Discussion

The ultimate goal of hepatitis C (HCV) treatment is to eradicate HCV infection and thereby reduce the risk of progression to HCV-related liver complications, including liver failure, hepatocellular carcinoma, and death. The endpoint of HCV treatment is a sustained virologic response (SVR), which correlates strongly with a permanent clearance of the virus and effectively a cure. There are, however, a number of intermediate viral endpoints—measurement of the HCV RNA level at specific time points during the course of HCV treatment—that inform the clinician about the patient's responsiveness to treatment and likelihood of SVR. These benchmarks reflect the second-phase kinetics of viral elimination, can vary from patient to patient, and correlate strongly with the final treatment outcome[1,2]. Understanding the virologic milestones measured during therapy, at the end of therapy, and post therapy is important in optimizing the treatment plan for the individual patient. All patients should have a baseline HCV RNA level obtained prior to starting treatment. Many of the following definitions include the term "undetectable" HCV RNA. The definition of undetectable varies based on the sensitivity of the assay used (which can range from 10 to 50 IU/ml in lower limit of detection) and stringency required for a particular treatment regimen. In general, a lower threshold of 10 to 15 IU/ml is used for the definition of undetectable when using triple therapy regimens and making response-guided therapy or stopping decisions.

HCV RNA Responses During Therapy

Rapid Virologic Response (RVR): The week 4 quantitative HCV RNA provides the earliest indication that treatment may be successful. A rapid virologic response, or RVR, is defined as an undetectable HCV RNA at week 4 (Figure 1) and remains one of the strongest predictors of SVR in patients on peginterferon and ribavirin, with up to 88% of those with RVR going on to SVR (for HCV genotypes 1, 2, 3, and 4)[2,3]. An HCV RNA level obtained 4 weeks after starting the protease inhibitor (as part of triple therapy) remains an important positive predictor for SVR[4]. Many of the same clinical factors that predict SVR also correlate with RVR, such as low pre-treatment HCV viral level and IL28B CC genotype[3,5]. The presence of an RVR can trump other well-known poor prognostic factors. For example, while African-American patients are overall less likely than Caucasian patients to achieve an SVR for a given week 4 decrease in HCV RNA level, the few patients who do achieve an RVR can attain SVR rates of 80 to 90%, which is comparable to rates observed in Caucasians who achieve RVR[3,6].

Extended Rapid Virologic Response (eRVR): Patients who have an undetectable HCV RNA level at week 4 through week 12 are considered to have an extended rapid virologic response (eRVR) (Figure 2). The eRVR plays an important role in response-guided therapy, particularly when using the protease inhibitor telaprevir[4].

Very Rapid Virologic Response (vRVR): In some research studies, investigators have now started to measure HCV RNA responses 2 weeks after initiating therapy and patients who have undetectable HCV RNA levels at week 2 are considered to have a very rapid virologic response (vRVR) (Figure 3)[4]. The clinical utility of vRVR has remains unclear.

Early Virologic Response (EVR): An early virologic response is defined as an undetectable serum HCV RNA or a 2 log10 or greater drop in HCV RNA at week 12 of therapy, and has generally been used in the setting of dual combination treatment with peginterferon and ribavirin, particularly for patients with genotype 1 HCV infection. The EVR is categorized as either a complete EVR (undetectable serum HCV RNA at week 12 of therapy) or a partial EVR (HCV RNA level decrease by at least 2 log10 but remaining detectable at week 12) (Figure 4). Failure to achieve an EVR remains the most accurate negative predictor of SVR in dual therapy[2]. Only about 1% of those patients who do not achieve an EVR will achieve an SVR[1]. A negative EVR has proved highly valuable in making a decision to stop therapy in those patients considered highly unlikely to achieve SVR. In contrast, a positive EVR in genotype 1 patients treated with peginterferon and ribavirin has less clinical utility in predicting an eventual SVR, as only 65 to 72% of patients with genotype 1 infection who reach EVR go onto achieve SVR on[1,2]. This 12-week benchmark currently has more historical interest since genotype 1 HCV patients should receive a triple therapy regimen that includes a protease inhibitor, and with triple therapy, different futility rules apply.

Nonresponse: The term nonresponse refers to patients who do not achieve an undetectable HCV RNA during the first 24 weeks of treatment. There are two forms of virologic non-response that are important to distinguish from each other: null response and partial response.

Null Response: The term null response is a subcategory of nonresponse and refers to the situation when a patient does not suppress their HCV level by at least 2 log10 by week 12 of treatment (Figure 5)[2]. It is worth noting that some of the literature refers to this group as non-responders rather than null responders so the exact definition would need to be noted when the non-response term is used. The distinction between a partial response versus a null response is important because the latter represents a more interferon-refractory group, even in the context of re-treatment with HCV protease inhibitor-based triple therapy. The phase 3 trial of Telaprevir (Incivek) in treatment-experienced patients showed SVR rates of only 29 to 33% in null responders compared with 54 to 59% in partial responders[7]. A boceprevir (Vitrelis) trial involving treatment-experienced patients excluded null responders so in the absence of evidence for efficacy in this group, both the Food and Drug Administration (FDA) and American Association for the Study of Liver Diseases (AASLD) urge caution on the use of boceprevir in this category of patients[8].

Partial Response: The term partial response is a subcategory of nonresponse and describes a decrease in HCV RNA levels by at least 2 log10 at week 12 of treatment, but detectable levels at week 24 (Figure 6). The 12-week HCV viral response has more relevance in the treatment-experienced patient who failed prior treatment with peginterferon and ribavirin.

Virologic Breakthrough: A virologic breakthrough refers to the reappearance of HCV RNA while still on therapy in a patient who had suppressed their viral level earlier in the course of therapy (Figure 7)[2]. Virologic breakthrough occurred relatively often in the days of standard interferon monotherapy, but now infrequently occurs with the use of dual therapy with peginterferon and ribavirin or triple therapy (peginterferon and ribavirin and a protease inhibitor). Virologic breakthrough is more likely to occur if the dose of either peginterferon or ribavirin is reduced significantly, or if the patient is non-adherent with therapy.

End of Treatment and Post-Treatment Responses

End-of-Treatment Response (ETR): An end-of-treatment response (ETR) refers to an undetectable HCV RNA level at the end of the course of therapy (Figure 8)[2]. An ETR does not accurately predict who will go onto an SVR but ultimately serves as a prerequisite for an SVR.

Sustained virologic response at Week 24 (SVR24): Sustained virologic response at week 24 is defined as an undetectable HCV RNA level 24 weeks after treatment discontinuation (Figure 9)[2]. Multiple studies have shown that SVR at 24 weeks post-treatment (SVR24) represents eradication of HCV infection in 99 to 100% of patients[9]. The absence of HCV RNA with SVR is a durable outcome, with the virus remaining undetected out to 5 years or more [9]. The HCV RNA detection for determination of SVR should utilize a sensitive assay that has a lower limit of detection of 50 IU/ml or less, ideally by real-time PCR. Testing HCV RNA beyond 6 to 12 months from the end of treatment is not necessary in most cases unless the patient or provider wants confirmation or if they are concerned about potential reinfection.

Sustained virologic response at Week 12 (SVR12): Sustained virologic response at week 12 is defined as an undetectable HCV RNA level 12 weeks after treatment discontinuation (Figure 10)[4]. Although the SVR24 has been the traditional benchmark measurement used in clinical practice and in research studies, several recent studies involving patients who completed peginterferon and ribavirin dual therapy suggest that an undetectable HCV RNA at 12 weeks post-treatment (SVR12) predicts permanent clearance of the virus as well as the SVR24[10,11]. Until more extensive research is conducted with SVR12, the SVR24 remains the gold standard definition of treatment success. The HCV RNA detection for determination of SVR should utilize a sensitive assay that has a lower limit of detection of 50 IU/ml or less, ideally by real-time PCR.

Virologic Relapse: A virologic relapse occurs when HCV RNA reappears in a patient who had an end-of-treatment response (Figure 11)[2]. The likelihood of a patient developing virologic relapse increases if there is a delay in the time to achieve an undetectable HCV RNA on therapy. Among all treatment-experienced patients, this group is the most likely to respond to retreatment with triple therapy (with either a telaprevir or boceprevir-based regimen). For example, in phase 3 trials involving treatment-experienced patients, those with prior virologic relapse had SVR rates of 69 to 75% in the boceprevir treatment arms and 83 to 88% in the telaprevir treatment arms [7,12].

Response-Guided Therapy

Among patients receiving a hepatitis C protease inhibitor combined with peginterferon and ribavirin, the use of response-guided therapy allows for shortening the duration of therapy in patients who have favorable early viral kinetics. Phase 3 clinical trials involving treatment-naïve patients who received telaprevir plus peginterferon and ribavirin demonstrated that patients with undetectable HCV RNA levels at weeks 4 and 12 (eRVR) had comparable SVR rates with a shortened treatment course of 24 weeks when compared with a standard 48-week course[13]. Similarly, in a phase 3 trial involving treatment-naïve patients who received boceprevir plus peginterferon and ribavirin, patients with a negative HCV RNA at week 8 had comparable SVR rates with a shortened 28-week course versus a standard 48-week course of therapy[14]. In addition, the use of response-guided therapy approach appears to be valid in a select subset of treatment-experienced patients who previously achieved an undetectable HCV RNA with prior peginterferon and ribavirin treatment, but had virologic relapse[15,16]. When using response-guided therapy for patients on triple therapy, those who have detectable HCV RNA levels at the specified timepoints—either week 4 or 12 with telaprevir and either week 8 with boceprevir—need to complete a full 48-week treatment course. The FDA and the AASLD have urged caution with the use of response-guided therapy in patients with cirrhosis and recommend a fixed 48-week course in those individuals[8]. Limited data also suggest the response-guided therapy approach may not work as well in black patients or in those with high baseline HCV RNA (greater than 800,000 IU/ml)[12,15].

Futility or Stopping Rules

Given the high cost and significant potential toxicity associated with HCV therapy, it is extremely important to identify early predictors of nonresponse that accurately determine which patients should stop therapy because of lack of efficacy. For dual therapy with peginterferon and ribavirin, experts recommend stopping therapy if either of the following two criteria occur: (1) lack of EVR (or less than 2 log10 drop in HCV RNA level) at week 12 or (2) persistently detectable HCV RNA at week 24 on treatment[2]. The need for futility or stopping rules is essential in the context of triple therapy since treatment failure with HCV protease inhibitors is often accompanied by the rapid selection of resistant HCV variants[8,16]. To minimize this risk and avoid unnecessary prolongation of therapy, the prescribing recommendations for both telaprevir and boceprevir include strict guidelines for discontinuing all three drugs if certain conditions are met (Figure 12Futility Rules Image 1Futility Rules Image 2)[8,16]. During telaprevir-based triple therapy, the presence of HCV RNA greater than 1000 IU/ml at week 4 or at week 12 mandates the cessation of treatment. For boceprevir-based triple therapy, treatment should be stopped if the HCV RNA level is 100 IU/ml or greater at week 12 (after 8 weeks of boceprevir). For both telaprevir and boceprevir triple therapy, the detection of any virus at week 24 also indicates treatment failure and mandates stopping therapy. It is important to note that the threshold for detectability is more stringent for triple therapy when considering shortening or stopping therapy—the HCV RNA assay used should be as sensitive as those used in the clinical trials with a lower limit of detection of less than 10 to 15 IU/ml.

[See References]

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    Figure 1. Rapid Virologic Response (RVR)

    A rapid virologic response (RVR) is defined as an undetectable HCV RNA at week 4. The definition of undetectable varies based on the sensitivity of the assay used (which can range from 10 to 50 IU/ml in lower limit of detection) and stringency required for a particular treatment regimen.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.

    Figure 1
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    Figure 2. Extended Rapid Virologic Response (eRVR)

    An extended rapid virologic response (eRVR) is defined as an undetectable HCV RNA at week 4 and through week 12. The definition of undetectable varies based on the sensitivity of the assay used (which can range from 10 to 50 IU/ml in lower limit of detection) and stringency required for a particular treatment regimen.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.

    Figure 2
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    Figure 3. Very Rapid Virologic Response (vRVR)

    A very rapid virologic response (vRVR) is defined as an undetectable HCV RNA at week 2. The definition of undetectable varies based on the sensitivity of the assay used (which can range from 10 to 50 IU/ml in lower limit of detection) and stringency required for a particular treatment regimen.
    Source: Wedemeyer H, Jensen DM, Godofsky E, et al. Recommendations for standardized nomenclature and definitions of viral response in trials of HCV investigational agents. Hepatology. 2012 Jun 18 [Epub ahead of print].


    Figure 3
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    Figure 4. Early Virologic Response (EVR)

    The early virologic response (EVR) is based on week 12 data and is defined as a 2 log10 or greater decrease in HCV RNA or undetectable HCV RNA. A partial EVR refers to a 2 log10 or greater decrease from baseline in HCV RNA at week 12, but persistent detectable HCV RNA. A complete EVR (cEVR) is defined as undetectable HCV RNA level at week 12. The definition of undetectable varies based on the sensitivity of the assay used (which can range from 10 to 50 IU/ml in lower limit of detection) and stringency required for a particular treatment regimen.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 4
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    Figure 5. Null Response

    A null response is defined by a failure to suppress HCV levels by at least 2 log10 by week 12 of treatment.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 5
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    Figure 6. Partial Response

    A partial response is defined as at least a 2 log1 decrease in HCV RNA levels at week 12 of treatment, but still detectable at week 24.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 6
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    Figure 7. Virologic Breakthrough

    Virologic breakthrough is defined as the reappearance of detectable HCV RNA while still on therapy in a patient who had suppressed their HCV RNA to an undetectable level earlier on therapy.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 7
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    Figure 8. End-of-Treatment Response  (ETR)

    End-of-treatment response is defined as an undetectable HCV RNA level at the end of the course of therapy.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 8
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    Figure 9. Sustained Virologic Response at Week 24 (SVR24)

    Sustained virologic response at week 24 (SVR24) is defined as an undetectable HCV RNA level 24 weeks after treatment discontinuation.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 9
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    Figure 10. Sustained Virologic Response at Week 12 (SVR12)

    Sustained virologic response at week 12 (SVR12) is defined as an undetectable HCV RNA level 12 weeks after treatment discontinuation.
    Source: Wedemeyer H, Jensen DM, Godofsky E, et al. Recommendations for standardized nomenclature and definitions of viral response in trials of HCV investigational agents. Hepatology. 2012 Jun 18 [Epub ahead of print].


    Figure 10
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    Figure 11. Virologic Relapse

    Virologic relapse is defined as reappearance of HCV RNA reappears in a patient who had an end-of-treatment response.
    Source: Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74.


    Figure 11
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    Figure 12: Futility Rules with the Use of HCV Protease Inhibitors. Image 1. Futility Rules with the Use of Telaprevir-Based Regimens. *In clinical trials, HCV-RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL.
    Figure 12