Discussion

Patients with untreated chronic hepatitis C have the potential to develop cirrhosis, liver failure, hepatocellular cancer, and death. The decision whether to treat hepatitis C virus (HCV) infection should take into account both potential risks and potential benefits. Although this decision can be difficult in an individual patient, a consensus now exists among experts that three key factors that should weigh heavily in the decision of whether or not to initiate therapy: (1) the likelihood of eradicating HCV infection based on baseline factors; (2) the need for treatment based on the stage and rate of progression of liver disease, and (3) the treatment efficacy and risks associated with treatment[1,2].

Baseline Predictors of Treatment Response

Overview of Baseline Factors that Predict Treatment Response: Since the chief benefit (and objective) of treatment is to eradicate HCV infection—referred to as attaining a sustained virologic response (SVR)—the probability of achieving this outcome factors heavily in the risk/benefit calculation. Multiple baseline factors have been identified that predict treatment response, including viral factors (HCV genotype, HCV RNA level), race/ethnicity, IL28B polymorphism, degree of liver fibrosis, coinfection with HIV, and prior hepatitis C treatment experience[3,4,5,6,7]. Each of these factors was identified with peginterferon and ribavirin therapy and many still apply with the new HCV protease inhibitors. Other factors, such as older age, obesity, and insulin resistance may play a role in treatment response, but data are less consistent and suggest these play a weaker role compared with the others.

Viral Factors (HCV Genotype and Baseline HCV RNA Level): Among the viral factors that may influence the response to therapy, the patient's HCV genotype and (to a lesser extent) HCV RNA level will most accurately predict whether the patient will attain an SVR[8,9]. Among all baseline parameters, HCV genotype remains the strongest predictor of treatment response (Figure 1) [10,11]. Numerous studies using peginterferon plus ribavirin have shown that patients with genotype 2 or 3 HCV clearly have better SVR rates (up to 80%) than those with genotype 1 HCV (45%) (Figure 2) [9,12]. Patients also have more favorable SVR response rates if they have lower baseline HCV RNA levels (less than 2 million copies/ml or 800,000 IU/ml)[8]. The impact of baseline HCV RNA levels is greatest in patients with genotype 1 who receive peginterferon and ribavirin (Figure 3) [8,9]. The disparity in SVR between patients with high and low viral levels is less with triple therapy with either telaprevir (Incivek) or boceprevir (Victrelis)[13].

Race/Ethnicity: African-American patients have historically had lower response rates to interferon-based therapy than Caucasian patients, with the literature reporting SVR rates of 19 to 28% among black patients with genotype 1 HCV infection treated with peginterferon and ribavirin compared with 52% among non-Hispanic whites. Race remained an independent predictor of response in a few studies after adjusting for viral level, medication adherence, and hepatic fibrosis[3,4]. Unfortunately, despite African-Americans having the highest HCV prevalence in the United States, they comprise only a small proportion of patients in most prospective treatment studies to date. The limited data suggest African-American patients with genotype 1 infection have improved SVR rates with triple therapy that includes a HCV protease inhibitor (telaprevir or boceprevir), but still have reduced rates compared with white patients who receive triple therapy[14,15].  Hispanic patients also appear to have reduced response rates, as shown in one prospective study of peginterferon and ribavirin[16].

IL28B Polymorphisms: In 2009, investigators identified a genetic polymorphism at the IL28B gene encoding interferon-lambda-3 and reported its association with spontaneous clearance of HCV during acute infection[17], as well as with better treatment responses to interferon-based HCV therapy for genotype 1 infection[18]. The distribution of IL28B alleles explains part but not all of the variability in treatment responses observed among different racial groups. The CC genetic variant, found in 37% of Caucasians compared with 14% of African-Americans, correlates with a favorable treatment response and a 5.2-fold greater likelihood of SVR than non-CC variants. Results from IL28B genotyping can also provide information on the probability of response-guided therapy in non-cirrhotic patients[43] and may help tip the balance in those patients on whom the risk-benefit calculation for HCV treatment is less clear.

Hepatic Fibrosis: The presence of cirrhosis attenuates response to HCV therapy and has long been linked with lack of response. Genotype 1 patients with cirrhosis in particular are at greater risk of non-response, or lack of viral suppression, on interferon-based therapy[11]. In one study of genotype 1 or 4 patients taking peginterferon and ribavirin, SVR rates decreased progressively from 60% in patients without advanced fibrosis to 51% in those with bridging fibrosis and 33% in those with cirrhosis[19]. This fibrosis-related decrement in response is still observed when treatment includes one of the HCV protease inhibitors[14,15]: among treatment-naïve genotype 1 patients, those with advanced fibrosis (stage 3 or cirrhosis) had SVR rates of 42 to 62% with triple therapy with peginterferon, ribavirin and either telaprevir or boceprevir compared with 70 to 81% in patients with minimal or early stage fibrosis (Figure 4 and Figure 5). Treatment of cirrhotic patients remains a high priority but precise estimates of treatment response to these new agents are not available since this group comprised only a small proportion of participants in the large phase 3 trials of telaprevir and boceprevir.

HIV Coinfection: Patients with HIV coinfection are also less responsive to interferon-based therapy for hepatitis C than persons with HCV monoinfection[5,6]. With HIV and HCV coinfection, SVR rates have historically been 10 to 20% lower than those of otherwise comparable HIV-uninfected patients in most studies of dual therapy. The major clinical trials using peginterferon and ribavirin reported SVR rates of only 14 to 29% in genotype 1 patients with HIV and HCV coinfection[20]. Early pilot data that included coinfected patients with high CD4 counts, most of whom were white, suggests this difference in SVR rates may narrow with the addition of telaprevir or boceprevir to peginterferon plus ribavirin[21,22].

Prior Treatment History: Previous response to interferon-based therapy will also influence how well a patient responds to retreatment. This history provides important clues to the intrinsic interferon responsiveness of these patients and correlates strongly with their likelihood of SVR even in the context of triple therapy. Previous relapsers, who managed to suppress their HCV RNA during treatment with peginterferon and ribavirin only to have the virus return, have the highest SVR rates among treatment-experienced patients, similar to those who are treatment naïve. Partial responders, on the other hand, whose HCV RNA declined at least 2 log10 IU/ml at week 12 but remained detectable, have a lower SVR rate—52 to 59% compared with 75 to 88% among relapsers with triple therapy with either telaprevir or boceprevir[23,24]. Null responders, whose HCV RNA declined less than 2 log10 IU/ml at week 12, are among the most treatment refractory patients and benefit the least from retreatment. In the boceprevir study, they were excluded. In the telaprevir study, null responders had SVR rates of only 29 to 33%[24].

Determining Need for Treatment

Overview of Treatment Need: The medical need for treatment figures strongly in the decision process regarding initiating therapy for HCV. Once chronic HCV infection is determined by RNA testing, the best way to ascertain the need for treatment is to evaluate the degree of liver fibrosis by performing a liver biopsy[1,2]. Hepatic aminotransferase levels, HCV RNA levels, and HCV genotypes do not accurately predict the severity or progression of disease. Treatment need can also be modified by other factors, such as HIV infection, that are known to accelerate fibrosis, as well as other life-limiting medical conditions, such as malignancy, that may override long-term concerns related to HCV infection. Overall, since HCV infection does not cause clinically recognizable problems in most persons, those with the greatest risk of developing end stage liver disease will derive the greatest benefit from treatment.

Role of Liver Biopsy: The role of liver biopsy in treatment decisions for patients with HCV has been widely debated and this issue remains a great source of controversy. In recent years, the reliance on liver biopsy to inform decisions about initiating treatment has diminished in clinical practice[2]. Liver biopsy is invasive and less accurate than most 'gold standard' invasive tests for other diseases[25,26]. In addition, liver biopsy is less reliable in distinguishing those with moderate fibrosis from mild fibrosis. Nevertheless, liver biopsy can provide valuable information and is still obtained in many patients, particularly those with genotype 1 HCV. Most experts agree that evidence of portal fibrosis (any extent greater than trivial), defined as a designation of greater than 1 in the Metavir system or greater than 2 in the modified Ishak system justifies treatment[27,28]. There is, however, modification of this gradient by duration of the infection: treatment is least indicated in persons with longstanding infection and no fibrosis, and most indicated in persons with cirrhosis occurring over a relatively short interval. For persons with either genotype 2 or 3 HCV, the high SVR rates coupled with the shorter duration of treatment has prompted many experts to proceed with treatment without obtaining a liver biopsy[1,2].

Noninvasive Markers of Fibrosis: In clinical practice, some experts use the results of multiple independent serum tests to predict the stage of liver fibrosis. Examples of surrogate markers for fibrosis that have been studied including the AST-to-platelet ratio index (APRI), a blood test that uses a combination of six serum markers known as the FibroTest (or HCV-FibroSURE), and a blood test combination of three markers (tissue inhibitory metalloprotease-1, hyaluronic acid, and alfa-2 macroglobulin) referred to as the (FIBROSpect II), Forns Fibrosis Index (age, platelet count, GGT, and cholesterol), and FIB-4 (platelets, ALT, AST, and age) [29,30,31,32]. In addition, an ultrasonic test called transient elastography (FibroScan) that measures the stiffness of liver tissue has also shown promise in predicting advanced stages of fibrosis[33], but is not currently not available in the United States. Existing noninvasive tests, however, tend to correctly classify only about half of patients and are less reliable in distinguishing those with moderate fibrosis from mild fibrosis. Widespread adoption of such noninvasive methods will require more extensive evaluation of their accuracy. In the interim, the role of liver biopsy and other staging tools may become less prominent as hepatitis C treatment evolves and reaches a point where it is broadly effective against all genotypes and across different stages of disease. At this time, because the management of cirrhosis differs from non-cirrhotic HCV infection (lengthier duration of therapy and necessity of screening for hepatocellular carcinoma), these noninvasive tests play an important role for confirming the presence of cirrhosis in those cases when biopsy is not indicated or the decision for treatment has already been made.

Treatment Efficacy and Risks

Treatment Efficacy: Early therapy utilizing interferon monotherapy resulted in sustained virologic responses in only 10 to 20% of patients. With modern therapies, very good treatment responses are expected in patients with all genotypes. For example, in treatment-naïve patients with genotype 2 or 3, multiple studies have shown sustained virologic response rates in the 75 to 80% range when using a regimen consisting of peginterferon plus ribavirin[8,9,12]. Treatment-naïve patients with genotype 1 who receive a NS3/4A hepatitis C serine protease inhibitor combined with plus peginterferon and ribavirin have sustained virologic responses in the 60 to 70% range[34]. As would be expected, as the treatment for hepatitis C has evolved and improved, the enthusiasm for treatment has significantly increased, both from the patient and the medical provider standpoint.

Treatment-Associated Risks: Although treatments for hepatitis C have become more effective, substantial risks remain with potential treatment-related adverse effects. Moreover, current treatments for HCV are very expensive. The potential major risks associated with HCV therapy include complications from interferon-based medications (thyroid disease, bone marrow suppression, and neuropsychiatric disturbances), as well as potential complications associated with ribavirin (anemia and rash), telaprevir (anemia, sensation of burning in the rectal region, and rash) or boceprevir (anemia and neutropenia[8,9,12]. Although these adverse reactions can occur in anyone receiving HCV therapy, certain patients are at increased risk. For example, anemia is of particular concern in persons with cardiovascular disease and in the elderly, and occurs with great severity and frequency in persons with cirrhosis taking HCV protease inhibitors. Underlying depression can also worsen on treatment. For patients with cirrhosis, it is important to determine if they have compensated cirrhosis (Child class A, or Child-Pugh-Turcotte score less than 7) or decompensated cirrhosis (Child class B or C) (Figure 6). Patients with compensated cirrhosis can be treated with interferon-based therapy if they have a total serum bilirubin is less than 1.5 g/dL, INR less than 1.5, serum albumin greater than 3.4 g/dL, and no evidence of hepatic decompensation (hepatic encephalopathy or ascites), but will require close monitoring[2]. Hepatitis C therapy carries greater risk of severe adverse effects in those patients who have decompensated cirrhosis.

Risk/Benefit Ratio: Many experienced clinicians will agree on whether HCV treatment is indicated in particular clinical situations. All published guidelines agree that persons without contraindications to treatment who have septate fibrosis or cirrhosis that is 'compensated' should be treated[1,2]. Many experts believe that the benefit of treatment (namely, achieving SVR) is sufficiently likely for persons with non-1 HCV genotypes, especially genotype 2, to recommend treatment without assessment of disease stage by liver biopsy. The strength of treatment recommendation may vary for persons who have intermediate amounts of liver fibrosis and factors that modify response rates and adverse reactions, although improved SVR rates in the era of direct-acting antivirals may shift this decision-making further towards treatment. The timing of treatment is another issue of some controversy. Even when a provider decides to treat, some may wait for the introduction of safer more tolerable medications, especially when the decision is made within a year of anticipated drug approval. The patient's enthusiasm for treatment is often the deciding factor in instances in which the risk-benefit calculation is not decisive. In addition, since some of these factors vary over time and the disease progresses slowly, the decision can often be made over months, rather than at a single office visit.

Decision for the Patient in Case Study

In the patient presented in this case, given that he has HCV genotype 1a, he has at least a 65 to 70% likelihood of eradicating HCV infection if treated with peginterferon plus ribavirin combined with either telaprevir or boceprevir. The biopsy findings showing septate fibrosis clearly establish his need for treatment. Although the patient's history of depression would generate concern, this problem could be managed by closely monitoring for any signs or symptoms of interferon-related worsening of depression and restarting an antidepressant if necessary. Taken together, after weighing the key factors involved in the decision of whether to initiate HCV therapy, those factors favoring initiating therapy outweigh those opposing therapy and thus the patient should receive therapy.

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    Figure 1. Independent Factors Associated with a Sustained Virologic Response

    Odds ratio equal to 1 (dashed line) indicates no difference between the subgroups defined according to the given factor.  Bars indicate 95% confidence intervals.

    Source: Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343:1666-72. Reproduced with permission from the Massachusetts Medical Society.  Copyright ©2000 Massachusetts Medical Society.  All rights reserved.

    Figure 1
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    Figure 2. Response to Peginterferon Alpha-2a plus Ribavirin Based on HCV Genotype

    This analysis of SVR is based on patients who received a 48-week course of peginterferon alpha-2a at a dose of 180 ug subcutaneously once weekly plus standard weight base dose of ribavirin (1000 or 1200 mg/d).

    Source: Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82.

    Figure 2
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    Figure 3. Response to Peginterferon Alfa-2a and Ribavirin According to HCV Genotype and Pre-treatment HCV RNA Level

    This analysis of SVR is based on patients who received a 48-week course of peginterferon alpha-2a (Pegasys) at a dose of 180 ug subcutaneously once weekly plus standard weight base dose of ribavirin (1000 or 1200 mg/d). The low viral load is defined as HCV RNA <2.0 x 106 copies/ml and high viral is defined as HCV RNA >2.0 x 106 copies/ml.

    Source: Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82.

    Figure 3
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    Figure 4. Telaprevir for Chronic Untreated HCV Infection: Response by Liver Histology

    The numbers listed indicated the duration of the medication given (in weeks)
    Abbreviations: SVR = sustained virologic response; PR = Peginterferon and Ribavirin; T = Telaprevir

    Source: Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-16.

    Figure 4
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    Figure 5. Boceprevir for Chronic Untreated HCV Infection: Response by Liver Histology

    The numbers listed indicated the duration of the medication given (in weeks)
    Abbreviations: SVR = sustained virologic response; PR = Peginterferon and Ribavirin ; T = Telaprevir

    Source: Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.

    Figure 5
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    Figure 6. Child Turcotte-Pugh Classification for Severity of Cirrhosis


    Figure 6