit: clinicaloptions.com
Bavinton BR, et al. IAS Abstract TUAC0506LB.

36. HIV Incidence, Actual vs Expected
Partners Demonstration Project: Combining Treatment as Prevention + PrEP in Africa
High-risk serodiscordant heterosexual couples in Uganda and Kenya (N = 1013 couples)
Continued oral daily TDF/FTC PrEP in uninfected partner for 6 mos after start of ART in infected partner
Follow-up through 24 mos
97% of HIV-uninfected partners initiated PrEP
78% of HIV-infected partners initiated ART; of these, 89% experienced viral suppression
96% reduction in expected infections (P < .001)
Both pts with seroconversion had no TFV detectable in plasma at time of seroconversion
HIV Incidence, Actual vs Expected
Group
Infected, n
Incidence/100 PY (95% CI)
Expected
39.7
5.2 ( )
Actual 2
0.2 ( )
ART, antiretroviral therapy; CI, confidence interval; FTC, emtricitabine; IRR, incident rate ratio; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.
Slide credit: clinicaloptions.com
Baeten JM, et al. PLoS Med. 2016;13:e

37. PARTNER: Risk of HIV Transmission With Condomless Sex on Suppressive ART
Observational study in heterosexual and MSM serodiscordant couples (N = 888 couples)[1]
No linked transmissions
Similar results in Opposites Attract study of ~ 6000 acts of condomless anal intercourse[2] 1 2 3 4
PARTNER: Rate of Within-Couple Transmission Events/100 CYFU, % (95% CI)*[1]
HT♀
Vaginal sex with ejaculation (CYFU = 246)
HT♂
Vaginal sex (CYFU = 383)
Receptive anal sex with ejaculation (CYFU = 137)
Receptive anal sex without ejaculation (CYFU = 220)
Insertive anal sex (CYFU = 370)
MSM
95% CI
Uncertainty over risk remains, particularly for receptive anal sex
ART, antiretroviral therapy; CI, confidence interval; CYFU, couple-years follow-up; HT, heterosexual; MSM, men who have sex with men.
*Median follow-up: 1.3 yrs; ~ 58,000 sex acts
Slide credit: clinicaloptions.com
1. Rodger A, et al. JAMA. 2016;316: Grulich A, et al. CROI Abstract 1019LB.

38. Family Planning for HIV-Discordant Couples
Multiple safe conception options for HIV discordant couples[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
ART, antiretroviral therapy; PrEP, pre-exposure prophylaxis.
1. DHHS Perinatal Guidelines Cohen et al. N Engl J Med ;365: DHHS Guidelines
Slide credit: clinicaloptions.com

39. 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]
FDA, US Food and Drug Administration; FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
Slide credit: clinicaloptions.com
1. CDC. PrEP Guideline DHHS Perinatal Guideline

40. CDC Guidance on PrEP for HIV Prevention: Candidates
MSM
Heterosexual Women and Men
Injection Drug Users
Potential indicators of substantial
risk of acquiring HIV infection
HIV-positive sexual partner
Recent bacterial STD
High number of sex partners
History of inconsistent or no condom use
Commercial sex work
In high-prevalence area or network
HIV-positive injecting partner
Sharing injection equipment
Recent drug treatment (but currently injecting)
Clinically eligible
Documented negative HIV test result; no signs/symptoms of acute HIV infection
Normal renal function; no contraindicated medications
Documented hepatitis B virus infection and vaccination status
CDC, Centers for Disease Control and Prevention; PrEP, pre-exposure prophylaxis; STD, sexually transmitted disease.
For training, please note that faculty can highlight whatever elements they want from this slide, or can skip
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

41. 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 if the HIV- uninfected partner is not monogamous
ART, antiretroviral therapy; PrEP, pre-exposure prophylaxis.
HIV-serodiscordant couple
Male 39 yrs of age, HIV-infected, CD4+ count 750 cells/mm3, treatment naive, healthy
Female 32 yrs of age, not infected with HIV, healthy
Planning to start a family

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

43. Case 3: HIV-Uninfected Woman With Substance Use at Risk for HIV Infection
33-yr-old white woman with history of heroin use
Just entered a substance use program after previous relapses
Presents after having sex yesterday with a male partner she believes may be infected with HIV
Rapid fourth-generation HIV antibody/antigen test is HIV antibody negative
Slide credit: clinicaloptions.com

44. Case 3: Recommended Steps
Confirm HIV status; if any symptoms of 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
Ask about substance use program; consider DOT with buprenorphine and naloxone or methadone
Refer to behavioral health program to address mental health and relationship dynamics
DOT, directly observed therapy; HBV, hepatitis B virus; PEP, post-exposure prophylaxis; STDs, sexually transmitted diseases.
Mayer KH, et al. J Acquir Immune Defic Syndr. 2012;59: NY nPEP Guideline DHHS HRSA Guideline. Integrating Buprenorphine Therapy Into HIV Primary Care Settings
Slide credit: clinicaloptions.com

45. CDC Guidelines: PEP for Adults With Nonoccupational 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 hrs after exposure
Counseling
Pts should receive counseling regarding the regimen (potential adverse events, the need for adherence, and future risk reduction)
CDC, Centers for Disease Control and Prevention; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; nPEP, nonoccupational postexposure prophylaxis; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir disoproxil fumarate.
Slide credit: clinicaloptions.com
CDC. nPEP Guideline

46. 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
PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis.
Slide credit: clinicaloptions.com
Jain S, et al. Clin Infect Dis. 2015;60(suppl 3):S200-S204. NY nPEP Guideline

47. CDC: Recommended Indications for PrEP 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
CDC, Centers for Disease Control and Prevention; IDU, injection drug user; PrEP, pre-exposure prophylaxis.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

48. Bangkok Tenofovir Study: PrEP Efficacy in IDUs
HIV-negative adults aged 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
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 = .11)
In pts with detectable TDF: 73.5% (16.6% to 94.0%; P = .03)
Kaplan-Meier Estimates of Time to HIV Infection in Modified ITT Population
Tenofovir Placebo 10 8 6 4 2
Cumulative Probability of HIV Infection (%) 12 24 36 48 60 72 84
Mos Since Randomization
DOT, daily observed treatment; IDU, injection drug user; ITT, intent-to-treat; PBO, placebo; PrEP, pre-exposure prophylaxis; QD, daily; TDF, tenofovir disoproxil fumarate.
For training, consider noting Susan Buchbinder’s advice: “I like to make the case here that high adherence may be important, as they only achieved >80% reduction in incidence with 97.5% adherence using DOT. That may be because the study used TDF alone, but could be route of transmission.”
Slide credit: clinicaloptions.com
Choopanya K, et al. Lancet. 2013;381:

49. 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
PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
33-yr-old white woman, in substance use program
Recent sex with male partner of unknown HIV status
HIV antibody negative on rapid HIV test

50. Practical Considerations for PrEP
PrEP, pre-exposure prophylaxis.

51. Current Status: 90-90-90 Targets
Global (2016)
People Living With HIV (Millions)
Diagnosed
On ART
Virologically Suppressed
18.5 37 50
100 75 25
Percent
70%
53%
44%
Eastern and Southern Africa (2016)
People Living With HIV (millions)
Percent
76%
60%
50% 5 20 50
100 75 25 15 10
Diagnosed
On ART
Virologically Suppressed
Western and Central Europe and North America (2015)
People Living With HIV (Thousands)
Percent
85%
76%
64%
500
2000 50
100 75 25
1500
1000
Current 90% achievement
Gap to reach 90% target
Above target
Diagnosed
On ART
Virologically Suppressed
Slide credit: clinicaloptions.com
UNAIDS. Ending AIDS: Progress Towards the Targets. July 2017.

52. PrEP Alone Is Not Sufficient
Decrease in
HIV transmission
Maintain viral
suppression
Treat
Enroll in care
HIV negative
Test
Interventions to Increase Testing
Positive
prevention
Linkage to care
Adherence to ART
ART initiation
Risk assessment PrEP, adherence
counseling
HIV positive
Address concomitant concerns:
depression, substance use, relationship dynamics, structural/social issues
ART, antiretroviral therapy; PrEP, pre-exposure prophylaxis.
Slide credit: clinicaloptions.com

53. 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)
18.5% of PWID (n = 115,000; 95% CI: 45, ,000)
0.4% of heterosexually active adults (n = 624,000; 95% CI: 404, ,000)
CI, confidence interval; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; PWID, people who inject drugs.
Slide credit: clinicaloptions.com
Smith DK, et al. MMWR Morb Mortal Wkly Rep. 2015;64:

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

55. Emerging PrEP Strategies and Timing Considerations
PrEP, pre-exposure prophylaxis.

56. Emerging PrEP Strategies
Strategy
Examples
Long-acting ARVs
Cabotegravir LA IM injection Q12W well tolerated in phase IIa study (ÉCLAIR)[1]
MK-8591 (EFdA) has extended half-life in early-phase studies[2]
HIV vaccines
HVTN100, APPROACH vaccines met immunogenic criteria required to move into phase IIb efficacy studies[3,4]
Other vaccine concepts in earlier phases of study
Broadly neutralizing antibodies
VRC01, 3BNC117 bNAbs have extended half-lives in early studies,[5,6] efficacy trials under way
Dapivirine vaginal rings
Significantly reduced the risk of HIV infection in African women; also assessed in early phase trials in US adolescents (MTN/IPM studies)[7,8]
1. Markowitz M, et al. Lancet HIV. 2017;4:e331-e Friedman EJ, et al. CROI Abstract 437LB. 3. Bekker LG, et al. IAC Abstract TUAX0102LB. 4. Schuitemaker H, et al. IAS Abstract MOSY Caskey M, et al. Nature. 2015;522: Lynch RM, et al. Sci Transl Med. 2015;7:319ra206.
7. Baeten JM, et al. N Engl J Med. 2016;375: Bunge K, et al. IAS Abstract TUAC0206LB.
Slide credit: clinicaloptions.com

57. 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
CDC, Centers for Disease Control and Prevention; FTC, emtricitabine; PK, pharmacokinetic; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

58. 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
Change in pt’s risk
If resuming PrEP after stopping, repeat standard pre-PrEP evaluation
PrEP, pre-exposure prophylaxis.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

59. Go Online for More CCO Coverage of HIV!
Additional slidesets on contemporary management of HIV with expert faculty commentary Postconference clinical updates available following CROI, the International AIDS Conference, and IDWeek
clinicaloptions.com/hiv