Johns Hopkins HIV GuideDiagnosisOpportunistic InfectionsViral

Hepatitis C

Juhi Moon, M.D., Justin R. Bailey, M.D., Ph.D.

PATHOGENS

Hepatitis C virus (HCV): small, enveloped, single-stranded RNA virus of the family Flaviviridae spread primarily by contact with blood and blood products. Sexual transmission, especially with receptive anal sex, also occurs.

CLINICAL

HIV/HCV coinfection common in U.S. and Europe due to shared routes of transmission (primarily IDU, but low level transmission with MSM also). In U.S. 30% of HIV+ pts are coinfected, with highest rates among IDUs (nearly 95%). HCV is 10x more infectious from needlestick than HIV. Co-infection uncommon in most of Africa.
After exposure, HIV+ pts more likely to progress to chronic HCV infection (>80%) especially pts with low CD4 counts. They also ave higher HCV RNA levels and are more likely to progress to liver disease fibrosis (7-26 vs 23-38 yrs) and cirrhosis than with HCV alone. Lower CD4 count associated with increased fibrosis.
ESLD is common cause of mortality in HIV+ pts, especially HCV co-infected. Sustained virologic response (SVR) to HCV therapy greatly reduces risk of decompensated liver disease and liver mortality.
Extra-hepatic manifestations of HCV: porphyria cutanea tarda, lichen planus, arthralgias, fatigue, mixed cryoglobulinemia (cutaneous and renal disease), lymphoma

DIAGNOSIS

HCV EIA (Ab) for screening; sensitivity AND specificity 99% with third-generation assay. All HIV+ pts should be tested in high HCV prevalence regions (such as U.S.).
Patients at high risk for HCV based on practices such as IDU and unprotected receptive anal sex with multiple partners should be considered for annual HCV screening if initially negative.
False negatives (1-5% among all HIV+ pts, 15% among IDUs) justify RNA testing in high risk pts with negative EIA (IDU, low CD4, unexplained high ALT). False negatives also occur during acute infection before seroconversion.
False positives of HCV Ab tests are common in Africa, where prevalence of HCV is low.
Positive EIA should be followed with HCV RNA to diagnose active (vs. cleared) infection.

Detectable HCV RNA should be followed with HCV genotype to determine treatment approach and to predict treatment response.
Liver staging methods
- Liver biopsy is gold standard to determine staging but is an invasive procedure with procedural risks and sample errors
- Vibration-controlled transient elastography (e.g Fibroscan) is a non-invasive point of care measurement of liver stiffness that can exclude severe fibrosis or cirrhosis
- Serum fibrosis markers (e.g Fibrosure or Fibrotest) use direct and indirect serum markers to calculate inflammation and degrees of fibrosis
- APRI (AST to platelet ratio index) and fibrosis-4 (FIB-4) calculations are helpful to estimate amount of fibrosis but are not sufficient to be surrogates for liver staging as opposed to elastography and fibrosis markers listed above.
ALT fluctuates during natural Hx and does not reflect disease activity or prognosis.
Other important labs: bilirubin, alkaline phosphatase, prothrombin time/INR, albumin, glucose (assess for insulin resistance or diabetes), TSH, CD4 and CD4%, and pregnancy test (as appropriate).
All patients initiating HCV DAA therapy should be assessed for HBV coinfection with HBsAg, anti-HBs, and anti-HBc testing.

TREATMENT

General Considerations

Treatment indications: All HIV/HCV coinfected individuals should be considered for HCV treatment regardless of fibrosis stage, given higher risk for progression of fibrosis and liver-related morbidity and mortality in coinfected individuals.
Reduce hepatic risks: vaccinate against HAV and HBV if non-immune. Counsel on abstinence from alcohol and IVDU, enroll in IVDU treatment and/or opiate replacement therapy i.e. methadone, buprenophrine when appropriate, achieve cessation from tobacco, control diabetes, manage psychiatric comorbidities, and start ART.
HIV-infected patients who have evidence of hepatitis B should be on ART with activity against HBV, preferably tenofovir disoproxil fumarate or tenofovir alafenamide.
Educate on HCV transmission modes: blood, shared IVDU needles and syringes; men who have sex with men, intranasal drug use, maternal-fetal.
Screen every 6 months for hepatocellular carcinoma in high-risk populations including those with cirrhosis and HBV coinfection with U/S or other imaging.
Complementary and alternative treatments: No clinical data supporting use of milk thistle, licorice root, thymus extract, or zinc, although they are generally well tolerated. Colloidal silver has no benefit and is toxic. Coffee may improve response to PEG-IFN and decrease fibrosis. These supplements should be stopped during HCV treatment, since interactions have not been studied

Use of ART During HCV therapy

HIV/HCV co-infected patients should be treated like patients without HIV infection, after consideration of interactions with antiretroviral (ARV) medications and DAA agents when selecting regimens.
Do not interrupt antiretroviral treatment to allow for HCV treatment.
Sofosbuvir can be co-administered with any antiretroviral except tipranavir.
Ledipasvir and velpatasvir increase tenofovir levels, so use of this combination of drugs should be avoided in those with CrCL< 60 mL/min. Effect is potentiated when tenofovir is used with ritonavir boosted protease inhibitors or cobicistat, so ledipasvir and velpatasvir should be avoided with these combinations. When used, careful monitoring of renal function is recommended. Switch to TAF-containing regimens is also an option.
Glecaprevir/pibrentasvir contraindicated with efavirenz, etravirine, nevirapine, atazanavir, ritonavir or cobicistat boosted darunavir
Elbasvir/grazoprevir contraindicated with efavirenz, etravirine, nevirapine, atazanavir, ritonavir or cobicistat boosted darunavir.
Sofosbuvir/velpatasvir contraindicated with efavirenz, etravirine, nevirapine
Sofosbuvir/velpatasvir/voxilaprevir contraindicated with atazanavir, efavirenz, etravirine, nevirapine
Ribavirin contraindicated with didanosine or zidovudine.

Treatment naive

Treatment of naïve patients with genotype 1a HCV:

Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) PO daily for 12 weeks for patients without baseline NS5A RASs for elbasvir or 16 weeks with baseline NS5A RAS at amino acid positions 28, 30, 31, or 93 known to confer antiviral resistance OR
Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 12 weeks OR
Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 8 weeks (no cirrhosis) or x 12 weeks (cirrhosis) OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily for 8 weeks in those patients who are non-black, HIV-uninfected, no cirrhosis, and whose HCV RNA level is < 6 million IU/mL

Treatment of naïve patients with genotype 1b HCV:

Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) PO daily for 12 weeks OR
Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 12 weeks OR
Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 8 weeks (no cirrhosis) or x 12 weeks (cirrhosis) OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily for 8 weeks in those patients who are non-black, HIV-uninfected, and whose HCV RNA level is < 6 million IU/mL

Treatment of naïve patients with genotype 2 and 3 HCV:

Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 8 weeks (no cirrhosis) or x 12 weeks (cirrhosis) OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks

Treatment of naïve patients with genotype 3 HCV:

Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 8 weeks (no cirrhosis) or x 12 weeks (cirrhosis) OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks
- RAS testing for Y93H is recommended for cirrhotic patients. If present, ribavirin should be included in the regimen or sofosbuvir/velpatasvir/voxilaprevir should be considered

Treatment of naïve patients with genotype 4 HCV:

Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 8 weeks (no cirrhosis) or x 12 weeks (cirrhosis) OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) PO daily for 12 weeks OR
Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 12 weeks

Treatment of naïve patients with genotype 5 or 6 HCV:

Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 8 weeks (no cirrhosis) or x 12 weeks (cirrhosis) OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 12 weeks

Treatment failures

Re-treatment of patients with genotype 1 HCV without cirrhosis with failed prior PEG-IFN and RBV treatment: No change from treatment naive.

Re-treatment of patients with genotype 1 HCV with compensated cirrhosis with failed prior PEG-IFN and RBV treatment:

Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg)PO daily for 12 weeks OR

Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 12 weeks OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks

Re-treatment of patients with genotype 1 HCV with or without cirrhosis who failed a non-NS5a, sofosbuvir containing regimen:

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) x 12 weeks

Re-treatment of patients with genotype 1 HCV who failed prior PEG-IFN, RBV, and NS3 protease inhibitor-containing regimen:

Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 12 weeks without cirrhosis only OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks with or without cirrhosis OR
Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 12 weeks with or without cirrhosis

Re-treatment of patients with genotype 1 HCV who failed prior treatment with NS5A inhibitor containing regimen:

Patients with minimal liver disease or cirrhosis: refer to provider with expertise in treatment of DAA-resistant HCV. Testing for NS3 protease inhibitor resistance, NS5A inhibitor resistance is indicated.
- Preferred: Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) x 12 weeks OR
- Alternative: Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg)except NS3/4 protease inhibitor inclusive DAA combination regimens

Re-treatment of patients with genotype 2 HCV who failed prior PEG-IFN and RBV treatment: No change from treatment naive.

Re-treatment of patients with genotype 2 HCV who failed prior sofosbuvir and RBV treatment:

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 12 weeks

Re-treatment of patients with genotype 2 HCV who failed prior sofosbuvir and NS5A inhibitor containing regimen:

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) x 12 weeks

Re-treatment of patients with genotype 3 HCV without cirrhosis who failed prior PEG-IFN and RBV treatment:

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks

Re-treatment of patients with genotype 3 HCV with cirrhosis who failed prior PEG-IFN and RBV treatment:

Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg ) plus sofosbuvir (400 mg) PO daily x 12 weeks OR
Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) PO daily x 12 weeks

Re-treatment of patients with genotype 3 HCV who failed DAA treatment (including NS5A inhibitors):

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) PO daily x 12 weeks. For patients with prior NS5A inhibitor failure and cirrhosis, addition of weight-based ribavirin is recommended.

Re-treatment of patients with genotype 4 HCV without cirrhosis who failed prior PEG-IFN and RBV treatment: No change from treatment naive.

Re-treatment of patients with genotype 4 HCV with cirrhosis who failed prior PEG-IFN and RBV treatment:

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) PO daily x 12 weeks OR
Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily x 12 weeks

Re-treatment of patients with genotype 4, 5, or 6 HCV with or without cirrhosis who failed DAA treatment:

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100mg) PO daily x 12 weeks

Re-treatment of patients with genotype 5 or 6 HCV with or without cirrhosis who failed prior PEG-IFN and RBV treatment: No change from treatment naive.

Treatment of patients with decompensated cirrhosis

Patients with decompensated cirrhosis (Child Turcotte Pugh class B or C) should be referred to a medical provider with expertise in that condition. Treatment is generally indicated and possible, but the decision to treat may be complicated, ideally refer to a liver transplant capable center.
Genotype 1, 4, 5, 6 HCV and ribavirin eligible
- Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 12 weeks with ribavirin - weight based OR
- Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 12 weeks with ribavirin - weight based.
- Ribavirin can be started at a low dose of 600mg and increased as tolerated.
Genotype 1, 4, 5, 6 HCV and ribavirin ineligible
- Fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) PO daily x 24 weeks OR
- Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) PO daily x 24 weeks
DO NOT treat with the following regimens
- Any IFN-based therapy
- Monotherapy with PEG, RBV, or a direct-acting antiviral (DAA)
- Protease inhibitor containing regimens

Chronic Kidney Disease

Treatment of patients with CKD Stage 1, 2, or 3 (eGFR≥30 ml/min): No change from treatment naive or experienced guidelines.
Treatment of patients with CKD Stage 4 or 5 (eGFR< 30 ml/min or End Stage Renal Disease):
- Fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) PO daily x 12 weeks for genotype 1 and 4 (C-SURFER) OR
- Fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) three tablets PO daily for genotypes 1-6. (EXPEDITION-4)
  - Duration of glecaprevir/pibrentasvir should be based on presence of cirrhosis and prior treatment experience (please refer to appropriate section).

Laboratory Monitoring

HCV RNA testing during and at completion of therapy to monitor therapeutic response, but response-guided therapy is generally not indicated.
Cure rates in HIV/HCV coinfected patients:
- Sofosbuvir/ledipasvir: 98% for treatment-naive genotype 1 non-cirrhotics (ERADICATE), 94% for treatment-naive cirrhotics (ION-4).
- Elbasvir/grazoprevir: 96% for treatment naive genotype 1, 4, and 6 (C-EDGE COINFECTION)
- Glecaprevir/pibrentasvir: 98% for treatment naive and experienced genotype 1, 2, 3, 4, 6 (EXPEDITION-2) (136/136 among those without cirrhosis, 14/15 in those with compensated cirrhosis.
- Sofosbuvir/velpatasvir: 95% for treatment naive genotype 1, 2, 3, 4 (ASTRAL-5)
- Sofosbuvir/velpatasvir/voxilaprevir: Regimen not studied in co-infected population, but it is expected that the response rates will be similar to those who are mono-infected.
Followup:
- HCV RNA should be tested at 12 wks after stopping treatment to determine cure; some experts recommend additional tests at 24 wks post-treatment.
- Patients with cirrhosis require lifetime surveillance for HCC following cure (liver ultrasound every 6 mos).

Management of Adverse Events

Most common side effects are fatigue, nausea, headaches for which common symptom management can be used.
Anemia (from RBV): if Hgb < 10 g/dL, decrease RBV (by 200 mg at a time); stop RBV if Hgb < 8.5 and support with epoeitin alfa (40K IU SQ qwk)

Basis for recommendation

Recommendations for Testing, Managing, and Treating Hepatitis C. (http://www.hcvguidelines.org). Accessed 11/19/2014.
Comment: Synthesis of clinical data into graded guidelines for HCV-monoinfected and HCV-HIV co-infected patients.

References

Hézode C, Asselah T, Reddy KR, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet. 2015;385(9986):2502-9. [PMID:25837829]
Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-98. [PMID:24725239]
Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology. 2014;146(3):736-743.e1. [PMID:24262278]
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370(3):211-21. [PMID:24428467]
Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594-603. [PMID:24720703]
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878-87. [PMID:23607594]
Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology. 2012;142(6):1293-1302.e4. [PMID:22537436]
Laguno M, Cifuentes C, Murillas J, et al. Randomized trial comparing pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients. Hepatology. 2009;49(1):22-31. [PMID:19085908]
Comment: RCT among HIV+ ots demonstrating similar SVR 24 wks after completing treatment with PEG-IFN alfa 2a & 2b (46 vs 42%).
Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon. N Engl J Med. 2008;359(23):2429-41. [PMID:19052125]
Comment: RCT demonstrating similar liver disease outcomes with no treatment vs. PEG-IFN alfa 2a 90 mcg qwk.
Chamie G, Bonacini M, Bangsberg DR, et al. Factors associated with seronegative chronic hepatitis C virus infection in HIV infection. Clin Infect Dis. 2007;44(4):577-83. [PMID:17243063]
Comment: Analysis of associations with seronegative chronic hepatitis C among 37 subjects drawn from multiple cohorts.
Sulkowski MS, Mehta SH, Torbenson M, et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS. 2005;19(6):585-92. [PMID:15802977]
Comment: Evaluates impact of HAART on steatosis in HIV-HCV coinfected patients.
Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351(5):451-9. [PMID:15282352]
Comment: Initial trials of PEG-IFN in HIV-HCV co-infection.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351(5):438-50. [PMID:15282351]
Comment: Initial trials of PEG-IFN in HIV-HCV co-infection.
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13):975-82. [PMID:12324553]
Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338(5):286-90. [PMID:9445408]
Comment: Of 17 pts with chronic HCV who acquired acute HAV infection, 7 (41%) developed fulminant hepatic failure.
AbbVie. Viekira Pak [package insert]. 2014.North Chicago IL, AbbVie, Inc.
Abbvie. Technivie [package insert]. 2015. North Chicago IL, AbbVie, Inc.
Bristol-Myers Squibb. Daklinza [package insert] 2015. Princeton NJ, Bristol-Myers Squibb, Inc.
Gilead Sciences I. Harvoni [package insert]. 2015.Foster City, CA, Gilead Sciences, Inc.
Gilead Sciences I. Sofosbuvir [package insert]. 2013.Foster City, CA, Gilead Sciences, Inc.
Janssen Therapeutics. Simeprevir [package insert]. 2013.Titusville, NJ, Janssen Therapeutics.
Sulkowski MS, Eron JJ, Wyles D, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015;313(12):1223-31. [PMID:25706092]