12/8/16. I have no conflicts of interest to disclose.

Transcription

1 I have no conflicts of interest to disclose. Jonathan E. Volk, MD MPH Kaiser Permanente San Francisco, Department of Medicine UCSF, Volunteer Assistant Clinical Professor December 2016 PrEP What is PrEP and why do we need it? Efficacy/Effectiveness Adherence Contraindications Side Effects Controversies & Clinical Challenges Serodiscordant relationships with undetectable partners: PrEP & Treatment as Prevention Risk compensation & sexually transmitted infections 23-year-old, HIV-uninfected, Black MSM Healthy, 1 st in-person medical visit in > 2 years No medications Reason for PrEP referral: My friends are on it 1

2 HIV risks: Condomless receptive ( bottoming ) & insertive ( topping ) anal sex with his boyfriend of 5 months Open relationship 7 additional partners in the last 3 months, 90% condom use Uses condoms when he bottoms, but not always for topping Rectal chlamydia ~6 months ago Hess et al, CROI# Truvada: Emtricitabine/Tenofovir Fixed-dose combination tablet FDA approved for PrEP in 2012 HIV-negative individuals before exposure on a daily basis during periods of risk NOT (yet) approved for intermittent use Why not PEP? PrEP rings, injectables, other oral agents Marcus et al, JAIDS, CDC Clinical Practice Guidelines, 2014; Grant et al

3 iprex: 42% - data from trial 92% - detectable drug 99% - modeling data 76% for 2/week 96% for 4/week 99% for 7/week Adherence likely does NOT need to be perfect for MSM Less forgiveness for women lower vaginal drug levels 6-7 doses/week may be needed Grant et al. NEJM ; Anderson PL. Sci Transi Med Grant et al. Lancet Infectious Diseases. 2014; Grant et al. AIDS. 2015;29: Reduction in incidence: 86% vs. placebo 97% in open-label vs. placebo Median: 15 pills/month in blinded study, 18/month in open-label I m still recommending daily dosing Molina et al. NEJM. 2015; Molina AIDS 2016 Breakthrough infections very rare Most new infections associated with low adherence TWO CASE REPORTS: 43MSM, seroconverted with multiclass resistance after 2 years of PrEP use Knox et al. CROI #160aLB A second PreP failure: pt with K65R & 184V, among other mutations Grossman et al. HIVr4P, October 2016 CDC guidelines: Sexually-active MSM, heterosexual men and women & IDU at substantial risk MORE SPECIFICALLY: 1. MSM or transgender women - condomless anal intercourse 2. Syphilis or rectal STI 3. Commercial sex workers 4. Serodiscordant relationships with positive partners with detectable viral load 5. Peri-conception 6. Persons who inject drugs 7. Individuals asking for PrEP Estimated 1.2 million people may benefit from PrEP Smith DK et al. MMWR. November 27 th,

4 ~ 3000 active PrEP users as of June 2016 in KP Northern CA 2200 PrEP starts at KP SF - 99% MSM PrEP referrals PrEP starts 23-year-old, HIV-uninfected MSM HIV risks: Condomless receptive & insertive anal sex Diagnosis of rectal chlamydia ~6 months ago High risk age & race/ethnicity Volk et al., Clin Infect Dis, Sept year-old Black, bisexual transgender woman Receptive anal sex with multiple male partners; no recent female partners Condoms ~90% of the time Heat of the moment No alcohol, occasional recreational MJ Rectal chlamydia 1 month prior to intake visit, more remote history of syphilis and gonorrhea OR for HIV infection 49 (95% CI 21-76) in meta-analysis Baral et al. Lancet ID

5 Minimal specific data for transgender women/men: iprex 29/2499 self-identified as transwomen (1.2%) 339 transgender women in new iprex analysis 11 HIV infections in PrEP group & 10 in placebo HR 1.1 (95% CI ) No new infections among transgender women taking PrEP, but drug detectable in only 18% More likely to report transactional sex, receptive anal intercourse without a condom, > 5 partners in prior 3 months Grant et al. NEJM. 2010; Deutsch BM et al. Lancet HIV. November 2015; Escudero et al. AIDS Care PrEP recommended Pt not ready to start Unable to reach patient through follow-up s, calls & outreach to PCP Areas for improvement: Meaningful PrEP messaging and recruitment & increased awareness Messaging NOT lumped with MSM Evidence based HIV prevention interventions for transgender women Gender discrimination, transphobia, violence Concerns re: Rx-Rx interactions with PrEP & hormones Need direct studies with hormone therapies 50% 40% 38% HIV seroconverters PrEP users 37-year-old, Latino MSM, open-relationship with HIV-negative partner % of patients 30% 20% 10% 0% 24% 4% Non-Hispanic Black 26% 20% 12% 2% 2% Hispanic Age <30 Female No condoms w/ primary partner 30% condoms with other partners I decide after talking to them about HIV Versatile, but usually receptive partner PMH: HTN, ADHD Meds: Lisinopril & Adderall Marcus et al, Am J Public Health, October

6 Kaiser Permanente screening labs: HIV-antibody Hepatitis testing for A, B & C Hepatitis A Hepatitis B Hepatitis C Creatinine and Urinalysis HIV VIRAL LOAD ALT AT INITIATION STI screening Syphilis Urine GC/CT Throat & Rectal GC/CT order as self collection in lab HIV viral load ordered at time of initiation PrEP started #90 days with refills HIV viral load returned 3 days later as negative Every 3 month follow-up Rx #90 HIV Creatinine Hep C screening with ALT Not in CDC guidelines STDs: urine/throat/rectal NG/CT & syphilis (recommended) More frequent STD testing, if desired Annual Hepatitis C antibody Urinalysis Q6 MONTHS: ADHERENCE, SIDE EFFECTS & BEHAVIORS 6

7 Refilled initial script for PrEP but no refills after that Outreach to patient: Pt self-d/c d PrEP because major lifestyle changes & low perceived risk Agreed pt would let me know if he wants to restart 5 months later, pt requests refill Had restarted 1 month prior with leftover medication, no labs prior Ordered labs & reviewed importance of adherence Rectal chlamydia positive Picked up next refill but then no additional refills Advised pt to come in for viral load prior to refill Pt lost to follow-up PrEP adherence as measured by medication possession ratio: 92% < 5% with <60% adherence (~ 4/week) Some patients require support & starting/stopping is common Factors associated with <80% adherence (N=915) Risk ratio * (95% CI) P Non-Hispanic Black 3.0 ( ) <0.001 PrEP copay >$50 per month 2.0 ( ) Smoking 1.6 ( ) * Risk ratios obtained from Poisson regression with robust variance and adjusted for age, sex, race/ethnicity, socioeconomic status, copay, smoking, drug/alcohol abuse, baseline STI, baseline renal function, hypertension, and diabetes Marcus et al., JAIDS, December % discontinued, defined as 120 days without drug Lost KP Coverage, decrease in risk, lost-to-follow-up, side effects (worsening renal function < 1%, neuropathy, fatigue, nausea, rash) Factors associated with discontinuation (N=972) Risk ratio * (95% CI) P Females (ref. males) 2.6 ( ) <0.001 Drug/alcohol abuse diagnoses 1.8 ( ) Smoking 1.3 ( ) * Risk ratios obtained from Poisson regression with robust variance and adjusted for age, sex, race/ethnicity, socioeconomic status, copay, smoking, drug/alcohol abuse, baseline STI, baseline renal function, hypertension, and diabetes Two HIV seroconversions in individuals who discontinued PrEP during gaps in insurance coverage Marcus et al., JAIDS, December

8 35-year-old MSM, newly single HIV risks: 6 partners in the last 3 months (4 for anal sex) Condoms most of the time (70%) Condomless receptive anal sex ~1 week prior Barriers to condoms: alcohol Lab work-up prior to referral normal HIV Ab negative, other labs fine Plan: Check HIV viral load in a few days Start PrEP after labs done ~ 5 days after visit, pt seen by PCP Sore throat, fevers/chills, malaise, congestion, decreased appetite Labs done at this visit, and PrEP initiation deferred Contraindications Symptoms concerning for acute HIV Fevers, fatigue, myalgia, rash, pharyngitis, cervical adenopathy, diarrhea, night sweats HIV-infected Poor kidney function (CrCl <60) Unwilling to take daily med or have lab follow-up Relative Contraindications Hep B infection with cirrhosis or substantial transaminitis caution w/ discontinuation Osteoporosis/history of fragility fractures (relative contraindication) Solomon et al. JAIDS. March 2016 Labs: Hepatitis C antibody positive Risks: condomless receptive anal intercourse & intranasal cocaine HIV viral load 8.3 million Started on elvitegravir/cobicistat/ftc/tdf pending genotype 2 HCV viral loads both negative HIV viral load now undetectable 8

9 Encourage viral load testing ~10-14 days after last high-risk exposure Doesn t always happen Risk of resistance vs. risks of delaying PrEP 46-year-old, Caucasian MSM, 50% condom use for topping PMH: morbid obesity, DM2, HTN, OSA, hip arthritis MEDS: Lisinopril, Metoprolol, Metformin Baseline screening labs normal PrEP started 3/2014 No side effects, excellent adherence F/U labs: Creatinine 1.1 PrEP started March June July August PrEP D/C d (CrCl <60) Opted to not pursue re-challenge? PrEP PrEP associated with renal dysfunction in trials Combined cohorts from clinical trials > 5300 ppts (Partner PREP and DEMO project) <1% had confirmed decline in CrCl < 60 ml/min within 12 months Higher risk if >45 yo, baseline CrCl 60-90, weight 55kg Guidelines recommend creatinine monitoring every 6 months during PrEP (KP: 3 months at most facilities) Few data on renal safety in clinical practice Older patients More comorbidities 9

10 Estimated glomerular filtration rate (egfr) <70 was common during PrEP use (15.5%) Low risk if egfr 90 at baseline Highest risk for older PrEP users with baseline egfr <90 Only 5 patients stopped PrEP indefinitely as a result of decreased egfr Coverage Uninsured and < 500% FPL* Uninsured and > 500% FPL* Medi-Cal Employer-sponsored health insurance Covered California How to access Gilead will provide meds at no cost May need to pay for office visit and labs $1250/month + office visits, lab costs Covered; No prior authorization Most cover; some require prior authorization Cost sharing varies Gilead offers $3600/year co-pay assistance Bronze: High deductibles, high copays TDF/FTC ~$800/mo (with co-pay assistance) Silver, Gold: Most have no cost after co-pay card Marcus et al., JAIDS, December 2016 * 500% FPL = ~$58,350 for a single person Source: Stephanie Cohen, MD, MPH Renal toxicity $$$ Start-up syndrome Bone density Recovery after PrEP d/c in younger patients HIV drug resistance Risk compensation 48-year-old Caucasian MSM rectal Chlamydia 4/2012, PEP 12/2012 At intake visit: I had always been vigilant about condoms, but expresses condom fatigue PrEP started 7/2013 Adherence based on pharmacy refill is good Mugwanya et al. JAMA Intern Med (2):246-54; Grant et al. CROI Abstract 48LB. 10

11 STI history: 1/2014 syphilis 3/2014 rectal gonorrhea 7/2014 rectal chlamydia & syphilis 9/2014 rectal chlamydia, q3 month ALT 549 (liver test) F/U hepatitis C viral load positive Hep C risk factors: condomless receptive anal sex (denies group sex, toys, fisting, IVDU, cocaine) Volk et al CID Not seen in 2 blinded-rcts Reassuring data from DEMO Project IPERGAY no change in number of partners, but increase in condomless receptive anal intercourse Mugwanya et al., Lancet ID 2013; Marcus, PLOS One 2013; Liu et al. JAMA Internal Medicine 2016; Molina, AIDS 2016 CHANGES IN REPORTED CONDOM USE AFTER STARTING PrEP (n=143) NO CHANGE 56% FEWER CONDOMS 41% NO ASSOCIATION WITH: Age STI history Condoms 3 months before PrEP use HIV+ partner Methamphetamines/cocaine Adherence Limitations of data: No control group Fewer condoms more HIV risk PrEP-sorting Undetectable viral loads Magnitude of change MORE CONDOMS 3% Volk et al. CID 2015 % of PrEP users 60% 50% 40% 30% 20% 10% 0% 50% 33% 33% 4 incident hepatitis C infections 28% 5.5% PrEP works -- If risk compensation is occurring, it does not appear to be resulting in increased HIV risk 0% Any STI Rectal STI Chlamydia Gonorrhea Syphilis HIV Volk et al., Clin Infect Dis, Sept 2015 Volk et al., Clin Infect Dis, June

12 43-year-old, HIV-negative Latino MSM with an HIV-infected partner In relationship x 2 years Condoms for receptive but not insertive anal intercourse No outside partners Partner has been on Atripla x years with an undetectable viral load Partner suggested patient come in for PrEP eval Recent HIV Ab negative, nl renal function Large RCT 96% decrease in HIV transmissions in serodiscordant couples w/ HIV treatment PARTNERS STUDY (n=888 couples, MSM & hetero) No phylogenetically linked transmissions seen in ~58K condomless sex acts Cohen MS et al. N Engl J Med. Aug ;365(6): ; Rodger JAMA 2016 After discussion or risks/benefits, pt chose to not start PrEP Very low risk if also using condoms NNT likely high Others in this situation start PrEP Intangible benefits from PrEP Reported decreased anxiety/fear re: HIV Improved satisfaction with sex reported Koester et al. IAS Reasons for NOT starting PrEP Did not respond to outreach or changed mind Medical exclusion: HIV+, abnormal kidneys, osteoporosis Enrolled in study Low risk / relationship change Sexual history-taking humility Anxiety PrEP $$$ Comprehensive HIV prevention strategies discussed Condoms, PEP, treatment as prevention, mental health & substance abuse treatment and counseling 12

13 23-year-old, Hispanic MSM, active methamphetamine use, newly diagnosed with HIV, presenting with rectal NG and secondary syphilis Last HIV-Ab negative ~2 years prior Reports intermittent use of PrEP (borrowed from sexual partners) x 1 year Started on Darunavir + Elvitegravir/cobicistat/Emtricitabine/Tenofovir pending genotype results Baseline genotype returned with M184V Antiretroviral resistance: No HIV in active PrEP users at KP = No resistance In trials, drug resistance risk is low, mostly when PREP is used during acute infection FTC/TDF estimated to prevent ~20 infections for every FTC resistant infection that occurred overall Grant, AIDS 2016, Durban PrEP successfully translated into clinical practice at KP PrEP works no seroconversions during PrEP use, but new infections after discontinuation highlight need for linkage to care High adherence Decreases in condoms may increase risk for STIs (including HCV) Discontinuation common, but discontinuations because of side effects rare Screen for use of PrEP in newly diagnosed HIV+ patients PrEP challenges: Disparities exist, even in insured populations Identifying those most at risk $$$ and access to care Adherence STI monitoring and treatment National PrEP Clinician Consultation Line (855) or (855) HIV-PrEP Monday Friday, 8 am 3 pm PST. SF Area PrEP training Experienced PrEP clinicians from SFDPH come to your practice to provide clinical resources & educational material prep@sfdph.org or alyson.decker@sfdph.org (415)

14 Leo Hurley Julia Marcus Susan Buchbinder Al Liu Stephanie Cohen Hyman Scott Julie Stoltey Derek Blechinger Monica Hahn Madeline Deutsch Darpun Sachdev Alyson Decker The KP SF PrEPTeam Tony Phengrasamy Phooey Nguyen Brad Hare Ed Chitty Ramon Ramirez Diana Manashirov Marc Solomon Ben Cox Ben Quintos Jenny Choo KP Community Benefits Grant 14