UPDATE IN HIV POST-EXPOSURE PROPHYLAXIS. Weerawat Manosuthi

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1 UPDATE IN HIV POST-EXPOSURE PROPHYLAXIS Weerawat Manosuthi

2 Outline Case scenario of postexposure prophylaxis Risks of and how to manage postexposure prophylaxis Current PEP guideline US PHS 2013 New York guideline 2012 Thai guideline 2010 WHO 2007 CDC 2005

3 Case presentation 1 Male paramedic splashed with large volume of bloody amniotic fluid onto open ulcers on his arm. He has DM II, HT, DLP, GERD, CKD, peripheral neuropathy. Source is HIV+ without any treatment during this pregnancy. Paramedic started on AZT, 3TC, and lopinavir/rtv. Two days later, he complains of overwhelming nausea and vomiting.

4 Case Presentation 2 Nurse stuck with a needle found on the floor of a patient s room. Patient in that room is HIV infected with VL >750,000. He had complex ARV Hx, marked with lots of non-adherence. His current regimen was AZT, 3TC and EFV. Nurse was started on AZT, 3TC, and NVP. Nurse s friend recommended changing to AZT, d4t and Kaletra.

5 Case Presentation 3 Phlebotomist stuck with vacutainer needle while transferring blood. Wearing gloves. Deep stick. Source is HIV+, and Hepatitis C +. Started on AZT, TDF and lopinavir/rtv one month ago when VL >750,000 and CD His doctor thinks adherence is good. Three months before starting new regimen, genotype while on d4t, 3TC, efavirenz had shown M184V and K103N.

6 Who is the most frequently reported occupational acquired HIV infection? 1. Nurses 2. Physicians 3. Lab technicians 4. House keepers

7 Occupational Acquired HIV infection Do A, et al. Infect Control Hosp Epidemiol 2003;24:86-96.

8 45 HCPs who reported accidental injuries in BIDI On exposed person analysis, 7.5% (3 of 40), 2.9% (1 of 34), 0% were positive for HBsAg, Anti-HCV and Anti-HIV, respectively. Seven of 45 (15.5%) events were severe exposures. 24 % (22of 45) of staffs initiated HIV PEP. 16 % initiated within 1 hour after exposure and half of them continued HIV PEP until 4 weeks. 53% (24 of 45) of staffs had previous history of HBV vaccination.

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12 Postexposure Management Step Management 1 Exposure site management 2 Exposure reporting 3 Evaluation of transmission risk 4 Counseling 5 Consideration of PEP 6 Follow-up

13 Postexposure Management Step Management 1 Exposure site management 2 Exposure reporting 3 Evaluation of transmission risk 4 Counseling 5 Consideration of PEP 6 Follow-up

14 Exposure Site Management Wound and skin: washed with soap and water Mucous membrane: flushed with water No evidence of benefit for: Application of antiseptics or disinfectants Squeezing ( milking ) puncture sites Avoid use of bleach and other agents caustic to skin

15 Postexposure Management Step Management 1 Exposure site management 2 Exposure reporting (1-4) 3 Evaluation of transmission risk 4 Counseling 5 Consideration of PEP 6 Follow-up

16 Exposure Report 1 (1) Details of procedure being performed Date and time of exposure Where and how exposure occurred Type and brand of device How and when in course of handling device (2) Details of exposure Type and amount of fluid, severity of exposure Percutaneous: depth of injury whether fluid was injected Skin or mucous membrane: estimated volume of material, condition of skin

17 Exposure Report 2 (3) Details of exposure source Source of material contained HBV, HCV or HIV? If HIV-infected: stage of disease, history of ARV, viral load, ARV resistance (4) Details of exposed person Anti HIV, Anti HBV, Anti HCV status Hepatitis B vaccination & vaccine response

18 Postexposure Management Step Management 1 Exposure site management 2 Exposure reporting 3 Evaluation of transmission risk 4 Counseling 5 Consideration of PEP 6 Follow-up

19 Evaluation of Transmission Risk 3 Type of HIV transmission Risk of transmission per exposure event Blood transfusion 0.95 Perinatal exposure 0.13 Needle sharing (IVDU) Needle stick (0.3%, 95%CI %) Unprotected receptive anal intercourse Needle sharing Unprotected receptive vaginal intercourse Mucous membrane exposure (0.09%, 95%CI %) Unprotected insertive vaginal intercourse Ingestion of human milk

20 Blood Potential fluid Body fluid containing visible blood CSF Pleural fluid Semen, Vg secretion Synovial fluid Pleural fluid Peritoneal fluid Non Potential fluid Feces Sweat Nasal secretion Tears Saliva Urine Sputum Vomitus Pericardial fluid Amniotic fluid Human bite Direct contact

21 Factors APPENDIX D. Associated LOGISTIC REGRESSION with ANALYSIS Transmission OF RISK FACTORS FOR HIV after INFECTION AFTER PERCUTANEOUS EXPOSURE TO HIV-INFECTED BLOOD Percutaneous Exposure Logistic Regression Analysis of Risk Factors for HIV Infection After Percutaneous Exposure to HIV-Infected Blood Risk Factor US Cases a All Cases b Adjusted odds ratio (95% CI) c Deep injury 16.1 ( ) Visible blood on device 5.2 ( ) Procedure involving needle in artery or vein 5.1 ( ) Terminal illness in source patient d 6.4 ( ) Postexposure use of zidovudine 0.2 ( ) Reprinted from Cardo DM, Culver DH, Ciesielski CA, et al. A case-control study of HIV seroconversion in health care workers after percutaneous exposure: Centers for Disease Control and Prevention Needlestick Surveillance Group. N Engl J Med 1997;337: [PubMed] a All risk factors were significant (P < 0.02). b All risk factors were significant (P < 0.01). c Odds ratios are for the odds of seroconversion after exposure in workers with the risk factor as compared with those without it. d Terminal illness was defined as disease leading to the death of the source patient from AIDS within two months after the health care worker s exposure. NEJM 1997; 337: Postgrad Med J 2003,79:324-8.

22 Average Risk for Transmission of HIV, HBV, and HCV after Needle stick Source Risk HBV HBeAg+ HBeAg- 22.0% % 1.0% - 6.0% HCV+ 1.8% HIV+ 0.3%

23 Postexposure Management Step Management 1 Exposure site management 2 Exposure reporting 3 Evaluation of transmission risk 4 Counseling 5 Consideration of PEP 6 Follow-up

24 HIV Postexposure Counseling 1. Possible side effects of PEP drugs 2. Possible drug interactions 3. Adherence 4. Signs and symptoms of acute HIV infection Fever, rash,flu-like illness 5. Prevention of secondary transmission Sexual abstinence or condom use No blood/tissue donation Transmission and PEP drug risks if breastfeeding No work restriction indicated

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26 Postexposure Management Step Management 1 Exposure site management 2 Exposure reporting 3 Evaluation of transmission risk 4 Counseling 5 Consideration of PEP 6 Follow-up

27 Considerations When Using PEP Risk of Transmission PEP Risk of Adverse Effects

28 Initiation of HIV PEP If indicated, start PEP as soon as possible after exposure Regard as an urgent medical concern Hours rather than days Interval after which PEP is no longer likely to be effective in humans is unknown Initiating PEP days or weeks after an exposure might be considered if warranted for increased risk exposure

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30 Animal Studies of PEP: Prevention of SIV in macaques with Tenofovir Initiation / duration % Protected 24h / 28d 100% 48h / 28d 50% 72h / 28d 50% 24h / 10d 75% 24h / 3d 0% Tsai et al, J Virol, 1998;72:4265 Tsai et al, J Virol 1998;72:4265.

31 CDC 2005: Definitions HIV-Positive, Class 1= Asymptomatic or low viral load HIV-Positive, Class 2 = Symptomatic, AIDS, acute seroconversion, high viral load Less severe = Solid needle and superficial injury More severe = Large-bore hollow needle, deep puncture, visible blood on device, needle used in artery/vein Small volume = A few drops Large volume = Major blood splash

32 PEP for Percutaneous Injuries Infection status of source Type HIV-Positive Class 1 HIV-Positive Class 2 Source of unknown HIV status Unknown source Less severe Recommended basic 2-drug PEP Recommended expanded 3-drug PEP Generally, no PEP; consider basic 2- drug PEP for source with HIV risk Generally, no PEP; consider basic 2-drug PEP in settings where exposure to HIVinfected persons is likely More severe Recommended expanded 3-drug PEP Recommended expanded 3-drug PEP HIV-Positive, Class 1= Asymptomatic or low viral load HIV-Positive, Class 2 = Symptomatic, AIDS, acute seroconversion, high viral load Less severe = Solid needle and superficial injury More severe = Large-bore hollow needle, deep puncture, visible blood on device, needle used in artery/vein MMWR Recomm Rep 2005; Sep 30; 54(RR-9):1-7.

33 PEP for Mucous Membrane and Non-intact Skin Exposures Infection status of source Type HIV-Positive Class 1 HIV-Positive Class 2 Source of unknown HIV status Unknown source Small volume Consider basic 2-drug PEP Recommended basic 2-drug PEP Generally, no PEP Generally, no PEP Large volume Recommended basic 2-drug PEP Recommended expanded 3-drug PEP Generally, no PEP; consider basic 2- drug PEP for source with HIV risk Generally, no PEP; consider basic 2-drug PEP in settings where exposure to HIVinfected persons is likely HIV-Positive, Class 1 = Asymptomatic or low viral load HIV-Positive, Class 2 = Symptomatic, AIDS, acute seroconversion, high viral load Small volume = A few drops Large volume = Major blood splash MMWR Recomm Rep 2005; Sep 30; 54(RR-9):1-7.

34 2-drug Regimen WHO Guideline drug Regimen 1 2

35 Which Drugs to Use? Basic 2-drug regimens: CDC Preferred: ZDV + 3TC TDF + 3TC or FTC Basic 2-drug regimens: WHO Preferred: ZDV + 3TC Alternative: d4t + 3TC ddi + 3TC Alternative: TDF + 3TC d4t + 3TC Expanded 3-drug PEP regimens: Preferred: LPV/RTV (Kaletra) + basic 2-drug regimen MMWR Recomm Rep 2005; Sep 30; 54(RR-9):1-7.

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37 Figure 1. PEP Following Occupational Exposure Two-drug regimen is not recommended. New York Guideline

38 Recommended Regimen for HIV PEP Table 3 Recommended Regimen for HIV PEP Following Occupational Exposure a Tenofovir b 300 mg PO qd + Emtricitabine b,c 200 mg PO qd Plus AZT is no longer recommended. Raltegravir d 400 mg PO bid a When the source is known to be HIV-infected, past and current ART experience, viral load data, and genotypic or phenotypic resistance data (if available) may indicate the use of an alternative PEP regimen. Consult with a clinician experienced in managing PEP. See Tables 4 and 5. b The dosing of tenofovir and emtricitabine/lamivudine should be adjusted in patients with baseline creatinine clearance <50 ml/min (see Appendix A for dosing recommendations). Tenofovir should be used with caution in exposed workers with renal insufficiency or who are taking concomitant nephrotoxic medications. Fixed-dose combinations should not be used in patients who need dose adjustment due to renal failure. c Lamivudine 300 mg PO qd may be substituted for emtricitabine. However, a fixed-dose combination is available when tenofovir is used with emtricitabine (Truvada 1 PO qd). d The dosing of raltegravir should be adjusted when co-administered with rifampin (see Appendix A for dosing recommendations). A. Duration of PEP Regimen New York Guideline

39 Preferred Alternative PEP Regimens New York Guideline

40 Antiretroviral Drugs to Avoid Drugs to avoid Efavirenz Nevirapine Abacavir Stavudine and Didanosine Nelfinavir and Indinavir CCR5 co-receptor antagonists Reasons - CNS side effects are common - Complicating the need to provide a first dose at any time of the day - Should be avoided in pregnant women - Substantial efavirenz resistance - Severe hepatotoxicity - Hypersensitivity reactions - Possibility of toxicities -Poorly tolerated - Lack of activity against potential CXCR4 tropic virus New York Guideline

41 US PHS Guideline 2013 Infection Control Hospital Epidimiology 2013;34:

42 US PHS Guideline 2013 Infection Control Hospital Epidimiology 2013;34:

43 US PHS Guideline 2013 Infection Control Hospital Epidimiology 2013;34:

44 Thai Guideline 2014

45 Thai Guideline 2010 Prefered basic regimens Alternative basic regimens Expanded regimens AZT/3TC d4t/3tc PI: LPV/r, IDV/r, ATV/r, SQV/r TDF/3TC ddi/3tc NNRTI: EFV TDF/FTC

46 Thai Guideline 2010 Prefered basic regimens Alternative basic regimens Expanded regimens AZT/3TC d4t/3tc PI: LPV/r, IDV/r, ATV/r, SQV/r TDF/3TC ddi/3tc NNRTI: EFV TDF/FTC Thai Guideline 2014 Antiretroviral Regimens A TDF + 3TC/FTC + Rilpivirine Remarks TDF + 3TC/FTC + Lopinavir/r B C TDF + 3TC/FTC + Atazanavir/r TDF +3TC/FTC + Raltegravir TDF + 3TC/FTC + Efavirenz Use AZT for regimen A or B If GFR < 60

47 Drug-drug Interactions!

48 Drug-drug interactions

49 Consideration of PEP PEP during pregnancy Efavirenz is NOT recommended during pregnancy because of possible teratogenicity? Cases of fatal lactic acidosis in pregnant women treated with d4t and ddi reported Indinavir should not be given shortly before delivery because of hyperbilirubinemia

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51 New York 2012: How to Follow-up New York Guideline

52 US PHS 2013: How to Follow-up Infection Control Hospital Epidimiology 2013;34:

53 Thai Guideline 2014

54 Case presentation 1 Male paramedic splashed with large volume of bloody amniotic fluid onto open ulcers on his arms. He has DM II, HT, DLP, GERD, CKD, peripheral neuropathy. Source is HIV+ without any treatment during this pregnancy. Paramedic started on AZT, 3TC, and lopinavir/rtv. Two days later he complains of overwhelming nausea and vomiting.

55 Management Assess injury: Large volume exposure to skin with compromised integrity. Assess source: Known HIV+, likely high viral load, but virus also likely wild-type. Recommend management: Manage symptoms using anti-emetics and consider pro-motility agent for diabetic gastroparesis. Consider other regimens: AZT/3TC/RTV/PI, AZT/3TC/EFV. Consider drug interactions.

56 Case Presentation 2 Nurse stuck with a needle found on the floor of a patient s room. Patient in that room is HIV infected with VL >750,000. He had complex ARV Hx, marked with lots of non-adherence. His current regimen was AZT, 3TC and EFV. Nurse was started on AZT, 3TC, and NVP. Nurse s friend recommended changing to AZT, d4t and Kaletra.

57 Management Assess injury: No characteristics of the needle available. Stick not deep. Assess source: Unknown source. Consider how likely it is that needle came from HIV+ source. Recommend management: If it is likely that this needle was used on an HIV+ patient recently, a full course of PEP is recommended, with choice of drugs taking into account possible resistance. Kaletra may maintain activity against resistant virus, but AZT and d4t not recommended in combination because of clinical and in vitro antagonism.

58 Case Presentation 3 Phlebotomist stuck with vacutainer needle while transferring blood. Wearing gloves. Deep stick. Source is HIV+, and Hepatitis C +. Started on AZT, TDF and lopinavir/rtv one month ago when VL >750,000 and CD4 73. His doctor thinks adherence is good. Three months before starting new regimen, genotype while on d4t, 3TC, efavirenz had shown M184V and K103N.

59 Management Recommend management: Recommend regimen for HIV PEP. 3TC likely ineffective. Protease inhibitor resistance unlikely to have developed during one month of therapy. Consider AZT, TDF, lopinavir/rtv (same as source regimen), as option most likely to combine effectiveness with tolerability. Follow closely for Hepatitis C seroconversion.

60 Summary of PEP Recommendation Time to initiate PEP Preferred PEP Thai 2014 US PHS 2013 New York 2012 < 72 hrs ASAP, <72 hrs Prefer <2 hrs, < 36 hrs LPV/r ATV/r RPV TDF/FTC TDF /3TC WHO 2007 CDC 2005 < 72 hrs <72 hrs RAL TDF/FTC RAL TDF/FTC LPV/r AZT/3TC LPV/r AZT/3TC TDF /3TC TDF/FTC Alternative PEP RAL EFV AZT/3TC RAL DRV/r ATV/r LPV/r ETR RPV TDF/FTC TDF/3TC AZT/3TC AZT/FTC DRV/r ATV/r FPV/r TDF/FTC ATV/r SQV/r APV/r TDF/FTC d4t/3tc ATV/r FPV/r IDV/r SQV/r NFV EFV d4t/3tc ddi/3tc

61 Summary of HIV Test Recommendation GUIDELINES Baseline Wk 4 Wk 6 Wk 12 Wk 16 Wk 24 Wk 48* Thai 2014 X X X US PHS 2013 X X X New York 2012 X X X WHO 2007 X X X CDC 2005 X X X X *In case of HCV co-infection

62 THANK YOU