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Update of the Management and Treatment of Hepatitis C Viral Infection, 2012: Supplement

for Health Care Providers


You are viewing outdated content. This information may no longer be accurate or relevant and is provided for research or recordkeeping purposes only.



The following supplemental recommendations for each subgroup of patients have taken into account the natural history of disease, the likelihood of achieving an sustained virologic response (SVR), and the adverse effects and need for dose discontinuations with treatment.


The optimal treatment for HCV genotype 2 or 3 infection remains peginterferon alfa (PegIFN) and ribavirin (RBV) (1) . Data from a small single randomized trial suggest some efficacy of telaprevir against genotype 2 infection, and limited efficacy in genotype 3 infection (2) . Overall, HCV genotype 3 infection is less responsive to PegIFN and RBV than is genotype 2 (SVR 66-79% and 75-93%, respectively) (3, 4) . SVR was associated with low baseline HCV RNA (<600,000 IU/ml), minimal fibrosis, lower body weight, age <40, and higher ALT (5, 6, 7) . Several studies suggest that weight-based dosing of RBV in genotype 3 is superior to fixed dosing, particularly in short course therapy, with lower relapse rates (6, 8, 9) . These studies suggest that treatment duration, clinical factors associated with impaired response to PegIFN and RBV, and RBV dose should be considered carefully (3, 6, 10) .

The most important predictor of SVR for genotype 2 or 3 infection remains achievement of rapid virologic response (RVR), with SVR rates of >80% with 24 weeks of therapy; if RVR is not achieved, SVR occurs in only 50-60% of patients (11) . In genotype 2-infected patients who achieve RVR, a treatment duration of 12-16 weeks might be sufficient but higher relapse rates (10-30%) have been reported (12, 13, 14) . In genotype 3-infected patients with low baseline viral load (HCV RNA <600,000 IU/ml) and RVR, SVR rates are similar with shortened treatment duration (12-16 weeks) versus standard therapy (24 weeks) (6, 12, 13, 14, 15) . Based on unacceptably high relapse rates, a shortened treatment duration is not recommended in genotype 3-infected patients with high baseline HCV RNA (>600,000 IU/ml), METAVIR 3 or 4 fibrosis, obesity, metabolic risk factors or viral co-infections (6, 16) .

Data of a retrospective pooled analysis of registration studies in non-RVR patients showed superior treatment outcome with weight based ribavirin and up to 48 weeks of therapy (17) . The role of treatment beyond 24 weeks has been evaluated only in a single prospective study (9) . Treatment up to 36 weeks in genotype 3-infected patients without RVR resulted in a small but statistically insignificant, improvement in SVR as compared to treatment with 24 weeks (62% and 51%, respectively).

The decision to retreat a patient with genotype 2 or 3 infection should take into account prior treatment regimen, duration, and response. Several trials have examined retreatment of genotype 2 and 3 infection, with SVR rates ranging from 53-63% with 48 weeks of therapy (18, 19, 20, 21) . EPIC 3 enrolled 367 genotype 2- and 3-infected treatment-experienced patients and reported SVR rates of 59% (genotype 2) and 55% (genotype 3), respectively. Relapsers had an SVR rate of 61%, whereas nonresponders had an SVR rate of 46%. Favorable predictors of retreatment response were: genotype (2 or 3 versus 1), low fibrosis score, previous treatment type, low viral load (<600,000 IU/ml), and previous response (relapser versus non-responder) (21) .

Recommendations for treatment-naive and -experienced patients with genotype 2 or 3 infection:

  1. Treatment-naive patients should be treated with peginterferon-ribavirin for 24 weeks (Class I, Level A).
  2. For patients with low viral load (HCV RNA <600,000 IU/ml) and mild fibrosis who achieve a rapid virologic response, 12-18 weeks of treatment may be sufficient (Class I, Level A).
  3. For patients with genotype 3 infection and a high HCV RNA (>600,000 IU/ml), steatosis or advanced fibrosis, treatment beyond 24 weeks may improve response (Class I, Level B).
  4. Retreatment duration is 48 weeks (Class I, Level A).

Patients with genotype 4 infection have higher SVR rates (69-79%) than patients with genotype 1 infection when treated with PegIFN and RBV for 48 weeks (22, 23, 24) . Insufficient clinical trial data are available in patients with HCV genotypes 5 and 6 to make treatment recommendations about optimal regimens at this time.

Recommendations in patients with genotype 4 infection:

  1. Appropriate candidates with HCV genotype 4 infection should be treated with peginterferon alfa-2a 180 mcg/week or peginterferon alfa-2b 1.5 mcg/kg/week plus ribavirin up to 1,400 mg/day for 48 weeks (Class I, Level A).

Up to 20% of patients with persistently normal ALT have bridging fibrosis or cirrhosis (25) . Consequently, ALT elevation has not been an inclusion criterion in most recent clinical trials (26, 27, 28, 29) and a normal ALT does not exclude patients from HCV treatment.


Once clinical decompensation occurs, as defined by variceal bleeding, formation of ascites, development of portosystemic encephalopathy, jaundice, or early-stage hepatocellular carcinoma, liver transplantation is the treatment of choice. HCV therapy is contraindicated in patients with decompensated cirrhosis because of an increased risk of life-threatening bacterial infections and further hepatic decompensation. In 2003, an expert panel proposed that patients with HCV cirrhosis and a Child-Pugh score <7 and MELD ≤18 should be considered for antiviral therapy. The panel further proposed that patients with Child-Pugh scores >11 or MELD >25 should not be treated. Those with intermediate scores could be considered on a case-by-case basis (30) . Several studies have examined the treatment of decompensated cirrhotics with standard interferon-ribavirin or peginterferon-ribavirin therapy (31, 32, 33, 34, 35) . SVR rates were consistently low in genotype 1- infected patients, ranging from 7% to 30%. There are limited pharmacokinetic data on boceprevir in patients with hepatic decompensation, although telaprevir exposure is reduced by 46% in patients with Child-Pugh Class B. Thus, telaprevir and boceprevir should not be administered to patients with hepatic decompensation (Child-Pugh Class B or C, score ≥7). Treatment-naive patients with low Child-Pugh and MELD scores who have favorable predictors of response such as genotype 2 or 3 infection may be considered for therapy with peginterferon and ribavirin, despite a history of clinical complications of liver disease.

Recommendations in patients with decompensated cirrhosis:

  1. Liver transplantation is the treatment of choice in patients with decompensated cirrhosis (Class I, Level B).
  2. Antiviral therapy is contraindicated in most patients with decompensated cirrhosis (Class II, Level B).
  3. Interferon-based therapy in combination with ribavirin may be considered in patients awaiting liver transplantation with a Child-Pugh score <7 and a MELD score ≤18 (Class I, Level A).
  4. If antiviral therapy is undertaken, reduced interferon doses should be used and growth factors can be given to counteract treatment-associated cytopenias (Class II, Level B).

In general, interferon therapy is contraindicated in renal, cardiac, or pulmonary transplant recipients because of an increased risk of severe allograft rejection. Treatment of HCV prior to transplant is advisable in patients who are otherwise good candidates for solid organ transplant.

After liver transplantation for HCV-related disease, graft reinfection is virtually universal. The timing of treatment for hepatitis C has been evaluated in multiple small trials. Pre-emptive therapy early after transplant is limited by significant adverse events, high patient dropout rates, and poor SVR rates. Patients with at least stage 2 fibrosis on liver histology from recurrent HCV disease may be considered for antiviral therapy under the guidance of a transplant specialist. Limited data suggest that treatment response in liver allograft recipients is lower than in immunocompetent individuals (36, 37, 38, 39) . Overall SVR was approximately 20-30% with 48 weeks of peginterferon alfa with or without ribavirin, but SVR may be somewhat higher with genotype 2 or 3 infection (37, 39) . Dose reductions for cytopenias are common and early growth factor support and/or transfusions are often necessary. Based on small case series, the incidence of acute cellular rejection associated with peginterferon alfa appears higher than for standard interferon, so immunosuppression must be maintained and patients must be monitored closely (40) . HCV antiviral treatment with boceprevir or telaprevir combined with peginterferon-ribavirin is not routinely recommended because safety and efficacy data are not available in this population. In addition, significant drug-drug interactions with boceprevir or telaprevir can occur with concomitant administration of certain immunosuppressants. (Refer to Supplementary Table 2 on Drug-Drug Interactions.) The optimal treatment regimen in these patients remains to be defined. If treatment is undertaken, therapy should be co-managed with a multidisciplinary team that includes experienced HCV providers and transplant specialists.

Recommendations in patients following solid organ transplantation:

  1. Interferon-based antiviral therapy is contraindicated following heart, lung or kidney transplantation (Class III, Level C).
  2. In patients with biopsy-proven chronic HCV disease following liver transplantation, peginterferon-ribavirin for 48 weeks may be considered (Class IIa, Level B).
  3. Toxicities of antiviral therapy should be managed with frequent monitoring, dose reductions and growth factor support (Class IIa, Level B).
  4. Post-liver transplant patients on antiviral therapy should be monitored closely for evidence of rejection and antiviral therapy should be stopped if rejection is documented (Class IIa, Level B).
  5. Pre-emptive antiviral therapy early post-transplantation in patients without histological recurrence should be avoided (Class IIa, Level B).

HCV infection is an independent predictor of morbidity and mortality due to increased progression to cirrhosis and hepatocellular carcinoma in patients with chronic kidney disease (CKD) (41, 42) . HCV-infected patients have a higher mortality rate post-renal transplant and reduced graft survival (43, 44) . Interferon remains contraindicated post-renal transplant; therefore, it is recommended to treat HCV infection in patients with concomitant kidney disease prior to kidney transplantation (45) .

If treatment is undertaken, therapy should be co-managed with a multidisciplinary team that includes experienced HCV providers and renal specialists. PegIFN needs to be renally adjusted for creatinine clearance below 50 ml/min (Refer to Table 3 in Main Document) (46, 47, 48, 49, 50, 51, 52) . Based on pharmacokinetic studies, low doses of ribavirin (Copegus) have been FDA-approved for use in CKD or hemodialysis patients (Refer to Table 3 in Main Document) (53, 54) . Increased side effects including severe hemolytic anemia requiring growth factors can occur.

A meta-analysis of 28 clinical trials reported an overall SVR of 39% and dropout rate of 19% in dialysis patients receiving standard interferon monotherapy (48) . Another meta-analysis of 16 clinical trials of PegIFN monotherapy in dialysis patients showed comparable SVR rates, but found PegIFN to be poorly tolerated (SVR 33%; dropout rate 23%) (49) . Small studies of standard IFN or PegIFN plus ribavirin (200 mg/day or 200 mg thrice weekly), however, found SVR rates in over 50% of dialysis patients if hemoglobin levels were maintained by erythropoietin and iron therapy (55, 56, 57, 58) . As HCV treatment in post-renal transplant patients has achieved only low SVR rates and graft rejection is a serious problem (59, 60) anti-HCV therapy post renal transplant is not recommended, although there may be a role in rare cases of acute, fibrosing cholestatic hepatitis (61) .

Efficacy data with protease inhibitor triple therapy in patients with CKD are lacking. No dosage adjustment of telaprevir or boceprevir is required in patients with any degree of renal impairment. The pharmacokinetics of telaprevir following a single dose of 750 mg has been evaluated in HCV-negative patients with Clcr <30 ml/min but telaprevir has not been evaluated in patients with ESRD or those on dialysis. The pharmacokinetics of boceprevir following a single 800 mg dose was evaluated in HCV-negative patients on dialysis; the mean AUC of BOC was 10% lower and <1% of BOC was removed by hemodialysis. In HCV-infected patients, telaprevir has not been evaluated in those with Clcr ≤50 ml/min. Boceprevir has not been evaluated in HCV-infected patients with renal impairment (62, 63) .

  1. Patients should be considered for antiviral therapy with interferon (standard or pegylated) with ribavirin at modified doses (Table 3) (Class IIa, Level C).
  2. Antiviral therapy for HCV treatment is not recommended in patients post-renal transplant; however, it may be considered if patients develop fibrosing cholestatic hepatitis (Class III, Level C).

Before treatment is undertaken in patients >65 years old and/or in those with significant concomitant medical problems (e.g., coronary artery disease, diabetes, renal insufficiency, or chronic obstructive pulmonary disease), careful consideration to initiating therapy should be undertaken in light of reduced life expectancy and increased risk of adverse events. However, age greater than 65 years per se is not a contraindication to treatment with peginterferon-ribavirin-protease inhibitor therapy.

  1. In patients with limited life expectancy from comorbid conditions, antiviral therapy is not recommended (Class I, Level C).
  2. In patients with significant comorbid conditions that will be exacerbated by peginterferon-ribavirin, treatment should be deferred (Class I, Level C).

Patients receiving stable methadone doses and who have not used injection drugs for six months may benefit from peginterferon-ribavirin treatment (64, 65) . Patients receiving methadone maintenance have higher discontinuation rates, but the SVR rate among those who completed treatment was similar to the SVR among patients not on methadone. Limited data are available about the use of peginterferon-ribavirin-protease inhibitor therapy in patients receiving methadone. When co-administered with telaprevir, methadone levels in the blood are reduced but only clinical monitoring and possible methadone dose-adjustment are recommended (63) . Co-administration with boceprevir can potentially either raise or lower blood levels of methadone or buprenorphine; clinical monitoring is recommended (62) .

Recommendations for patients on methadone:

  1. Antiviral therapy should be offered to patients enrolled in a methadone maintenance program who meet criteria for therapy (Class I, Level A).
  2. Treatment should be coordinated between HCV treatment providers and substance abuse specialists (Class I, Level B).

To reduce the risk of liver disease progression, patients with HCV should limit or abstain from alcohol consumption. Abstinence from alcohol for six months prior to HCV therapy is usually recommended despite limited data to indicate that treatment responses are improved. Patients who drink alcohol have greater early treatment discontinuation rates with interferon-based therapy. However, among those who completed therapy, SVR rates were similar in drinkers and nondrinkers (66) .

Recommendations in patients with ongoing alcohol use:

  1. Patients should be encouraged to decrease alcohol consumption or to abstain, and should be referred for behavioral intervention to reduce alcohol use (Class I, Level B).
  2. Antiviral therapy should be offered to patients who are otherwise appropriate candidates regardless of prior alcohol use (Class I, Level B).
  3. Alcohol consumption should be discouraged during antiviral treatment because alcohol reduces adherence and treatment response (Class I, Level B).

In multivariate analyses from two large registration trials of PegIFN and RBV, increased body weight was associated with decreased antiviral response (5, 67) . Lifestyle changes such as exercise and weight loss should be recommended as adjuncts to antiviral therapy. Metabolic disorders should be managed aggressively prior to interferon therapy.

Recommendations in obese patients and those with hepatic steatosis:

  1. Patients with a body mass index >30 should be considered for antiviral treatment (Class I, Level A).
  2. Comorbid conditions common in obese patients such as diabetes, hypertension and hyperlipidemia should be controlled prior to initiation of antiviral therapy (Class I, Level C).

The combination of PegIFN and RBV remains the current standard of care for the treatment of HIV/HCV coinfection. Three pivotal trials established that combination therapy with PegIFN (alfa-2a or alfa-2b) plus ribavirin was superior to combination therapy with standard interferon plus ribavirin (68, 69, 70) . Initial trials in HIV/HCV co-infected patients used lower RBV doses of 800 mg/day, which resulted in lower SVR rates among genotype 1 infected subjects. The PRESCO trial employed RBV 1000-1200 mg daily in HIV/HCV coinfected patients, at times with extended duration of therapy; SVR rates were achieved in 35% of those with genotype 1 infection and 72% with genotype 2/3 infection (71) . Thus higher RBV doses may be preferable to lower doses, although additional studies are needed. Cytopenias related to HCV antiviral treatment are more common, and may require erythropoietin and granulocyte colony stimulating factors in order to continue therapy. Concomitant use of didanosine and ribavirin should be avoided. HIV/HCV coinfected patients with cirrhosis and a Child-Pugh score ≥6 should not receive HCV antiviral therapy. For more information, see VA Recommendations for the Treatment and Management of Hepatitis C Virus Infection in Patients with HIV Infection (72) .

Recommendations in patients with HIV-HCV coinfection:

  1. Patients with controlled HIV infection and evidence of liver disease on biopsy should be considered for HCV antiviral therapy (Class I, Level B).
  2. Patients should be treated with peginterferon-ribavirin at doses similar to those with HCV monoinfection (Class I, Level B).
  3. Patients should be treated with peginterferon-ribavirin for 48 weeks, regardless of genotype (Class I, Level A).

Patients with HBV/HCV coinfection have an increased risk for cirrhosis, HCC and death. Pre-treatment detailed serological and virological evaluations are required for HBV/HCV coinfected patients before antiviral therapy. PegIFN and RBV has been successfully used to treat HCV in HBV coinfected patients. No data are available on the use of HCV protease inhibitors in HBV/HCV coinfected patients although there is no reason why coinfection with HBV would deter use of a protease inhibitor. After reaching SVR for HCV infection, HBV rebound may occur and thus, close monitoring for both viruses is recommended even for patients with initially suppressed HBV DNA. In some instances, treatment with PegIFN and RBV has successfully cleared hepatitis C and hepatitis B infection (73) .


Studies of treatment for acute HCV infection have been heterogeneous and limited by small sample size, lack of randomization, differences in dose and schedule of administration, and duration of follow-up. Because spontaneous viral clearance usually occurs within the first three to six months of exposure, most studies have delayed treatment for 12 weeks after diagnosis (74, 75) . Studies with peginterferon alfa or interferon alfa monotherapy for 24 weeks have resulted in SVR of 80-100%. The addition of ribavirin differs among experts. Appropriate management of acute infection in active injection drug users is difficult. More than one third of such patients decline treatment, and of those who initiate therapy, fewer than half complete treatment, largely because of dose-limiting psychiatric side effects (76) .

Recommendations in patients with acute HCV infection:

  1. Patients should be observed for a period of 8-20 weeks from time of initial exposure to monitor for spontaneous resolution of infection (Class I, Level C).
  2. For those who fail to resolve infection spontaneously, treatment should be initiated with peginterferon alfa with or without ribavirin for 24-48 weeks, based on genotype and HCV RNA response during therapy (Class I, Level B).


Veterans Health Administration, Office of Public Health/Clinical Public Health, Washington, DC: Janet Durfee, RN, MSN, APRN (acting chief consultant); Technical Advisory Group: Matt B. Goetz, MD, Samuel B. Ho, MD; Core Working Group for the VA HCV Treatment Recommendations: Helen S. Yee, PharmD, Michael F. Chang, MD, Christine Pocha, MD, Joseph Lim, MD, David Ross, MD, PhD, Timothy R. Morgan, MD, and Alexander Monto, MD

Supplemental Table 1: Treatment Monitoring Guidelines for Patients on Peginterferon-Ribavirin ± Protease Inhibitor (Boceprevir or Telaprevir)

*Intervals may need to be increased based on patient tolerance and response to treatment in patients with significant declines in blood counts, renal insufficiency, diabetes, cirrhosis or other indications.

**Recommended for all patients at baseline and periodically during antiviral treatment in patients with diabetes, hypertension or as needed for visual complaints.

Necessary02481224Every 4-weeks ThereafterEnd-of-Treatment24 weeks Post-treatment
HCV RNA Follow Algorithm for additional timepoints
CBC with differential√*
Liver function tests√*
Psychiatric/Substance Use Screening√*
Renal panel *
Glucose *
Uric acid (if on telaprevir)*
Pregnancy test
Fundoscopic Exam**
Urine Toxicology Screen

Print table

Supplemental Table 2: Telaprevir and Boceprevir Drug-Drug Interactions

Supplemental Table 2: Telaprevir and Boceprevir Drug-Drug Interactions

(See full table)


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