1. HIV Alert: ART for HIV Prevention: Current Best Practices and Emerging Strategies
These slides include notes based on commentary provided by Jared M. Baeten, MD, PhD.
This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.

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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. Faculty
Jared M. Baeten, MD, PhD Professor, Departments of Global Health and Medicine
University of Washington
Seattle, Washington
Myron S. Cohen, MD Associate Vice Chancellor for Global Health Director, UNC Institute for Global Health & Infectious Diseases Chief, Division of Infectious Diseases Yeargan-Bate Eminent Professor Medicine, Microbiology and Immunology, and Epidemiology University of North Carolina Chapel Hill Chapel Hill, North Carolina

4. Faculty Disclosure Information
Jared M. Baeten, MD, PhD, has no real or apparent conflicts of interest to report. Myron S. Cohen, MD, has disclosed that he has received consulting fees from Merck and Roche.

5. Program Overview PrEP: Current Best Practices
Potential Future HIV Prevention Strategies
Question and Answer Session
PrEP, pre-exposure prophylaxis.
This program reviews pre-exposure prophylaxis (PrEP), including current information and best practices, and the future of HIV prevention strategies, with an emphasis on potential new PrEP options.
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6. PrEP: Current Best Practices
PrEP, pre-exposure prophylaxis.

7. Four Prevention Opportunities
Status
Prevention Measure
Timing
Uninfected, unexposed
Behavioral, structural interventions (eg, condoms, circumcision)
Years
Uninfected, exposed (precoital/coital)
PrEP
Hours
Uninfected, exposed (postcoital)
PEP
72 hours
Infected
Treatment of HIV to reduce infectivity
PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis.
From a broad perspective on HIV prevention, many different potential points for intervention exist, and each of these opportunities is incredibly important at the population level for making an impact.
For individuals who are uninfected and unexposed, major changes in behavior or education, as well as structural changes, can make a big difference. Condoms and circumcision are 2 interventions suggested for this group. Such measures can occur over a period of years.
This program will focus heavily on what prescribers can do to influence HIV transmission in individuals who are exposed to HIV. We will talk principally about PrEP, highlighted in the second row, for individuals who are HIV uninfected but who are exposed. PrEP has typically been used during a period of hours preceding exposure. For individuals who have had an exposure and were not taking PrEP, postexposure prophylaxis (PEP) as an HIV prevention tool can be initiated up to 72 hours after an exposure.
Finally, it is incredibly important to remember that HIV-infected individuals who take treatment can markedly reduce their infectivity. This reduced risk of transmission begins very soon after initiation of antiretroviral therapy (ie, within the first several months) and extends on from there as long as the patient is adherent and virally suppressed.
Cohen MS, et al. J Clin Invest. 2008;118:
Cohen MS, et al. J Int AIDS Soc. 2008;11:4.
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8. ART for Prevention of HIV Transmission in Serodiscordant Couples
HPTN 052: HIV-infected partner in healthy serodiscordant couples randomized to early or deferred ART (N = couples)[1]
Overall 93% reduction in risk of transmission with early therapy
No linked HIV transmissions where index partner suppressed on ART
PARTNER: observational study in serodiscordant couples where HIV-infected partner on suppressive ART and condoms not used (N = 888 couples)[2]
No linked transmissions recorded in any couple
Median follow-up: 1.3 yrs; ~ 58,000 sex acts
ART, antiretroviral therapy.
Suppressive antiretroviral treatment is one of the most effective strategies available for HIV prevention and is also beneficial for patient health.
The HPTN 052 study recruited predominantly heterosexual (97%), serodiscordant couples where one partner was HIV positive and the other negative. The HIV-infected partners were randomized to early or deferred therapy where deferred therapy was initiated after 2 consecutive CD4+ counts ≤ 250 cells/mm3. Overall, there was a 93% reduction in the risk of transmission with early therapy, and no linked HIV transmissions occurred where the HIV-positive partner was suppressed on antiretroviral therapy.
Similarly, the observational PARTNER study analyzed transmission risk in serodiscordant couples composed of either men who have sex with men or heterosexuals. Here, the HIV-infected partner was on suppressive ART and reported not using condoms. No linked HIV transmissions were recorded in the couples over a median follow-up of 1.3 years or about 58,000 sex acts.
1. Cohen MS, et al. N Engl J Med. 2016;375:
2. Rodger A, et al. JAMA. 2016;316:
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9. Does PrEP Work?
PrEP, pre-exposure prophylaxis.

10. Oral TDF-Based PrEP: Rationale
Numerous completed phase III PrEP trials have used daily oral TDF-based pills
TDF had several advantages for choice as a first- generation PrEP agent:
Potent: broad, potent activity (all HIV subtypes), rapidly active
Safe: favorable safety and tolerability, large treatment experience
Easy: low pill burden, no food restrictions, few drug interactions
TDF/FTC coformulated for daily oral use
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
A number of phase III PrEP trials have tested daily oral tenofovir disoproxil fumarate (TDF) in pill form. TDF has several advantages for choice as a first-line PrEP agent. It is potent, broadly active against all HIV subtypes, and acts very quickly after being taken. It is also well tolerated with a favorable safety profile and has a large amount of treatment experience backing its use. Finally, it is easy to take: 1 pill a day, no food restrictions, and few drug interactions.
TDF and emtricitabine (FTC) have been coformulated for daily oral use. This combination is the most commonly tested PrEP agent and a main regimen of focus in this program.
Slide credit: clinicaloptions.com

11. 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.
Overall, these randomized clinical trials of PrEP using TDF/emtricitabine have shown that HIV incidence decreases with patient adherence. The y axis depicts the effectiveness of HIV protection in each trial while the x axis documents each trial’s adherence level. Adherence was based on pill counts or the detection of study drug in plasma.
A very clear and strong linear relationship exists where greater adherence across the study population tracks with greater HIV protection. This emphasizes how important it is to be adherent to PrEP. The TDF2, Partners PrEP, and PROUD studies all demonstrated very high degrees of HIV protection in populations that took PrEP consistently.
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.

12. PrEP Is Highly Effective When Taken
Randomized, placebo-controlled trial[1] or open-label extension[2] in which HIV-uninfected people received once-daily oral TDF/FTC
Study
TFV Level*
HIV Acquisition Risk Reduction, %
Partners PrEP[1]
Any detectable
90†
iPrEx OLE[2]
Any detectable to < 2 doses/wk
44‡
2-3 doses/wk
84‡
4-6 doses/wk
100‡
7 doses/wk
FTC, emtricitabine; PBO, placebo; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.
This slide specifically reviews 2 studies where HIV-uninfected individuals received once-daily oral TDF/FTC. In Partners PrEP, a randomized, placebo-controlled trial in heterosexuals, people who had any detectable amount of tenofovir in their blood demonstrated a 90% risk reduction for HIV acquisition. Similarly, risk reduction for men and transgender women who have sex with men enrolled in the iPrEx open-label extension (OLE) who took at least 4 doses a week was 100%.
This emphasizes that PrEP is highly effective when taken and may provide near-perfect HIV protection when taken well. The iPrEx OLE also demonstrated that adherence need not be perfect. Taking 4-6 of 7 doses per week appeared to provide protection. This flexibility allows individuals to miss an occasional dose, even though they are trying for daily dosing.
*In plasma (Partners PrEP) or DBS (iPrEx OLE) from people who became infected with HIV during the study or a random subgroup who did not become infected. †Detectable vs no detectable TFV. ‡PrEP vs no PrEP.
1. Baeten JM, et al. N Engl J Med. 2012;367: Grant RM, et al. Lancet Infect Dis. 2014;14:
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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
PrEP: immediate vs deferred for 12 mos
Fewer new HIV infections with immediate vs deferred PrEP (3 vs 20)
Risk behaviors similar between arms
HIV Incidence 10
9.0 9 8 7
86%
reduction
(P = .0001) 6
HIV Incidence/100 PY 5 4 3
FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; PY, patient-years; TDF, tenofovir disoproxil fumarate.
At the time of this next study, the United Kingdom was deciding whether PrEP could be effectively rolled out within its high-risk populations. PROUD tested PrEP in a real-world setting. It was a randomized, open-label trial of daily oral TDF/FTC in uninfected men who have sex with men at high risk for HIV who were attending sexual health clinics in England. Patients were randomized to receive PrEP immediately or after a 12-month deferral period.
All patients received counseling, provision of condoms, STI treatment, and other measures that would reduce their HIV risk. However, fewer infections occurred among those who received immediate PrEP compared with those who received deferred PrEP (3 vs 20, respectively). This made for HIV incidence rates of 9.0/100 person-years and 1.2/100 person-years, respectively, or a statistically significant 86% reduction in HIV risk with immediate treatment.
The risk behaviors were similar between the arms, suggesting that the provision of PrEP did not increase HIV acquisition risks. It should be noted that the HIV incidence in the deferred arm is one of the highest seen in any population in the last decade anywhere in the world. Thus, PrEP can work in an incredibly high-risk population in a real-world setting with real-world counseling when given immediately.
The 3 new infections in the immediate PrEP arm occurred in individuals who were not taking PrEP at the time they became infected because their infection predated study enrollment or they had discontinued PrEP or were nonadherent. These infections were not, therefore, breakthrough infections but instead represent individuals acquiring HIV while not on PrEP. 2
1.2 1
Deferred (n = 269)
Immediate
(n = 275)
Slide credit: clinicaloptions.com
McCormack S, et al. Lancet. 2016;387:53-60.

14. Who Should Receive PrEP?
PrEP, pre-exposure prophylaxis.

15. 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 STI
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 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; STI, sexually transmitted infection.
CDC guidelines discuss indicators of substantial risk of HIV infection that might make PrEP a welcome prevention option. For men who have sex with men, this can include having an HIV-positive sexual partner, a recent bacterial sexually transmitted infection such as gonorrhea, chlamydia, or syphilis, a high number of sex partners, history of inconsistent or no condom use, or commercial sex work. These same indicators apply to heterosexual women and men with the addition of being located in a high prevalence area or network. For people who inject drugs, risk factors include HIV-positive injecting partners, sharing of injection equipment, and continuing to inject even after recent drug treatment.
Clinical eligibility for PrEP is relatively simple and includes a documented negative HIV test and no signs of acute HIV infection at the time of PrEP initiation, normal renal function and no contraindicated medications, and documented hepatitis B virus infection or vaccination status. Careful management in coordination with an HBV expert is warranted if someone is hepatitis B coinfected when initiating PrEP. The provision of vaccination is important for those who are at risk and have not been vaccinated before.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

16. CDC: Lifetime HIV Infection Risk by Subgroup
Lifetime Risk of
HIV Diagnosis by Ethnicity
Lifetime Risk of HIV Diagnosis Among MSM
Black Men
1 in 20
MSM
1 in 6
Black Women
1 in 48
Black MSM
1 in 2
Hispanic Men
1 in 48
Hispanic Women
1 in 227
Hispanic MSM
1 in 4
White Men
1 in 132
CDC, Centers for Disease Control and Prevention; MSM, men who have sex with men.
The lifetime risk of HIV infection varies quite considerably by subgroup in the United States. The lifetime risk of HIV for black men is 1 to 20. For black women and Hispanic men, it’s 1 in 48, and then for Hispanic women and white men it’s 1 in over 100. For white women, the risk is the least at 1 in 800. For men who have sex with men, the overall risk is 1 in 6 but can be subdivided by ethnicity: 1 in 2 for black MSM, 1 in 4 for Hispanic MSM, and 1 in 11 for white MSM.
People living in the South and the Northeast of the United States are more likely to be diagnosed with HIV than other Americans, with the highest risk in Washington, DC, (1 in 13) and the lowest risk in North Dakota (1 in 670). This underscores the great heterogeneity in HIV risk that exists across the country with some populations particularly at risk of HIV and in need of new prevention options like PrEP.
White Women
1 in 880
White MSM
1 in 11
People living in the South and Northeast are more likely to be diagnosed with HIV vs other Americans, with the highest risk in Washington, DC (1 in 13) and the lowest risk in North Dakota (1 in 670)
Slide credit: clinicaloptions.com
Hess K, et al. CROI Abstract 52.

17. How Should PrEP Be Prescribed?
PrEP, pre-exposure prophylaxis.

18. CDC Guidance on PrEP for HIV Prevention: Approaches
Prescription
TDF/FTC (300/200 mg) QD; continuing, oral dose, ≤ 90-day supply
TDF alone can be considered as an alternative regimen in IDUs and heterosexually active adults
Not recommended: other ARVs, coitally timed PrEP, or other noncontinuous daily use
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
MSM
Do oral/rectal STI testing
Heterosexual Women
Assess pregnancy intent
Pregnancy test every 3 mos
Injection Drug Users
Access to clean needles/syringes and drug treatment services
AE, adverse event; ARVs, antiretrovirals; CDC, Centers for Disease Control and Prevention; FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STI, sexually transmitted infection; TDF, tenofovir disoproxil fumarate.
CDC guidance on PrEP for HIV prevention is very straightforward and clear. The CDC recommends continuous TDF/FTC at 300/200 mg per day, the standard combination daily oral dose, with up to a 90-day supply prescribed.
For individuals who inject drugs or are heterosexual, there is some data that TDF alone, not in combination with emtricitabine, can be considered as an alternative, although people are generally prescribing TDF/FTC.
At this time, other antiretrovirals, coitally timed PrEP, and other noncontinuous daily uses are not recommended.
Follow-up visits are recommended at least every 3 months for HIV testing, adherence counseling, behavioral risk reduction support, assessment of ongoing side effects and safety, and STI symptom management. At 3 months and every 6 months thereafter, renal function should be assessed, and testing for bacterial STIs should occur every 6 months.
For men who have sex with men, STI testing would include both oral and rectal testing. For heterosexual women, pregnancy intent should be assessed, and pregnancy tested administered every 3 months. For injection drug users, PrEP should be combined with harm reduction, including clean needles and syringes and drug treatment services.
This package of prevention services is provided together with a relatively simple base of primary care services to assess for safety before starting PrEP, and to monitor safety thereafter.
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CDC. PrEP Guidelines

19. Stopping PrEP
Lack of guidance on when to stop PrEP in relationship to exposures
Reasons to stop PrEP:
Pt choice
Evidence of HIV infection
Adverse events
Chronic nonadherence
If resuming PrEP after stopping, repeat standard pre-PrEP evaluation
PrEP, pre-exposure prophylaxis.
Stopping PrEP is to be expected. Reasons to stop PrEP include patient choice, evidence of HIV infection, adverse events, and chronic nonadherence in a way that would be unsafe. Of these, patient choice will likely be the most common reason, and adverse events are expected to be rare.
PrEP can be stopped and restarted and stopped again all very safely, because PrEP is a prevention option that should work within people’s lives when they have risk. One can imagine an individual taking PrEP for a year, maybe taking a year off when risk is lower, and then maybe a year or 2 years later coming back and starting PrEP again if risk resumes. In this way, PrEP is somewhat analogous to an oral contraceptive. It is effective when it is taken, but people’s risks change on and off over time. Individuals may be able to be on and off PrEP depending on their individual risk at the time.
Slide credit: clinicaloptions.com
CDC. PrEP Guidelines

20. What Are Additional Considerations for PrEP Use?
PrEP, pre-exposure prophylaxis.

21. 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 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 PBO 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 following discontinuation
AE, adverse event; BMD, bone mineral density; FTC, emtricitabine; MSM, men who have sex with men; PBO, placebo; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TGW, transgender women.
A meta-analysis of data from randomized, placebo-controlled PrEP trials demonstrated that the risk of any adverse event or of high-grade adverse events was no different for TDF-based PrEP compared to placebo. Thus, PrEP did not increase the risk of adverse outcomes overall.
Several trials have assessed bone safety during PrEP treatment, including an iPrEx substudy. In high-risk men and transgender women who have sex with men who received daily TDF/FTC PrEP, there was a small net decrease in spine and total hip bone mineral density (BMD) vs placebo at 24 weeks. However, there was no difference in the fracture rate between the groups, and BMD loss that was associated with PrEP recovered once PrEP was discontinued.
As previously discussed, PrEP users are expected to discontinue. In general, PrEP is not expected to be a lifelong medication. So while there appear to be changes in bone mineral density, they have not been clinically relevant, and bone mineral density is recovered when PrEP is discontinued.
1. Fonner VA, et al. AIDS. 2016;30:
2. Mulligan K, et al. Clin Infect Dis. 2015;61:
3. Grant R, et al. CROI Abstract 48LB.
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22. Mean eGFR Change From BL (mL/min/1.73 m2)
PrEP and Renal Safety
Analysis of eGFR changes with TDF ± FTC PrEP in Partners PrEP (N = 4640)[1]
Over 36 mos of continuous use, PrEP use did not result in a progressive change in renal function 15
TDF
TDF/FTC
Placebo 10 5
Mean eGFR Change From BL (mL/min/1.73 m2) -5
BL, baseline; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir.
Renal safety during PrEP is an interesting topic. In the Partners PrEP study, where mean baseline eGFR was 130 mL/min, PrEP consisting of TDF with or without FTC did not result in large progressive changes in renal function over 36 months of continuous use. However, for individuals in iPrEx OLE who had baseline eGFRs less than 90 mL/min or who were older than 40 years, a decrease in estimated glomerular filtration rate to less than 70 mL/min was more frequent at higher levels of tenofovir exposure.
Thus, it is recommended that individuals have normal renal function upon initiating PrEP. Individuals with mildly reduced renal function (eg, eGFR of mL/min) or who are more than 40 years old might be at higher risk for an eGFR drop with PrEP, but these individuals can still receive PrEP with ongoing monitoring of renal function.
-10
-15 3 6 9 12 15 18 21 24 27 30 33 36
Mos
Analysis of renal function in iPrEx OLE (N = 220): eGFR decrease to < 70 mL/min more frequent at higher levels of TFV exposure among those with BL eGFR < 90 mL/min or who were older than 40 yrs[2]
1. Mugwanya KK, et al. JAMA Intern Med. 2015;175:
2. Gandhi M, et al. CROI Abstract 866.
Slide credit: clinicaloptions.com

23. STIs Will Occur for Persons Using PrEP
Analysis of HIV/STI incidence in PrEP users in large healthcare system (Kaiser Permanente San Francisco) from 2012 to 2015[1]
STIs in PrEP Initiators (N = 657) 50 50 40 33 30 28
12 Mos PrEP Use (%)
STI During 20
PrEP, pre-exposure prophylaxis; STI, sexually transmitted infection; PY, patient-years.
Sexually transmitted infections will occur in persons who are receiving PrEP. That is why STI screening at least every 6 months, or potentially more often by clinical discretion, is recommended for PrEP recipients.
The graph on this slide derives from a large healthcare system, Kaiser Permanente San Francisco, where STI rates were measured in about 700 MSM who had initiated PrEP. In the first year of treatment, 50% of individuals developed an STI. In total, 33% had chlamydia, 28% had gonorrhea, and 6% had syphilis, but there were no HIV infections. The MSM in this population likely demonstrated high rates of STI acquisition even prior to PrEP use. This is certainly true for individuals enrolled in the PROUD study where HIV acquisition was reduced by 86% with immediate PrEP use. That population had an STI rate of 63% in the 12 months before starting PrEP and 57% in the 12 months after starting PrEP, showing no new increase in STI rates with PrEP, but really high STI rates overall. This emphasizes that for populations who choose PrEP, STI rates will be high. This is also where PrEP is most needed. 10 6
Any STI
Chlamydia
Gonorrhea
Syphilis
HIV
PROUD: similar rates of any STI in 12 mos before starting PrEP (63%) vs during 12 months of PrEP (57%)[2]
1. Volk JE, et al. Clin Infect Dis. 2015;61: McCormack S, et al. Lancet. 2016;387:53-60.
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24. What Are Potential Future Strategies in HIV Prevention?
This section reviews future prevention strategies that may utilize PrEP, and these range from things that have already been tested in large studies to things that are in the earlier stages of development.

25. On-Demand (Non-Daily) PrEP Dosing
Study
Design and Findings
IPERGAY[1]
N = 400
Event-driven oral TDF/FTC vs PBO for high-risk MSM
Dosing: 2 tablets 2-24 hrs before sex, 1 tablet 24 hrs after first dose, 1 tablet 48 hrs after first dose
86% reduction in risk with PrEP vs PBO (P = .002)
Plasma TFV detected in 86% of pts in PrEP group (n = 113)
HPTN 067/ ADAPT[2-4]
N = 536
Once-daily, time-driven, or event-driven oral TDF/FTC for MSM/TGW/women in 3 locations
Dosing: time driven = 1 dose twice weekly + 1 dose after sex; event driven = 1 dose before and after sex
Level of complete coverage (adherence) varied by location and population
In 2 locations, decreased coverage with time/event driven vs once-daily PrEP
AE, adverse events; FTC, emtricitabine; GI, gastrointestinal; MSM, men who have sex with men; PBO, placebo; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TGW, transgender women.
On-demand, non-daily PrEP dosing that follows an intermittent schedule has been tested in both the IPERGAY and HPTN 067/ADAPT studies.
The IPERGAY study tested event-driven oral TDF/FTC vs placebo in high-risk men who have sex with men. PrEP was dosed as 2 tablets taken 2-24 hours before sex and then 1 tablet each day for the 2 days after sex. Overall, rather than taking 30 doses in a month, in this study, the median number of pills taken in a month was 15, which corresponds with about 4 sex acts in a month. This study showed an 86% reduction in the risk of HIV with PrEP compared to placebo, and this was highly statistically significant. PrEP adherence appeared to be high, with 86% of participants in the PrEP group having detectable plasma tenofovir. This provides some evidence in MSM that nondaily PrEP use could be effective for HIV prevention. However, as mentioned before, nondaily PrEP use is not recommended by the CDC at this time because the evidence base is still relatively limited.
The ADAPT study tested adherence to different oral TDF/FTC PrEP strategies in MSM, transgender women, and women: once daily, time driven (ie, a dose every week and then a dose after sex), or event driven (a dose before and after sex). The study was conducted in 3 different countries, the United States (New York), Thailand (Bangkok), and South Africa (Cape Town), and the level of adherence varied by location and population. In 2 of the locations, there was decreased coverage with the time- and event-driven approaches compared to once-daily dosing. This emphasizes that time- or event-driven strategies may not always yield the best protection or adherence, in part because it may be hard to remember something that is not done every day.
One of the challenges with on-demand or any nondaily approach to PrEP is getting individuals to take the pills when they need to. A daily strategy might work because taking a pill on a regular basis becomes a habit. More data are needed before nondaily dosing can be universally recommended, but a reduced dosing frequency is something that could potentially work in the future for adherent individuals.
1. Molina JM, et al. N Engl J Med. 2015;373: Mannheimer S, et al. IAS Abstract MOAC0305LB Holtz TH, et al. IAS Abstract MOAC0306LB Bekker L, et al. CROI Abstract 978LB.
Slide credit: clinicaloptions.com

26. TAF/FTC for HIV Prevention
TAF may offer improved bone/renal safety vs TDF[1]
TAF: TFV prodrug
TAF/FTC approved in combination with other ARVs for HIV treatment[2]; not currently approved for PrEP
Systemic TFV levels reduced 90% with TAF 25 mg vs TDF 300 mg[3]
Randomized phase III PrEP trial now under way[4]
Wk 96
ARV, antiretroviral; FTC, emtricitabine; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; TGW, transgender women.
References
1. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.
2. TAF/FTC [package insert]
3. Ruane PJ, et al. J Acquir Immune Defic Syndr. 2013;63:
4. ClinicalTrials.gov. NCT
This slide reviews an alternative formulation of tenofovir called tenofovir alafenamide (TAF). TAF/FTC is being tested for HIV prevention but was recently approved in the United States for the treatment of HIV infection in combination with other antiretrovirals (ARVs). TAF appears to offer improved bone and renal safety compared to TDF in HIV-infected individuals. Interestingly, the levels of tenofovir achieved with TAF are considerably lower than with TDF, which may account for the improved bone and renal profiles with TAF.
One question is whether the reduced tenofovir levels accompanying TAF administration would compromise its PrEP effects, and we do not know yet. There is an ongoing, randomized PrEP trial of men who have sex with men and transgender women at high risk for HIV infection comparing daily oral TAF/FTC and TDF/FTC. This study was initiated in September 2016, with an estimated primary completion date of February Until then, TAF/FTC is not yet recommended as a PrEP agent because of the lack of information available.
Adult MSM/TGW at high risk for HIV infection (planned N = 5000)
TAF/FTC 25/200 mg PO QD
TDF/FTC 300/200 mg PO QD
*Plus TDF/FTC placebo tablet QD. †Plus TAF/FTC placebo tablet QD.
Slide credit: clinicaloptions.com
References in slidenotes.

27. Long-Acting Injectable Therapy for HIV Prevention
May address daily oral tablet adherence issues
Cabotegravir: INSTI formulated as oral tablet and for long-acting intramuscular injection
CAB Trial
Design and Findings
ECLAIR[1]
Phase IIa
N = 127
CAB LA IM (Q12W) vs PBO IM for men at low risk for HIV infection
Oral CAB vs PBO phase preceded injection phase
Encouraging results in terms of pt satisfaction and safety
HPTN 083[2]
Phase IIb/III
Planned N = 4500
CAB LA IM (Q8W after 2 inj. 4 wks apart) vs TDF/FTC PO QD for MSM/TGW at high risk for HIV infection; trial opening soon
CAB vs TDF/FTC oral phase will precede injection phase
CAB, cabotegravir; FTC, emtricitabine; IM, intramuscular; LA, long acting; MSM, men who have sex with men; TDF, tenofovir disoproxil fumarate; TGW, transgender women.
Long-acting (LA) injections may hold great promise for use in HIV prevention. For individuals who struggle with daily oral dosing, LA injections could address adherence issues. Cabotegravir is an integrase strand inhibitor formulated as an oral tablet and also a long-acting intramuscular injection. It has been tested in the phase IIa ECLAIR study and is now moving into the phase IIb/III HPTN 083 study.
ECLAIR, which treated men at low risk for HIV infection with LA cabotegravir or placebo, demonstrated encouraging results in terms of patient satisfaction and safety. HPTN 083 is currently recruiting MSM and transgender women at high risk for HIV infection. These participants will be randomized to either LA cabotegravir injection or to daily oral pills of TDF/FTC. Time will tell if cabotegravir as a long-acting injection provides long-term protection from HIV acquisition.
There are additional long-acting injectable agents such as MK-8591 (EFdA), which has been tested in early-phase trials and might be an alternative preventative agent in the future, as well. At this time, though, these options are not available for PrEP, as they require much more extensive evaluation of their safety and efficacy.
MK-8591 (EFdA)[3]: NRTI that has shown extended half-life and antiviral activity in early-phase trials
1. Markowitz M, et al. CROI Abstract ClinicalTrials.gov. NCT Grobler J, et al. CROI Abstract 98.
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28. Broadly Neutralizing Antibodies (bNAbs) for HIV Prevention
May be used similarly to other long-acting injectables
VRC01: monoclonal antibody directed against the HIV-1 CD4 binding site[1]
Terminal half-life in PK study: ~ 15 days; demonstrated antiviral activity in HIV-infected pts[1,2]
Randomized phase II prevention trials now under way[3,4]
Low-dose/high-dose IV VRC01 or placebo Q8W for adults at high risk for HIV infection
MSM/TGW (North/South America) and women (sub-Saharan Africa); planned overall enrollment, N = 4200
Other bNAbs in development: 3BNC117, [5,6]
bNAbs, broadly neutralizing antibodies; MSM, men who have sex with men; PK, pharmacokinetic; TGW, transgender women.
References
1. Ledgerwood JE, et al. Clin Exp Immunol. 2015;182:
2. Lynch RM, et al. Sci Transl Med. 2015;7:319ra206.
3. ClinicalTrials.gov. NCT
4. ClinicalTrials.gov. NCT
5. Caskey M, et al. Nature. 2015;522:
6. ClinicalTrials.gov. NCT
Broadly neutralizing antibodies (bNAbs) provide a different, non-ARV–based strategy for HIV prevention. These synthetic monoclonal antibodies target HIV and may provide the kind of strong attack on HIV that could provide protection. Randomized phase II prevention trials are now under way. VRC01, a bNAb directed against the HIV-1 CD4 binding site, is being tested internationally in thousands of men and women. Other broadly neutralizing antibodies such as 3BNC117 and are also being tested in smaller-scale studies at this time. These bNAbs might provide HIV protection in the future.
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References in slidenotes.

29. Vaginal Rings for HIV Prevention
Potential for better adherence vs oral PrEP; sustained and controlled drug release
Dapivirine ring: silicone elastomer vaginal matrix ring containing NNRTI dapivirine
Trials
Design and Findings
MTN-020/ASPIRE[1] and IPM-027/Ring[2] studies
Phase III
N = 4588
Dapivirine vaginal ring Q4W + HIV prevention services for sexually active HIV-uninfected African women
Dapivirine ring associated with significant reductions in the risk of HIV infection vs PBO ring (27% to 31%; P ≤ .05)
No clinically relevant safety differences between dapivirine and PBO ring groups
PBO, placebo; PrEP, pre-exposure prophylaxis.
Finally, vaginal rings have been tested for HIV prevention. A vaginal ring containing the antiretroviral dapivirine was tested in 2 phase III studies of sexually active, HIV-uninfected African women, MTN-020/ASPIRE and IPM-027/RING. The silicone elastomer rings released the antiretroviral slowly over the period of a month and reduced HIV risk by about a third overall or by a greater amount in individuals with increased adherence. Dapivirine rings may offer a new HIV prevention strategy for individuals in whom pills do not work well.
1. Baeten JM, et al. N Engl J Med. 2016;[Epub ahead of print]. 2. Nel A, et al. CROI Abstract 110LB.
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30. Additional Emerging HIV Prevention Strategies
Strategy
Findings
Vaccines
HVTN100 vaccine met immunogenic criteria required to move into phase IIb/III efficacy study (HVTN702)[1,2]
Other vaccine concepts in earlier phases of study
Implants
Several approaches using subdermal implant models in preclinical development[3,4]
Vaccines and implants are in the earlier phases of development but are worth noting because of how encouraging they could be. A vaccine that provides complete HIV protection would obviously be revolutionary, and implants, like injectables or dapivirine rings, could offer a prevention opportunity that would remove some of the barriers to adherence.
1. Bekker LG, et al. IAC Abstract TUAX0102LB. 2. ClinicalTrials.gov. NCT
3. Gunawardana M, et al. Antimicrob Agents Chemother ;59:
4. Schlesinger E, et al. Pharm Res. 2016;33:
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31. Summary PrEP should be part of an overall HIV prevention strategy
TDF/FTC QD oral therapy safe and effective
Emerging PrEP strategies may eventually allow clinicians and individuals at high risk for HIV infection to choose the optimal delivery method for prophylaxis
Daily or on-demand tablets
Long-acting injectables
Vaginal rings
Implants
FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate.
In summary, PrEP is part of an overall HIV prevention strategy. Once-daily oral TDF in combination with FTC is safe and effective. Emerging PrEP strategies may eventually allow clinicians and individuals at high risk for HIV infection to choose among multiple PrEP options for the optimal delivery of prophylaxis. This includes daily or on-demand tablets, long-acting injectables, vaginal rings, and implants.
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32. Go Online for More CCO Coverage of HIV!
Timely Webinars with expert faculty that address important developments in HIV care as they occur Downloadable Webinar slides and audio for self-study and use in your own presentations
clinicaloptions.com/hiv