Disclosure. Learning Objectives. Epidemiology. Transmission. Risk of Transmission PRE-EXPOSURE PROPHYLAXIS (PREP) FOR HIV PREVENTION 50,000.

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1 Disclosure PRE-EXPOSURE PROPHYLAXIS (PREP) FOR HIV PREVENTION I have no financial interest in and/or affiliation with any external organizations in relation to this CE program. DaleMarie Vaughan, PharmD PGY-1 Pharmacy Practice Resident Virginia Commonwealth University Health System Learning Objectives 1. Describe the rationale for pre-exposure prophylaxis (PrEP) for the prevention of HIV in the United States 2. Evaluate the clinical trial results for the use of PrEP 3. List the required monitoring parameters for patients on PrEP 4. Determine the necessary counseling points for patients on PrEP Epidemiology Worldwide 2.1 Worldwide 35 Incidence Prevalence million million US, Incidence 1.2 US Prevalence million CDC estimates that 1 in 6 people with HIV are unaware of their. Ann Intern Med 213;159(1):51-6 Transmission Risk of Transmission Fluids Blood Semen Pre-seminal fluid Rectal fluids Vaginal fluids Breast milk Direct contact Mucous membranes Damaged tissue Injected into bloodstream MMWR 25;54:1-19

2 New HIV Infections by Transmission Prevention Methods Men who have sex with men (MSM) 64% Heterosexual contact 25.5% Injectable drug users (IDU) 7% Less risky sexual behaviors Nonpharmacologic Non-pharmacologic Circumcision MSM + IDU 3% Other.5% Needle exchange program HIV testing Ann Intern Med 213;159(1):51-6 Prevention Methods Effectiveness of HIV Prevention Using PEP Pharmacologic Efficacy (%) PEP (Post-Exposure Prophylaxis) ART (Antiretroviral Therapy) Time (h) MMWR 25;54:1-19 AIDSinfo 214 HIV Exposure Effectiveness of HIV Prevention Using PrEP PrEP Time (h) Efficacy (%) Tenofovir disoproxil fumarate (TDF) 3 mg and emtricitabine (FTC) 2 mg (Truvada ) FDA approved in July 212 for PrEP Tenofovir disoproxil fumarate (TDF) 3 mg (Viread ) Alternative regimen for IDU and heterosexually active men and women HIV Exposure

3 TDF/FTC Mechanism of Action PrEP tenofovir emtricitabine Daily oral PrEP has been shown to be safe and effective in reducing the risk of HIV MSM Heterosexually active men and women IDU Pharmacotherapy 9e212 Injection Drug Users (IDU) Bangkok Tenofovir Study (BTS) Must be: An adult Any sharing of injection or drug preparation equipment in past 6 months Without acute or established HIV Any injection of drugs not prescribed by a clinician in past 6 months Been in a methadone, buprenorphine, suboxone treatment program in past 6 months Risk of sexual acquisition of HIV Design Population Intervention Results Phase 3 randomized, double-blind, placebo-controlled 2,413 IDUs in Bangkok, Thailand 2-6 years old HIV-negative Reported injecting drugs during previous year TDF daily (n=1,24) Placebo daily (n=1,27) All participants offered condoms and methadone treatment participants became infected: 17 in TDF group (.35 per person-yrs) 33 in placebo group (.68 per person-yrs) No TDF resistant mutations 48.9% reduction in HIV incidence (95% CI , p=.1) TDF = tenofovir disoproxil fumarate Lancet 213;381:283-9 Bangkok Tenofovir Study (BTS) MSM Must be: An adult male Any anal sex without condoms in past 6 months Without acute or established HIV Any male sex partners in past 6 months Any STI diagnosed or reported in past 6 months Is in an ongoing sexual relationship with an HIV-positive male partner Not in a monogamous partnership with a recently tested, HIV-negative man Daily oral tenofovir reduces the risk of HIV in people who inject drugs Lancet 213;381:283-9

4 iprex (Pre-exposure Prophylaxis Initiative) Trial iprex (Pre-exposure Prophylaxis Initiative) Trial Design Phase 3 randomized, double-blind, placebo-controlled Population 2,499 HIV-seronegative men or transgender women who have sex with men in Peru, Ecuador, Brazil, Thailand, South Africa, and US Intervention TDF/FTC daily (n=1,251) Placebo daily (n=1,248) All participants received risk-reduction counseling, condoms, and management of STIs Results participants became infected: 36 in TDF/FTC group 64 in placebo group No TDF or FTC resistance was detected 44% reduction in HIV incidence (95%CI, 15-63, p=.5) TDF = tenofovir disoproxil fumarate, FTC = emtricitabine, STIs = sexually transmitted s NEJM 2;363: Daily oral TDF/FTC reduces the risk of HIV in men and transgender women who have sex with men NEJM 2;363: iprex (Pre-exposure Prophylaxis Initiative) Trial PROUD Study Percent Risk Reduction Risk of HIV Infection and Adherence All Subjects Detectable Drug Replicated results of iprex study in the real world Follow-up every 3 months Results: 86% reduction in HIV NNT = 13 Immediate (n=276) 545 enrolled 86% of days covered 5% used PEP Deferred (n=269) 31% used PEP Daily oral TDF/FTC reduces the risk of HIV in men and transgender women who have sex with men Oral daily TDF/FTC is effective to reduce the risk of HIV in MSM NEJM 2;363: Heterosexual Men and Women Partners PrEP Trial Must be: An adult Is a man who has sex with both women and men (behaviorally bisexual) Without acute or established HIV Not in a monogamous partnership with a recently tested HIV-negative partner Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk of HIV (IDU or bisexual male partner) Is in an ongoing sexual relationship with an HIV-positive partner 4,758 HIVdiscordant heterosexual couples TDF daily (n=1,589 couples) TDF/FTC daily (n=1,583 couples) Placebo (n=1,586 couples) 17 HIV s 67% reduction of HIV 13 HIV s 75% reduction of HIV 53 HIV s TDF = tenofovir disoproxil fumarate, FTC = emtricitabine NEJM 212;367:399-4

5 Partners PrEP Trial Partners PrEP Trial Percent Risk Reduction Risk Reduction Difference Between Men and Women 63 TDF TDF/FTC Men Women Daily oral TDF and TDF/FTC both protect against HIV-1 in heterosexual men and women Daily oral TDF and TDF/FTC both protect against HIV-1 in heterosexual men and women TDF = tenofovir disoproxil fumarate, FTC = emtricitabine NEJM 212;367:399-4 TDF = tenofovir disoproxil fumarate, FTC = emtricitabine NEJM 212;367:399-4 FEM-PrEP Trial FEM-PrEP Trial Design Population Intervention Results Phase 3 randomized, double-blind, placebo-controlled trial 2,12 heterosexual women in South Africa, Kenya, and Tanzania TDF/FTC daily (n=1,62) Placebo daily (n=1,58) All participants received risk-reduction and adherence counseling, free condoms and non-barrier contraception 68 HIV s occurred 33 in TDF/FTC group 3 developed resistance to FTC 35 in placebo group Daily TDF/FTC did not significantly reduce the rate of HIV among women TDF = tenofovir disoproxil fumarate, FTC = emtricitabine NEJM 212;367: NEJM 212;367: VOICE (Vaginal and Oral Interventions to Control the Epidemic) Trial VOICE (Vaginal and Oral Interventions to Control the Epidemic) Trial Design Phase 2B randomized, double-blind trial Population 5,29 heterosexual women in South Africa, Uganda, and Zimbabwe years old Not pregnant or breast-feeding Normal renal, hematologic, and hepatic function Intervention 1. TDF daily (n=1,7) 2. TDF/FTC daily (n=1,3) 3. Oral placebo daily (n=1,9) 4. Topical tenofovir (TFV) 5. Topical placebo All participants received risk-reduction and adherence counseling, free condoms and hepatitis B immunization Results 312 HIV-1 s occurred (5.7 per person-years) TDF (HR 1.49, 95% CI, ) TDF/FTC (HR 1.4, 95% CI, ) 1 developed resistance to FTC TFV gel (HR.85, 95% CI, ) TDF = tenofovir disoproxil fumarate, FTC = emtricitabine, STIs = sexually transmitted s NEJM 215;372:9-18 Science 2;329: No regimen significantly reduced the risk of HIV NEJM 215;372:9-18

6 PrEP in Women Pharmacokinetics FEM-PrEP < 4% of plasma samples had detectable drug 95 % adherence reported by interview 88 % adherence reported by pill count VOICE ~3% of plasma samples had detectable drug 9% adherence reported by interview 88% adherence reported by computerized questionnaire 86% adherence reported by pill count Concentration (ng/g) Tenofovir concentration in mucosal tissues 1 24h Emtricitabine concentration in mucosal tissues 1 24h Rectal tissue Vaginal tissue Cervical tissue NEJM 212;367: NEJM 215;372:9-18 Sci Tansl Med 211;3:112re4 Time to Protection Effectiveness of PrEP in Clinical Trials Unknown Pharmacokinetics of TDF and FTC vary by tissue Pharmacokinetic studies evaluating the maximum intracellular concentrations of tenofovir diphosphate (TFV-DP) in non-hiv infected men and women suggest Blood = 2 days Rectal tissue = 7 days Cervicovaginal tissue = 2 days Percent (%) BTS 44 iprex 66 Partners PrEP TDF/FTC (women) 84 Partners PrEP TDF/FTC (men) 6 FEM-PREP -4.4 VOICE (TDF/FTC) Social Perspectives Unanswered Questions What is the effect of PrEP on risk behavior? What are the resistance implications of seroconversion while on PrEP? What is the onset of protection? How quickly does protection wane? Long-term safety in diverse populations? How do we best support adherence? Who takes control of these patients? Are less-than-daily dosing regimens protective?

7 On Demand PrEP On Demand PrEP Results: 86% risk reduction in HIV NNT = h before sex 24 h later 24 h later Sexual encounter On demand oral PrEP with TDF/FTC is an alternative to daily PrEP in high risk MSM. Patient Case Patient Case NK is a 25 YO MSM Reports multiple sexual partners and does not always use condoms Is NK a good candidate for PrEP? PMH: Depression SH: College graduate, manages a trampoline arena Occasional alcohol Non-smoker Home Medications: Sertraline mg daily Adult without HIV Indications for PrEP IDU MSM Heterosexual Any injection of drugs not prescribed by a clinician in past 6 months Any sharing of injection or drug preparation equipment in past 6 months Been in a methadone, buprenorphine, or suboxone treatment program in past 6 months Risk of sexual acquisition of HIV Adult man without HIV Any male sex partners in past 6 months Not in a monogamous partnership with a recently tested, HIV-negative man Any anal sex without condoms in past 6 months Any STI diagnosed or reported in past 6 months Is in an ongoing sexual relationship with an HIVpositive male partner Adult without HIV Any sex with opposite sex partners in past 6 months Not in a monogamous partnership with a recently tested, HIV-negative partner Is a man who has sex with both women and men Infrequently uses condoms during sex with 1 or more partners of unknown HIV status who are known to be at substantial risk of HIV Is in an ongoing sexual relationship with an HIVpositive partner Patient Case What is the first step to take when considering PrEP? HIV testing Previous HIV test on 1//15 = negative HIV test on 2/12/15 = negative

8 Patient Case What other information is needed before considering starting PrEP? Initiation of PrEP HIV testing documentation of results are required before initiation of PrEP Renal function contraindicated in patients with egfr < 6 ml/min HBV/HCV testing Insurance status Monitoring Every 3 Months HIV testing Every 6 Months Renal function Pregnancy testing in ecrcl women STI testing Testing is required before prescriptions are refilled or reissued Every 12 Months: Evaluate need to continue PrEP for HIV prevention Patient Case NK returns to clinic for 3 months follow-up HIV testing on 5/14/15 = positive Prevention Methods Role of the Pharmacist Less risky sexual behaviors Non-pharmacologic Circumcision Counseling Medication adherence Common side effects TDF: nausea/flatulence FTC: rash, headache Monitoring ecrcl HIV test Pregnancy status Vaccination Needle exchange program HIV testing Ann Intern Med 213;159(1):51-6

9 Summary Learning Assessment Daily oral PrEP with a fixed dose of TDF 3 mg and FTC 2 mg has been shown to be safe and effective in reducing the risk of HIV PrEP should be used in combination with other effective prevention methods Patients starting PrEP should be counseled on the importance of adherence 1. The iprex student was the first of all the PrEP trials. What is true about the results of the iprex study? A. Daily tenofovir/emtricitabine resulted in an 86% risk reduction of HIV in men who have sex with men. B. No regimen significantly reduced the risk of HIV. C. Daily tenofovir/emtricitabine resulted in a 44% risk reduction of HIV in men who have sex with men. This increased to a 92% risk reduction in participants who had detectable plasma drug levels. D. Daily tenofovir resulted in a 44% risk reduction of HIV in men who have sex with men. Learning Assessment Learning Assessment 2. Why did the results of the FEM-PrEP and VOICE studies differ in effectiveness from previous PrEP trials? A. One-half of the participants were found to be infected with HIV at time of enrollment in the study. B. Ninety percent of the participants were using depomedroxyprogesterone as their contraceptive of choice, which has been shown to increase the risk of HIV by 4%. C. The results of FEM-PrEP and VOICE supported a high adherence rate as compared to the other PrEP trials. D. One-half to one-third of the participants were truly adherent to the study regimens (as measured by plasma drug levels) when compared to the adherence rate reported by the participants. 3. Which medication is approved for PrEP in the United States? A. Tenofovir/Emtricitabine B. Tenofovir/Lamivudine C. Tenofovir D. Raltegravir 4. Which of the following is NOT a high risk group indicated for HIV prevention using PrEP? A. Pregnant women who are HIV positive B. Injection drug users C. Men who have sex with men D. High risk heterosexual men and women Learning Assessment 5. All of the following tests are required before initiation of PrEP EXCEPT: A. HIV testing B. HBV testing C. Renal function D. Bone mineral density 6. What is the most important counseling point for a person prescribed PrEP? A. Take PrEP medication on an empty stomach B. Increased adherence leads to maximum effectiveness C. PrEP is taken twice daily with meals D. Monitor for signs and symptoms of visual disturbances PRE-EXPOSURE PROPHYLAXIS (PREP) FOR HIV PREVENTION DaleMarie Vaughan, PharmD PGY-1 Pharmacy Practice Resident Virginia Commonwealth University Health System