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Recommendations for Testing, Managing, and Treating Hepatitis C from AASLD and IDSA

Feb 09, 2014 - 1 comments
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hepatitis c treatment

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Retreatment of Hepatitis C

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Hep C prior treatment failed



Below are two sections from the recently released AASLD and IDSA recommendations for testing, managing, and treating Hepatitis C, specifically retreatment of persons in whom prior therapy has failed.  Links are posted below each section.
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Recommendations for Testing, Managing, and Treating Hepatitis C

RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED

A summary of recommendations for retreatment

This section provides guidance on the retreatment of a person with chronic HCV infection in whom prior therapy has failed. In general, treatment responses of patients achieving an undetectable level of virus during a prior treatment course who relapse following cessation of therapy (relapser) are similar to those of treatment-naive persons. Treatment responses are generally lower in prior non-responders, which includes null responders (those in whom serum HCV RNA levels declined less than 2 log10 IU/mL by week 12 during a prior treatment course) and partial responders (those with a > 2 log10 IU/mL response whose virus remained detectable up to 24 weeks or the end of treatment). This section assumes that a decision to treat has been made and advises on the optimal treatment. In many instances, however, it may be advisable to delay treatment for some patients with documented early fibrosis stage (F 0-2), because waiting for future highly effective, pangenotypic, combinations in IFN-free regimens may be prudent. Potential advantages of waiting to begin to treatment will be provided in a future update to this guidance.

The level of the evidence supporting the best treatment for each patient and the corresponding confidence in the recommendation varies as does the strength of the recommendation, and is graded in the same manner as the section on initial treatment of treatment-naive patients. In addition, when treatment differs for a particular group (eg, those infected with various genotypes) specific recommendations are given. Regimens are classified as "Recommended" when it is favored for most patients or "Alternative" when it might be optimal in a particular subset of patients in that category. When a treatment is clearly inferior or should not be used, it is classified as "Not Recommended."

As always, patients receiving antiviral therapy require careful pretreatment assessment for comborbidities that may influence treatment response. All patients should have careful monitoring during treatment, particularly for anemia if ribavirin is included in the regimen.

I. Genotype 1

Recommended regimen for HCV genotype 1 PEG/RBV (without an HCV protease inhibitor) nonresponder patients:
Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [75 kg]) for 12 weeks is recommended for retreatment of HCV genotype 1 infection, regardless of subtype or IFN eligibility

Rating: Class IIa, Level B

COSMOS is a phase 2a randomized trial in which participants received sofosbuvir (400 mg once daily) plus simeprevir (150 mg once daily) with or without weight-based RBV (1000 mg to 1200 mg daily) for 12 or 24 weeks (Jacobson, 2013b). Of the 80 null responders with a Metavir fibrosis stage of 2 or less included in this trial, 79% to 96% achieved SVR (79%-96% in RBV-containing arms and 93% in both RBV-free arms). Among those null responders with a Metavir fibrosis stage of 3 or 4 (n=47) who received 12 weeks of sofosbuvir and simeprevir, SVR4 was observed in 14 (93%) of 15 patients in the ribavirin-containing arm and 100% (all 7 participants) in the RBV-free arm. Although benefit from RBV is not apparent from these preliminary results, it cannot be excluded before availability of SVR12 data. Post-treatment results are not yet available for the 24-week arms. Excluding nonvirologic failures, patients with HCV genotype 1a with Q80K mutations had slightly lower numeric response rates (fibrosis stage 0-2: SVR12=89% [n=27]; fibrosis stage 3 or 4: SVR4=91% [n=11]) than genotype 1a patients without Q80K and genotype 1b (fibrosis stage 2: SVR12 100%, n=47; fibrosis stage 3 or 4: SVR4=100% [n=29]). However, because the study was not powered to assess this comparison, insufficient evidence exists on the role of testing for the Q80K mutation at this time. These regimens were well tolerated, although adverse events (eg, anemia and hyperbilirubinemia) were seen more often in patients on RBV-containing regimens. (Jacobson, 2013b)
The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The uncertain impact of cholestasis and the occasional association of SMV with elevated transaminases create potential for drug accumulation or impaired hepatic function during SMV use. Clinical trials with SMV have been limited to patients with compensated disease who have CTP class A, total bilirubin of 1.5 x ULN or lower, and transaminases 10 x ULN or lower. For these reasons, simeprevir use should be limited to patients with compensated liver disease. Use of simeprevir is not recommended in patients with moderate to severe hepatic impairment. The combination of PEG/RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C).

Alternative regimen for PEG/RBV (with or without an HCV protease inhibitor) nonresponder patients with HCV genotype 1 who are eligible to receive IFN.

Daily sofosbuvir (400 mg) for 12 weeks and weight-based RBV (1000 mg [75 kg]) plus weekly PEG for 12 to 24 weeks is an alternative for retreatment of IFN-eligible persons with HCV genotype 1 infection, regardless of subtype.

Rating: Class IIb, Level C

NEUTRINO is an open-label, single-arm trial that evaluated 12 weeks of sofosbuvir plus PEG/RBV in treatment-naive subjects with HCV genotypes 1, 4, 5, or 6; 89% had HCV genotype 1, and 17% had cirrhosis. The SVR was 89% (261 of 292) and was somewhat lower in patients with genotype 1b than 1a (82% and 92%, respectively) and those with cirrhosis versus those without (80% versus 92%, respectively). (Lawitz, 2013a) Although treatment-experienced subjects were not included in this study, FDA estimates that the response rate in such patients would approximate the observed response rate in those NEUTRINO subjects with baseline factors traditionally associated with a lower response to IFN-based treatment. (US FDA, 2013a) In the NEUTRINO trial, SVR rate was 71% among participants with HCV genotype 1 with IL28B non-C/C alleles, high HCV RNA levels, and METAVIR 1 fibrosis stage F3 or F4 (37 of 52 patients). (Gilead Sciences, 2013; Solvadi package insert)

Alternative regimen for PEG/RBV (without an HCV protease inhibitor) nonresponder patients with HCV genotype 1 who are eligible to receive IFN.

Daily simeprevir (150 mg) for 12 weeks plus weight-based RBV (1000 mg [75 kg]) and weekly PEG for 48 weeks is an alternative for IFN-eligible persons with HCV genotype 1 infection. (All patients with cirrhosis who are receiving simeprevir should have well compensated liver disease.)

Rating: Class IIa, Level A

Simeprevir was combined with PEG/RBV in patients who had previously failed to respond to PEG/RBV dual therapy in the Phase 2b ASPIRE trial. (Zeuzem, 2013a); (Janssen Therapeutics, 2013) (www.fda.gov; package insert). SVR24 after 48 weeks of triple therapy in the simeprevir 150 mg/day arm was 65% in patients with a previous partial response (n=23) and 53% in patients with a prior null response (n=17). Patients with HCV genotype 1a infection had inferior response rates compared with those with genotype 1b (SVR24: 47% vs 77% in patients with a partial response and 41% vs 47% in patients with a null response, respectively). Despite lower SVR in patients with HCV genotype 1a infection, SVR rates were similar with and without the presence of the Q80K mutations at baseline. SVR rates in patients with advanced fibrosis (METAVIR stage F3 or F4) treated with simeprevir (150 mg daily) plus PEG/RBV for 48 weeks were 59% in patients with a partial response (n=33) and 35% in patients with a null response (n=34). Safety in patients exposed to simeprevir was similar to that of persons in the placebo arms; however, there was a higher incidence of hyperbilirubinemia (8%) and photosensitivity/rash (5%). (Zeuzem, 2013a)

The safety and efficacy of simeprevir have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The uncertain impact of cholestasis and the occasional association of simeprevir with elevated transaminases pose potential for impaired hepatic function during simeprevir use. Clinical trials with simeprevir have been limited to patients with compensated disease who have CTP class A, total bilirubin level of 1.5 x ULN or lower, and transaminase level of 10 x ULN or lower. For these reasons, simeprevir use should be limited to patients with compensated liver disease. Use of simeprevir is not recommended in patients with moderate to severe hepatic impairment. Use of the drug in this population is not recommended at this time. The combination of PEG/RBV is contraindicated in patients with decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C).

The following regimens are NOT recommended for PEG/RBV (with or without an HCV protease inhibitor) nonresponder patients with HCV genotype 1:

PEG/RBV with or without telaprevir or boceprevir
Rating: Class IIb, Level A

Monotherapy with PEG, RBV, or a DAA
Rating: Class III, Level A

For nonresponder patients with genotype 1 and a history of decompensated cirrhosis (moderate or severe hepatic impairment; CTP class B or C), treatment is not indicated because of the risks of PEG and boceprevir and telaprevir in this population.

Triple therapy with boceprevir plus PEG/RBV for 48 weeks may result in SVR for up to 52% of PEG/RBV partial responders (RESPOND 2; (Bacon, 2011)) and 38% of null responders (PROVIDE; (Di Bisceglie, 2013)). Similarly, telaprevir plus PEG/RBV resulted in SVR24 of 54% to 59% among partial responders and an SVR24 of 29% to 33% among null responders (REALIZE;  (Zeuzem, 2011)). Due to the relatively poor efficacy, prolonged duration of therapy (48 weeks), and poor tolerability, these regimens are no longer recommended.

Monotherapy with PEG, RBV, or any of the available DAAs is ineffective; further, DAA monotherapy leads to rapid selection of resistant variants.

Patients with advanced liver disease are at increased risk for sepsis, worsening decompensation, and death when treated with dual or triple IFN-based therapy. (Crippin, 2002); (Coilly, 2014) Simeprevir is primarily metabolized by the liver and should not be used in patients with advanced cirrhosis (CTP B or C), as the AUC is increased 2.4- to 5.2-fold. (Janssen Therapeutics, 2013) (Olysio package insert, Janssen).

http://hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed


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Retreatment Box. Recommendations for Patients in Whom Previous PEG/RBV Treatment Has Failed

Genotype Recommended Alternative NOT Recommended

Patients in whom previous PEG/RBV has failed*

1 SOF + SMV ± RBV x 12 weeks SOF x 12 weeks + PEG/RBV 12 weeks
SMV x 12 weeks + PEG/RBV x 24 weeks** PEG/RBV ± telaprevir or boceprevir Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG or SMV

2 SOF + RBV x 12 weeks SOF + PEG/RBV x 12 weeks PEG/RBV ± telaprevir or boceprevir
Monotherapy with PEG, RBV, or a direct-acting antiviral agent
Do not treat decompensated cirrhosis with PEG

3 SOF + RBV x 24 weeks SOF + PEG/RBV x 12 weeks PEG/RBV ± any current protease inhibitor
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG

4 SOF x 12 weeks + PEG/RBV 12 weeks
SOF + RBV x 24 weeks SMV x 12 weeks + PEG/RBV x 24-48 weeks PEG/RBV ± any current HCV protease inhibitor
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG

5 or 6 SOF x 12 weeks + PEG/RBV 12 weeks SOF + RBV x 24 weeks PEG/RBV ± any current HCV protease inhibitor
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG

Patients in whom previous treatment with PEG/RBV plus either telaprevir or boceprevir*** has failed †† †††
1a SOF x 12 weeks + PEG/RBV x 24 weeks SOF + RBV x 24 weeks PEG/RBV ± telaprevir or boceprevir or SMV
Monotherapy with PEG, RBV, or a DAA
Do not treat decompensated cirrhosis with PEG or SMV

1b SOF x 12 weeks + PEG/RBV x 12-24 weeks SOF + RBV x 24 weeks
*Non-responder is defined as partial or null response to treatment with PEG/RBV. Relapse to prior therapy should be treated the same as treatment-naive

**For genotype 1a, baseline resistance testing for Q80K should be performed and alternative treatments considered if this mutation is present

*** Non-responder is defined as partial or null response to treatment with PEG/RBV plus telaprevir or boceprevir. Relapse to prior therapy should be treated the same as treatment naive
† Consideration should be given to postponing treatment, pending release of new drugs for patients with limited (F 0-2) hepatic fibrosis

†† A recommendation for simeprevir use for patients with previous telaprevir or boceprevir exposure not provided due to potential risk of preexistant resistance to protease inhibitor treatment.

††† Given the lack of prior approval PI therapy for genotypes 2, 3, 4, 5, 6 and the lack of sufficient data, no recommendations are given for these genotype at this time

http://hcvguidelines.org/full-report/retreatment-box-recommendations-patients-whom-previous-pegrbv-treatment-has-failed


Comments
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317787 tn?1473358451
by Dee1956, Feb 10, 2014
Thank you, this is really interesting. I am so grateful to my doctor for treating me for 24 weeks vs the 48 that was suggested back then.
D

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