Hepatitis C Treatment & Management

Patients with acute hepatitis C virus (HCV) infection appear to have an excellent chance of responding to 6 months of standard therapy with interferon (IFN). Because spontaneous resolution is common, no definitive timing of therapy initiation can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.

Treatment of chronic HCV infection has 2 goals. The first is to achieve sustained eradication of HCV (ie, sustained virologic response [SVR]), which is defined as the persistent absence of HCV RNA in serum 6 months or more after completing antiviral treatment. The second goal is to prevent progression to cirrhosis, hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver transplantation.

Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria^[34] :

• Age greater than 18 years
• Positive HCV antibody and serum HCV RNA test results
• Compensated liver disease (eg, no hepatic encephalopathy or ascites)
• Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm³, serum creatinine < 1.5 mg/dL)
• Willingness to be treated and to adhere to treatment requirements
• No contraindications for treatment

A further criterion is liver biopsy findings consistent with a diagnosis of chronic hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be helpful in certain situations, such as in patients with normal transaminase levels, particularly those with a history of alcohol dependence, in whom little correlation may exist between liver enzyme levels and histologic findings.

Patients with normal liver enzyme levels and minimal histologic damage noted on liver biopsy may elect to defer treatment until more effective and less toxic medications become available, whereas patients with more advanced liver injury may prefer to initiate treatment sooner. Patients should be informed that the treatment of HCV infection in the setting of normal liver enzyme levels remains controversial.

The treatment of hepatitis C has evolved over the years (see the following image). Initial studies used IFN monotherapy, but current treatments are combination therapy consisting of ribavirin and IFN or of IFN to which polyethylene glycol (PEG) molecules have been added (ie, PEG-IFN).

Protease inhibitors are emerging as a third feature of combination therapy. The first protease inhibitor indicated for use in HCV infection, boceprevir (Victrelis), was approved by the FDA in May 2011.

Patients with HCV-related decompensated cirrhosis should be referred for consideration of liver transplantation.

The 2 most frequently used recombinant IFN preparations in clinical trials are IFN alfa-2b (Intron-A) and IFN alfa-2a (Roferon), which differ from each other by only a single amino acid residue. IFN alfacon-1 (Infergens), or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs.

IFN alfacon-1 has greater cytokine-induction, antiviral, antiproliferative, natural killer cell, and gene-induction activities than both IFN alfa-2a and IFN alfa-2b on an equal-mass basis. However, initial studies of the recommended consensus IFN dose of 9 mcg in IFN-naive patients with chronic hepatitis C, such as that by Tong et al,^[35] have resulted in viral response rates similar to those of standard IFN-alfa monotherapy.

The addition of propylene glycol (PEG) molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.

Two PEG-IFN preparations are available. PEG-IFN alfa-2b (PEG-Intron) consists of IFN alfa-2b attached to a single 12-kd PEG chain; it is excreted by the kidneys. PEG-IFN alfa-2a (Pegasys) consists of IFN alfa-2a attached to a 40-kd branched PEG molecule; it is metabolized predominantly by the liver.

IFN monotherapy in acute hepatitis C

Although the short courses of standard IFN monotherapy introduced in the 1980s by Hoofnagle et al,^[36] Davis et al,^[2] and Di Bisceglie et al^[37] led to sustained improvement in liver disease and loss of virus in less than 10% of patients, these therapies were the first to cure chronic viral hepatitis. While combination therapy with IFN or PEG-IFN and ribavirin have become the standard of care for chronic disease, IFN monotherapy may play a role in the treatment of acute HCV infection.

Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44 German patients with acute hepatitis C.^[38] In this study, patients received 5 million U/day of IFN alfa-2b subcutaneously for 4 weeks and then 3 times per week for another 20 weeks; the IFN alfa-2b was well tolerated in all patients but one.^[38] Because spontaneous resolution is common, no definitive timing of therapy can be recommended; however, waiting 2-4 months after the onset of illness seems reasonable.

PEG-IFN monotherapy

Several reports have documented improved SVR with PEG-IFN monotherapy. In a randomized study of patients with chronic hepatitis C, Zeuzem et al found that PEG-IFN alfa-2a at 180 mcg subcutaneously administered once per week was associated with a higher rate of virologic response than IFN alfa-2a at 6 million U subcutaneously administered 3 times per week for 12 weeks followed by 3 million U 3 times per week for 36 weeks.^[39] Findings were 69% versus 28% at week 48 of therapy and 39% versus 19% at week 72 of therapy.^[39]

In a controlled trial of persons with cirrhosis, Heathcote and colleagues reported an SVR rate of 30% after 48 weeks of therapy with PEG-IFN alfa-2a, compared with 8% for patients treated with standard IFN alfa. Adverse effects were not significantly higher with the pegylated product.^[40]

A major advance in the treatment of chronic hepatitis C was the addition of the oral nucleoside analogue ribavirin to the IFN regimen. As reported in the landmark 1998 studies by McHutchison et al^[41] and Poynard et al,^[42] IFN alfa-2b and ribavirin combination therapy for 6-12 months resulted in sustained eradication rates of 30-40%. However, patients with HCV genotype 1 who were treated for 12 months had a much less favorable response than patients infected with genotypes 2 and 3 who received a 6-month course of therapy.

PEG-IFN therapy with ribavirin

As with IFN alfa, the addition of ribavirin to PEG-IFN heralded a new era in the treatment of chronic HCV. The benefits of combination therapy were documented in 3 landmark trials: Manns et al from 2001,^[43] Fried et al from 2002,^[44] and Hadziyannis et al from 2004.^[45]

Manns et al reported a significantly higher SVR rate in patients given higher-dose PEG-IFN alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus ribavirin or given IFN alfa-2b plus ribavirin.^[43] Adverse-effect profiles in the 3 treatment groups were similar. Secondary analyses identified body weight and HCV RNA viral load less than 1 million copies per milliliter as important predictors of SVR. (See the image below.)

Fried at al found that patients who received PEG-IFN alfa-2a plus ribavirin had a significantly higher SVR rate than patients who received IFN alfa-2b plus ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%).^[44] The SVR rates for patients with HCV genotype 1 were 46%, 36%, and 21%, respectively, for the 3 regimens.

Hadziyannis et al reported that in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks, and standard-dose ribavirin was statistically superior to low-dose ribavirin.^[45] In this study, 1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk for 24 or 48 weeks plus a low dose (800 mg/day) or standard weight-based dose (1000 or 1200 mg/day) of ribavirin.^[45] In patients with HCV genotypes 2 or 3, there were no statistically significant differences in SVR rates in the 4 treatment groups.

In a study of ribavirin in combination with either PEG-IFN alfa-2b or PEG-IFN alfa-2a for the treatment of chronic HCV infection, Ascione et al reported a higher SVR rate with PEG-IFN alfa-2a than with PEG-IFN alfa-2b (68% versus 54.4%).^[46] SVR rates were not statistically different in patients with a baseline HCV RNA of 500,000 IU/mL or less or in those with cirrhosis.^[46]

In a similar trial, Rumi et al reported that treatment with ribavirin plus PEG-IFN alfa-2a resulted in a significantly higher SVR rate than ribavirin plus PEG-IFN alfa-2b. The 2 regimens showed a similar safety profile.^[47]

In conclusion, treatment with PEG-IFN alfa-2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotype 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.^[48]

Adverse effects

Adverse effects are common with IFN and ribavirin combination therapy. Approximately 75% of patients experience one or more of adverse effects.

Adverse effects of IFN include the following:

• Hematologic complications (ie, neutropenia, thrombocytopenia)
• Neuropsychiatric complications (ie, memory and concentration disturbances, visual disturbances, headaches, depression, irritability)
• Flulike symptoms
• Metabolic complications (ie, hypothyroidism, hyperthyroidism, low-grade fever)
• Gastrointestinal complications (ie, nausea, vomiting, weight loss)
• Dermatologic complications (ie, alopecia)
• Pulmonary complications (ie, interstitial fibrosis)

Adverse effects of ribavirin include the following:

• Hematologic complications (ie, hemolytic anemia)
• Reproductive complications (ie, birth defects)
• Metabolic complications (ie, gout)

Because of the risk of reproductive complications from ribavirin, recommend that patients and their spouses not become pregnant while either is on therapy and for 6 months after the completion of treatment.

Growth factors, such as granulocyte-stimulating factor (GSF) and erythropoietin, are frequently used to counteract the adverse hematologic effects of IFN and ribavirin, respectively. Despite the encouraging early results reported by Afdhal et al^[49] and Van Thiel et al,^[50] cost-effectiveness data supporting the routine use of these agents as a means of avoiding IFN and ribavirin dose reductions are insufficient.

In patients who are at risk of depression or who develop depression during treatment, any antidepressant is better than none. Because available evidence suggests that all antidepressants will have an effect, Schaefer et al reported that treatment must be individualized on the basis of adverse effect profile, drug-to-drug interactions, and general considerations (eg, speed of onset, efficacy).^[51]

Despite the improved results achieved with the addition of ribavirin to PEG-IFN, the current available therapies for chronic HCV infection are effective in fewer than 50% of patients with HCV genotype 1. Protease inhibitors used in conjunction with pegylated interferon and ribavirin is becoming the new standard of care for the treatment of chronic HCV infection.

Boceprevir (Victrelis) and telaprevir (Incivek) are HCV NS3/4A protease inhibitors and were approved by the US Food and Drug Administration in May, 2011. Each is indicated for treatment of chronic HCV genotype 1 infection in combination with PEG-IFN alfa and ribavirin in adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.

Boceprevir was evaluated in 2 phase 3 clinical trials with nearly 1,500 participants. In both trials, two thirds of patients receiving boceprevir in combination with peginterferon alfa and ribavirin experienced a significantly increased sustained virologic response (ie, undetectable HCV RNA level) compared with those taking peginterferon alfa and ribavirin alone.^{[52, 53]}

The safety and effectiveness of telaprevir was evaluated in 3 phase III clinical trials with about 2,250 adult patients who were previously untreated or who had received prior therapy. In previously untreated patients, 79% of those receiving telaprevir experienced a sustained virologic response (SVR) compared with PEG-IFN alfa and ribavirin treatment alone. SVR for patients treated with telaprevir across all studies and across all patient groups was 20-45% higher than the current standard of care.^[54]

The Protease Inhibition for Viral Evaluation 1 (PROVE1) study demonstrated that the addition of telaprevir to the current treatment regimen improved virologic response to HCV.^[55] In early studies, there was a rapid reduction of chronic HCV RNA levels. However, the telaprevir groups had a higher rate of discontinued treatment (21%) compared with the placebo group (11%) because of adverse effects, particularly rash.

Of persons infected with HIV, 30-50% are coinfected with HCV. Coinfection with HIV both accelerates the clinical progression of hepatitis C and increases the risk of perinatal HCV transmission, from 5% (range, 3-8%) to 17% (range, 7-36%). Two 2004 studies supported the use of PEG-IFN alfa-2a plus ribavirin for HIV patients with chronic HCV infection.

In the first study, Torriani et al showed that among patients coinfected with HIV and HCV, the combination of PEG-IFN alfa-2a plus ribavirin is significantly more effective than either IFN alfa-2a plus ribavirin or PEG-IFN alfa-2a monotherapy.^[56] In persons infected with HCV genotype 1, the SVR rates were 29% with PEG-IFN alfa-2a plus ribavirin, 14% with PEG-IFN alfa-2a plus placebo, and 7% with IFN alfa-2a plus ribavirin. The corresponding rates in persons infected with HCV genotype 2 or 3 were 62% with PEG-IFN alfa-2a plus ribavirin, 36% with PEG-IFN alfa-2a plus placebo, and 20% with IFN alfa-2a plus ribavirin.^[56]

In the second study, a multicenter, randomized trial by Chung et al, the combination of PEG-IFN and ribavirin proved superior to the combination of IFN and ribavirin, with SVR rates of 27% vs 12%, respectively.^[57] An important finding was that liver biopsy showed histologic improvement in 35% of patients with no virologic response, suggesting that the effects of IFN and ribavirin on hepatic histology may be independent of its antiviral activity. Thus, treatment may provide clinical benefit even in the absence of virologic clearance.

No trials have compared PEG-IFN alfa-2a plus ribavirin with PEG-IFN alfa-2b plus ribavirin in patients with chronic hepatitis C and HIV infection. However, in a 2004 Spanish, open-label, randomized study comparing PEG-IFN alfa-2b plus ribavirin with IFN alfa-2b plus ribavirin, Laguno and colleagues reported that SVRs were significantly better with the pegylated combination (44% vs 21%).^[58]

Ribavirin increases the toxicity of didanosine; therefore, these agents should not be coadministered.

Coinfection with HCV and hepatitis B virus (HBV), in the absence of HIV infection, is relatively uncommon in the United States, and optimal treatment regimens have not been established. However, 2 important studies are worth mentioning. Villa et al reported that 9 million U of standard IFN 3 times weekly for 3 months could clear HCV in 31% of patients with HCV-HBV coinfection.^[59] Liu et al used standard IFN and ribavirin and discovered that sustained HCV eradication was achieved at rates comparable to those in patients with HCV alone and, interestingly, up to 21% of their patients lost the hepatitis B surface antigen.^[60]

Given the superior efficacy of PEG-IFN over standard IFN, Liu et al subsequently conducted a multicenter study using PEG-IFN and ribavirin in HVC-HBC coinfected patients. This regimen proved equally effective in patients with HCV monoinfection and in those with chronic HCV-HBV infection.^[61]

Several small studies have reported a lower response rate to IFN alfa in black patients with chronic hepatitis C infection than in white patients. The increased prevalence of infection with HCV genotype 1, which is associated with a lower response rate than other genotypes, has been suggested as the cause.

However, in a study that enrolled equal proportions of black and non-Hispanic white patients with chronic hepatitis from HCV genotype 1, Muir et al reported that the SVR rate was significantly higher among non-Hispanic white patients (52%) than among black patients (19%) after treatment with PEG-IFN alfa-2b and ribavirin for 48 weeks.^[62] Multivariate analyses examining sociodemographic and clinical characteristics found that black race was the only variable significantly associated with the difference in response rates.

Hepburn et al analyzed data from 661 patients in 2 multicenter trials and found that compared with white patients, Asians were more likely to respond to treatment, and Hispanics and blacks were less likely to respond.^[63] The role of ethnicity in predicting successful viral eradication emerged after multiple logistic regression analyses adjusted for factors known to impact outcome (eg, genotype).

HCV is prevalent in patients with end-stage renal disease and can also be an important cause of renal failure. Treatment of HCV infection in patients with end-stage renal disease is problematic, because ribavirin is contraindicated and IFN monotherapy is not as effective as combination therapy. IFN doses also frequently have to be reduced.

Before undergoing kidney transplantation, patients are frequently referred for consideration of HCV treatment and liver-kidney transplantation in the event of having silent-but-advanced liver disease. Under these circumstances, liver biopsies are frequently performed to stage the degree of fibrosis.

If cirrhosis is present and the patient is asymptomatic, he or she is frequently considered for combined liver-kidney transplantation. However, because IFN is contraindicated after kidney or kidney-liver transplantation, attempting to eradicate HCV in such patients before organ transplantation is recommended.

A meta-analysis by Fabrizi et al found that tolerance to initial IFN monotherapy was lower in dialysis patients than in nonuremic patients with chronic hepatitis C. The dropout rate was 17%. The most frequent adverse effects requiring interruption of treatment were flulike symptoms (17%), neurologic symptoms (21%), and gastrointestinal symptoms (18%). However, more than one third of hemodialysis patients achieved an SVR. A longer duration of IFN monotherapy did not appear to have a beneficial effect on the response rate.^[64]

In a study by Liu et al of PEG-IFN alfa-2a monotherapy for acute HCV infection in patients on hemodialysis, all patients who received more than 12 weeks of therapy had early and end-of-treatment virologic responses. These researchers recommend that patients with acute hepatitis C who do not have spontaneous clearance by week 16 should receive therapy.^[65]

For patients who do not achieve an SVR after a full course of PEG-IFN plus ribavirin, retreatment is not recommended, even if a different type of PEG-IFN is used.^[34] Patients who do not respond to antiviral therapy and who have advanced fibrosis should be screened for hepatocellular carcinoma (HCC) and varices and should be evaluated for liver transplantation if they are appropriate candidates. Patients with mild fibrosis should be monitored without treatment.^[34]

Hayashi and Kasahara noted that exposure to IFN, irrespective of HCV eradication status, was associated with a reduced incidence of HCC.^[66] An important randomized study by Kubo et al, first conducted in 1996 with follow-up in 2002, also demonstrated that the administration of IFN to patients undergoing liver resection for HCC was associated with reduced tumor recurrence and improved survival.^[67] Although IFN may have a role in reducing the incidence of HCC, it remains unclear as to which subgroup of HCV patients are most likely to benefit.

The aim of treating decompensated cirrhotic patients is to achieve sustained viral eradication before liver transplantation in an attempt to prevent recurrent HCV infection. However, this intervention is not recommended outside of clinical trials because the risks of treatment can outweigh the benefits.^[68] Although viral titers may decrease during treatment and possibly diminish the severity of recurrent HCV infection, complications and successful eradication are less likely in patients with more advanced liver disease.^[69]

Recurrence after liver transplantation

Recurrent HCV infection is universal after liver transplantation, can lead to cirrhosis in 30% of patients within 5 years, and is emerging as the most common cause of retransplantation in the United States.^[70] IFN is contraindicated after organ transplantation because of its high risk of precipitating rejection, in part due to upregulation of the human leukocyte antigen (HLA) system by IFN. Liver transplantation is a possible exception, however, as allograft rejection is uncommon in liver transplant recipients with recurrent HCV infection who are treated with IFN-based therapies.

Several pilot studies have been conducted to evaluate IFN-based therapies for recurrent HCV infection. One of the most important of these was reported by Samuel et al, who found that the combination of IFN alfa-2b plus ribavirin induced an SVR in 21% of transplant recipients with recurrent hepatitis C.^[71] However, no significant histologic improvement was noted, and antiviral therapy was discontinued in 43% of treated patients because of adverse events (primarily severe anemia).

This study randomized patients to receive either placebo (n = 24) or therapy with IFN alfa-2b (3 million U 3 times/wk; n = 28) plus 1000-1200 mg/day of ribavirin for 1 year. Patients were followed for 6 months after the end of treatment. The primary endpoint was loss of HCV RNA 6 months after the end of treatment.^[71] In the treated group, serum HCV RNA was undetectable in 9 patients (32%) at the end of treatment and in 6 (21.4%) at the end of the follow-up period, whereas no patient in the control group lost HCV RNA at any point.^[71]

Despite the low rates of sustained viral eradication in patients with posttransplantation HCV recurrence, Narayanan Menon et al identified a subgroup of patients who demonstrated improved fibrosis scores despite failure to eradicate the virus.^{[71, 72]} This suggests that some patients may benefit from maintenance therapy and emphasizes the benefit of performing pretreatment and posttreatment biopsies in this group of patients.

Two 2003 pilot studies on the use of PEG-IFN alfa-2b and ribavirin in these patients, by Mukherjee et al^[73] and Rodriguez-Luna et al,^[74] found that sustained eradication rates were less than 30%. No evaluations of PEG-IFN alfa-2b and ribavirin for recurrent HCV infection or randomized studies using PEG-IFN and ribavirin have been reported in this cohort of patients.

The treatment for these patients remains controversial, because previous studies have demonstrated that they frequently have mild liver disease, do not tolerate therapy, or can develop new elevations in liver chemistry parameters after starting treatment. Liver biopsy can be valuable in these cases. Hui et al reported that ALT levels and histologic findings are not well correlated and patients can have advanced fibrosis or cirrhosis in the presence of normal liver enzyme levels.^[75]

Jacobson et al reported that sustained HCV eradication rates in patients with HCV infection and normal ALT values were comparable to those in patients with elevated liver enzyme levels.^[76] However, the authors used both high-dose (5 million U) and low-dose (3 million U) IFN with ribavirin in their study, and only 1 patient had cirrhosis.^[76]

In addition, Jacobson et al did not investigate the role of previous alcohol use on liver injury, although all patients abstained from alcohol for at least 12 months. Future trials will most likely evaluate PEG-IFN with ribavirin in this cohort of patients, and the hope is they will adjust for confounders, such as alcohol use.

In 1998, Wiley et al reported that significant alcohol use (>40 g alcohol/d in women and >60 g of alcohol/day in men for >5 y) in HCV-infected patients resulted in a twofold to threefold greater risk of liver cirrhosis and decompensated liver disease. In addition, cirrhosis developed more rapidly in alcohol users.^[77] Because of the risk that alcohol use poses for rapid liver fibrosis, hepatoma, and deleterious effects on treatment response, complete alcohol abstinence is recommended during treatment.

Practice guidelines from the American Association for the Study of Liver Diseases recommend that HCV treatment not be withheld from patients who use illicit drugs or are on a methadone maintenance program, provided they are willing to maintain close monitoring, including practicing contraception.^[78] However, the guidelines note that "it is important to consider the individual issues that may affect the risks and benefits of treatment of HCV infection in persons who use illicit drugs, rather than to make categorical recommendations."^[34]

The complexity of HCV treatment in these patients is aided by a multidisciplinary team approach composed of physicians, nurses, and substance abuse and mental health professionals.

Currently, no products are available to prevent HCV infection. The development of immunoprophylaxis for this disease is proving difficult; an effective neutralizing immune response has not been demonstrated.

Patients with hepatitis C should be advised to abstain from alcohol use. Patients with hepatitis C should be advised to use barrier protection during sexual intercourse. Screening high-risk patients and initiating appropriate treatment may decrease the prevalence of cirrhosis and HCC.

Consultation with a gastroenterologist and hepatologist is recommended in the treatment of HCV infection. Consultation with a psychiatrist may be helpful before and during treatment in patients at risk of depression or other psychiatric illnesses. Consultation with a surgeon may be necessary for patients in whom hepatic resection for HCC or liver transplantation is being considered.

At week 12 of treatment, the patient should be evaluated for an early virologic response by repeating the quantitative HCV RNA and IFN-associated thyroid dysfunction screening. If the HCV RNA level is undetectable or if a greater than 2-log-fold reduction in HCV RNA level is present, therapy should be continued because, according to Fried et al, up to 65% of patients go on to develop an SVR.^[44]

Conversely, if an early virologic response is not present, treatment should be stopped, because the chance of developing a sustained response of HCV eradication is less than 3%. Poynard et al reported that the one exception is in the context of clinical trials or treatment of recurrent HCV infection in liver transplant recipients^[79] ; improved fibrosis scores have been reported in patients in whom the virus has not been eradicated, thus identifying a subgroup of patients who may benefit from maintenance therapy.

The HCV RNA level should be rechecked 6 months after the completion of treatment; if HCV RNA is detectable, the patient has had a relapse of disease and an alternative treatment should therefore be considered. If HCV RNA is undetectable and test results remain negative, the patient has developed an SVR.

Patients with HCV infection should be monitored closely for adverse effects as well as response to therapy. Tests to help monitor drug toxicity include the following:

• Complete blood count with differential
• Renal function testing
• Liver function tests (including alanine aminotransferase [ALT] level)
• Thyrotropin level

While measurement of ALT levels is useful for monitoring the effectiveness of therapy for HCV infection, ALT levels can fluctuate. Consequently, a single value in the reference range does not rule out active infection, progressive liver disease, or cirrhosis. ALT normalization with therapy is not proof of cure.

Patients with cirrhosis should be screened for HCC and esophageal varices. They should also be monitored for the development of decompensated liver disease. Vaccination against hepatitis A virus (HAV) and HBV before or after completing HCV treatment has been recommended.^[80] Patients should be offered vaccination for HAV and HBV before they develop decompensated liver disease, after which they may be less likely to mount an immune response.