PONE-D-20-24228

Non-invasive fibrosis algorithms are clinically useful for excluding cirrhosis in prisoners living with hepatitis C

PLOS ONE

Dear Dr. Thompson,

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Chen-Hua Liu

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Papaluca et al investigated the performance of APRI and FIB-4 for excluding cirrhosis in a large cohort of 1007 prisoners with hepatitis C virus infection using a liver stiffness measurement (LSM) of ≥12.5 kPa through transient elastography (TE, e.g. FibroScan) as the reference standard for cirrhosis. They demonstrated that an APRI cutoff of 1.0 and FIB-4 cutoff of 1.45 had negative predictive values (NPVs) of 96.1% and 96.6% for cirrhosis, respectively. The implementation of this triage strategy would spare the need for TE by 71%. In those aged >35, an APRI cutoff of 1.0 had a NPV of 95.1%. They concluded that such strategy can simplify the cascade of care in prisoners with hepatitis C. While the finding of this study is of interest, there are several issues that need to be addressed to improve the scientific merit of this manuscript.

Major Comments:

1. The diagnosis of cirrhosis may be relevant to the decision of DAA regimen ± ribavirin/duration and referral for the ultrasonographic surveillance of hepatocellular carcinoma (HCC) and endoscopic surveillance of gastroesophageal varices. In the setting of prisons, I am not sure how feasible is the immediate referral for surveillance of cirrhosis-related complications. Moreover, the identification of patients with advanced cirrhosis (METAVIR F3 and F4) is equally important because this subgroup of patients are at risk of HCC and therefore are recommended to continue their HCC surveillance despite achieving sustained virological response to DAA treatment. In the present cohort, there were 87 patients who were judged to have advanced fibrosis (METAVIR F3) according to LSM, which was a significant number of patients, compared with the number of patients with presumed cirrhosis (n = 124). The cutoffs of 1.45 and 3.25 for FIB-4 were originally selected to specifically rule out and maximize the positive predictive value (PPV) for diagnosing advanced fibrosis (METAVIR F3), respectively, in patients with HCV/HIV coinfection (Reference 19) and HCV monoinfection (Vallet-Pichard A et al, Hepatology 2007; 46: 32-36). Therefore, I would suggest the authors use these cutoffs to determine the sensitivity, specificity, PPV and NPV of FIB-4 for diagnosing advanced fibrosis (METAVIR F3) in the present cohort, using an LSM of ≥9.5 kPa as the reference standard. This analysis may provide us a clue about how feasible is this strategy in reducing the need for TE in identifying patients with advanced fibrosis. Perhaps by combining the use of FIB-4 and APRI at cutoffs of 1.45 and 1.0, respectively, an effective and cost-saving algorithm can be proposed to identify hepatitis C patients with METAVIR F3 and F4 for improving the cascade of care in prisoners. Please also discuss this finding.

2. The authors did not follow the standard way of presentation in describing the performance of APRI, FIB-4 and age for predicting cirrhosis in Tables 3 and 4, and Supplementary Tables 1 and 2. Please refer to the Table 4 in Reference 18 (Wai CT et al, Hepatology 2003; 38: 518-526) and Table 5A in the paper by Vallet-Pichard A et al (Hepatology 2007; 46: 32-36) for a correct presentation to allow readers to keep track of the number of patients in each category.

3. The paper by Vallet-Pichard A et al (Hepatology 2007; 46: 32-36) is more relevant to patients with HCV monoinfection. Please cite this paper in addition to Reference 19.

Reviewer #2: This study describes the utility of APRI and FIB4 in categorizing liver fibrosis severity of 1007 prisoners with chronic HCV infection. Furthermore, the utility of age threshold as a trigger for transient elastography was also explored. They found that APRI and FIB-4 scores can exclude cirrhosis in prisoners. In addition, fibroscan could be reserved for those prisoners >35 years who have APRI >1.0. The data and analysis are generally well described, and the analysis and conclusions are reasonable. This article comes to a similar conclusion about the utility of APRI and FIB-4 in hospital cohort. The major limitations include the lack of validation cohort and the operator variability in transient elastography for liver fibrosis assessment.

Specific comments

1. In the study design, the authors need a validation cohort to confirm the utility of the combination of age and APRI for liver cirrhosis assessment.

2. As a retrospective study, APRI and FIB-4 were calculated based on the laboratory parameters from chart review. Although fibrosis staging should be rather static, biochemical parameters can change more rapidly. Thus, it is important to report the mean interval between the blood tests and liver stiffness measurement.

3. The issue of interoperator variability in transient elastography for liver fibrosis may be addressed.

4. Is there any reason why the authors choose APRI, not FIB4, for fibrosis assessment in the figure 2?

5. The causes of the discordance between APRI/FIB4 and liver stiffness measurement by fibroscan should be discussed.

Reviewer #3: General comments

The study by Papaluca et al evaluated the usefulness of APRI and FIB-4 as simple markers in detecting hepatic cirrhosis in a cohort of prisoners with chronic hepatitis C. Using transient elastography (TE) as a reference, this retrospective study enrolled 1,007 patients including 124 (12%) cirrhotic patients. With cutoff 1.0 and 1.45 for APRI and FIB-4, the negative predictive value (NPV) were >96% in cirrhosis diagnosis. With the cutoff of 35 years for age, the NPV was also 96.5%. The authors proposed a simple fibrosis assessment algorithm to reduce the need of TE by 78%. For this special group of chronic hepatitis C patients, this study provided a simple and useful algorithm for cirrhosis evaluation to minimize the use of TE and barrier of HCV treatment in clinical practice. However, some points needed to be clarified.

Major comments

1. For HCV treatment with current DAA, the diagnosis of compensated cirrhosis seemed not so important in general. The authors might mention the rationale to diagnose cirrhosis for this special group of prisoners?

2. Active or previous alcohol consumption might be a problem for this special group of prisoners. Using 12.5 kPa by TE as cutoff in cirrhosis diagnosis might overestimate the patient numbers. How many patients with alcohol in this group of patients?

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Non-invasive fibrosis algorithms are clinically useful for excluding cirrhosis in prisoners living with hepatitis C

PONE-D-20-24228R1

Dear Dr. Thompson,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Chen-Hua Liu

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: This revised manuscript is much improved and all previous comments were responded on point-to-point basis. I have no additional comments.

Reviewer #3: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No