Preexposure Prophylaxis (PreP) for the Prevention of HIV Amy L. Davis, M.D., MPH March 15, 2017

Learning Objectives Identify candidates for preexposure prophylaxis (PrEP) Describe monitoring and lab testing approaches used for PrEP Recognize candidates for transitioning from postexposure prophylaxis (PEP) to PrEP

This slide, from the CDC, presents the number and 95% confidence intervals (CI) of new HIV infections from 2007-2010 overall and by sex in the United States. Between 2007 and 2010, the year before PrEP was first recommended by the CDC, there was no significant change in new HIV infections. (However, the number of new HIV infections among females decreased 21% reaching statistical significance, indicated by an asterisk.) The CDC cites this stable incidence as evidence of the need for additional HIV prevention methods, including PrEP, in order to reduce overall incidence of HIV infection.

Diagnoses of HIV Infection among Adults and Adolescents, by Sex 2010–2014—United States and 6 Dependent Areas From 2010 through 2014, in the United States and 6 dependent areas, the number of diagnoses of HIV infection among female adults and adolescents decreased; the number among males remained stable. In 2014, 40,697 adults and adolescents were diagnosed with HIV infection; of these, 81% of diagnoses were among males and 19% were among females.   Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis.

This CDC slide shows that some groups are more affected by HIV than others, and if we were to look at the group highlighted at the bottom of the slide: YMSM of color, specifically black YMSM, incidence is rising nationally in YMSM: comparing 2008 to 2010, there was a 22% increase among MSM aged 13-24 from 7200 new infections in 2008 to 8800 in 2010 (CDC). In NYC, overall incidence is going down, over the period of 2008 to 2012, there was a reduction in estimated HIV incidence from 3584 cases in 2008 to 2076 cases in 2012. In MSM <30, there was a decrease in 2012, but the pattern follows alternating increase and decrease in estimated incidence in the period between 2008-2012.

Multimodal HIV Prevention Biomedical Interventions Behavioral Interventions Structural Interventions HIV prevention includes the combination of a variety of strategies, including biomedical, behavioral and structural interventions. Biomedical interventions use medical and public health approaches to block infection, decrease infectiousness and reduce susceptibility. Behavioral interventions discourage risky behaviors and reinforce protective ones, by addressing knowledge, attitudes, skills, and beliefs. Structural interventions address social, economic, and cultural factors that contribute to HIV risk and vulnerability.

Biomedical Interventions PrEP Post-exposure prophylaxis Treatment as prevention Diagnosis and treatment of sexually transmitted infections Prevention of mother-to-child transmission of HIV Contraception to prevent unplanned pregnancy among women with HIV Voluntary male circumcision Blood safety Injection safety Microbicides Here are some examples of biomedical interventions used to prevent HIV transmission worldwide.

PrEP: Pre-exposure Prophylaxis How does it work? Uninfected person takes antiretrovirals May prevent replication of virus & infection Daily adherence to TDF/FTC Theoretically, if HIV replication can be inhibited from the moment it enters the body, it may not be able to establish a permanent infection. Right now the medications recommended for PrEP are daily Tenofovir/emtricitabine in a fixed dose combination pill. These 2 drugs were chosen out of the almost 30 drugs available for HIV treatment for their potency, safety, tolerability, convenience. In the future we are likely to see recommendations for PrEP with new drugs, new formulations of existing drugs, and maybe new dosing regimens for existing drugs. PrEP is not necessarily a lifelong prevention strategy: it’s recommended for use during periods of time when people are at high risk of acquiring HIV. PrEP is prescribed as one part of a prevention plan.

CDC PrEP Guidelines US Public Health Service PREEXPOSURE PROPHYLAXIS FOR THE PREVENTION OF HIV INFECTION IN THE UNITED STATES - 2014 A CLINICAL PRACTICE GUIDELINE https://www.cdc.gov/hiv/pdf/prepguidelines20 14.pdf

PrEP Guidelines Provide clear criteria for determining a person’s HIV risk and indications for PrEP use. Negative status before starting PrEP. Adherence counseling and HIV risk reduction Regular monitoring of HIV infection status, side effects, adherence, and sexual or injection risk behaviors. The new federal guidelines recommend that PrEP be considered for people who are HIV-negative and at substantial risk for HIV. For sexual transmission, this includes anyone who is in an ongoing relationship with an HIV-positive partner. It also includes anyone who 1) is not in a mutually monogamous* relationship with a partner who recently tested HIV-negative, and 2) is a gay or bisexual man who has had anal sex without a condom or been diagnosed with an STD in the past 6 months; or heterosexual man or woman who does not regularly use condoms during sex with partners of unknown HIV status who are at substantial risk of HIV infection (e.g., people who inject drugs or have bisexual male partners). For people who inject drugs, this includes those who have injected illicit drugs in the past 6 months and who have shared injection equipment or been in drug treatment for injection drug use in the past 6 months.

Truvada= tenofovir disoproxil fumarate (TDF) + emtricitabine (3TC) Nucleoside reverse transcriptase inhibitor (NRTI) Approved in 2004 for HIV treatment Approved in 2012 for PrEP Descovey= tenofovir alafenamide + emtricitabine (not yet approved for PrEP)

PrEP Use and HIV/STI Incidence in a Clinical Practice Setting Analysis of PrEP use and HIV/STI incidence in PrEP users in large healthcare system (Kaiser Permanente San Francisco) from 2012 to 2015 1045 referrals for PrEP; 801 individuals with ≥ 1 intake visit 657 initiated PrEP (82%*); mean duration of use 7.2 mos Key results (PrEP initiators): No HIV diagnoses (388 PY follow-up) After 12 months, 50% diagnosed with any STI 33% rectal STI; 33% chlamydia; 28% gonorrhea After 6 mos PrEP, self-reported condom use was decreased in 41% of individuals PrEP, pre-exposure prophylaxis; STI, sexually transmitted infection; PY, patient-years. Volk JE, et al. Clin Infect Dis. 2015;61:1601-1603.

Rate of Within-Couple Transmission Events per 100 CYFU, % (95% CI) PARTNER: Risk of HIV Transmission With Condomless Sex on Suppressive ART 1 2 3 4 20 40 60 80 100 Risk Behaviors, % Vaginal sex with ejaculation Vaginal sex Receptive anal sex Receptive anal sex with ejaculation Only insertive anal sex MSM HT♀ HT♂ Rate of Within-Couple Transmission Events per 100 CYFU, % (95% CI) Vaginal sex with ejaculation (CYFU = 192) Vaginal sex (CYFU = 272) Receptive anal sex with ejaculation (CYFU = 93) Receptive anal sex without ejaculation (CYFU = 157) Insertive anal sex (CYFU = 262) Estimated rate 95% CI Observational study of rate of HIV transmission in heterosexual and MSM serodiscordant couples (N = 767 couples) HIV+ partner on suppressive ART Condoms not used No linked transmissions recorded in any couple during study period Uncertainty over risk remains, particularly regarding receptive anal sex with ejaculation ART, antiretroviral therapy; CI, confidence interval; CYFU, couple-years follow-up; HT, heterosexual; MSM, men who have sex with men. Between September 2010 and May 2014 the PARTNER study prospectively enrolled 1166 serodifferent couples at 75 clinical sites in 14 European countries.  Rodger A, et. al JAMA 2016.

Linked HIV Transmissio ns, n Opposites Attract Study: HIV Transmission in Male Serodiscordant Couples Observational study of HIV transmission in serodiscordant MSM in Australia, Brazil, Thailand: interim analysis[1] On ART, 84% (of whom 83% had HIV-1 RNA < 200 c/mL); nonmonogamous relationship, 43%[1]; any condomless anal intercourse (CLAI) with outside partners in previous 3 mos: 17%[2] No linked HIV transmission in ~ 6000 acts of CLAI Type of CLAI Reported by HIV-Negative Partner Linked HIV Transmissio ns, n CYFU CLAI Acts, N IR per 100 CYFU (95% CI) Overall 149.96 5905 0 (0-2.46) Any CLAI 90.83 0 (0-4.06) Insertive CLAI 77.87 3569 0 (0-4.74) Receptive CLAI 57.08 2337 0 (0-6.46) Any CLAI when HIV-1 RNA < 200 c/mL 88.59 5656 0 (0-4.16) Any CLAI when HIV-1 RNA > 200 c/mL 2.00 237 0 (0-184.31) ART, antiretroviral therapy; CI, confidence interval; CLAI, condomless anal intercourse; CYFU, couple-years of follow-up; IR, incidence rate; MSM, men who have sex with men. 1. Grulich A, et al. CROI 2015. Abstract 1019LB. 2. Bavinton BR, et al. AIDS 2015. Abstract TUAC0306.

PrEP Timeline Guidance for PrEP Clinical Practice Guideline for PrEP August 2012 TDF2 Partners PrEP June 2013 Bangkok TDF Study November 2010 iPrEx July 2012 FEM-PrEP March 2013 VOICE June 2013 CDC Interim Guidance: PrEP for IDU July 2012 FDA Approval TDF/FTC PrEP This is a timeline for selected PrEP research, shown with green arrows above the timeline, and approval and guidance documents for PrEP, shown with blue arrows below the line. iPrEx studied TDF/FTC as PrEP in MSM and male-to-female transgender women. Those who took PrEP were less likely to be infected with HIV. FEM-PrEP, a study testing TDF/FTC oral daily as PrEP in females was stopped due to inability to determine effectiveness: there were equal numbers of infections in the TDF/FTC and the placebo arms. These results were thought to be related to adherence, and were published in July 2012. VOICE, a study testing 3 regimens for PrEP in females: oral TDF, intravaginal TDF, and oral TDF/FTC found that none of the approaches were effective, and this result is believed to be related to poor adherence in the treatment arms. The oral TDF arm was halted in September, 2011, the vaginal TDF arm halted in November, 2011, and the TDF/FTC arm continued until the planned completion date in August, 2012. TDF2 and Partners PrEP tested daily TDF/FTC oral formulation as PrEP in high risk heterosexual men and women and found that those who took PrEP were less likely to become infected with HIV. The Bangkok TDF Study tested daily TDF in injection drug users, and found that the participants who used TDF were less likely to become infected with HIV. Reference: http://www.cdc.gov/hiv/prevention/research/prep/ PrEP was FDA approved in July 2012. CDC has released interim guidance in line with major PrEP studies, and in 2014 both the NYS AIDS Institute and the CDC released guidelines for PrEP. These guidelines are referenced extensively in this set of slides. January 2011 CDC Interim Guidance: PrEP for MSM January 2014 NYS AIDS Institute Guidance for PrEP August 2012 CDC Interim Guidance: PrEP for heterosexuals May 2014 US Public Health Service Clinical Practice Guideline for PrEP

CDC Guidance on PrEP for HIV Prevention: Candidates MSM Heterosexual Women and Men Injection Drug Users Potential indicators of substantial risk of acquiring HIV infection HIV-positive sexual partner Recent bacterial STI High number of sex partners History of inconsistent or no condom use Commercial sex work In high-prevalence area or network HIV-positive injecting partner Sharing injection equipment Recent drug treatment (but currently injecting) Clinically eligible Documented negative HIV test result; no signs/symptoms of acute HIV infection Creatinine clearance ≥ 60 mL/min; no contraindicated medications Documented hepatitis B virus infection and vaccination status CDC, Centers for Disease Control and Prevention; MSM, men who have sex with men; PrEP, pre-exposure prophylaxis; STI, sexually transmitted infection. CDC. PrEP Guidelines. 2014.

CDC: Time to Achieving Protection on PrEP Time from initiation of daily TDF/FTC to maximal protection against HIV infection is unknown No scientific consensus on what intracellular concentrations are protective for either drug or the protective contribution of each drug in specific body tissues TDF and FTC PK vary by tissue Preliminary PK data on lead-time to achieve maximal intracellular TFV-DP concentrations with daily TDF dosing: Blood: ~ 20 days Rectal tissue: ~ 7 days Cervicovaginal tissues: 20 days Penile tissues: no data CDC, Centers for Disease Control and Prevention; FTC, emtricitabine; PK, pharmacokinetic; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate. CDC. PrEP Guidelines. 2014.

CDC Guidance on PrEP for HIV Prevention: Approaches MSM Heterosexual Women and Men Injection Drug Users Prescription TDF/FTC (300/200 mg) QD; daily, continuing, oral dose, ≤ 90-day supply TDF alone can be considered as an alternative regimen in IDUs and heterosexually active adults Other ARVs, coitally timed PrEP, or other noncontinuous daily use is not recommended Other services Follow-up visits at least every 3 mos to provide HIV test, adherence counseling, behavioral risk reduction support, AE assessment, STI symptom assessment At 3 mos and every 6 mos thereafter, assess renal function Every 6 mos, test for bacterial STIs Do oral/rectal STI testing Assess pregnancy intent Pregnancy test every 3 mos Access to clean needles/syringes and drug treatment services AE, adverse event; ARVs, antiretrovirals; CDC, Centers for Disease Control and Prevention; FTC, emtricitabine; IDU, injection drug user; PrEP, pre-exposure prophylaxis; QD, daily; STI, sexually transmitted disease; TDF, tenofovir disoproxil fumarate. CDC. PrEP Guidelines. 2014.

Providing PrEP Every visit: Assess adherence Risk reduction counseling Provide condoms Providing PrEP Before starting PrEP: Clinical eligibility Educate Side effects Limitations Daily adherence Symptoms of seroconversion Monitoring schedule Safety Criteria for discontinuation Partner information Social history: housing, substance use, mental health, domestic violence NYS AIDS Institute guidelines have useful checklists for pre-prescription assessment and education. The most common side effects of TDF are nausea and flatulence. The most common side effects of emtricitabine are rash and headache. Side effects are more common in the first month of treatment and often subside after a few weeks, which is known as the “start-up syndrome.” If a patient considering PrEP has an HIV infected partner, ask about whether they are on antiretrovirals and if there is resistance information available. a patient’s social history can identify potential barriers to adherence to PrEP and indications for referral for services. www.hivguidelines.org

Providing PrEP After confirmation of clinical eligibility: Every visit: Assess adherence Risk reduction counseling Provide condoms Providing PrEP After confirmation of clinical eligibility: Prescribe no more than 90-day supply of PrEP Truvada 1 tablet PO daily (tenofovir 300mg + emtricitabine 200mg) Insurance prior approval Truvada for PrEP Medication Assistance Program CDC guidance recommends prescribing no more than a 90-day supply at the first prescription. TDF 300mg daily is an acceptable alternative only for IDU and heterosexually active adults. The CDC does not recommend: Alternate medications in place of or in addition to TDF/FTC or TDF Intermittent or episodic dosing Expedited partner treatment for PrEP http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf

Providing PrEP 3-month visit: HIV test Assess for acute infection Every visit: Assess adherence Risk reduction counseling Provide condoms Providing PrEP 3-month visit: HIV test Assess for acute infection Check for side effects Pregnancy testing Prescribe 90-day supply of medication CDC guidelines recommend visits every 3 months after the first prescription for PrEP. Consider the NYS AIDS Institute guidelines recommendation for closer follow up, especially for adherence-related concerns: check in with patients at 2-weeks to assess for medication toleration and side effects. Visit at 30-days to check for side effects, assess renal function in those at increased risk of kidney disease and for risk reduction, adherence and condom provision. The AIDS Institute guideline recommends continuation of visits every 30 days if adherence is an issue. (www.hivguidelines.org) http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf

Providing PrEP Every visit: Assess adherence Risk reduction counseling Provide condoms Providing PrEP 6-month 9-month 12-month HIV test STI test STI tests Pregnancy test Renal function 90 day prescription Assess the need to continue PrEP Continue seeing patients every 3 months. Renal function is monitored with estimated creatinine clearance. Consider the NYS AIDS Institute recommendation of a urinalysis for proteinuria and rechecking hepatitis status at the 12 month mark. http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf

Discontinuing PrEP Positive HIV result Acute HIV signs or symptoms Non-adherence Renal disease Changed life situation: lower HIV risk If a patient seroconverts on PrEP, check CD4 and VL, send genotype and link to HIV care. Counsel on HIV transmission prevention and offer partner notification services. Upon discontinuation, document: HIV status, reason for discontinuation, and recent adherence and reported sexual risk behavior. http://www.cdc.gov/hiv/pdf/guidelines/PrEPguidelines2014.pdf

PEP to PrEP Transition PEP is a response to an acute exposure Some pts who present for PEP may be at recurrent risk for HIV When monitoring PEP, ascertain if the pt would benefit from PrEP It is important to confirm if the pt is HIV infected prior to transitioning from PEP to PrEP PEP entails taking up to 3 medications daily for 28 days; PrEP entails 1 pill/day while risk persists Counseling about the importance of adherence is indicated PEP, post-exposure prophylaxis; PrEP, pre-exposure prophylaxis. Jain S, et al. Clin Infect Dis. 2015;60(suppl 3):S200-S204. NY nPEP Guideline. 2014.