M. Jacobson; F. Poordad; R. S. Brown Jr; P. Y. Kwo; K. R. Reddy; E. Schiff
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.
IntroductionOver 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 AssaysWhen 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 HCV3–7
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.
|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|
|Quest Diagnostics Heptimax||5||5–69 000 000|
Current Terminology in the Context of Novel TherapiesIn 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'. 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.
Table 2. Current definitions for virological response8
HCV, hepatitis C virus; PCR, polymerase chain reaction.
|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|
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.
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(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).
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. 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). 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.
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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
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. The US Food and Drug Administration has also used 'DAA' in the HIV arena and, more recently, in the HCV arena. 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 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.
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 or initial undetectability at week 12 after HCV RNA was positive at week 8. 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'.
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.
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.
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
|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.
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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