PREPARING FOR PREP: UNDERSTANDING ACCESS AND CLINICAL PRACTICE Janie Caplan, MD, Infectious Diseases Fellow, UCLA Gifty-Maria Ntim, MD, MPH Medical Director, APLA Health & Wellness David Evans, Director of Research Advocacy, Project Inform

Describe PrEP Usage and Approved Medications Currently Provided at Community Health Centers and their Effectiveness Gifty-Maria Ntim, MD, MPH Medical Director, APLA Health & Wellness

Disclosures I have nothing to disclose personally however APLA Health & Wellness has received funding in the past from Gilead

HIV in Los Angeles County

HIV Prevention Comprehensive Approach Behavioral Interventions Biomedical Interventions TasP PrEP PEP Structural Interventions

Pre-Exposure Prophylaxis with Truvada The only medication regimen approved by the Food and Drug Administration and recommended for PrEP with all the populations specified in this guideline is daily TDF (Tenofovir) 300 mg co-formulated with FTC (Emtricitabine) 200 mg (Truvada) (IA) TDF alone has shown substantial efficacy and safety in trials with IV drug users and heterosexually active adults and can be considered as an alternative regimen for these populations, but not for MSM, among whom its efficacy has not been studied. (IC) The use of other antiretroviral medications for PrEP, either in place of or in addition to TDF/FTC (or TDF) is not recommended. (IIIA) The prescription of oral PrEP for coitally-timed or other non- continuous daily use is not recommended. (IIIA)

Let’s Talk About Sex

Who May Benefit from PrEP

California PrEP Coverage at a Glance Medi-Cal covers PrEP 100% if a single household income is less than $16,243 a year Covered California offers reasonable access if you choose an appropriate plan (Bronze, Silver, Enhanced Silver 73,87,94, Gold, Platinum) Gilead offers co-pay assistance to help cover up to $3,600 /year Assistance can be used to cover pharmacy deductibles and co-pays for medication itself (no income requirements) Gilead offers free medication to those who do not have insurance (i.e. undocumented individuals, those who are not eligible to sign-up through market place, Medi-Cal pending, waiting for open enrollment, etc)

Sequence of Appearance of Laboratory Markers for HIV-1 Infection

Prescribing Truvada for PrEP

Adherence and Counseling Establish trust and bidirectional communication with your patient Provide simple explanations and education Discuss medication dosage and schedule Discuss management of common side effects Discuss the relationship of adherence to the efficacy of PrEP Discuss signs and symptoms of acute HIV infection and recommended actions Support adherence Tailor daily dose to patient’s daily routine Identify reminders and devices to minimize forgetting doses Identify and address barriers to adherence Monitor medication adherence in a non-judgmental manner Normalize occasional missed doses, while ensuring patient understands importance of daily dosing for optimal protection e.g. ‘how many doses did you miss in the last 7 days?’ Reinforce success Identify factors interfering with adherence and plan with patient to address them Assess side effects and plan how to manage them

Concerns Raised by PrEP Side-effects and toxicity Drug resistance Adherence Risk compensation Access Cost Truvada’s ‘street value’

Common Asked Questions 1. How soon after starting PrEP can I have some protection? 2. What side effects should I watch for? 3. What happens when I miss a dose of Truvada? 4. Why do I need to come in for refills? 5. Do I still need to use condoms? 6. What about the guy who was taking PrEP who recently tested positive for HIV? 7. Is my body going to look weird after I start taking Truvada? 8. Will Truvada affect my sex drive?

Sexually Transmitted Infections and PrEP Test for STIs every 3m and as needed based on exposure vs. testing every 6m per CDC guidelines

Helpful ICD 10 Codes Z72.51 High Risk Heterosexual Behavior Z72.52 High Risk Homosexual Behavior Z72.53 High Risk Bisexual Behavior

EVIDENCE FOR USE OF PRE-EXPOSURE PROPHYLAXIS IN AT RISK POPULATIONS Margaret “Janie” Caplan, MD Fellow physician Division of Infectious Diseases David Geffen School of Medicine at UCLA

Disclosures  I have nothing to disclose!

Clinical Trials of Oral PrEP iPrExTDF 2 Partners PrEP Population MSM and Transgender women Heterosexual men and women Heterosexual HIV serodiscordant couples Location US, Brazil, Ecuador, Peru, South Africa, Thailand Botswana Kenya and Uganda Sample size2,4991,2194,758 InterventionDaily oral TDF/FTC* Daily oral TDF or TDF/FTC* Efficacy of TDF/FTC (ITT analysis) 44% 36 vs. 64 (95% CI, 15-63%) 62% 9 vs. 24 (95% CI, 22-83%) 75% 17 vs. 13 vs. 52 (95% CI, %) Grant et al N Engl J Med 2010 Thigpen et al N Engl J Med 2012 Baeten et al N Engl J Med 2012

*All as part of a comprehensive prevention package*  HIV testing  Risk-reduction counseling and condoms  Diagnosis and treatment of symptomatic STIs (gonorrhea, chlamydia, syphilis, and HSV-2), as well as screening in asymptomatic individuals and partners  +/- Referral for PEP if reporting a recent exposure to HIV  +/- Hepatitis B vaccination

Purple overall Red yo Green < 18yo Blue US participants Participants in PrEP Clinical Trials Pace et al. CID 2013; 56 (8)

Clinical Trials in Women* Only FemPrEPVOICE Location Kenya, South Africa, and Tanzania Uganda, South Africa, Zimbabwe Sample size2,1205,029 Intervention Daily oral tablet (TDF/FTC)* Daily oral tablet (TDF or TDF/FTC) or vaginal gel (TDF)* Efficacy of TDF/FTC (ITT analysis) 6% 33 vs. 35 (95% CI, %) -4.4% 61 vs. 60 (95% CI, %) Van Damme et al. N Engl J Med 2012 Marrazzo et al. N Engl J Med 2015 *cis-gender

Women in Clinical Trials iPrExTDF 2 Partners PrEP Population MSM and Transgender women Heterosexual men and women Heterosexual HIV serodiscordant couples Location US, Brazil, Ecuador, Peru, South Africa, Thailand Botswana Kenya and Uganda Sample size2,4991,2194,758 InterventionDaily oral TDF/FTC* Daily oral TDF or TDF/FTC* Efficacy of TDF/FTC (ITT analysis) 44% 36 vs. 64 (95% CI, 15-63%) 62% 9 vs. 24 (95% CI, 22-83%) 75% 17 vs. 13 vs. 52 (95% CI, 55-87%) Grant et al N Engl J Med 2010 Thigpen et al N Engl J Med 2012 Baeten et al N Engl J Med 2012 Men: 80% (25-97) Women: 49% (-22-81)

iPrExTDF 2 Partners PrEP Population MSM and Transgender women Heterosexual men and women Heterosexual HIV serodiscordant couples Location US, Brazil, Ecuador, Peru, South Africa, Thailand Botswana Kenya and Uganda Sample size2,4991,2194,758 InterventionDaily oral TDF/FTC* Daily oral TDF or TDF/FTC* Efficacy of TDF/FTC (ITT analysis) 44% 36 vs. 64 (95% CI, 15-63%) 62% 9 vs. 24 (95% CI, 22-83%) 75% 17 vs. 13 vs. 52 (95% CI, 55-87%) Grant et al N Engl J Med 2010 Thigpen et al N Engl J Med 2012 Baeten et al N Engl J Med 2012 Men: 84% (54-94) Women: 66% (28-84) Women in Clinical Trials

What happened? ADHERENCE Pharmacology Clinical Efficacy

Relationship Between Effectiveness and Adherence in Microbicide & PrEP Trials Pearson correlation = 0.86, p=0.003 R Landovitz, SS Abdool Karim, personal communication Partners PrEP (TDF) Partners PrEP (Truvada)

TDF Concentrates x More in Rectal Tissue than in Cervico-vaginal Tissues Patterson KB et al. Sci Transl Med Days post single-dose

TDF/FTC (~7x/week) 99% TDF/FTC (~1x/24°) % Maximizing the Potential Effectiveness Anderson P et al, Sci Transl Med Donnell D et al, JAIDS Cottrell ML et al, R4P, Some adherence forgiveness with retained protection 6-7 doses per week likely required ~1 WEEK to reach protective levels ~3 WEEKS to reach protective levels CI: CI:

Dosing Strategies  Intermittent dosing is NOT recommended at this point.  IPERGAY study: “On Demand” PrEP with TDF/FTC, only in MSM 1  HPTN067 (ADAPT): non-daily PrEP in South African women 2  Prelim data: Daily dosing fostered better adherence, better coverage of potential sexual exposure, and more sustained use  Take Home Point: Daily dosing! 1.Molina JM, et al. CROI, Bekker LG, et al. CROI, 2015.

 Next Step Counseling 1  CDC Guidance 2  Text messaging 3,4  “Smart” devices 5,6 1. Amico KR et al. AIDS Behav CDC Clinical Practice Guidelines Finitsis DJ et al. PLoS ONE Moore D et al. CCTG Bekker LG et al. HPTN Gulick RM et al. HPTN 069 Efficacy Depends on Adherence

Risk Compensation  Theory that people adjust their behaviors in response to perceived level of risk  Historical example: Birth control and concern that its increased availability would promote risky sexual behavior  Does PrEP use result in increase in risky behavior (e.g. less condom use)?  PrEP trials have not seen risk compensation.  HOWEVER, in these trials, participants knew they might be getting a placebo.  What will happen in the real world setting?  iPrEX Open Label Extension (OLE): no significant change in sexual practices

Sexually Transmitted Infections  High incidence of STIs during follow-up in PrEP studies: increase in unprotected sex or increase in detection/screening?  Screening for STIs during PrEP use  CDC recommendation: Based on symptoms, and/or every 6 months for bacterial STIs  Evidence from PrEP implementation studies in New York and San Francisco suggesting more frequent, routine screening q3months might detect more incident STIs

Number of HIV Seroconverters on Active PrEP Arms With HIV Resistance Trial N mITT (oral drug) HIV Infected After Enrollment, Resistant / Seroconverters (randomized to active drug) iPrEx [1,2] 12240/36 Partners PrEP [3,4] 31404/51 TDF2 [5] 6010/10 FEM-PrEP [6,7] 10244/33 VOICE [8] 19781/113 TOTAL79679/243 (3.7%) Modified Total§79675/243 (2.0%) or 0.06% of exposed 1.Liegler T, et al. J Inf Dis Grant RM, et al. N Engl J Med Baeten JM, et al. N Engl J Med Lehman DA, et al. J Inf Dis Thigpen MC, et al. N Engl J Med Van Damme L, et al. N Engl J Med Grant RM, et al. AIDS Marrazzo JM, et al. NEJM §After exclusion of resistance likely to be transmitted HIV Resistance  Resistance is rare in clinical trials of PrEP  Resistance when PrEP is started accidentally during undiagnosed primary HIV infection – 8/29 (27.5%)

Ongoing Research  Other oral antiretrovirals as PrEP  Maraviroc (HPTN069)  Long Acting Therapies  Vaginal rings – dapivirine  Injectables – rilpivirine; cabotegravir  Immunotherapies – VRC01  Intermittent (i)PrEP  Demonstration projects  Cis-gender and transgender women

22 February 2016

ASPIREThe Ring Study PopulationHeterosexual, cis-gender, HIV-negative, year-old women FundingNIH/MTNIPM Location15 sites in South Africa, Zimbabwe, Uganda, Malawi 7 sites in South Africa and Uganda Sample Size (randomized)2,629 (1:1)1,959 (2:1) Interventionmonthly dapivirine vaginal ring Follow-upOne yearTwo year #HIV infections (d vs placebo) 71 vs (5.9%) vs 56 (8.6%) Efficacy (reduced risk of HIV infection) Overall27% (1, 26)31% (0.9, 51) Age < 21y-27% (-133,31)15% Age >21y56% (31,71)37% (3.5,59)

Ongoing Research  Local demonstration projects funded by California HIV/AIDS Research Program (CHRP)  Currently completing follow-up of MSM projects  Project in cis-gender women nearing start of enrollment  Funding for projects focusing on transgender persons

Ongoing Research AEGiS – PrEP Adherence Enhancement Guided by iTAB and Drug Levels for Women  Los Angeles and San Diego  Truvada® as part of a combination prevention package with enhanced adherence support in the forms of counseling, text messaging, and drug levels for 135 heterosexual, cis-gender women at risk of HIV infection  5 sites (4 in LAC, 1 in SD)  Estimated enrollment beginning ~late April 2016

David Evans, Director of Research Advocacy PrEP Awareness, Access and Roll-Out Considerations for Advocacy and Policy

Project Inform receives restricted and unrestricted funding from pharmaceutical companies, including Gilead. Today’s educational forum and presentation have been created independently of pharmaceutical influence or review. Disclosures

About Project Inform An HIV and Hepatitis C advocacy, education and policy organizations that has been in existence since Work on biomedical prevention began in 2011, with calls for demonstration projects to determine real world efficacy and more recently work on implementation of PrEP programs in California and elsewhere. Project Inform is one of the oldest organizations working on pricing of and access to HIV medications both for those living with HIV and now those at risk of HIV as well.

EFFECTIVENESS: What have we learned about the effectiveness of PrEP in men who have sex with men (MSM) and cis-gender heterosexual women and men? DOSING: How adherent does someone need to be? How long must you take it for it to be effective and how long do you need to keep taking it after risk stops? ACCEPTANCE AND AWARENESS: What do various communities think and know about PrEP and how might that affect its use? What don’t we know? ROLL-OUT: How is PrEP being taken up? What are barriers to access? Are they changing? NEW STRATEGIES: What might PrEP look like in 2020? New drugs, new delivery methods. Over-all topics for today:

PrEP Use: LA County

AWARENESS and ACCEPTANCE: Presentation by Kevin Delaney of CDC at CROI 2016 on PrEP awareness, acceptability and use among MSM in the United States. Two surveys: May to August 2012 (n=2,794) and October 2014 to May 2015 (n=8,406) Awareness increased from 45% to 68% Willingness to consider increased from 39% to 50% Use increased from 0.5% to 4.9%

AWARENESS and ACCEPTANCE: Hypothetical acceptability is a somewhat poor predictor of uptake of new innovations, but can prompt the need for research. First PrEP study exclusively in black MSM reported at CROI 2016 (HPTN073). 226 men (40% under 25 yrs) offered PrEP. Most (79%) decided to take it. 68% remained on PrEP for at least 26 weeks. Periodic surveys among MSM in NYC have found an increase of PrEP use over time, starting at 2% in 2013 to 14.8% in Race did not affect likelihood of PrEP use, nor did age or income, but increased risk increased it. Being uninsured reduced the likelihood of PrEP use.

AWARENESS and ACCEPTANCE: Three surveys or focus groups among cis-gender women indicated moderate levels of acceptance of PrEP, though more studies are needed. Data in trans women and MSM are greatly needed. Neither mentioned in CDC guidance. Concerns reported over interactions with gender conforming hormones and PrEP and effect on genital tissues. Almost no work has been done around persons who inject drugs.

PrEP Use: U.S. EMR Scan by Gilead Presented by Robert Grant, Gladstone 2015

PrEP Use: Kaiser Permanente SF Presented by Robert Grant, Gladstone 2015

ROLL-OUT: Some factors influencing access: Stigma from friends, the community and providers Lack of health insurance Incomplete health insurance with high deductibles and co-pays Lack of knowledgeable and willing providers Lack of access to regular STI and lab tests Low perception of HIV risk

ROLL-OUT: Signs of improvement: Increased co-pay assistance New PrEP clinics and PrEP services expanding even within cities with low resources More money for PrEP from local, state and federal government More culturally competent educational resources Greater recognition of the need to expand existing PrEP services. Successful state budget request for PrEP navigation and other services

ROLL-OUT: Other challenges and questions Continued disagreement about who should deliver PrEP services. ID and HIV specialists or PCP and NPs? Other task shifting? Pharmacists? Ensuring the absence of acute infections (access to 4 th generation AB/AG test) Proper levels of adherence and prevention support (Scale up, scale down, scrape by with limited resources?) Co-location or collaborative agreement with support services?

Policy opportunities and discussions: Follow NY PrEP-DAP model in California – free testing and medical visits – Gilead, PAN and PAF pay for drugs. Expanded support for rural and low-resource areas that allows flexibility while maintaining high standards. Clearinghouse for PrEP education, implementation and medical practice best practices. Education that Ryan White infrastructure can be used for non-funded services (e.g. RW admin can support PrEP, which is not RW funded) Changing Ryan White to allow HIV prevention

We have 5 printed materials on PrEP (order free copies): Is PrEP the right choice for you? (for both cisgender and transgender MSM) PrEP: A new option for women for safer loving How to get PrEP Transcending barriers for safer pleasure (for transgender women) PrEP Flow Chart (an access guide to obtaining a prescription and coverage for PrEP) Pocket point of access card Materials from Project Inform

Resources Clinical Recommendations, Guidelines and Tools LA County pdf CDC Medication and Co-Pay Assistance Provider Directory for LA County Support and Resourceswww.PrepFacts.org

Contact Us Janie Caplan, MD – David Geffen School of Medicine at UCLA Phone: Gifty-Maria Ntim, MD, MPH – APLA Health & Wellness Phone: David Evans, Project Inform Phone: