Authors: Jordan J. Feld, MD, MPH, Hemant Shah, MD, FRCPC
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Preview Of Topics
Goals of Therapy
In patients with chronic hepatitis C virus (HCV) infection, the goal of therapy is virologic cure. Eradication of HCV RNA, which persists long-term off therapy, is referred to as a sustained virologic response (SVR). Although SVR is equivalent to virologic cure, the term cure has traditionally been avoided. Initially, there was concern that despite undetectable HCV RNA following treatment, there might potentially be dormant virus that could return in the future. However, long-term follow-up data show that patients with an SVR following treatment with peginterferon and ribavirin have a relapse rate < 1% after a mean of 1.8 years from the end of antiviral treatment.....
Types of Therapy
Combination therapy is necessary to optimize hepatitis C virus treatment response rates. Currently recommended treatment options include pegylated interferon, ribavirin, and (for patients with genotype 1 HCV infection) the protease inhibitors boceprevir and telaprevir.
Several factors must be considered when deciding to treat a patient with hepatitis C virus (HCV) infection, including stage of disease, natural history, treatment efficacy, the potential for adverse events, and response to previous treatment. In general, all patients with histologic and serologic evidence of HCV infection should be considered as treatment candidates
A thorough patient history should be obtained before prescribing hepatitis C virus (HCV) therapy. Several issues need to be explored to aid decision-making, including the patient’s medical history, socioeconomic status, and any psychiatric comorbidities.
Table covers-cardiac history, thyroid history, autoimmune history and more.
A thorough physical examination is necessary before initiating hepatitis C virus (HCV) therapy This is partly to identify health issues that need to be addressed before therapy, but it also is to serve as a baseline for comparison once therapy is initiated.
Pretreatment laboratory testing is essential in patients commencing hepatitis C virus (HCV) therapy and serves to rule out coexistent liver disease, ensure safety parameters before therapy, and aid in posttreatment monitoring
Role of Liver Biopsy and Noninvasive Tests in Determining Fibrosis
An assessment of hepatic fibrosis is needed before commencing hepatitis C virus (HCV) therapy and selected noninvasive markers commonly used in the setting of hepatitis C are summarized
The degree of fibrosis has an impact on treatment duration and response. In addition, cirrhotic patients should be surveyed for hepatocellular carcinoma even if they go on therapy and ultimately achieve sustained virologic response. Until recently, most patients with HCV had liver biopsies to assess fibrosis. However, there are now several other modalities available to assess fibrosis by noninvasive means. In many patients, the use of noninvasive measures for hepatic fibrosis assessment is sufficient.
Pretreatment Optimization of the Cirrhotic Patient
Although cirrhotic patients have lower response rates to hepatitis C virus (HCV) therapy than noncirrhotic patients, achievement of sustained virologic response in this group has a marked effect on the risk of liver-related mortality.
Therapeutic Regimens: Which Therapy for Which Patient?
Non–Genotype 1 Patients
For non–genotype 1 patients, standard-of-care hepatitis C virus (HCV) therapy is a combination of peginterferon alfa-2a or peginterferon alfa-2b and ribavirin
Genotype 1 Patients
For patients with genotype 1 HCV, standard-of-care treatment is now a triple-therapy combination of peginterferon alfa-2a or peginterferon alfa-2b, ribavirin, and a protease inhibitor (either boceprevir or telaprevir). Recommended dosing for ribavirin is weight-based only according to the guidelines used for the peginterferon of choice. ©2003-2011 Clinical Care Options, LLC. All Rights Reserved.
Peginterferon and Ribavirin
Monitoring and Determining Treatment Efficacy With Peginterferon/Ribavirin Dual Therapy
Boceprevir (Genotype 1 Only)
Telaprevir (Genotype 1 Only)
Any discussion of treatment efficacy must be considered according to hepatitis C virus (HCV) genotype, the most important determinant of treatment outcome with interferon-based therapy. Genotype 1 is the least interferon-responsive HCV genotype and has therefore been the primary focus for the development of direct-acting antiviral agents (DAAs). First-generation DAAs were specifically developed for genotype 1 HCV, and although telaprevir and boceprevir may have some efficacy against other genotypes (particularly genotype 2), they are only approved for use in genotype 1 infection.
Using Protease Inhibitors
Pretreatment Predictors of Response
This section provides practical information about using approved protease inhibitors (PIs) in patients with hepatitis C virus (HCV) infection
Note that the approved indications for use of telaprevir and boceprevir in Europe differ somewhat from those approved by the US FDA
On-Treatment Predictors of Response
Once hepatitis C virus (HCV) treatment is started, initial viral kinetics are helpful in predicting treatment outcome. Patients who have cleared viremia by Week 4 of therapy, whether with protease inhibitor (PI)–based triple therapy or with peginterferon/ribavirin alone, are very likely to achieve sustained virologic response (SVR). By contrast, those who still have detectable HCV RNA levels by Week 12 of therapy have very low likelihood of obtaining SVR
Protease Inhibitor Resistance
Mechanisms of Resistance
Significance of Resistance
Current Understanding of Protease Inhibitor Resistance
Prevention of Resistance
The development of direct-acting antiviral agents (DAAs) has been a major therapeutic advance in the treatment of hepatitis C virus (HCV) infection, but it has also introduced new challenges. True viral resistance to peginterferon and ribavirin has not been described (although host resistance to interferon is well characterized). By contrast, resistance-associated variants have been identified for all DAAs and have been shown to emerge rapidly with the use of DAA monotherapy. This section will discuss resistance to telaprevir and boceprevir.
Adverse Effects and Management Strategies
Protease Inhibitors: Boceprevir and Telaprevir
The use of either peginterferon/ribavirin dual therapy or in combination with direct-acting antiviral agents can lead to significant adverse effects that necessitate dose reduction or discontinuation of treatment. Early recognition and intervention can help clinicians ensure patients are able to complete therapy where possible and achieve the goal of viral eradication. Although every patient will experience adverse effects to differing degrees, a systematic approach to their management can be very helpful.
Sustained virologic response (SVR) is determined with measurement of HCV RNA using a highly sensitive assay 24 weeks following the end of treatment. For patients who obtain an SVR and do not have cirrhosis, no long-term monitoring is necessary. In some centers, such patients undergo hepatitis C virus (HCV) RNA testing 1 year after completion of treatment to confirm that HCV RNA remains undetectable.
For patients who obtain an SVR and have cirrhosis, long-term follow-up is required
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