Management of Untreated and Nonresponder Patients with Chronic Hepatitis C

• ABSTRACT
• PATIENT EVALUATION
• GENERAL MANAGEMENT ISSUES
• Alcohol
• Obesity
• Use of Medications
• Vaccinations
• Personal Hygiene and Sexual Practices
• JUSTIFICATION FOR TREATMENT
• THE NEED FOR A LIVER BIOPSY
• TREATMENT OBJECTIVES
• TREATMENT REGIMENS
• PREDICTORS OF RESPONSE
• ADVERSE EFFECTS OF TREATMENT
• Factors Influencing Retreatment Decisions
• Management Strategies for Nonresponders
• Observation without Immediate Treatment
• Other Therapeutic Options for Nonresponders to Peginterferon and Ribavirin: High-Dose Peginterferon Induction Therapy Plus Ribavirin Together with Extended Duration Therapy
• ALTERNATIVE INTERFERON PREPARATIONS
• Consensus Interferon
• Albumin Interferon
• Maintenance Therapy
• Investigational Agents
• SUMMARY
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Hepatitis C infection has evolved in the past quarter century from a newly recognized entity without a known pathogen (non-A, non-B hepatitis) to one of the world's most prevalent causes of liver disease, an important source for hepatocellular carcinoma, and the major indication for liver transplantation. It is caused by a virus with a complex replication cycle that occurs in multiple genotypes, of which the four most prevalent (1, 2, 3, and 4) exhibit differences in clinical behavior and responses to therapy. Chronic hepatitis C virus (HCV) in particular has evolved from a disease with no known treatment to one with several primary treatment options, none of which is uniformly effective, and a growing list of secondary treatment options for those who have failed to respond to, or relapsed after initial therapy. As treatment is often associated with significant side effects, it is now a disease that presents clinicians with multiple important decisions: whom to treat, when and with what to treat them initially, and how to manage patients who have failed during initial therapy to achieve a sustained virological response, the gold standard of effective therapy. This review examines each of these important decisions, presenting evidence to help guide clinicians in their choices. The decisions are addressed sequentially as they arise during the initial evaluation and subsequent treatment of a typical, newly recognized patient with chronic HCV, and the considerations facing the clinician when the patient has failed to achieve an SVR.

Hepatitis C virus (HCV) has evolved over the past 25 years from a disease with no known treatment to one with several primary treatment options and a growing list of secondary treatment options for the appreciable numbers of patients who have failed to respond to, or relapsed after initial therapy. Because treatment is often associated with significant side effects, HCV is now a disease that presents clinicians with multiple important decisions: whom to treat, when and with what to treat them initially, and how to manage patients who have failed during initial therapy to achieve a sustained virological response (SVR), the endpoint of treatment. This review examines each of these important decisions, presenting evidence available as of August 2010 to help guide the clinician in his or her choices. The decisions are addressed sequentially as they would arise during the initial evaluation and subsequent treatment of a typical, newly recognized patient with chronic HCV, and subsequently when the patient has failed to achieve an SVR. Steps in the evolution of the patient's “case report” are presented in italics.

A 59-year-old Caucasian man presented to a hepatologist seeking advice about recently discovered abnormal liver-associated enzymes. Two months earlier, he had been found to be in good physical condition during a routine physical examination, but laboratory tests revealed that he had moderate elevations of his serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values (ALT, 137 U/L; AST 101 U/L). Other liver-associated biochemical tests (alkaline phosphatase, serum bilirubin) were within normal ranges, as were his hematologic and routine chemistry values. He expressed great surprise when further evaluation revealed positive test results for antibody to the hepatitis C virus (anti-HCV) and HCV RNA, but his tests for hepatitis A, B, and HIV were negative. He denied using prescription, herbal or over-the-counter medications other than occasional nonsteroidal antiinflammatory drugs (NSAIDS) for muscle pain or stiffness after vigorous exercise. However, he did admit to briefly using intravenous narcotic drugs while a college student, discontinuing the practice after he graduated. His alcohol intake after graduation consisted of occasional wine with meals and, rarely, a glass of beer or hard liquor on social occasions. He stated that he led a physically active lifestyle and was unaware of having had symptoms suggestive of hepatitis. The examining physician then recommended that he consult a gastroenterologist or hepatologist to determine the next steps regarding management and potential treatment of his HCV infection.

At the initial liver clinic visit, the hepatologist repeated the historical evaluation and physical examination, finding no clinical evidence of chronic liver disease. A blood draw was ordered to measure the hepatitis C viral load and to determine the viral genotype. An abdominal ultrasound was also requested.

Persons with these historical and clinical findings are currently the most common attendees at liver clinics. Faced with this situation, the hepatologist must consider what further information and evaluation is needed, what the general management issues should be, and whether or not antiviral treatment is indicated.

PATIENT EVALUATION

Abnormal liver-associated chemistries identified in a person with HCV viremia are almost always a consequence of the HCV infection, but other medical disorders may occasionally be responsible. Therefore, it is important during the initial evaluation and workup to begin by excluding all other conditions that could account for abnormal serum enzymes in a person with chronic HCV. Among the most common are coinfection with other hepatitis viruses, hepatitis A and B in particular; the adverse effect of prescription drugs or herbal products taken at the time; and heavy alcohol use or nonalcoholic steatohepatitis (NASH).

The hepatitis A and B test results in the patient had already been found negative, he had denied using prescription or herbal medications other than an occasional NSAID, his alcohol use was quite modest and he was not overweight.

At the primary visit, it may initially be uncertain whether the patient has acute or chronic HCV, although the vast majority of such persons already have chronic HCV when first attending a liver clinic. This distinction is important because treatment strategies differ between the two.[1] One way to differentiate them is to assess the results of the two HCV assays (HCV RNA and anti-HCV), although interpreting their pattern can be complicated.[2] Early in the course of acute HCV, HCV RNA alone is detectable, anti-HCV appearing only several weeks later. However, this pattern is found also in immunocompromised persons with chronic HCV infection. Positive results for both HCV RNA and anti-HCV are seen in acute and chronic HCV, requiring that the distinction be based on clinical context (e.g., a recent known exposure, rare to find markedly elevated aminotransferase and bilirubin levels in persons with chronic HCV, or an alternative explanation for the abnormal serum enzymes). The third pattern of a positive test for anti-HCV and a negative assay for HCV RNA generally defines ultimate resolution of acute HCV, but may be found also in persons with acute hepatitis who are in the process of clearing their HCV viremia.

Identifying symptoms such as fatigue, malaise, nausea, and vomiting might be thought useful in distinguishing acute from chronic HCV, but the vast majority of persons with both acute and chronic HCV are asymptomatic. However, if a history is obtained of an unexplained recent abrupt onset of such symptoms, the diagnosis is most likely to be acute HCV because symptoms do occur in 10 to 25% of persons with acute, but rarely in those with chronic HCV until they have reached end-stage liver disease. In general, continuing to monitor the patient for several months will allow the distinction of acute from chronic HCV. However, establishing a diagnosis of acute HCV early is important because treatment optimally should be instituted within 3 months of presentation and definitely within 6 months. After this period, response rates begin to decline. Although the generally accepted definition for chronic hepatitis is the presence of abnormal aminotransferase levels for ~6 months, a diagnosis of chronic HCV can be considered likely by finding persistently abnormal serum enzymes that fluctuate little for even a shorter period, such as 3 months. Finally, acute can generally be differentiated from chronic HCV by studying liver biopsy tissue, but performing a liver biopsy for the sole purpose of diagnosing acute HCV is rarely done, nor is it necessary

The patient had blood tests performed at the liver clinic at 2 to 4 week intervals over a period of 6 months that revealed unwaveringly modest elevations of aminotransferase values (ALT, AST), and normal serum alkaline phosphatase and bilirubin values. Thus, it was concluded that he had chronic HCV. After results of the viral load (590,000 IU/mL) and the genotype (1a) had been received, the hepatologist began a discussion with the patient about general management issues and the consideration of starting antiviral therapy.

GENERAL MANAGEMENT ISSUES

Managing patients with chronic HCV infection involves not only the use of antiviral drugs aimed at suppressing or eradicating the virus, but also the effort to reduce exposure to factors that may further enhance progression of the chronic liver disease and factors that prevent spread to close contacts. This requires thoughtful and sensitive dialogue with the patient because some of these factors have social connotations.

Alcohol

Alcohol used in excess is clearly a potential hepatotoxin, even among persons without chronic HCV. However, persons with chronic HCV are at even greater peril from heavy exposure to alcohol because it is reported to enhance existing fibrosis progression and to augment development of hepatocellular carcinoma (HCC).[3] [4] Moreover, alcohol appears to increase HCV RNA replication and interfere with the effectiveness of antiviral treatment.[5] [6] The quandary is that the amount of alcohol required to have these adverse effects is unknown. Some believe that consuming more than 50 gm/day greatly increases the likelihood of fibrosis progression, but lesser amounts have also been reported to be harmful.[7] Nevertheless, heavy alcohol intake obviously warrants treatment itself, preferably before initiating antiviral therapy, but is not a reason to deny such treatment altogether. In the absence of alcohol dependence, a prudent approach is to recommend either complete suspension of alcohol intake, especially during the course of the antiviral treatment, or to restrict alcohol intake to only an occasional drink.

Obesity

Obesity is often accompanied by hepatic steatosis or steatohepatitis that may augment fibrosis progression in persons with chronic HCV and adversely affect response to antiviral therapy due to the associated insulin resistance. It is therefore also prudent to urge overweight persons to work toward losing weight, using body mass index (BMI) measurement as an indicator of success. Weight loss is, of course, beneficial not only for the liver disease, but also for the other harmful conditions associated with obesity.

Use of Medications

Patients with chronic HCV should also be advised to restrict use of medications to only those deemed vital. This does not imply that persons chronically infected with HCV are at any greater risk of developing drug-induced liver injury than are noninfected persons. However, using nonessential medications creates an added dilemma should there be an unexpected worsening of liver-related chemistries. Particularly concerning is the use of unregulated herbal products and dietary supplements. Because of the stringent antiviral therapeutic regimen required for treating chronic HCV, and because of the associated drug adverse effects, persons with chronic viral HCV commonly utilize herbal products, either in place of or in conjunction with antiviral agents, believing that they may be effective treatments on their own or that they may reduce the frequency of the antiviral side effects.[8] [9] There is also trust that they are safe. With respect to efficacy, relatively few well-designed, controlled trials of any herbal product have shown convincing evidence of an antiviral effect or true clinical benefit.[10] Recent evidence, however, indicates that silymarin (milk thistle), the herbal product most frequently used by persons with chronic viral hepatitis, does appear to have an antiviral effect both in HCV-infected humans when given intravenously in large doses[11] as well as when it is studied in vitro,[12] but these are preliminary data, not yet clinically applicable. Regarding safety, there are much data showing that herbals are no less safe than conventional prescription medications and, because they are not regulated by the U.S. Food and Drug Administration, some may in fact be more harmful.[13]

Vaccinations

Coinfection with the hepatitis A and B viruses has been reported to have an adverse effect on persons with chronic HCV. An unconfirmed report has implicated hepatitis A as a source for fulminant hepatitis in patients with chronic liver disease due to HCV,[14] and there are several reports indicating that persons infected with both hepatitis B and C have a worse prognosis than those infected with HCV alone.[15] This has prompted the recommendation that the hepatitis A vaccine be administered to persons with chronic HCV-infection who are susceptible to hepatitis A. No official recommendation exists with regard to hepatitis B, but it seems prudent to administer the hepatitis B vaccine also if the HCV-infected person lacks evidence of previous exposure.[1]

Personal Hygiene and Sexual Practices

Because sharing of personal hygiene items, such as toothbrushes and razors, may be a source of transmission, HCV-infected persons should be counseled not to share them with other household members.[16] They should be advised also not to donate blood, semen, or body organs. Sharing of eating or drinking utensils has not been shown to be a mode of transmission of HCV. Sexual transmission is sufficiently uncommon to require changes in sexual practice for partners in monogamous relationships, but “safer” sex should always be practiced.

The patient required few management recommendations; his alcohol use was sparse, he did not routinely use prescription or herbal medications, and he was not obese. However, lacking serologic evidence of exposure to both hepatitis A and B, he was administered vaccines against both viruses. The issue of antiviral therapy was then raised taking into account its justification, whether a liver biopsy was required, the proposed treatment regimen, the treatment objectives, the factors predictive of a positive response, and the potential adverse effects of the drugs.

JUSTIFICATION FOR TREATMENT

Having chronic HCV is a threat both to the carrier of the virus and to contacts. The risk for the carrier is progression to end-stage liver disease; the risk to contacts is transmission of the virus through percutaneous blood to blood exposure. Natural history studies have shown that 55 to 85% of acutely infected persons fail to spontaneously clear the virus, among whom 5 to 25% advance to cirrhosis over 25 to 30 years.[17] [18] Children and young women account for the higher rate of viral clearance and the lower rate of progression to cirrhosis. Once advanced fibrosis or cirrhosis has emerged, there is an annual risk of 1 to 3% of developing HCC.[18]

Factors associated with the likelihood of advancing liver disease include HCV infection in older age, the presence of obesity, insulin resistance, the immunocompromised state (such as HIV coinfection or chronic renal disease), and consuming more than 50 g of alcohol per day.[1] Also predictive of progression is the finding of bridging fibrosis on liver biopsy, although this may not be a universal determinant.[19]

THE NEED FOR A LIVER BIOPSY

Although a liver biopsy is not essential for managing patients with chronic HCV, it is helpful in establishing the status of HCV-related liver disease, in aiding the decision to undertake treatment, and in identifying non-HCV related conditions that might affect outcome. The biopsy is assessed for grade (degree of necro-inflammation) and stage (extent of fibrosis) that help predict the likelihood of disease progression.[20] Several scoring systems (Metavir, Batts-Ludwig, International Association for the Study of the Liver, Ishak)[21] [22] [23] [24] have been devised for this purpose. Alternative approaches for assessing the extent of fibrosis, such as transient elastography, are being evaluated, but are not yet ready to replace the liver biopsy. A primary reason for evaluating a liver biopsy is to identify those most at risk of liver disease progression and who therefore clearly warrant treatment, an important consideration because current antiviral therapy is only variably successful and is commonly associated with unpleasant and sometimes serious adverse events. The liver biopsy reveals the extent of fibrosis (staged by one of the scoring systems mentioned above), a strong determinant of disease progression. The liver biopsy may also identify other conditions that may accelerate fibrosis progression such as iron overload and steatosis and uncover further diagnoses that could coexist with chronic HCV and contribute to the ongoing liver disease, for example α-1 antitrypsin. The biopsy is of most value for persons infected with HCV genotypes 1 and 4 because their response rates to treatment ranges from ~30% (African Americans) to ~50% (Caucasians), but is of far less value for patients infected with genotypes 2 and 3 among whom the response rate exceeds 80%.

TREATMENT OBJECTIVES

If the response rate to therapy were high (>80%), all HCV-infected persons, whether or not they had abnormal liver-associated chemistries, would likely be treated unless there were specific reasons not to do so. This high response rate is generally achieved in persons infected with genotypes 2 and 3, but not in those with genotypes 1 and 4 infections.[1] Therefore, for the latter group, treatment focuses on those most likely to have progressive liver disease, defined largely by the presence and extent of fibrosis. This approach is likely to change when the newer antiviral agents, such as protease and polymerase inhibitors, are approved and become available. Treatment success is judged by the complete elimination of HCV RNA from serum 24 weeks after treatment is discontinued. This is, in reality, a surrogate measure because the actual outcome hoped for—a decrease in the frequency of end-stage liver disease and death—requires decades of follow-up to establish. Other surrogate outcomes aimed for are normalization of the initially abnormal liver biochemical tests and histologic improvement (reduction in necro-inflammation without worsening fibrosis).

TREATMENT REGIMENS

The drugs and doses used, and the durations of treatment derive from the results of several registration and nonregistration controlled trials.[25] [26] [27] These differ depending upon the implicated viral genotype. Current standard treatment consists of a combination of a pegylated interferon, either alfa-2b (Peg-Intron, Schering Plough Corp., Kenilworth, NJ) or alfa-2a (Pegasys, Hoffman-LaRoche, Nutley, NJ), together with ribavirin. The dose for peginterferon alfa-2b given subcutaneously is 1.5 μg/kg/week dosed by body weight, combined with weight-based ribavirin (800 mg for weight <65 kg; 1,000 mg for weights 65 to 85 kg; 1,200 mg for weights 85 to 105 kg; 1,400 mg for weights >105 kg). Peginterferon alfa-2a is given subcutaneously in a fixed dose, 180 μg/week together with ribavirin, 1,000 mg daily for weight ≤75 kg; 1,200 mg for weight >75 kg.

Treatment of persons with uncomplicated genotype 1 and 4 infections generally last for 48 weeks, whereas the treatment duration for persons with genotypes 2 and 3 infections generally runs for 24 weeks. In both cases, treatment success is defined by finding a negative test for HCV RNA 24 weeks after completion of treatment, referred to as a sustained virological response (SVR); this represents “cure” of the infection because the virus remains undetectable as much as 10 years later, but not necessarily “cure” of the disease. Follow-up studies ranging from 5 to 12 years in sustained responders report regression of fibrosis and lower rates of hepatic decompensation and liver-related death,[28] [29] [30] [31] [32] but ongoing risk for HCC, particularly in those with advanced disease, when compared with nonresponders.[29] [31] [32]

The virological responses at various time intervals during the course of treatment are predictive of treatment response and might modify the duration of therapy (Table [1]). The earliest assessed response is a rapid virological response (RVR), representing conversion of a positive to a negative result for HCV RNA at week 4 of treatment using a sensitive PCR-based quantitative assay (Fig. [1]). This is reported to occur in 15 to 25% of persons with genotype 1 and in 66% of those with genotype 2 and 3 infections. The finding of an RVR is highly predictive of an SVR (~85 to 90%) and may permit shortening of the treatment course for genotypes 2 and 3 infections and possibly genotype 1 with a low viral load. The results obtained at 12 weeks of treatment, referred to as the early virological response (EVR), are more predictive of nonresponse.[33] They may be categorized as a partial EVR (≥2 log reduction of HCV RNA relative to the baseline level) or a complete EVR (HCV RNA assay negative), These results are particularly relevant for persons with genotype 1 infection. If an EVR is not achieved, 97 to 100% of patients with genotype 1 infections will not develop an SVR; therefore, it is futile to continue treatment. In contrast, achieving an EVR is less predictive of a response because only 65 to 72% with genotype 1 infection who do will ultimately develop an SVR (complete EVR, 83% predictive of SVR, partial EVR, 21% predictive of SVR). An EVR is less relevant for persons with genotypes 2 and 3 infections because most have already cleared virus by that time. The last treatment virological response is termed end-of-treatment response (ETR), referring to the HCV RNA status at completion of therapy (24 weeks for genotypes 2 and 3; 48 weeks for genotypes 1 and 4 infections). Unless an ETR occurs, an SVR will not develop.

1 Results quoted are for patients whose initial treatment was peginterferon and ribavirin.

Other defined virological responses include breakthrough (reappearance of HCV RNA while still on treatment), relapse (reappearance of HCV RNA after completing therapy), nonresponse (persistent HCV RNA after 12 weeks of therapy), null response (failure to decrease HCV RNA by <2 logs after 24 weeks of therapy), and partial response (HCV RNA present at week 24, but decreased by 2 logs) (Fig. [1]). Each of these requires a modification of the routine therapeutic regimen, as will be described.

PREDICTORS OF RESPONSE

The four most prominent pretreatment predictors of a likely positive treatment response are the viral genotype (a higher SVR rate in persons with genotypes 2 and 3 than genotypes 1 and 4), the viral load (higher response rate in persons with a viral load <800,000 IU/mL), the absence of cirrhosis, and genotype of the IL-28B gene (higher response in those with CC and CT versus TT genotype).[34] [35] [36] [37] [38] Other less robust indicators include female gender, age <40 years, non-African American race (probably related to IL-28B genotype), a lower body weight (<75 kg), the absence of insulin resistance and hepatic steatosis, ALT levels threefold higher than the upper limit of normal, and higher administered doses of pegylated interferon and ribavirin. In contrast are the persons who have a lower likelihood of responding to treatment, generally referred to as difficult-to-treat patients, and who therefore require modification of the routine treatment strategy.[1] These include persons coinfected with HIV, and those with advanced kidney disease, with compensated and especially decompensated cirrhosis, and who have received solid organ transplants (heart, lung, liver). Other groups requiring different treatment strategies are those identified as having acute HCV (a relatively rare discovery), infected children, infected active injection drug users, and those with psychiatric illnesses.

ADVERSE EFFECTS OF TREATMENT

Virtually all treated patients experience side effects from treatment, some of which (~10 to 14%) are severe enough to require curtailing treatment.[25] [26] [27] Approximately one-half of persons treated with peginterferon develop flu-like symptoms that can be severe, whereas about one-quarter to a third develop psychiatric side effects, predominantly depression. Laboratory abnormalities may also occur that would necessitate dose reduction. These include neutropenia requiring a reduction of 50% if the absolute neutrophil count drops to 750 mm³ and discontinuation if it falls to <500 mm³. Other hematologic abnormalities include anemia and thrombocytopenia. Treatment of these conditions with growth factors (granulocyte colony stimulating factor, erythropoietin, darbepoetin, eltrombopag) is occasionally attempted, but their use is controversial.[39] [40] [41] [42] [43] Although they may improve the sense of well-being and tolerance to therapy, and may permit treatment for patients who are not otherwise candidates for therapy, their use has not been associated with an increase in the rate of SVR. Furthermore, utilizing these products adds substantially to the cost of therapy, and even though they are generally safe, erythropoietin and darbepoetin use has been associated with serious side effects including cardiovascular and thromboembolic events, pure red cell aplasia, progression of certain cancers, and death; eltrombopag use has been associated with portal vein thrombosis.[44] Peginterferons may also induce autoimmune disorders such as thyroiditis, or even worsen other preexisting autoimmune diseases. The most prominent adverse effect of ribavirin is the induction of hemolytic anemia that may compromise the treatment strategy. It has also been reported to cause fetal abnormalities in animals; therefore, there is a mandatory requirement that treated patients utilize strict contraception during and for 6 months after treatment.

A liver biopsy was performed that revealed moderate inflammation and portal fibrotic expansion (Ishak stage 2). After discussing the benefits, risks and side effects of therapy, the patient opted for treatment. He was initiated on pegylated interferon alfa-2a 180 μg per week with oral ribavirin 1,200 mg daily. He tolerated therapy reasonably well, experiencing the common side effects of fatigue, chills, and muscle aches. At treatment week 12, his ALT was normal, but his HCV RNA had decreased only 1-log compared to baseline. Thus, he failed to achieve an EVR and could be classified a null responder. After discussion with his hepatologist, the decision was made to stop therapy. He asked about alternative management strategies, and if none were available, how he should be monitored until such time that other treatments become available.

Persons who fail therapy are a heterogenous group, consisting of those who develop a virological breakthrough, who have a virological relapse, or are complete nonresponders (partial or null). Approximately, 35% of patients infected with HCV genotype 1 and 7% of those with HCV genotypes 2 or 3 are nonresponders whereas 23% with HCV genotype 1 and 13% with HCV genotypes 2 or 3 relapse to standard therapy.[25] [26] [27] In these circumstances, the dilemma is whether to recommend observation without treatment or to consider retreatment with the understanding that therapeutic options are limited.

Factors Influencing Retreatment Decisions

The outcome of retreatment varies depending upon the category of the prior nonresponse; those who experienced a breakthrough or relapse are more likely to respond to retreatment than those who were complete nonresponders. It is also advisable to review factors that have been associated with a reduced likelihood of achieving an SVR because correcting or modifying these factors may increase the likelihood of an SVR with retreatment. One of these is whether the initial therapeutic regimen was suboptimal, namely the use of interferon or peginterferon monotherapy or of standard interferon plus ribavirin, as was practiced in the past, instead of the currently accepted regimen of peginterferon plus ribavirin. Others include whether significant dose reductions were necessary during the course of treatment, whether the patient was fully compliant with the therapeutic regimen and whether the treatment duration was shortened or inadequate. In addition, several host and viral factors should be considered in the decision to retreat or observe. Subjects with milder degrees of fibrosis (Metavir scale, F0-F2 fibrosis), who are of Caucasian or Asian race, who have a normal BMI, who are infected with HCV genotype 2 or 3, or who have a low baseline viral load are more likely to respond to retreatment. Among these latter factors, the BMI is the only one that is potentially modifiable before retreatment is undertaken. Of note is that these factors are also associated with slow progression of liver fibrosis, which would also favor a watch and wait approach.

Management Strategies for Nonresponders

Patients who fail treatment with peginterferon and ribavirin are not candidates for retreatment using the same regimen even if a different type of pegylated interferon is administered because the SVR rate with this approach is less than 10%. In one large illustrative trial (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis [EPIC]) involving patients with advanced liver disease who had failed initial treatment, 80% of whom were infected with HCV genotype 1 and 42% of whom had cirrhosis, retreatment with peginterferon alfa 2b, 1.5 μg/kg/week and weight-based ribavirin resulted in an overall SVR rate of 22%.[45] The response rate was significantly higher in relapsers (38%) than in nonresponders (14%). Moreover, the SVR rate in nonresponders whose original regimen was peginterferon and ribavirin was only 6%. Relapsers to peginterferon and ribavirin had an SVR rate of 33%. In view of the poor response to retreatment using the same regimen, other approaches have been attempted such as the use of a higher dose of peginterferon, extending the duration of therapy from 48 to 72 weeks, using different preparations of interferon, the use of maintenance interferon, and enrollment into trials evaluating investigational agents. A sensible option in some circumstances may be to withhold treatment until the emerging new drugs are approved and become available.

Observation without Immediate Treatment

Prolonged observation is a reasonable option, particularly for patients with mild degrees of fibrosis (F0-F2) because of the generally slow rate of fibrosis progression. Reassuringly, 80% of patients with cirrhosis are still alive 10 years after diagnosis.[46] However, patients who opt for continued observation must be closely monitored to seek a change in their disease status. A reasonable monitoring interval would be every 6 months, although patients could be seen more frequently based on their disease severity. Patients with cirrhosis should be screened for varices and HCC and referred for liver transplantation if there is evidence of decompensation.

Other Therapeutic Options for Nonresponders to Peginterferon and Ribavirin: High-Dose Peginterferon Induction Therapy Plus Ribavirin Together with Extended Duration Therapy

One approach to retreatment has been to use a higher dose of peginterferon as induction therapy together with a longer duration of therapy. One such trial (the Repeat Trial) focused on nonresponders to an initial course of peginterferon alfa-2b plus ribavirin.[47] Patients were randomized to receive one of four treatment regimens: patients in arms A and B received high doses of peginterferon alfa-2a, 360 μg weekly for 12 weeks followed by 180 μg weekly for 48 or 72 weeks. Patients in arms C and D received standard peginterferon180 μg weekly for either 48 or 72 weeks. All patients received weight-based ribavirin, 1,000 mg to 1,200 mg daily. Ninety-one percent of patients were infected with HCV genotype 1 and 25 to 30% had cirrhosis. The primary endpoint of the trial was an SVR. In the intention-to-treat analysis, high-dose induction therapy administered for 12 weeks did not increase the end of treatment response rate when compared with standard therapy, suggesting that there is no benefit from the high-dose induction strategy. However, extending therapy to 72 weeks was associated with a significant increase in the SVR rate, primarily due to the prevention of virological relapse. In a modified intention-to-treat analysis comparing all patients who received 72 weeks of extended therapy (with or without induction) to those who received 48 total weeks of treatment, the SVR rate was significantly higher in the former than the latter, 16% versus 8% (p = 0.0006).[47] Thus, high-dose induction cannot be recommended, but extending therapy to 72 weeks results in a small, albeit significant increase in the SVR rate. It is important to note, however, that as in other treatment extension trials, premature withdrawal was more common in the longer duration than in the standard treatment groups (in this trial, 12% with 72 weeks of treatment compared with 6% with 48 weeks of therapy).

ALTERNATIVE INTERFERON PREPARATIONS

Consensus Interferon

The DIRECT trial was an open label, multicenter trial designed to evaluate retreatment of prior nonresponders to peginterferon plus ribavirin with low and high doses of consensus interferon together with weight-based ribavirin for 48 weeks.[48] Consensus interferon, as its name implies, is a synthetic interferon created from the most common amino acid sequences occurring in natural α interferons.[49] It exhibits more potent antiviral activity in vitro than interferon alfa-2a or 2b.[49] In this trial 94% of patients were infected with HCV genotype 1 and three-quarters of subjects had bridging fibrosis or cirrhosis. The primary endpoint of the trial was an SVR. The SVR rate was not significantly higher in the 15 μg compared with the 9 μg arm (11% vs 7%, respectively) and overall was poor.[48] In addition, the 15 μg/day dose of consensus interferon is not approved for use by the Food and Drug Administration and this strategy requires a highly motivated patient. As a consequence, this approach is unlikely to be widely adopted as an option for nonresponders.

Albumin Interferon

The albumin interferon (albinterferon) alfa-2b molecule consists of recombinant interferon alfa-2b fused to human albumin. The rationale for creating this compound was to increase the exposure to interferon and prolong the dosing interval. A small phase 2 study evaluated the safety/efficacy of albinterferon in patients with chronic HCV who had not responded to interferon-based regimens.[50] Ninety-three percent were infected with HCV genotype 1, the baseline HCV RNA was >800,000 IU in 84% of patients and 30% had bridging fibrosis or cirrhosis. Albinterferon was administered at a dose of 1,200 μg every 4 weeks or 900, 1,200, 1,500, or 1,800 μg every 2 weeks, plus oral ribavirin, for 48 weeks.[50] The primary efficacy endpoint was achievement of an SVR. The overall SVR rate was 17% and 11% in previous nonresponders to pegylated interferon-alfa plus ribavirin.[50] The highest reductions in HCV RNA in the nonresponders to pegylated interferon-alfa/ribavirin with genotype 1 infection were observed in the 1,800 μg arm of the trial. The overall discontinuation rate because of adverse events was 10.4%. The types of adverse events were similar across groups, although pulmonary toxicity was associated with the higher doses of albinterferon. This may limit its usefulness in a nonresponder population.

Maintenance Therapy

Three large randomized trials (Hepatitis C Long-term Treatment Against Cirrhosis [HALT-C],[51] Colchicine versus Peginterferon Alfa 2b Long-term Therapy [COPILOT],[52] and EPIC3[53]) examined the role of maintenance monotherapy with lower doses of peginterferon in patients who did not achieve an SVR with standard therapies. The rationale for this approach was based on prior studies, which suggested that interferon may have antiinflammatory and antifibrotic effects independent of its antiviral activity. Thus, its use may slow progression of the disease without necessarily achieving viral eradication.[54] [55] [56] The three trials were similar in design and included patients with relatively advanced stages of disease. The HALT-C trial enrolled 1050 patients who had failed prior interferon-based therapy, 40% of whom had cirrhosis at study entry. Patients were randomized to low-dose peginterferon, 90 μg weekly or observation for 31/2 years and monitored for progression to cirrhosis or clinical decompensation. The COPILOT study enrolled 600 peginterferon and ribavirin or interferon and ribavirin failures, 83% of whom had cirrhosis at baseline. Patients were randomized to peginterferon alfa-2b, 0.5 μg weekly, or colchicine 6 mg twice daily for 4 years. The EPIC trial randomized 978 patients who failed peginterferon and ribavirin or interferon and ribavirin, 42% with cirrhosis, to low-dose peginterferon alfa-2b 0.5 μg weekly or no therapy for 4 years. The HALT-C and EPIC3 studies included a lead-in phase with standard-dose peginterferon/ribavirin before the maintenance dosing period, whereas the COPILOT study did not include a lead-in phase. The findings did not show an overall improvement with maintenance therapy compared with observation or colchicine treatment regarding the significant endpoints of fibrosis progression, the development of HCC, or mortality. In the COPILOT trial, 49% of patients did not achieve 4-year event-free survival. In the HALT-C Trial, no significant difference was observed between maintenance therapy and nontreatment observation in any of the primary outcomes, and in the EPIC3 study, clinical events were not significantly reduced by maintenance therapy versus observation. However, there may have been some benefits of maintenance monotherapy observed in these studies. In the EPIC3 study, for example, patients who had portal hypertension at baseline were noted to have fewer events of variceal bleeding. Nevertheless, although some categories of patients may benefit from maintenance peginterferon monotherapy, the majority do not. In summary, the poor results of these studies demonstrate that maintenance therapy with low-dose peginterferon cannot be recommended for nonresponders to peginterferon and ribavirin.

Investigational Agents

Several investigational agents are currently in phase I–III development for treatment of chronic HCV. Two protease inhibitors, telaprevir and boceprevir, appear to be the most promising direct-acting antivirals for treatment of chronic HCV. Currently, these agents must be used in combination with peginterferon and ribavirin to prevent the development of viral resistance. Data from the PROVE (Protease Inhibitor for Viral Evaluation) trial that evaluated telaprevir, and the SPRINT (Serine Protease Inhibitor Therapy) trial that evaluated boceprevir, suggest that protease inhibitors in combination with PEG-IFN/RBV can achieve SVR rates approaching 70 to 75% in genotype 1, treatment-naive patients.[57] [58] Results from the PROVE 3 and SPRINT-1 trials provide tantalizing evidence of the efficacy of these agents in peginterferon and ribavirin treatment failures. PROVE 3 enrolled nonresponders, relapsers, and those with virologic breakthrough to prior therapy with peginterferon alfa-2a and ribavirin. Patients were randomized to one of four arms, telaprevir for 12 weeks and peginterferon alfa-2a and ribavirin for 24 weeks; telaprevir for 24 weeks and peginterferon alfa-2a and ribavirin for 48 weeks; a ribavirin-sparing arm of telaprevir and peginterferon alfa-2a for 24 weeks; and a control group, who received peginterferon alfa-2a and ribavirin for 48 weeks.[59] The primary endpoint was an SVR. The SVR rates were significantly higher in all three telaprevir-containing arms. However, the ribavirin-sparing arm of telaprevir plus peginterferon alfa-2a achieved much lower SVR rates than those who received ribavirin with telaprevir and peginterferon alfa-2a, highlighting the importance of ribavirin in preventing virological relapse. Overall, the highest SVR rates, 51% and 53%, occurred among patients treated with triple therapy for either 12 or 24 weeks, respectively, followed by the same duration of peginterferon alfa-2a and ribavirin alone. Surprisingly, longer exposure to telaprevir did not seem to have a major effect on the SVR rates.[59] Previous nonresponders to peginterferon and ribavirin treated with triple therapy for 12 or 24 weeks followed by the same duration of peginterferon alfa-2a and ribavirin alone had SVR rates of 38% to 39% compared with 9% with standard therapy. This represents an almost fourfold improvement in SVR rates over standard therapy following retreatment in nonresponders. Even higher SVR rates were achieved in relapsers and breakthrough patients, 69% to 76% and 57% to 63%, respectively.[59]

The SPRINT-1 trial assessed the efficacy and safety of adding boceprevir, another HCV NS3 protease inhibitor, to peginterferon alfa-2b/ribavirin in treatment-naive patients with genotype 1 HCV.[58] A retrospective analysis was conducted of null responders (defined as <1.0 log₁₀ IU/mL reduction in HCV RNA after 4 weeks of peginterferon alfa-2b/ribavirin) to peginterferon and ribavirin from the two lead-in arms of the SPRINT-1 trial. Following the lead-in phase, patients received 24 or 44 weeks of boceprevir plus peginterferon alfa-2b/ribavirin.[60] An SVR was achieved in 25% and 55% of null responder patients treated with 24 or 44 weeks of triple therapy. Although this analysis pertains to null responders assessed after only 4 weeks of peginterferon and ribavirin, the majority of these patients would have failed to achieve an SVR. These findings suggest that protease inhibitors may hold promise for this difficult to treat population.

One concern is whether nonresponders to peginterferon and ribavirin who receive triple therapy will be at higher risk for development of drug resistance because, in effect, they are receiving monotherapy. Data from the PROVE 3 trial reported rates of viral breakthrough at week 24 of 13% in the 12-week telaprevir group, 12% in the 24-week telaprevir group, 32% in the telaprevir group without ribavirin, and 3% in the control group.[59] However, in nonresponders, rates of virological breakthrough were much higher, 20% in the 12-week telaprevir group, 22% in the 24-week telaprevir group, 45% in the telaprevir group without ribavirin, and 3% in the control group.[59] Another concern is the absence of data regarding the long-term durability of an SVR with these agents.

Nitazoxanide, is an antiviral drug of the thiazolide class, originally developed for the treatment of parasitic infections, that was shown to have antiviral activity in treatment-naive and treatment-experienced patients with chronic genotype 4 HCV infection.[61] A small-phase II, randomized, double-blind, placebo-controlled study of nitazoxanide, 500 mg twice daily plus peginterferon alfa-2a and ribavirin, was done in peginterferon/ribavirin nonresponders infected with HCV genotype 1.[62] In this trial, patients were randomized to a lead-in phase of nitazoxanide alone versus placebo for 4 weeks followed by peginterferon/ribavirin plus nitazoxanide or placebo for 44 weeks. The SVR rate with the nitazoxanide-containing regimen was only 7% compared to 0% with retreatment with peginterferon and ribavirin.[62]

RG7128 is a nucleoside analogue that inhibits HCV polymerase with potent in vitro activity across all HCV genotypes.[63] RG7128 was compared with placebo, each in combination with peginterferon alfa-2a/ribavirin for 4 weeks, followed by continued peginterferon/ribavirin treatment for 24 to 48 weeks, depending on the patient's previous response to therapy and initial response to therapy.[64] Ninety-five percent of patients who received RG7128 achieved an RVR compared with 60% who received standard peginterferon plus ribavirin and placebo, but SVR rates were 65% versus 60%, respectively. SVR rates were similar between patients infected with HCV genotypes 2 and 3, 63% versus 67%, respectively.[64] Thus, this agent may be promising, but it appears that a longer duration of therapy may be necessary to prevent the high relapse rates.

SUMMARY

Relapser and breakthrough patients have several good options for retreatment (Table [2]). However, nonresponders, the null responder in particular, remain a difficult to treat group with fewer options. At present, nonresponder patients with mild disease probably should be observed until more effective therapies become available. For patients with more advanced disease, the decision to retreat is not straightforward. Using different preparations of interferon or extending the treatment duration results in small increases in the SVR rate and should be recommended only for highly motivated patients with well-compensated liver disease. Treatment should be discontinued after 12 weeks for persons who do not achieve an EVR. Studies involving nonresponders treated with protease inhibitors in combination with peginterferon and ribavirin seem to be more promising, but only one-third of patients will achieve an SVR. In contrast, up to 45% of patients, depending on the regimen used, will be at risk of developing antiviral resistance, which may limit future treatment options. The combination of multiple direct acting antivirals might be a better option for null responders; however, these combinations will not be available for years. In the interim, nonresponder patients should be monitored for disease progression and the development of HCC, particularly those who have advanced liver disease.

Observation with scheduled monitoring was recommended for this patient given his relatively mild liver disease and the absence of poor prognostic factors and of symptoms. The patient was counseled to limit his alcohol use, avoid herbal and over-the-counter medications, and advised to wait for the next generation of therapy.

ABBREVIATIONS

• ALT alanine aminotransferase

• AST aspartate aminotransferease

• BMI body mass index

• ETR end of treatment response

• EVR early virological response

• HCC hepatocellular carcinoma

• HCV hepatitis C virus

• NSAID nonsteroidal antiinflammatory drugs

• RVR rapid virological response

• SVR sustained virologic response

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Leonard SeeffM.D. 

Hepatology Consultant, The Hill Group

6903 Rockledge Drive, Suite 540, Bethesda, MD 20817

Email: Mahler68@hotmail.com

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Leonard SeeffM.D. 

Hepatology Consultant, The Hill Group

6903 Rockledge Drive, Suite 540, Bethesda, MD 20817

Email: Mahler68@hotmail.com