(最新美国丙型肝炎治疗指南）(Updated Treatment Guidelines for Hepatitis C Virus)

2011年度美国肝病年会（AASLD）于2011年11月4--8日在美国旧金山举行，本次会议中丙型肝炎诊治方面取得了很大进展，介绍了美国FDA批准的两种新药物，更新了丙型肝炎指南，现转载原文，供感兴趣的同道尤其青年医生参考学习。（由于图片不支持上传，故不显示，请谅解）。潍坊市人民医院传染科褚瑞海

AASLD PRACTICE GUIDELINE

An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases

Marc G. Ghany,1 David R. Nelson,2 Doris B. Strader,3 David L. Thomas,4 and Leonard B. Seeff5*

 

This practice guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and endorsed by the Infectious Diseases Society of America, the American College of Gastroenterology and the National Viral Hepatitis Roundtable.

Preamble

These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (MEDLINE search up to June 2011); (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines;1 (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association’s Policy Statement on the Use of Medical Practice Guidelines;2 and (4) the experience of the authors in regard to hepatitis C.

Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines).3,4

Introduction

The standard of care (SOC) therapy for patients with chronic hepatitis C virus (HCV) infection has been the use of both peginterferon (PegIFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5, and 6) or for 24 weeks (HCV genotypes 2 and 3), inducing sustained virologic response (SVR) rates of 40%-50% in those with genotype 1 and of 80% or more in those with genotypes 2 and 3 infections.5-7 Once achieved, an SVR is associated with long-term clearance of HCV infection, which is regarded as a virologic ‘‘cure,’’ as well as with improved morbidity and mortality.8-10 Two major advances have occurred since the last update of treatment guidelines for chronic hepatitis C (CHC) that have changed the optimal treatment regimen of genotype 1 chronic HCV infection: the development of direct-acting antiviral (DAA) agents11-17 and the identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection.18,19 . Although PegIFN and RBV remain vital components of therapy, the emergence of DAAs has led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients with genotype 1 chronic HCV infection. A revision of the prior treatment guidelines is therefore necessary, but is based on data that are presently limited. Accordingly, there may be need to reconsider some of the recommendations as additional data become available. These guidelines review what treatment for genotype 1 chronic HCV infection is now regarded as optimal, but they do not address the issue of prioritization of patient selection for treatment or of treatment of special patient populations.

Direct-Acting Antiviral Agents

There are multiple steps in the viral lifecycle that represent potential pharmacologic targets. A number of compounds encompassing at least five distinct drug classes are currently under development for the treatment of CHC. Presently, only inhibitors of the HCV nonstructural protein 3/4A (NS3/4A) serine protease have been approved by the Food and Drug Administration (FDA).

Protease Inhibitors

The NS3/4A serine protease is required for RNA replication and virion assembly. Two inhibitors of the NS3/4A serine protease, boceprevir (BOC) and telaprevir (TVR), have demonstrated potent inhibition of HCV genotype 1 replication and markedly improved SVR rates in treatment-naı¨ve and treatment-experienced patients.12,13,16,17 Limited phase 2 testing has shown that TVR also has activity against HCV genotype genotype 2 infection but not against genotype 3.20 With regard to BOC, there are limited data indicating that it too, has activity against genotype 2 but also against genotype 3 HCV infection.21 However, at this time, neither drug should be used to treat patients with genotype 2 or 3 HCV infections, and when administered as monotherapy, each PI rapidly selects for resistance variants, leading to virological failure. Combining either PI with PegIFN and RBV limits selection of resistant variants and improves antiviral response.15

Patients Who Have Never Received Therapy (Treatment-Naı¨ve Patients)

Boceprevir. The SPRINT-2 trial evaluated BOC in two cohorts of treatment-naı¨ve patients: Caucasian and black patients.12 The number of patients in the black cohort was small in comparison to that of the Caucasian cohort and may have been insufficient to provide an adequate assessment of true response in this population. All patients were first treated with PegIFN alfa-2b and weight-based RBV as lead-in therapy for a period of 4 weeks, followed by one of three regimens:(1) BOC, PegIFN, and RBV that was administered for 24 weeks if, at study week 8 (week 4 of triple therapy), the HCV RNA level became undetectable (as defined in the package insert as <10-15 IU/mL), referred to as response-guided therapy (RGT); if, however, HCV RNA remained detectable at any visit from week 8 up to but not including week 24 (i.e., a slow virological response), BOC was discontinued and the patient received SOC treatment for an additional 20 weeks (2) BOC, PegIFN, and RBV administered for a fixed duration of 44 weeks; and (3) PegIFN alfa-2b and weight-based RBV alone continued for an additional 44 weeks, representing SOC therapy.12 The BOC dose was 800 mg, given by mouth three times per day with food. The overall SVR rates were higher in the BOC arms, (63% and 66% respectively) than in the SOC arm (38%), but differed according to race (Fig. 1). The SVR rates among Caucasian patients were 67% in the RGT, 69% in the fixed duration, and 41% in the SOC arms, respectively.12 In black patients, the SVR rates were 42% in the RGT, 53% in the fixed duration, and 23% in the SOC arms, respectively (Fig. 1).12 A total of 54% of Caucasian recipients of BOC experienced a rapid virological response (RVR; HCV RNA undetectable, <10-15 IU/mL at week 8, this interval selected because of the 4 week lead-in). By contrast, only 20% of black recipients of BOC experienced an RVR. Regardless of race, among those patients who became HCV RNA negative at week 8 (_57% in both BOC arms and 17% in SOC arm), the SVR rates were 88% in the RGT arm, 90% in the fixed duration arm and 85% in the arm treated by SOC, compared to SVR rates of 36%, 40%, and 30%, respectively, if HCV RNA remained detectable at week 8 (Fig. 2).12

In subgroup analysis, SVR rates were higher in BOCcontaining regimens across all the pretreatment variables that had been identified in previous studies to influence response to SOC therapy, including advanced fibrosis, race, and high pretreatment HCV viral load. Moreover, the SVR rate in subgroups was similar in both the RGT and fixed duration arms and therefore, the AASLD and the FDA support the use of RGT for treatment-naı¨ve patients without cirrhosis. The FDA recommends that not meet criteria for RGT, i.e., a slow virological response, the FDA recommends (based on modeling) triple therapy for 32 weeks preceded by the 4 weeks of SOC treatment), followed by 12 weeks of PegIFN and RBV alone; a strategy that differs from the phase 3 trial design. All therapy should be discontinued if the HCV RNA level is _100 IU/mL at week 12 or _10 to 15 IU/mL at week 24.

Telaprevir. Two phase 3 trials evaluated the efficacy of TVR in combination with PegIFN alfa-2a and RBV in treatment-naı¨ve patients with genotype 1 chronic HCV infection.16,22 Black patients were included but not as a separate cohort and were insufficient in number to provide an adequate assessment of true response in this population. In the ADVANCE trial, patients received TVR together with PegIFN and RBV for either 8 (T8PR) or 12 (T12PR) weeks followed by PegIFN and RBV alone in a response-guided paradigm. 16 The TVR dose was 750 mg given by mouth every 8 hours with food (in particular, a fatty meal). Patients in the T8PR and T12PR groups who achieved an ‘‘extended RVR’’ (eRVR)?which for this drug was defined as undetectable (<10-15 IU/mL) HCV RNA levels at weeks 4 and 12?stopped therapy at week 24, whereas those in whom an eRVR did not occur received a total of 48 weeks of PegIFN and RBV. All patients in the control group received PegIFN and RBV therapy for 48 weeks. The overall SVR rates patients with compensated cirrhosis should not receive RGT, however, this is based on limited data and requires further study. Of note, if the virological response did among patients in the T8PR and T12PR groups were 69% and 75%, respectively,16 compared with a rate of 44% in the control group (Table 2 and Fig. 3). Using the RGT approach, 58% and 57% of patients in the T12PR and T8PR groups, respectively, attained an eRVR, 89% and 83% of whom ultimately achieved an SVR.16 Thus, developing an eRVR appears to be the strongest predictor that an SVR will occur.

SVR rates were higher in TVR-containing regimens compared to SOC treatment among patients with disease characteristics found previously to be associated with a poorer response to SOC treatment. Although few black patients and other difficult-to-treat patient populations were included in the TVR phase 3 trials, an improved SVR rate was observed regardless of race, ethnicity, or level of hepatic fibrosis. With regard to race, treatment with a TVR-based regimen significantly improved SVR rates in black patients (T8PR, 58% and T12PR, 62%) compared to the SVR rates achieved in those treated with the SOC regimen (25%) (Fig. 3). Moreover, the SVR rate was >80% among black patients who achieved an eRVR on a TVR-based regimen. A total of 62% of patients in the T12PR group and 53% in the T8PR group with advanced fibrosis achieved an SVR, the rate improving to >80% among those with an eRVR. In the T12PR group, the impact of high versus low viral load (>800,000 or <800,000 IU/mL) on SVR rates was minimal; the SVR rate was 74% in patients with a high viral load and 78% in those with a low viral load.

The ILLUMINATE trial focused on defining the utility of RGT in patients with an eRVR. All patients received an initial 12 weeks of TVR-based triple therapy followed by PegIFN and RBV therapy alone.22 Those who achieved an eRVR were randomized at week 20 to receive either an additional 4 or an additional 28 weeks of PegIFN and RBV whereas those who failed to achieve an eRVR were not randomized and received an additional 28 weeks of PegIFN and RBV. The overall SVR rate for all patients was 72% (Fig. 4), similar to the 75% rate found in the ADVANCE trial.22 Among the 65% of patients who achieved an eRVR and received either an additional 4 or 28 weeks of PegIFN and RBV, SVR rates were 92% and 88%, respectively (Fig. 4). By contrast, the SVR rate was only 64% among patients who did not achieve an eRVR.22 These data suggest that a response-guided strategy based on eRVR permits a shortened duration of therapy without jeopardizing the SVR response rate and may be appropriate for up to two-thirds of patients with genotype 1 chronic HCV infection. The use of RGTmay, however, be unsuitable for patients with cirrhosis, but at present the data are insufficient to guide management in this difficult-to treat population. Therapy should be discontinued in all patients if HCV RNA levels are _1,000 IU/mL at weeks 4 or 12 and/or >10-15 IU/mL at week 24.

Recommendations:

1. The optimal therapy for genotype 1, chronic HCV infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A).

2. Boceprevir and telaprevir should not be used without peginterferon alfa and weight-based ribavirin (Class 1, Level A).

For Treatment-Naı¨ve Patients:

3. The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A).

4. Patients without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, whose HCV RNA level at weeks 8 and 24 is undetectable, may be considered for a shortened duration of treatment of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks of triple therapy) (Class 2a, Level B).

5. Treatment with all three drugs (boceprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class 2a, Level B).

6. The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A).

7. Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, whose HCV RNA level at weeks 4 and 12 is undetectable should be considered for a shortened duration of therapy of 24 weeks (Class 2a, Level A).

8. Patients with cirrhosis treated with either boceprevir or telaprevir in combination with peginterferon and ribavirin should receive therapy for a duration of 48 weeks (Class 2b, Level B).

9. Treatment with all three drugs (telaprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24 (Class 2a, Level B).

Patients Who Have Previously Received Therapy

Three categories have been defined for persons who had received previous therapy for CHC but who had failed the treatment. Null responders are persons whose HCV RNA level did not decline by at least 2 log IU/mL at treatment week 12; partial responders are persons whose HCV RNA level dropped by at least 2 log IU/mL at treatment week 12 but in whom HCV RNA was still detected at treatment week 24; and relapsers are persons whose HCV RNA became undetectable during treatment, but then reappeared after treatment ended. Taking these categories into account, phase 3 trials have been performed also in treatment-experienced patients with genotype 1 chronic HCV infection using BOC and TVR in combination with PegIFN and RBV. The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy (BOC plus PegIFN and RBV for 32 weeks; patients with a detectable HCV RNA level at week 8 received SOC for an additional 12 weeks) and a fixed duration of triple therapy given for 44 weeks (total 48 weeks of therapy), to SOC therapy.13 The TVR trial design consisted of three arms: in the first arm, patients received triple therapy for 12 weeks followed by SOC treatment or 36 weeks; in the second arm, patients received lead-in treatment with SOC for 4 weeks, followed by triple therapy for 12 weeks, ending with SOC treatment for 32 weeks; the third arm consisted of SOC treatment for 48 weeks.17 In both trials, an SVR occurred significantly more frequently in those who received the triple therapy regimens than in those who received the SOC therapy. In the BOC trial (RESPOND-2 Trial), the SVR rates were 66% and 59% in the two triple therapy arms compared to 21% in the control arm, prior relapsers achieving higher SVR rates (75% and 69%, respectively) than prior partial responders (52% and 40%, respectively) compared to the rates attained in the SOC arm (29% and 7%, respectively); null responders were excluded from this trial (Table 3 and Fig. 5).13 Similarly, the SVR rates in the TVR trial (REALIZE Study) were 64% and 66% in the TVR-containing arms (83% and 88% in relapsers, 59% and 54% in partial responders, and 29% and 33% in null responders) and 17% in the control arm (24% in relapsers, 15% in partial responders and 5% in null responders) (Fig. 6).17 Thus, the response to the triple therapy regimen in both the BOC and TVR trials was influenced by the outcome of the previous treatment with PegIFN and RBV which highlights the importance of reviewing old treatment records to document previous treatment response. In the BOC trial, the SVR rate was higher in those who were relapsers than in those who were partial responders. In the TVR trial also, the highest SVR rate occurred in prior relapsers, a lower rate in partial responders, and the lowest rate in null responders (defined as patients who had <2 log10 decline in HCV RNA at week 12 of prior treatment)(Table 3 and Fig. 6).17

Thus, the decision to re-treat patients should depend on their prior response to PegIFN and RBV, as well as on the reasons for why they may have failed, such as inadequate drug dosing or side effect management. Relapsers and partial responder patients can expect relatively high SVR rates to re-treatment with a PI-containing triple regimen and should be considered candidates for re-treatment. The decision to re-treat a null responder should be individualized, particularly in patients with cirrhosis, because fewer than one-third of null responder patients in the TVR trial achieved an SVR; there are no comparable data for BOC because null responders were excluded from treatment. In addition, a majority of null responders developed antiviral resistance. The FDA label, however, indicates that BOC can be used in null responders but, given the lack of definitive information from phase 3 data, caution is advised in the use of BOC in null responders until further supportive evidence becomes available. Accordingly, any potential for benefit from treating nonresponders must be weighed against the risk of development of antiviral resistance and of serious side effects, and the high cost of therapy.

Response-guided therapy, based on achieving an eRVR, was evaluated for retreatment in the BOC trial. Shortening the duration of therapy from the standard 48 weeks to 36 weeks in patients who received triple therapy and who achieved an eRVR (which for this drug was defined as HCV RNA negative weeks 8 through 20) did not significantly lower the SVR rate (59% for RGT versus 66% for fixed duration treatment).13 In patients with cirrhosis, however, the SVR rate was statistically lower in those who received RGT therapy than in those who were treated for the full 48-week duration (35% versus 77%, respectively).13 The emergence of BOC resistant variants was more common among patients who responded poorly to interferon treatment (<1 log decline in HCV RNA level) during the lead-in phase and who were treated with RGT compared to those with >1 log decline in HCV RNA level and treated for 48 weeks (32% and 8%, respectively).13 There are no comparable data for RGT using TVR. Nonetheless, SVR rates are at least as high in relapsers as in treatment-naı¨ve patients, and TVR exposure is 12 weeks with both RGT and 48-week treatment options. Accordingly, although there are no direct data to support the recommendation that relapsers could be treated with TVR using an RGT approach, the FDA does endorse such a recommendation, as is the case for BOC.

Utility of Lead-In

There is uncertainty about the benefit of a lead-in phase. Theoretically, a PegIFN and RBV lead-in phase may serve to improve treatment efficacy by lowering HCV RNA levels which would allow for steady-state PegIFN and RBV levels at the time the PI is dosed, thereby reducing the risk of viral breakthrough or resistance. In addition, a lead-in strategy does allow for determination of interferon responsiveness and on-treatment assessment of SVR in patients receiving either BOC or TVR. Patients whose interferon response is suboptimal, defined as a reduction of the HCV RNA level of less than 1 log during the 4-week lead-in, have lower SVR rates than do patients with a good IFN response during lead-in treatment.12 Nevertheless, the addition of BOC to poor responders during lead-in still leads to significantly improved SVR rates (28% to 38% compared with 4% if a PI is not added) and thus a poor response during the lead-in phase should not be used to deny patients access to PI therapy.

A direct comparison of the lead-in and non-lead-in groups in the BOC phase 2 study, however, did not show a significant difference in SVR rates for either the 28 week regimen, 56% and 54%, or the 48 week regimen, 75% and 67%, treated with and without lead-in, respectively.11 Combining data across all treatment groups in the phase 2 trial demonstrated a trend for a higher rate of virological breakthrough in the BOC-treated patients without a lead-in, 9%, than in those who received lead-in treatment, 4%, (P  0.06). However, because all the phase 3 data were based on the lead-in strategy, until there is evidence to the contrary, BOC should be used with a 4-week lead-in. A lead-in strategy was not evaluated in the phase 3 TVR treatment-naı¨ve trial, and therefore no recommendation can be made for this drug.

Recommendations:

For treatment-experienced patients:

 10. Re-treatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class 1, Level A).

11. Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B.)

12. Response-guided therapy of treatment-experienced patients using either 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).

13. Patients re-treated with boceprevir plus

peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 100 IU at week 12

should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).

14. Patients re-treated with telaprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 1,000 IU at weeks 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).