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

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Presentation on theme: "2014: HIV, HCV, and HBV Update David Spach, MD Professor of Medicine, Division of Infectious Diseases University of Washington Last Updated: June 12, 2013."— Presentation transcript:

1 2014: HIV, HCV, and HBV Update David Spach, MD Professor of Medicine, Division of Infectious Diseases University 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 virus B. Hepatitis B virus C. Hepatitis C virus D. HIV

3 Age-Adjusted Mortality Rates from HBV, HCV, & HIV United States, Source: Ly KN, et al. Ann Intern Med. 2012:156: Rate per 100,000 PY Year HIV Hepatitis C Hepatitis B

4 Source: Rein DR, et al. Dig Liver Dis. 2011:43: Forecasted Annual HCV-Related Deaths in the United States Persons with Chronic Hepatitis C and no Cirrhosis in 2005 Peak

5 Hepatitis C Update

6 Hepatitis C: Progression of Disease years Normal Liver Chronic Hepatitis HCC ESLD Death HCV Infection years Cirrhosis Time

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

8 Virologic Responses with HCV Therapy Sustained Virologic Response (SVR12) Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment End of Treatment 12 Weeks Undetectable SVR12 TreatmentPost 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 2011

11 Therapy for Hepatitis C SVR Rates with DAA-Based Therapy Timeline

12 Therapy for Hepatitis C SVR Rates with Multiple DAAs Timeline

13 Hepatitis C Virus Structural and Nonstructural Proteins Hepatitis C Proteins Vioporin Cysteine Protease Serine Protease RNA Helicase Serine Protease Cofactors Membranous Web Induction RNA-Dependent RNA Polymerase C C NS4B NS5A NS2 NS3 E1 NS4 A p7 E2 NS5B Structural ProteinsNonstructural (NS) Proteins RNA binding and assembly recognition complex

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

15 Future HCV Direct Acting Agents (DAAs) Faldaprevir Daclatasvir Danoprevir Asunaprevir Mericitabine Vaniprevir Ledipasvir Simeprevir Sofosbuvir Ombitasvir Dasabuvir ABT-450/r NS5A NS3 NS5B IDX-719 BMS Protease InhibitorsPolymerase InhibitorsNS5A Inhibitors BI NS4A

16 Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design Source: Lawitz E, et al. N Engl J Med. 2013;368: Week 012 Sofosbuvir + PEG + RBV N =327 SVR12 Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

17 Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results NUTRINO: SVR 12 by Genotype Source: Lawitz E, et al. N Engl J Med. 2013;368: GT = genotype 261/292206/22554/6634/35

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 weeks B. Peginterferon + Ribavirin + Sofosbuvir x 12 weeks C. Peginterferon + Ribavirin + Sofosbuvir x 12 weeks D. Sofosbuvir + Simeprevir x 24 weeks

19 AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Recommended Therapy for Patients with Chronic HCV Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).www.hcvguidelines.org HCV: Recommended Initial Treatment & Retreatment of Relapsers* GT1 Interferon Eligible Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Interferon Eligible Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks GT2 Sofosbuvir + Ribavirin x 12 weeks GT3 Sofosbuvir + Ribavirin x 24 weeks GT4 Interferon Eligible Sofosbuvir + Peginterferon + Ribavirin x 12 weeks Not Interferon Eligible Sofosbuvir + Ribavirin x 24 weeks *Patients who experienced relapse after Peginterferon plus Ribavirin therapy

20 Hepatitis C Genotype 1 Costs of Different Regimens for Treatment of Genotype 1 Estimated Medication Cost for Treatment of Genotype 1 Chronic HCV Regimen and DurationRegimen Cost Sofosbuvir + Ribavirin + Peginterferon x 12 weeks$97,000 Sofosbuvir x 12 weeks + [Ribavirin + Peginterferon] x 24 weeks$109,000 Sofosbuvir + Ribavirin x 24 weeks$169,000 Sofosbuvir + Simeprevir +/- Ribavirin x 12 weeks$150,000 Simeprevir x 12 weeks + [Ribavirin + Peginterferon] x 24 weeks $79,000 Simeprevir x 12 weeks + [Ribavirin + Peginterferon] x 48 weeks $104,000 Note: sofosbuvir cost = $1000 per day of treatment

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

22 Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-1 Study: Results ION-1: SVR 12 by Treatment Duration and Regimen Source: Afdhal N, et al. N Engl J Med. 2014;370: / Week Regimen 211/217212/217215/217 LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin 24-Week Regimen INVESTIGATIONAL

23 Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-1 Study: Results ION-1: SVR12 by Treatment Regimen and Liver Disease Source: Afdhal N, et al. N Engl J Med. 2014;370: /33 12-Week Treatment24-Week Treatment 179/17933/33178/17831/32181/18236/36179/179 Note: subgroup results do not include patients who withdrew consent or were lost to follow-up INVESTIGATIONAL

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

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 Hepatitis C Online: University of Washington: Hepatitis C Online

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. 4 th generation p24 antigen-antibody assay B. Western blot C. HIV RNA

30 Traditional Approach to HIV Diagnostic Testing InitialSupplemental EIA Western blot or IFA Optimized for SensitivityOptimized 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 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 Timing of HIV RNA, HIV p24 antigen, and HIV Antibody HIV p24 antigen HIV Antibody HIV RNA

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

33 HIV-1 NAT (+) 2014 CDC Recommendations Recommended Laboraatory HIV Testing Algorithm Source: Centers for Disease Control and Prevention (-)(-) (+)(+) HIV-1 (+) HIV-2 (-) HIV-1 (-) HIV-2 (+) HIV-1 (-) or Indeterminate HIV-2 (-) HIV-1 NAT (-) Negative for HIV-1 and HIV-2 antibodies and p24 Ag HIV-1 antibodies detected Acute HIV-1 infectionNegative for HIV-1 HIV-1/2 Antigen/Antibody Combination Immunoassay HIV-1 NAT HIV-2 antibodies detected HIV-1 (+) HIV-2 (+) HIV antibodies detected HIV-1/HIV-2 Ab Differentiation Immunoassay

34 Antiretroviral Therapy

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

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

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

38 Source: Cohen M, et al. N Engl J Med. 2011;36: HIV Prevention Trials Network (HPTN) Study Early Therapy CD cells/mm Deferred Therapy CD4 < 250 cells/mm 3 or AIDS Related Event

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

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

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

42 . Dolutegravir Phase 3 Studies in Treatment-Naïve Subjects 1 Raffi F, et al. Lancet 2013;381: Walmsley S. N Engl J Med. 2013:369: Clotet B, et al. Lancet March 31 [Epub ahead of print]

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

44 Occupational PEP

45 Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:

46 Case History HIV 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/mm 3. Based on USPHS 2013 Guidelines, what is recommended? A. 2 drugs: Zidovudine-lamivudine B. 2 drugs: Tenofovir-emtricitabine C. 3 drugs: Tenofovir-emtricitabine + Raltegravir D. 3 drugs: Tenofovir-emtricitabine + Darunavir + ritonavir

47 2013 USPHS Occupational PEP Guidelines Number of Antiretroviral Medications to Use Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34: “…the PHS working group recommends prescribing 3 (or more) tolerable drugs as PEP for all occupational exposures to HIV.”

48 2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral Regimens Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:

49 Post-Exposure Prophylaxis Line (PEPline)

50 HBV Update

51 HBV Treatment and Entecavir Resistancne What percentage of patients with chronic HBV and long term entecavir treatment will develop resistance?

52 Resistance with Entecavir 222 nucleoside-naïve patients treated for 3 years - Cumulative -resistance to entecavir of 1.3% at 3 years Yuen MF, et al. Am J Gastroenterol. 2011;106: nucleoside-naïve treated for 4 years - Cumulative resistance to entecavir of 0.4% Ono A, et al. J Hepatol. 2012;57:508. Overall Estimates of Resistance Rates - Treatment naïve: < 1% at 5 years - Prior lamivudine failure: approximately 50% at 5 years

53 Duration of HBV Therapy with Entecavir Can you stop entecavir after long-term treatment (> 2 years) for patients with HBeAg- chronic HBV and HBeAg- and sustained virologic suppression?

54 Duration of HBV Therapy with Entecavir Background patients with HBeAg- chronic HBV - On entecavir for ≥ 2 years - Undetectable HBV DNA on ≥3 occasions 6 months apart Following Entecavir Cessation - Virologic relapse at 24 weeks: 74% - Virologic relapse at 48 weeks: 91% “…therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance.” Source: Seto WK, et al. Gut. 2014; May 15 [E pub Ahead of Print]


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