Postexposure Prophylaxis (PEP)

NORTHWEST AIDS EDUCATION AND TRAINING CENTER Postexposure Prophylaxis (PEP) Hillary Liss, MD Clinical Assistant Professor of Medicine, University of Washington Medical Program Director, NW AETC Last Updated: May 2014

Postexposure Prophylaxis (PEP) 2013 HIV Occupational PEP Guidelines HIV Non-Occupational PEP (npep) Management of Exposure to HBV and HCV

Estimated Prevalence of Chronic Viral Diseases 1.2 Million Persons Living with HIV 2.7-3.9 million Persons Living with HCV 0.8-1.4 Million Persons Living with HBV *N = 1,106,400 (95% CI 1,056,400 1,156,400) Source: Institute of Medicine. Hepatitis and Liver Cancer. Jan 2010.

HIV Occupational PEP

Case A 45-year-old offender janitor working in Health Services is cleaning behind a trash can and is stuck with a needle in the hand. The needle is hollow-bore with visible blood in the syringe and on the needle. He was wearing gloves but has a skin puncture and noticed bleeding. He washed the area thoroughly. He has no past medical history. Are you concerned about this exposure? What qualifies as an exposure?

2013 USPHS Occupational PEP Guidelines Infectious Fluids Involved in Exposure Relative Risk of Infectious Fluids in Occupational Exposure to HIV Category of Infectivity Infectious Fluids Potentially Infectious Body Fluids Not Considered Infectious (unless visibly bloody) Fluid Blood Visibly bloody body fluids Semen and vaginal secretions Cerebrospinal fluid Synovial fluid Pleural fluid Peritoneal fluid Pericardial fluid Amniotic fluid Saliva, vomitus, and feces Nasal secretions and sputum Sweat and tears Urine Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines At Risk Exposures Contact of blood, tissue, or other potentially infectious body fluids via: - Percutaneous injury - Mucous membrane exposure - Contact with nonintact skin Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

Estimated Risk of HIV Transmission with Different Exposures Risk of HIV Transmission in Health Care Workers Type of Exposure to Blood Risk of HIV Transmission Percutaneous Exposure 0.3% Mucous Membrane Exposure 0.09% Nonintact Skin Exposure < 0.09% Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Estimated Risk of Seroconversion with Percutaneous Injury 60 Seroconversion (%) 50 40 30 20 30 50 10 0 0.3 2 HIV Hepatitis C HBsAg+ HBeAg- HBsAg+ HBeAg+ Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Would you offer this offender HIV postexposure prophylaxis? A. Yes, tenofoviremtricitabine B. Yes, tenofoviremtricitabine plus raltegravir C. Yes, tenofoviremtricitabine plus another ARV D. No, I would not offer PEP in this situation

us public health service guideline Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis 2013 David T. Kuhar, MD; 1 David K. Henderson, MD; 2 Kimberly A. Struble, PharmD; 3 Walid Heneine, PhD; 4 Vasavi Thomas, RPh, MPH; 4 Laura W. Cheever, MD, ScM; 5 Ahmed Gomaa, MD, ScD, MSPH; 6 Adelisa L. Panlilio, MD; 1 for the US Public Health Service Working Group This report updates US Public Health Service recommendations for the management of healthcare personnel (HCP) who experience occupational exposure to blood and/or other body fluids that might contain human immunodeficiency virus (HIV). Although the principles of exposure management remain unchanged, recommended HIV postexposure prophylaxis (PEP) regimens and the duration of HIV followup testing for exposed personnel have been updated. This report emphasizes the importance of primary prevention strategies, the prompt reporting and management of occupational exposures, adherence to recommended HIV PEP regimens when indicated for an exposure, expert consultation in management of exposures, follow-up of exposed HCP to improve adherence to PEP, and careful monitoring for adverse events related to treatment, as well as for virologic, immunologic, and serologic signs of infection. To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures. The following is a summary of recommendations: (1) PEP is recommended when occupational exposures to HIV occur; (2) the HIV status of the exposure source patient should be determined, if possible, to guide need for HIV PEP; (3) PEP medication regimens should be started as soon as possible after occupational exposure to HIV, and they should be continued for a 4-week duration; (4) new recommendation PEP medication regimens should contain 3 (or more) antiretroviral drugs (listed in Appendix A) for all occupational exposures to HIV; (5) expert consultation is recommended for any occupational exposures to HIV and at a minimum for situations described in Box 1; (6) close follow-up for exposed personnel (Box 2) should be provided that includes counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity; follow-up appointments should begin within 72 hours of an HIV exposure; and (7) new recommendation if a newer fourth-generation combination HIV p24 antigen HIV antibody test is utilized for follow-up HIV testing of exposed HCP, HIV testing may be concluded 4 months after exposure (Box 2); if a newer testing platform is not available, follow-up HIV testing is typically concluded 6 months after an HIV exposure. Infect Control Hosp Epidemiol 2013;34(9):875-892 Preventing exposures to blood and body fluids (ie, primary prevention) is the most important strategy for preventing occupationally acquired human immunodeficiency virus Source: Kuhar (HIV) infection. DT, et Both al. individual Infect Control healthcare providers Hosp and Epidemiol. the 2013;34:875-92. institutions that employ them should work to ensure adherimportant element of workplace safety. This document provides updated recommendations concerning the management of occupational exposures to HIV. The use of antiretrovirals as postexposure prophylaxis (PEP) for occupational exposures to HIV was first considered

2013 USPHS Occupational PEP Guidelines Challenges Addressed Difficulties determining level of risk and determining appropriateness of 2 versus 3-drug PEP High rates of side effects and intolerability of previously recommended ARV s for PEP Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines Number of Antiretroviral Medications to Use As less toxic and better-tolerated medications for the treatment of HIV infection are now available, minimizing the risk of PEP noncompletion, and the optimal number of medications needed for HIV PEP remains unknown, the PHS working group recommends prescribing 3 (or more) tolerable drugs as PEP for all occupational exposures to HIV. Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines Reasons For Recommending 3-Drug PEP Studies of 3-drug effectiveness for treating HIV Concerns about possible resistance to agents used for PEP Safety and tolerability of newer ARV s Clinicians facing challenges such as medication availability, adherence or toxicity issues might still consider a 2-drug regimen in consultation with an expert Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

Tolerability of HIV PEP in HCW Percent of HCWs 100 90 80 70 60 50 40 30 20 10 0 Incidence of Common Side Effects Nausea Fatigue Headache Vomiting Diarrhea Myalgias Wang SA. Infect Control Hosp Epidemiol 2000;231:780-5.

2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral Regimens Recommended Antiretroviral Regimens for Occupational PEP (28-Day Duration) Preferred Regimen INSTI NNRTI Pill Burden Raltegravir (Isentress) 400 mg twice daily Tenofovir-Emtricitabine (Truvada) 1 pill daily Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral Regimens Alternative Antiretroviral Regimens for Occupational PEP (28-Day Duration) INSTI, PI, or NNRTI NNRTI Alternative Regimens: Combine from both columns (listed in order of preference) Raltegravir (Isentress) Darunavir (Prezista) + Ritonavir (Norvir) Etravirine (Intelence) Rilpivirine (Edurant) Atazanavir (Reyataz) + Ritonavir (Norvir) Lopinavir-Ritonavir (Kaletra) Tenofovir-Emtricitabine (Truvada) Tenofovir (Viread) + Emtricitabine (Emtriva) Tenofovir (Viread) + Lamivudine (Epivir) Zidovudine-Lamivudine (Combivir) Zidovudine (Retrovir) + Lamivudine (Epivir) Zidovudine (Retrovir) + Emtricitabine (Emtriva) Alternative Regimen: Fixed-Drug Combination Elvitegravir-Cobicistat-Tenofovir-Emtricitabine (Stribild) Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

Effectiveness of Tenofovir (TDF) PEP in Macaques Study Hour SIV Inoculation 0 24 Start PEP 48 72 Study Features 24h Placebo x 28d N = 24 macaques Randomized to 6 treatment arms SIV inoculated intravenously SIV dose 10x 50% infective dose PEP started at 24, 48, or 72 hours PEP duration: 3, 10, or 28 days PEP regimen: tenofovir (TDF) SQ Analyzed for antibody and viremia 24h TDF x 3d 24h TDF x 10d 24h TDF x 28d 48h TDF x 28d 72h TDF x 28d Source: Tsai CC, et al. J Virol. 1998;72:4265-73.

Effectiveness of Tenofovir PEP in Macaques Persistent SIV Infection (%) 60 50 40 30 20 10 0 100 Placebo 50 Start @ 24h 25 Start @ 24h 0 Start @ 24h 50 50 Start @ 48h Start @72h 3-Day Rx 10-Day Rx 28-Day Rx 28-Day Rx 28-Day Rx Source: Tsai CC, et al. J Virol. 1998;72:4265-73.

Effectiveness of Tenofovir (TDF) PEP in Macaques Conclusion: These results clearly show that both the time between virus exposure and initiation of tenofovir treatment as well as the duration of treatment are crucial factors for prevention of acute SIV infection in the macaque model. Source: Tsai CC, et al. J Virol. 1998;72:4265-73.

2013 USPHS Occupational PEP Guidelines Additional Key Points PEP should be initiated as soon as possible after exposure, preferably within hours PEP should be provided for 28 days Whenever possible, the HIV status of the source patient should be determined, but should NOT delay starting PEP An exposed individual should be advised to use precautions (eg. barrier contraception, avoid blood donations, pregnancy and, if possible, breast feeding) during first 6-12 weeks after exposure Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines Situations for Which Expert Consultation Advised Delayed exposure report (eg. longer than 72 hours) Unknown source (eg. needle in sharps disposal) Known or suspected pregnancy in exposed person Exposed person breast-feeding Known or suspected ARV drug resistance in source patient Serious medical illness in exposed persons Toxicity occurring in exposed person taking PEP regimen Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

Postexposure Prophylaxis Line (PEPline) 888-448-4911

What if the Source Patient has an Undetectable Viral Load? A 32-year-old physician has a needlestick injury on her hand that involves an HIV-infected patient. The source patient is taking tenofovir-emtricitabine-efavirenz (Atripla) and had an undetectable HIV RNA level 3 months prior. Based on USPHS 2013 Guidelines, would you recommend antiretroviral PEP for this physician?

Would you offer PEP if the source pa;ent had an undetectable viral load when checked 1 month ago? A. Yes B. No

2013 USPHS Occupational PEP Guidelines PEP when Source Patient has Undetectable HIV RNA Level Exposure to a source patient with an undetectable serum viral load does not eliminate the possibility of HIV transmission or the need for PEP and follow-up testing. While the risk of transmission from an occupational exposure to a source patient with an undetectable serum viral load is thought to be very low, PEP should still be offered. Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines Baseline and Follow-Up for Occupational PEP Early Reevaluation after Exposure (within 72 hours) Baseline and Follow-up HIV Testing - Baseline HIV testing - Follow-up HIV testing 6, 12, and 24 weeks after exposure - Follow-up HIV testing at 6 and 16 weeks if 4 th generation assay* used Baseline and Follow-up Laboratory Testing - Baseline renal and hepatic function tests - Follow-up renal and hepatic function tests at 2 weeks *4 th generation combination assay = HIV p24 antigen-hiv antibody test Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

2013 USPHS Occupational PEP Guidelines Summary of Major Changes Eliminates evaluation of level of risk to stratify PEP regimen; all regimens should contain 3 or more ARV s New recommended and alternative PEP regimens; encourages regimens that are optimally tolerated Follow-up may conclude at 4 months if 4 th generation HIV testing used Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

HIV Non-Occupational PEP (npep)

Case Two offenders are caught engaging in anal sex without a condom. Although this falls under Prison Rape Elimination Act (PREA), the officers believe it to be consensual, and bring the offenders directly to segregation. Medical incidentally finds out about the event the next day and notes that one of the offenders has HIV. His HIV RNA level is 2,340 copies/ml and he is not currently taking ART.

What would you offer the uninfected offender for HIV PEP? A. Tenofovir- emtricitabine B. Tenofovir- emtricitabine plus raltegravir C. Tenofovir- emtricitabine plus another ARV D. Something else E. I wouldn t offer PEP

Estimated Per Act Risk for Acquisition of HIV, by Exposure Route Exposure Route Blood transfusion 90% Needle-sharing IVDU 0.67% Receptive anal intercourse 0.50% Percutaneous needle stick 0.30% Receptive penile-vaginal intercourse Per-act risk of transmission 0.10% Insertive anal intercourse 0.06% Insertive penile-vaginal intercourse 0.05% Receptive oral intercourse 0.01% Insertive oral intercourse 0.0005% Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2005;54(RR-2).

Non-occupational PEP Algorithm Adapted from MMWR January 21, 2005, Vol 54, No. RR-2. Reproduced from www.hivwebstudy.org

What is considered Substantial Risk? Substantial Risk Exposure of - Vagina, rectum, eye, mouth or other mucous membrane, nonintact skin, or percutaneous contact With - Blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood When - The source is known to be HIV infected Negligible Risk Exposure of - Vagina, rectum, eye, mouth or other mucous membrane, intact or nonintact skin, or percutaneous contact With - Urine, nasal secretions, saliva, sweat, or tears if not visibly contaminated with blood Regardless - Of the known or suspected HIV status of the source

Recommended Lab Evaluation for HIV npep Baseline During npep 4-6 Wks 3 Mos 6 Mos HIV Antibody E, S E E E CBC with differential E E LFTs E E BUN/Cr E E STD screen (GC/CT/RPR) E, S E E Hep B serology E, S E E Hep C serology E, S E E Pregnancy test E E E HIV viral load/cd4 cells S E E E HIV resistance testing S E E E

2-Drug vs. 3-Drug ART for npep The recommendation for a three-drug HAART regimen is based on the assumption that the maximal suppression of viral replication afforded by HAART will provide the best chance of preventing infection in a person who has been exposed. Clinicians and patients who are concerned about potential adherence and toxicity issues associated with a three-drug HAART regimen might consider the use of a two-drug regimen. Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2005;54(RR-2).

Tenofovir-Emtricitabine (TDF-FTC) plus Raltegravir for npep Mayer et al, JAIDS, 2012 100 participants enrolled at Fenway Health - 98% male, 83% MSM, mean age 33 Prescribed TDF-FTC plus raltegravir for npep 85 had 3-months follow-up 57% finished the regimen as prescribed - Comparable to historic controls (AZT-3TC or TDF-FTC + PI/r) - Biggest limitation = missed second dose of raltegravir by 27% Well tolerated and fewer side effects than historic controls Mayer K, et al. J Acquir Immune Defic Syndr. 2012;59(4):354-359.

Other Reminders Regarding npep Remember possible reverse exposure - Sexual assault victim may have HIV or other transmissible infection - Evaluate all involved offenders - Remember to screen for STDs Human bites and altercations may lead to exposure - For human bites, clinical evaluation must include the possibility that both the person bitten and the person who inflicted the bite were exposed to bloodborne pathogens

HCV Occupational PEP

An offender and his cellie are found with new taooos and the cellie has known HCV. Would you offer HCV PEP? A. Yes B. No

Postexposure Prophylaxis for HCV HCW with Exposure to HCV (+ ) Source No Postexposure Prophylaxis Recommended Source: CDC. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Pilot Study of Postexposure Prophylaxis with Peginterferon for Hepatitis C Virus in Health Care Workers HCW with Exposure to HCV (+ ) Source (n = 213) HCW who Participated in PEP Protocol (n = 51) High-Risk Exposure (n = 25) Low Risk Exposure (n = 26) PEP (n = 21) No PEP (n = 4) PEP (n =23) No PEP (n = 3) PEP = Peginterferon alpha-2b (1.0 ug/kg subcutaneously) once weekly x 4 weeks Source: Corey KE, et al. Infect Control Hosp Epidemiol. 2009;30:1000-5.

Pilot Study of Postexposure Prophylaxis with Peginterferon for Hepatitis C Virus in Health Care Workers Summary of Results - 29 (66%) of 44 completed 4-week course of Peginterferon - None of 44 who randomized to PEP had HCV seroconversion - None of 169 HCW who did not receive PEP had HCV seroconversion Source: Corey KE, et al. Infect Control Hosp Epidemiol. 2009;30:1000-5.

Pilot Study of Postexposure Prophylaxis with Peginterferon for Hepatitis C Virus in Health Care Workers On the basis of these findings and given the low frequency of transmission, the high adverse event rate and impaired quality of life, and the effectiveness of peginterferon alfa-2b for acute HCV infection, we do not recommend routine postexposure prophylaxis with peginterferon alfa-2b for occupational exposures. Source: Corey KE, et al. Infect Control Hosp Epidemiol. 2009;30:1000-5.

Possible Future Oral PEP for Hepatitis C Exposure NS3A/4A Protease Inhibitor Nucleoside Analogue Nucleotide Analogue Non-Nucleoside Analogue Non-Nucleotide Analogue $$$$ Well-tolerated, oral treatments with high cure rates available or coming soon! NS5A Inhibitor

Follow-Up for Exposure to Hepatitis C Baseline: anti-hcv and ALT Follow-up testing (at 4-6 months) for anti-hcv and ALT activity Consider HCV RNA testing at 4-6 weeks if earlier diagnosis desired Confirm all anti-hcv results reported by enzyme immunoassay with supplemental test Source: CDC and Prevention. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

HBV Occupational PEP

Postexposure Prophylaxis for Hepatitis B Previously HBV-Vaccinated, Unknown Response HBV Exposure Check HBsAb Titer HBsAb > 10 miu/ml HBsAb <10 miu/ml No Treatment 1 Dose HBIG (.06 ml/kg), 1 Vaccine Booster Dose Source: CDC. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Postexposure Prophylaxis for Hepatitis B Previously HBV-Vaccinated, Known Response* HBV Exposure No Treatment *Known HBsAb 10 miu/ml after HBV Immunization Source: CDC. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Postexposure Prophylaxis for Hepatitis B Previously HBV-Vaccinated, No Response* HBV Exposure 1 Dose HBIG (.06 ml/kg), Repeat HBIG in 1 Month or 1 Dose HBIG (.06 ml/kg), Vaccine Series *Failed to respond to HBV vaccine series Source: CDC. MMWR Morb Mortal Weekly Rep. 2001;50(RR-11):1-42.

Postexposure Prophylaxis for Hepatitis B Previously HBV-Vaccinated, No Response* HBV Exposure Lamivudine? Entecavir? Tenofovir? *Failed to respond to HBV vaccine series

Hepatitis B Virus: Natural History after Infection Neonatal HBV Infection 95% 95% Childhood HBV Infection 30% Chronic HBV Infection Adult HBV Infection 5% Source: Lee WM. N Engl J Med 1997;337:1733-45.

PEP Update Summary HIV occupational PEP guidelines updated in 2013 emphasize early initiation of 3-drug PEP with well-tolerated ARV s and potential shortened follow-up course with 4 th generation Ag/Ab assay testing PEP is recommended for both occupational & non-occupational HIV exposures No antivirals currently recommended for HCV PEP; well-tolerated treatments are available or coming soon HBV PEP depends on risk of exposure, previous vaccination and known or unknown vaccine response

Questions Feel free to email: hliss@uw.edu