1. Elliot DeHaan, MD Clinical Assistant Professor Division of Infectious Diseases/S.T.A.R. Program SUNY Downstate Medical Center November 13, 2014

2.  The presenter has no significant disclosures.

3.  Discuss the epidemiology of new HIV infections  Discuss evidence behind Pre-Exposure Prophylaxis (PrEP)  Understand current guidelines (CDC, NYS DOH) for PrEP  Review research regarding provider and patient attitudes  Understand Payment options for PrEP

5.  40 states and 5 US dependent areas CDC. HIV surveillance in men who have sex with men (MSM). 2011. Male-to-male sexual contact Heterosexual contact* Other † Injection drug use Yr of Diagnosis 2006200720082009 0 5000 10,000 15,000 20,000 25,000 Diagnoses (n) *Heterosexual contact with a person known to have or to be at high risk for HIV infection. † Includes hemophilia, blood transfusion, perinatal exposure, and risk factor not reported or identified. Note: Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing risk-factor information but not for incomplete reporting. Male-to-male sexual contact and injection drug use

6.  40 states and 5 US-dependent areas 35-44 25-34 45-54  55 Yr of Diagnosis 2006200720082009 0 1000 3000 4000 6000 7000 Diagnoses (n) 13-24 5000 2000 CDC. HIV surveillance in men who have sex with men (MSM). 2011 Note: Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing risk-factor information but not for incomplete reporting.

7. 77% 66% 89% 77% Multiplies to 28% 850,000 HIV+ Americans (72%) lack viral control MMWR 2011; Gardner CID 2011; Burns CID 2010 80%

8.  A more recent MMWR report found in a survey of 421,186 adults at HIV clinics from Jan-April 2009 in the US and Puerto Rico  88.7% received ART  71.6% viral load <200 copies/mL last visit Blair JM, Fagan JL, Frazier EL et al. MMWR 2014; 63(ss05): 1-22

10. Single transmission in patient in immediate HAART arm believed to have occurred close to time therapy began and prior to suppression of genital tract HIV Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 P<.001 Immediate Arm: 1 Delayed Arm: 27 Cohen MS, et al. N Engl J Med. 2011;365:493-505.

11.  Observational study of rate of HIV transmission in heterosexual and MSM serodiscordant couples (N = 767 couples) – HIV+ partner on suppressive ART – Condoms not used  Analyses: 6-monthly risk behavior questionnaire, HIV-1 RNA (HIV+ persons), HIV test (HIV-negative persons)  Endpoint: phylogenetically linked transmissions  No linked transmissions recorded in any couple during study period Rodger A, et al. CROI 2014. Abstract 153LB. Reproduced with permission. 0204060 80100 Risk Behaviors, % Vaginal sex with ejaculation Vaginal sex Receptive anal sex Receptive anal sex with ejaculation Only insertive anal sex MSM HT♀ HT♂ 0123 4 Rate of Within-Couple Transmission Events Per 100 CYFU, % (95% CI) HT♀ Vaginal sex with ejaculation (CYFU = 192) HT♂Vaginal sex (CYFU = 272) Receptive anal sex with ejaculation (CYFU = 93) Receptive anal sex without ejaculation (CYFU = 157) Insertive anal sex (CYFU = 262) MSM Estimated rate95% CI

12. Answer: Treatment AND Prevention Gardner EM, et al. Clin Infect Dis. 2011;52:793-800. 200,000 600,000 0 800,000 1,000,000 1,200,000 400,000 19% 22% 34% 28% 21% 66% Number of Individuals CurrentDX 90% Engage 90% Treat 90% VL < 50 in 90% Dx, Engage, Tx, and VL < 50 in 90% Undiagnosed HIV Not linked to care Not retained in care ART not required ART not utilized Viremic on ART Undetectable HIV-1 RNA

14.  Phase 3, double-blind, randomized, placebo-controlled, 11 sites in 6 countries  Adult HIV-MSM or transgender women in the US, Peru, Ecuador, Brazil, Thailand, South Africa  Two study arms:  TDF/FTC (300mg/200mg) orally once daily  Placebo  Primary Outcome: Prevention of HIV Grant RM, Lama JR, Anderson PL, et al. N Engl J Med 2010;363:2587-2

15. Inclusion Criteria  Male sex at birth  Age 18+  HIV-seronegative  High risk for HIV acquisition  Lab inclusion criteria:  CBC, BMP, LFTs Exclusion Criteria  Serious and active illness:  Diabetes, TB, Cancer  Active substance abuse  Nephrotoxic agents  Pathological bone fractures Grant RM, Lama JR, Anderson PL, et al.N Engl J Med 2010;363:2587-2

16. 44% reduction, P=0.002 95% CI (15-63%) Grant RM, Lama JR, Anderson PL, et al. N Engl J Med 2010;363:2587-2

18.  TDF/FTC was well tolerated  Nausea (2% versus 5% (2% versus 1%) were more common among those taking medication than those on placebo  No differences in severe (grade 3) or life-threatening (grade 4) laboratory abnormalities were observed between groups  No drug resistant virus was found in the 100 participants infected afterenrollment Grant RM, Lama JR, Anderson PL, et al. N Engl J Med 2010;363:2587-2

19. GroupDrug DetectionHIV InfectionsIncidence Density PlaceboNo643.86 FTC/TDFNo Yes 33 3 4.04 0.35 Relative Rate Reduction by use of FTC/TDF 91% Grant RM, Lama JR, Anderson PL, et al.N Engl J Med 2010;363:2587-2

20. iPrEX OLE: 100% Adherence With Daily PrEP Not Required to Attain Full Benefit  TFV-DP: tenofovir diphosphate (measurable tenofovir in dried blood spots) Grant R, et al. AIDS 2014. Abstract TUAC0105LB. Graphic used with permission. HIV Incidence and Drug Concentrations 5 4 3 2 1 0 150012501000700500 350LLOQ0 Off PrEP On PrEP TFV-DP in fmol/punch 7 Tablets/Wk4-6 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 21 100 12 100 86 to 100 (combined) 12 84 21 to 99

21.  4758 HIV-1 serodiscordant heterosexual couples in Kenya and Uganda  Three study arms:  TDF (300 mg) orally once daily  TDF/FTC (300mg/200mg) orally once daily  Placebo  Primary Outcome: Prevention of HIV-1 infection in HIV- negative partner Baeten JM, Donnell D, Ndase P et al. N Engl J Med 2012;367:399-410

23. 67% efficacy TDF 75% efficacy TDF-FTC

24. Baeten JM, Donnell D, Ndase P et al. N Engl J Med 2012;367:399-410

25.  1219 HIV-uninfected adults  Randomized to  TDF-FTC  Placebo Thigpen MC, Kebaabetswe PM, Paxton LA, et al. New Engl J Med 2012; 367(5): 423-434

27.  Phase 3, randomized, double-blind, placebo-controlled trial  2120 women from Tanzania, Kenya, and South Africa  Two study arms:  TDF/FTC (300mg/200mg) orally once daily  Placebo  Primary Outcome: Prevention of HIV-1 infection  NO EFFICACY WAS OBSERVED  Lack of difference driven by poor adherence to study drug Damme LV, Corneli A, Ahmed K, et al. New Engl J Med 2012; 367(5): 411-422

28.  Randomly selected 150 participants from 3 study sites to determine drug adherence at 4 week intervals  Plasma tenofovir level  Intracellular tenofovir-diphosphate  Assigned an adherence composite score Corneli AL, Deese J, Wang M, et al. J AIDS 2014;66(3):324-331

30. Phase IIB placebo-controlled trial of > 5000 women in South Africa, Uganda, and Zimbabwe of daily oral TDF, daily oral TDF/FTC, daily vaginal TFV 1% gel as PrEP DSMB stopped daily oral TDF arm in September 2011 and daily vaginal gel arm in November 2011, both for lack of efficacy; daily oral TDF/FTC arm continued 334 infections seen across 5 arms; 22 infected at enrollment Primary Efficacy Results (mITT) TDF* (n = 1007) Oral Placebo* TDF/FTC (n = 1003) Oral Placebo TFV Gel (n = 1007) Gel Placebo Infections, n523561606170 Infections/100 PY6.34.24.74.65.96.8 Protective Efficacy vs Placebo HR (95% CI)1.49 (0.97-2.30)1.04 (0.7-1.5)0.85 (0.6-1.2) P value.07>.2 *Censored when sites took women off TDF and TDF placebo. N = 1009. Marrazzo J, et al. CROI 2013. Abstract 26LB.

31.  Despite high self-reported adherence, < 40% of women had detectable plasma TFV at first study visit  TFV detected in mean of ≤ 30% of samples in each arm – ≥ 50% of women in each arm had no TFV detected in any sample  TFV detection less likely if unmarried, younger than 25 yrs, partner younger than 28 yrs – Highest rates of HIV acquisition in unmarried, younger than 25 yrs Marrazzo J, et al. CROI 2013. Abstract 26LB. Graphic used with permission. Pts With Detectable TFV* (%) 100 80 60 40 20 123456 TDF/FTC TDF TFV 1% gel n = n = n = 0 123 119 156 111 80 107 117 56 82 95 28 52 61 16 30 Quarterly Visits Plasma TFV Detection in Random Cohort Sample *Level of TFV detection: ≥ 0.3 ng/mL. 135 147 166

32.  Phase III, randomized, double-blind, placebo-controlled trial – HIV-uninfected IDUs (N = 2413) received TDF or placebo – DOT at drug treatment clinics between 2005 and 2010  Significantly fewer new infections with TDF vs placebo (0.35/100 PY vs 0.68/100 PY; P =.01) – Overall efficacy: 49% – Detectable TDF at study end: 74%  Higher adherence associated with greater efficacy  Safety and tolerability similar to other TDF-containing PrEP trials Choopanya K, et al. IAS 2013. Abstract WELBC05.

33. Choopanya K, et al. IAS 2013. Abstract WELBC05. Graphic used with permission. 100 80 60 40 20 0 Efficacy (%) mITT > 67 > 75 > 90 > 95 > 97.5 Adherence (%) 49 54 58 68 72 84

34. Study NamePopulationNResults Partners PrEPHeterosexual couples 4,758TDF: 67% efficacy FTC/TDF: 75% efficacy TDF2 StudyHeterosexual Men and Women 1,219FTC/TDF: 62% efficacy iPrExMSM2,499FTC/TDF: 44% efficacy FEM-PrEPWomen1,951FTC/TDF: futility VOICEWomen5,029TDF, TDF/FTC, Vaginal TFV gel: futility Thai IVDUIVDU2,413TDF: 49% efficacy Kahle E, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAC0102

35. June 2013 CDC Interim Guidance: PrEP for IDU November 2010 iPrEx January 2011 CDC Interim Guidance: PrEP for MSM August 2012 TDF2 Partners PrEP August 2012 CDC Interim Guidance: PrEP for heterosexuals July 2012 FEM-PrEP June 2013 Bangkok TDF Study July 2012 FDA Approval TDF/FTC PrEP January 2014 NYS AIDS Institute Guidance for PrEP March 2013 VOICE May 2014 US Public Health Service Clinical Practice Guideline for PrEP Slide courtesy of Katherine Marx, MS, MPH, FNP, NYNJ AETC

36.  PrEP should not be offered as a sole intervention and should include counseling and education about:  Consistent and correct condom use  Safer-sex practices and risk-reduction counseling  Intravenous drug use (IVD), harm reduction methods  Adherence to PrEP  Importance of frequent HIV testing and screening of STIs that can facilitate HIV transmission  For sero-discordant couples, the importance of suppressive ART for HIV-infected partners http://www.hivguidelines.org/clinical-guidelines/pre-exposure-prophylaxis/guidance-for-the-use-of-pre- exposure-prophylaxis-prep-to-prevent-hiv-transmission/

37.  PrEP is indicated for individuals who have a documented negative HIV test and are at ongoing, high risk for HIV infection  Negative, HIV test result needs to be confirmed as close to initiation of PrEP as possible  PrEP is not meant to be used as a lifelong intervention, but rather as a method of increasing prevention during “high risk” periods http://www.hivguidelines.org/clinical-guidelines/pre-exposure-prophylaxis/guidance-for-the-use-of-pre- exposure-prophylaxis-prep-to-prevent-hiv-transmission/

38. MSM who engage in unprotected anal intercourse 1,2 Stimulant drug use, especially methamphetamine 4 Individuals in a sero-discordant sexual relationship, especially during attempts to conceive Individuals with ≥ 1 ano-genital STI per year 5 Transgendered individualsIndividuals who have been prescribed nPEP with continued high-risk behavior or multiple courses 6 IDUs, including injecting hormones 3 Individuals engaging in transactional sex 1. Smith DK, et al. Development of a clinical screening index predictive of incident HIV infection among men who have sex with men in the United States. J Acquir Immune Defic Syndr 2012;60:421-427. 2. Grov C, et al. HIV risk in group sexual encounters: An event-level analysis from a national online survey of MSM in the U.S. J Sex Med 2013;10:2285-2294 3. Choopanya K, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand. 4. Zule WA, et al. Methamphetamine use and risky sexual behaviors during heterosexual encounters. Sex Transm Dis2007;34:689-694 5. Menza TW, et al. Prediction of HIV acquisition among men who have sex with men. Sex Transm Dis 2009;36:547-555. 6. Heuker J, et al. High HIV incidence among MSM prescribed postexposure prophylaxis, 2000-2009: Indications for ongoing sexual risk behaviour. AIDS 2012;26:505-512.

39.  Documented HIV infection  CrCl<60 mL/min  Lack of readiness to adhere to daily regimen  NOTE: lack of condom use is NOT a contraindication to PrEP http://www.hivguidelines.org/clinical-guidelines/pre-exposure-prophylaxis/guidance-for-the-use- of-pre-exposure-prophylaxis-prep-to-prevent-hiv-transmission/

40.  Symptoms of Acute HIV Infection  Febrile, “flu”, or “mono”-like illness in last 6 weeks  Medication List  Substance Use and Mental Health Screening  Knowledge about PrEP  Patient understanding and misconceptions  Health Literacy  Readiness and Willingness to adhere to PrEP  Primary Care  Does the patient have a PCP?  Partner Information  Determine status of partners  Domestic Violence Screening  Housing Status  Means to Pay for PrEP  Is patient insured?  Reproductive Plans (for Women) http://www.hivguidelines.org/clinical-guidelines/pre-exposure-prophylaxis/guidance-for-the-use- of-pre-exposure-prophylaxis-prep-to-prevent-hiv-transmission/

41. HIV Test Obtain 3 rd or 4 th generation HIV test Perform viral load test for HIV for: Patient with sxs of AHI or whose HIV AB is negative but reports unprotected sex in last month Basic Metabolic Panel Do not start PrEP if CrCl <60 mL/min Urinalysis Identify pre-existing proteinuria Serology for Hep A, B and C (Immunize for A and B if not immune) Screen for sexually transmitted infections, GC and chlamydia (genital, rectal, pharyngeal) RPR for syphilis Consider vaccinations for HPV and meningococcus, if indicated Pregnancy Test http://www.hivguidelines.org/clinical-guidelines/pre-exposure-prophylaxis/guidance- for-the-use-of-pre-exposure-prophylaxis-prep-to-prevent-hiv-transmission/

42. The first prescription of TDF/FTC should only be for 30 days At the 30 day visit (after assessing adherence, tolerance and commitment), a prescription for 60 days may be given Creatinine and CrCl for patients with borderline renal function or at increased risk for kidney disease (>65 years of age, black race, HTN or DM) After 3 month visit, prescriptions can be given for 90 days provided that patient is adherent Patient should then return for 3-month visits for HIV testing and other assessments: http://www.hivguidelines.org/clinical-guidelines/pre-exposure-prophylaxis/guidance-for-the-use-of-pre- exposure-prophylaxis-prep-to-prevent-hiv-transmission/

43. Tellalian et al. AIDS Patient Care and STDs. October 2013, 27(10): 553-559.

44.  Survey of ID physicians (n=573)  74% supported PrEP  9% have actually prescribed PrEP  14% would not provide PrEP Karris et al. (2014). Clin Infec Dis 58(5): 704-12.

45.  One survey (n=86, 56% male, 70% heterosexual) showed that a majority (94%) of participants were willing to use PrEP  In a survey of men visiting an online gay social networking site (n=9,179) 1.2% reported using PrEP Tripathi, et al. (2013). Southen Med J Oct;106(10):558-64 Mayer, et al. (2014). Early Adopters: Correlates of chemoprophylaxis use in an online sample of US Men who have sex with Men. CROI 2014 Abstrat 952

46.  Most insurances paying for PrEP including Medicaid HMOs  Prior authorizations  Truvada® for PrEP Medication Assistance Program  200% federal poverty threshold  ICD09 codes  V69.2 High risk sexual behavior  V01.79 Exposure to other viral diseases  CPT codes  99401-99404 (Preventive Counseling 15/30/45/60 mins)

47.  Targeting high risk populations  Partners of known HIV-infected persons  Includes pregnant women  MSM and TG women as per NYS DOH guidelines  IVDs  Other  Discuss a case and possible referral?  Elliot DeHaan, MD (718) 270-2471  Elliot.dehaan@downstate.edu

48.  PrEP as daily fixed-dose tenofovir-emtricitabine has a strong evidence basis in multiple populations of individuals at high- risk for HIV-infection (heterosexual, MSM, IVDs)  Needs to be prescribed as part of a comprehensive prevention plan that includes use of condoms, harm reduction for IVDs  Strong consideration should be given to its use in populations as defined by NYS DOH and the CDC  Both providers and patients are open to the idea of its use  Insurance plans are covering the cost of drug, though prior authorization may be necessary