1. Beyond Fear: Bloodborne Pathogens and the Health Care Worker National HIV/AIDS Clinicians’ Consultation Center National Clinicians’ Post-Exposure Prophylaxis Hotline

2. Scope of the Problem Recent epidemiology of bloodborne pathogens (BBP) Recent epidemiology of occupationally acquired BBP How post-exposure management can affect delivery of care

3. Recent United States Epidemiology HIV –Estimated 800,000-900,000 people with HIV –40,000 new cases each year Hepatitis C –Estimated 3.9 million total US infections (1.8% of US population) Hepatitis B –750,000-1 million carriers in the US

4. Recent Occupational Epidemiology HIV –57 documented occupational infections in U.S. health care workers, 138 possible infections Hepatitis C –1-2% of health care workers infected (same as general population) Hepatitis B –400/year in 1995 compared to 16,000/yr in 1983

5. Exposure management makes a difference! Health care workers put themselves at risk in their work. Prevention of exposures is critical. Appropriate treatment, including PEP, after exposures reduces risk. Awareness of post-exposure options may allay fears of caring for infected patients.

6. Components of Post-exposure Treatment Crisis Management Risk Assessment Laboratory Assessment of Source Post-Exposure Prophylaxis Follow-up Care

7. Case Slide 27 year old nurse sustained a deep stick from a bloody needle after placing an IV. The source patient was HIV+ and being treated with AZT/3TC/nelfinavir. His viral load was 122,000 several weeks earlier and he was admitted for bacterial pneumonia.

8. Crisis Management BBP exposures can be turning points for health care workers. Extreme anxiety can be directly confronted. –Reassure without dismissing feelings. –Bridge gap between objective and subjective assessment. Base approach on philosophy of advocacy for the worker.

9. Case Slide Due to the high risk nature of this exposure, this nurse was seen immediately by the infectious diseases consultant to occupational health. He consulted with several colleagues to choose the optimal regimen for PEP and to ensure that he was maintaining his objectivity.

10. DETERMINING RISK Assessment of the Exposure Assessment of the Source

11. Defining Exposure - PHS Definition “…a percutaneous injury…or contact of mucous membrane or non-intact skin…with blood, tissue or other body fluids that are potentially infectious.” Updated Public Health Service Guidelines for the management of Occupational Exposures to HBV, HCV and HIV and Recommendations for PEP. June 29, 2001.

12. Defining Exposure - General Principles HIV, HBV and HCV do not spontaneously penetrate intact skin. Airborne transmission of these viruses does not occur. Beltrami, et al. ClinMicroRev July 2000.

13. Defining Exposure: Infectious Body Fluids Definitely infectious: –blood –semen –vaginal secretions –any visibly bloody body fluid

14. Defining Exposure: Infectious Body Fluids Potentially infectious: –cerebrospinal fluid –synovial fluid –pleural fluid –peritoneal fluid –pericardial fluid –amniotic fluid –pus

15. Defining Exposure: Infectious Body Fluids Not infectious unless visibly bloody: –feces, urine –nasal secretions, sputum –saliva –sweat –tears –vomitus

16. Defining Risk - Per-exposure Estimates HIV percutaneous 0.3% mucocutaneous 0.09% HCV percutaneous 1.8% HBV percutaneous –eAg+ 40% –eAg- 1.5-10%

17. Defining Risk Public Health Service Guidelines Needlestick –Less severe (eg. Solid needle and superficial injury) –More severe (eg. Large-bore hollow needle, deep puncture, visible blood on device, or needle used in patient’s artery or vein) Mucous membrane and nonintact skin –Small volume (i.e. a few drops) –Large volume (i.e.. major blood splash)

18. Stratifying Risk - Case-control Study

19. Stratifying Risk - In vitro Studies In vitro studies –Larger needles and deeper sticks are associated with larger blood volume transfer. Mast et al. JID 1992 168:1589-92 –Gloves reduce blood volume transfer. –Bennett, Howard. J.Am.Coll.Surg. 1994 178:107-110 Needles used for injection likely less risky than those used to draw blood.

20. Stratifying Risk Splash to mucous membrane or non-intact skin. –Longer exposure to higher volume likely more risky. Bite exposures. –Bite victim not at risk unless blood in saliva. –Biter has sustained blood to mucous membrane exposure.

21. Stratifying Risk - Source Assessment If source is HIV+ –What is viral load/stage of disease? If HIV status is unknown –What is history of risk factors? –Any symptoms of primary HIV infection? –What is history of testing ? If source is unknown –What is prevalence where exposure occurred? –How long has sharp been environmentally exposed?

22. Source Assessment: Laboratory Management Do not delay PEP while awaiting source patient laboratory results. The decision to start PEP is based on the clinical risk assessment. Consider testing options: –rapid vs standard HIV antibody test kit –antibody testing vs direct virus assay –no option currently to test discarded needles

23. Source Assessment: Laboratory Management Rapid EIA should be considered. –A negative result allays anxiety and prevents overuse of PEP. –The false positive rate is higher than the standard EIA. This is particularly significant in low risk populations. –All positive tests must be confirmed with a Western Blot or Immunofluoresence assay.

24. Source Assessment: Laboratory Management Standard EIA may be preferred, especially if it can be performed in 24-48 hours. Direct virus assays (p24 or viral load) not recommended, unless source is suspected to be in the window period. –Not standardized for diagnosis. –High false positive rate (2-5%).

25. Source Assessment: Addressing the Window Period Median time to seroconversion is estimated at 4 weeks. If source is HIV- and has no history of recent (last 3 months) risk behavior and no symptoms of primary HIV infection, consider HIV ruled out.

26. PEP for HIV - General Principles Most exposures do not result in transmission of HIV, so risk and benefit must be weighed carefully. Consider risk of exposure and source. Consider factors in the health care worker. –concurrent illness or medication. –pregnancy or breastfeeding.

27. Side effects may outweigh benefits Low risk exposure Low risk source Found needle Delay (>72 hrs) Drug interactions/co- existing medical conditions. Pregnancy??? PEP likely beneficial High risk exposure Known positive source High risk source No delay to rx Choice of drugs minimizes toxicity

28. PEP for HIV: Plausibility Rhesus macaque model: –intravaginal exposure to SIV. at 24 hours, SIV detected in vaginal dendritic cells. by 48 hours, SIV detected in regional lymph nodes. by 5 days SIV detected in peripheral blood. The time to disseminated infection provides a window for intervention.

29. PEP for HIV: Efficacy Macaque model: IV inoculation with SIV. PMPA prophylaxis started 48 h before, 4 h after or 24 h after inoculation and continued for 28 days. Controls untreated. No treated animal were infected; all controls were infected. Tsai CC et al. Science270:1197-1199.

30. PEP for HIV: Efficacy ACTG 076: randomized controlled trial to assess ability of AZT to reduce perinatal transmission in humans. Risk of vertical transmission reduced from 22.6% in placebo treated controls to 7.6% in treatment arm (AZT alone). Reduction in viral load only partially explains reduction in transmission.

31. PEP for HIV: Efficacy NY DPH Perinatal Transmission

32. PEP for HIV: Timing Macaques inoculated IV with SIV PEP with PMPA for 28 d initiated 24, 48 and 72 h after inoculation. Controls mock treated. –All controls infected –All animals treated at 24 h protected –Half of the animals in the other treatment groups showed persistent viremia. Tsai CC et al. J Virology 1998

33. PEP for HIV: Timing Rhesus monkeys inoculated IV with SIV AZT PEP initiated 1, 8, 24 and 72 h after inoculation. Controls mock treated –Infection prevented in 1/5 in the 1 and 8 h groups –Antigenemia delayed and reduced in all other treated animals. Martin LN et al. JID 1993

34. PEP for HIV: Timing SCID-hu mice inoculated IV with HIV AZT PEP initiated 0.5, 1, 2, 4, 8, 24, 36, and 48 h later. –All mice treated at 0.5, 1, and 2 h protected. –80% of mice treated at 8 h protected. –40% of mice treated at 24 h protected. –No effect of treatment initiated at 48 h. Shih CC et al. JID 1991

35. PEP for HIV: Timing 13 yo girl transfused w/ one unit of blood from donor in the window period Infection risk estimated at 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

36. PEP for HIV: Duration Macaques inoculated IV with SIV PEP with PMPA initiated at 24 h after exposure, and continued for 3, 10 and 28 d. –All animals treated for 28 days protected. –¼ animals treated for 10 days had persistent infection, ¾ with antibody response, –2/4 animals treated for 3 days had persistent infection, 4/4 with antibody response.

37. PEP for HIV: Choosing a regimen Basic regimen? Alternate basic regimen? Expanded regimen? –Protease inhibitors –NNRTIs –Abacavir Drugs for use with consultation?

38. Case slide The exposed health care worker was in good health, on no medications and not pregnant or breastfeeding. After extensive counseling and discussion, a regimen of ddI/d4T/nevirapine was initiated.

39. PEP Regimen Options Basic Regimens For use after low risk exposure to HIV+, ARV naïve source, or when source not known HIV+. AZT 300 mg BID+3TC 150BID Side effects: nausea, headache, fatigue, rare anemia from AZT

40. PEP Regimen Options Alternative Basic Regimens For use when source virus likely resistant to or health care worker intolerant of Basic Regimen ddI 200mg BID(400qD)+d4T 40 mg BID d4T 40 mg BID+3TC 150 BID AZT 300 mg BID+ddI 200 mg BID(400qD) Side effects: ddI – nausea, diarrhea, pancreatitis, neuropathy. d4T - neuropathy

41. PEP Regimen Options Expanded Regimens For use after high risk exposures to HIV+ source or when source virus resistant. Basic regimen plus one of the following: –Protease inhibitor –Dual PI –NNRTI –Third nucleoside (abacavir)

42. PEP Regimens Why NOT expanded regimen? Transmission is rare. No evidence that 3 drugs is better than 2 (or 2 better than 1). 3 drug regimens associated with more toxicity and decreased adherence.

43. PEP Registry: 4-6 week follow up n=449

44. PEP Registry: Reasons for discontinuation* *Reasons not mutually exclusive (48%) (50%) (31%) (13%) (2%) (5%)

45. Expanded Regimen - Single Protease Inhibitor nelfinavir 750 mg TID/1250 BID OR indinavir 800 mg q 8hr. Nelfinavir - diarrhea, nausea, vomiting, increased LFT’s Indinavir - nausea, vomiting, increased LFT’s, kidney stones, difficult adherence.

46. Expanded Regimen - Dual PI Saquinavir + Ritonavir Indinavir + Ritonavir Amprenavir + Ritonavir Lopinavir + Ritonavir Dual PIs may have added activity. BID regimens more convenient. Potentially increased toxicities and complex drug interactions.

47. Expanded Regimens - NNRTI Efavirenz 600 mg qD Nevirapine not recommended. Potent agent in treatment. >50% of patients have CNS effects. Teratogenic in monkeys

48. Case slide She tolerated the regimen well for 14 days when she noted the onset of fever to 101 F, sore throat, disseminated lymphadenopathy (most marked cervically), a fine macular rash on her trunk, and arthralgias. She was seen immediately by the ID consultant who noted no thrush, or oral/genital ulcers.

49. Symptom Management in PEP: Acute infection vs. drug effect Symptoms of acute HIV or hepatitis can resemble those of an adverse drug reaction (fever, rash, abnormal liver function tests). Follow patients closely with complete physical, medication adjustment, and targeted laboratory assessment.

50. PEP Laboratory Monitoring At baseline and q 2 weeks while on PEP. –CBC –Renal panel –LFT’s –UA if on IDV Consider glucose if on PI. Baseline serology Follow-up serology at 6 weeks, 3 months, 6 months post exposure. Can recheck at 1 year. –May be more important if HCW infected with HCV from same exposure.

51. Typical Course of Primary HIV 1 mil 100,000 10,000 1,000 100 10 + _ HIV RNA HIV-1 Antibodies Exposure P24 + 020304050 Symptoms Days HIV RNA Ab

52. Primary HIV Infection: Symptoms and Signs Fever87% Rash68% Pharyngitis48% Oral Ulcers40% Genital Ulcers/Discharge36% Myalgias42% Also, headache, diarrhea, abdominal pain, arthralgias, nausea and vomiting in 29-39%.

53. Quantitative HIV RNA Test for Dx of Acute HIV Not licensed for diagnosis 2-5% false positive rate (of 100 HIV negative persons, 2-5 will test positive). Most false positives are low level, < 1,000 Under 3,000 should probably be considered “indeterminant”

54. Case study Multiple lab studies were obtained, including: WBC 3.1, 20% lymphocytes, transaminases 1.5X normal, HIV VL undetectable, p24 antigen negative. Additional studies were all negative: RPR, blood cx, CMV IgM/IgG, Toxo IgM/IgG, HCV/HBV serologies, HCV VL, Parvovirus serology, tularemia serology

55. Case from the PEPline Nevirapine was stopped and ritonavir and saquinavir were added to the regimen. Symptoms continued for several weeks.

56. Nevirapine: Serious Adverse Events MMWR 1/5/2001 report of 22 cases of severe toxicity in people taking NVP for PEP from 3/97 through 9/2000. Clinical syndromes reported –12 cases of hepatotoxicity (2 of fulminant hepatitis, one requiring liver transplantation) –14 cases of skin reaction (1 Stevens-Johnson) –1 case of rhabdomyolysis

57. Nevirapine in PEP: PEPline recommendations Nevirapine should not be used unless all of the following criteria are met: –Exposure was high risk. –Source is known or suspected to have high level resistance to most other antivirals. –Efavirenz is contraindicated. –Exposed person has no preexisting liver disease and takes no hepatotoxic medications.

58. PEP for HIV: Pregnant worker Known or suspected pregnancy is not a contraindication to PEP. Avoid efavirenz, due to teratogenicity in monkeys, as well as the combination of d4T and ddI which has been associated with lactic acidosis.

59. PEP for HIV: Failures of PEP 21 reported cases of failure –16 cases used AZT alone –2 cases used AZT + ddI –3 cases used 3 or more drugs Factors implicated in failure –Viral resistance –Large inoculum –Delayed or shortened PEP

60. PEP for HIV: Summary Limited data, much of which is indirectly related to occupational exposure. Occupational infection is rare, so decision to use PEP must always balance assessment of infection risk with risk of toxicity. If PEP is used, it should be started as soon as possible, preferably within 24 h and continued for 28 days.

61. Case from the PEPline Because of concern about acute infection, PEP was continued for 3 months. Six and twelve month HIV serologies were negative. Six month CMV IgG was positive.

62. Hepatitis B– When is HBIG Necessary? When HCW is unprotected (unvaccinated or non- responder) AND SP known hepatitis B SAg+

63. Hepatitis B– When can HBIG be Considered? When HCW is unprotected (unvaccinated or non- responder) AND SP at high risk for hepatitis B infection OR exposure occurred in area where there a high risk of hepatitis B infection

64. HBIG- Dosing and Administration Ideal if can be given 24-72 hours but can be given up to 7 days after an exposure –Have time to evaluate both HCW and SP hepatitis B status Dose 0.06 mL/kg (NTE 5 mL)

65. Hepatitis C No prophylaxis currently available –Immunoglobulin donors screened out if HepC+ –Interferon/ribavirin toxic in treatment and not studied in PEP New data on early treatment promising (NEJM 11/11/01) –PEPline recommends baseline Hepatitis C Ab and ALT, ALT at 6 weeks, and Hepatitis C Ab and ALT at 3 months and 6 months to make early diagnosis