Reviewer's report
Title:Management of the HBV reactivation in isolated HBcAb positive patients
affected with Non Hodgkin Lymphoma
Version:2Date:8 December 2013
Reviewer: Juan R Larrubia
Reviewer's report:
'Management of the HBV reactivation in isolated HBcAb positive patients affected
with Non Hodgkin Lymphoma'
Mario Masarone, Amalia De Renzo, Vincenzo La Mura, Ferdinando C Sasso,
Marco Romano, Giuseppe Signoriello, Valerio Rosato, Fabiana Perna, Fabrizio
Pane and Marcello Persico
The persistence of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)
negative individuals is termed occult HBV infection (OBI). An important clinical
manifestation of HBV occult infection is HBV reactivation during
immunosupression. In this condition, the restoration of immune system, after
finishing the immunosupressive treatment, could cause a flare-up and liver
failure. In this manuscript Masarone et al describe retrospectively the single
centre experience on HBV reactivation in Non Hodgking Lymphoma (NHL)
treated patients. They only observed reactivation in HBsAg- HBcAb+ cases,
since all the HBsAg+ cases were on treatment. They did observed reactivation
neither in HBsAb+ nor in HBsAg- HBcAb-. Surprisingly, they found the same rate
of reactivation in rituximab treated cases than in other less potent
immunosuppressive treatments. Anti-HBV prophylactic treatment was not used
but “rescue treatment” strategy after HBV reactivation diagnosis was carried out.
Authors do not report any life-threatening outcome, and based on that they
suggest monitoring and treating as the best strategy instead of prophylactic
strategy. This statement should be tuned down, at least for rituximab treated
cases. Several reports show the high incidence of HBV reactivation on HBcAb+
rituximab treated patients and the potential development of life-threatening
outcomes. Moreover, meta-analysis carried out on data from NHL cases
suggests that prophylaxis with NUCs is better than monitoring and treating. In
any case, the question raised in the study is of interest since HBV reactivation in
OBI cases submitted to immunosuppressive treatment is rare and data about it
are scarce. The design is appropriate and the analysis is right, although it colud
be informative to give the risk value of developing reactivation on HBcAb+
according to NHL treatment. Discussion is well documented but should be
stressed that the suggested monitoring strategy for rituximab patients instead of
NUCs prophylaxis should be tested in a clinical trial before recommending its
general use. (Discretionary Revision)
Authors should have shown a risk measurement of developing reactivation in
HBcAb+ according to the NHL treatment. This value would be informative and
could allow the reader to compare this paper with other similar ones. For
instance, authors could have shown the Odds Ratio with its confidence interval. I
also suggest showing the statistics used to calculate the p values in table
legends. (Discretionary Revision)
1. Is the question posed by the authors well defined?
The question analysed by the authors is clearly defined. They study a group of
OBI patients with Non Hodgkin Lymphoma characterized by HBcAb+ HBsAg-
serology with serum HBV DNA negative. In those patients authors described
retrospectively the occurrence of HBV reactivation, paying special attention to
those cases submitted to strong immunosupression.
2. Are the methods appropriate and well described?
Authors define properly inclusion criteria but they do not comment about
exclusion criteria, which should be included in methods item (Discretionary
Revision). The criteria for Non Hodgkin Lymphoma are well established as
happens with HBV reactivation criteria. The statistical methods are also well
described. Unfortunately, authors used univariate analysis but it could have been
more adequate a multivariate analysis to control confusion and interaction,
especially to describe the risk of HBV reactivation according to rituximab
treatment. Authors should give the odds ratio of HBV reactivation for the
rituximab and non-rituximab containing protocols. (Discretionary Revision)
3. Are the data sound?
Yes they are. Patients are properly recruited retrospectively. They show and
adequate recruitment flow-chart. Patient’s clinical data are properly described.
Authors should state in table legends which statistic test was used for
comparisons.
4. Does the manuscript adhere to the relevant standards for reporting and data
deposition?
The report of the data is appropriate and authors do not comment about data
deposition.
5. Are the discussion and conclusions well balanced and adequately supported
by the data?
Discussion and conclusions are correctly carried out, but they should tune down
their comments about two issues. Authors comment a similar reactivation rate
independently of the immunosupressive regimen. Nevertheless, other studies
show a higher reactivation rate in rituximab protocols with a 16 HR for rituximab
containing regimens (Hui et al; Gastroeneterology 2006). This difference should
be commented and clarified, trying to explain the reason for it. In fact, 12-23% of
anti-HBc+ patients treated on rituximab plus steroids combination develop HBV
reactivation (Kusumotos J Gastroenterol 2010). Another important issue is about
recommending preventive vs “rescue” treatment based on the 10 reactivation
observed in this study on NHL HBcAb+ cases. It is true that using “rescue”
strategy they did not observe any fatal outcome, but a meta-analysis run by
Ziakas (Hematologica 2009) on NHL cases conclude that is better the
prophylactic approach. Even if the rescue strategy could be more cost-effctive, it
should be bear in mind that HBV reactivation could be a life-threatening
complication. (Discretionary Revision)
6. Are limitations of the work clearly stated?
The main limitation of the study is its retrospective nature that does not allow
obtaining a strong conclusion about recommending or not prophylactic treatment
in HBcAb+ HBV DNA- patients submitted to strong immunosupression. Authors
suggest that in rituximab treated cases, it is similar to give prophylactic
lamivudine treatment than the monitoring approach. According to their
retrospective data, including ten rituximab cases with HBV reactivation treated
with rescue therapy, the evidence is weak to suggest not giving prophylactic
NUC treatment in this life-threatening situation although all the cases did well.
(Discretionary Revisions)
7. Do the authors clearly acknowledge any work upon which they are building,
both published and unpublished?
Authors carried out an extent review of previous work related to HBV reactivation
in OBI patients.
8. Do the title and abstract accurately convey what has been found?
Title and abstract summarize appropriately the paper’s content
9. Is the writing acceptable?
It is acceptable..
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare I have no competing intersts
Reviewer's report
Title:Management of the HBV reactivation in isolated HBcAb positive patients
affected with Non Hodgkin Lymphoma
Version:2Date:8 December 2013
Reviewer: Juan R Larrubia
Reviewer's report:
'Management of the HBV reactivation in isolated HBcAb positive patients affected
with Non Hodgkin Lymphoma'
Mario Masarone, Amalia De Renzo, Vincenzo La Mura, Ferdinando C Sasso,
Marco Romano, Giuseppe Signoriello, Valerio Rosato, Fabiana Perna, Fabrizio
Pane and Marcello Persico
The persistence of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)
negative individuals is termed occult HBV infection (OBI). An important clinical
manifestation of HBV occult infection is HBV reactivation during
immunosupression. In this condition, the restoration of immune system, after
finishing the immunosupressive treatment, could cause a flare-up and liver
failure. In this manuscript Masarone et al describe retrospectively the single
centre experience on HBV reactivation in Non Hodgking Lymphoma (NHL)
treated patients. They only observed reactivation in HBsAg- HBcAb+ cases,
since all the HBsAg+ cases were on treatment. They did observed reactivation
neither in HBsAb+ nor in HBsAg- HBcAb-. Surprisingly, they found the same rate
of reactivation in rituximab treated cases than in other less potent
immunosuppressive treatments. Anti-HBV prophylactic treatment was not used
but “rescue treatment” strategy after HBV reactivation diagnosis was carried out.
Authors do not report any life-threatening outcome, and based on that they
suggest monitoring and treating as the best strategy instead of prophylactic
strategy. This statement should be tuned down, at least for rituximab treated
cases. Several reports show the high incidence of HBV reactivation on HBcAb+
rituximab treated patients and the potential development of life-threatening
outcomes. Moreover, meta-analysis carried out on data from NHL cases
suggests that prophylaxis with NUCs is better than monitoring and treating. In
any case, the question raised in the study is of interest since HBV reactivation in
OBI cases submitted to immunosuppressive treatment is rare and data about it
are scarce. The design is appropriate and the analysis is right, although it colud
be informative to give the risk value of developing reactivation on HBcAb+
according to NHL treatment. Discussion is well documented but should be
stressed that the suggested monitoring strategy for rituximab patients instead of
NUCs prophylaxis should be tested in a clinical trial before recommending its
general use. (Discretionary Revision)
Authors should have shown a risk measurement of developing reactivation in
HBcAb+ according to the NHL treatment. This value would be informative and
could allow the reader to compare this paper with other similar ones. For
instance, authors could have shown the Odds Ratio with its confidence interval. I
also suggest showing the statistics used to calculate the p values in table
legends. (Discretionary Revision)
1. Is the question posed by the authors well defined?
The question analysed by the authors is clearly defined. They study a group of
OBI patients with Non Hodgkin Lymphoma characterized by HBcAb+ HBsAg-
serology with serum HBV DNA negative. In those patients authors described
retrospectively the occurrence of HBV reactivation, paying special attention to
those cases submitted to strong immunosupression.
2. Are the methods appropriate and well described?
Authors define properly inclusion criteria but they do not comment about
exclusion criteria, which should be included in methods item (Discretionary
Revision). The criteria for Non Hodgkin Lymphoma are well established as
happens with HBV reactivation criteria. The statistical methods are also well
described. Unfortunately, authors used univariate analysis but it could have been
more adequate a multivariate analysis to control confusion and interaction,
especially to describe the risk of HBV reactivation according to rituximab
treatment. Authors should give the odds ratio of HBV reactivation for the
rituximab and non-rituximab containing protocols. (Discretionary Revision)
3. Are the data sound?
Yes they are. Patients are properly recruited retrospectively. They show and
adequate recruitment flow-chart. Patient’s clinical data are properly described.
Authors should state in table legends which statistic test was used for
comparisons.
4. Does the manuscript adhere to the relevant standards for reporting and data
deposition?
The report of the data is appropriate and authors do not comment about data
deposition.
5. Are the discussion and conclusions well balanced and adequately supported
by the data?
Discussion and conclusions are correctly carried out, but they should tune down
their comments about two issues. Authors comment a similar reactivation rate
independently of the immunosupressive regimen. Nevertheless, other studies
show a higher reactivation rate in rituximab protocols with a 16 HR for rituximab
containing regimens (Hui et al; Gastroeneterology 2006). This difference should
be commented and clarified, trying to explain the reason for it. In fact, 12-23% of
anti-HBc+ patients treated on rituximab plus steroids combination develop HBV
reactivation (Kusumotos J Gastroenterol 2010). Another important issue is about
recommending preventive vs “rescue” treatment based on the 10 reactivation
observed in this study on NHL HBcAb+ cases. It is true that using “rescue”
strategy they did not observe any fatal outcome, but a meta-analysis run by
Ziakas (Hematologica 2009) on NHL cases conclude that is better the
prophylactic approach. Even if the rescue strategy could be more cost-effctive, it
should be bear in mind that HBV reactivation could be a life-threatening
complication. (Discretionary Revision)
6. Are limitations of the work clearly stated?
The main limitation of the study is its retrospective nature that does not allow
obtaining a strong conclusion about recommending or not prophylactic treatment
in HBcAb+ HBV DNA- patients submitted to strong immunosupression. Authors
suggest that in rituximab treated cases, it is similar to give prophylactic
lamivudine treatment than the monitoring approach. According to their
retrospective data, including ten rituximab cases with HBV reactivation treated
with rescue therapy, the evidence is weak to suggest not giving prophylactic
NUC treatment in this life-threatening situation although all the cases did well.
(Discretionary Revisions)
7. Do the authors clearly acknowledge any work upon which they are building,
both published and unpublished?
Authors carried out an extent review of previous work related to HBV reactivation
in OBI patients.
8. Do the title and abstract accurately convey what has been found?
Title and abstract summarize appropriately the paper’s content
9. Is the writing acceptable?
It is acceptable..
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare I have no competing intersts
Please review this paper.
user
Reviewer's report
Title:Management of the HBV reactivation in isolated HBcAb positive patients
affected with Non Hodgkin Lymphoma
Version:2Date:8 December 2013
Reviewer: Juan R Larrubia
Reviewer's report:
'Management of the HBV reactivation in isolated HBcAb positive patients affected
with Non Hodgkin Lymphoma'
Mario Masarone, Amalia De Renzo, Vincenzo La Mura, Ferdinando C Sasso,
Marco Romano, Giuseppe Signoriello, Valerio Rosato, Fabiana Perna, Fabrizio
Pane and Marcello Persico
The persistence of hepatitis B virus (HBV) in hepatitis B surface antigen (HBsAg)
negative individuals is termed occult HBV infection (OBI). An important clinical
manifestation of HBV occult infection is HBV reactivation during
immunosupression. In this condition, the restoration of immune system, after
finishing the immunosupressive treatment, could cause a flare-up and liver
failure. In this manuscript Masarone et al describe retrospectively the single
centre experience on HBV reactivation in Non Hodgking Lymphoma (NHL)
treated patients. They only observed reactivation in HBsAg- HBcAb+ cases,
since all the HBsAg+ cases were on treatment. They did observed reactivation
neither in HBsAb+ nor in HBsAg- HBcAb-. Surprisingly, they found the same rate
of reactivation in rituximab treated cases than in other less potent
immunosuppressive treatments. Anti-HBV prophylactic treatment was not used
but “rescue treatment” strategy after HBV reactivation diagnosis was carried out.
Authors do not report any life-threatening outcome, and based on that they
suggest monitoring and treating as the best strategy instead of prophylactic
strategy. This statement should be tuned down, at least for rituximab treated
cases. Several reports show the high incidence of HBV reactivation on HBcAb+
rituximab treated patients and the potential development of life-threatening
outcomes. Moreover, meta-analysis carried out on data from NHL cases
suggests that prophylaxis with NUCs is better than monitoring and treating. In
any case, the question raised in the study is of interest since HBV reactivation in
OBI cases submitted to immunosuppressive treatment is rare and data about it
are scarce. The design is appropriate and the analysis is right, although it colud
be informative to give the risk value of developing reactivation on HBcAb+
according to NHL treatment. Discussion is well documented but should be
stressed that the suggested monitoring strategy for rituximab patients instead of
NUCs prophylaxis should be tested in a clinical trial before recommending its
general use. (Discretionary Revision)
Authors should have shown a risk measurement of developing reactivation in
HBcAb+ according to the NHL treatment. This value would be informative and
could allow the reader to compare this paper with other similar ones. For
instance, authors could have shown the Odds Ratio with its confidence interval. I
also suggest showing the statistics used to calculate the p values in table
legends. (Discretionary Revision)
1. Is the question posed by the authors well defined?
The question analysed by the authors is clearly defined. They study a group of
OBI patients with Non Hodgkin Lymphoma characterized by HBcAb+ HBsAg-
serology with serum HBV DNA negative. In those patients authors described
retrospectively the occurrence of HBV reactivation, paying special attention to
those cases submitted to strong immunosupression.
2. Are the methods appropriate and well described?
Authors define properly inclusion criteria but they do not comment about
exclusion criteria, which should be included in methods item (Discretionary
Revision). The criteria for Non Hodgkin Lymphoma are well established as
happens with HBV reactivation criteria. The statistical methods are also well
described. Unfortunately, authors used univariate analysis but it could have been
more adequate a multivariate analysis to control confusion and interaction,
especially to describe the risk of HBV reactivation according to rituximab
treatment. Authors should give the odds ratio of HBV reactivation for the
rituximab and non-rituximab containing protocols. (Discretionary Revision)
3. Are the data sound?
Yes they are. Patients are properly recruited retrospectively. They show and
adequate recruitment flow-chart. Patient’s clinical data are properly described.
Authors should state in table legends which statistic test was used for
comparisons.
4. Does the manuscript adhere to the relevant standards for reporting and data
deposition?
The report of the data is appropriate and authors do not comment about data
deposition.
5. Are the discussion and conclusions well balanced and adequately supported
by the data?
Discussion and conclusions are correctly carried out, but they should tune down
their comments about two issues. Authors comment a similar reactivation rate
independently of the immunosupressive regimen. Nevertheless, other studies
show a higher reactivation rate in rituximab protocols with a 16 HR for rituximab
containing regimens (Hui et al; Gastroeneterology 2006). This difference should
be commented and clarified, trying to explain the reason for it. In fact, 12-23% of
anti-HBc+ patients treated on rituximab plus steroids combination develop HBV
reactivation (Kusumotos J Gastroenterol 2010). Another important issue is about
recommending preventive vs “rescue” treatment based on the 10 reactivation
observed in this study on NHL HBcAb+ cases. It is true that using “rescue”
strategy they did not observe any fatal outcome, but a meta-analysis run by
Ziakas (Hematologica 2009) on NHL cases conclude that is better the
prophylactic approach. Even if the rescue strategy could be more cost-effctive, it
should be bear in mind that HBV reactivation could be a life-threatening
complication. (Discretionary Revision)
6. Are limitations of the work clearly stated?
The main limitation of the study is its retrospective nature that does not allow
obtaining a strong conclusion about recommending or not prophylactic treatment
in HBcAb+ HBV DNA- patients submitted to strong immunosupression. Authors
suggest that in rituximab treated cases, it is similar to give prophylactic
lamivudine treatment than the monitoring approach. According to their
retrospective data, including ten rituximab cases with HBV reactivation treated
with rescue therapy, the evidence is weak to suggest not giving prophylactic
NUC treatment in this life-threatening situation although all the cases did well.
(Discretionary Revisions)
7. Do the authors clearly acknowledge any work upon which they are building,
both published and unpublished?
Authors carried out an extent review of previous work related to HBV reactivation
in OBI patients.
8. Do the title and abstract accurately convey what has been found?
Title and abstract summarize appropriately the paper’s content
9. Is the writing acceptable?
It is acceptable..
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare I have no competing intersts
assistant