Hypergammaglobulinemia before Starting DAA Therapy Is A Strong Predictor of Disease Progression in Cirrhotic Patients Even after HCV Clearance
, Roberto Filomia 2, Gaia Caccamo 2, Concetta Pitrone 2, Angela Alibrandi 3, Carlo Saitta 1,2, Amalia Rita Caspanello 1,2, Clelia Asero 1,2, Vittoria Arcadi 1,2, Giovanni Raimondo 1,2 and Irene Cacciola 1,2,*Round 1
Reviewer 1 Report
The treatment of viral hepatitis C has been a concern for us as physicians since 1989, and the rate of SVR's son from 5% of our applications has reached 100% in the decade. In fact, we are now talking about the eradication of HCV and we have succeeded. Even after eradication, we see that cirrhosis is also panned and there are even HCC complica- tions and related deaths. To learn the way of what to do with them and to behave well and exhibit our behavior in order to be small. This study we did caused us to open the path of hypergaglobin before the application of DAA and cause us to change our orientation. You have contributed a lot for this beautiful work.Author Response
We thank the reviewer for observations and we are very grateful for compliments about our contribution with this work.
Reviewer 2 Report
REVIEWER COMMENTS
Comment 1- Mention the risk factors of hepatocellular carcinoma linked with HCV infection.
Comment 2- Include the role of liver in metabolism in introduction section.
https://www.researchgate.net/publication/355162808_Indicators_and_risk_factors_associated_with_Malnutrition_among_patients_with_Liver_Cirrhosis_Nursing_Perspective.
https://doi.org/10.1155/2021/6661937.
https://doi.org/10.3390/app10186200.
Comment 3- Mention the names of some liver function biomarkers linked with liver cirrhosis and fatty liver.
Comment 4- The mechanism of direct-acting antivirals work against new hepatitis C viruses should be provided.
Comment 5- The conclusion should be rewritten.
Comment 6- Provide the brief classification of direct-acting antiviral agents in HCV treatment regimens.
Comment 7- What are the serum protein changes occurring in liver disease associated with parenchymal damage, especially in gamma globulin levels.
Comment 8- Significance of biochemical investigation for gamma-globulin level in liver cirrhosis.
Author Response
- We thank the reviewer for observations and we are very grateful for compliments about our contribution with this work.
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Mention the risk factors of hepatocellular carcinoma linked with HCV infection.
Hepatitis C virus (HCV) infection represents an independent risk factor for the development of hepatocellular carcinoma (HCC), but the prognosis is worse in patients with advanced liver disease. In fact, cirrhosis represents the substrate for HCC development with a major risk of death. After HCV eradication, the risk of HCC development persists due to the underlying chronic liver disease, but the HCC occurrence seems progressively reduced with the time after sustained virological response (SVR) achievement. According to the reviewer’s suggestion, we added the following sentence: “In fact, the risk of HCC occurrence could also persist due the underlying chronic liver disease” (page 2, lines 46-47).
The mechanism of direct-acting antivirals work against new hepatitis C viruses should be provided.
- The structure of HCV polyprotein and nonstructural viral proteins allowed the development of the IFN-free antiviral drugs. In fact, HCV is a positive single-stranded RNA virus that appear released in the host cytoplasm and the ribosomes on the endoplasmic reticulum translate the genetic material into the HCV polyprotein. The nonstructural proteins (NS) of HCV represent the direct-acting antivirals (DAAs) targets, because they are needed for viral amplification. Thus, the DAAs are identified as protease or polymerase inhibitors, and they interfere at different steps of the HCV replication. In particular, NS3/4A protease inhibitors block the processing of the HCV polyprotein, NS5B inhibitors interfere with the viral RNA polymerase and the viral replication, whereas NS5A inhibitors block with unknown mode the interactions between viral and host proteins. (page 2 , Lines 76-77)
Provide the brief classification of direct-acting antiviral agents in HCV treatment regimens.
- Direct antiviral regimens usually consist of at least two drug classes with different antiviral action. Since the first class of DAAs, treatment decisions (type and duration) were based on liver disease stage and HCV genotype, but today there are pangenotypic regimens. In our study, we enrolled patients treated from 2015 to 2016, and according with the “Agenzia Italiana del Farmaco” prescription limitations, the DAA therapy prescribed was represented by first available therapeutic lines: Sofosbuvir/Ledipasvir, Sofosbuvir plus Daclatasvir, Sofosbuvir plus Simeprevir, Sofosbuvir plus Ombitasvir/Paritaprevir/Ritonavir plus Dasabuvir.
What are the serum protein changes occurring in liver disease associated with parenchymal damage, especially in gamma globulin levels.
- One of the principal diagnostic features of patients affected with liver diseases is an increased antibody production. In particular, serum gamma-globulin levels may be considered an indirect marker of the persistent high grade of intrahepatic inflammation. The exact mechanism underlying the large antibody formation is not completely understood. It was hypothesized that liver dysfunction causes activation and proliferation of circulating plasma cells, and the liver is unable to effectively dispose of the gut antigens and endotoxins, which results in markedly elevated levels of immunoglobulin. However, the gamma-globulin levels may normalize in patients undergoing effective curative treatment, but several studies have also demonstrated that increased gamma globulin levels are biochemical predictors of severe fibrosis in HCV patients.
Significance of biochemical investigation for gamma-globulin level in liver cirrhosis.
- Gamma-globulins are usually not considered as a possible prognostic indicator in patients with cirrhosis, although several studies have identified increased gamma-globulins levels as a predictor of severe fibrosis development. Moreover, it has also been demonstrated that hypergammaglobulinemia was predictive of Child-Pugh score progression over time in patients with HCV or cryptogenic cirrhosis, and that patients with increased gamma-globulin levels had a higher risk of developing HCC and death. In this way, it is clear that hypergammaglobulinemia may help to identify compensated cirrhotic patients with a major risk of worse prognosis. Thus, gamma-globulin test could be a useful cheap prognostic tool to be routinely used in patients with liver diseases.
Conclusion
Pages 12-13 lines 332-337
