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2013 Asilomar HIV Medical Update

2013 Asilomar HIV Medical Update. David Spach, MD Clinical Director, Northwest AETC Professor of Medicine, Division of Infectious Diseases University of Washington. Last Updated: October 21, 2013. 2013 Asilomar Update. New Occupational PEP Guidelines Dolutegravir ( Tivicay )

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2013 Asilomar HIV Medical Update

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  1. 2013 Asilomar HIV Medical Update David Spach, MDClinical Director, Northwest AETCProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington Last Updated: October 21, 2013

  2. 2013 Asilomar Update • New Occupational PEP Guidelines • Dolutegravir (Tivicay) • Hepatitis C Update

  3. Occupational PEP 2013 Guidelines

  4. 2013 Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

  5. Case HistoryHIV Exposure in a Health Care Worker • A 41-year-old male nurse has a needlestick injury on his left thumb. The site bled for about 2 minutes after the injury. The source patient has documented HIV infection, has never taken antiretroviral medications, and most lab studies showed HIV RNA level of 2,350 copies/ml and CD4 count of 658 cells/mm3. • Based on USPHS 2013 Guidelines, what is recommended?A. 2 drugs: Zidovudine-lamivudineB. 2 drugs: Tenofovir-emtricitabineC. 3 drugs: Tenofovir-emtricitabine + RaltegravirD. 3 drugs: Tenofovir-emtricitabine + Darunavir +ritonavir

  6. 2013 USPHS Occupational PEP GuidelinesNumber of Antiretroviral Medications to Use “As less toxic and better-tolerated medications for the treatment of HIV infection are now available… thePHS 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.

  7. 2013 USPHS Occupational PEP GuidelinesRecommendations for Antiretroviral Regimens Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

  8. Case HistoryHIV Exposure in a Health Care Worker • 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?

  9. 2013 USPHS Occupational PEP GuidelinesPEP 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.

  10. HIV Occupational Postexposure Prophylaxis What are situations in which expert consultation is advised?

  11. 2013 USPHS Occupational PEP GuidelinesSituations 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.

  12. Post-Exposure Prophylaxis Line (PEPline)888-448-4911 Sou

  13. 2013 USPHS Occupational PEP GuidelinesBaseline 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 4th 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 *4th generation combination assay = HIV p24 antigen-HIV antibody test Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.

  14. Occupational HIV Postexposure Prophylaxis Suggestions for Training • Incorporate Occupational PEP into Larger Trainings • Provide 3 Point Takeaway Training(1) When PEP given, use 3 or more ARV drugs(2) Use Tenofovir-emtricitabine + Raltegravir(3) Know when and how to get expert consultations • C. Give trainees PEPLine information/pamphlet

  15. Dolutegravir (Tivicay)

  16. Raltegravir (Isentress) & Dolutegravir (Tivicay)Tablet Size Raltegravir Dolutegravir Source: Slide courtesy of Brian Wood, MD.

  17. Dolutegravir Source: Dolutegravir Prescribing Information

  18. Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of Creatinine Bowman’s Capsule Proximal Tubule Distal Tubule Organic Cation Transporter 2 (OCT2) Dolutegravir CollectingTubule Inhibits tubular secretion of creatininevia inhibition of OCT2 Loop of Henle Excretion Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6.

  19. Dolutegravir (Tivicay) Should dolutegravir replace raltegravir in clinical practice?

  20. Dolutegravir Phase 3 Studies . (1) Raffi F, et al. Lancet 2013;381:735-43. (2) Walmsley S. 52nd ICAAC 2012. Abstract H556b. (3) Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a. (4) Cahn P, et al. Lancet 2013;382:700–8. (5) Nichols G, et al. 7th Conference IAS 2013: Abstract TULBPE19.

  21. Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Design Dolutegravir + 2NRTIs(n = 242) Darunavir + 2NRTIs(n = 242) *Dolutegravir dose = 50 mg once daily; Darunavir dose = 800 mg once daily Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.

  22. Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result Week 48 Virologic Response Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.

  23. Dolutegravir Does the NRTI backbone with dolutegravir matter? Tenofovir-emtricitabine Abacavir-lamivudine

  24. Dolutegravir+ 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result Week 48 Virologic Response: Background Dual NRTI Therapy Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.

  25. Dolutegravir-ABC-3TC versus Efavirenz-TDF-FTCSINGLE: Result Week 48 Virologic Response Source: Walmsley S, et al. 52nd ICAAC. 2012: Abstract H-556-b.

  26. Dolutegravir+ 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result Week 96 Virologic Response: Background Dual NRTI Therapy Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.

  27. Dolutegravir+ 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result Week 96 Virologic Response: Background Dual NRTI Therapy Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.

  28. Dolutegravir+ 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result Week 96: Background Dual NRTI Therapy in Patients on Dolutegravir Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.

  29. Major Pathways of Resistance with Raltegravir Raltegravir Early N155H Delayed Q148H/K/R Secondary Mutations(L74M, E92Q, T97A, V151I, G163R) Secondary Mutations(L74M, G140A/S, E138K) Source: Fransen S, et al. J Virol. 2009;83:11440-6.

  30. Integrase Resistance Testing • Integrase Genotype✔- Quest Diagnostics- Lab Corp (Monogram Biosciences)- Virco • Integrase Phenotype- Lab Corp (Monogram Biosciences)- Virco

  31. Dolutegravir in Treatment-Experienced with Integrase ResistanceVIKING-3 Dolutegravir 50 mg BID + Failing Regimen Dolutegravir 50 mg BID + OBT Functional monotherapy phase (7 days) Day 8  Sources: 1) ViiV Healthcare Press release. Nov 2012. 2) Nichols G et al. IAS 2013. 3) http://www.viivhealthcare.com/media/58599/us_tivicay.pdf

  32. Dolutegravir in Patients with Raltegravir ResistanceVIKING-3: Results *without additional INSTI mutations Source: Dolutegravir Product Information.

  33. Dolutegravir Discussion How should we use dolutegravir in clinical practice? - In treatment naïve? - In treatment experienced (intregrase naïve)? - In treatment experience and integrase resistant?

  34. Use of Dolutegravir • Treatment naïve- Excellent first line agent- Likely will become a preferred agent in DHHS Guidelines • Treatment experienced (Integrase-naïve)- Attractive as component of salvage regimen • Treatment experience (Integrase resistant or experienced)- Parameters for once or twice daily dosing poorly defined- Avoid use with Q148 + ≥ 2 secondary mutations

  35. Hepatitis C Update

  36. Hepatitis C Epidemiology in United States Annual Deaths from HCV? .

  37. Age-Adjusted Mortality Rates* from HBV, HCV, & HIV United States, 1999-2007 7 HIV n = 15,106 6 5 4 Hepatitis C Rate per 100,000 PY 3 2 Hepatitis B 1 0 2005 1999 2000 2001 2006 2007 2002 2003 2004 Year *Mortality Rates = HBV, HCV, HIV listed as cause of death Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.

  38. Forecasted 2010-2060 Annual HCV-Related Deaths in the United StatesPersons with Chronic Hepatitis C and no Cirrhosis in 2005 45,000 Deaths 40,000 35,000 30,000 25,000 Number 20,000 15,000 10,000 5,000 0 2010 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058 Year Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.

  39. Hepatitis C Cascade of Care in United States 100% 50% 35% 9% 6% Source: Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.

  40. HCV-HIV Coinfection HIV-Infected Persons in United States HIV Monoinfection HIV-HCV Coinfection Source: Sulkowski M, et al. Ann Intern Med. 2003;138:197-207.

  41. Cause of Death (Incidence) in the D:A:D Study N = 1,246 deaths Source: Weber R, et al. Arch Intern Med. 2006;166:1632-41.

  42. Testing for Hepatitis C • A 34-year-old man is diagnosed with HIV infection. His risk factor for acquiring HIV is having sex with other men. He has about 8-10 male sexual partners per year.Hehas never injected drugs. His CD4 count is 684 cells/mm3. He is referred for routine HIV care. • At his initial evaluation, should you test this patient for hepatitis C infection? • If the HCV antibody test is negative, should he have repeat testing?

  43. Entry into CareRecommendations for HCV Testing Source: 2013 Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov)

  44. Recommendations for Repeat Testing for Hepatitis C in HIV-Infected Persons Source: Page R-2. 2013 Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov)

  45. Hepatitis C and Cure Why can antiviral cure hepatitis C but not HIV? Sustained Virologic Response (SVR) with HCV Treatment = Cure

  46. Comparative Treatment Goals with Antiviral Therapy HIV(latent reservoir) HBV(latent reservoir) HCV(no latent reservoir) HCV RNA ccDNA Proviral DNA Host DNA Host DNA Host DNA Host Cell Host Cell Host Cell Lifelong suppression of viral replication Long-term reductionof viral replication Definitive Viral Clearance Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:2012-12

  47. Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs) Timeline 1986 1998 2001 2002

  48. Therapy for Hepatitis CProjected SVR Rates with Multiple DAAs Timeline 2011 2014 2015

  49. Simeprevir: October 24, 2013 Sofosbuvir: October 25, 2013

  50. Hepatitis C VirusGenome HCV Genome 5’ 3’ Structural Non-Structural

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