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, 1999-20076 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 (

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 (

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 (

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 (

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]