Reviewer's report
Title:Early virological response is a predictor of treatment response in
sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center
"real-life" cohort
Version:1Date:18 May 2015
Reviewer: Malte Wehmeyer
Reviewer's report:
Steinebrunner et al provide a multi-center, “real-life“ study which evaluates the
safety and efficacy of sofosbuvir-based triple-therapy (SOF/PR) or dual therapy
with sofosbuvir and ribavirin (SOF/RBV) in 118 consecutive patients. Importantly,
they included a large number of patients with liver cirrhosis and treatment
experienced patients. Interestingly, contradictory to previous studies, early
virological response (or rapid virological response, RVR) was predictive for
SVR12 in this study. Taking the high costs of the new all-oral treatment regimens
into account (such as sofosbuvir/ledipasvir or
ombitasvir/paritaprevir/ritonavir/dasabuvir with or without RBV), the results are
still of interest, as SOF/PR and SOF/RBV may remain the standard of care for
chronic HCV infections in many regions of the world for some time. Especially the
data on HCV genotype 3 infected patients is of importance, as genotype 3
patients are considered “difficult to treat” in the era of direct acting antivirals.
However, some major and minor issues have to be addressed:
Minor issues:
Abstract:
1. Line 34-41: The results section of the abstract should be rewritten to include
more detail on the impact of a RVR on the treatment outcome (numbers of
patients, p-value).
2. Line 42-44: The impact of a RVR should be briefly discussed in the
conclusions section of the abstract, because it represents the key finding of this
analysis.
3. Line 29: Please write “limited data” instead of “restricted data”.
Introduction:
4. The second paragraph of the introduction section should be abbreviated, as
telaprevir- and boceprevir-based regimens are now only of historical interest.
Therefore, from my point of view the lines 59 to 64 could be deleted from the
manuscript. Alternatively, “real-life” studies on the first gen PIs which showed
inferior results as compared to the phase III studies should be cited.
Patients and Methods:
5. Line 90: Which HCV-PCR (e.g. TaqMan?) was used and what was the lower
limit of detection?
6. Line 93-96: SVR12 is widely recognized as a parameter to assess cure rates
in patients with chronic HCV infection. I think this fact needs no further discussion
in the Methods section.
7. Line 99-100: The sentence “These non-invasive assessments are considered
sufficient for identifying patients with cirrhosis as described in the EASL
guidelines [16]” is unnecessary in the Methods section, as Fibroscan is
universally accepted in daily clinical routine. Therefore, this sentence may be
deleted from the revised manuscript.
Results:
8. If there were no severe adverse events, this should be clearly stated in the
manuscript. Furthermore, were there any baseline predictors of side-effects
besides the use of peginterferon (e.g. thrombocytes and/or albumin)?
9. Was there an impact of the interleukin 28B haplotype on treatment outcome? If
there are no such data, it should be discussed as a limitation of the study. Maybe
IL28B is available in a subset of patients?
10. Are there any data with regard to dose reduction of pegIFN and/or RBV?
How many patients needed a dose reduction of the respective drug and were
patients with a need for dose reduction at an increased risk for virological failure?
Discussion:
11. Line 158-165: As discussed above, I do not think that the historical
restrictions and problems with the first generational NS3/4A inhibitor-based
treatment regimens are relevant to this study. Instead, the discussion should
begin with a presentation of the key findings of this study.
12. Are there available data on baseline and post-treatment RAVs? This might be
one of the most important topics in HCV treatment in the future. If such data are
not available, it should be discussed as a limitation of the study.
13. The discussion section should be shortened, as large paragraphs only
discuss the findings of the phase II and III trials for sofosbuvir.
14. Line 230-235: The important question is, if an improvement of the MELD
score translates to an improvement of the patients’ outcome.
Major issues:
Results:
15. I think the readers of a “real-life” study want the manuscript to include an
additional “intention to treat” analysis. Therefore, the patient who was
non-compliant should be included in this additional analysis.
16. As some SOF/PR patients received 24 weeks of treatment, was there an
impact of the treatment duration on the virological outcome? Please provide an
appropriate analysis.
17. It would be interesting to know, if the impact of a RVR on the chance for SVR
was associated with peginterferon. Therefore, what was the impact of an early
virological response in patients receiving SOF/PR and in patients who only
received SOF/RBV. I am aware that this subgroup analysis may be difficult in this
small number of patients, but I think it would be most important to address this
issue.
18. A change in bilirubin from baseline to SVR12 is described: please provide the
change in the MELD score in the cirrhotic patients from baseline to SVR12. Was
there a statistical significant improvement of the MELD score?
Discussion:
19. Line 221-229: You correctly cite that RVR was only of limited use in previous
studies on modern DAA-containing regimens. Therefore, it should be analyzed
and discussed, if a RVR is only a predictor for SVR in patients receiving an
interferon-containing regimen or in general.
Conclusions:
20. Formally, the conclusion that SOF-based therapies are superior to first gen
PI-based therapies cannot be drawn of the data from this study, as there was no
(historical) control group. Therefore it should be concluded that SOF-based
therapy leads to high rates of SVR12 and is safe.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
Publishing of manuscripts in the same field. Otherwise, I declare that I have no
competing interests.
Reviewer's report
Title:Early virological response is a predictor of treatment response in
sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center
"real-life" cohort
Version:1Date:18 May 2015
Reviewer: Malte Wehmeyer
Reviewer's report:
Steinebrunner et al provide a multi-center, “real-life“ study which evaluates the
safety and efficacy of sofosbuvir-based triple-therapy (SOF/PR) or dual therapy
with sofosbuvir and ribavirin (SOF/RBV) in 118 consecutive patients. Importantly,
they included a large number of patients with liver cirrhosis and treatment
experienced patients. Interestingly, contradictory to previous studies, early
virological response (or rapid virological response, RVR) was predictive for
SVR12 in this study. Taking the high costs of the new all-oral treatment regimens
into account (such as sofosbuvir/ledipasvir or
ombitasvir/paritaprevir/ritonavir/dasabuvir with or without RBV), the results are
still of interest, as SOF/PR and SOF/RBV may remain the standard of care for
chronic HCV infections in many regions of the world for some time. Especially the
data on HCV genotype 3 infected patients is of importance, as genotype 3
patients are considered “difficult to treat” in the era of direct acting antivirals.
However, some major and minor issues have to be addressed:
Minor issues:
Abstract:
1. Line 34-41: The results section of the abstract should be rewritten to include
more detail on the impact of a RVR on the treatment outcome (numbers of
patients, p-value).
2. Line 42-44: The impact of a RVR should be briefly discussed in the
conclusions section of the abstract, because it represents the key finding of this
analysis.
3. Line 29: Please write “limited data” instead of “restricted data”.
Introduction:
4. The second paragraph of the introduction section should be abbreviated, as
telaprevir- and boceprevir-based regimens are now only of historical interest.
Therefore, from my point of view the lines 59 to 64 could be deleted from the
manuscript. Alternatively, “real-life” studies on the first gen PIs which showed
inferior results as compared to the phase III studies should be cited.
Patients and Methods:
5. Line 90: Which HCV-PCR (e.g. TaqMan?) was used and what was the lower
limit of detection?
6. Line 93-96: SVR12 is widely recognized as a parameter to assess cure rates
in patients with chronic HCV infection. I think this fact needs no further discussion
in the Methods section.
7. Line 99-100: The sentence “These non-invasive assessments are considered
sufficient for identifying patients with cirrhosis as described in the EASL
guidelines [16]” is unnecessary in the Methods section, as Fibroscan is
universally accepted in daily clinical routine. Therefore, this sentence may be
deleted from the revised manuscript.
Results:
8. If there were no severe adverse events, this should be clearly stated in the
manuscript. Furthermore, were there any baseline predictors of side-effects
besides the use of peginterferon (e.g. thrombocytes and/or albumin)?
9. Was there an impact of the interleukin 28B haplotype on treatment outcome? If
there are no such data, it should be discussed as a limitation of the study. Maybe
IL28B is available in a subset of patients?
10. Are there any data with regard to dose reduction of pegIFN and/or RBV?
How many patients needed a dose reduction of the respective drug and were
patients with a need for dose reduction at an increased risk for virological failure?
Discussion:
11. Line 158-165: As discussed above, I do not think that the historical
restrictions and problems with the first generational NS3/4A inhibitor-based
treatment regimens are relevant to this study. Instead, the discussion should
begin with a presentation of the key findings of this study.
12. Are there available data on baseline and post-treatment RAVs? This might be
one of the most important topics in HCV treatment in the future. If such data are
not available, it should be discussed as a limitation of the study.
13. The discussion section should be shortened, as large paragraphs only
discuss the findings of the phase II and III trials for sofosbuvir.
14. Line 230-235: The important question is, if an improvement of the MELD
score translates to an improvement of the patients’ outcome.
Major issues:
Results:
15. I think the readers of a “real-life” study want the manuscript to include an
additional “intention to treat” analysis. Therefore, the patient who was
non-compliant should be included in this additional analysis.
16. As some SOF/PR patients received 24 weeks of treatment, was there an
impact of the treatment duration on the virological outcome? Please provide an
appropriate analysis.
17. It would be interesting to know, if the impact of a RVR on the chance for SVR
was associated with peginterferon. Therefore, what was the impact of an early
virological response in patients receiving SOF/PR and in patients who only
received SOF/RBV. I am aware that this subgroup analysis may be difficult in this
small number of patients, but I think it would be most important to address this
issue.
18. A change in bilirubin from baseline to SVR12 is described: please provide the
change in the MELD score in the cirrhotic patients from baseline to SVR12. Was
there a statistical significant improvement of the MELD score?
Discussion:
19. Line 221-229: You correctly cite that RVR was only of limited use in previous
studies on modern DAA-containing regimens. Therefore, it should be analyzed
and discussed, if a RVR is only a predictor for SVR in patients receiving an
interferon-containing regimen or in general.
Conclusions:
20. Formally, the conclusion that SOF-based therapies are superior to first gen
PI-based therapies cannot be drawn of the data from this study, as there was no
(historical) control group. Therefore it should be concluded that SOF-based
therapy leads to high rates of SVR12 and is safe.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
Publishing of manuscripts in the same field. Otherwise, I declare that I have no
competing interests.
Please review this paper.
user
Reviewer's report
Title:Early virological response is a predictor of treatment response in
sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center
"real-life" cohort
Version:1Date:18 May 2015
Reviewer: Malte Wehmeyer
Reviewer's report:
Steinebrunner et al provide a multi-center, “real-life“ study which evaluates the
safety and efficacy of sofosbuvir-based triple-therapy (SOF/PR) or dual therapy
with sofosbuvir and ribavirin (SOF/RBV) in 118 consecutive patients. Importantly,
they included a large number of patients with liver cirrhosis and treatment
experienced patients. Interestingly, contradictory to previous studies, early
virological response (or rapid virological response, RVR) was predictive for
SVR12 in this study. Taking the high costs of the new all-oral treatment regimens
into account (such as sofosbuvir/ledipasvir or
ombitasvir/paritaprevir/ritonavir/dasabuvir with or without RBV), the results are
still of interest, as SOF/PR and SOF/RBV may remain the standard of care for
chronic HCV infections in many regions of the world for some time. Especially the
data on HCV genotype 3 infected patients is of importance, as genotype 3
patients are considered “difficult to treat” in the era of direct acting antivirals.
However, some major and minor issues have to be addressed:
Minor issues:
Abstract:
1. Line 34-41: The results section of the abstract should be rewritten to include
more detail on the impact of a RVR on the treatment outcome (numbers of
patients, p-value).
2. Line 42-44: The impact of a RVR should be briefly discussed in the
conclusions section of the abstract, because it represents the key finding of this
analysis.
3. Line 29: Please write “limited data” instead of “restricted data”.
Introduction:
4. The second paragraph of the introduction section should be abbreviated, as
telaprevir- and boceprevir-based regimens are now only of historical interest.
Therefore, from my point of view the lines 59 to 64 could be deleted from the
manuscript. Alternatively, “real-life” studies on the first gen PIs which showed
inferior results as compared to the phase III studies should be cited.
Patients and Methods:
5. Line 90: Which HCV-PCR (e.g. TaqMan?) was used and what was the lower
limit of detection?
6. Line 93-96: SVR12 is widely recognized as a parameter to assess cure rates
in patients with chronic HCV infection. I think this fact needs no further discussion
in the Methods section.
7. Line 99-100: The sentence “These non-invasive assessments are considered
sufficient for identifying patients with cirrhosis as described in the EASL
guidelines [16]” is unnecessary in the Methods section, as Fibroscan is
universally accepted in daily clinical routine. Therefore, this sentence may be
deleted from the revised manuscript.
Results:
8. If there were no severe adverse events, this should be clearly stated in the
manuscript. Furthermore, were there any baseline predictors of side-effects
besides the use of peginterferon (e.g. thrombocytes and/or albumin)?
9. Was there an impact of the interleukin 28B haplotype on treatment outcome? If
there are no such data, it should be discussed as a limitation of the study. Maybe
IL28B is available in a subset of patients?
10. Are there any data with regard to dose reduction of pegIFN and/or RBV?
How many patients needed a dose reduction of the respective drug and were
patients with a need for dose reduction at an increased risk for virological failure?
Discussion:
11. Line 158-165: As discussed above, I do not think that the historical
restrictions and problems with the first generational NS3/4A inhibitor-based
treatment regimens are relevant to this study. Instead, the discussion should
begin with a presentation of the key findings of this study.
12. Are there available data on baseline and post-treatment RAVs? This might be
one of the most important topics in HCV treatment in the future. If such data are
not available, it should be discussed as a limitation of the study.
13. The discussion section should be shortened, as large paragraphs only
discuss the findings of the phase II and III trials for sofosbuvir.
14. Line 230-235: The important question is, if an improvement of the MELD
score translates to an improvement of the patients’ outcome.
Major issues:
Results:
15. I think the readers of a “real-life” study want the manuscript to include an
additional “intention to treat” analysis. Therefore, the patient who was
non-compliant should be included in this additional analysis.
16. As some SOF/PR patients received 24 weeks of treatment, was there an
impact of the treatment duration on the virological outcome? Please provide an
appropriate analysis.
17. It would be interesting to know, if the impact of a RVR on the chance for SVR
was associated with peginterferon. Therefore, what was the impact of an early
virological response in patients receiving SOF/PR and in patients who only
received SOF/RBV. I am aware that this subgroup analysis may be difficult in this
small number of patients, but I think it would be most important to address this
issue.
18. A change in bilirubin from baseline to SVR12 is described: please provide the
change in the MELD score in the cirrhotic patients from baseline to SVR12. Was
there a statistical significant improvement of the MELD score?
Discussion:
19. Line 221-229: You correctly cite that RVR was only of limited use in previous
studies on modern DAA-containing regimens. Therefore, it should be analyzed
and discussed, if a RVR is only a predictor for SVR in patients receiving an
interferon-containing regimen or in general.
Conclusions:
20. Formally, the conclusion that SOF-based therapies are superior to first gen
PI-based therapies cannot be drawn of the data from this study, as there was no
(historical) control group. Therefore it should be concluded that SOF-based
therapy leads to high rates of SVR12 and is safe.
Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being
published
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
Publishing of manuscripts in the same field. Otherwise, I declare that I have no
competing interests.
assistant