HCV & other Hepatitis Viral Infection

HEPATITIS C: One of 3 stages of Infection 
  • Stage of Infection: 
    • Acute: Mostly asymptomatic, Flu-like symptoms, Acute Liver Failure (Uncommon); Patient with CC IL28B Gene more likely to spontaneously clear than CT or TT (53 vs 28%)
    • Chronic (74 -86 %):  Most present with abnormal LFT (many have normal LFT; 20 % with normal LFT may have fibrosis)
      • 15-20 % with chronic infection progress to Cirrhosis
        • 1-3 % of the Cirrhotic with Hep C develop HCC per year 
    • Resolved:
  • Epidemiology: 6 genotypes Genotype 1a (US, Northern Europe) 1b (Global, Southern Europe), 2 (Europe, North Africa), 3 (Southeast Asia), 4 (Middle East), 5 (South Africa), 6 (Asia); Age 20-59 Prevalance is around 45% (NEJM 2011)
  • Extrahepatic Manifestations: 
    • Rheum: Arthritis, 
    • Skin/Mucus Membrane: PCT (Porphyria Cutanea Tarda), LeucocytocalsticVasculitis, Lichen Planus, Raynaud Phenomenon, Sicca Syndrome,
    • Heme/Onc: ITP, Essential Mixed Cyroglubulinemia, MGUS, NHL
    • Renal: MPGN, Membranous Nephropathy (MN),
    • Endo: Hypo/Hyperthyroidism, DM, 
    • Autoimmune: 
    • Extrahepatic manifestations of hepatitis C virus infection Up-To-Date
  • Factors associated with rapid disease progression
  • Diagnosis: Antibody to HCV (ELISA) - PCR RNA (PCR Quantification does not predict severity of infection) - Reflex to Genotype 
    • Previously: Once diagnosed, Liver Biopsy Recommended (even in those normal ALT as they can have fibrosis;  on biopsy those with moderate-severe fibrosis would undergo treatment)
    • Non-invasive detection of fibrosis: FibroSURE, FibroSCAN 

Diagnostic Tests : FDA approved

Additional tests upon diagnosis

Other lab tests to order
  • NS5A RAV if 1a (impacts treatment with elbasvir NS5A inhibitor (50 mg)/grazoprevir NS3/4A protease inhibitor(100 mg) with or without ribavirin ZEPATIER). Duration should be extended to 16 weeks.
    • It does not impact the SVR in 1b
    • 1 a: Better treat with Harvoni
    • 1B: Zepatier or Harvoni can be used
  • Baseline Q80 K. Does not impact SVR in sofosbuvir NS5B polymerase inhibitor (400 mg) SOVALDI (Gilead) plus simeprevir (150 mg) OLYSIO in genotype 1

Treatment : 
Ref: Uptodate

Understanding Hep C pharmacology 
  • NS 3/4A protease inhibitor
      • 3 regimen
      • 2 fixed dose 
    • grazoprevir (100 mg) Zepatier 
    • paritaprevir (150 mg) Viekira PAKor Viekira XR
    • simeprevir (150 mg) with sofosbuvir, 
  • NS 5A inhibitor  
      • 5 regimen have NS5A inhibitor except sofosbuvir + simeprevir 
      • Includes all fixed dose regimen 
    • ledipasvir (90 mg) Harvoni
    • velpatasvir (100 mg) Epclusa 
    • elbasvir (50 mg) Zepatier 
    • ombitasvir (25 mg) Viekira PAKor Viekira XR
    • daclatasvir (60 mg); with Sofosbuvir 
  • NS 5B polymerase inhibitor 
      • 5 regimen have NS5B polymerase inhibitors except Zepatier. 
      • 4 regimen have  sofosbuvir 400 mg. Viekira pak or XR has Dasabuvir
    • sofosbuvir (400 mg) Harvoni, Epclusa, with daclatasvir, with simeprevir 
    • dasabuvir (250 mg) Viekira PAKor Viekira XR
6 regimens are available. 
        • Except for one, others may be used with ribavirin. 
        • 4 fixed dose regimen. Two are not. 
      • 3/4a, 5a: Fixed dose: elbasvir (50 mg)/grazoprevir (100 mg) with or without ribavirin ZEPATIER Jan 2016 (54K, Merck)
      • 3/4a, 5b: sofosbuvir (400 mg) SOVALDI (Gilead) plus simeprevir (150 mg) OLYSIO with or without ribavirin 
      • 3/4a, 5a, 5b: Fixed dose: sofosbuvir (400 mg) / ledipasvir (90 mg) with or without ribavirin HARVONI Oct 2014 (83K, Gilead)
      • 5a, 5b: Fixed dose: sofosbuvir (400 mg)/ velpatasvir (100 mg) EPCLUSA June 2016
      • 5a, 5b: Fixed dose: paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) p lus twice-daily dasabuvir (250 mg) VIEKIRA PAK (Dec 2014) or Viekira XR (July 2016)(94K, AbbVie)  and weight-based ribavirin for 12 weeks 
      • 5a, 5b: sofosbuvir (400 mg) SOVALDI  plus daclatasvir (60 mg) DAKLINZA (July 2015 for genotype 3, Feb 2016 for genotype 1) with or without ribavirin 
  • HCV genotype 1 infection that cannot be subtypes should be treated as genotype 1a infection.
  • Approximately 10%-15% of HCV genotype 1-infected patients without prior exposure to NS5A inhibitors will have detectable HCV NS5A RAVs at the population level prior to treatment. While the clinical impact of NS5A RAVs remains to be fully elucidated, in patients with genotype 1a infection the presence of baseline NS5A RAVs that cause a large reduction in the activity of NS5A inhibitors (>5 fold) adversely impact response to NS5A-containing regimens
  • Given that baseline NS5A RAVs are one of the strongest pre-treatment predictors of treatment outcome with certain regimens in patients with genotype 1a infection, testing for these RAVs prior to deciding on a therapeutic course is recommended in select situations. (Zeuzem, 2015c)
  • Reference
Additional tips regarding each regimen 
  • elbasvir (50 mg)/grazoprevir (100 mg) with or without ribavirin
    • The presence of certain baseline NS5A RAVs appears to be the single best predictor of relapse with the 12-week elbasvir/grazoprevir regimen
    • Extension of therapy to 16 weeks or 18 weeks with the addition of weight-based ribavirin increased response rates to 100% regardless of presence of baseline NS5A RAVs, suggesting this approach can overcome the negative impact of NS5A RAVs seen in the 12-week arms
    • Based on the known inferior response in patients with specific NS5A RAVs, NS5A resistance testing is recommended in genotype 1a patients who are being considered for therapy with elbasvir/grazoprevir. If these RAVs are present, treatment extension to 16 weeks with the addition of weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [≥75 kg]) is recommended to decrease the risk of relapse.
    • Lack of RAV testing results or lack of access to RAV testing should not be used as a means to limit access to HCV therapy.
    • Some medicines cannot be taken with Zepatier – including prescription and over-the-counter medicines, vitamins, and herbal supplements
    • Ref
  • ledipasvir (90 mg)/sofosbuvir (400 mg) with or without ribavirin HARVONI
    • Ledipasvir and Sofosbuvir for Previously Treated HCV Genotype 1 Infection (ION - 2)  NEJM 2014
    • This regimen was given for 12 weeks or 24 weeks, with or without ribavirin
    • This regimen was well tolerated in all groups, with no serious adverse events reported in the 12-week regimen with or without ribavirn.
    • In the population with cirrhosis, patients treated for 24 weeks had higher SVR rates than those treated for 12 weeks, supporting the recommendation that HCV treatment-experienced patients with cirrhosis receive 24 weeks of treatment without ribavirin.
    • ledipasvir/sofosbuvir plus ribavirin for 12 week was similar to ledipasvir/sofosbuvir for 24 weeks
    • Baseline NS5A RAVs adversely impact responses to ledipasvir/sofosbuvir therapy; though the magnitude of this impact varies based on a number of factors including virus (genotype subtype, specific RAV), regimen (companion drugs, use of ribavirin), and patient factors (treatment experience, presence of cirrhosis). 
    • The impact is likely to be larger in a genotype 1a only population. Given the vulnerable nature of this population, baseline NS5A resistance testing should be considered in genotype 1a treatment-experienced patients with cirrhosis prior to use of ledipasvir/sofosbuvir. If ledipasvir associated RAVs are detected consideration should be given to adding weight-based ribavirin to the regimen and extending therapy to 24 weeks
    • Side effects: Fatigue, and Headache
  • paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dasabuvir (250 mg) and weight-based ribavirin for 12 weeks
    • is also approved 
      • for HCV/HIV co-infection and 
      • people who have had a liver transplant.
  • sofosbuvir (400 mg)/velpatasvir (100 mg)
    • The single treatment-experienced patient who did not have a response to this regimen was a genotype 1b black patient with cirrhosis and IL28 TT genotype who had a persistently detectable HCV viral load during previous PEG-IFN/ribavirin therapy. 
    • This regimen was well tolerated and there was no significant difference in the rate of adverse events in the sofosbuvir/velpatasvir group (78%) when compared to the placebo group (77%).
Additional learning tips
  • When to test for NS5A RAVs?
    • Although NS5A inhibitor is used in various combination, it is tested for genotype 1 a when Zepatier is considered. 
    • it changes the duration of EPCLUSA
    • it can impact HARVONI response 
    • should be checked 
  • When to test for Q80K?
  • When to add ribavirin?
  • When to extend duration to 16 or 24 weeks instead of 12 weeks?

Additional references
  • Follow up
    • SVR 12 (12 weeks after the completion of therapy)
    • SVR 24 (24 weeks after the completion of therapy) 

Treatment options: 

1. HCV Rx 
2. HCV + HIV
  • In antiretroviral-naive patients with a CD4 count greater than 500 cells/mm3, antiretroviral therapy could be deferred until after treatment of HCV.
  • For those patients whose CD4 counts are less than 200 cells/mm3 it may be advisable to first initiate antiretroviral therapy and defer HCV therapy until the patient is stable on antiretroviral therapy.
  • Epclusa (can be used with most regimen): 
    • Okay with Triumeq 
    • Okay with TAF OR TDF (Genvoya) if CrCl > 60. Velpatasvir increases the level of TAF or TDF e
  • Harvoni (can be used with most regimen) 
    • Okay with TAF or TDF (Genvoya) if the baseline creatinine clearance is greater than 60 ml/min. Ledipasvir increases level of TAF or TDF 
  • Viekiera okay with 
    • Descovey (emtricitabine/TAF) + Tivicay (Dolutegravir)
    • Any of these: atazanavir, dolutegravir, emtricitabine, enfuvirtide, lamivudine, raltegravir, and tenofovir. 
  • Zepatier: Okay to use with 
    • Rilpivirine/Tenofovir Alafenamide/Emtricitabine (Odefsey) 
    • Abacavir/dolutegravir/lamivudine (Triumeq) 
    • Any of these: abacavir, emtricitabine, enfuvirtide, lamivudine, raltegravir, dolutegravir, rilpivirine, and tenofovir
  • Studies
    • ALLY2 (1,2,3,4): 
      • daclatasvir plus sofosbuvir
      • The HIV entry criteria required a CD4 count greater than 350 cells/mm3 if the patient was not taking antiretroviral therapy or at least 100 cells/mm3if on antiretroviral therapy and an HIV RNA less than 50 copies/ml
      • 12 wk is needed. 8 wk was not enough
    • C212: 
    • C-Edge confection (1,4,6)
      • elbasvir-grazoprevir once daily for 12 weeks
      • 86% had genotype 1a or 1b infection and 35 (16%) had compensated cirrhosis
    • NIAID eradicate (1)
      •  Allowed HIV medication: tenofovir-emtricitabine, efavirenz, and rilpivirine
      • 13/50 pts not on HIV meds
      • 98% SVR12
    • ION 4
      • 12-week course of ledipasvir-sofosbuvir
      • patients also included compensated cirrhosis
      • ART could include tenofovir-emtricitabine plus either efavirenz, rilpivirine, or raltegravir
      • HIV RNA less than 50 copies/ml, CD4 count greater than 100 cells/mm3
      • 96 % SVR 12
    • Photon 1 (1,2,3)
    • Photon 2
    • Sofosbuvir ..
    • Turquoise
  • Not to use 
      • Elbasvir/grazoprevir should NOT be used with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor. Rating: Class III, Level B

      • Sofosbuvir/velpatasvir should NOT be used with efavirenz, etravirine, or nevirapine. Rating: Class III, Level B

      • Zepatier should NOT be used with darunavir, efavirenz, ritonavir-boosted lopinavir, ritonavir-boosted tipranavir, etravirine, nevirapine, cobicistat, or rilpivirine. Rating: Class III, Level B

      • Paritaprevir/ritonavir/ombitasvir with or without dasabuvir should NOT be used in HIV/HCV- coinfected individuals who are not taking antiretroviral therapy.
        Rating: Class III, Level B

      • Simeprevir should NOT be used with cobicistat, efavirenz, etravirine, nevirapine, or any HIV protease inhibitor. Rating: Class III, Level B 

  • Ref

3. HCV + CKD or  ESRD 

Associated Diseases 
mixed cryoglobulinemia, 
membranoproliferative glomerulonephritis (MPGN), and 
possibly membranous nephropathy 
Assess for 
  • Life expectancy
  • Is prompt treatment necessary? Patient with advanced fibrosis and cirrhosis are the preferred candidate? 
  • Vasculitis or GN - is immunosuppressive drug also indicated?
  • Genotype? 1 and 4 -Zepatier is safe and has lower threshold for treatment (Phase III study  on renal patients). Other genotype - higher threshold. 
  • GFR staging 
    • GFR > 30: Similar drug selection if ribavirin or PEG-IFN is not used.
    • GFR < 30
      • Zepatier or Vekira PAK, but both are CI if Child Pugh B and C 

Case based learning
Case 1
ATA: Hep C 2b

Case 2
FR: Genotype Not Done

Case 3
MB, 64 yo M
1a, but very low titer 

Case 4
RRL, 60 yo,
No genotype 

Case 5
FKE, 55 F
8/15/16 Hep C RNA was low in amount that genotyping could no the done 

Case 6
WJM, 66 F
Prevoiusly treated. No RNA detected

Case 7
JL 67 M
Genotype Not done. Concern for Acute Hepatitis C with Cryo 

Case 8
RSF, 56 F
Genotyping not done

Hep C Managment Template 
  • Exposure year / Mode : presumptive / unknown
  • Ongoing risk factor for transmission or acquiring infection:
    • IV drug use:
  • Psychiatric History 
  • Assessment of Risk factors for Disease Progression
    • Modifiable:
      • Alcohol consumption:
        • Alcohol Use
          • Have you ever felt you should cut down on your drinking? 
          • Have people annoyed you by criticizing your drinking? 
          • Have you ever felt bad or guilty about your drinking? 
          • Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (eye opener)? 
      • Obesity (BMI):
      • NAFLD: 
      • Insulin Resistance:
    • Non-modifiable
      • Associated HIV Infection
      • Associated Hep B Infection
      • Male gender
      • Older age at the time on onset of infection
      • (Preexisting Cirrhosis) Fibrosis Stage
      • Inflammation Stage
  • Any additional associated extra hepatic symptoms / signs / labs (bold if present)
    • Arthritis: 
    • PCT (Porphyria Cutanea Tarda): 
    • LeucocytocalsticVasculitis:
    • Lichen Planus:
    • Raynaud Phenomenon: 
    • Sicca Syndrome:
    • ITP:
    • Essential Mixed Cyroglubulinemia: 
    • MGUS:
    • NHL
    • MPGN:
    • Membranous Nephropathy (MN),
    • Hypo/Hyperthyroidism, 
    • DM: Higher incidence of Insulin Resistance and DM 
    • What happens to these disease after treatment 
  • Genotype: 
    • If we are to wait for 6 months, can we do this test before treatment and not up front
    • How much is the cost of genotyping compared to the cost of PCR that usually needs to be done at 48 hr, 12 wks, and 24 weeks
  • Viral Load Tests usually done at 
    • 48 hr: 
    • 12 weeks: 
    • 24 weeks: If persistent consider treatment 
  • LFT 
    • 48 hr
    • 12 weeks
    • 24 weeks
  • When to initiate treatment
    • > 24 weeks with persistent viral load
    • Earlier if there are risk factors for rapid worsening of disease or spread of infection or lost to follow up
  • Monitoring during treatment