Boceprevir benefits null, partial responders to prior HCV therapy with peginterferon/ribavirin

Provided by Healio

June 4, 2013

ORLANDO, Fla. — Therapy with boceprevir in addition to pegylated interferon and ribavirin led to high sustained virologic response rates in patients with hepatitis C who failed previous interferon-based treatment in a study presented at Digestive Disease Week.

In the single-arm, open-label, multicenter roll-over PROVIDE study, researchers randomly assigned 168 patients with chronic HCV genotype 1 to 800 mg boceprevir three times daily, in addition to a standard dose of peginterferon alfa-2a and weight-based ribavirin (PR), for up to 44 weeks. All participants had been in control arms of prior phase 2 and 3 boceprevir studies and had experienced relapse or null or partial response to PR (51% partial responders, 31% null responders and 17% relapse responders, with 1% not classifiable).

Patients enrolled more than 2 weeks after their previous therapy also received a 4-week lead-in with PR alone (n=156). Four patients discontinued treatment during this period, leaving 164 boceprevir recipients for analysis.

Sustained virologic response (SVR) at 24 weeks occurred in 41% of null responders, 67% of partial responders and 96% of relapsers in final analysis, for an overall SVR rate of 65%. Relapse occurred in 13% of null responders, 15% of partial responders and no relapsers (11% average rate). Most patients who experienced SVR were men, not of black race, and had viral loads of 800,000 IU/mL or lower upon initiation. SVR rates were similar among those with HCV genotype 1a and 1b, and poorer among patients with platelet counts less than 200,000.

Commonly reported adverse events included anemia (49% of cases), dysgeusia (35%) and neutropenia (23%), and the safety profile was similar to previous studies. Eight percent of the cohort discontinued treatment because of adverse events.

“Overall, the data of this final analysis led to the conclusion that boceprevir combined with peginterferon/ribavirin therapy is efficacious in subjects with all three categories of nonresponse: relapsers, partial responders; and, most importantly, null responders,” researcher John M. Vierling, MD, professor of medicine and surgery, director of Baylor Liver Health and chief of hepatology at Baylor College of Medicine in Houston, said.

Disclosure: The researchers report numerous financial disclosures.

For more information:

Vierling JM. 869c: Sustained Virologic Response (SVR) in Prior PegInterferon/Ribavirin (PR) Treatment Failures After Retreatment With Boceprevir (BOC) and PR: Final Results of the PROVIDE Study. Presented at: Digestive Disease Week 2013; May 18-21, Orlando, Fla

Source

Standardization of Terminology of Virological Response in the Treatment of Chronic Hepatitis C

From Journal of Viral Hepatitis

Panel Recommendations

M. Jacobson; F. Poordad; R. S. Brown Jr; P. Y. Kwo; K. R. Reddy; E. Schiff

Posted: 05/03/2012; J Viral Hepat. 2012;19(4):236-243. © 2012 Blackwell Publishing

Abstract and Introduction

Abstract

Summary. The treatment paradigm for hepatitis C virus (HCV) infection is at a critical point in its evolution. The addition of a protease inhibitor to peginterferon plus ribavirin has become the new standard-of-care treatment for most patients. Data from clinical trials of new antivirals have been difficult to interpret and compare, partly because of heterogeneity in trial design, and partly because of inconsistencies in terminology used to define viral responses and the populations evaluated. Present definitions of viral responses for treatment with peginterferon and ribavirin are insufficient for novel treatment paradigms. Further, categorization of prior patient treatment experience in clinical trials, particularly of nonresponders to prior therapy, is inconsistent. Existing terms and definitions must be updated, standardized and/or redefined for easier interpretation of data and effective communication among clinicians. A panel of experts in HCV infection treatment met on 3 December 2009. Goals of the panel were to evaluate terms and definitions used traditionally in treatment with peginterferon and ribavirin, to refine and clarify definitions of existing terms that have varying meanings and to propose new terms and definitions appropriate for novel treatment paradigms emerging with development of new agents. A number of recommendations were accepted unanimously by the panel. Adoption of these terms would improve communication among investigators, enhance comparability among clinical trials, facilitate development of therapeutic guidelines and provide a standardized terminology for use in clinical practice.

Introduction

Over the past decade, the standard of care for the treatment of infection with HCV – 48 weeks of peginterferon alfa-2a or 2b plus ribavirin – yielded overall sustained virological response (SVR) rates of 42–46%.^[1,2] The recent approval of direct-acting antiviral agents (DAA), such as the protease inhibitors telaprevir and boceprevir, represent a new standard of care for treatment-naïve and experienced patients. Many other DAAs are in development as well.

Not unexpectedly, these new agents have brought with them novel study designs, patient categorizations and treatment paradigms, which has led to some confusion over the terminology used at scientific meetings and in published articles, especially for terms relating to on-treatment virological response. The desirability of a standardized set of terms to allow comparisons between clinical trials led to the roundtable discussion among the investigators described herein. The purpose of the discussion was to evaluate, refine and standardize the definitions of existing terminology and to propose, where necessary, new terms and definitions appropriate for the novel treatment paradigms resulting from the next generation of antiviral agents.

Diagnostic Precision of Hepatitis C Virus RNA Assays

When seeking to apply standardized terminology that focuses on the presence, absence or degree of virological response experienced in patients with HCV, it is important to consider the diagnostic tests used to detect and quantify viral load. Previous qualitative HCV assays (e.g. Roche HCV Amplicor 2.0, Pleasanton, CA, USA) that measured viral load using endpoint polymerase chain reaction (PCR) have been replaced by quantitative assays that utilize real-time PCR (e.g. Roche COBAS TaqMan, Pleasanton, CA, USA; Abbott Realtime HCV RNA, Des Plaines, IA, USA) and transcription-mediated amplification technology (Quest Diagnostics Heptimax, Madison, NJ, USA). These newer commercial assays allow for the more accurate representation of HCV RNA levels given their high sensitivity, broad dynamic range and improved lower limits of detection (Table 1).^[3–7] Given these differences, it is important to consider which HCV RNA assay is being used when utilizing the nomenclature or making cross-study comparisons of efficacy.

Table 1. Commercially available diagnostic assays for HCV^3–7

 

Diagnostic assay*	Lower limit of detection (IU/mL)	Dynamic range of quantitation (IU/mL)
Roche HCV Amplicor 2.0	50	600–500 000
Roche COBAS TaqMan 2.0 HCV	10	25–390 000 000
Abbott Realtime HCV RNA	12	12–100 000 000 begin_of_the_skype_highlighting 12–100 000 000 end_of_the_skype_highlighting
Quest Diagnostics Heptimax	5	5–69 000 000

HCV, hepatitis C virus. *The COBAS Ampliprep is often used for sample preparation (i.e. automated vs manual RNA extraction) in conjunction with the listed diagnostic assays.

Current Terminology in the Context of Novel Therapies

In the two decades since the advent of interferon-based therapy for hepatitis C, investigators have developed terminology to characterize patient response to treatment. The term 'SVR' has been defined as being HCV RNA negative 6 months following treatment cessation. This became the standard endpoint for clinical trials and, given exceedingly low rates of relapse after that time point, has been interpreted as a 'cure'.^[8] Other terms are associated with specific milestones in viral response that have been shown to be predictive of eventual SVR and are listed in Table 2.^[8]

Table 2. Current definitions for virological response⁸

 

Virological response	Definition	Clinical utility
Rapid virological response (RVR)	HCV RNA negative at treatment week 4 by a sensitive PCR-based quantitative assay	May allow shortening of course for genotype 2 and 3 and possibly genotype 1 with low viral load
Early virological response (EVR)	≥2 log reduction in HCV RNA level compared with baseline HCV RNA level (partial EVR) or HCV RNA negative at treatment week 12 (complete EVR)	Predicts lack of SVR
End-of-treatment response (ETR)	HCV RNA negative by a sensitive test at the end of 24 or 48 weeks of treatment
Sustained virological response (SVR)	HCV RNA negative 24 weeks after cessation of treatment	Sustained clearance or cure
Breakthrough	Reappearance of HCV RNA in serum while still on therapy
Relapse	Reappearance of HCV RNA in serum after therapy is discontinued
Nonresponder	Failure to clear HCV RNA from serum after 24 weeks of therapy
Null responder	Failure to decrease HCV RNA by >1 log10 at 4 weeks or >2 log10 at 12 weeks of therapy
Partial responder	2-log10 decrease in HCV RNA, but still HCV RNA positive at week 24

HCV, hepatitis C virus; PCR, polymerase chain reaction.

The existing terminology has, for the most part, proved adequate for use in the development of study designs, communication of results and patient management in the context of peginterferon and ribavirin treatment. However, with new treatment paradigms and the introduction of new terms in recent studies of novel drugs, limitations of the current terminology have become apparent.

One example of this new terminology involves phase 3 studies of the protease inhibitor telaprevir, in which treatment-naïve patients evaluated response-guided therapy, with HCV RNA levels measured at weeks 4 and 12 (Fig. 1a,b). Patients with undetectable levels at each time point were said to have achieved 'extended rapid viral response' (eRVR),^[9,10] which was required to stop therapy after a 24-week course instead of the 48-week course non-eRVR patients received.

Figure 1. (a) ADVANCE and (b) ILLUMINATE study design. eRVR, extended rapid viral response (undetectable hepatitis C virus RNA at week 4 and week 12); PEG, peginterferon alfa-2a; RBV, ribavirin; TVR, telaprevir.

Lead-in dosing with peginterferon and ribavirin, used in the phase 3 development programme for boceprevir and incorporated into its approved treatment regimen, also poses particular terminological challenges because of potential ambiguity in designating response at various time points (Fig. 2a,b).^[11,12] In the phase 3 SPRINT-2 trial, rapid virological response (RVR) criteria differed from the standard used in peginterferon/ribavirin trials: HCV RNA negativity by PCR after 4 weeks of peginterferon plus ribavirin treatment.^[12] Instead, the SPRINT-2 trial criterion for the equivalent of 'RVR' was HCV RNA negativity at week 4 of boceprevir treatment, which was overall treatment week 8. For patients who achieved this milestone and remained negative at treatment week 24, all therapy was stopped. Meanwhile, patients with detectable HCV RNA at week 4 of boceprevir treatment to week 20, yet had undetectable HCV RNA at week 24, continued to receive peginterferon plus ribavirin alone for a total treatment duration of 48 weeks (Fig. 2b).^[12] Thus, referring to response at week 4 of boceprevir as RVR may be confusing because that term refers to response at week 4 of treatment overall.

Figure 2. (a) SPRINT-1 and (b) SPRINT-2 study design.^11,12 Patients in all arms were followed for 24 weeks after the end of treatment. Lead-in = peginterferon alfa-2b (1.5 μg/kg/week) + ribavirin (800–1400 mg/day) for 4 weeks. BOC, boceprevir; PEG, peginterferon alfa-2b; RBV, ribavirin; TID, 3 times daily; 4/24/48, 4-week/24-week/48-week treatment duration; TW, treatment week.

With such challenges in mind, the panel proposed recommendations for terminology to be used in the reporting of clinical data pertaining to the treatment of chronic HCV infection, particularly data generated from studies of the new antiviral agents

Recommendations

Terminology for New Treatment Paradigms in Development

Two general terms have been widely used to describe new antiviral agents for the treatment of HCV infection. One is 'specifically targeted antiviral therapy for hepatitis C' (STAT-C), and the other is 'DAAs'. While STAT-C has appeal from the standpoint of pronunciation and specificity for the context of HCV therapy, the term 'DAA' has been adopted by the European Medicines Agency (EMEA) as its term of choice.^[13] The US Food and Drug Administration has also used 'DAA' in the HIV arena and, more recently, in the HCV arena.^[14] In recognition of the need to align with the terminology that appears likely to be adopted by regulatory agencies and others, the panel supports the future use of 'DAA'.

Terminology Relating to Treatment Experience

While the panel agreed that the term 'treatment naïve' is clear, 'treatment failure' was the subject of some debate. First, it does not adequately describe patients who stop therapy for reasons other than lack of response, such as discontinuation of treatment because of adverse events. Second, patient advocates argue that the word 'failure' should be avoided because of its pejorative connotations. While an alternative term 'treatment experienced' was discussed by the panel, it was decided to be too vague with regard to prior treatment success/failure. Therefore, the panel recommended that the term 'treatment failure' be retained but that physicians remain aware that this term may be perceived to have a negative connotation by patients or their families.

Recommendation 1: The terms 'treatment naïve' and 'treatment failure' should be retained in their current usages. The term 'treatment failure' may be refined with specific information about the nature of the failure (e.g. the regimen on which the patient failed and the nature of the failure – relapse, nonresponse and premature discontinuation for adverse events).

Definitions of Response

Sustained Virological Response The most common primary endpoint for clinical trials is SVR, which is defined as undetectable HCV RNA at 24 weeks after the end of treatment. Panel members felt that adding a number to the end of the acronym to represent the time of last-confirmed viral negativity, as has already been adopted in some presentations, would provide added clarity (e.g. SVR12 would stand for viral negativity at week 12 post-treatment). This may be important as the duration of therapy continues to shorten and late relapse may be seen beyond 24 weeks. The panel believes that a minimum follow-up period of 12 weeks is required before any terminology related to 'SVR' is used.

Recommendation 2: SVR is defined as undetectable HCV RNA levels at 24 weeks post-treatment. The term may be modified by adding a number to the end to indicate the time of the last documented negative HCV RNA result (e.g. SVR12 would mean negative HCV RNA levels at 12 weeks post-treatment).

End-of-treatment Response End-of-treatment response has been defined previously as HCV RNA negativity at the completion of treatment. The panel supported the continued use of this definition and agreed that the abbreviation 'end-of-treatment response' (ETR) is most appropriate.

Recommendation 3: An ETR is defined as undetectable HCV RNA levels at the end of treatment regardless of treatment duration.

Rapid Virological Response and Complete Early Virological Response Rapid virological response is generally defined as undetectable HCV RNA using a sensitive PCR assay at week 4 of therapy, while a complete early virological response (EVR) is defined as undetectable HCV RNA at week 12 of therapy. To simplify the nomenclature, the panel suggested that a new term be established: complete virological response (CVR), defined as an undetectable level of HCV RNA while the patient is still on treatment. To clarify the time point at which a patient achieves CVR, a number can be added to indicate the week of treatment (e.g. CVR4 and CVR12). Under this scheme, the term RVR will be replaced by CVR4, and complete EVR will be replaced by CVR12. These new terms will be very relevant to clinical studies of the DAAs, because in many trials complete viral suppression within a certain time frame will be required to allow continuation of therapy. Given the central role accorded 'extended' RVR (eRVR, attainment of RVR with maintenance of HCV RNA undetectability at subsequent time points) in studying response-guided therapy in major DAA trials to date, the term CVR allows for greater precision because it may be followed by a designation of the weeks at which HCV undetectability is required to have been demonstrated. Thus, HCV RNA undetectability at weeks 4 and 12 would be designated 'CVR4,12', while its undetectability at multiple time points, for example, weeks 4, 12, 16, 20, could be designated 'CVR4–20'.

Recommendation 4: A complete virological response (CVR#) is defined as an undetectable HCV RNA level during treatment, where # is the total treatment week at which time a negative HCV RNA level is first documented. CVR4 should thus replace the term 'RVR', and CVR12 should replace the term 'complete EVR'. The term eRVR should be replaced by CVR at the intended time points, starting with the first time point at which HCV RNA became undetectable.

Partial Early Viral Response and Partial Responder The panel agreed that that the term partial EVR has been a useful clinical tool. Clinicians have typically stopped peginterferon/ribavirin treatment for patients who fail to achieve at least a partial EVR because their likelihood of achieving an SVR is extremely low, but patients who do achieve a partial EVR still have a chance for SVR and may benefit from an extended treatment period. A partial responder has usually been defined as a patient who achieves at least a 2-log₁₀ decline in HCV RNA level at treatment week 12 but who does not achieve an undetectable viral level by the end of treatment. However, this does not specify the duration of therapy to which the term applies. The panel proposed that the terms 'partial EVR' and 'partial responder' be supplanted by the more precise term 'partial virological response' (PVR), defined as a 2-log₁₀ decline in HCV RNA level with detectable viraemia at a given treatment week. A number can be added to indicate the first or any subsequent treatment week at which the latest HCV RNA level was documented (e.g. PVR12). Using this nomenclature, the term 'partial EVR' is replaced by 'PVR12'. A partial response that persists to a subsequent time point can be designated by the addition of a second number, for example, a partial response that occurred at week 12 and persisted to week 24 could be designated as PVR12, 24. Note that the designation of PVR# can be adapted to novel treatment regimens using other criteria for degree of viral decline that may be more suitable in the context of such therapies.

Recommendation 5: A partial response (PVR#) is defined as a ≥ 2-log₁₀ decrease in HCV RNA level but with detectable viraemia at treatment week #. A 'partial EVR' on peginterferon and ribavirin should be referred to as a PVR12.

Slow responder The term 'slow responder' has been used to describe a patient with detectable viraemia at treatment week 12 (generally with at least a 2-log₁₀ decline) and whose HCV RNA level is undetectable at treatment week 24. Studies have suggested that extending therapy to 72 weeks can increase the chance of SVR in such patients.^[15–17] However, some studies evaluating prolongation of extended therapy have used different criteria, such as failure to attain HCV RNA undetectability by week 4^[18] or initial undetectability at week 12 after HCV RNA was positive at week 8.^[19] The panellists decided there was no need for a term that is open to various interpretations when the time point can be specified in the term itself. The proposed term CVR24 clearly indicates that the first documentation of an undetectable HCV RNA level occurred at treatment week 24. In this context, a 'slow responder' would be referred to as 'PVR12, CVR24'. This terminology can be readily adapted to the study of other time points for initial HCV RNA undetectability as a determinant of treatment duration.

Recommendation 6: Use the term 'CVR24' to indicate the initial attainment of a complete response by treatment week 24 instead of 'slow responder'.

Nonresponder The panel agreed that the term should be defined as a patient who never achieved an undetectable (i.e. CVR) level of HCV RNA during or at the end of treatment.

Recommendation 7: A nonresponder is defined as any patient who never achieved undetectable serum HCV RNA level on treatment or at the end of treatment.

Null Responder The historical definition of a null responder has been either a patient who achieves less than a 1-log₁₀ decline in HCV RNA level at treatment week 4 or one who achieves less than a 2-log₁₀ decline in HCV RNA at treatment week 12. The panel proposed using the term 'null response' (NuR) followed by a number indicating the last time point of evaluation, with the following definitions:

Recommendation 8: NuR is defined as:

• NuR4 = <1-log₁₀ decline in HCV RNA level at treatment week 4.
• NuR12 = <2-log₁₀ decline in HCV RNA level at treatment week 12.

The patient should be categorized by last time point of evaluation. When used in clinical trials on retreatment, study investigators should define patients' degree of exposure to prior treatment. The use of these terms allows for additional refinement of patient groups. Thus, the term NuR4PVR12 denotes a patient with <1-log decline in HCV RNA at treatment week 4 but a ≥ 2-log decline by week 12.

Breakthrough and Viral Rebound The panel noted that there has been much confusion about the precise definition of the terms 'breakthrough' and 'viral rebound'. In the past, both 'breakthrough' and 'viral rebound' have been defined as greater than a 1-log₁₀ increase in HCV RNA from nadir and a minimum level of 1000 IU/mL. Others have used the term 'breakthrough' to indicate at least a 2-log₁₀ increase in HCV RNA level from nadir and a minimum level of 50 000 IU/mL. Still another definition of 'breakthrough' has been a greater than 1-log₁₀ increase in HCV RNA from nadir or an increase to >100 IU/mL, provided that the HCV RNA level had been undetectable at some point during treatment. The panel suggested that the key difference between the terms 'breakthrough' and 'rebound' is whether the patient has achieved HCV RNA negativity (a CVR) at any point on treatment. A patient who has had a CVR on treatment but then becomes viraemic would fall into the category of breakthrough, but a patient who has had a decline in HCV RNA levels that stops short of a CVR and then experiences a rise in HCV RNA level would fall into the category of viral rebound.

Recommendation 9: Breakthrough is defined as the on-treatment presence of detectable HCV RNA on 2 consecutive serum tests conducted after a previous on-treatment serum test showed an undetectable level of HCV RNA with a real-time quantitative PCR or similarly sensitive test. The HCV RNA level must be at least 100 IU/mL on the second positive serum test.

Recommendation 10: Viral rebound is defined as an on-treatment 1-log₁₀ increase in HCV RNA level from nadir and an absolute level of at least 1000 IU/mL in a patient who has not achieved an undetectable HCV RNA level during the current treatment regimen.

Terminology for Agents Utilizing the Lead-in Strategy

There was much discussion among the panel members about clarifying the terminology for the lead-in strategy. There was a consensus that the language must facilitate comparisons of clinical trial results among various agents, both those that are dosed with and without a lead-in strategy of peginterferon and ribavirin alone. Further, it was unanimously agreed that the new terminology should not create the misperception that treatment begins with the initiation of the targeted antiviral; the panel was definitive that treatment begins at the start of the lead-in period. It was agreed that the abbreviation Li4 (lead-in 4) before an abbreviation for response (e.g. Li4-CVR8) would be a clear way to indicate the exact time point during treatment at which the HCV RNA test was conducted. Another example of defining patterns of response using the terminologies proposed in this manuscript would be the term Li4-NuR4 (see 'recommendation 8'). This would indicate that at the end of a 4-week lead-in phase, the patient has had <1 log decline in HCV RNA. To stratify treatment outcomes between patients with intrinsically poor vs better interferon responsiveness, one could apply the terms Li4-NuR4 or Li4-R4, where the latter denotes a ≥ 1 log decline in HCV RNA after 4 weeks of lead-in therapy.

Recommendation 11: The abbreviation Li4 should be added as a prefix to on-treatment response terminology when the clinical study utilizes the lead-in strategy in which patients receive 4 weeks of treatment with peginterferon and ribavirin before the addition of the DAA to the regimen. Under this system, Li4-CVR8 would indicate an undetectable level of HCV RNA at triple therapy week 4 and total treatment week 8. As another example, Li4-CVR8, 24 would indicate an absence of detectable HCV RNA at total treatment weeks 8 and 24 after 4 weeks of lead-in therapy followed by the addition of a protease inhibitor, as is currently required to stop all therapy at total treatment week 28 in a response-guided therapy regime containing boceprevir. Finally, Li4-NuR4 would indicate a failure of HCV RNA to decline by at least 1 log after 4 weeks of lead-in therapy.

A summary of recommended terminology, with definitions, is presented in Table 3.

 

Table 3. Summary of recommendations for updated terminology

Term	Definition
Treatment failure	Patient who failed to achieve sustained virological response
Sustained virological response (SVR)	Undetectable HCV RNA level at 24 weeks post-treatment
End-of-treatment response (ETR)	Undetectable HCV RNA level at end of treatment regardless of treatment duration
Complete virological response (CVR); number at end represents week at which HCV RNA negativity is noted	Undetectable HCV RNA level during treatment CVR4 should replace the old term RVR CVR12 should replace the old term cEVR CVR24 should replace the old term slow responder CVRx,y or x-y should replace the term eRVR
Partial virological response (PVR)	≥2-log10 decrease in HCV RNA level but with detectable viraemia at treatment week no. PR12 should replace the old term pEVR
Nonresponder	Any patient who never achieved undetectable serum HCV RNA level on treatment or at the end of treatment
Null response (NuR)	NuR4 = <1-log10 decline in HCV RNA level at treatment week 4 NuR12 = <2-log10 decline in HCV RNA level at treatment week 12
Breakthrough	On-treatment presence of detectable HCV RNA on two consecutive serum tests conducted after a previous on-treatment serum test showed an undetectable level of HCV RNA with a real-time quantitative PCR or similarly sensitive test. The HCV RNA level must be at least 100 IU/mL on the second positive serum test
Viral rebound	On-treatment 1-log10 increase in HCV RNA level from nadir and an absolute level of at least 1000 IU/mL in a patient who has not achieved an undetectable HCV RNA level during the current treatment regimen
Lead-in 4 (Li4)	The abbreviation Li4 should be added as a prefix to on-treatment response terminology when the clinical study utilizes the lead-in strategy in which patients receive 4 weeks of treatment with peginterferon and ribavirin before the addition of the DAA to the regimen. Li4-CVR8 indicates an undetectable level of HCV RNA at triple therapy week 4 and total treatment week 8

DAA, direct-acting antiviral agent; HCV, hepatitis C virus; PCR, polymerase chain reaction; eRVR, extended rapid viral response.

Conclusions

The changing treatment landscape of HCV infection has highlighted a number of difficulties with the current definitions and terminology used in the standard-of-care HCV treatment paradigm. The authors of this report have presented recommendations that are intended both to clarify historical terminology and introduced new terms. The definitions contained in this report were designed to reflect current and future clinical practice and to standardize clinical trial design. It is of note that unanimous agreement was obtained on all issues in the present report. Although this proposal is not intended to represent guidelines for diagnosis or treatment, it is the hope of the panel that these recommendations will prove valuable for the development of a language common to clinical trials, the dissemination and comparison of clinical trial data, the development of new clinical guidelines, as well as for everyday use in clinical practice. It is very possible that future treatment paradigms will require a further modification of the nomenclature used to describe various scenarios in the treatment of hepatitis C.

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Source

The new standard of HCV therapy: Retreatment in experienced patients

Clinical Liver Disease

Volume 1, Issue 1, pages 16–19, February 2012

Naveen Gara M.D., Marc G. Ghany M.D., M.H.Sc.^§,*

Article first published online: 6 MAR 2012

DOI: 10.1002/cld.4

Copyright © 2012 the American Association for the Study of Liver Diseases

^† This research was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute (National Institutes of Health).

^‡ Potential conflict of interest: Nothing to report

Abstract

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As the treatment for chronic hepatitis C virus (HCV) infection has improved over the last 2 decades, the number of patients for whom therapy fails has declined substantially. However, more than half of patients with HCV genotype 1 infections fail to achieve a sustained virological response (SVR) to pegylated interferon (PEG-IFN) and ribavirin (RBV).1–4 Subjects for whom combination therapy fails are a heterogeneous group and include individuals who experience virological breakthrough (detectable HCV RNA in serum during therapy after the achievement of an initial response) or virological relapse (the reappearance of HCV RNA in serum after the discontinuation of treatment and the achievement of an end of-treatment response) as well as individuals who fail to achieve an initial virological response [i.e., partial responders (≥2-log IU/mL decline in HCV RNA from the baseline to treatment week 12 but detectable HCV RNA at week 24) and null responders (≤2-log IU/mL reduction in HCV RNA from the baseline to treatment week 12; Fig. 1].

Figure 1. Virological responses during and after therapy for chronic HCV. Relapse refers to the reappearance of HCV RNA in serum after treatment is discontinued and an end-of-treatment response is documented. A nonresponse may be partial (>2-log decline in HCV RNA by week 12 but still positive results at week 24) or null (<2-log decline in HCV RNA by week 12).

DAA, direct-acting antiviral; FDA, Food and Drug Administration; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RBV, ribavirin; RGT, response-guided triple-drug therapy; SOC, standard of care; SVR, sustained virological response.

The reasons for treatment failure are not well understood. Resistance to interferon is believed to be an important cause. Specific polymorphisms of the interleukin-28b gene probably explain 50% or more of the resistance to PEG-IFN, but other host and viral factors are likely involved.5–7 Poor compliance with the prescribed regimen and adverse events requiring a dose reduction or discontinuation of therapy also contribute to treatment failure.8, 9 The latter two causes may be amenable to interventions, and successful retreatment with PEG-IFN and RBV may be permitted.

Until recently, retreatment options were limited for persons for whom a PEG-IFN/RBV regimen failed. Studies evaluating retreatment with PEG-IFN and RBV yielded SVR rates of only 6% to 9% in partial and null responders and 33% in prior relapsers with an HCV genotype 1 infection.10, 11 In comparison with standard therapy, a higher dose of PEG-IFN as induction therapy had no effect on either the end-of-treatment response rate or the SVR rate.10 However, extending therapy to 72 weeks resulted in a marginal increase in the SVR rate from 9% to 16%, primarily because of the prevention of virological relapse.10 Similarly, a different preparation of interferon, consensus interferon, was minimally effective.12 Three studies have evaluated the role of maintenance, low-dose PEG-IFN in prior nonresponders with advanced liver disease.3–5 All three studies showed no differences in clinical outcomes between treated and control subjects and suggested no benefit of maintenance, low-dose PEG-IFN in this group of patients. However, the Colchicine Versus PegIntron Long-Term study and the Evaluation of PegIntron in Control of Hepatitis C Cirrhosis 3 study hinted at a lower rate of complications (particularly variceal bleeding) in patients with portal hypertension who were receiving colchicine or a placebo, respectively, instead of PEG-IFN.14, 15

In May 2011, two new direct-acting antiviral (DAA) agents belonging to a class of drugs known as protease inhibitors, boceprevir and telaprevir, were approved for use in combination with PEG-IFN and RBV for both previously untreated and treatment-experienced subjects.6–9 In comparison with PEG-IFN and RBV, these drugs led to 2- to 3-fold increases in SVR rates for patients with previous treatment failures17, 19 (Figs. 2 and 3). Consequently, boceprevir or telaprevir in combination with PEG-IFN and RBV now represent the new standard of care (SOC) for the retreatment of relapsers, prior partial responders, and null responders.17, 19

Figure 2. Boceprevir plus PEG-IFN/RBV: overall SVR rates and SVR rates according to prior responses in treatment-experienced subjects. Overall, the SVR rates were significantly higher for patients receiving a boceprevir-containing regimen versus patients receiving PEG-IFN and RBV (59% and 66% versus 21%). The response was dependent on the prior response, with prior relapsers responding better than prior partial responders. Adapted with permission from New England Journal of Medicine.17 RGT means response guided therapy. PR48 means pegylated interferon and ribavirin taken for 48 weeks.

Figure 3. Telaprevir plus PEG-IFN/RBV: overall SVR rates and SVR rates according to prior responses in treatment-experienced subjects. The SVR rates were significantly higher for patients receiving telaprevir with or without a lead-in phase. The SVR rates were not improved with a lead-in phase. There was a gradient in the response, with the highest SVR rates achieved by relapsers and partial responders and the lowest rates achieved by null responders. T12PR48: telaprevir × 12 weeks, pegylated interferon and ribavirin × 48 weeks; LI means ‘lead-in’ phase using pegylated interferon and ribavirin; SOC is ‘standard of care’ i.e., pegylated interferon and ribavirin.

The Retreatment With HCV Serine Protease Inhibitor Boceprevir and Peginterferon/Rebetol 2 study, also known as RESPOND-2, (a phase 3 boceprevir trial) enrolled relapsers and partial responders; previous null responders were excluded.17 The study design began with a 4-week lead-in phase of PEG-IFN and RBV for all subjects, after which the subjects were stratified to one of three study arms:

• Response-guided triple-drug therapy (RGT). The duration of PEG-IFN and RBV was tailored to the HCV RNA response after 4 and 8 weeks of triple therapy; all subjects in this arm received 32 weeks of boceprevir plus PEG-IFN and RBV and completed therapy at week 36 if HCV RNA was undetectable at weeks 8 and 12. Slow responders, that is, those for whom HCV RNA was detectable at week 8 but undetectable at week 12, received another 12 weeks of PEG-IFN and RBV alone after week 36 for a total duration of 48 weeks.
• Fixed-duration triple therapy for 44 weeks.
• SOC therapy. This comprised PEG-IFN and RBV plus a placebo for 48 weeks.

The study × demonstrated that SVR rates were significantly higher among subjects receiving a boceprevir-containing regimen versus patients receiving SOC therapy: 59% in the RGT arm and 66% in the fixed-duration arm versus 21% in the SOC arm (Fig. 2). Successful treatment was more common in prior relapsers (69%-75%) than prior partial responders (40%-52%); the response was lower in patients with cirrhosis, particularly in the RGT arm. Anemia, dry skin, dysgeusia, and rashes were reported more commonly by subjects who received boceprevir versus subjects who received SOC. On the basis of this phase 3 trial, the Food and Drug Administration (FDA) approved the regimen shown in Fig. 4. Because of low response rates in patients with cirrhosis receiving RGT,17 the FDA has recommended that this group of patients receive lead-in therapy and then triple therapy for a fixed duration of 44 weeks.20

Figure 4. Boceprevir plus PEG-IFN/RBV for previous partial responders and relapsers: the FDA-approved regimen. Subjects should start treatment with PEG-IFN and RBV for 4 weeks; after this, boceprevir (800 mg three times a day with food) is given. The duration of boceprevir use depends on the response to treatment at weeks 8 and 24. If HCV RNA is undetectable at weeks 8 and 24, patients should receive 32 weeks of triple therapy. If a patient is slow to respond and has detectable HCV RNA at week 8 but HCV RNA is undetectable at week 24, then triple therapy should be given for 32 weeks and should be followed by another 12 weeks of PEG-IFN and RBV. TW, treatment week.

The REALIZE study, a phase 3 trial of telaprevir with PEG-IFN and RBV in treatment-experienced patients, compared 12 weeks of triple therapy with or without a 4-week lead-in phase of PEG-IFN and RBV plus 36 or 32 weeks of PEG-IFN and RBV, respectively, for a total treatment period of 48 weeks to SOC therapy for 48 weeks. A response-guided approach was not investigated. The study included previous relapsers, partial responders, and null responders. SVR rates were significantly higher for patients receiving telaprevir with or without the lead-in phase (64% and 66%) versus patients receiving SOC therapy (17%). The SVR rates were similar for the arms with and without a lead-in strategy, and this demonstrated no advantage from a lead-in phase. There was a gradient in the response based on prior response, with the highest SVR rates found in relapsers (followed by partial responders) and the lowest rates noted in null responders. These results serve to emphasize the importance of knowing the previous response to treatment when retreatment is being considered. Among previous relapsers, SVR rates with telaprevir plus PEG-IFN and RBV were independent of the liver fibrosis stage. However, among partial and null responders, SVR rates declined with worsening fibrosis.19 Thus, the lowest response rate was observed for null responders with cirrhosis. Adverse events were more common in subjects receiving triple therapy containing telaprevir versus those receiving SOC, and they included fatigue, pruritus, rashes, nausea, anemia, anorectal symptoms, and diarrhea. On the basis of these results, the FDA approved the regimen shown in Fig. 5.20

Figure 5. Telaprevir for partial and null responders: the FDA-approved regimen. Partial and null responders should receive 12 weeks of triple therapy and then another 36 weeks of PEG-IFN and RBV. Relapsers should be treated in the same way as treatment-naive subjects and are eligible for response-guided therapy. This regimen resulted in SVR rates of 83%, 59%, and 29% for relapsers, partial responders, and null responders, respectively.

A majority of patients who fail to achieve an SVR in response to triple therapy (including boceprevir or telaprevir) develop antiviral resistance.17, 19 Some of these viral variants may persist over the long term, but the clinical significance of resistance mutations is unclear at this time.

Whether a subject should be retreated now or wait for potentially better therapy in the future depends on many factors, including the individual's desire to be retreated, the reasons underlying the failure (e.g., inadequate drug dosing or side-effect management), the severity of the underlying liver disease, the prior response to therapy, and the risk of disease progression over the next 3 to 5 years. More effective therapies that do not include interferon are likely to be available in the future. Indeed, a recent pilot trial compared a four-drug regimen (PEG-IFN, RBV, a protease inhibitor, and a nonstructural 5A inhibitor) to a combination of DAA agents without PEG-IFN or RBV in previous null responders. This pilot trial reported an impressive 100% response rate with the four-drug regimen, and 36% of nonresponders achieved an SVR after only 24 weeks of a combination of DAAs alone.21

There are currently no data on the management of individuals for whom a protease inhibitor–containing regimen has failed. Until such data become available, the implementation of futility rules and strict adherence to the drug regimen will be important to prevent the development of resistance and to optimize the chances for SVR while more effective and safer treatment is awaited.

In response to these registration studies, the guidelines committee of the American Association for the Study of Liver Diseases has approved the following guidelines for the use of antiviral therapy in treatment-experienced patients with HCV genotype 1:22

• Retreatment with boceprevir or telaprevir, together with PEG-IFNβ and weight-based RBV, can be recommended for patients who experienced virological relapse or were partial responders after a previous course of treatment with standard interferon-β or PEG-IFNβ and/or RBV (class 1, level A).
• Retreatment with telaprevir, together with PEG-IFNβ and weight-based RBV, may be considered for patients who were previously null responders to a course of standard interferon-β or PEG-IFNβ and/or weight-based RBV (class 2b, level B.)
• In the case of treatment-experienced patients, response-guided therapy with a boceprevir- or telaprevir-based regimen can be considered for relapsers (class 2a, level B for boceprevir; class 2b, level C for telaprevir), may be considered for partial responders (class 2b, level B for boceprevir; class 3, level C for telaprevir), but cannot be recommended for null responders (class 3, level C).
• Patients retreated with boceprevir plus PEG-IFNβ and RBV who continue to have detectable HCV RNA at levels > 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (class 1, level B).
• Patients retreated with telaprevir plus PEG-IFNβ and RBV who continue to have detectable HCV RNA at levels > 1000 IU at week 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (class 1, level B).

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