1. HIV Prevention Nate Summers, MD March 30, 2016

2. Case: A 47 yoAAM presents to your clinic… No active symptoms, negative ROS PMH: HTN PSH: Appendectomy in his teens FHx: Noncontributory Home Meds: Amlodipine Allergies: NKDA

3. Case, continued: Social: Works in finance Does not smoke, drink, or use illicit drugs MSM; has had 3 partners in the 6 months Uses condoms intermittently No recent STI, but has had gonorrhea years ago He asks to be screened for HIV, and wants to discuss ways to reduce his risk for contracting HIV

4. Objectives Review some of the basics of HIV Discuss various methods of HIV prevention Explore future areas of research

5. HIV Life Cycle

6. Methods of Transmission HIV is only present in blood, semen, pre-seminal fluid, vaginal fluids, rectal fluids, and breast milk HIV can live up to 42 days on a used needle HIV transmission via needle stick injuries (in which the patient has HIV) occurs <1% of the time HIV transmission during pregnancy occurs approx. 2% of the time http://www.cdc.gov/hiv

7. Risk Factors for HIV Infection http://www.cdc.gov/hiv

8. Risk Factors for HIV Infection Increased Risk: Having an ulcerative STI (RR of 2.65) The partner with HIV having an ulcerative STI (RR of 2.58) The partner with HIV being in the acute phase of the infection (RR of 7.25) http://www.cdc.gov/hiv

9. Methods of HIV Prevention Treatment as Prevention Condom Use PrEP Others

10. HIV Care Continuum Infection Diagnosis Retention in medical care Prescription of ART Virologic suppression

11. Treatment as Prevention Treatment Cascade:

12. Randomized controlled trial across nine countries including 1,763 serodiscordant couples Evaluated early therapy (at time of randomization) vs. delayed therapy (at time of two consecutive CD4 counts < 250 or AIDS defining illness) Found a 96% reduction in risk for transmission with early therapy NEJM. 2011;365(6):493-505

13. Treatment as Prevention Prevention of HIV-1 Infection with Early Antiretroviral Therapy. Cohen, et al. NEJM. 2011;365(6):493-505. Tested the non-infected partner every three months for conversion If the non-infected partner became infected, they sequenced the HIV-1 pol gene and assessed the probability of linkage

14. Treatment as Prevention Prevention of HIV-1 Infection with Early Antiretroviral Therapy. Cohen, et al. NEJM. 2011;365(6):493-505.

15. Treatment as Prevention Prevention of HIV-1 Infection with Early Antiretroviral Therapy. Cohen, et al. NEJM. 2011;365(6):493-505.

16. Treatment as Prevention Of the 28 HIV-1 infected participants who had a linked transmission to a partner, 61% had a CD4 count of >350 There was a 96% relative reduction in the number of linked HIV-1 transmissions resulting from the early initiation of ART (89% regardless of viral linkage) Also saw a relative reduction of 41% in the number of HIV-1 related clinical events in the early treatment group Prevention of HIV-1 Infection with Early Antiretroviral Therapy. Cohen, et al. NEJM. 2011;365(6):493-505.

17. International, randomized, controlled trial Stable, healthy, sexually active, HIV-discordant couples with 350-550 CD4+ cells/mm 3 (N = 1763 couples) Early ART Arm Initiate ART immediately (n = 886 couples) Delayed ART Arm Initiate ART at CD4+ cell count ≤ 250 cells/mm 3 or at development of AIDS-defining illness (n = 877 couples)  Participants informed of interim results beginning May 2011; ART offered to all index participants in delayed ART arm; study continued until May 2015 to determine durability of HIV transmission prevention  84% of pts in delayed ART arm had initiated ART at year 1; 98% of pts had initiated ART prior to study closure Cohen MS, et al. IAS 2015. Abstract MOAC0101LB. Slide courtesy of Dr. Barbara Gripshover Treatment as Prevention

18. 8 linked HIV infections diagnosed after seropositive pt started ART 4 infections likely occurred before, or soon after, ART initiation, and 4 infections occurred after ART failure in seropositive pt Unlinked partner infection rates similar between study arms No linked HIV transmissions were observed when index participant stably suppressed on ART! Cohen MS, et al. IAS 2015. Abstract MOAC0101LB. Slide courtesy of Dr. Barbara Gripshover. April 2005 - May 2011May 2011 - May 2015 Overall (April 2005 - May 2015) Partner Infections, n (rate/100 PY) Early (1751 PY F/U) Delayed (1731 PY F/U) Early (2563 PY F/U) Delayed (2449 PY F/U) Early (4314 PY F/U) Delayed (4180 PY F/U) All4 (0.23)42 (2.43)15 (0.59)17 (0.69)19 (0.44)59 (1.41) Linked1 (0.06)36 (2.08)2 (0.08)7 (0.29)3 (0.07)43 (1.03) Risk Reduction With Early ART, % All infections91--14--69-- Linked infections 97--72--93-- Treatment as Prevention

19. Used data from 2009, combining data from the National HIV Surveillance System, National HIV Behavior Surveillance System, and the Medical Monitoring Project to create a computer model to estimate the rate and number of HIV transmissions at each of the five steps in the HIV care continuum Used data from previous study (and others) for the computer model Illustrated the effect each sequential step along the HIV care continuum would have on HIV transmission rates JAMA Intern Med. 2015;175(4):588-596

20. HIV Transmission at Each Step in the Care Continuum in the US. JAMA Intern Med. 2015;175(4):588-596

23. Limitations include the fact that this was a computer model and not a controlled trial Illustrated the importance of moving along the care continuum to decrease transmission HIV Transmission at Each Step in the Care Continuum in the US. JAMA Intern Med. 2015;175(4):588-596 Treatment as Prevention

24. Condom Use http://www.cdc.gov/hiv

25. PrEP: Pre-Exposure Prophylaxis General idea is to give one or two drug combinations to HIV negative patients at risk of contracting HIV to prevent transmission Requires very high engagement HIV testing every three months Frequent office visits Most beneficial in very high risk populations Wait, what?

26. The Day the (flat?) Earth Stood Still… January 25, 2016: Atlanta native, rapper B.o.B takes to twitter, claiming that we have all been misled and that the Earth is indeed flat “A lot of people are turned off by the phrase "flat earth"... but there's no way u can see all the evidence and not know... grow up” http://www.twitter.com

27. What Can We Learn from This? “Just ‘cause you feel it, doesn’t mean it’s there.” Thom Yorke In other words, we should be careful not to let our faulty assumptions stand in the way of evidence, just as rapper B.o.B did with his flat Earth comments

28. Multinational randomized controlled double blinded trial aimed to evaluate the safety & efficacy of once daily Truvada (FTC-TDF) vs. placebo for the prevention of HIV acquisition in MSM 2499 subjects were enrolled from 11 sites in 6 countries NEJM 2010;363:2587-99.

29. Preexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex with Men. NEJM 2010;363:2587-99. Once daily FTC-TDF (Truvada) provided 44% additional protection from HIV among MSM Among those with a detectable serum drug level, the relative reduction in HIV risk was 92%, highlighting the importance of adherence Of those who contracted HIV while on FTC-TDF, no resistance was detected except in those who had acute infection at the time of enrollment PrEP

30. NEJM 2012;367:399-410. Randomized controlled double-blinded, three group trial comparing TDF, TDF- FTC, and placebo in the prevention of HIV acquisition among heterosexual serodiscordant couples in Kenya and Uganda 4758 couples were enrolled

31. Antiretrviral Prophylaxis for HIV Prevention in Heterosexual Men and Women. NEJM 2012;367:399-410. PrEP Once daily TDF and TDF-FTC were associated with risk reductions of 67% and 75%, respectively. These findings were similar in both men and women. Only 31% of those who contracted HIV had detectable drug levels, compared to 82% of randomly selected subjects who remained HIV negative. Resistance was only seen in those who were acutely infected at the time of initiation of PrEP, not in those infected while taking PrEP.

33. PrEP Limitations

34. These two studies found no significant reduction in risk for HIV acquisition using PrEP, but were limited by very low adherence rates This begs the question, will PrEP work outside of clinical trials?

35. Open label randomized trial enrolling HIV negative MSM who had had anal intercourse without a condom in the previous 90 days in England Intervention was daily TDF-FTC (Truvada) immediately or after a 1 year deferral period Lancet. 2016 Jan 2;387(10013):53-60.

36. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection. Lancet. 2016 Jan 2;387(10013):53-60. PrEP In Action Enrolled 544 participants (275 in the immediate group, 269 in the deferred group) Midway through the trial, the steering committee recommended all deferred participants be offered PrEP based on early results on effectiveness

37. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection. Lancet. 2016 Jan 2;387(10013):53-60. PrEP In Action HIV incidence in the immediate group was 1.2 cases per 100 person-years as opposed to 9.0 cases per 100 person-years in the deferred group, giving an 86% risk reduction 13 men in a similar population would need access to PrEP for 1 year to avert 1 HIV infection The only cases of resistance were again in those who had acute HIV infection at time of enrollment; none were seen with later infections.

38. Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection. Lancet. 2016 Jan 2;387(10013):53-60. Applicability of This Study Being open label allowed us to see if there were any indirect effects on behavior on patients who knew they were taking PrEP No significant difference between the two groups in rates of other STIs, including rectal gonorrhea or chlamydia Broad eligibility criteria

39. PrEP in Action San Francisco has implemented a city-wide initiative to reduce HIV transmission, focusing on three key concepts: Zero Infections Zero Deaths Zero Stigma They are doing this primarily through three efforts: PrEP expansion Rapid ART Program for HIV Diagnoses Retention in care http://www.gettingtozerosf.org

40. PrEP in Action Ongoing PrEP demonstration study to evaluate PrEP use and efficacy in real-world use Aims to answer Will people want PrEP? How will people use PrEP? How will sexual practices change for those taking PrEP? Where should PrEP be delivered? Will PrEP be safe in the real world? http://www.gettingtozerosf.org

41. PrEP in Summary Generally well tolerated (GI distress, AKI) Very efficacious if taken as prescribed (upwards of 90% risk reduction) Does not lead to increased resistance except in patients in the acute phase of infection during initiation

42. Who to Consider for PrEP For sexual transmission: Anyone in an ongoing relationship with an HIV+ partner Anyone who is not in a mutually monogamous relationship and Gay or bisexual man who has had anal sex without a condom or been diagnosed with an STI in the past 6 months Heterosexual man/woman who does not regularly use condoms during sex with partners of unknown HIV status who are at substantial risk of HIV infection For people who inject drugs: Anyone who has injected illicit drugs in the past 6 months and who have shared injection equipment Anyone who has been in drug treatment for injection drug use in the past 6 months http://www.cdc.gov/hiv

43. How to initiate PrEP TDF-FTC (Truvada) is FDA approved for once daily use Negative HIV screen before starting PrEP and no signs/symptoms of acute HIV infection Normal GFR and documented HBV immune status http://www.cdc.gov/hiv

44. How to initiate PrEP http://www.cdc.gov/hiv

45. Others Methods of Prevention Circumcision (limited, observational studies suggest may decrease risk by 50% in heterosexual males 1, but many studies found no benefit, and this did not decrease risk for women or MSM 2 ) Serosorting (only having sex with others who match your HIV status; limited by partner honesty and partner’s knowledge of their status) may reduce risk of HIV acquisition by approx. 54% compared to condomless anal sex 3 3 http://www.cdc.gov/hiv 1 Siegfried Int J of Epi 2010 2 Wawer Lancet 2009

46. Future Areas of Research Vaccine Cure The Berlin Man Finding a reservoir

47. Summary Progression along the HIV care continuum toward viral suppression can greatly reduce transmission (96% reduction in risk of transmission with early treatment) Consistent condom use should be encouraged PrEP should be offered to at-risk populations, with the caveat that it is only useful if taken every day as prescribed

48. Acknowledgements Dr. Barbara Gripshover Dr. Marion Skalweit B.o.B Thom Yorke, Radiohead The Notorious B.I.G.