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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,

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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,"— 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, 1999-2007
6 5 4 Hepatitis C Rate per 100,000 PY 3 2 Hepatitis B 1 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.

4 Forecasted Annual HCV-Related Deaths in the United States Persons with Chronic Hepatitis C and no Cirrhosis in 2005 Number Year 2010 Deaths 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 45,000 Peak 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 HCC ESLD Death 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 reduction of viral replication Definitive Viral Clearance Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:

8 Virologic Responses with HCV Therapy Sustained 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 C SVR Rates with DAA-Based Therapy
Timeline 1986 1998 2001 2002 2011 2014

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

13 Hepatitis C Virus Structural and Nonstructural Proteins
Hepatitis C Proteins C NS4B NS5A NS2 NS3 E1 NS4A p7 E2 NS5B Structural Proteins Nonstructural (NS) Proteins Cysteine Protease Serine Protease Cofactors RNA binding and assembly recognition complex Vioporin Serine Protease RNA Helicase 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 Vaniprevir BI ABT-450/r

16 Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design
Week 12 24 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 Source: Lawitz E, et al. N Engl J Med ;368:

17 NUTRINO: SVR 12 by Genotype
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 ;368:

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 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 *Patients who experienced relapse after Peginterferon plus Ribavirin therapy Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org).

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 Duration Regimen 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 INVESTIGATIONAL Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-1 Study: Study Design Week 12 24 36 GT-1 Naive n = 214 LDV-SOF SVR12 n = 217 LDV-SOF + RBV SVR12 GT-1 Naive n = 217 LDV-SOF SVR12 n = 217 LDV-SOF + RBV SVR12 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 N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Afdhal N, et al. N Engl J Med. 2014;370:

22 ION-1: SVR 12 by Treatment Duration and Regimen
INVESTIGATIONAL Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-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:

23 ION-1: SVR12 by Treatment Regimen and Liver Disease
INVESTIGATIONAL Ledipasvir-Sofosbuvir +/- Ribavirin in Treatment-Naïve HCV GT 1 ION-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:

24 INVESTIGATIONAL 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:

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:

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 assay B. Western blot C. HIV RNA

30 Traditional Approach to HIV Diagnostic Testing
Initial Supplemental EIA Western blot or IFA 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 Recommendations Recommended Laboraatory HIV Testing Algorithm
HIV-1/2 Antigen/Antibody Combination Immunoassay (+) (-) Negative for HIV-1 and HIV-2 antibodies 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 Indeterminate HIV-2 (-) HIV-1 antibodies detected HIV-2 antibodies detected HIV antibodies detected HIV-1 NAT HIV-1 NAT (+) HIV-1 NAT (-) Acute HIV-1 infection Negative for HIV-1 Source: Centers for Disease Control and Prevention

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: 2013 Initiating 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:

38 HIV Prevention Trials Network (HPTN) Study 052
+ + 550 Early Therapy CD cells/mm3 350 250 Deferred Therapy CD4 < 250 cells/mm3 or AIDS Related Event Source: Cohen M, et al. N Engl J Med. 2011;36:

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

40 HHS Antiretroviral Therapy Guidelines: May 1, Recommended Regimens Regardless of Baseline HIV RNA or CD4 Count Class Therapy Pill Burden NNRTI-Based Efavirenz-Tenofovir-Emtricitabine PI-Based Atazanavir + Ritonavir + Tenofovir-Emtricitabine Darunavir + Ritonavir + Tenofovir-Emtricitabine INSTI-Based Raltegravir + Tenofovir-Emtricitabine ^Elvitegravir-Cobicistat-Tenofovir-Emtricitabine Dolutegravir + *Abacavir-Lamivudine Dolutegravir + Tenofovir-Emtricitabine ^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
Study ARV History Comparison Results 1 SPRING-2 ARV-Naïve Dolutegravir QD versus Raltegravir Non-inferior (88% versus 85%) 2 SINGLE Dolutegravir QD versus Efavirenz Dolutegravir superior (88% versus 81%) 3 FLAMINGO Dolutegravir QD versus Darunavir-RTV Dolutegravir superior (90% versus 83%) 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 2013 Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;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/mm3. 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
“…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 Hosp Epidemiol ;34:

48 Raltegravir (Isentress) 400 mg twice daily
2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral Regimens Recommended Antiretroviral Regimens for Occupational PEP (28-Day Duration) Preferred Regimen INSTI NNRTI Pill Burden Raltegravir (Isentress) 400 mg twice daily Tenofovir-Emtricitabine (Truvada) 1 pill daily Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:

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

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: 474 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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