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Management of Hepatitis C Infection

Stefan Zeuzem, MD
Program Director
Jordan J. Feld, MD, MPH
Hemant Shah, MD, MScCH HPTE
Released: June 17, 2019

Pretreatment Evaluation


A thorough patient history should be obtained before prescribing HCV therapy (Table 25). Several issues need to be explored to aid decision making. For patients in whom you are considering using an interferon-containing regimen, several important topics must be addressed to assess adequacy of treatment (Table 25). For patients in whom you plan to use an oral regimen, fewer issues need to be considered and can be limited to identifying major medical comorbidities with a worse prognosis than HCV infection (eg, incurable cancer, unstable cardiac disease).

Table 25. Important Topics to Cover During Patient History


Physical Examination

A thorough physical examination is necessary before initiating HCV therapy (Table 26). This is partly to identify health issues that need to be addressed before therapy, but it also serves as a baseline for comparison once therapy is initiated.

Table 26. Features of the Physical Examination in Patients Prior to HCV Therapy


Laboratory Testing

Pretreatment laboratory testing is essential in patients commencing HCV therapy and serves to rule out coexistent liver disease, ensure safety parameters before therapy, and aid in posttreatment monitoring (Table 27).

Table 27. Features of Laboratory Testing in Patients Before HCV Therapy


Role of Liver Biopsy and Noninvasive Tests in Determining Fibrosis

The AASLD/IDSA HCV guidance panel recommends an assessment of hepatic fibrosis using liver biopsy, imaging, and/or noninvasive tests before commencing HCV therapy.[54] The degree of fibrosis has an impact on treatment duration and response. In addition, cirrhotic patients should be surveyed for hepatocellular carcinoma, even if they go on therapy and ultimately achieve SVR.

Although some patients with HCV used to have liver biopsies to assess fibrosis, there are now several other modalities available to assess fibrosis by noninvasive means. Selected noninvasive markers commonly used in the setting of HCV infection are summarized in Table 28. These methods include equations that incorporate indirect or direct serum biomarkers and vibration-controlled transient elastography, an ultrasound-based technique approved by the FDA for assessment of fibrosis in April 2013. In transient elastography, a vibration wave is transmitted into the liver using a probe. The velocity with which the wave passes through the liver correlates to liver stiffness, and results are expressed in kilopascals. The estimated stiffness of the liver correlates with fibrosis stage as assessed by liver biopsy. Repeated (typically 10) measurements are taken, and the median reading is recorded. To be reliable, the interquartile range (difference between 25th and 75th percentile of readings) should be < 30% of the median stiffness, and at least 60% of readings should yield a successful estimate. Based on a meta-analysis, the sensitivity and specificity of transient elastography for cirrhosis are 87% and 91%, respectively, using a cutoff of 12.5 kPa for cirrhosis in HCV infection.[90,91] According to an analysis of transient elastography used to assess liver stiffness in patients with chronic HCV infection, an 8.7 kPa cutoff corresponds to Metavir F2 or higher, a 9.5 kPa cutoff corresponds to F3 or higher, and a 14.5 kPa cutoff corresponds to F4/cirrhosis.[92] Notably, in some clinical trials a cutoff of ≥12.5 kPa is used, which is more sensitive but less specific than a cutoff of 14.5 kPa for F4/cirrhosis. Although transient elastography has several positive attributes of a diagnostic test (ie, it is noninvasive, quick, painless, and provides immediate results), it is subject to technical limitations in patients who are obese, have heart failure, or who have active severe hepatitis, in which readings may be unreliable.[93-95] However, the introduction of the FibroScan XL probe has increased the reliability of transient elastography in obese patients.[96] In addition to the diagnostic value, elastography readings continue to increase with worsening fibrosis even after the diagnosis of cirrhosis and may provide prognostic information. Elastography readings ≥ 19 kPa have a sensitivity of 85% and specificity of 68% for the detection of large esophageal varices.[97] Longitudinal assessment of fibrosis progression using elastography has not yet been validated.

The AASLD/IDSA HCV guidance panel recommends assessing fibrosis in patients with chronic HCV infection with a combination of transient elastography and direct serum biomarkers.[54,98] Liver biopsy should be considered for patients with discordant results between the 2 tests if the findings will affect clinical decisions. In settings where transient elastography or direct serum biomarkers are unavailable, the guidance panel notes that helpful information can be gained from the AST to platelet ratio index (APRI) or the FIB-4 index score.[54] In such cases, a liver biopsy is recommended whenever a more accurate assessment of fibrosis would affect the treatment decision or management approaches. Additional liver disease staging via noninvasive tests or biopsy is not required for patients with clinical evidence of cirrhosis.

Guidelines from the EASL recommend use of noninvasive methods to assess liver disease severity prior to initiation of HCV therapy.[88] These guidelines also recommend that liver biopsy should be reserved for patients in whom noninvasive tests are inconclusive or those whose liver disease may have additional etiologies.

Table 28. Selected Noninvasive Systems to Assess Liver Fibrosis in Chronic Hepatitis C


In patients for whom HCV treatment is deferred, the AASLD/IDSA guidance panel recommends ongoing liver disease assessment.[54] However, the optimal assessment interval has not been established. The panel advises an annual patient evaluation that includes a discussion of modifiable risk factors for liver disease progression, repeat hepatic function testing, and repeat evaluation of markers of disease progression. Risk factors that are associated with more rapid fibrosis progression include the following[70,102,103]:

  • Nonmodifiable host factors
    • Fibrosis stage
    • Inflammation grade
    • Older age at the time of infection
    • Male sex
    • Organ transplantation
  • Modifiable host factors
    • Alcohol consumption
    • Nonalcoholic fatty liver disease
    • Obesity
    • Insulin resistance
  • Viral factors
    • Genotype 3 HCV
    • HIV or HBV coinfection

Patients who have advanced fibrosis (ie, Metavir F3 or F4) should undergo screening for hepatocellular carcinoma every 6 months.

Pretreatment Optimization of the Cirrhotic Patient

Although cirrhotic patients have lower response rates to HCV therapy than noncirrhotic patients with some currently available regimens, achievement of SVR in this group has a marked effect on the risk of liver-related mortality.[104] Guidance published by the AASLD and the IDSA recommend that treatment-naive patients with compensated cirrhosis (including patients with hepatocellular carcinoma) should be treated in largely the same manner as patients without cirrhosis, although the length of treatment may need to be extended with some regimens and/or ribavirin may be added.[54]

In settings where newer therapies are not available, management of cirrhotic patients remains more complicated. Hepatic decompensation during therapy is a significant risk in patients with more advanced disease when using peginterferon-based therapy. The risk of complications during therapy in patients with cirrhosis appears to be further increased with the addition of the first-generation protease inhibitors, boceprevir and telaprevir.

Patients with decompensated cirrhosis should be referred for liver transplantation. However, clinicians experienced in the treatment of HCV may consider treatment with antiviral therapy in some patients. In decompensated patients, interferon-based therapy is tolerated poorly, with high discontinuation rates,[105] a high incidence of infection, and a risk of further hepatic decompensation. Treatment may precipitate the need for liver transplant. If viremia is suppressed to undetectable levels at the time of transplant, the rate of posttreatment-recurrent HCV is reduced.[106,107] In one study, sofosbuvir combined with ribavirin was given to 61 patients with compensated cirrhosis awaiting liver transplantation for hepatocellular carcinoma.[65] At 12 weeks posttransplantation, therapy prevented posttransplantation HCV recurrence in 70% of patients with undetectable HCV RNA before engraftment. Of those with HCV RNA suppression for 30 days or more, only 1 of 24 developed recurrent HCV following transplantation. Notably, these patients had well-compensated liver disease, and although this regimen may be safe and effective in patients with decompensated cirrhosis, there are few data in this population currently. Studies with ledipasvir/sofosbuvir plus ribavirin in patients with decompensated liver disease have shown high SVR12 rates (86% to 89%) whether given for 12 or 24 weeks.[108] Patients tolerated therapy well with improvements in MELD score in most patients. However longer-term follow-up is required to assess the clinical benefits of therapy in this setting.

Guidelines from the AASLD/IDSA recommend that patients with decompensated cirrhosis should be referred to a practitioner with expertise in managing such patients, preferably in a liver transplantation center.[54] Recommended antiviral therapies for patients with decompensated cirrhosis include ledipasvir/sofosbuvir with ribavirin, daclatasvir plus sofosbuvir with ribavirin, and sofosbuvir/velpatasvir with ribavirin depending on HCV genotype, ribavirin eligibility, and other patient factors. These treatments should only be administered by highly experienced physicians. It should be noted that data on the use of DAAs in this setting are limited. The use of interferon-based therapy, monotherapy, or protease inhibitor–based regimens is not recommended in decompensated patients

Before receiving HCV therapy, optimization of overall health status is essential for decompensated patients. Specific measures that may minimize the risk of complications during treatment include prophylactic banding or initiation of beta-blocker therapy for patients with large esophageal varices, control of ascites (or use of antibiotic prophylaxis on treatment if complete control is not possible and interferon is to be used), and administration of lactulose for encephalopathy prevention. Although the clinical impact of these strategies on the outcomes of therapy in decompensated patients has not been studied prospectively, they are used in many centers treating decompensated cirrhotics.

Treat Now or Wait for New Therapy? In Most Cases, Treat Now

Drug development for HCV has progressed extremely rapidly with the discovery of new DAAs. Currently available therapies offer greater effectiveness, shorter duration, and improved tolerability than historical interferon-based regimens. Unlike first-generation protease inhibitors, many of the new DAA agents or combinations have activity against a broader spectrum of and possibly all HCV genotypes. As a result, the vast majority of patients today have the option of well-tolerated, effective HCV therapy. However, virologic response rates remain suboptimal for select patient groups, even with newly approved DAAs (eg, patients with decompensated cirrhosis and/or severe renal impairment). For these patients, individualized decisions about the timing of therapy must be made between the physician and patient, depending on the specific circumstances of the person’s HCV infection. Relevant issues to consider are the severity of liver fibrosis, the probability of SVR with current therapies, the tolerability of and willingness to accept interferon-based treatment where appropriate, and the anticipated timeline of when more effective treatments may become available.

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