Reviewer's report
Title:Safety and efficacy of protease inhibitor based combination therapy in a
single-center "real-life" cohort of 110 hepatitis C genotype 1 patients
Version:2Date:30 January 2014
Reviewer: Benjamin Maasoumy
Reviewer's report:
The study by Wehmeyer et al. concerns an interesting topic that is still up-to date
for many countries where TPR or BOC have just been approved or will be
approved. The paper is well written. Strengths of the study include the detailed
information on certain aspects of triple therapies with P/R/PI. The short case
reports about the patients with severe side effects are nice. The additional figures
are well prepared and offer much important information. However, there are
important aspects that need consideration.
Major Compulsory Revisions
1. Why did the authors not assess the fibrosis stage in almost 10 % of the
patients? What was the rational to treat these patients if the stage of fibrosis was
unknown? How could the authors determine the optimal treatment duration, as
patients with liver cirrhosis (even those without obvious clinical signs) are
ineligible for response-guided therapy?
2. What was the rational to treat patients with comorbidities that raised safety
concerns for an interferon based treatment and would have been exclusion
criteria in the phase III trials. i.e. why did the authors treat a patient with Chron`s
disease or with major depression. Were these patients with liver cirrhosis and
subsequently an urgent need for therapy?
3. What was the rational to treat previous DAA failures? How much time was
between the two therapies? Specific detailed information about these patients
would be important (which DAAs?). Did the authors exclude the presence of PI
resistant variants? Have the patients been pretreated with TPR or BOC or with
other PIs?
4. How were patients selected to receive an off-label lead-in phase? Why is the
mean duration 1.2 weeks? What was the reason to abbreviate or extend the
lead-in phase?
5. Due to the selected time period there is a selection bias. In my opinion it would
have been more appropriate to perform the final analysis 15 months after end of
recruitment. This approach allows every patient that started treatment to achieve
SVR12. According to the selected design of the authors’ outcome data of all
patients that started treatment after October 2012 were only included if a
treatment failure occurred. Four patients are still awaiting SVR assessment. Why
did the authors decide to submit a preliminary analysis instead of performing an
analysis of the final data. What prevented waiting for the last four SVR results if
they are short before week 12 after EOT? Final data should be included.
6. The authors state that SVR results a similar to pivotal drug trials. I agree that
the difference is not as significant as it has been documented in other cohorts
(including more patients with advanced liver disease). Still, the here observed
SVR rates in relapsers and treatment-naïve patients are 12-15% lower than
those observed in the phase III trials.
7. What was the p-value limit for a suspected association? While the authors
state a p-value of <0.05 was considered as significant, they are inconsistent in
assuming possible associations if the significance criteria were not fulfilled.
Author state that RBV dose reduction was associated (not statistically significant
p=0.15)) with SVR and i.e. that patients with HCV GT 1b were more likely to
achieve SVR (this was also not significant, p=0.1). On the other side they see no
impact of the duration of the lead-in phase, although a similar p-value was
calculated (p=0.11 for telaprevir). This is absolutely not accurate. The statements
are not supported by the data.
8. The authors state that early peg-IFN/RBV discontinuation led to treatment
failure. Was this statistically significant?
9. It is surprising that patients treated with BOC experienced fatigue more often
compared with TPR. Was there a difference in the severity of fatigue? What was
the impact of the duration of interferon treatment? This would be important to
conclude whether fatigue is a more severe problem in BOC treated patients.
10. The authors describe their cohort as difficult-to-treat due to the fact that many
patients would have been ineligible for drug trials. I think this is not precise
enough. In previous reports the difficult-to-treat patients occurred to be those with
liver cirrhosis or older age. Interestingly patients with psychiatric disorders did not
have a higher rate of treatment failures or a higher risk for SAE. Therefore the
definition of a difficult-to-treat cohort should be discussed in more detail. More
than half of the treated patients had only mild or even not liver fibrosis. This
seems to be not a difficult-to-treat cohort.
11. The impact of treatment individualization was adequately studied. This should
be removed from the abstract as well as from the discussion section. There is no
clear algorithm how authors decided how to individualize. Furthermore there is
no control group. Authors only analysed the impact of early discontinuation or
RBV dose reduction.
12. While there are no data available to compare the different real-life studies
concerning the frequency of individualized regimens, there are obvious
differences in terms of the studied patient cohort. There no data that support that
a different way of treatment individualization was responsible for a higher SVR
rate. An obvious explanation, which is supported by data, is that the portion of
patients with advanced liver disease (F3/F4) and treatment-experienced patients
was far higher in CUPIC or the here compared Hanover cohort (F3/F4 86% vs.
45% and treatment-experienced 73 vs. 54%).
13. Table 1 should also include information on baseline albumin, bilirubin,
platelets and other lab values.
14. In the discussion authors recommend a careful patient selection. What are
the recommended criteria for the patient selection? What are these based on?
Minor Essential Revisions
1. Are the previous DAA also included in the number of null, partial responder
and relapsers or are they a separate group?
2. Which Roche assay was used for HCV RNA quantification? I do not think that
the officially approved LOD is 10.
3. Table 1 should also include information on baseline albumin, bilirubin, platelets
and other lab values.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
Financial interests:
Fees for speaking/teaching and/or advisory boards from Janssen-Cilaq, MSD,
Roche, Abbott Molecular; Travel support from Abbvie, Janssen-Cilaq, Gilead
Non-financial interests:
Publishing papers in the same field.
Reviewer's report
Title:Safety and efficacy of protease inhibitor based combination therapy in a
single-center "real-life" cohort of 110 hepatitis C genotype 1 patients
Version:2Date:30 January 2014
Reviewer: Benjamin Maasoumy
Reviewer's report:
The study by Wehmeyer et al. concerns an interesting topic that is still up-to date
for many countries where TPR or BOC have just been approved or will be
approved. The paper is well written. Strengths of the study include the detailed
information on certain aspects of triple therapies with P/R/PI. The short case
reports about the patients with severe side effects are nice. The additional figures
are well prepared and offer much important information. However, there are
important aspects that need consideration.
Major Compulsory Revisions
1. Why did the authors not assess the fibrosis stage in almost 10 % of the
patients? What was the rational to treat these patients if the stage of fibrosis was
unknown? How could the authors determine the optimal treatment duration, as
patients with liver cirrhosis (even those without obvious clinical signs) are
ineligible for response-guided therapy?
2. What was the rational to treat patients with comorbidities that raised safety
concerns for an interferon based treatment and would have been exclusion
criteria in the phase III trials. i.e. why did the authors treat a patient with Chron`s
disease or with major depression. Were these patients with liver cirrhosis and
subsequently an urgent need for therapy?
3. What was the rational to treat previous DAA failures? How much time was
between the two therapies? Specific detailed information about these patients
would be important (which DAAs?). Did the authors exclude the presence of PI
resistant variants? Have the patients been pretreated with TPR or BOC or with
other PIs?
4. How were patients selected to receive an off-label lead-in phase? Why is the
mean duration 1.2 weeks? What was the reason to abbreviate or extend the
lead-in phase?
5. Due to the selected time period there is a selection bias. In my opinion it would
have been more appropriate to perform the final analysis 15 months after end of
recruitment. This approach allows every patient that started treatment to achieve
SVR12. According to the selected design of the authors’ outcome data of all
patients that started treatment after October 2012 were only included if a
treatment failure occurred. Four patients are still awaiting SVR assessment. Why
did the authors decide to submit a preliminary analysis instead of performing an
analysis of the final data. What prevented waiting for the last four SVR results if
they are short before week 12 after EOT? Final data should be included.
6. The authors state that SVR results a similar to pivotal drug trials. I agree that
the difference is not as significant as it has been documented in other cohorts
(including more patients with advanced liver disease). Still, the here observed
SVR rates in relapsers and treatment-naïve patients are 12-15% lower than
those observed in the phase III trials.
7. What was the p-value limit for a suspected association? While the authors
state a p-value of <0.05 was considered as significant, they are inconsistent in
assuming possible associations if the significance criteria were not fulfilled.
Author state that RBV dose reduction was associated (not statistically significant
p=0.15)) with SVR and i.e. that patients with HCV GT 1b were more likely to
achieve SVR (this was also not significant, p=0.1). On the other side they see no
impact of the duration of the lead-in phase, although a similar p-value was
calculated (p=0.11 for telaprevir). This is absolutely not accurate. The statements
are not supported by the data.
8. The authors state that early peg-IFN/RBV discontinuation led to treatment
failure. Was this statistically significant?
9. It is surprising that patients treated with BOC experienced fatigue more often
compared with TPR. Was there a difference in the severity of fatigue? What was
the impact of the duration of interferon treatment? This would be important to
conclude whether fatigue is a more severe problem in BOC treated patients.
10. The authors describe their cohort as difficult-to-treat due to the fact that many
patients would have been ineligible for drug trials. I think this is not precise
enough. In previous reports the difficult-to-treat patients occurred to be those with
liver cirrhosis or older age. Interestingly patients with psychiatric disorders did not
have a higher rate of treatment failures or a higher risk for SAE. Therefore the
definition of a difficult-to-treat cohort should be discussed in more detail. More
than half of the treated patients had only mild or even not liver fibrosis. This
seems to be not a difficult-to-treat cohort.
11. The impact of treatment individualization was adequately studied. This should
be removed from the abstract as well as from the discussion section. There is no
clear algorithm how authors decided how to individualize. Furthermore there is
no control group. Authors only analysed the impact of early discontinuation or
RBV dose reduction.
12. While there are no data available to compare the different real-life studies
concerning the frequency of individualized regimens, there are obvious
differences in terms of the studied patient cohort. There no data that support that
a different way of treatment individualization was responsible for a higher SVR
rate. An obvious explanation, which is supported by data, is that the portion of
patients with advanced liver disease (F3/F4) and treatment-experienced patients
was far higher in CUPIC or the here compared Hanover cohort (F3/F4 86% vs.
45% and treatment-experienced 73 vs. 54%).
13. Table 1 should also include information on baseline albumin, bilirubin,
platelets and other lab values.
14. In the discussion authors recommend a careful patient selection. What are
the recommended criteria for the patient selection? What are these based on?
Minor Essential Revisions
1. Are the previous DAA also included in the number of null, partial responder
and relapsers or are they a separate group?
2. Which Roche assay was used for HCV RNA quantification? I do not think that
the officially approved LOD is 10.
3. Table 1 should also include information on baseline albumin, bilirubin, platelets
and other lab values.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
Financial interests:
Fees for speaking/teaching and/or advisory boards from Janssen-Cilaq, MSD,
Roche, Abbott Molecular; Travel support from Abbvie, Janssen-Cilaq, Gilead
Non-financial interests:
Publishing papers in the same field.
Please review this paper.
user
Reviewer's report
Title:Safety and efficacy of protease inhibitor based combination therapy in a
single-center "real-life" cohort of 110 hepatitis C genotype 1 patients
Version:2Date:30 January 2014
Reviewer: Benjamin Maasoumy
Reviewer's report:
The study by Wehmeyer et al. concerns an interesting topic that is still up-to date
for many countries where TPR or BOC have just been approved or will be
approved. The paper is well written. Strengths of the study include the detailed
information on certain aspects of triple therapies with P/R/PI. The short case
reports about the patients with severe side effects are nice. The additional figures
are well prepared and offer much important information. However, there are
important aspects that need consideration.
Major Compulsory Revisions
1. Why did the authors not assess the fibrosis stage in almost 10 % of the
patients? What was the rational to treat these patients if the stage of fibrosis was
unknown? How could the authors determine the optimal treatment duration, as
patients with liver cirrhosis (even those without obvious clinical signs) are
ineligible for response-guided therapy?
2. What was the rational to treat patients with comorbidities that raised safety
concerns for an interferon based treatment and would have been exclusion
criteria in the phase III trials. i.e. why did the authors treat a patient with Chron`s
disease or with major depression. Were these patients with liver cirrhosis and
subsequently an urgent need for therapy?
3. What was the rational to treat previous DAA failures? How much time was
between the two therapies? Specific detailed information about these patients
would be important (which DAAs?). Did the authors exclude the presence of PI
resistant variants? Have the patients been pretreated with TPR or BOC or with
other PIs?
4. How were patients selected to receive an off-label lead-in phase? Why is the
mean duration 1.2 weeks? What was the reason to abbreviate or extend the
lead-in phase?
5. Due to the selected time period there is a selection bias. In my opinion it would
have been more appropriate to perform the final analysis 15 months after end of
recruitment. This approach allows every patient that started treatment to achieve
SVR12. According to the selected design of the authors’ outcome data of all
patients that started treatment after October 2012 were only included if a
treatment failure occurred. Four patients are still awaiting SVR assessment. Why
did the authors decide to submit a preliminary analysis instead of performing an
analysis of the final data. What prevented waiting for the last four SVR results if
they are short before week 12 after EOT? Final data should be included.
6. The authors state that SVR results a similar to pivotal drug trials. I agree that
the difference is not as significant as it has been documented in other cohorts
(including more patients with advanced liver disease). Still, the here observed
SVR rates in relapsers and treatment-naïve patients are 12-15% lower than
those observed in the phase III trials.
7. What was the p-value limit for a suspected association? While the authors
state a p-value of <0.05 was considered as significant, they are inconsistent in
assuming possible associations if the significance criteria were not fulfilled.
Author state that RBV dose reduction was associated (not statistically significant
p=0.15)) with SVR and i.e. that patients with HCV GT 1b were more likely to
achieve SVR (this was also not significant, p=0.1). On the other side they see no
impact of the duration of the lead-in phase, although a similar p-value was
calculated (p=0.11 for telaprevir). This is absolutely not accurate. The statements
are not supported by the data.
8. The authors state that early peg-IFN/RBV discontinuation led to treatment
failure. Was this statistically significant?
9. It is surprising that patients treated with BOC experienced fatigue more often
compared with TPR. Was there a difference in the severity of fatigue? What was
the impact of the duration of interferon treatment? This would be important to
conclude whether fatigue is a more severe problem in BOC treated patients.
10. The authors describe their cohort as difficult-to-treat due to the fact that many
patients would have been ineligible for drug trials. I think this is not precise
enough. In previous reports the difficult-to-treat patients occurred to be those with
liver cirrhosis or older age. Interestingly patients with psychiatric disorders did not
have a higher rate of treatment failures or a higher risk for SAE. Therefore the
definition of a difficult-to-treat cohort should be discussed in more detail. More
than half of the treated patients had only mild or even not liver fibrosis. This
seems to be not a difficult-to-treat cohort.
11. The impact of treatment individualization was adequately studied. This should
be removed from the abstract as well as from the discussion section. There is no
clear algorithm how authors decided how to individualize. Furthermore there is
no control group. Authors only analysed the impact of early discontinuation or
RBV dose reduction.
12. While there are no data available to compare the different real-life studies
concerning the frequency of individualized regimens, there are obvious
differences in terms of the studied patient cohort. There no data that support that
a different way of treatment individualization was responsible for a higher SVR
rate. An obvious explanation, which is supported by data, is that the portion of
patients with advanced liver disease (F3/F4) and treatment-experienced patients
was far higher in CUPIC or the here compared Hanover cohort (F3/F4 86% vs.
45% and treatment-experienced 73 vs. 54%).
13. Table 1 should also include information on baseline albumin, bilirubin,
platelets and other lab values.
14. In the discussion authors recommend a careful patient selection. What are
the recommended criteria for the patient selection? What are these based on?
Minor Essential Revisions
1. Are the previous DAA also included in the number of null, partial responder
and relapsers or are they a separate group?
2. Which Roche assay was used for HCV RNA quantification? I do not think that
the officially approved LOD is 10.
3. Table 1 should also include information on baseline albumin, bilirubin, platelets
and other lab values.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, but I do not feel adequately qualified to assess the
statistics.
Declaration of competing interests:
Financial interests:
Fees for speaking/teaching and/or advisory boards from Janssen-Cilaq, MSD,
Roche, Abbott Molecular; Travel support from Abbvie, Janssen-Cilaq, Gilead
Non-financial interests:
Publishing papers in the same field.
assistant