Genetically fused interferon alpha with serum human albumin Increased dosing interval of two to four weeks
Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN, interferon; IMPDH, inosine monophosphate dehydrogenase; PEGIFN, peginterferon; RBV, ribavirin.
Abbreviations: ALT, alanine aminotransferase; HCV, hepatitis C virus; IFN, interferon; IMPDH, inosine monophosphate dehydrogenase; PEGIFN, peginterferon; RBV, ribavirin.
clinical trials or be discarded during preclinical testing. Pharmaceutical companies, clinical research organizations, and governmental web sites can help patients and physicians to remain abreast of drug development and emerging clinical trials with new agents for patients with chronic hepatitis C.
Several agents available to physicians are being evaluated in clinical trials as a potential treatment for patients with chronic HCV infection and NR to previous PEGIFN/RBV therapy. Other trials are investigating the efficacy of higher doses of IFN or PEGIFN or a longer duration of therapy with these agents. Several of these strategies are discussed here because they may potentially be used by physicians for their patients with chronic hepatitis C. Only preliminary data are available regarding the use of these agents in this "off-label" manner. Discussing these approaches in this article does not advocate their use or suggest that they may be effective for treatment of patients who have HCV infection and NR to PEGIFN/RBV. Safety and efficacy will be determined when the results of these ongoing trials become available.
Anti-viral therapy with first generation protease inhibitors has been undergoing evaluation for the past few years. Initially, significant results were seen with BILN 2061 used as monotherapy with 3 log reductions in HCV RNA. Studies were halted, however, after the development of cardiac toxicities in animal models . The enthusiasm for this class of agents has been renewed with the development of three new drugs, NM283, VX-950, and SCH 503034. Each of these agents have been shown to significantly suppress HCV RNA when used either alone or in combination with PEGIFN [49-51]. Given prior experience with these agents, and the early phase of their trials, therapy with anti-HCV protease inhibitors should be approached with caution. Further studies of their use in combination therapy with interferon or triple therapy with interferon and ribavirin need to be evaluated.
Consensus interferon (CIFN) is a synthetic IFN product with an amino acid sequence that reflects all a-IFNs. CIFN has been shown to be effective in the retreatment of patients who failed to achieve SVR after 24 weeks of treatment with standard IFN monotherapy . In that study, SVR was achieved in 58% of patients with previous relapse and in 13% with previous NR. High-dose daily CIFN using an "induction" approach has recently been evaluated for patients who have NR after treatment with PEGIFN/ RBV in two small, single-center trials [53,54]. In one of these studies, CIFN was administered at doses of 27 or 18 mg daily for 4 weeks followed by 18 or 9 mg daily for 8 weeks, followed by 9 mg daily plus RBV (10001200 mg/d) for an additional 36 weeks. In the other study, CIFN was dosed at 15 mg/d plus RBV (1000-1200 mg/d) for 12 weeks followed by CIFN
15 mg TIW and RBV (1000-1200 mg/d) for 36 weeks. Preliminary data from these studies suggested that 37% to 42% of patients with previous PEGIFN/RVN could achieve SVR with these high-dose daily CIFN treatment regimens. One of these studies has suggested that this approach may be particularly helpful in African Americans , a group with a significantly lower SVR to PEGIFN/RBV therapy . Based upon these single-center preliminary studies, a large, multicenter, clinical trial has been initiated in which CIFN (15 or 9 mg/d) plus RBV (1000-1200 mg/d) is being evaluated for the treatment of HCV patients with NR to previous PEGIFN/RBV therapy. Until this trial has been completed and this approach has been shown to have a positive impact, the use of high-dose daily CIFN along with RBV should be considered "off-label" and investigational.
Higher doses and longer duration of peginterferon and ribavirin
Another approach to the retreatment of patients who have NR to PEGIFN/RBV is to use these same agents but at a higher dose. In a preliminary study, patients with previous NR to IFN/RBV were retreated with 180, 270, or 360 mg of PEGIFNa-2a and RBV (1000-1200 mg/d). Although VR at the end of treatment was similar in all three groups, SVR increased stepwise from 21% to 46% in the highest PEGIFN dose group . The increase in SVRs observed with higher doses of PEGIFN/RBV was therefore the result a marked reduction in relapse after discontinuation of this therapy. These data have led to the initiation of multicenter trials in which higher doses of PEGIFN and RBV are being used in patients who have NR to previous treatment with PEGIFN/RBV.
It has been hypothesized that patients who relapse after treatment with PEGIFN/RBV may have not been treated long enough to achieve long-lasting viral suppression. Preliminary results from a treatment trial in which patients were randomized to receive 48 or 72 weeks of therapy has demonstrated that relapse was reduced from 48% to 13% in patients treated for a longer period of time . This study suggested that genotype 1 patients who relapsed after a standard course of PEGIFN/RBV may fare better if retreated for a longer period of time. The duration of retreatment and doses necessary to optimize SVR using this approach remains to be defined. In contrast, current data suggest that retreating patients with genotype 2 or 3 for a longer duration does not affect SVR because 24 and 48 weeks of therapy yield similar rates of SVR .
Peginterferon, ribavirin, and amantadine
Amantadine is an antiviral agent initially used for the treatment of influenza A . Over the past several years, studies have investigated the possible role of amantadine for the treatment of chronic HCV infection. Amantadine has been used alone , with IFN , and as triple therapy with IFN and RBV [61,62] as initial therapy and for retreatment of patients with previous NR. Although most of these studies have yielded conflicting results, a recent meta-analysis has demonstrated that SVR might be about 5% to 7% higher in patients who received amantadine as part of triple therapy compared with IFN/RBV . Preliminary reports evaluating amantadine, PEGIFN, and RBV triple therapy in patients with chronic HCV and previous NR remain inconclusive [64,65]. It is unclear what role amantadine will play in the management of patients who have failed to achieve SVR with PEGIFN/RBV.
It is well established that patients who achieve SVR have an improvement in liver histology, a reduction in hepatic fibrosis [66-68], a reduced risk for developing hepatocellular carcinoma [69,70], and prolonged survival [70,71]. In contrast, it is doubtful that patients with NR achieve such benefit. Although it does seem that some nonresponders can achieve histologic improvement, this is probably limited to patients with partial VR and a marked decline in serum HCV RNA from the pretreatment baseline level [66,67,72]. Furthermore, the improvement in liver histology associated with partial VR seems to be limited to changes in hepatic inflammation. An overall improvement in liver fibrosis has not been convincingly demonstrated to occur in patients with NR after a single course of IFN [66,72]. Although one study implied that marked regression in fibrosis may occur in some patients with NR, this is unlikely because an equal percentage of patients in this study had fibrosis progression, over 60% of patients had no change in fibro-sis, and the mean fibrosis scores from before and after treatment were not significantly different . It is therefore, most likely that sampling variation accounted for the improvement in fibrosis reported to occur in a subset of patients who had NR.
Fibrosis progression in patients who have chronic HCV is mediated by hepatic inflammation [73,74]. As a result, it is possible that a reduction in hepatic inflammation may reduce the rate of fibrosis progression or allow fibrosis to resolve. This hypothesis forms the basis for the concept of maintenance therapy.
Maintenance therapy using standard IFN was evaluated in a controlled trial of patients who achieved partial VR and a reduction in hepatic inflammation after an initial course of IFN therapy . These patients were randomly assigned to continue IFN for an additional 2 years or to stop treatment and be followed as a control group. Patients who remained on IFN (3 MU tiw) therapy maintained the initial reduction in serum HCV RNA and improvement in hepatic inflammation observed after initial therapy. In contrast, serum HCV RNA and hepatic inflammation returned to the pretreatrnent baseline in patients randomized to stop therapy. Changes in mean fibrosis scores after 2.5 years in these two groups of patients were small and not statistically significant. Nevertheless, these findings were encouraging and led to the initiation of a several large, multicenter clinical trials to investigate the possibility that long-term maintenance therapy using PEGIFN could prevent fibrosis progression, reduce hepatic decompensation, lower the incidence of hepatocellular carcinoma, reduce the need for liver transplantation, and improve survival in patients who have HCV with NR and advanced fibrosis or cirrhosis. The HALT-C trial is the largest and most well publicized of these studies .
Preliminary results from another trial of maintenance PEGIFN (CoPilot) have recently been reported . After 2 years of maintenance therapy (PEGIFNa-2b 0.5 mg/kg/wk), a significant reduction in the incidence of var-iceal hemorrhage was observed compared with patients treated with colchi-cine. No reduction in the incidence of liver failure, the development of hepatocellular carcinoma, the need for liver transplantation, or death was observed. This suggests that continuing PEGIFN as maintenance therapy may selectively reduce portal pressure but may not affect the natural progression of chronic hepatitis C in patients who have advanced fibrosis or cirrhosis.
Final results from the various clinical trials evaluating PEGIFN maintenance therapy will not be available for several years. Based upon available data, it is possible to consider maintenance therapy for patients with advanced fibrosis or stable cirrhosis who have relapsed after treatment with PEGIFN/RVN and who can tolerate the side effects of long-term treatment. Initiating PEGIFN at full dose and gradually tapering the dosage every 3 months to the lowest dose that maintains HCV RNA undetectable is a rational approach to patients with chronic HCV infection and advanced fibrosis or cirrhosis. In contrast, maintenance therapy should probably not be considered at this time in patients who have already developed complications of cirrhosis, in patients who do not achieve VR during treatment with PEGIFN and RBV, or in patients who do not remain HCV RNA undetectable with maintenance PEGIFN monotherapy. There are no data to suggest that patients who remain HCV RNA positive while on maintenance therapy achieve significant benefit from ongoing treatment.
One study has evaluated the benefit of continuing RBV as maintenance therapy in patients who have HCV with NR . Although RBV monotherapy does not reduce serum HCV RNA levels, serum alanine aminotransferase (ALT) declines significantly . This implies that RBV may act as an anti-inflammatory agent to reduce hepatic inflammation and serve as a basis for the use of RBV as maintenance therapy. In this pilot trial, 38 patients who had NR to IFN/RBV were randomized to discontinue IFN and remain on RBV (1000-1200 mg/d) or placebo. After discontinuation of IFN, serum HCV RNA levels rose back to the pretreatment baseline levels in both groups. Although mean serum ALT levels also rose after discontinuation of IFN, patients who remained on RBV had a lower mean serum ALT levels compared with placebo-treated patients. After 48 weeks of RBV maintenance therapy, repeat liver biopsy demonstrated that 47% of patients had a significant decline in inflammation, whereas this was not observed in the placebo group. Although no significant improvement in fibrosis was observed with RBV maintenance therapy, the decline in hepatic inflammation suggests that this approach could be useful for the management of patients who have HCV with NR. It remains unknown which subgroup of patients who have NR could benefit from RBV maintenance therapy and if this decline in inflammation could be maintained without suppressing serum HCV RNA levels. As a result, the use of RBV as maintenance therapy should be considered un-proven at this time.
Modifying lifestyle factors associated with fibrosis progression
Many patients with chronic HCV infection and NR to PEGIFN/RBV have no, mild, or moderate fibrosis. Many of these patients are not at risk for developing fibrosis progression to cirrhosis for 5 to 15 years or longer [73,79,80]. It is estimated that 25% to 33% of patients who have chronic HCV infection will never develop fibrosis. It is therefore rational for many patients who have chronic HCV infection to be observed at periodic intervals until definitive improvements in therapy have been established. During this period, a focus on modifying lifestyle factors that seem to enhance fibrosis progression seems rational.
Several studies have demonstrated that patients who have HCV who consume alcohol on a regular basis have an increased rate of fibrosis progression to cirrhosis and a higher percentage of cirrhosis than patients who consume ethanol rarely or not at alt [42,43,79,81,82]. The minimum amount of alcohol that seems to be safe and not associated with an enhanced rate of fibrosis progression in HCV patients remains undefined. It is therefore prudent to counsel HCV patients not to consume alcohol except on rare occasions.
Another factor that seems to be associated with more rapid fibrosis progression to cirrhosis is hepatic steatosis secondary to nonalcoholic fatty liver disease (NAFLD). Several recent studies have suggested that patients who have chronic hepatitis C and NAFLD, or more importantly nonalcoholic steatohepatitis, have more fibrosis and a higher prevalence of cirrhosis than patients who have HCV infection without fatty liver [83,84]. NAFLD is strongly associated with obesity, insulin resistance, and hyperlipidemia and seems to be improved by weight loss, improved control of diabetes mellitus, and lowering of serum lipids [85,86], Such recommendations are strongly encouraged for patients with chronic HCV infection and coexistent NAFLD.
Patients who have chronic HCV infection should be vaccinated to prevent other forms of viral hepatitis [87,88]. A recent study has demonstrated that patients with chronic hepatitis C who acquire acute hepatitis A virus (HAV) are at increased risk for developing fulminant hepatic failure . Although this same study did not find an increased risk of liver failure after acute infection with hepatitis B virus (HBV), patients coinfected with HCV and HBV seem to progress to cirrhosis at a faster rate . Because exposure to HAV is sporadic and cannot be predicted, it is recommended that all patients with chronic HCV infection be vaccinated against HAV [87,88]. In contrast, the great majority of adults with acute hepatitis B acquired this infection by participating in some sort of risk behavior, most commonly sexual activity or illicit drug use. It is not always possible to predict which HCV patients might indulge in these risk behaviors. As a result, vaccination of patients with chronic HCV and NR against HAV and HBV seems prudent.
The combination of PEGIFN and RBV is the most effective therapy for patients with chronic hepatitis C. Although more than half of all patients are able to achieve SVR, a significant proportion of patients, particularly those with genotype 1, fail to have undetectable HCV RNA during treatment or relapse after completing therapy with return of detectable HCV RNA. An approach in the management of these patients is to identify factors that could have led to the NR or relapse and that could be corrected before or during a second course of therapy. Because fibrosis progression occurs slowly over decades for many patients with chronic hepatitis C, avoiding alcohol or other factors that could lead to fibrosis progression may be sufficient for the vast majority of patients. Other options that could be considered in patients who have more advanced disease include retreating with one of several new antiviral agents; retreating with higher doses of IFN or PEGIFN and RBV; or using IFN, PEGIFN, or RBV monotherapy long-term as maintenance therapy. The safety and efficacy of these approaches is being evaluated in numerous clinical trials.
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