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Release Date: 06/28/07
Expiration Date: 06/27/08
Hepatitis C virus (HCV) is a major cause of chronic liver disease and the leading indication for liver transplantation in the United States.[1,2] Approximately 4 million Americans are infected with hepatitis C virus (HCV) and an estimated 170 million people are infected globally.[3,4] Chronic infection occurs in 70% to 80% of those who contract the virus and can progress to cirrhosis within 2-3 decades of infection. Complications from chronic infection include liver failure and hepatocellular carcinoma (HCC), which are major worldwide causes of morbidity and mortality.
The combination of peginterferon alfa and ribavirin is the current standard treatment for chronic HCV infection.[5-7] This regimen is very effective in patients infected with genotype 2 or 3, and approximately 76% of these individuals will achieve a sustained virologic response (SVR) to therapy, defined as undetectable HCV RNA 24 weeks after treatment cessation. However, a significant proportion of patients in the United States are infected with genotype 1 HCV. Unfortunately, the effectiveness of peginterferon/ribavirin is not as robust in those infected with genotype 1 HCV when compared with those infected with HCV genotypes 2 and 3. Although the majority of patients with genotype 1 infection have some degree of virologic response, only 40% to 45% will go on to achieve an SVR. There are 3 basic patterns by which patients may fail to achieve an SVR: 1) Treatment is unable to produce undetectable HCV RNA levels, 2) virologic breakthrough occurs after achieving undetectable HCV RNA levels, or 3) relapse occurs when treatment is stopped.
Clinicians are observing a growing number of nonresponders and relapsers in their practices. There are many pretreatment and on-treatment characteristics that lead to therapy failure, and overcoming these obstacles has the potential to substantially increase the chance for achieving an SVR among patients. This module will discuss factors that lead to initial treatment failure as well as retreatment strategies for patients who have previously failed treatment or relapsed.
The primary goal of HCV treatment is to eradicate the virus from infected individuals in order to slow liver disease progression, prevent cirrhosis complications, and reduce the risk of developing HCC. Complete HCV eradication is evidenced by undetectable HCV RNA levels at the end of treatment and 6 months after stopping therapy (ie, an SVR). Findings from a recent meta-analysis indicate that patients who achieve an SVR following standard treatment can be considered cured of their HCV infection, as the subsequent rate of detectable HCV RNA is < 1% (excluding reinfection) out to 4 years after the end of therapy.
To optimize HCV treatment and understand a patient’s response to therapy, it is critical to frequently monitor and quantitate HCV RNA levels during therapy to identify the pattern of virologic response or nonresponse. Key time points at which to measure HCV RNA to monitor a patient’s treatment response include baseline, Week 4, Week 12, Week 24, the end of treatment, and 12-24 weeks after the discontinuation of therapy. To obtain an easy tool for measuring HCV RNA and tracking your patient’s progress graphically, follow this link and click on HCV RNA Monitoring: An Interactive Decision Support Tool. Table 1 lists the response patterns that can be recognized with frequent HCV RNA monitoring.
<font>Figure 1. Virologic response patterns seen during HCV therapy.</font>
Several studies, including those by Sanchez-Tapias and colleagues, by Ferenci and colleagues, and by Mangia and colleagues have found that achieving RVR and EVR strongly predicts the later endpoint of SVR, and the absence or presence of these responses can be used to tailor the duration of therapy for the individual patient (Capsule Summaries 1, 2, and 3).[13-16]
Not all HCV-infected patients will respond to treatment, and various nonresponse patterns can be discerned when measuring serum HCV RNA. Nonresponders initially included patients who did not achieve undetectable HCV RNA levels during treatment. However, definitions have been updated such that nonresponders are currently composed of 3 different but distinct groups: 1) null responders, 2) partial virologic responders, and 3) patients experiencing virologic breakthrough.[9,18] In addition to nonresponse, patients may also experience relapse following successful HCV treatment. These response patterns are graphically depicted in Figure 1.
Factors associated with risk of null response include noncompliance with the drug regimen or dose reduction of peginterferon and/or ribavirin secondary to adverse events. In addition, a null response can occur when therapy is temporarily or permanently discontinued.[19-21]
Partial Virologic Response
Partial virologic response may occur in those treated with maximum doses of peginterferon and ribavirin by Week 24. However, it is unknown why there is a rapid reduction of HCV RNA followed by persistent viremia. Factors associated with partial virologic response can include treatment discontinuation, interruption of peginterferon and ribavirin, or dose reduction before Week 24 of therapy.
Treatment of HCV should be considered for all HCV-infected individuals, particularly those at risk for progression to cirrhosis, according to the National Institutes of Health consensus guidelines. This includes persons with detectable HCV RNA levels and liver histology that has advanced beyond portal fibrosis. A thorough pretreatment assessment is recommended for any patient in need of HCV treatment. This is the pertinent time to identify contraindications to HCV treatment, as well as factors that can contribute to treatment failure. Aside from genotype 1 HCV and resistance to therapies, key factors that have the potential to reduce the effectiveness of HCV treatment include 1) drug and/or alcohol use, 2) psychiatric conditions, 3) coinfection with hepatitis B virus or HIV, 4) advanced fibrosis and cirrhosis, 5) advanced age, 6) black or Hispanic race, 7) obesity, 8) insulin resistance and diabetes, 9) previous treatment with suboptimal therapy, 10) adverse events leading to dose reductions, and 11) treatment noncompliance.
Drug or Alcohol Abuse
There are few large-scale studies on the effect of current alcohol use on HCV treatment outcomes, given that alcohol users are categorically excluded from clinical trials. However, early studies suggested that the use of alcohol during HCV therapy can adversely affect a patient’s chances of responding to treatment. Ohnishi and colleagues showed a dose-response relationship between alcohol consumption and HCV RNA clearance: No individuals who consumed > 69 g of alcohol per day achieved an SVR to interferon treatment (n = 17), whereas 27.7% of 47 infrequent drinkers successfully cleared the virus. In another study, Okazaki and colleagues found that nondrinkers were significantly more likely to achieve undetectable HCV RNA levels following interferon treatment (53.8%) than those who drank > 70 g of alcohol daily (12.5%) and those who consumed < 70 g per day (20.0%).
Among alcohol users, an analysis published in 2006 showed that individuals who recently used alcohol had a higher treatment discontinuation rate during HCV therapy than those who never used alcohol (40% vs 26%, respectively; P = .0002) and had a lower SVR rate (14% vs 20%, respectively; P = .06). However, when the analysis was restricted to patients who completed the full course of treatment, there was no difference in SVR rates between drinkers and nondrinkers (25% vs 23%, respectively). As such, alcohol users need not be excluded from HCV therapy, but abstinence from alcohol is strongly recommended both before and during antiviral therapy to maximize chances of SVR, given that no clear relationship between level of alcohol and adverse treatment outcomes has been established.
A history of injection drug use is not associated with reduced rates of response to HCV treatment.[30,31] Moreover, the 2002 National Institutes of Health consensus guidelines for HCV management indicate that hepatitis C treatment is possible in the setting of ongoing drug use. Among injection drug users, Backmund and colleagues found the SVR rate to be comparable between injection drug users undergoing inpatient methadone detoxification who did not relapse to drug use during HCV therapy and those who relapsed to drug use but remained on HCV therapy (40% vs 53%, respectively; P > .05). In another study of 76 individuals maintained on methadone as a substitute for heroin use, Sylvestre and colleagues identified an overall SVR rate of 28% for the cohort, with no apparent association between virologic outcome and drug use while on treatment (P = .09) or the duration of drug abstinence before HCV therapy (P = .18). Rates of SVR have also been shown to be comparable between HCV-infected injection drug users on methadone maintenance and a control group of HCV-infected patients with no history of injection drug use (42% vs 56%, respectively; P = .16), although discontinuation rates were significantly higher in the former group than the latter during the first 8 weeks of treatment (22% vs 4%, respectively; P = .02). These findings suggest that methadone treatment is not a contraindication to HCV therapy, and this group of patients can be treated successfully. For a comprehensive Treatment Update of HCV treatment in patients receiving methadone maintenance therapy, click here.
Patients using drugs or alcohol should be evaluated on an individualized basis to assess their treatment candidacy. Patients currently using injection drugs or partaking in heavy alcohol use (> 14 drinks/week or > 4 drinks/day for men, > 7 drinks/week or > 3 drinks/day for women) should be referred to an addiction specialist before HCV treatment is initiated. Those with stabilized substance use disorders who initiate treatment require close monitoring and should be strongly encouraged to participate in drug and/or alcohol treatment programs and in methadone clinics when applicable to increase their opportunities for successful HCV therapy. To review an Interactive Case Challenge on the management of patients with a history of substance abuse, click here.
Several studies indicate that individuals with a history of psychiatric illness can be successfully treated for hepatitis C infection. For example, Gardenier and colleagues found that an integrated approach to the management of patients with mental illness using concomitant medical and psychiatric care positively affected treatment outcomes. Similarly, in a study of 184 patients with hepatitis C, Knott and colleagues found that individuals who received specialized psychiatric care in addition to medical care were more likely to receive antiviral therapy and to adhere to therapy. Many individuals with mental illness also have substance abuse issues. Despite the fact that these comorbidities often cluster together and provide a greater challenge for the clinician, a recent retrospective study performed by Chainuvati and colleagues found that 72% of 294 veterans with mental illness and substance abuse (some of whom were previous nonresponders, 83% of whom were infected with genotype 1 HCV, and some of whom received treatment with standard interferon plus ribavirin) completed HCV therapy compared with 59% of 353 controls without mental illness or substance abuse (P value is not significant), and the SVR rates were similar between the 2 groups at 20% and 25%, respectively (P value is not significant). Of note, these SVR rates are lower than those reported in clinical trials but are in line with those reported previously for the veteran population.
Although uncontrolled psychiatric disorders are a contraindication to HCV treatment, patients with stabilized or remitting mental illness are eligible for therapy. Standardized instruments for the assessment of psychiatric illness include the Beck’s Depression Inventory and the Center for Epidemiologic Studies Depression Scale (click here for the CES-D scale). The use of multiple scales may be required to accurately diagnose mental illness among substance users because of the possibility of discordant results. Treatment with interferon and weight-based ribavirin and a history of depression have been associated with an increased risk of developing moderate to severe depressive symptoms during treatment, so careful evaluation of depression at baseline and throughout treatment is warranted to limit neuropsychiatric morbidity. Some patients may benefit from pretreatment with an antidepressant before initiating HCV therapy. A recent study by Raison and colleagues evaluated the use of pretreatment with paroxetine (n = 28) vs placebo (n = 33) for 2 weeks before initiating treatment with 24 weeks of interferon plus ribavirin. Antidepressant therapy was continued during HCV treatment. The proportion of patients who had mild, moderate, or severe depression according to the Montgomery-Asberg Depression Rating Scale during therapy was significantly greater in those receiving placebo vs paroxetine (P = .02). A robust psychosocial support network comprising medical providers as well as friends and family is critical for the successful completion of HCV treatment.
Strategies for managing substance abuse and psychiatric comorbidities to maximize treatment success are outlined in Table 2. To review an Interactive Case Challenge on the management of patients with a history of depression, click here.
Coinfection With HIV
Three randomized, controlled trials by Carat and colleagues, by Torriani and colleagues, and by Chung and colleagues have demonstrated that 48 weeks of treatment with peginterferon/ribavirin is safe and effective in HCV/HIV-coinfected individuals (Table 3) (Capsule Summaries 1, 2, and 3). In summary, the SVR rates achieved with therapy were lower in coinfected patients (27% to 40%) when compared with the rates typically observed in HCV-monoinfected patients (40% to 76%), particularly for individuals with genotype 1 HCV. However, given that peginterferon/ribavirin produced superior outcomes compared with standard interferon/ribavirin, these trials helped to garner US Food and Drug Administration (FDA) approval for peginterferon alfa-2a 180 µg/week plus ribavirin 800 mg/day as treatment for HCV-infected patients with stable HIV disease. Coinfected patients with HCV genotype 1 may benefit from higher ribavirin dosing (1000-1200 mg/day) given that insufficient ribavirin levels likely contribute to a lower SVR rate among this population, although this is currently being studied prospectively.
Although a sizeable proportion of HCV/HIV-coinfected patients will not achieve an undetectable HCV RNA on treatment, they may still attain improvements in liver histology. In 1 study, 32% to 43% of patients who did not achieve an SVR on treatment still showed histologic improvement, leading the researchers to suggest that improvement in biopsies might be an alternative goal of therapy.
The optimal time to start HCV therapy in relation to starting antiretrovirals is not well defined. Patients with high CD4+ cell counts appear to have the best response to HCV therapy, suggesting that good immune status may facilitate sustained clearance of HCV. Highly active antiretroviral therapy for HIV can slow fibrosis progression even though it does not improve the virologic response to HCV treatment.[53,54] Therapy initiation should involve weighing the risks of an expected, transient CD4+ count decline while on interferon with the benefits of improving tolerance to HIV medications if HCV is treated first.
Patients with a BMI > 30 should be considered for HCV therapy, but lifestyle changes, such as diet and exercise, should be prescribed as adjuncts to antiviral therapy, and their implementation before treatment may help patients’ opportunities for response. Decreased hepatic steatosis can be achieved with even modest weight loss (5.9 kg) and has the potential to improve treatment outcomes as well as patient quality of life (Capsule Summary).[57-59] Pharmacologic weight management with orlistat or sibutramine may be considered for individuals with a BMI > 30 or with a BMI > 27 along with other comorbidities (eg, sleep apnea).
Insulin Resistance and Diabetes Mellitus
An increased incidence of type 2 diabetes mellitus is associated with chronic hepatitis C infection. A prospective study conducted by Simo and colleagues found that HCV-infected patients who achieved an SVR to peginterferon/ribavirin compared with those who did not achieve an SVR were much less likely to develop glucose abnormalities (14.6% vs 34.1%, respectively; P = .001) and diabetes (0 vs 9 cases, respectively; P = .007) during at least 3 years of follow-up. These findings indicate that clearing HCV infection significantly reduces the incidence of glucose abnormalities in chronically infected patients and supports the idea that HCV infection is linked to type 2 diabetes.
All metabolic disorders, including diabetes mellitus, insulin resistance, and the metabolic syndrome, should be aggressively managed before HCV treatment is initiated because interferon can exacerbate these medical conditions. Two classes of drugs are effective at correcting insulin resistance—biguanides (eg, metformin) and thiazolidinediones (eg, rosiglitazone and pioglitazone)—but evidence of their use in the setting of HCV and steatohepatitis is limited. To review an Interactive Case Challenge on the management of patients with overweight and insulin resistance, click here.
Advanced Fibrosis and Cirrhosis
Recent studies have also shown that Hispanic patients tend to have poorer responses to HCV therapy compared with non-Hispanic whites. In a retrospective analysis of 661 treatment-naive patients from 2 multicenter treatment trials who received interferon plus ribavirin, Hepburn and colleagues found that only 23% of Hispanics and 14% of blacks achieved an SVR compared with 39% of whites and 61% of Asians. Both Hispanic and black races were associated with a lower probability of achieving an SVR according to multiple logistic regression analysis that adjusted for known response predictors, including genotype. The poor treatment response among Hispanics appeared to be most pronounced in patents infected with HCV genotype 2 or 3,[80,81] although a recent analysis has also identified a reduced response rate among Hispanics infected with HCV genotype 1 (Capsule Summary). This disparity in response for Hispanic individuals may be associated with poorer baseline biochemical profiles (aspartate aminotransferase, alanine aminotransferase, bilirubin, albumin) and a higher prevalence of insulin resistance compared with whites.[83,84]
Previous Treatment With Inferior Therapy
Adverse Events Leading to Dose Reductions
Appropriate management of hematologic abnormalities during HCV treatment is a critical strategy for maximizing patient outcomes and adherence to therapy. Although the package inserts for ribavirin and peginterferon recommend dose reduction or treatment discontinuation when specific blood counts drop below a given threshold, pharmacologic treatment of these conditions can ameliorate hematologic abnormalities, allow patients to remain on the full dose of peginterferon/ribavirin therapy, and improve patient outcomes. Also of note, the prescribing information for ribavirin recommends a dose reduction scheme that is less than optimal for maximizing SVR and is frequently modified in clinical practice. For example, smaller, step-wise dose reductions of ribavirin may be considered depending upon the severity of anemia, rather than a 40% to 50% reduction as noted above. Several studies support the use of epoetin alfa for the management of treatment-related anemia in individuals on HCV therapy,[85-87] and a another study suggests that darbepoietin alfa, which has a longer half-life and therefore requires less frequent dosing, may likewise be effective for managing anemia in HCV. It should be noted that the FDA recently issued a public health advisory on erythropoiesis-stimulating agents in March 2007. The advisory was prompted by recent studies showing higher rates of serious and life-threatening adverse effects and deaths in patients exposed to these products and a greater number of deaths in patients treated with these agents. Therefore, the FDA is re-evaluating the safe use of this drug class and recommend that clinicians 1) understand that this drug class is given to decrease the need for red blood cell transfusions, 2) weigh the risks of transfusions vs erythropoiesis-stimulating agents, and 3) adjust dosing of erythropoiesis-stimulating agents to maintain the lowest hemoglobin level necessary to avoid the need for transfusions.
Filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF), has been shown to be effective for managing neutropenia and maintaining full peginterferon dosing in HCV-infected individuals on treatment.[90,91] Recombinant human interleukin-11, also known as oprelvekin, has been evaluated for the management of peginterferon-associated thrombocytopenia, but the results to date have been mixed and somewhat disappointing.[92,93] Therefore, no therapy is currently available for interferon-induced thrombocytopenia. However, many experienced hepatologists will allow the platelet count to decline to 25,000-30,000 cells/mm3 before reducing the dose or discontinuing therapy.
In a more recent study, Reddy and colleagues evaluated the impact of dose reductions on treatment outcomes in HCV genotype 1 patients—the group of patients who receives a more extended course of HCV therapy (typically 48 weeks) because of the association with genotype and response. Among 569 patients who were assigned to receive 48 weeks of peginterferon alfa-2a plus ribavirin, Week 4 and 12 responses as well as SVR were correlated with cumulative drug exposure. In this study, dose reductions of ribavirin did not affect treatment outcomes if the cumulative dosage remained > 60%, whereas the SVR rates were significantly reduced among individuals with dose reductions leading to a cumulative ribavirin dosage of < 60%. In addition, among patients who achieved RVR (Week 4 undetectable HCV RNA), ribavirin dose reductions to levels of < 60% cumulative dosage had little impact on treatment outcomes, while dose reductions had a greater impact on individuals who did not achieve RVR.
A recent study by Shiffman and colleagues focused on the importance of treatment adherence during retreatment. In this study, 936 genotype 1–infected patients with advanced fibrosis or cirrhosis and previous nonresponse to unpegylated interferon with or without ribavirin were retreated with weight-based ribavirin and peginterferon alfa-2a 180 μg/week. The investigators found that individuals who received 60% or less of their prescribed peginterferon dosage during the first 20 weeks of treatment were significantly less likely to achieve SVR when compared with those who received the full dosage (defined as 98% or more of the prescribed dosage), with SVR rates of 5% vs 17%, respectively. The same relationship was not found for ribavirin, unless the dosage was interrupted for more than 7 days in a row. However, discontinuation of ribavirin, regardless of proportion of peginterferon received, was associated with lower SVR rates.
Medical personnel who assist in managing patients with chronic HCV infection, such as physician assistants and nurse practitioners, can play an influential role in enhancing treatment adherence by closely monitoring patients, controlling treatment adverse effects, and offering support to patients. This is of particular importance in patients who do not meet early goals of therapy, such as RVR, for whom dose adherence is especially crucial for achieving SVR. To download a worksheet for patients to record contact information for all members of their multidisciplinary treatment team, click here.
All HCV-infected individuals who fail to respond to treatment or who relapse following treatment have a series of fixed or correctable factors that contributed to their negative outcome (Table 4).
<font>Table 4. Factors to Assess When Considering Retreatment of Treatment-Experienced Patients</font>
Among individuals who are candidates for retreatment, these factors must be identified before the start of a second regimen to ensure the best possible outcome. Fixed factors cannot be altered, but in the future, therapy may be tailored to overcome the limitations posed by these factors. Correctable factors, on the other hand, are modifiable and efforts should be taken to reduce or eliminate these factors before the initiation of a second round of therapy.
The population of nonresponders and relapsers to interferon-based therapy is growing. These individuals make up a heterogeneous group with variable sensitivity to interferon retreatment. There is no clear strategy or widely accepted consensus guidelines for managing nonresponders and relapsers. The decision to retreat a patient must be made on a case-by-case basis after careful evaluation of patient’s HCV disease status, past treatment profile, and factors related to previous nonresponse (Table 5). The following section reviews retreatment strategies. For a comprehensive review of management strategies in patients seeking retreatment, please refer to Table 6. SEE THE END OF THIS DOCUMENT BELOW
Relapsers and Nonresponders to Standard Interferon With or Without Ribavirin