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2014: HIV, HCV, and HBV Update

2014: HIV, HCV, and HBV Update. David Spach, MD Professor of Medicine, Division of Infectious Diseases University of Washington. Last Updated: June 12 , 2013. Chronic Viral Diseases and Mortality in United States.

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2014: HIV, HCV, and HBV Update

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  1. 2014: HIV, HCV, and HBV Update David Spach, MDProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington Last Updated: June 12, 2013

  2. Chronic Viral Diseases and Mortality in United States • Which one of the chronic viral diseases was responsible for the most number of deaths in the United States in 2007?A. Hepatitis A virusB. Hepatitis B virusC. Hepatitis C virusD. HIV

  3. Age-Adjusted Mortality Rates from HBV, HCV, & HIV United States, 1999-2007 7 HIV 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 Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.

  4. Forecasted 2010-2060 Annual HCV-Related Deaths in the United StatesPersons with Chronic Hepatitis C and no Cirrhosis in 2005 45,000 Peak 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.

  5. Hepatitis C Update

  6. Hepatitis C: Progression of Disease Time 20-25 years 25-30 years Normal Liver Chronic Hepatitis Cirrhosis HCCESLDDeath HCV Infection

  7. 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 AntimicrobChemother. 2010:65:2012-12

  8. Virologic Responses with HCV TherapySustained Virologic Response (SVR12) Treatment Post Treatment SVR12 End of Treatment 12 Weeks Undetectable Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment

  9. Evolution of Hepatitis C Treatment • In 2015, what is the realistic expectation for achieving SVR (cure) of hepatitis C with state-of-the-art treatment?A. 60%B. 75%C. 85%D. 95%

  10. Therapy for Hepatitis C: Historical Milestones Timeline 1986 1998 2001 2002 2011

  11. Therapy for Hepatitis CSVR Rates with DAA-Based Therapy Timeline 1986 1998 2001 2002 2011 2014

  12. Therapy for Hepatitis CSVR Rates with Multiple DAAs Timeline 1986 1998 2001 2002 2011 2014 2015

  13. Hepatitis C VirusStructural and Nonstructural Proteins Hepatitis C Proteins Structural Proteins Nonstructural (NS) Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B CysteineProtease Serine Protease Cofactors RNA binding and assembly recognition complex Vioporin Serine Protease RNAHelicase Membranous Web Induction RNA-Dependent RNA Polymerase

  14. Categories of Direct Acting Antiviral Agents Hepatitis C Direct Acting Antiviral Agent (DAA) Categories NS3/4A Protease Inhibitor NS5A Inhibitor NS5B Polymerase Inhibitor NS3 NS4A NS5A NS5B Serine Protease Serine Protease Cofactors RNA binding and assembly recognition complex RNA-Dependent RNA Polymerase

  15. Future HCV Direct Acting Agents (DAAs) NS3 NS4A NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Asunaprevir Daclatasvir Mericitabine Danoprevir Ledipasvir Sofosbuvir Faldaprevir Ombitasvir Dasabuvir Simeprevir IDX-719 BMS-791325 Vaniprevir BI-207127 ABT-450/r

  16. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design 0 12 24 Week SVR12 Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyRibavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg Sofosbuvir + PEG + RBV N =327 Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

  17. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results NUTRINO: SVR 12 by Genotype 261/292 206/225 54/66 34/35 GT = genotype Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

  18. Hepatitis C Treatment • According to 2014 AASLD/IDSA/IAS-USA guidance, which on of the following regimens is recommended for initial treatment of patients with genotype 1 chronic HCV? Assume the patient is eligible to receive interferon.A. Peginterferon + Ribavirin + Telaprevir x 12 weeksB. Peginterferon + Ribavirin + Sofosbuvir x 12 weeksC. Peginterferon + Ribavirin + Sofosbuvir x 12 weeksD. Sofosbuvir + Simeprevir x 24 weeks

  19. AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsInitial Recommended Therapy for Patients with Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).

  20. Hepatitis C Genotype 1Costs of Different Regimens for Treatment of Genotype 1 Note: sofosbuvir cost = $1000 per day of treatment

  21. INVESTIGATIONAL Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Study Design 0 12 24 36 Week n =214 SVR12 GT-1Naive LDV-SOF n =217 SVR12 LDV-SOF + RBV n =217 SVR12 GT-1Naive LDV-SOF n =217 SVR12 LDV-SOF + RBV Drug DosingLedipasvir-sofosbuvir (90/400 mg): fixed dose combination; one pill once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  22. INVESTIGATIONAL Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Results ION-1: SVR 12 by Treatment Duration and Regimen 211/214 211/217 212/217 215/217 12-Week Regimen 24-Week Regimen LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  23. INVESTIGATIONAL Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1ION-1 Study: Results ION-1: SVR12 by Treatment Regimen and Liver Disease 179/179 32/33 178/178 33/33 181/182 31/32 179/179 36/36 12-Week Treatment 24-Week Treatment Note: subgroup results do not include patients who withdrew consent or were lost to follow-up Source: Afdhal N, et al. N Engl J Med. 2014;370:1889-98.

  24. INVESTIGATIONAL 3D (ABT-450/r-Ombitasvir + Dasabuvir) + RibavirinGT 1 and Compensated Cirrhosis: TURQUOISE-II Study TURQUOISE II: SVR12 Source: Poordad F, et al. N Engl J Med. 2014;370:1973-82.

  25. HCV Treatment: Key Concepts • Very high SVR rates with new therapies • Excellent SVR rates regardless of cirrhosis, race • Excellent SVR rates in treatment experienced • Genotype 3 is most difficult to treat • All oral therapies wave of future • Cost of new therapies is huge barrier

  26. University of Washington: Hepatitis C Online Hepatitis C Online: www.hepatitisc.uw.edu

  27. HIV Update

  28. New HIV Testing Recommendations

  29. HIV Testing • Which one of the following best describes the initial recommended HIV screening test in the 2014 CDC recommendations? A. 4th generation p24 antigen-antibody assayB. Western blotC.HIV RNA

  30. Traditional Approach to HIV Diagnostic Testing Initial Supplemental EIA Western blotorIFA Optimized for Sensitivity Optimized for Specificity • Drawbacks with Conventional HIV Diagnostic Algorithm • Does not detect acute HIV • Does not differentiate HIV-1 and HIV-2 • Problems with indeterminate Western blot

  31. Laboratory Diagnosis of Early HIV Infection HIV Antibody HIV RNA HIV p24 antigen Timing of HIV RNA, HIV p24 antigen, and HIV Antibody

  32. 4th Generation HIV Ag/Ab Combination Assays HIV p24 Antigen HIV Antibodies Detects HIV-1 p24 antigen and antibodies to HIV-1 and HIV-2

  33. 2014 CDC RecommendationsRecommended Laboraatory HIV Testing Algorithm HIV-1/2 Antigen/Antibody Combination Immunoassay (-) (+) Negative for HIV-1 and HIV-2antibodies and p24 Ag HIV-1/HIV-2 Ab Differentiation Immunoassay HIV-1 (+)HIV-2 (-) HIV-1 (-)HIV-2 (+) HIV-1 (+)HIV-2 (+) HIV-1 (-) or IndeterminateHIV-2 (-) HIV-1 antibodiesdetected HIV-2 antibodiesdetected HIV antibodiesdetected HIV-1 NAT HIV-1 NAT (+) HIV-1 NAT (-) Acute HIV-1 infection Negative for HIV-1 Source: Centers for Disease Control and Prevention. 2014.

  34. Antiretroviral Therapy

  35. US Health and Human Services (HHS) May 1, 2014 Antiretroviral Therapy Guidelines Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

  36. HHS Antiretroviral Therapy Guidelines: 2013Initiating Therapy in Treatment-Naïve Patients Antiretroviral therapy (ART) is recommended for all HIV-infected individuals to reduce the risk of disease progression. Recommend (BIII) 500 Strongly Recommend (AII) 350 Strongly Recommend (AI) Source: 2013 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

  37. HIV Prevention Trials Network (HPTN) Study 052 1,763 HIV Serodiscordant Couples (97% heterosexual) - + + - n = 873 n = 890 Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

  38. HIV Prevention Trials Network (HPTN) Study 052 + + 550 Early TherapyCD4 350-550 cells/mm3 350 250 Deferred TherapyCD4 < 250 cells/mm3 or AIDS Related Event Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

  39. HIV Prevention Trials Network (HPTN) Study 052 96% Reduction P < 0.001 Source: Cohen M, et al. N Engl J Med. 2011;36:493-505.

  40. HHS Antiretroviral Therapy Guidelines: May 1, 2014 Recommended Regimens Regardless of Baseline HIV RNA or CD4 Count ^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine: only for patients with pre-ART CrCl ≥ 70 ml/min*Abacavir recommended only if HLA-B5701 negative Source: 2014 HHS Antiretroviral Therapy Guidelines. AIDS Info (www.aidsinfo.nih.gov)

  41. Single Tablet Antiretroviral Regimens Efavirenz-Tenofovir-Emtricitabine Atripla Rilpivirine-Tenofovir-Emtricitabine Complera Elvitegravir-Cobicistat-Tenofovir-Emtricitabine Stribild

  42. Dolutegravir Phase 3 Studies in Treatment-Naïve Subjects . 1 Raffi F, et al. Lancet 2013;381:735-43. 2 WalmsleyS. N Engl J Med. 2013:369:1807-18. 3 ClotetB, et al. Lancet. 2014 March 31 [Epub ahead of print]

  43. Future Single Tablet Regimen Dolutegravir-Abacavir-Lamivudine “Tri Pill”

  44. Occupational PEP

  45. 2013 Source: Kuhar DT, et al. Infect Control HospEpidemiol. 2013;34:875-92.

  46. 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

  47. 2013 USPHS Occupational PEP GuidelinesNumber of Antiretroviral Medications to Use “…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 HospEpidemiol. 2013;34:875-92.

  48. 2013 USPHS Occupational PEP GuidelinesRecommendations for Antiretroviral Regimens Source: Kuhar DT, et al. Infect Control HospEpidemiol. 2013;34:875-92.

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

  50. HBV Update

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