………………..…………………………………………………………………………………………………………………………………….. Pre-Exposure Prophylaxis: The Time is Now Carlos Malvestutto, MD, MPH Medical Director FACES Clinic Assistant Professor OSU Medical Center

Disclosures No disclosures to report

Objectives Define PrEP Review the scientific evidence supporting PrEP –Review clinical trial data –Review recent “real world” experience with PrEP Review guidelines for PrEP Implementation of PrEP in Columbus What are the next steps?

What Is PrEP? Pre-exposure Prophylaxis: A pharmacologic HIV prevention intervention for persons at high risk of becoming infected with HIV. An HIV-uninfected individual takes antiretroviral medication(s) before potential HIV exposure The use of medication for prophylaxis is well established: –Use of contraceptive methods to prevent pregnancy –Use of antimalaria medications before traveling to endemic areas

Use of Antiretrovirals for HIV Prevention: Prevention of mother-to-child transmission –Antiretrovirals given to the mother during pregnancy, labor, and delivery and to the infant postpartum [1] –PMTCT has nearly eliminated perinatal HIV infection in the US and other developed countries Postexposure prophylaxis –Antiretrovirals given within hours of a known or suspected HIV exposure (eg, needle stick injury, rape, unprotected sexual intercourse with someone whose HIV status is unknown ) 1.DHHS. Perinatal Guidelines ;34: MMWR. 2005;54(RR-2):1-20.

Pre- vs Postexposure Prophylaxis After exposure to HIV, infection may become established Postexposure prophylaxis (initiated soon after exposure) reduces the chance of infection Pre-exposure prophylaxis begins treatment earlier (before exposure) HIV infection 0 hr 36 hrs 72 hrs HIV exposure 1 mos3 mos5 mos Postexposure prophylaxis Pre-exposure prophylaxis

How were the drugs used in PrEP selected? Tenofovir disiproxil fumarate (TDF) and emtricitabine (FTC) well established nucleoside reverse transcriptase inhibitors already used for treatment of HIV-1 Clinical trials have evaluated oral TDF, oral TDF/FTC combination and TDF vaginal gel –Safe, potent and well tolerated –Available co-formulated in single pill (Truvada) –Both FTC and TDF have long plasma (10 to 17 hours) and intracellular (39 1 and hours) half-lives –Have high penetration in vaginal and rectal tissues 1.Duwal et al, PLoS One 2012;7(7):e Jackson et al, JAIDS 2013;62(3):

What is the scientific evidence supporting PrEP?

iPrEx: Eligibility Male sex at birth (N = 2499) 18 yrs of age or older HIV-seronegative status Evidence of risk for acquisition of HIV infection Grant RM, et al. N Engl J Med. 2010;363:

iPrEx: Baseline Demographics Characteristic, % Overall (N = 2499) Age  Younger than 25 yrs 50  yrs 40  40 yrs or older 10 Race  White 17  Black 9  Asian 5  Mixed/other 69  Latino 72 Completed some college 43 Grant RM, et al. N Engl J Med. 2010;363:

iPrEx: Efficacy Efficacy at study end: 44% (95% CI: 15% to 63%) P =.002 Placebo TDF/FTC Cumulative Probability of HIV Infection Wks Since Randomization Pts at Risk, n Placebo TDF/FTC Grant R, et al. CROI Abstract 92.

Partners PrEP: TDF vs TDF/FTC vs Placebo in HIV-Serodiscordant Couples HIV-negative partners in HIV-serodiscordant heterosexual couples (N = 4747) Oral Tenofovir QD (n = 1584) Oral Tenofovir/Emtricitabine QD (n = 1579) Oral Placebo* (n = 1584) *Placebo arm terminated early on July 2011, by data and safety monitoring board. Follow-up: 36 mos Baeten JM, et al. N Engl J Med. 2012

Partners PrEP: Both PrEP Strategies Significantly Reduced HIV Acquisition Both PrEP strategies associated with significant reduction in HIV acquisition vs placebo in both men and women –TDF efficacy: 71% in women, 63% in men –TDF/FTC efficacy: 66% in women, 84% in men Primary Efficacy Outcome, mITT Analysis TDF (n = 1584) TDF/FTC (n = 1579) Placebo (n = 1584) HIV acquisitions, n HIV incidence/100 PY Efficacy vs placebo, % (95% CI) 67 (44-81) 75 (55-87) --  P value < Baeten JM, et al. N Engl J Med. 2012

TDF2: PrEP With TDF/FTC in HIV- Negative Heterosexuals in Botswana Thigpen MC, et al N Engl J Med. 2012;[Epub ahead of print]. Oral Tenofovir/Emtricitabine (n = 601) Oral Placebo (n = 599) HIV-uninfected adults, heterosexually active, aged yrs (N =1219)* ≥ 12-mo follow-up

TDF2: PrEP With TDF/FTC Significantly Reduces HIV Acquisition Thigpen MC, et al N Engl J Med  Overall protective efficacy of TDF/FTC: 62.2% (95% CI: ; P = 0.03) )  Reduction in HIV acquisition with TDF/FTC observed in both men and women Failure Probability Weeks TDF/FTC Placebo 0.10 Treat Analysis

PrEP Trials Have Shown Efficacy in MSM, Heterosexual Men and Women, and IDUs 2 additional trials of PrEP (FEM-PrEP [5] and VOICE [6] ), both conducted among high-risk African women, did not demonstrate protection against HIV; in both trials, PrEP adherence was very low TrialPopulation/SettingIntervention HIV Infections, n Reduction in HIV Infection Rate, % (95% CI) PrEPPlacebo iPrEX [1] (N = 2499) MSM, transgender women, 11 sites in US, South America, Africa, Thailand TDF/FTC (15-63) Partners PrEP [2] (N = 4747) Serodiscordant couples in Africa TDF (44-81) TDF/FTC1375 (55-87) TDF2 [3] (N = 1219) Heterosexual males and females in Botswana TDF/FTC92462 (21-83) Thai IDU [4] (N = 2413) Volunteers from 17 drug Thai treatment centers TDF (10-72) 1. Grant RM, et al. N Engl J Med. 2010;363: Baeten JM, et al. N Engl J Med. 2012;367: Thigpen MC, et al. N Engl J Med. 2012;367: Choopanya K, et al. Lancet. 2013;381: Van Damme L, et al. N Engl J Med. 2012;367: Marrazzo J, et al. CROI Abstract 26LB.

Disappointing Results of PrEP in Women: FEM-PrEP and VOICE  FEM-PrEP: Study of oral TDF/FTC for 3900 high-risk women in Africa (2120 randomized) – Study ended early by DSMB due to lack of efficacy – 35 vs 33 new HIV infections in the placebo and TDF/FTC arms [1] – TDF blood levels show that adherence was too low (< 40%)  VOICE: Phase IIB placebo-controlled trial of > 5000 women in South Africa, Uganda, and Zimbabwe [2] – Daily oral TDF; daily oral TDF/FTC; daily vaginal TFV 1% gel – DSMB stopped the daily oral TDF arm and daily vaginal gel arm for lack of efficacy – Daily oral TDF/FTC arm continued but recently shown to have low efficacy due to poor treatment adherence 1.Van Damme L, et al N Engl J Med Jul 11. [Epub ahead of print]. 2.Marrazzo J, et al. CROI Abstract 26LB.

Importance of PrEP Adherence

PrEP Works, but Adherence Is Critical StudyEfficacy Overall, % Blood Samples With TFV Detected, % Efficacy By Blood Detection of TFV, % iPrEx [1] iPrEx OLE [2] 4971NR Partners PrEP [3] 67 (TDF) 75 (TDF/FTC) (TDF) 90 (TDF/FTC) TDF2 [4] Thai IDU [5] Fem-PrEP [6] No efficacy< 30NR VOICE [7] No efficacy< 30NR 1. Grant RM, et al. N Engl J Med. 2010;363: Grant RM, et al. Lancet Infect Dis. 2014; 14: Baeten JM, et al. N Engl J Med. 2012;367: Thigpen MC, et al. N Engl J Med. 2012;367: Choopanya K, et al. Lancet. 2013;381: Van Damme L, et al. N Engl J Med. 2012;367: Marrazzo J, et al. CROI Abstract 26LB. Among those who took PrEP (confirmed by tenofovir detection in blood) efficacy was 74-92%!

Oral PrEP Reduces HIV Incidence in MSM, Even With Incomplete Adherence iPreX OLE: open-label extension of iPrEX trial of daily TDF/FTC oral PrEP in MSM and transgender women (N = 1603) 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 1. Grant R, et al. IAC Abstract TUAC0105LB. 2. Grant R, et al. Lancet Infect Dis. 2014;14: HIV Incidence and Drug Concentrations LLOQ 0 Off PrEP On PrEP TFV-DP in fmol/punch 7 Tablets/ Wk 4-6 Tablets/Wk< 2 Tablets/ Wk 2-3 Tablets/ Wk HIV Incidence per 100 Person-Yrs Follow-up Risk Reduction 95% Cl 26% 44% -31 to 77% 12% 84% 21 to 99% 21% 100% 12% 100% 86 to 100% (combined) Higher levels of sexual risk taking at baseline associated with increased adherence to PrEP

Why poor results in VOICE and FEM-PrEP? Why were there differences between these studies and the other TDF-based studies? –Very poor adherence. –Poor adherence in MSM may be more forgiving due to high TDF concentration in rectal tissue.

Safety and Tolerability

Adverse Events Very few and mild AEs observed in PrEP trials [1] –iPrEx: small but significant early nausea and weight loss [2] Potential bone and renal toxicity –Known risk associated with TDF Potential for drug-resistant HIV infection –Infrequent in clinical trials but must exclude HIV infection 1. CDC. PrEP Guideline Grant RM, et al. N Engl J Med. 2010;363:

iPrEx: Adverse Events No significant differences in adverse events between arms Adverse EventTDF/FTC (n = 1251) Placebo (n = 1248) P Value %Events% Any grade 3/4 event Death < Serious adverse event Elevated creatinine Creatinine elevation confirmed on next visit Grant R, et al. CROI Abstract 92.

iPrEx: Bone Mineral Density Changes and Fractures  Bone mineral density changes were small (~1%); no clear negative effect on health [1]  No differences in fracture rates between groups [1,2]  All fractures were trauma related 1. Liu AY, et al. PLoS One. 2011;6:e Grant RM, et al. N Engl J Med. 2010;363:

iPrEx: Nausea Grant RM, et al. N Engl J Med. 2010;363: Placebo TDF/FTC Patients Reporting Nausea (%) Wks Since Randomization

iPrEx: Weight Gain Placebo TDF/FTC Patients Reporting Weight Gain (%) Wks Since Randomization Grant RM, et al. N Engl J Med. 2010;363:

Risk Behavior

iPrEx [1] Partners PrEP [2] Follow-up Time (Mos) Subjects Reporting Unprotected Sex (%) TDF TDF/FTC Placebo PrEP Trials Found Decreasing Risk Behavior Over Time Wks Since Randomization Subjects Reporting Unprotected Receptive Anal Sex (%) TDF/FTC Placebo 1. Grant RM, et al. N Engl J Med. 2010;363: Baeten JM, et al. N Engl J Med. 2012;367:

Risk Behavior: Partners decreased NEJM, Nov 23, 2010

Risk Behavior: Condom use increased NEJM, Nov 23, 2010

Risk exposure similar in both groups (iPrEX) NEJM, Nov 23, 2010: Grant et al, 2011

Drug Resistance

Number of HIV Seroconverters on Active PrEP Arms With HIV Resistance Trial HIV Infected After Enrollment, n/N Seronegative Acute HIV Infection at Enrollment, n/N HIV Infections Averted, n iPrEx [1,2] 0/362/228 Partners PrEP [3] 0/302/874 TDF2 [4] 0/101/116  Resistance was rare in PrEP clinical trials, except for those with acute infection at baseline  Resistance mutations seen: K65R (TDF) or M184V/I (FTC)  Although M184V one of most commonly transmitted mutations, TDF in TDF/FTC remains protective PrEP and HIV Resistance 1. Liegler T, et al. CROI Abstract 97LB. 2. Grant RM, et al. N Engl J Med. 2010;363: Baeten JM, et al. N Engl J Med. 2012;[Epub ahead of print] (supplementary appendix). 4. Thigpen MC, et al. N Engl J Med. 2012;[Epub ahead of print] (supplementary appendix).

“Real World” Experience

PROUD: “Real World” Use of PrEP was highly effective. Randomized, open-label trial of daily oral TDF/FTC PrEP in HIV- MSM in 13 clinics in London –Immediate (n = 267) vs –Deferred for 12 mos (n = 256) Primary endpoint: HIV infection in first 12 mos 86% reduction in risk seen over 60 wks with immediate PrEP (90% CI: 58% to 96%, P =.0002) –Rate difference: 7.6 (90% CI: ) –Number needed to treat to prevent 1 infection: 13 (90% CI: 9-25)  2 of 3 infected persons in immediate group seroconverting at study entry or shortly after first dose of PrEP  M184V/I observed in 3/6 patients who seroconverted – No K65R mutation against TDF  High rate of STIs seen in both groups (suggests no risk compensation!)  DMSB stopped trial; recommended that all participants be offered PrEP McCormack S, et al. CROI Abstract 22LB.

Mos Ipergay: “On-Demand” Oral PrEP in High-Risk MSM Randomized double-blind trial of oral TDF/FTC* (n = 199) vs placebo (n = 201) in France –2 tablets taken 2-24 hrs before sex –1 tablet 24 hrs after sex –1 tablet 48 hrs after first event-driven dose Primary endpoint: HIV seroconversion 86% reduction in risk seen in PrEP arm (95% CI: 40% to 99%, P =.002) –Number needed to treat for 1 yr to prevent 1 infection: 18 –Median of 16 pills taken per mo in each arm In pts with infection, no tenofovir found in serum in last 2 visits 4 cases of acute HCV infection noted among lab abnormalities DSMB stopped trial early and recommended all participants start PrEP Molina JM, et al. CROI Abstract 23LB. *On-demand PrEP strategy not FDA approved. 2 infections; incidence 0.94/100 PY 14 infections; incidence 6.6/100 PY Pts at Risk, n Placebo TDF/FTC Placebo TDF/FTC P =.002 Probability of HIV Infection Kaplan-Meier Estimate of Time to HIV Infection

PrEP + ART as Prevention in Serodiscordant Couples Partners Demonstration Project in Uganda –Oral daily TDF/FTC PrEP for HIV- uninfected partner in serodiscordant couple continued 6 mos beyond initiation of ART for infected partner –High-risk couples: younger age, fewer children, uncircumcised HIV-negative male, cohabitating, unprotected sex in past mo, high HIV-1 RNA in HIV- positive 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: ; P <.0001  In pts with seroconversion, no tenofovir 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 Abstract 24. HIV Incidence, Actual vs Expected GroupInfected, n Incidence/100 PY (95% CI) Expected ( ) Actual2 0.2 ( )

PrEP Implementation: Pre- PrEP Counseling, Testing, and Clinical Evaluation

CDC PrEP Guideline: For Which Patients Is PrEP Recommended? PrEP is recommended as one prevention option for the following adults at substantial risk of HIV acquisition –Sexually active MSM –Heterosexually active men and women –Injection drug users MSMHeterosexual Women and MenInjection 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  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) CDC. PrEP Guideline

CDC Guideline: Clinical Eligibility for PrEP The following are required before prescribing PrEP to identify patients for whom PrEP would be harmful or may present risks to health: –Documented negative HIV test result –No signs or symptoms of acute HIV infection –Normal renal function; no use of contraindicated medications –Documented HBV infection status and vaccination status CDC. PrEP Guideline

HIV Screening Exclude acute and chronic HIV infection [1,2] –May need to use 4th-generation HIV Ag/Ab or HIV-1 RNA using nucleic acid–based tests if acute infection is suspected –Document negative antibody test within the week before starting PrEP –Do not accept patient-reported results –Avoid use of oral rapid HIV testing due to lower sensitivity 1. CDC. PrEP Guideline Daar ES, et al. Curr Opin HIV AIDS. 2008;3:10-15.

Documenting HIV Status CDC. PrEP Guideline HIV immunoassay blood test (rapid test if available) Retest antibody in 1 mo; defer PrEP decision Retest VL; defer PrEP decision Green = HIV status unclear; defer PrEP decision VL < level of detection with signs/symptoms on day of blood draw; retest in 1 mo; defer PrEP decision NegativeIndeterminatePositive Consider HIV+ (pending confirmatory testing) NoYes Option 1Option 2Option 3 Positive Negative HIV- HIV+ HIV- HIV+ VL > 50,000 copies/mL VL < level of detection; no signs/ symptoms on day of blood draw HIV- Orange = HIV+, not eligible for PrEP Blue = HIV-, eligible for PrEP VL < 50,000 copies/mL Signs/symptoms of acute HIV infection anytime in previous 4 wks Send blood for HIV antibody/antigen assay* Send blood for HIV-1 RNA assay

Acute HIV Infection Patients who are candidates for PrEP are at substantial risk of HIV infection Acute HIV infection should be suspected in patients with recent HIV exposure [1] –Signs and symptoms include fever, rash, pharyngitis, lymphadenopathy, myalgia, headache, diarrhea, arthralgia [2] All PrEP candidates with a negative or indeterminate HIV antibody test MUST be asked about symptoms of viral illness in the previous month or on the day of evaluation –Additional confirmatory testing is needed in patients reporting recent signs or symptoms suggestive of acute HIV 1. CDC. PrEP Guideline Daar ES, et al. Curr Opin HIV AIDS. 2008;3:10-15.

Additional Clinical and Laboratory Evaluation Evaluate for comorbidities that may complicate PrEP use, such as renal disease or hepatitis, and drug interactions –Any person with an estimated CrCl of < 60 mL/min should not be prescribed PrEP with TDF/FTC –Document HBV and HCV status before PrEP use; vaccinate patients who are HBV susceptible Optional assessments –Metabolic panel, urinalysis, STI, and pregnancy screening CDC. PrEP Guideline

CDC Guideline: Follow-up and Monitoring CDC. PrEP Guideline Follow-upAt Least Every 3 MosAfter 3 Mos and at Least Every 6 Mos Thereafter At Least Every 6 Mos At Least Every 12 Mos All patients  HIV test  Medication adherence counseling  Behavioral risk reduction support  Adverse event assessment  STI symptom assessment  Assess renal function  Test for bacterial STIs  Evaluate need to continue PrEP Women  Pregnancy test (where appropriate) HBsAg+  HBV DNA by quantitative assay* *Every 6-12 mos.

Opportunity for Engagement/Education of High Risk Individual  Patient with knowledge of impending risk  Seeks out provider recommendation and/or prescription  Opportunity for education – Risk avoidance techniques – Risks of exposure to disease if non-compliant

Medication Adherence Counseling Address adverse events [1] Identify barriers to adherence [1] Respond to missed doses in nonjudgemental manner, and stress importance of adherence [1] Patient self-reporting may not reflect actual adherence [2,3] 1. CDC. PrEP Guideline Van Der Straten A, et al. CROI Abstract Baxi SM, et al. CROI Abstract 953.

Stopping PrEP PrEP is not meant to be a “permanent” intervention. PrEP should be used during periods of high risk. Reasons to stop PrEP: –Evidence of HIV infection –Adverse events –Chronic nonadherence –Change in level of risk –Patient choice If restarting PrEP after stopping, repeat standard pre- PrEP evaluation CDC. PrEP Guideline

PrEP: An Opportunity for Engagement/Education of High Risk Individual Open discussion about risk behavior Patient goes through “seasons of risk” which may require different prevention tools Opportunity for education/STI testing –Disease avoidance techniques –Risks of exposure to disease if non-compliant –Presentation of disease if prophylaxis not efficacious –Frequent STI testing

PrEP in Clinical Practice: What Are the Barriers to PrEP Uptake? Users –Unaware of HIV risk, PrEP availability, or how to access it –No or delayed access to clinical preventive care –Lack of knowledge about insurance coverage –Adherence challenges –Concern about disclosure and stigma Providers –Unaware of intervention –Wary of complexity and time involved –Discomfort with assessing risk –Uncertain how to bill for intervention

Family AIDS Clinic and Education Services (FACES) PrEP Clinic Weekly PrEP Clinic started in December 2014 Resources –Social worker to help with insurance coverage/enrollment –Nursing –Peer navigators help with adherence counseling Enrolled Patients –Uninfected sexual partners of recently diagnosed HIV patients –Uninfected partners in serodiscordant couples wishing to become pregnant –High number of missed initial visits –11 Patients started on PrEP since December 2014 –Referrals from adolescent medicine clinic, internally from HIV clinic and word of mouth.

Promotional Card

FACES Experience with PrEP Access: –Many new referrals are uninsured. SW works with patient to enroll in health insurance –Health insurance plans cover PrEP –Copay assistance offered by manufacturer –Uninsured with income up to 500% above poverty line covered by manufacturer’s Patient Assistance Next Steps –Advertising and Promotion of clinic in the community –Development of information materials –Addition of weekly PrEP clinic at Neighborhood House –Training and support of primary care providers within NCH

Educational Materials: Pamphlets Projectinform.org

NYC DOH PrEP Posters

PrEP in the Future  Rectal/vaginal gels  Availability of Tenofovir Alafenamide (TAF)  reduced risk of BMD and renal complications  New dosing protocols for Truvada and other oral PrEP formulations  Long-acting injectable PrEP (cabotegravir and rilpivirine injectables animal studies and early human studies very promising)!

Recommendations for PrEP Implementation Coordinated effort to educate potential users Visible marketing campaign needed Need to engage and educate providers PrEP works in a continuum with PEP and HIV testing Increase education and availability of PEP Promote HIV testing in adherence with CDC guidelines (opt out, universal for all 13-64, no pre-test counseling)

Conclusions/Recommendations PrEP Works! Most efficacious if we coordinate our efforts in the community We all have a role to play: public health officials, community activists, educators, providers. Don’t forget other pillars of prevention: –HIV Testing that adheres to CDC/USPTF guidelines –Treatment as Prevention –PEP Provider education and buy-in is key Raise awareness in the community to increase uptake and reduce stigma