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

Adverse Events

Adverse events occurred more frequently in patients treated with PIs than in those treated with PegIFN and RBV therapy alone. In the BOC trials, anemia and dysgeusia were the most common adverse events, whereas in the TVR trials, rash, anemia, pruritus, nausea, and diarrhea developed more commonly among those who received TVR than who received SOC therapy. 12,16 In the phase 3 TVR trials, a rash of any severity was noted in 56% of patients who received a TVR-based regimen compared to 32% of those who received a PegIFN and RBV regimen.16 The rash was typically eczematous and maculopapular in character, consistent with a drug-induced eruption. In most patients, the rash was mild to moderate in severity but was severe (involving >50% of the body surface area) in 4% of cases. The development of rash necessitated discontinuation of TVR in 6% and of the entire regimen in 1% of the cases. The Stevens Johnson Syndrome or Drug-Related Eruption with Systemic Symptoms (DRESS) occurred in <1% of subjects but at a higher frequency than generally observed for other drugs. The response of the rash to local or systemic treatment with corticosteroids and oral antihistamines is uncertain. Pruritus, commonly but not always associated with rash, was noted in _50% of patients who received TVR therapy.16潍坊市人民医院传染科褚瑞海

Anemia developed among recipients of both PIs. Hemoglobin decreases below 10 g/dL (grade 2 toxicity) occurred in 49% of patients who received a BOC regimen compared to 29% of those who received the SOC regimen, whereas 9% had a hemoglobin decline of <8.5 g/dL (grade 3 toxicity).12 Among patients treated with T12PR, hemoglobin levels of <10 g/dL were observed in 36% of patients compared to in 14% of patients who received SOC, and 9% had hemoglobin decreases to <8.5 g/dL.16 Because hematopoietic growth factors were not permitted during the TVR trials, there was a 5%-6% higher rate of treatment discontinuation among those who developed anemia than among those who did not. However, neither anemia nor RBV dose reduction adversely affected the SVR rate. Of note is that in the BOC trial, SVR rates in patients managed by RBV dose reduction alone were comparable to those in patients managed with erythropoietin therapy.23 Similarly, in the TVR trials, dose reduction of RBV had no effect on SVR rates, and therefore dose reduction should be the initial response to management of anemia.24 Because the duration of BOC therapy (24 to 44 weeks) is longer than the duration of TVR therapy (12 weeks), the frequency of anemia is likely to be greater in BOC-containing regimens, leading to more RBV dose reductions and consideration of erythropoietin use. However, the potential benefits of erythropoietin must be weighed against its potential side effects, the fact that its use in HCV therapy is not approved by the FDA, and its considerable cost. If a PI treatment?limiting adverse event occurs, PegIFN and RBV can be continued provided that an on-treatment response had occurred. There are no data to help guide substitution of one for the other HCV PI. If a patient has a serious adverse reaction related to PegIFN and/or RBV, the PegIFN and/or RBV dose should be reduced or discontinued. If either PegIFN and/or RBV are discontinued, the HCV PI should be stopped. Additional information on management of other adverse events can be found in the package insert.

Drug?Drug Interactions

Because patients with CHC frequently receive medications in addition to those used to treat HCV infection, and because the PIs can inhibit hepatic drugmetabolizing enzymes such as cytochrome P450 2C (CYP2C), CYP3A4, or CYP1A, both BOC and TVR were studied for potential interactions with a number of drugs likely to be coadministered. These included statins, immune suppressants, drugs used to treat HIV coinfection, opportunistic infections, mood disorders, and drug addiction support medications. Both BOC and TVR, were noted to cause interactions with several of the drugs examined, either increasing or decreasing pharmacokinetic parameters. It is particularly important, therefore, that the medical provider review this information as listed in the package insert for each of the drugs before starting treatment for CHC. This information can be obtained at the FDA Web site: www.accessdata.fda. gov/scripts/cder/drugsatfda/index.cfm. Other helpful sites are: http//:222.drug-interactions.com and www. hep-druginteractions.org

Viral Resistance and Monitoring

Emergence of antiviral-resistant variants during PI-based therapy has been observed during all trials and is associated with virological failure and relapse (Tables 2 and 3). Mutations that confer either high or low level resistance to BOC and TVR cluster around the catalytic site of the NS3/4A serine protease. Similar variants were detected in both BOC and TVR treated subjects, suggesting that some degree of crossresistance exists between the two PIs. In both phase 3 studies, sequence analysis of the NS3/4A region was performed in all subjects at baseline and for all subjects who failed to achieve an SVR. Antiviral resistant variants were detected in a small proportion of patients at baseline, 7% in the BOC studies and 5% in the TVR trials, but did not appear to impact response to either PI.25,26 Therefore, there is currently no clinical indication for baseline resistance testing.

Among treatment-naı¨ve patients receiving a BOC regimen, antiviral resistant variants developing during treatment were observed overall in 16% of patients (Table 2).12 During treatment, TVR-associated antiviral variants occurred in 12% of treatment-naı¨ve patients and 22% of treatment-experienced patients (Tables 2 and 3).16,17 A majority (80%-90%) of patients who experienced virological breakthrough or incomplete virological suppression on therapy, or virological relapse after discontinuation of PI therapy, were found to have antiviral resistant variants. In the BOC studies, poor response to interferon (<1 log decline in HCV RNA during the lead-in phase) was associated with a higher rate of development of resistance.12 Among TVR-treated patients, population sequencing has suggested that high-level resistance develops more commonly when virological failure occurs during the initial 12 weeks of treatment, whereas low-level resistance variants are more likely when virological failure occurs later, during treatment with PegIFN and RBV alone. These observations highlight the importance of response to interferon for the prevention of emergence of antiviral resistance.

The clinical significance of antiviral resistant variants that emerge during PI therapy is uncertain. In longitudinal follow-up of patients enrolled in phase 2 trials, BOC-resistant variants were detected in 43% of subjects after 2 years of follow-up. Similarly, among patients with documented TVR-resistant variants who were enrolled in the TVR phase 3 trials, 40% still had detectable resistant variants after a median follow-up period of 45 weeks.27 In general, the decline or loss of variants appears to be related to their level of fitness.

Further data are needed to determine whether selection of these variants during and after PI therapy affects subsequent treatment choices. In phase 3 studies, the emergence of resistant variants and virological breakthrough was more common in patients infected with HCV subtype 1a than 1b, a result of a higher genetic barrier required for selection of resistant variants in HCV subtype 1b compared to 1a.28 Thus, HCV subtyping may play a role in helping to select future treatment regimens and predict the development of resistance. Finally, minimizing development of compensatory mutations would involve early discontinuation of PI therapy when antiviral therapy is unlikely to succeed. Although viral stop rules varied widely in the phase 2 and 3 trials, week 4 and 12 time points on triple therapy are still key decision points for stopping therapy based on HCV RNA levels. Current data suggest that for patients receiving BOC, therapy should be stopped at week 12 if the viral level is >100 IU/mL or >10-15 IU/mL at treatment week 24 and, for TVR, therapy should be stopped at either week 4 or 12 if the viral level is >1,000 IU/mL or if week 24 HCV RNA is detectable.

Recommendations:

15. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A).

16. Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and the protease inhibitors should be discontinued if virological breakthrough (>1 log increase in serum HCV RNA above nadir) is observed (Class 1, Level A).

17. Patients who fail to have a virological response, who experience virological breakthrough, or who relapse on one protease inhibitor should not be re-treated with the other protease inhibitor (Class 2a, Level C).

Role of IL28B Testing in Decision to Treat and Selection of Therapeutic Regimen

The likelihood of achieving an SVR with PegIFN and RBV and of spontaneous resolution of HCV infection differ depending on the nucleotide sequence near the gene for IL28B or lambda interferon 3 on chromosome 19.18,19 One single-nucleotide polymorphism that is highly predictive is detection of the C or Tallele at position rs12979860.18 The CC genotype is found more than twice as frequently in persons who have spontaneously cleared HCV infection than in those who had progressed to CHC. Among persons with genotype 1 chronic HCV infection who are treated with PegIFN and RBV, SVR is achieved in 69%, 33%, and 27% of Cauca Caucasians

who have the CC, CT, and TT genotypes, respectively; among black patients, SVR rates were 48%, 15%, and 13% for CC, CT, and TT genotypes, respectively.29 The predictive value of IL28B genotype testing for SVR is superior to that of the pretreatment HCV RNA level, fibrosis stage, age, and sex, and is higher for HCV genotype 1 virus than for genotypes 2 and 3 viruses.29,30 There are other polymorphisms near the gene for IL28B that also predict SVR, including detection of the G or T allele at position rs8099917, where T is the favorable genotype, and essentially provides the same information in Caucasians as C at rs12979860.31,32

In one study, as well as in preliminary analyses of the phase 3 registration data, IL28B genotype remained predictive of SVR even in persons taking BOC or TVR.33 In Caucasian patients randomized in the SPRINT 2 trial to take BOC for 48 weeks, SVR was achieved by 80%, 71%, and 59% of patients with CC, CT, and TT genotypes, respectively.34 In Caucasian patients randomized in the ADVANCE trial to take TVR for 12 weeks, SVR was achieved by 90%, 71%, and 73% of patients with CC, CT, and TT genotypes, respectively.35 IL28B genotype also predicts the likelihood of qualifying for RGT. In treatment-naı ¨ve Caucasian patients randomized in SPRINT 2 to BOC, the week 8 HCV RNA threshold was achieved in 89% and 52% of patients with CC and CT/TT genotypes, respectively.34 In treatment-naı¨ve Caucasian patients randomized in the ADVANCE study to TVR, eRVR was achieved in 78%, 57%, and 45% of patients with CC, CT, and TT genotypes, respectively.35 Although the IL28B genotype provides information regarding the probability of SVR and abbreviated therapy that may be important to provider and patient, there are insufficient data to support withholding PIs from persons with the favorable CC genotype because of the potential to abbreviate therapy and the trend for higher SVR rates observed in the TVR study. In addition, the negative predictive value of the Tallele with PI-inclusive therapy is not sufficiently high to restrict therapy for all patients, because SVR was achieved by more than half of Caucasians with the TT genotype.34,35

In summary, these data indicate that IL28B genotype is a significant pretreatment predictor of response to therapy. Consideration should be given to ordering the test when it is likely to influence either the physician’s or patient’s decision to initiate therapy. There are insufficient data to determine whether IL28B testing can be used to recommend selection of SOC over a PI-based regimen with a favorable genotype (CC) and in deciding upon the duration of therapy with either regimen.

Recommendation:

18. IL28B genotype is a robust pretreatment predictor of SVR to peginterferon alfa and ribavirin as well as to protease inhibitor triple therapy in patients with genotype 1 chronic hepatitis C virus infection. Testing may be considered when the patient or provider wish additional information on the probability of treatment response or on the probable treatment duration needed (Class 2a, Level B).

Special Populations

There is a paucity of information for many of the subgroups with the greatest unmet need for treatment (e.g., patients coinfected with HIV and HCV, those with decompensated cirrhosis, and those after liver transplantation). Data from phase 1 and 2 trials have provided interim information that may guide related treatment issues. BOC and TVR undergo extensive hepatic metabolism, BOC primarily by way of the aldoketoreductase (AKR) system but also by the cytochrome P450 enzyme system, whereas TVR is metabolized only by the cytochrome P450 enzyme system, and the main route of elimination is via the feces with minimal urinary excretion. Thus, no dose adjustment of BOC or TVR is required in patients with renal insufficiency. No clinically significant differences in pharmacokinetic parameters were observed with varying degrees of chronic liver impairment in patients treated with BOC and therefore, no dosage adjustment of this drug is required in patients with cirrhosis and liver impairment. Although TVR may be used to treat patients with mild hepatic impairment (Child-Turcotte-- Pugh class A, score 5 or 6), it should not be used in HCV-infected patients with moderate to severe hepatic impairment, because no pharmacokinetic or safety data are available regarding its use in such patients. As noted above, BOC and TVR are both inhibitors of CYP3A4, and concomitant administration of medications known to be CYP3A4 substrates should be done with caution and under close clinical monitoring. Pharmacokinetic interactions have particular implications in HIV-coinfected and transplant populations, where drug?drug interactions will complicate treatment paradigms, so that any use of BOC or TVR in transplant or HIVcoinfected populations of patients with HCV should be done with caution and under close clinical monitoring. TVR and BOC are not recommended for use in children and adolescents younger than 18 years of age, because the safety and efficacy has not been established in this population. Thus, whereas BOC and TVR have great promise for improved SVR in special populations, many complex treatment issues remain to be evaluated

in further phase 2 and 3 testing.

 

 

Table 1. Grading System for Recommendations

Classification          Description

Class 1               Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective

Class 2               Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure, or treatment

Class 2a              Usefulness/efficacy is less well established by evidence/opinion

Class 3               Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful

Level of Evidence      Description

Level A              Data derived from multiple randomized clinical trials or meta-analyses

Level B              Data derived from a single randomized trial, or nonrandomized studies

Level C              Only consensus opinion of experts, case studies, or standard-of-care

 

Fig. 1. Sustained virological response (SVR) rates, overall and according to race, in treatment-naı ¨ve patients with genotype 1 chronic HCV infection: Boceprevir (BOC) plus peginterferon (PegIFN) and ribavirin (RBV) versus standard of care (SOC). All patients were first treated with PegIFN t RBV for 4 weeks as lead-in therapy followed by one of three regiments: (1) BOC/PegIFN/RBV RGT - triple therapy for 24 weeks provided HCV RNA levels were negative weeks 8 thorugh 24 ? response guided therapy; those with a detectable HCV RNA level between weeks 8 and 24 received SOC for an additional 20 weeks; (2) BOC/PegIFN/RBV fixed duration - triple therapy for a fixed duration of 44 weeks; and (3) SOC - consisted of PegIFN and weight based RBV administered for 48 weeks.12

 

 

Fig. 2. Sustained virological response (SVR) rates, overall and based on a rapid virological response (RVR, undetectable HCV RNA at week 8 [week 4 of triple therapy]) in treatment-naı ¨ve patients with genotype 1 chronic HCV infection: Boceprevir (BOC) plus peginterferon (PegIFN) versus standard of care (SOC). All patients were first treated with PegIFN t RBV for 4 weeks as lead-in therapy followed by one of three regiments: (1) BOC/PegIFN/RBV RGT - patients who achieved an RVR (undetable HCV RNA at week 8 [week 4 of triple therapy]) continued treatment for an additional 24 weeks (RGT - response guided therapy); if an RVR did not develop, treatment with triple therapy continued to week 28 followed by SOC treatment for 20 weeks. SOC treatment consisted of PegIFN and RBV administered for 48 weeks.12 Note that the combined numbers of RVR-positive and RVR-negative patients are not equivalent to the total number of patients enrolled, presumably because of missing HCV RNA values at the week 8 time point.

 

Table 2. Comparison of Protease Inhibitors in Combination with Peginterferon Alfa (PegIFN) and Ribavirin (RBV) in Treatment-Naive Subjects

Variable                           Boceprevir (BOC)12                          Telaprevir (TVR)16        

Study design                       RCT                                        RCT       

4-Week lead-in PegIFN/RBV          Yes                                         No

Duration of triple therapy             24 or 44 weeks in combination with PegIFN/RBV*   12 weeks followed by 12 or 36 weeks PegIFN/RBV†

Response-guided therapy (RGT)        Yes                                         Yes

Eligible for response-guided therapy (%)  44                                         58

SVR (%)                           BOC44/PR: 66                               T8PR: 69

 BOC/PR/RGT: 63                            T12PR: 75

SOC: 38                                    SOC: 44

End of treatment response (%)           BOC44/PR: 76                              T8PR: 81

 BOC/PR/RGT: 71                            T12PR: 87 SOC: 53 SOC: 63

Relapse (%)                         BOC44/PR: 9                                T8PR: 9

BOC/PR/RGT: 9                             T12PR: 9 SOC: 22 SOC: 28

Treatment emergent resistance (%)       16                                         12

Adverse event more frequent in

triple therapy arm compared to SOC      Anemia, dysgeusia                            Rash, anemia, pruritus, nausea, diarrhea Adverse events leading to

treatment discontinuation (%)           NA                                        12

Serious adverse events s

tudy drug vs SOC (%)                11 vs 9                                      9 vs 7

NA, not available; PR, peginterferon plus ribavirin; RCT, randomized, controlled trial; SOC, standard of care; SVR, sustained virological response. *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/PR/RGT: 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) BOC44/PR: BOC, PegIFN, and RBV administered for a fixed duration of 44 weeks; and (3) SOC: PegIFN alfa-2b and weight-based RBV alone continued

for an additional 44 weeks. †Telaprevir (TVR) plus peginterferon and ribavirin (PR) treatment for 8 (T8PR) or 12 (T12PR) weeks versus standard of care (SOC). 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.

 

 

Fig. 3. Sustained virological response (SVR) rates, overall and according to race, in treatment naı ¨ve patients with genotype 1 chronic HCV infection: Telaprevir (TVR) plus peginterferon and ribavirin (PR) treatment for 8 (T8PR) or 12 (T12PR) weeks versus standard of care (SOC). Patients in the triple therapy arms who developed an eRVR (extended rapid virological response; defined as undetectable HCV RNA at weeks 4 and 12) stopped treatment at week 24 (responseguided therapy, RGT); if eRVR did not develop, treatment continued to 48 weeks. SOC treatment consisted of PegIFN and RBV administered for 48 weeks.16

Fig. 4. Sustained virological response (SVR) rates in treatment naıve patients with genotype 1 chronic HCV infection: Telaprevir (TVR) plus peginterferon and ribavirin (PR) results overall and among those who did or did not achieve an eRVR (extended rapid virological response; undetectable HCV RNA at weeks 4 and 12). Patients who achieved an eRVR were randomized at week 20 to receive an additional 4 or an additional 28 weeks of SOC therapy; those who did not develop an eRVR were not randomized and all received an additional 24 weeks of SOC therapy.22

 

Table 3. Comparison of Protease Inhibitors in Combination with Peginterferon Alfa (PegIFN) and Ribavirin (RBV) in Treatment-Experienced Patients

Variable                     Boceprevir (BOC)13                 Telaprevir (TVR)17 Study design                  RCT                              RCT

4-Week lead-in PegIFN/RBV    Yes                               Yes/No*

Duration of triple therapy                  32 or 44 weeks in combination with PegIFN and RBV**  12 weeks followed by 36 weeks of PegIFN and RBV***

Response-guided therapy (RGT)  Yes                               No

Eligible for RGT (%)           46                                NA

Prior response to PegIFN/RBV (%)

Relapser                     64                                53

Partial responder               36                               19

Null responder                NA                               28

Efficacy, SVR (%)

Relapser                     BOC/PR48: 75                      T12/PR48: 83

BOC/RGT: 69                       LI-T12/PR48: 88

PR48: 29                           PR48: 24

Partial responder              BOC/PR48: 52                      T12/PR48: 59

BOC/RGT: 40                       LI-T12/PR48: 54

PR48: 7                            PR48: 15

Null responder                NA                               T12/PR48: 29

LI-T12/PR48: 33

PR48: 5

Overall relapse (%)            12-15                              NA

Relapser                     NA                               T12/PR48: 7

LI-T12/PR48: 7

PR48: 65

Partial responder               NA                              T12/PR48: 21

LI-T12/PR48: 25

PR48: 0

Null responder                  NA                               T12/PR48: 27

LI-T12/PR48: 25

PR48: 60

Adverse events

Discontinuation (%)            8-12                              NA

SAE (%)                     10-14                             11-15

Adverse event more frequent

in triple therapy arm            Anemia, dysgeusia                  Rash, anemia, pruritus         nausea, diarrhea

NA, not available; PR, peginterferon plus ribavirin; RCT, randomized, controlled trial; SAE, serious adverse event; SVR, sustained virological response. *A lead-in arm was included in the telaprevir retreatment trial but the FDA approved regimen did not include a lead-in strategy. †The BOC trial design included a 4-week lead-in phase of PegIFN and RBV and compared response-guided triple therapy and a fixed duration triple therapy given for 44 weeks to peginterferon and ribavirin therapy. BOC/RGT responseguided therapy patients who achieved an eRVR (undetectable HCV RNA at week 8 [week 4 of triple therapy]) received an additional 24 weeks (total 32 weeks of therapy). If an eRVR was not achieved but HCV RNA became undetectable at week 12, BOC was stopped at week 32, and patients received an additional 12 weeks of SOC treatment (total 48 weeks of therapy). BOC/PR48: 4-week lead-in with peginterferon and ribavirin followed by a fixed duration of triple therapy for 44 weeks; PR48: PegIFN and RBV administered for 48 weeks. ‡Telaprevir (TVR) plus peginterferon and ribavirin (PR) administered with and without a 4 week SOC treatment lead in versus standard of care (SOC). T12PR48: TVR administered for 12 weeks followed by 36 weeks of peginterferon and ribavirin; LI-T12/PR48: peginterferon and ribavirin for 4 weeks followed by TVR plus peginterferon and ribavirin for 12 weeks, followed by peginterferon and ribavirin for 32 weeks; PR48: peginterferon and ribavirin administered for 48 weeks.

 

Fig. 5. Sustained virological response (SVR) rates, overall and among relapsers and partial responders, in treatment experienced patients with genotype 1 chronic HCV infection: Boceprevir (BOC) plus peginterferon and ribavirin (PR) versus standard of care (SOC). All patients were first treated with PegIFN and RBV for 4 weeks as lead-in therapy followed by one of 3 regimens: (1) BOC/PR48 triple therapy for 44 weeks. (2) BOC RGT triple therapy for 32 weeks if an eRVR was achieved (undetecatble HCV RNA at week 8 and 12). If an eRVR was not achieved, but HCV RNA became undetectable at week 12, BOC was stopped at week 32 and patients received an additional 12 weeks of SOC treatment (total 48 weeks of therapy). (3) SOC treatment consisted of PegIFN and RBV administered for 48 weeks.13

 

Fig. 6. Sustained virological response (SVR) rates, overall and among relapsers, partial responders, and null responders, in treatment-experienced patients with genotype 1 chronic HCV infection. T12PR48: Telaprevir (TVR) plus peginterferon and ribavirin (PR) administered for 12 weeks followed by 36 PR for 12 weeks followed by PR for 32 weeks; SOC consisted of PegIFN and RBV administered for 48 weeks.17