Pre-exposure Prophylaxis for HIV Prevention What’s New in Medicine Conference Joanne Stekler, MD MPH Associate Professor, UW Department of Medicine September 9, 2016

Disclosures and Disclaimers

Topics To Be Covered Efficacy, medication adherence, and side effects Sexual behavior and STIs in persons on PrEP Drug resistance and PrEP Implementing the guidelines: prescribing and monitoring Paying for PrEP and insurance billing

Key HIV PrEP Trials Using Oral Tenofovir (TDF) or Tenofovir-Emtricitabine (TDF-FTC) Study Study Population Study Randomization HIV Incidence Impact IPrEx (Brazil, Ecuador, South Africa, Thailand, US) 2499 MSM and transgender women Daily oral TDF-FTC or placebo TDF-FTC: 44%  Partners PrEP Study (Kenya, Uganda) 4147 heterosexual HIV discordant couples Daily oral TDF, TDF-FTC, or placebo TDF: 67%  TDF-FTC: 75%  TDF2 Study (Botswana) 1219 heterosexual men and women TDF-FTC: 63%  FEM-PrEP (Kenya, South Africa, Tanzania) 2120 women TDF-FTC: no protection VOICE (South Africa, Uganda, Zimbabwe) 5029 women Randomized to daily oral TDF, TDF-FTC, oral placebo, TDF vaginal gel, or gel placebo TDF: no protection TDF-FTC: no protection TDF gel: no protection Bangkok TDF Study (Thailand) 2413 injection drug users Randomized to daily oral TDF or placebo TDF: 49%  IPERGAY (France, Quebec) 400 MSM Randomized to “on-demand” TDF-FTC or placebo TDF-FTC: 86%  PROUD (United Kingdon) 545 MSM and transgender women Randomized to daily oral TDF-FTC immediately or delayed Immediate TDF-FTC: 86% 

The Relationship Between Adherence and Efficacy Efficacy in randomized comparison % of blood samples with tenofovir detected Partners PrEP 75% 81% TDF2 62% 79% Bangkok TDF 49% 67% iPrEx 44% 51% FEM-PrEP 6% 26% VOICE - 29% Baeten et al N Engl J Med 2012 Van Damme et al N Engl J Med 2012 Grant et al N Engl J Med 2010 Thigpen et al N Engl J Med 2012 Choopanya et al Lancet 2013 Marrazzo et al CROI 2013 #26LB

The Relationship Between Adherence and Efficacy Lessons from iPrEx Detectable Drug Levels in Patients on Tenofovir-Emtricitabine A. Intracellular Emtricitabine Levels B. Intracellular Tenofovir-DF Levels 9% 52% 6% 50% Adjusted RR reduction (any detectable level) = 95% Source: Grant RM, et al. N Engl J Med. 2010;363:2587-99.

Adherence and Efficacy in Open-label Projects iPrEx OLE (open label extension) Overall adherence 71% Estimated adherence (TDF in DBS) Incidence Not detected 4.7/100 person-years <2 tab/week 2.3/100 person-years 2-3 tab/week 0.6/100 person-years 4-7 tab/week 0/100 person-years Source: Grant et al, Lancet. 2014: 14; 819-829.

PrEP Side Effects and Safety In trials, nausea more common with TDF-FTC than placebo Nausea, headache, or fatigue may occur in first 2-4 weeks Generally resolves; OTC or PRN meds may help “Startup Syndrome” In trials, changes in renal function not more frequent with TDF-FTC than placebo, though follow-up limited Monitoring at least every 6 months recommended Renal Safety In trials, TDF-FTC associated with small change (~1%) in bone density, though generally stabilized or improved No increase in fractures seen Bone Effects Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Behavioral disinhibition Risk compensation could negate prevention benefits of PrEP. BUT Careful of our own morality/judgement (PrEP stigma) Important to remember: Birth control has not led to increased sexual risk. Needle exchange has not led to increased IDU. HPV vaccine has not led to earlier sexual debut. We prescribe lipid-lowering agents to reduce MI risk for people who continue to eat French fries.

PrEP and sexual behavior in RCTs In RCTs, condomless sex was less common over time. BUT subjects did not know if they were on PrEP or placebo. iPrEx Partners PrEP 50 40 30 Proportion of HIV – participants with any unprotected sex (%) 20 10 3 6 9 12 15 18 21 24 27 30 Follow-up time (Month) TDF FTC/TDF Placebo

PrEP and sexual behavior in the “real world”

Behavior change and STIs in the Demo Project (San Francisco, Miami, Washington D.C.) Liu et al. JAMA Intern Med. 2016;176(1):75-84

STIs among PrEP users and persons at risk for HIV Kaiser-Permanente, CA, 12-month cumulative % N=657 PROUD Study, UK 12 months prior to enrollment N=544 Volk et al. Clin Infect Dis 2015 McCormack et al. Lancet 2016

Syphilis in King County

Drug resistance in PrEP Trials Infected at Entry Incident Infection Study Drug Placebo Study Resist/Tot iPrEx 2/2 1/8 0/48 0/83 Partners PrEP 1/3 0/6 0/13 0/52 TDF2 1/1 0/2 0/9 0/24 FEM-PrEP 0/1 4/33 1/35 VOICE 2/9 1/61 0/60 Total % (95% CI) 6/16 37.5% (18 to 61%) 1/18 5% (1 to 26%) 5/164 3% (1 to 7%) 1/254 0.3% (.06 to 2%) 9 excess DR infections: 11 active, 2 placebo 92 infections averted by FTC/TDF PrEP = (254+18)-(164+16) 8 (92/9) infections averted per DR infection overall Excluding acute infections when PrEP was started: 22 (90/4) infections averted per DR infection. IAS: Grant, oral abstract TUAC0104

www.cdc.gov/hiv/pdf/prepguidelines2014.pdf Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Summary of Clinical Eligibility for HIV PrEP Considered to be at “substantial risk” of HIV infection Documented negative HIV test before prescribing PrEP No symptoms of acute HIV infection Normal renal function (>60 mL/min) Documented hepatitis B viral immune status Able to adhere to a daily medication Able to adhere to follow-up visits (at least every 3 months) Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Who Should Be Considered for PrEP Who Should Be Considered for PrEP? Individuals with “Substantial Risk” of Acquiring HIV Indications for PrEP use by men-who-have-sex-with-men (MSM) Adult man Without acute or established HIV infection Any male sex partners in past 6 months Not in a monogamous partnership with an HIV-negative man AND at least one of the following Any anal sex without condoms in past 6 months Any STI diagnosed or reported in past 6 months In an ongoing sexual relationship with an HIV-positive male partner Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Who Should Get PrEP? (Results from iPrEx) Buchbinder et al., Lancet ID 2014

Who Should Get PrEP? (Results from iPrEx) Buchbinder et al., Lancet ID 2014

Summary of Clinical Eligibility for HIV PrEP Considered to be at “substantial risk” of HIV infection Documented negative HIV test before prescribing PrEP No symptoms of acute HIV infection Normal renal function (>60 mL/min) Documented hepatitis B viral immune status Able to adhere to a daily medication Able to adhere to follow-up visits (at least every 3 months) Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Symptoms of acute HIV infection Approximately 50-90% of individuals have ≥1 symptoms ~2 weeks after Infection Fever Fatigue Sore throat Muscle/joint aches Night sweats Headaches Diarrhea Rash

Recommended HIV Screening Prior to PrEP Initiation At a minimum, document a negative screening test within 1 week before initiating (or reinitiating) PrEP (A) Blood (serum) lab-based testing, or (B) Rapid, point-of-care, fingerstick blood testing* If negative or indeterminate screening result in a patient with recent signs and symptoms of acute HIV (A) Repeat screening test in 1 month and defer PrEP decision, or (B) Send HIV RNA PCR (preferred) *Per the guidelines, oral rapid tests should not be used to screen for HIV infection when considering PrEP because they can be less sensitive than blood tests Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Sequence of test positivity relative to WB 166 specimens, 17 Seroconverters Architect Combo (-20) Bio-Rad Combo (-19) Determine Combo (-15) Reveal G3 (-6) COMPLETE HIV-1/2 (-5) GS 1/2+O (-12) HIV-1/2 STAT-PAK (-5) Vironostka (+) 2 APTIMA (-26) INSTI (-9) Multi-Spot (-7) OraQuick (-1) Unigold (-2) WB positive 25 20 15 10 5 Days before WB positive Modified from Masciotra et al, J Clin Virol 2011; Owen et al, J Clin Micro 2008 Slide courtesy of Bernie Branson

(starting PrEP during AHI → resistance) HIV testing in PrEP · When starting PrEP, use the test with shortest window period available. Do not use oral fluid tests. (starting PrEP during AHI → resistance) · Do not ask people to remain abstinent/use condom while waiting out the window period. · Screen for symptoms of AHI If symptoms and recent exposure → delay PrEP start *Almost all* symptomatic AHI will test pos on lab 4th gen But…. There is a 2nd window period…. · PrEP may lead to delayed seroconversion and false-negative tests, particularly with oral fluid tests.

Summary of Clinical Eligibility for HIV PrEP Considered to be at “substantial risk” of HIV infection Documented negative HIV test before prescribing PrEP No symptoms of acute HIV infection Normal renal function (>60 mL/min) Documented hepatitis B viral immune status Able to adhere to a daily medication Able to adhere to follow-up visits (at least every 3 months) Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Recommended Follow-Up Counseling and Services Recommended Follow-Up Counseling and Services for Patients Taking PrEP Follow-up services Every 3 months Adherence counseling ✔ Behavioral risk reduction support and condoms Assessment for side effects Assessment for STI symptoms and symptoms of acute HIV For women, discuss pregnancy intent and contraceptive options Access to clean needles/syringes and drug treatment services Provide a refill of daily TDF/FTC for no more than 90 days Abbreviations: STI = sexually transmitted infection; TDF/FTC = tenofovir/emtricitabine Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Monitoring Adherence to PrEP Lessons from iPrEx 510 subjects with plasma levels drawn at wk 24 Among subjects reporting 100% adherence 51% had any drug detected 35% had levels consistent w regular dosing Self-report CASI Pharmacy data 100% 55% 43% 65% 90-99% 22% 29% 50-89% 13% 18% 10% <50% 2% 3% Missing/unknown 7% 9% Source: Amico et al., JAIDS. 2014: 66(5); 530-537.

Adherence and Efficacy in Open-label Projects The Demo Project (SF, Miami, DC) Source: Liu et al., JAMA Intern Med, 2016

How to Monitor Adherence to PrEP Does your patient show up to appointments? Did your patient pick up their prescriptions? Single best questions - How many pills missed in the last month? - How many pills missed in the last week? - How good has your adherence been over the last month? (very poor, poor, fair, good, very good, excellent)

How to Promote Adherence to PrEP At baseline Provide education about PrEP Importance of adherence, side effects Help to establish a dosing routine What to do about missed doses Discuss reminder systems and tools Medisets, alarms (clocks, phones, smartwatches), apps, text messaging/email Address financial, substance abuse, mental health needs Facilitate social support During follow-up Assess adherence and identify barriers to adherence Assess and help manage side-effects Normalize missed doses Reinforce success Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Summary of Clinical Eligibility for HIV PrEP Considered to be at “substantial risk” of HIV infection Documented negative HIV test before prescribing PrEP No symptoms of acute HIV infection Normal renal function (>60 mL/min) Documented hepatitis B viral immune status Able to adhere to a daily medication Able to adhere to follow-up visits (at least every 3 months) Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Recommended Follow-Up Counseling and Services Recommended Follow-Up Counseling and Services for Patients Taking PrEP Follow-up services Every 3 months Adherence counseling ✔ Behavioral risk reduction support and condoms Assessment for side effects Assessment for STI symptoms and symptoms of acute HIV For women, discuss pregnancy intent and contraceptive options Access to clean needles/syringes and drug treatment services Provide a refill of daily TDF/FTC for no more than 90 days Abbreviations: STI = sexually transmitted infection; TDF/FTC = tenofovir/emtricitabine Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Summary of Recommended Laboratory Evaluation Baseline and Routine Monitoring for Patients taking PrEP Recommended Laboratory Testing and Frequency for Patients Taking PrEP Laboratory test Baseline Every 3 months At least every 6 months Notes HIV screening assay ✔ Consider need for HIV RNA PCR HBV antibody panel and HCV antibody Offer HBV vaccination if not immune Serum creatinine Avoid PrEP if CrCl <60 mL/min General STI screen Include oral/rectal screen for MSM if risk Pregnancy test for women Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Recommended Follow-Up Counseling and Services Recommended Follow-Up Counseling and Services for Patients Taking PrEP Follow-up services Every 3 months Adherence counseling ✔ Behavioral risk reduction support and condoms Assessment for side effects Assessment for STI symptoms and symptoms of acute HIV For women, discuss pregnancy intent and contraceptive options Access to clean needles/syringes and drug treatment services Provide a refill of daily TDF/FTC for no more than 90 days Abbreviations: STI = sexually transmitted infection; TDF/FTC = tenofovir/emtricitabine Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Asymptomatic STIs among persons on PrEP Cohen et al, CROI 2016

Summary of Clinical Eligibility for HIV PrEP Considered to be at “substantial risk” of HIV infection Documented negative HIV test before prescribing PrEP No symptoms of acute HIV infection Normal renal function (>60 mL/min) Documented hepatitis B viral immune status Able to adhere to a daily medication Able to adhere to follow-up visits (at least every 3 months) Insurance coverage or other ability to pay for PrEP Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014.

Paying for PrEP Project Inform: www.projectinform.org

Thank you.

ICD-10 codes to consider using for PrEP prescribing Visit and HIV/STD testing Z20 Z20.6 Contact with and (suspected) exposure to HIV Z72.5 High risk behavior (main category not billable) Z72.51 Z72.52 Z72.53 High risk heterosexual behavior High risk homosexual behavior High risk bisexual behavior Z11 Encounter for screening infectious and parasitic diseases (not billable) Z11.3 Z11.4 Encounter for screening for infectious with a predominantly sexual mode of transmission Encounter for screening for HIV Laboratory monitoring Z51.81 Encounter for therapeutic drug level monitoring Z79.899 Other long-term (current) use of drug/prophylactic therapy Source: US Public Health Service. Clinical practice guidelines for PrEP. May 2014

What is wanted = prevention options. PrEP in the future Pill Gel Vaginal film Vaginal ring Injectable Tenofovir-containing pills are not feasible for everyone. There is an encouraging pipeline of new PrEP prevention products that will deliver additional options. However, we would be naïve to imagine that any one of these will work or be workable for every person. What is wanted = prevention options. 42

“Highly active HIV prevention” HIV Testing & Serosorting? Needle Exchange Condoms HIV and STI Vaccines Treatment PEP & PrEP

PrEP as part of the larger puzzle Mental health Drug treatment PrEP Relationships Housing Conception

How can I learn more? General Information www.cdc.gov/hiv/basics/prep.html www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf www.facebook.com/groups/PrEPFacts www.prepfacts.org UCSF Clinician Consultation Center 1-855-HIV-PrEP (1-855-448-7737), M-F 11-6 EST How to Pay for PrEP - Gilead’s Medication Assistance Program http://www.gilead.com/responsibility/us-patient-access/us%20advancing%20access - Washington PrEP DAP (also has list of PrEP providers by county) www.doh.wa.gov/YouandYourFamily/IllnessandDisease/HIVAIDS/HIVCareClientServices/PrEPDAP

Conclusions PrEP is safe, easy to prescribe, covered by insurance and drug-assistance programs, and an important part of HIV prevention and End AIDS Washington. PrEP is intended for people who, for whatever reason, cannot/will not/do not use condoms. PrEP decreases that person’s risk for HIV acquisition (i.e. harm reduction). Frequent STI screenings are important in high-risk populations, whether or not persons are on PrEP. There are many resources for you to learn more. Do not hesitate to call/email me if you have any questions about PrEP.

Questions?

Intermittent or “On-Demand” PrEP for High-Risk MSM IPERGAY: Background Study Features N = 400 high-risk men-who-have-sex-with-men (MSM) Setting: France and Canada Condomless anal sex with ≥2 partners in prior 6 months eGFR >60 mL/min All received risk-reduction counseling, condoms, and HAV and HBV vaccines if needed, as well as information about PEP Randomized to one of two arms Source: Molina JM, et al. CROI. 2015; Abstract 23LB.

Intermittent or “On-Demand” Preexposure Prophylaxis IPERGAY Event-Driven Strategy HIV Exposure Event Time 2 tabs 2-24 hours before sex (or 1 pill if most recent dose taken between 1-6 days prior) 1 tab 24 and 48 hours after the last pre-sex dose

Intermittent or “On-Demand” PrEP for High-Risk MSM IPERGAY: Results ⇓ 86% Additional data that could be added: Median follow-up was 8.8 months (IQR: 4.3 to 20.5). The average number of sexual partners participants had had in the previous two months was eight. Seventy per cent had had condomless anal sex in the previous two months. The two participants in the Truvada arm who acquired HIV did not become infected until late in the study – one 16 and one 21 months after entering the study. Principal investigator Jean-Michel Molina said that the two had pretty certainly stopped taking PrEP by that time – they had even been returning unused pill bottles to the clinic. During the study, 35% of participants were diagnosed with a sexually transmitted infection including 20% with gonorrhoea and 10% with syphilis; Jean-Michel Molina reported two in a hundred participants acquired hepatitis C, equating to six infections. Pts used a median of 14 pills/month (IQR: 8-20). Reference: Molina J-M et al. On Demand PrEP With Oral TDF-FTC in MSM: Results of the ANRS Ipergay Trial. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, USA, abstract 23LB, 2015. Due to high effectiveness of PrEP, participants unrandomized and all offered PrEP Source: Molina JM, et al. CROI. 2015; Abstract 23LB.

How far in advance do MSM “plan” for sex? N=1013 Volk et al, JAIDS, 2012