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\begin{document}

\title{Hepatoprotective effects of metformin in hepatitis C virus-infected
adolescents with beta thalassemia major}



\author[1]{Ali Talebi}%
\author[1]{Mona Kargar}%
\affil[1]{Tehran University of Medical Sciences}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\textbf{Hepatoprotective effects of metformin in hepatitis C
virus-infected adolescents with beta thalassemia major}

Dear Editor;

We read the recently published article by Abdel Monem et
al.\textsuperscript{1} with great interest. The authors reported that
metformin in antiviral na\selectlanguage{ngerman}ïve adolescents with beta thalassemia major
(\selectlanguage{greek}β-\selectlanguage{english}TM) infected with hepatitis C virus (HCV), can improve oxidative
stress, as well as liver fibrosis, transaminases, and some symptoms.
They proposed metformin as an option for its hepatoprotective effects in
these patients until the initiation of antiviral agents.

Repeated transfusions expose patients with thalassemia to HCV
infection\textsuperscript{2}. Although cirrhosis and hepatocellular
carcinoma are infrequent in children with this infection, in patients
with thalassemia the presence of iron overload can increase the
likelihood of progression of liver fibrosis \textsuperscript{3}. So, the
idea of using hepatoprotective agents in these patients seems appealing.
Based on the importance of the issue, we think several points regarding
the article are worth to be discussed.

Abdel Monem et al. included ``HCV-infected \selectlanguage{greek}β-\selectlanguage{english}TM patients'' in their
study. However, the diagnosis of HCV was based only on detecting
anti-HCV antibody. Although spontaneous clearance of HCV infection in
patients with thalassemia occurs less compared with patients without
thalassemia, there is still a chance for it \textsuperscript{4}. Hence,
the interpretation of a positive HCV antibody test and differentiation
of current infection from a resolved infection, or even a false-positive
result \textsuperscript{5} is not possible. Indeed, it is emphasized to
confirm the diagnosis of HCV in patients with positive anti-HCV
antibody, with detecting viremia \textsuperscript{6}.

Moreover, the study record in the registry of clinical trials raises
questions regarding the inclusion criteria. The authors addressed the
ClinicalTrials.gov registration number of NCT02984475. The inclusion
criteria of the registered trial are patients with thalassemia
regardless of their HCV serostatus. It is quite informative for the
audiences if the authors elaborate on why the inclusion criteria have
changed.

In the study, the score of liver stiffness and fibrosis grade were
investigated by FibroScan. In table 3, changes in liver stiffness score
for 30 patients in the control group and 27 patients in the metformin
group were shown. However, for the fibrosis grade at baseline (table 1)
and its changes (figure 4), only the data of 26 and 25 patients in the
control and metformin group were presented, respectively. Since both
parameters were assessed with the same scan, it was presumed to have the
data of the same number of patients for liver stiffness score and
fibrosis grade.

In the method section, it was mentioned that randomization of the
patients into two groups was based on 1:1 allocation. Thus, within the
60 patients randomized, it was assumed to have two groups of 30
participants. However, the control and the placebo group included 31 and
29 patients, respectively.

Among the participants, there were 12 patients with liver fibrosis of
grade [?] 3 at baseline. Moreover, in 19 patients, the grade of liver
fibrosis deteriorated at the end of the study. So, deciding to postpone
the initiation of antiviral treatment seems to be discussable. The
authors mentioned that during the recruitment after the approval of
direct acting antivirals (DAAs) if patients ``had the chance to receive
antiviral treatment'' they could leave the study. As shown in figure 1,
there was only one patient who left the study for this reason. It is not
clear what the chance of receiving antiviral treatment depended on. It
should be noted that even before the era of DAAs, there was evidence
supporting the treatment of patients with \selectlanguage{greek}β-\selectlanguage{english}TM and HCV with pegylated
interferon and ribavirin \textsuperscript{7-9}.

Author Contributions: Both authors contributed in the concept and
drafting the manuscript

Funding: None

Acknowledgements; None

Disclosures: The authors declare that they have no conflict of interest.

References:

1. Abdel Monem MS, Farid SF, Abbassi MM, et al. The potential
hepatoprotective effect of metformin in hepatitis C virus-infected
adolescent patients with beta thalassemia major: Randomised clinical
trial. \emph{International Journal of Clinical Practice.} 2021:e14104.

2. Daher HB, Sharara AI. Treatment of Chronic HCV Infection in Patients
With Thalassemia. \emph{Clinical liver disease.} 2019;14(6):199.

3. Spearman CW, Dusheiko GM, Hellard M, et al. Hepatitis C.\emph{Lancet}
. 2019; 394: 1451--1466

4. Kamal S, Abdelhakam S, Ghoraba D, et al. The course of hepatitis C
infection and response to anti-viral therapy in patients with
thalassemia major and hepatitis C infection: a longitudinal, prospective
study. \emph{Mediterranean journal of hematology and infectious
diseases.} 2019;11(1).

5. Squires JE, Balistreri WF. Hepatitis C virus infection in children
and adolescents. \emph{Hepatology communications.} 2017;1(2):87-98.

6. Ghany MG, Morgan TR, panel AIhCg. Hepatitis C guidance 2019 update:
American Association for the Study of Liver Diseases--Infectious
Diseases Society of America recommendations for testing, managing, and
treating hepatitis C virus infection.
\emph{Hepatology.}2020;71(2):686-721.

7. Di Marco V, Capra M, Angelucci E, et al. Management of chronic viral
hepatitis in patients with thalassemia: recommendations from an
international panel. \emph{Blood, The Journal of the American Society of
Hematology.} 2010;116(16):2875-2883.

8. Aminizadeh E, Alavian SM, Sari AA, Daryani NE, Behnava B. Safety and
efficacy of adding ribavirin to interferon or peginterferon in treatment
of hepatitis C infection in patients with thalassemia: a systematic
review on randomized controlled trials. \emph{Hepatitis
monthly.}2016;16(3).

9. Borgna-Pignatti C, Gamberini MR. Complications of thalassemia major
and their treatment. \emph{Expert review of
hematology.}2011;4(3):353-366.

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