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Mountain West AIDS Education and Training Center 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 This presentation is intended for educational use only, and does not in any way constitute medical consultation or advice related to any specific patient. 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 2499 MSM and transgender women Daily oral TDF-FTC or placebo TDF-FTC: 44% 4147 heterosexual HIV discordant couples Daily oral TDF, TDF-FTC, or placebo TDF: 67% TDF-FTC: 75% 1219 heterosexual men and women Daily oral TDF-FTC or placebo TDF-FTC: 63% 2120 women Daily oral TDF-FTC or placebo TDF-FTC: no protection (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 2413 injection drug users Randomized to daily oral TDF or placebo TDF: 49% 400 MSM Randomized to “on-demand” TDF-FTC or placebo TDF-FTC: 86% 545 MSM and transgender women Randomized to daily oral TDFFTC immediately or delayed Immediate TDF-FTC: 86% (Brazil, Ecuador, South Africa, Thailand, US) Partners PrEP Study (Kenya, Uganda) TDF2 Study (Botswana) FEM-PrEP (Kenya, South Africa, Tanzania) VOICE (Thailand) IPERGAY (France, Quebec) PROUD (United Kingdon) The Relationship Between Adherence and Efficacy Efficacy in randomized % of blood samples comparison with tenofovir detected 80 70 TDF2 Efficacy (risk reduction) Partners PrEP 60 50 40 TDF Bangkok iPrEx 30 20 FEM-PrEP 75% 81% 62% 79% 49% 67% 44% 51% 6% 26% - 29% 10 VOICE 0 0 10 Baeten et al N Engl J Med 2012 Grant et al N Engl J Med 2010 Choopanya et al Lancet 2013 20 30 40 50 60 % blood specimens with TDF detected Van Damme et al N Engl J Med 2012 Thigpen et al N Engl J Med 2012 Marrazzo et al CROI 2013 #26LB 70 80 90 The Relationship Between Adherence and Efficacy Lessons from iPrEx Detectable Drug Levels in Patients on Tenofovir-Emtricitabine A. Intracellular Emtricitabine Levels 9% B. Intracellular Tenofovir-DF Levels 52% 6% Adjusted RR reduction (any detectable level) = 95% Source: Grant RM, et al. N Engl J Med. 2010;363:2587-99. 50% 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 “Startup Syndrome” • 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 Renal Safety • 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 Bone Effects • In trials, TDF-FTC associated with small change (~1%) in bone density, though generally stabilized or improved • No increase in fractures seen 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. Partners PrEP Proportion of HIV – participants with any unprotected sex (%) iPrEx 50 40 30 20 10 0 0 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 60% 50% 30% 40% Z E R O 30% 20% 25% 20% 15% 10% 10% 5% 0% Any CT GC Volk et al. Clin Infect Dis 2015 TP HIV 0% Rectal GC Rectal CT Urethral Urethral GC CT McCormack et al. Lancet 2016 Syphilis 450 4500 400 4000 350 3500 300 3000 250 2500 200 2000 150 1500 100 1000 50 500 0 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Incidence per 100,000 Syphilis cases/year Syphilis in King County non-MSM HIV- MSM HIV+ MSM Incidence (HIV+ MSM) Incidence (HIV- MSM) Drug resistance in PrEP Trials Infected at Entry Study iPrEx Partners PrEP TDF2 FEM-PrEP VOICE Total % (95% CI) • • • • Incident Infection Study Drug Resist/Tot 2/2 Placebo Resist/Tot 1/8 Study Drug Resist/Tot 0/48 Placebo Resist/Tot 0/83 1/3 0/6 0/13 0/52 1/1 0/1 2/9 6/16 37.5% 0/2 0/1 0/1 1/18 5% (1 to 26%) 0/9 4/33 1/61 5/164 3% (1 to 7%) 0/24 1/35 0/60 1/254 0.3% (.06 to 2%) (18 to 61%) 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? 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. 20 15 Slide courtesy of Bernie Branson 10 5 0 Days before WB positive Modified from Masciotra et al, J Clin Virol 2011; Owen et al, J Clin Micro 2008 Vironostka (+) 2 Unigold (-2) OraQuick (-1) WB positive COMPLETE HIV-1/2 (-5) HIV-1/2 STAT-PAK (-5) Multi-Spot (-7) Reveal G3 (-6) INSTI (-9) GS 1/2+O (-12) Determine Combo (-15) 25 Architect Combo (-20) Bio-Rad Combo (-19) APTIMA (-26) Sequence of test positivity relative to WB 166 specimens, 17 Seroconverters 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 falsenegative 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 Self-report CASI Pharmacy data 100% 55% 43% 65% 90-99% 22% 29% 22% 50-89% 13% 18% 10% <50% 2% 2% 3% Missing/unknown 7% 9% • Among subjects reporting 100% adherence - 51% had any drug detected - 35% had levels consistent w regular dosing Source: Amico et al., JAIDS. 2014: 66(5); 530-537. Adherence and Efficacy in Open-label Projects The Demo Project (SF, Miami, DC) 100% Protective TFV-DP in DBS 90% Rating scale: very good/excellent 80% 70% Medication Possession Ratio (mean) Percent 60% • 50% • 40% • 30% • 20% 10% 0% 4 12 24 Visit week Source: Liu et al., JAMA Intern Med, 2016 36 48 2 infections (incidence 0.43/100py) 63% had protective DBS levels at all visits 3% always had DBS levels <2 doses/week PrEP dispensation interrupted in 15%: most commonly due to side effect concerns or low perceived risk How to Monitor Adherence to PrEP 1) Does your patient show up to appointments? 2) Did your patient pick up their prescriptions? 3) 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 HIV screening assay Baseline Every 3 months ✔ ✔ HBV antibody panel and HCV antibody ✔ Serum creatinine ✔ General STI screen ✔ Pregnancy test for women ✔ At least every 6 months Notes Consider need for HIV RNA PCR Offer HBV vaccination if not immune ✔ Avoid PrEP if CrCl <60 mL/min ✔ Include oral/rectal screen for MSM if risk ✔ 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 Proportion of infections for which treatment would have been delayed with q6 month screening 100% 20.4 90% 80% 34.3 35.3 40 70% 60% 50% 79.6 40% 30% 65.7 64.7 60 20% 10% 0% Gonorrhea n=181 Chlamydia n=210 Detected Cohen et al, CROI 2016 Syphilis n=54 Delayed Total n=445 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 ICD-10 codes to consider using for PrEP prescribing Visit and HIV/STD testing Z20 Z20.6 Z72.5 Z72.51 Z72.52 Z72.53 Z11 Z11.3 Z11.4 Contact with and (suspected) exposure to HIV High risk behavior (main category not billable) High risk heterosexual behavior High risk homosexual behavior High risk bisexual behavior Encounter for screening infectious and parasitic diseases (not billable) 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 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. “Highly active HIV prevention” HIV Testing & Serosorting? Needle Condoms Exchange Vaccines 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 drugassistance 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 Number of HIV Infections 25 P = 0.002 20 15 14 ⇓ 86% 10 5 2 0 Placebo Tenofovir-Emtricitabine 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