Is there still a role for liver biopsy in managing hepatitis C virus infections?

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Abbreviations.

A2M, alpha‐2‐macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response‐guided therapy; CDS, cirrhosis discriminant score; DAA, direct‐acting antiviral; GGT, gamma‐glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; ITT, intention to treat; Pbo, placebo; PIIINP, amino‐terminal propeptide of type III collagen; PR48, peginterferon/ribavirin for 48 weeks; SVR, sustained virological response; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks; TIMP1, tissue inhibitor of metalloproteinase 1.

Current guidelines emphasize the importance of liver biopsy in the management of patients with hepatitis C because liver histology provides patients and their physicians with important prognostic information and helps to guide therapy decisions and treatment regimens.1,2 Recent improvements in antiviral therapy along with the development of alternate modes of evaluating fibrosis have led to a global reassessment of the risks and benefits and the overall wisdom of performing liver biopsy in these patients.

The presence of advanced or worsening fibrosis has traditionally served as an unequivocal indication for therapy,3 and clinicians still use the degree of fibrosis as a means for justifying therapy sooner rather than later. The availability of direct‐acting antiviral (DAA) agents, which bring the promise of rapid viral negativity with therapy, intuitively appears to lessen the need for biopsy in therapeutic decision making; this is analogous to previously held perceptions about genotype 2/3 patients, who had higher sustained virological response (SVR) rates. Because of the increased efficacy of the newer regimens and even better regimens around the corner, clinicians and patients may choose to forgo biopsy with the compelling argument that the benefits of such effective therapy justify its use, even in those with minimal disease.

On the basis of the results of pivotal registration trials, the US Food and Drug Administration has suggested that therapy with DAA agents mandates an assessment of the degree of fibrosis because of the vastly different therapeutic regimens for patients with more advanced fibrosis. The recommended treatment with peginterferon/ribavirin and either telaprevir or boceprevir must be longer (48 weeks) because of the consistently lower efficacy of the therapy in patients with cirrhosis2 (Figs. 1, 2, 3). Accordingly, an assessment of the degree of fibrosis is crucial before the initiation of therapy. Treatment with interferon and ribavirin has led to higher rates of adverse events, including anemia, in the face of cirrhosis,8,9 and this information must be discussed with patients with cirrhosis before the initiation of current DAA‐based therapies that include peginterferon and ribavirin.

Figure 1.

SVR rates by the degree of fibrosis in the ADVANCE and ILLUMINATE studies. Abbreviations: ITT, intention to treat; PR48, peginterferon/ribavirin for 48 weeks; T12PR, telaprevir for 12 weeks and peginterferon/ribavirin. Adapted with permission from New England Journal of Medicine.4, 5

Figure 2.

SVR rates for patients with bridging fibrosis or cirrhosis in the Serine Protease Inhibitor Therapy 2 trial. Abbreviations: BOC44, boceprevir for 44 weeks; BOC RGT, boceprevir and response‐guided therapy; PR48, peginterferon/ribavirin for 48 weeks. Adapted with permission from Journal of Hepatology.6

Figure 3.

SVR rates by the degree of fibrosis in the REALIZE trial. Abbreviations: Pbo, placebo; PR48, peginterferon/ribavirin for 48 weeks; T12/PR48, telaprevir for 12 weeks and peginterferon/ribavirin for 48 weeks. Adapted with permission from the European Association for the Study of the Liver.7

In comparison with peginterferon/ribavirin dual therapy, the telaprevir‐ and boceprevir‐based regimens have superior efficacy,4,10‐14 but the field is moving forward quite rapidly, and we are currently learning about (1) far more potent DAA agents with better pharmacokinetic profiles, (2) interferon‐sparing regiments, and (3) SVR rates approaching 100%. Thus, there is the likelihood that superior regimens will become available over the next few years. As physicians and patients with hepatitis C virus ponder their options, information obtained from liver biopsy samples may greatly assist in the decision to wait yet longer for future regimens with improved efficacy, shorter durations, and lower side‐effect profiles.

The establishment of the fibrosis stage remains a key parameter that guides the management of patients with chronic hepatitis C. The presence of advanced fibrosis requires future lifelong screening for the development of varices and hepatocellular carcinoma, regardless of future responses to antiviral therapy. Unfortunately, an all‐too‐common scenario in clinical practice is the patient with known or unknown hepatitis C who learns of his cirrhosis only after the discovery of liver cancer or a large variceal bleed. Advanced fibrosis may exist in patients with normal liver enzyme levels and synthetic parameters.15 The identification of fibrosis at biopsy can be used as a realistic justification for encouraging reduced alcohol intake and weight reduction, which are factors that would otherwise accelerate the progression to cirrhosis.16, 17, 18, 19, 20, 21

For the post–liver transplant patient with chronic hepatitis C, liver biopsy information is essential not only for assessing patients for fibrosis but also for differentiating between recurrent hepatitis C–induced inflammation and acute cellular rejection. Accelerated fibrosis progression in the posttransplant patient with chronic hepatitis C leads to graft loss in up to 30% of infected patients.22, 23, 24 Preemptive antiviral therapy without the guidance of biopsy information is often precluded by cytopenias, renal insufficiency, increased side effects, and the possibility of rejection.25,26 Current guidelines suggest the initiation of therapy only after the demonstration of significant cholestasis or fibrosis on liver biopsy.1,27 Accordingly, the information gained from liver biopsy, including the demonstration of either fibrosis progression or a lack of rejection, before the institution of antiviral therapy is vital to the posttransplant care of the hepatitis C patient.

The risks of liver biopsy include severe pain, organ perforation, and bleeding.28,29 This potential for complications has generated an increasing acceptance of alternative assessments of hepatic fibrosis, especially in patients with hepatitis C (Table 1). Unfortunately, for many such panels, availability, third‐party payment, or widespread clinical consensus is lacking. Fibrosis related to chronic hepatitis C progresses slowly (on average 0.15 stages per year30), and a feasible alternative to liver biopsy must be able to measure this progression over time. Evaluations using standard laboratory tests, including the aspartate aminotransferase/alanine aminotransferase ratio, the cirrhosis discriminant score, the age‐platelet index, the Pohl score, the aspartate aminotransferase to platelet ratio index, and platelet counts, lack either the sensitivity or the specificity needed to be useful in clinical practice.31,34,35 In addition, these noninvasive fibrosis markers may have reduced performance in hepatitis C patients with normal alanine aminotransferase levels.36 Larger test panels, including Hepascore, Liverscore, and FibroTest, have high potential for false‐positive results and are not readily available in clinical practice.32,37‐39 These laboratory tests and panels have not reliably detected intermediate stages of fibrosis or the progression of fibrosis, and this is valuable information for clinical decision making.30,40 Transient elastography produces suboptimal results in obese patients and in tracking changes in fibrosis.41, 42, 43 The reproducibility of transient elastography is significantly reduced (P < 0.05) in patients with steatosis, an increased body mass index, or lower degrees of hepatic fibrosis.

Table 1.

Noninvasive Markers for Liver Histological Assessments (Including Tests for Fibrosis, Necroinflammation, and Steatosis)

Test	Components	Sensitivity/Specificity for Advanced Fibrosis (%/%)
FibroTest‐ActiTest	Age, sex, A2M, GGT, haptoglobin, total bilirubin, apolipoprotein A1, ALT	87/59
FIBROSpect II	HA, TIMP1, A2M	83/66
European Liver Fibrosis Group algorithm	Age, PIIINP, HA, TIMP1	90/41
FibroMeter	Age, sex, A2M, HA, platelet count, AST, prothrombin	82/−
Hepascore	Age, sex, HA, A2M, GGT	67/92
AST‐to‐platelet ratio index	AST, platelet count	41/95
AST/ALT ratio	AST, ALT	53/100
Forns index	Age, platelet count, GGT, cholesterol	94/51
Pohl score	AST, ALT, platelets	18/98
Age‐platelet index	Age, platelet count	68/55
Cirrhosis discriminant score	AST, ALT, platelet count, INR	10/100
Fibrosis prediction index	Age, AST, cholesterol, past alcohol use, insulin resistance	85/48
FibroScan	Hepatic transient elastography	64/87
FIB‐4	Age, AST, ALT, platelet count	71/65

The data for this table were taken from Rockey and Bissell,30 Lackner et al.,31 Adams et al.,32 Sanai and Keeffe,33 and Sebastiani et al.36

Abbreviations: A2M, alpha‐2‐macroglobulin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma‐glutamyl transpeptidase; HA, hyaluronic acid; INR, international normalized ratio; PIIINP, amino‐terminal propeptide of type III collagen; TIMP1, tissue inhibitor of metalloproteinase 1.

Percutaneous liver biopsy is considered the gold standard for histology assessment, yet it has a widely recognized sampling error rate as high as 20% for the detection of encircling fibrotic nodules with the evaluation of just 1/50,000 of the total organ.44 Such samples can be useful only if there are an adequate number of complete portal tracts, and with a length of 2 cm and a width of 1.4 mm, this goal is often not achieved in clinical practice. Moreover, the discordance between biopsy samples taken from right and left lobes further demonstrates the inherent limitations of this time‐honored diagnostic test.44,47 Despite these challenges, a liver biopsy sample from a patient with hepatitis C in the new antiviral era remains a source of invaluable information. This information can be combined with available clinical and laboratory evidence (often surrogate markers with their own inherent limitations) to best serve the patient. A physician's or patient's reluctance to undertake the risks of biopsy should not represent a contraindication to antiviral therapy but rather should serve as the basis for a discussion of our limitations in assessing liver function and disease severity.