Approach to the Management of Patients with Chronic Hepatitis C Who Failed to Achieve Sustained Virologie Response

Amrita Sethi, MD, Mitchell L. Shiffman, MD*

Hepatology Section, Virginia Commonwealth University Medical Center, Box 980341, Richmond, VA 23298. USA

Therapy for chronic hepatitis C virus (HCV) infection has improved dramatically since interferon (IFN) was first introduced for treatment of non-A, non-B hepatitis over 15 years ago [1-3]. Historically, standard IFN monotherapy yielded a sustained virologic response (SVR) in less than 15% of patients. The addition of ribavirin (RBV) [4,5], and later the substitution of peginterferon (PEGIFN) for standard IFN [6-9], led to dramatic improvements in SVR rates, which can now be achieved in 45% to 50% of patients who have HCV genotype 1 and approximately 80% of patients who have genotypes 2 or 3 [10-12]. As each new improvement in HCV therapy has emerged, many patients who had failed to achieve SVR with previous, less effective therapy have been retreated. Recently, several large multicenter clinical trials have demonstrated the impact of retreating such patients with PEGIFN/RBV [13-16]. In the largest of these trials, 18% of patients who had a nonresponse (NR) after treatment with IFN or IFN/RBV achieved SVR after being retreated with PEGIFN/RBV. Certain subgroups, particularly those with previous relapse, HCV genotypes 2 and 3, without cirrhosis, or with low serum HCV RNA levels, faired better and seemed to be excellent candidates for retreatment (Table 1). In contrast, African Americans had a SVR of only 6%, and patients with multiple poor prognostic factors (HCV genotype 1, high serum HCV RNA levels, cirrhosis, and previous NR to IFN/RBV therapy) had poor SVR rates [13]. Given these findings, a thorough discussion regarding the pros and cons of retreatment should be

A version of this article originally appeared in the 8:2 issue of Clinics in Liver Disease. Supported by NIH contract N01-DK-9-2322.

* Corresponding author.

E-mail address: [email protected] (M.L. Shiffman).

0891-5520/06/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2006.01.002 id.theclinics.com

Table 1

Response to retreatment with peginterferon and ribavirin in patients who failed to achieve sustained virologic response after treatment with interferon and ribavirin

Sustained virologic response

Prior relapse to IFN/RBVa 40-50%

Prior nonresponse to 1FN or IFN/RBVb Race Caucasian African American Genotype 1

non-1

Serum HCV RNA level: <l.5 million IU/mL >1.5 million IU/mL Cirrhosis Yes No

Abbreviations: IFN, interferon; RBV, ribavarin. a Data from Ref. [14]. b Data from Refs. [13-15].

undertaken with each patient who failed to achieve SVR with IFN or IFN/ RBV.

The majority of patients who have received therapy for chronic hepatitis C have been treated with PEGIFN/RBV as initial therapy or as retreatment after previous NR or relapse. No alternative with proven superiority is available for patients who have failed to achieve SVR after treatment with PEGIFN/RBV. Although the management of these patients represents a formidable challenge, several approaches are available that have the potential to yield SVR during retreatment or reduce the rate of disease progression. This article outlines an approach for managing patients who have failed to achieve SVR and reviews preliminary results of promising new therapies for these patients.

Identifying reasons for treatment failure

A number of factors may have contributed to the development of relapse or NR during previous therapy with PEGIFN and RBV. One possibility is that the patient was responding to treatment, had a marked decline in serum HCV RNA, and achieved early virologic response (EVR) or became HCV RNA undetectable (ie, the patient had a virologic response [VR], but this response was not recognized by the treating physician who subsequently discontinued therapy). Another possibility is that the physician significantly reduced the dosage of PEGIFN or RBV in the first several months of instituting treatment in response to the development of various side effects

related to these medications. Finally, the patient may have been participating in behaviors that reduced the effectiveness of therapy. We refer to these three categories as ''correctable factors''; the most important aspect of assessing a patient who has NR is to look for these factors because they can often be corrected before or during retreatment (Box 1). The successful correction of one or more of these factors has the potential to result in SVR during retreatment.

Failure to recognize virologic response

The use of testing for HCV RNA is essential to the diagnosis of HCV infection and to monitoring patients during therapy. Three basic methods are available to assess serum HCV RNA: polymerase chain reaction (PCR), branched chain DNA (b-DNA), and transmission mediated amplification (TMA). These assays, their limitations, and the proper manner by which virologic assays should be used to monitor HCV RNA during therapy were recently reviewed [17]. VR cannot be identified and patients cannot be appropriately monitored if the various HCV RNA response patterns that occur during therapy are not recognized. The definitions of VR were

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