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Successful hepatitis C treatment with twice-weekly PEG-IFN, RBV in patient failed to standard therapy

Issue: August 2013

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More than 170 million individuals worldwide are infected with hepatitis C virus. In the United States, more than 3 million individuals are chronically infected with HCV and 15,000 to 20,000 additional people acquire HCV each year.

According to published data, the incidence of sustained virological response (SVR) after 6 months of completing the standard therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) is 70% to 90% for HCV patients infected with the genotype-2 virus. The failure of the 10% to 30% has been attributed to noncompliance or viral level rebound in between IFN doses. Some studies have attempted to use high induction doses of PEG-IFN along with RBV at the beginning of each week to prevent the end-of-the-week rebound phenomenon. These efforts, however, failed to improve the SVR rates. Other researchers have investigated the use of twice-weekly dosing of IFN along with RBV. This method has shown to be more efficacious compared with standard therapy in patients with HCV viral rebound.

Roula Baroudi

Edward Grace

To our knowledge, this is the first known case report in the United States of a patient with HCV genotype-2 who was treated with twice-weekly PEG- IFN and RBV who achieved SVR after failing standard therapy.

Case report

The patient is a 46-year-old male who was evaluated in 2008 by the infectious diseases clinic for consideration of HCV treatment. At that time, the decision was made to defer therapy due to the patient’s ongoing alcohol use. In October 2009, the patient was re-evaluated after being abstinent from alcohol for approximately a year (a prerequisite for therapy at the institution involved) and was sent for a liver biopsy to determine whether HCV therapy was warranted. The liver biopsy showed grade 3 inflammation along with stage 2 fibrosis based on the Batts-Ludwig system for hepatic grading and staging.

Further serology testing revealed the patient was infected with the HCV genotype-2b virus. Liver function tests were within normal limits, and the HCV viral load was 8,573,694 copies/mL. Other hematological examinations revealed a normal hemoglobin and white cell count, but a low platelet count of 146,103/mcL. The patient was started on the standard HCV therapy that consisted of 180 mcg pegylated interferon alpha-2a (PEG-IFN-A2A) administered subcutaneously once weekly in addition to 400 mg RBV orally twice daily for 24 weeks.

As shown in Figure 1, liver biopsy using Masson Trichrome shows portal fibrosis with peripheral extension. Hematoxylin and eosin (H&E) stain of the liver shows portal chronic necroinflammatory activity, as shown in Figure 2.

Source: Baroudi R

The baseline HCV viral load before initiation of combination HCV therapy was 6,471,687 copies/mL. After 4 weeks of treatment, the patient failed to achieve a rapid virological response (RVR), which is defined as an undetectable HCV viral load after 4 weeks of combination therapy.

At 12 weeks of therapy, the patient’s HCV viral load was 5,602,598 copies/mL, which indicated that he failed to achieve an early virological response (EVR). An EVR is defined as a 2-log drop (99.9% decrease) in HCV viral load from baseline. Due to the failure to achieve EVR, the HCV treatment was stopped per national guidelines.

A liver biopsy using Masson Trichrome Stain shows portal fibrosis, as shown in Figure 3.

One month after stopping therapy, a new treatment approach was considered. The approach was based on available literature and optimized therapy in HCV patients who have failed standard therapy by utilizing a high dose of PEG-IFN-A2A. Administering 180 mcg PEG-IFN-A2A subcutaneously twice weekly in addition to the standard dose of RBV at 400 mg orally twice daily for a total of 24 weeks was discussed with the patient, who agreed to proceed. The baseline HCV viral load was 6,823,658 copies/mL (4 weeks after discontinuation of the conventional HCV therapy). The dose of RBV was gradually reduced to 200 mg twice daily due to treatment-induced anemia that was attributed to RBV therapy.

The patient achieved RVR after 4 weeks of dual therapy using twice-weekly PEG-IFN and 200 mg RBV twice daily. The patient subsequently completed the entire course of new therapy (24 weeks). An undetectable end of treatment viral load followed by a successful SVR at 12 and 48 months after therapy halted the progression of liver disease in this patient.

Patients who do not respond to therapy

The success rate of achieving SVR using a standard dose of PEG-IFN and RBV for 24 weeks in HCV genotype-2 patients has been shown to be more than 80%. Very few studies, however, address the retreatment of HCV genotype-2 nonresponders and relapsers.

In one study that examined the rate of SVR in HCV genotype-2 patients who were retreated with a combination of PEG-IFN and RBV for up to 48 weeks, only 23% of nonresponders achieved SVR. Similar results were demonstrated by a subsequent study that showed only 15% of nonresponders to a standard dose combination of PEG-IFN and RBV achieved SVR after 48 weeks of retreatment. Further analyses of these patients illustrated neither genotype nor degree of liver fibrosis affected the rate of SVR after the retreatment with both PEG-IFN and RBV. The only factor that correlated with achieving SVR was the ability to achieve EVR. The only other option for this patient was to use twice-weekly PEG-IFN-A2A combined with twice-daily RBV. The current combination has been used in a small group of studies and was based on older HCV pharmacokinetic models published in the 1990s.

Source: Baroudi R

Of the four main studies examining the use of twice-weekly PEG in HCV nonresponders and relapsers, two studies compared the use of PEG-IFN-A2A once weekly vs. twice weekly, whereas the other two studies utilized PEG-IFN-A2B. Several viral kinetics studies examined PEG-IFN-A2A and PEG-IFN-A2B serum pharmacokinetics, which have shown a biphasic decline in serum concentration levels with subtherapeutic levels occurring up to 72 hours before the next dose. Subtherapeutic PEG-IFN levels resulted in HCV viral rebound, which may help explain possible treatment failures. The plan to use a full dose of PEG-IFN-A2A twice weekly in our patient was supported by a previously published study. Two subsequent published studies have supported twice-weekly dosing in HCV genotype-1 patients.

The first study by Murphy and colleagues, published in 2011, compared the efficacy and safety of 180 mcg PEG-IFN-A2A per dose given once weekly vs. twice weekly combined with 1,000 mg to 1,200 mg of RBV per day for up to 48 weeks. In the studied population of 19 genotype-1 patients, the incidence of RVR, EVR and liver function tests normalization in the twice-weekly PEG-IFN-A2A arm was significantly higher than in the once-weekly PEG-IFN-A2A arm. However, the incidence of SVR did not differ between the two groups, and the researchers attributed this to the small sample size of the study.

The second trial was the SYREN trial that compared four different dosing regimens in genotype-1 nonresponders and rebounders. The four treatment arms consisted of placing the patients on either 360 mcg PEG-IFN-A2A once weekly or 180 mcg twice weekly combined with either 1,000 mg to 1,200 mg daily or 1,200 mg to 1,600 mg daily of RBV. All patients were treated for 48 weeks with the exception of a few patients who were treated for up to 72 weeks. Patients in all groups responded more favorably to therapy despite no statistical difference between the four arms with regard to achieving SVR. The authors of the study attributed the enhanced response to therapy to the presence of genetic variability between patients, especially in patients with the interleukin-28B mutation. Despite the inability to determine whether the presented patient had the IL-28B mutation, it is the authors’ opinions that the given patient was likely to harbor the IL-28B mutation, thus explaining his remarkable response to higher doses of PEG-IFN-A2A.

The current case supports possible success with using twice-weekly PEG-IFN-A2A in the retreatment of HCV genotype-2 patients who failed conventional therapy. SVR can be achieved by increasing the PEG-IFN-A2A dose even in the presence of a reduced RBV dose for the majority of the treatment duration. Such unconventional retreatment regimens can provide clinical success to some patients who failed to respond to conventional therapy. This second chance of achieving SVR will likely have a prolonged benefit to the patient by preventing progression of liver disease and secondary complications due to HCV infection.

Chronic problem

Hepatitis C is a chronic health issue requiring medications that may cause many side effects. Genotype-2 patients may not achieve SVR after combination therapy due to viral level rebound in between IFN doses. High doses of PEG-IFN-A2A given twice weekly in addition to the standard dose of RBV at 400 mg administered orally and twice daily for a total of 24 weeks has been demonstrated to be a successful alternative treatment in halting the progression of liver disease in HCV genotype-2 patients.

The documented success of this treatment makes it worthy of consideration in patients infected with HCV genotype-2 who have not responded adequately to standard dosing. Additional research is recommended in larger populations to evaluate the evidence of current practice and improved quality of life for these patients.

Disclosure: The authors report no relevant financial disclosures.