Reviewer ’s report  
Title: Case report: lactic ac idosis and rhabdomyolysis during telb ivudine and tenofovir treatment 
for chronic hepatitis B  
 
Version: 1 Date: 04 Dec 2017  
 
Reviewer: Yee Hui Yeo  
 
Reviewer's report:  
The authors have made significant improvement this time. Replies and edits are attached:  
1. We  agreed that we should have mentioned the patient`s medical history. The patient hadn`t 
other comorbidities like diabetes and chronic kidney disease. We added the information about 
the medical history in page 5, row 15 -16. 
Reply: It is good to add the pati ent's medical history. It would be better to say "the patient denied 
a past history of significant comorbidities including…" instead of "the patient didn`t has other 
disease history".  
 
2. We were sorry for not presenting important drug history of the patie nt. He didn`t take 
concurrent drugs or Chinese herbs or nutritional supplements except telbivudine and tenofovir. 
The information about drug history was added in page 5, row 16 -17. 
Reply: sounds reasonable now  
 
3. We considered necessary to present the results of other liver function test in page 4, row 21 -
22. His aspartate transaminase was 129U/L. Total bilirubin and indirect bilirubin were normal.  
Reply: It is good to add the patient's ALT and bil data. It woul d be better to write "Total bilirubin 
and indirect bilirubin levels were normal" or "Total bilirubin and indirect bilirubin levels were 
within normal limits" instead of "Total bilirubin and indirect bilirubin were normal".  
 
4. Thank you for pointing out tha t the indication of MRI was not clear. The patient had a history 
of cirrhosis, MRI was aimed to rule out liver cancer. We justified the indication of MRI in page 
4, row 22 and page 5, row 1.  
Reply: Sounds reasonable, would be better if you could say "to ru le out liver cancer" instead of 
"To differentiate liver cancer".  
 
5. We considered it`s right to give more information about the therapy for his acidosis before 
admission. The patient received sodium bicarbonate as the revision showed in page 5, row 4 -5.  
 
6. We appreciated the suggestion about giving more details like urine color and output to 
establish the diagnosis of RM. His urine color was black and urine output was about 200ml per 
day. The electrolytes test was normal, while uric acid was 1.019mmol/L H is follow -up arterial 
blood gas analysis returned to normal, showing pH between 7.40 and 7.45. We added the 
information in page 5, row 7 -8, 10 and page 6, row 11 -12. 
Reply: Sounds reasonable.  
 
7. We agreed that we should have given more details to rule out other cause of RM, like 
infection, injury and other concurrent drugs. To rule out infection, we added the information 
about normal white blood cell count and percentage of neutrophils in page  
5, row 6 -7. Physical examination about no redness and higher ski n temperature on lower 
extremities can also help differentiate infection of muscle, which presented in page 5, row 14 -15. 
To rule out injury and concurrent d rugs, t he information was added in page 5, row 16 -17. The 
description of differential diagnosis was  added in page 6, row 6 -7. 
Reply: please use "warm skin" instead of "higher skin temperature".  
 
8. We agreed to make it clear about the changing strategy of antiviral treatment. The explanation 
and discussion was added in page 10, row 3 -14. At first, we co nverted antiviral therapy to 
entecavir because its lower reporting portion of muscle -related adverse drug reaction. As 
entecavir and telbivudine shared cross -resistance in some HBV variants, it was recommended 
that tenofovir should be the rescue strategy w hen telbivudine resistance occurred according to 
EASL guidelines in 2017. On the other side, tenofovir disoproxil fumarate was recommended as 
first-line monotherapy against hepatitis B with a high barrier to resistance. So far, tenofovir was 
only reported a side effect of rhabdomyolysis during antiretroviral t reatment in HIV patients, 
which combined with other concurrent antiretroviral drugs. In a clinical trialstudying the safety 
of tenofovir monotherapy for 5 years (Marcellin, P., et al., Kinetics of hepa titis B surface antigen 
loss in patients with HBeAg -positive chronic hep atitis B treated with tenofovir disoproxil 
fumarate. J Hepatol, 2014. 61(6): 1228 -37.), the researchers reported no fatal adverse reaction 
like LA or RM. So, we thought tenofovir monot herapy was safe. When the patients` condition 
was steady, we used tenofovir under close monitoring.  
Reply: sounds reasonable now.  
 
9. We did as suggest, moving the clues to clinical presentation part in page 6, row 3 -4. 
 
10. We agreed that it was very import ant to compare the severe adverse events of trials that have 
investigated the safety of Telbivudine +Tenofovir combination therapy in chronic hepatitis B 
patients. Additional discussion is presented in page 10, row 14 - 20. There were no muscle -
related seve re adverse events reported during at most 1 year`s follow -up. For the patient we 
reported, he took telbivudine for two years and suffered myalgia immediately after addition of 
tenofovir, so we conjure that tenofovir sometimes may still have a synergistic e ffect on the 
development of myopathy after much longer medication time, especially in patients with 
cirrhosis.  
Reply: sounds reasonable to refer to the incidence of severe adverse events in previous clinical 
trials. In clinical trials, however, the inclus ion/exclusion criteria is stricter. Therefore, it is 
important to have this case report to demonstrate the real -world findings.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
Yes 
Does the work include the necessary controls?  
If not, ple ase specify which controls are required in your comments to the authors.  
Unable to assess  
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manuscrip t or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
Not relevant to this manuscript  
Quality of written Eng lish 
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past  five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation tha t may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
4. Have you received reimbursements, fee s, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
5. Do you have any other financial competing interests?  
6. Do  you have any non -financial competing interests in relation to this paper?  
If you can answer no to al l of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
'I declare that I have no competing interests'  
 
I agree to the open peer review policy of the journal. I understand that my na me will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made availab le under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will n ot be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
Title: Case report: lactic ac idosis and rhabdomyolysis during telb ivudine and tenofovir treatment 
for chronic hepatitis B  
 
Version: 1 Date: 04 Dec 2017  
 
Reviewer: Yee Hui Yeo  
 
Reviewer's report:  
The authors have made significant improvement this time. Replies and edits are attached:  
1. We  agreed that we should have mentioned the patient`s medical history. The patient hadn`t 
other comorbidities like diabetes and chronic kidney disease. We added the information about 
the medical history in page 5, row 15 -16. 
Reply: It is good to add the pati ent's medical history. It would be better to say "the patient denied 
a past history of significant comorbidities including…" instead of "the patient didn`t has other 
disease history".  
 
2. We were sorry for not presenting important drug history of the patie nt. He didn`t take 
concurrent drugs or Chinese herbs or nutritional supplements except telbivudine and tenofovir. 
The information about drug history was added in page 5, row 16 -17. 
Reply: sounds reasonable now  
 
3. We considered necessary to present the results of other liver function test in page 4, row 21 -
22. His aspartate transaminase was 129U/L. Total bilirubin and indirect bilirubin were normal.  
Reply: It is good to add the patient's ALT and bil data. It woul d be better to write "Total bilirubin 
and indirect bilirubin levels were normal" or "Total bilirubin and indirect bilirubin levels were 
within normal limits" instead of "Total bilirubin and indirect bilirubin were normal".  
 
4. Thank you for pointing out tha t the indication of MRI was not clear. The patient had a history 
of cirrhosis, MRI was aimed to rule out liver cancer. We justified the indication of MRI in page 
4, row 22 and page 5, row 1.  
Reply: Sounds reasonable, would be better if you could say "to ru le out liver cancer" instead of 
"To differentiate liver cancer".  
 
5. We considered it`s right to give more information about the therapy for his acidosis before 
admission. The patient received sodium bicarbonate as the revision showed in page 5, row 4 -5.  
 
6. We appreciated the suggestion about giving more details like urine color and output to 
establish the diagnosis of RM. His urine color was black and urine output was about 200ml per 
day. The electrolytes test was normal, while uric acid was 1.019mmol/L H is follow -up arterial 
blood gas analysis returned to normal, showing pH between 7.40 and 7.45. We added the 
information in page 5, row 7 -8, 10 and page 6, row 11 -12. 
Reply: Sounds reasonable.  
 
7. We agreed that we should have given more details to rule out other cause of RM, like 
infection, injury and other concurrent drugs. To rule out infection, we added the information 
about normal white blood cell count and percentage of neutrophils in page  
5, row 6 -7. Physical examination about no redness and higher ski n temperature on lower 
extremities can also help differentiate infection of muscle, which presented in page 5, row 14 -15. 
To rule out injury and concurrent d rugs, t he information was added in page 5, row 16 -17. The 
description of differential diagnosis was  added in page 6, row 6 -7. 
Reply: please use "warm skin" instead of "higher skin temperature".  
 
8. We agreed to make it clear about the changing strategy of antiviral treatment. The explanation 
and discussion was added in page 10, row 3 -14. At first, we co nverted antiviral therapy to 
entecavir because its lower reporting portion of muscle -related adverse drug reaction. As 
entecavir and telbivudine shared cross -resistance in some HBV variants, it was recommended 
that tenofovir should be the rescue strategy w hen telbivudine resistance occurred according to 
EASL guidelines in 2017. On the other side, tenofovir disoproxil fumarate was recommended as 
first-line monotherapy against hepatitis B with a high barrier to resistance. So far, tenofovir was 
only reported a side effect of rhabdomyolysis during antiretroviral t reatment in HIV patients, 
which combined with other concurrent antiretroviral drugs. In a clinical trialstudying the safety 
of tenofovir monotherapy for 5 years (Marcellin, P., et al., Kinetics of hepa titis B surface antigen 
loss in patients with HBeAg -positive chronic hep atitis B treated with tenofovir disoproxil 
fumarate. J Hepatol, 2014. 61(6): 1228 -37.), the researchers reported no fatal adverse reaction 
like LA or RM. So, we thought tenofovir monot herapy was safe. When the patients` condition 
was steady, we used tenofovir under close monitoring.  
Reply: sounds reasonable now.  
 
9. We did as suggest, moving the clues to clinical presentation part in page 6, row 3 -4. 
 
10. We agreed that it was very import ant to compare the severe adverse events of trials that have 
investigated the safety of Telbivudine +Tenofovir combination therapy in chronic hepatitis B 
patients. Additional discussion is presented in page 10, row 14 - 20. There were no muscle -
related seve re adverse events reported during at most 1 year`s follow -up. For the patient we 
reported, he took telbivudine for two years and suffered myalgia immediately after addition of 
tenofovir, so we conjure that tenofovir sometimes may still have a synergistic e ffect on the 
development of myopathy after much longer medication time, especially in patients with 
cirrhosis.  
Reply: sounds reasonable to refer to the incidence of severe adverse events in previous clinical 
trials. In clinical trials, however, the inclus ion/exclusion criteria is stricter. Therefore, it is 
important to have this case report to demonstrate the real -world findings.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
Yes 
Does the work include the necessary controls?  
If not, ple ase specify which controls are required in your comments to the authors.  
Unable to assess  
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manuscrip t or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
Not relevant to this manuscript  
Quality of written Eng lish 
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past  five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation tha t may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
4. Have you received reimbursements, fee s, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
5. Do you have any other financial competing interests?  
6. Do  you have any non -financial competing interests in relation to this paper?  
If you can answer no to al l of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
'I declare that I have no competing interests'  
 
I agree to the open peer review policy of the journal. I understand that my na me will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made availab le under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will n ot be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
Title: Case report: lactic ac idosis and rhabdomyolysis during telb ivudine and tenofovir treatment 
for chronic hepatitis B  
 
Version: 1 Date: 04 Dec 2017  
 
Reviewer: Yee Hui Yeo  
 
Reviewer's report:  
The authors have made significant improvement this time. Replies and edits are attached:  
1. We  agreed that we should have mentioned the patient`s medical history. The patient hadn`t 
other comorbidities like diabetes and chronic kidney disease. We added the information about 
the medical history in page 5, row 15 -16. 
Reply: It is good to add the pati ent's medical history. It would be better to say "the patient denied 
a past history of significant comorbidities including…" instead of "the patient didn`t has other 
disease history".  
 
2. We were sorry for not presenting important drug history of the patie nt. He didn`t take 
concurrent drugs or Chinese herbs or nutritional supplements except telbivudine and tenofovir. 
The information about drug history was added in page 5, row 16 -17. 
Reply: sounds reasonable now  
 
3. We considered necessary to present the results of other liver function test in page 4, row 21 -
22. His aspartate transaminase was 129U/L. Total bilirubin and indirect bilirubin were normal.  
Reply: It is good to add the patient's ALT and bil data. It woul d be better to write "Total bilirubin 
and indirect bilirubin levels were normal" or "Total bilirubin and indirect bilirubin levels were 
within normal limits" instead of "Total bilirubin and indirect bilirubin were normal".  
 
4. Thank you for pointing out tha t the indication of MRI was not clear. The patient had a history 
of cirrhosis, MRI was aimed to rule out liver cancer. We justified the indication of MRI in page 
4, row 22 and page 5, row 1.  
Reply: Sounds reasonable, would be better if you could say "to ru le out liver cancer" instead of 
"To differentiate liver cancer".  
 
5. We considered it`s right to give more information about the therapy for his acidosis before 
admission. The patient received sodium bicarbonate as the revision showed in page 5, row 4 -5.  
 
6. We appreciated the suggestion about giving more details like urine color and output to 
establish the diagnosis of RM. His urine color was black and urine output was about 200ml per 
day. The electrolytes test was normal, while uric acid was 1.019mmol/L H is follow -up arterial 
blood gas analysis returned to normal, showing pH between 7.40 and 7.45. We added the 
information in page 5, row 7 -8, 10 and page 6, row 11 -12. 
Reply: Sounds reasonable.  
 
7. We agreed that we should have given more details to rule out other cause of RM, like 
infection, injury and other concurrent drugs. To rule out infection, we added the information 
about normal white blood cell count and percentage of neutrophils in page  
5, row 6 -7. Physical examination about no redness and higher ski n temperature on lower 
extremities can also help differentiate infection of muscle, which presented in page 5, row 14 -15. 
To rule out injury and concurrent d rugs, t he information was added in page 5, row 16 -17. The 
description of differential diagnosis was  added in page 6, row 6 -7. 
Reply: please use "warm skin" instead of "higher skin temperature".  
 
8. We agreed to make it clear about the changing strategy of antiviral treatment. The explanation 
and discussion was added in page 10, row 3 -14. At first, we co nverted antiviral therapy to 
entecavir because its lower reporting portion of muscle -related adverse drug reaction. As 
entecavir and telbivudine shared cross -resistance in some HBV variants, it was recommended 
that tenofovir should be the rescue strategy w hen telbivudine resistance occurred according to 
EASL guidelines in 2017. On the other side, tenofovir disoproxil fumarate was recommended as 
first-line monotherapy against hepatitis B with a high barrier to resistance. So far, tenofovir was 
only reported a side effect of rhabdomyolysis during antiretroviral t reatment in HIV patients, 
which combined with other concurrent antiretroviral drugs. In a clinical trialstudying the safety 
of tenofovir monotherapy for 5 years (Marcellin, P., et al., Kinetics of hepa titis B surface antigen 
loss in patients with HBeAg -positive chronic hep atitis B treated with tenofovir disoproxil 
fumarate. J Hepatol, 2014. 61(6): 1228 -37.), the researchers reported no fatal adverse reaction 
like LA or RM. So, we thought tenofovir monot herapy was safe. When the patients` condition 
was steady, we used tenofovir under close monitoring.  
Reply: sounds reasonable now.  
 
9. We did as suggest, moving the clues to clinical presentation part in page 6, row 3 -4. 
 
10. We agreed that it was very import ant to compare the severe adverse events of trials that have 
investigated the safety of Telbivudine +Tenofovir combination therapy in chronic hepatitis B 
patients. Additional discussion is presented in page 10, row 14 - 20. There were no muscle -
related seve re adverse events reported during at most 1 year`s follow -up. For the patient we 
reported, he took telbivudine for two years and suffered myalgia immediately after addition of 
tenofovir, so we conjure that tenofovir sometimes may still have a synergistic e ffect on the 
development of myopathy after much longer medication time, especially in patients with 
cirrhosis.  
Reply: sounds reasonable to refer to the incidence of severe adverse events in previous clinical 
trials. In clinical trials, however, the inclus ion/exclusion criteria is stricter. Therefore, it is 
important to have this case report to demonstrate the real -world findings.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
Yes 
Does the work include the necessary controls?  
If not, ple ase specify which controls are required in your comments to the authors.  
Unable to assess  
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manuscrip t or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
Not relevant to this manuscript  
Quality of written Eng lish 
Please indicate the quality of language in the manuscript:  
Needs some language corrections before being published  
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
1. Have you in the past  five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation tha t may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
3. Do you hold or are you currently applying for any patents  relating to the content of the 
manuscript?  
4. Have you received reimbursements, fee s, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
5. Do you have any other financial competing interests?  
6. Do  you have any non -financial competing interests in relation to this paper?  
If you can answer no to al l of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
'I declare that I have no competing interests'  
 
I agree to the open peer review policy of the journal. I understand that my na me will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made availab le under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will n ot be published.  
 
I agree to the open peer review policy of the journal  
assistant