1. The Role of Pre-Exposure Prophylaxis (PrEP) for the Prevention of HIV Sarah Kemink, PharmD, AAHIVP WMSHP Spring Seminar 5/05/2015

2. HIV

3. AIDS CD4 less than 200 +/- AIDS-defining illness – Most common: Candidiasis of esophagus, bronchi, trachea, or lungs Pneumocystis jiroveci pneumonia Cytomegalovirus Mycobacterium avium Mycobacterium tuberculosis Toxoplasmosis

4. Brief History of HIV Late 1970’s – 1996 – Fear, death, misinformation, outrage, civil disobedience – Focus on hospice care/treating opportunistic infections 1996 – present – Combination treatment for HIV – Disease became chronic, manageable disease – Focus on compliance and managing adverse effects

5. Global HIV Infection More than 34 million people worldwide living with HIV Annual AIDS-related mortality – Decreased from peak of 2.2 million in mid-2000s to 1.7 million in 2011 – Estimated 2.5 million deaths averted since 1995 due to ART Only 8 million people with ART coverage UNAIDS. World AIDS Day Report. 2011.

6. Global HIV Trends UNAIDS. World AIDS Day Report. 2011.

7. Rates of New Infections Decreasing – Sub-Saharan Africa, Asia, Oceania Increasing – Eastern Europe, Central Asia, Middle East, North Africa Stable – Latin America, North America, Western and Central Europe UNAIDS. World AIDS Day Report. 2011.

8. Transmission Unprotected sex between men who have sex with men (MSM) Unprotected transactional sex in commercial sex workers (CSW) Sharing of contaminated needle-injecting equipment UNAIDS. World AIDS Day Report. 2011.

9. HIV in the United States Approximately 1.2 million people with HIV/AIDS – Estimated 1 in 6 are undiagnosed – Approximately 50,000 new infections yearly New HIV infections – MSM account for ~60% of new cases of HIV in US – Heterosexuals account for ~18% of all new HIV infections but >80% of new cases in women CDC. HIV Surveillance Supplemental Report. 2014.

10. New HIV Infections CDC. HIV Surveillance Supplemental Report. 2014.

11. Rates of New Infection Stable incidence Increasing among specific communities – African Americans – Hispanics and Latinos – MSM – Injection drug users (IDUs) CDC. HIV Surveillance Supplemental Report. 2014.

12. HIV Transmission Risk Blood Transfusion (9,250) Receptive Anal Sex (138) Needle-sharing During IV Drug Use (63) Needle Stick (23) Insertive Anal Intercourse (11) Receptive Penile-Vaginal Intercourse (8) Insertive Penile-Vaginal Intercourse (4) Receptive Oral Intercourse (low) Insertive Oral Intercourse (low) Biting/Spitting (negligible) Risk per 10,000 Exposures CDC. Transmission Risk – HIV Policies and the Law. 2014.

13. HIV Prevention

14. Behavioral Interventions Education/Counseling Screening for Behavioral Risk Factors – Number/sex of partners – HIV status of partners – Types of sexual activities – Barriers to abstinence Condom use Male Circumcision Screening and Treatment of STI’s

15. Treatment as Prevention HTPN 052 Cohen, et al. NEJM 2011; 365: 492-505

16. Perinatal Prophylaxis Use of ART to prevent HIV transmission from mother-to-child Incidence reduced by 40% – 570,000 in 2003 – 330,000 in 2011 UNAIDS. World AIDS Day Report. 2011.

17. Post Exposure Prophylaxis (PEP) Use of ART after exposure – accidental needlestick – sexual assault Not as effective as prevention of HIV transmission by avoiding exposures Less likely to be effective if initiated >72 hours after exposure Not likely to benefit persons with frequent, repeated exposures Kuhar, et al. Inf Control 2013; 34(9): 875-92

18. Pre-Exposure Prophylaxis (PrEP) Temporary Prevention of HIV during periods of high-risk behaviors Limit infected cells below a theoretical threshold under which infection cannot be established Block viral replication to allow host responses to clear infection CDC. PrEP Guidelines. 2014.

19. Ideal PrEP Medication High potency against HIV Simple dosing schedule Low rates of adverse events Low frequency of drug-induced resistance High genital and rectal tissue concentrations Active in resting CD4 cells and during pre- integration phase Derdelinckxl, et al. PLoS Med. 2006; 3(11): e454

20. PrEP Options Tenofovir (Viread) – Available as oral tablet or 1% vaginal gel Tenofovir disoproxil fumarate(TDF)/ Emtricitabine (ETV) (Truvada) – Available as oral tablet CDC. PrEP Guidelines. 2014.

21. TDF/FTC (Truvada) Nucleotide/nucleoside reverse transcriptase inhibitors (NRTI’s) Long intracellular half-lives High genital tissue concentrations Active in both active and resting CD4 cells Few drug interactions Both components active against Hepatitis B Truvada® [package insert]. Foster City, CA; Gilead Sciences, Inc; 2013

22. TDF/FTC (Truvada) Common adverse events: – GI, tiredness, headache – Typically short-term and mild Rare adverse events: – Lactic acidosis – rare case reports – Renal dysfunction Acute risk = 1 – 4% – Decrease bone mineral density 3-4% decline Truvada® [package insert]. Foster City, CA; Gilead Sciences, Inc; 2013

23. TDF/FTC Resistance FTC resistance – M184V – Rapidly selected (within 15 days) TDF resistance – K65R – May take up to 28 days – Less likely if taking TDF/FTC Hurt, et al. Clin Inf Dis 2011; 53(12): 1265-70

24. Comparative effectiveness of current HIV prevention strategies Karim, et al. Lancet 2011; 378: e23-5

25. FEM-PrEP 2,120 women in Africa Trial stopped early for futility Compliance – Self-reported adherence: 95% – Pill counts: 88% – Drug level testing: drug detected in < 40% participants – High pregnancy rates in women on oral contraceptives Patient motivation is crucial! – 70% perceived themselves to be at no or low risk for HIV infection Van Damme, et al. NEJM 2012; 367(5): 411-22

26. TDF2 1,219 heterosexual participants in Africa 62% overall efficacy – 49% in females, 80% in males Compliance – Self-reported: 84% – Significantly lower serum drug levels in infected participants vs. noninfected Thigpen, et al. NEJM 2012; 367(5): 423-34

27. Partners PrEP 4758 heterosexual HIV serodiscordant couples in Africa 66% efficacy in women, 84% efficacy in men Compliance – Pill counts: 97% – Drug level testing: Infected participants: <30% had detectable levels of TDF/FTC Uninfected participants: >80 % had detectable levels of TDF/FTC Baeten, et al. NEJM 2012; 367(5): 399-410

28. iPrEx 2,499 MSM, transgender women in 11 sites (US, South America, Africa, Thailand) 44% reduction in HIV Infection Rate Compliance – Pill use > 50% = risk reduction by 50% – Pill use > 90 % = risk reduction by 73% Case control study – 92% reduction with detectable levels of TDF Grant, et al. NEJM 2010; 363(27): 2587-99

29. iPrEx OLE Grant, et al. Lancet Inf Dis 2014; 14: 820-29

30. CDC PrEP Guidelines - 2014 CDC. PrEP Guidelines. 2014.

31. PrEP Eligibility HIV NEGATIVE patients – Serodiscordant couples – High Risk MSM – High Risk Heterosexual Men/Women – High Risk Injection Drug Users (IDU) CDC. PrEP Guidelines. 2014.

32. Risk Determination CDC. PrEP Guidelines. 2014.

33. Pre-Treatment Testing HIV negative test result Rule out acute HIV infection Normal renal function (serum creatinine) Documented Hepatitis B infection or vaccination status Bacterial STI testing – Gonorrhea – Chlamydia – Syphillis CDC. PrEP Guidelines. 2014.

34. HIV Testing Western Blot – No longer recommended 2 nd /3 rd Generation Antibody – May miss acute HIV infection HIV RNA (Viral Load) – Not covered by many insurance plans unless HIV antibody positive 4 th Generation Antigen/Antibody Testing (p24 Antigen) – Recommended per updated CDC guidelines in 2014 – Not widely available CDC. PrEP Guidelines. 2014.

35. Action for Aids. 2014.

36. CDC. PrEP Guidelines. 2014.

37. Prescribing PrEP TDF/FTC (Truvada) – One tablet daily – 90 day prescription only – Renew every 3 months ONLY after negative HIV test + compliance assessment CDC. PrEP Guidelines. 2014.

38. Patient Counseling/Education Sexual risk reduction counseling Medication education Adherence counseling Provide condoms CDC. PrEP Guidelines. 2014.

39. Baseline Compliance

40. Follow-up and Monitoring Every 3 months: – HIV Test – Adherence Counseling – Behavioral Risk Reduction Support – Adverse Event Assessment – STI Symptom Assessment – Pregnancy Test (if appropriate) CDC. PrEP Guidelines. 2014.

41. Ongoing Compliance Every 3 months – Evaluate current medication list for interactions – Ongoing compliance assessment

42. Ongoing Compliance

43. Follow-up and Monitoring Every 6 months: – Assess Renal Function Metabolic panel Urinalysis – Test for Bacterial STI’s CDC. PrEP Guidelines. 2014.

44. PrEP Barriers Patient Stigma Patient Motivation Lack of Access/Cost of Treatment – Insured/Uninsured – Copay/Deductible Cost

45. Stigma Primarily within/among/against the gay community PrEP is only for people who are promiscuous – PrEP will lead to increased risky behaviors such as decreased condom use

46. Condom Use and PrEP 70 - 80% efficacy in preventing HIV CDC study in 2013 showed declining condom use among gay men prior to PrEP (48% in 2005, 57% in 2011) iPrEx – No change in condom use if patients thought they were on placebo vs. treatment Both iPrEx and Partners PrEP found DECREASING risk behavior over time CDC. MMWR 2013; 62(47): 958-62 Grant, et al. NEJM 2010; 363(27): 2587-99 Baeten, et al. NEJM 2012; 367(5): 399-410

47. PrEP Barriers Patient Stigma Patient Motivation Lack of Access/Cost of Treatment – Insured/Uninsured – Copay/Deductible Cost

48. Patient Motivation Unwillingness to take pill daily Fear of side effects Lack of perceived risk – False belief that HIV is an older generation’s issue – Avoiding sexual partners with known HIV

49. PrEP Barriers Patient Stigma Patient Motivation Lack of Access/Cost of Treatment – Insured/Uninsured – Copay/Deductible Cost

50. PrEP Cost Manufacturer patient assistance program – Uninsured patients High copay cost: – Manufacturer copay card available – Covers up to $300/month for Truvada High deductible – Patient Access Network – Will cover $4,000/year for eligible patients (500% federal poverty level)

51. Important Points Reserved for high-risk individuals – Serodiscordant couples, IDU, high-risk sexual behavior Adherence is crucial for prevention Significant barriers to treatment – Need for increased education for providers and high-risk patients

53. On Demand PrEP ANRS IperGay: – 2 tablets 2 - 24 hours prior to sex – 1 tablet 24 hours after sex – 1 tablet 48 hours after initial dose – 86% reduction in HIV – Median of 16 tablets taken per month Molina, et al. CROI 2015. Abstract 23LB.

54. Pipeline Medications TAF – Tenofovir alafenamide fumarate – Prodrug of tenofovir – Less serum drug exposure – Can be dosed at 1/10 th dose of TDF – Decreased renal/bone long term side effects – Low levels in genital tissues Horn, et al. HIV Preventative Technologies 2014; 55-82

55. Pipeline Medications Oral – Maraviroc (monotherapy or combination) (phase II) Long-Acting Injectables – Cabotegravir (phase II) – Rilpivirine LA (phase II) Vaginal Rings – Dapivirine vaginal ring (phase III) Horn, et al. HIV Preventative Technologies 2014; 55-82

56. UNAIDS “Getting to Zero” Goals for HIV Prevention Sexual transmission of HIV reduced by half, including among young people, men who have sex with men and transmission in the context of sex work Vertical transmission of HIV eliminated and AIDS-related maternal mortality reduced by half All new HIV infections prevented among people who use drugs UNAIDS. Getting to Zero: 2011-2015 Strategy.

57. Questions?

58. Question 1 Which of the following patients would be candidates for PrEP? – 27 year old MSM with ongoing high risk sexual behavior of unprotected anal sex – 30 year old nurse working in an HIV clinic who administers vaccines and other injections to HIV sero- positive patients – 35 year old HIV sero-negative man in a monogamous relationship with his sero-positive husband (husband has undetectable HIV viral load) – A and C – All of the above

59. Question 2 Which of the following laboratory tests are recommended prior to initiating PrEP with TDF/FTC (Truvada)? – Baseline third or fourth generation HIV test – Serum Creatinine – Serology for Hepatitis B and C – STI screening – All of the above

60. Question 3 Which of the following are barriers to starting PrEP therapy? – Treatment coverage/cost – Stigma – Patient motivation – All of the above