Post-Exposure Prophylaxis an evidence-based review

1. Post-Exposure Prophylaxisan evidence-based review Christopher Behrens, MD Hillary Liss, MD Northwest AIDS Education & Training Center University of Washington

2. Post-Exposure Prophylaxis (PEP) • The use of therapeutic agents to prevent infection following exposure to a pathogen • Types of exposures include percutaneous (needlestick), splash, bite, sexual • For health-care workers, PEP commonly considered for exposures to HIV and Hepatitis B

3. Hepatitis B PEP • Prevalence of chronic hepatitis B infection in U.S. relatively low • Most health-care workers vaccinated against hepatitis B • Hepatitis B PEP: immunization + HBIG (hepatitis B Immune Globulin) • HBIG effective up to one week following exposure Grady GF et al. JID 1978;138:625-38.

4. HIV PEP • Exposures common • 56 documented cases of health care workers contracting HIV from exposures; 138 other possible cases • Area of considerable concern but little data MMWR June 29, 2001 / 50(RR11);1-42

5. Case Presentation • 27 yo medical exam assistant (MA) presents to Urgent Care for evaluation of needlestick injury 2 days ago from a diabetic lancet • Source patient (SP): 35 yo male, known HIV+ • Would you offer her PEP?

6. Case Presentation continued • What is her risk for contracting HIV? • Are there factors that might affect this risk? • How effective is PEP? • Is it too late to start PEP? • What are the drawbacks of starting PEP? • Which regimen(s) should be considered? • What follow-up should be arranged?

7. What is her risk of contracting HIV? What factors affect this risk?

8. Risk of HIV Transmission Following Percutaneous (Needlestick) Exposure • Pooled analysis of prospective studies on health care workers with occupational exposures suggests risk is approximately 0.3% (95% CI, 0.2% - 0.5%)1 • Presence or absence of key risk factors may influence this risk in individual exposures 1. Bell DM. Am J Med 1997;102(suppl 5B):9-15.

9. Risk Factors for Seroconversion Following Needlesticks • CDC-sponsored case-control study • 33 cases, 665 controls with needlesticks from confirmed HIV+ SPs • Zidovudine (AZT) monotherapy as PEP Cardo DM et al. NEJM 1997;337:1485-90

10. Risk Factors for Seroconversion *p<0.01 for all Cardo DM et al. NEJM 1997;337:1485-90

11. Other Likely Risk Factors • Viral load • Glove use • 50% decrease in volume of blood transmitted1 • Hollow bore vs solid bore • Large diameter needles weakly associated with increased risk (p = 0.08)2 • Drying conditions • tenfold drop in infectivity every 9 hours3 1. Mast ST et al. JID 1993;168(6):1589-92. 2. Cardo DM et al. NEJM 1997;337:1485-90 3. Resnick L et al, JAMA 1986;255(14):1887-91. 3.

12. How effective is PEP?

13. Evidence of Efficacy of PEP • Animal models: high level of protection when started within 24 hours1 • OR = 0.19 for zidovudine use in case-control study2 • Two drugs, three drugs: • No direct evidence that more effective than 1 drug • Cases of seroconversion despite 3-drug PEP imply efficacy less than 100%3,4 1. Tsai C-C et al. J Virol 1998;72:4265-73. 2. Cardo DM et al. NEJM 1997;337:1485-90. 3. Jochinsen EM et al. Arch Int Med 1999;159:2361-3. 4. MMWR June 29, 2001 / 50(RR11);1-42

14. What are the drawbacks of PEP?

15. Tolerability of HIV PEP in Health Care Workers Incidence of Common Side Effects Percent of HCWs Wang SA. Infect Control Hosp Epidemiol 2000;231:780-5.

16. HIV Postexposure ProphylaxisSerious Adverse Events Associated with Nevirapine 22 Serious Adverse events - 12 hepatotoxicity - 2 cases of liver failure - 14 dermatologic Number Year MMWR 2001;49(51):1153-6.

17. When should PEP be started?

18. When should PEP be started? • Efficacy of PEP thought to wane with time • At what point is PEP “no longer worth it”? benefits of PEP risks of PEP time exposure

19. Timing of PEP: what’s the evidence? • Animal models and animal PEP studies: suggest substantially less effective beyond 24 - 36 hours1,2 • Case-control study: most subjects in each group received PEP within 4 hours3 • Analysis of PEP failures does not suggest a clear cut-off4 1. Tsai C-C et al. J Virol 1998;72:4265-73. 2. Shih CC et al. JID 1991. 3. Cardo DM et al. NEJM 1997;337:1485-90. 4. MMWR June 29, 2001:50(RR11);1-42.

20. Timing of PEP: An Anecdote • 13 yo girl in Italy transfused with one unit of blood from donor who was acutely infected with HIV but not yet HIV-antibody positive • Seroconversion risk estimated to be virtually 100% • 3-drug PEP initiated 50 hours post-transfusion, continued for 9 months • No evidence of HIV infection 15 months later Ann Int Med 2000;133:31-4.

21. Timing of PEP: CDC Guidelines • “PEP should be initiated as soon as possible, preferably within hours rather than days of exposure.” • Interval after which there is no benefit for humans is not known • Obtain expert advice when interval has exceeded 24-36 hours MMWR 2005;54(No. RR-9).

22. How Long Should PEP be Administered? • N = 24 macaques inoculated with SIV intravenously • PEP initiated 24 hours post-inoculation • PEP administered for 3, 10, or 28 days Tsai C-C et al. J Virol 1998;72:4265-73.

23. Duration of PEP • In animal model, 28 days more effective than 10 days or 3 days of PEP1 • 4 weeks (28 days) used in case-control study2 and recommended by CDC guidelines3 1. Tsai C-C et al. J Virol 1998;72:4265-73. 2. Cardo DM et al. NEJM 1997;337:1485-90. 3. MMWR June 29, 2001:50(RR11);1-42.

24. Back to the Case • 27 yo Medical Assistant presents to Urgent Care for evaluation of needlestick 2 days ago from a diabetic lancet • Source patient (SP): 35 yo male, known HIV+ • What other questions do you have for her?

25. Back to the Case • According to the MA, the SP has never received treatment for his HIV. She does not know his VL or CD4 count, but “he looks pretty healthy.” • The lancet was visibly bloody and stuck her through her glove, causing her to bleed • Exam: pinpoint puncture wound on thumb • What are your PEP recommendations?

26. Which PEP regimen should be considered?

27. PEP Regimens: Basic regimens • Two NRTIs • Simple dosing, fewer side effects • Preferred basic regimens: zidovudine (AZT) OR tenofovir (TDF) plus lamivudine (3TC) OR emtricitabine (FTC) • Alternative basic regimens: stavudine (d4T) OR didanosine (ddI) plus lamivudine (3TC) OR emtricitabine (FTC) MMWR 2005;54(No. RR-9).

28. Expanded PEP Regimens • Basic regimen plus a third agent • Rationale: 3 drugs may be more effective than 2 drugs, though direct evidence is lacking • Consider for more serious exposures or if resistance in the source patient is suspected • Adherence more difficult • More potential for toxicity

29. Expanded PEP Regimens • Preferred Expanded Regimen: • Basic regimen plus lopinavir/ritonavir (Kaletra) • Alternate Expanded Regimens: • Basic regimen plus one of the following: • Atazanavir* +/- ritonavir • Fosamprenavir +/- ritonavir • Indinavir +/- ritonavir • Saquinavir (hgc; Invirase) + ritonavir • Nelfinavir • Efavirenz MMWR 2005;54(RR-9) *Atazanavir requires ritonavir boosting if used with tenofovir

30. Adverse Effects: Basic vs Expanded Regimens % of individuals Puro V et al. 9th CROI, February 2002, Abstract 478-M

31. Other Antiretrovirals • ARVs to be considered only with expert consultation: • Enfuvirtide (Fuzeon; T-20) • ARVs not generally recommended for PEP: • Delavirdine • Zalcitabine • Abacavir • Nevirapine MMWR 2005;54(No. RR-9).

32. 0 MMWR 2005;54(No. RR-9).

33. Back to the Case • After extensive counseling, she decides to take zidovudine + lamivudine (Combivir) basic regimen • You write the prescription and arrange for follow-up, but before the patient leaves, the triage nurse informs you that she has finally tracked down the SP’s Primary Care Provider

34. Back to the Case, continued • The SP’s PCP tells you the following: • His CD4 count was 450 cells/mm3 two months ago, his CD4 nadir is 280 cells/mm3, he has never had an OI. • SP is not naïve to therapy; for the past year he has been on AZT/3TC/RTV/IDV (1st regimen). • Viral load 2 months ago was around 60,000 copies/mL. • What do you do with this information?

35. HELP! • Expanded regimens and expert advice indicated for severe exposures or when resistance is suspected • Northwest AETC • Hillary Liss (206) 541-7082 pager • Chris Behrens (206) 994-8773 pager • National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline) • (888) HIV-4911

36. Case: PEP options • Source patient’s high-level VL despite ART suggests that he is either not taking his medications, or that he has developed resistance to his regimen • Turn-around time for a resistance assay too long for this to be a useful tool in designing her PEP regimen – Must make best guess about patterns of anticipated resistance to SP’s regimen • If resistance has developed, would suspect resistance to lamivudine, zidovudine, and possibly ritonavir/indinavir • Cross-resistance considerations would suggest that resistance to stavudine and abacavir may also exist; resistance to tenofovir and didanosine also possible but less likely

37. Case: PEP options • Given concerns over efficacy of a 2-NRTI regimen, would recommend a 3 or 4 drug PEP regimen • Resistance to PIs: difficult to estimate, but PI resistance generally evolves less rapidly than does resistance to the NRTI components of typical ART regimens • Would not expect any resistance to NNRTI class • One reasonable PEP regimen: tenofovir + d4T + (efavirenz OR lopinavir/ritonavir) • Notes: • Efavirenz is contraindicated in pregnancy • Combining ddI + tenofovir + efavirenz no longer recommended in ART regimens

38. CDC Post-Exposure Prophylaxis Guidelines MMWR 2005;54(No. RR-9). http://www.aidsinfo.nih.gov

39. CDC Post-Exposure Prophylaxis Guidelines MMWR 2005;54(No. RR-9).

40. CDC Post-Exposure Prophylaxis Guidelines MMWR 2005;54(No. RR-9).

41. Situations for which expert consultation* for HIVpostexposure prophylaxis (PEP) is advised * Either with local experts or by contacting the National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline), 888-448-4911. MMWR 2005;54(No. RR-9).

42. 0 Follow-up of health-care personnel (HCP) exposed to known or suspected HIV-positive sources • Exposed HCP should be advised to use precautions (e.g., avoid blood or tissue donations, breastfeeding, or pregnancy) to prevent secondary transmission, especially during the first 6–12 weeks post-exposure. • For exposures for which PEP is prescribed, HCP should be informed regarding: • need for monitoring • possible drug interactions • the need for adherence to PEP regimens. • Consider re-evaluation of exposed HCP 72 hours post-exposure, especially after additional information about the exposure or SP becomes available. MMWR 2005;54(No. RR-9).

43. Follow-up HIV Testing • CDC recommendations: HIV Ab testing for 6 months post-exposure (e.g., at 6 weeks, 3 months, 6 months) • Extended HIV Ab testing at 12 months is recommended if health care worker contracts HCV from a source patient co-infected with HIV and HCV • VL testing not recommended unless primary HIV infection (PHI) suspected MMWR 2005;54(No. RR-9).

44. Case 2: Non-occupational exposure • 34 yo woman presents to ED after being sexually assaulted by someone that she says is HIV-infected • Physical exam reveals perineal bruising, shallow vaginal lacerations • What is her level of risk? • Should PEP be considered? • Are there guidelines that cover this situation?

45. Exposure Risks (average, per episode, involving HIV-infected source patient)

46. Is PEP effective for non-occupational exposures? • Brazilian non-randomized trial of PEP following sexual assault: rate of HIV transmission was 2.7% in control subjects compared with 0% in those who received PEP (P < .05). • Buenos Aires study involving MSM: HIV transmission occurred in 4.2% of 131 men who did not receive PEP, compared with 0.6% of 66 men who received PEP (P < .05). Schechter M. Program and abstracts of the Sixth International Congress on Drug Therapy in HIV Infection; November 17-21, 2002; Glasgow. Abstract PL6.1.

47. Guidelines???

49. Non-occupational PEP: Evaluation & Treatment Algorithm MMWR January 21, 2005, Vol 54, No. RR-2

50. Non-occupational PEP Regimens MMWR January 21, 2005, Vol 54, No. RR-2