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Treatment of hepatitis C virus infection with direct-acting antivirals plus ribavirin eliminates viral RNA from peripheral blood mononuclear cells and reduces virologic relapse in diverse hepatic parenchymal changes

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Abstract

Elimination of hepatitis C virus (HCV) may fail, leading to a non-response outcome because of inappropriate testing for viral RNA in peripheral blood mononuclear cells (PBMCs). Sequelae of HCV genotype 4 therapy with sofosbuvir and daclatasvir ± ribavirin were assessed in our study at the 12th week after end of treatment (EOT) by screening for viral genomic RNA in serum and PBMCs with correlation to hepatic parenchymal changes. We recruited 102 out of 2165 patients who had received sofosbuvir/daclatasvir, either alone (n = 1573) or together with ribavirin (n = 592). Subjects were classified into three groups based on testing by single-step reverse transcription PCR: group I, HCV negative in both serum and PBMCs (n = 25); group II, HCV positive in PBMCs only (n = 52); and group III, HCV positive in both serum and PBMCs (n = 25). Groups I and II (n = 77) were selected out of 2102 (every 27th subject), while group III (n = 25) were selected from every second or third serologic relapse (n = 63). The pre-sampling population (n = 2165) showed sustained virologic response (SVR) in 33.21%; serologic relapse in 2.91%; HCV RNA only in PBMCs (66.79%) compared to serologic relapses and potential cure (P < 0.0001); higher serologic (38 out of 63, P = 0.03210) and cellular (36 out of 52, P = 0.0002) relapses in dual therapy than in triple therapy. The post-sampling population (n = 102) showed more HCV relapses in dual (50 out of 60) than in triple (27 out of 42) therapy (P = 0.0351); increased HCV antisense RNA strand in relapses compared to positive-sense strands alone (P < 0.001); and significant SVR events in undetectable (15 out of 31) compared to early (10 out of 55, P = 0.0058) and cirrhotic liver tissue changes (0 out of 16, P = 0.0006). In summary, HCV treatment with sofosbuvir/daclatasvir is followed by higher rates of serologic and intracellular viral RNA relapse than treatment with sofosbuvir/daclatasvir plus ribavirin. Cellular and serum viral RNA relapses are accompanied by HCV-induced hepatic pathology. An increased SVR with no detectable liver tissue changes was observed after triple therapy due to elimination of HCV RNA from PBMCs.

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Abbreviations

PBMCs:

Peripheral blood mononuclear cells

SRT:

Single-step reverse transcription

DAAs:

Direct-acting antiviral agents

SVR:

Sustained virologic response

OCI:

Occult HCV infection

EOT:

End of treatment

TACE:

Treatment-associated challenge evaluation

PPV:

Positive predictive value

NPV:

Negative predictive value

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Acknowledgements

Financial support for this study was provided by the Faculty of Medicine at Al-Azhar University and National Research Center (Cairo, Egypt).

Funding

Funding for this study came from Department of Hepatology, Gastroenterology, and Infectious Diseases; Faculty of Medicine at Al-Azhar University; Cairo, Egypt. The institutes have no conflict of interest.

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Authors and Affiliations

  1. Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo, 11675, Egypt

    Mohamed Darwish Ahmed Abd Alla, Hassan Abd EL-Hafeth Rashed, Galal Farrag, Islam Abdelmawla Emran Ammar, Mohamed Mahmoud Abdel-Halim Mahmoud & Ahmed Mohamed Abdulhamid Altanbouly

  2. Department of Microbial Biotechnology, National Research Center, Cairo, Egypt

    Reham M. Dawood, Ghada M. Salum, Mai A. El Meguid & Mostafa K. El Awady

Authors
  1. Mohamed Darwish Ahmed Abd Alla
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  2. Reham M. Dawood
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  3. Hassan Abd EL-Hafeth Rashed
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  4. Galal Farrag
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  5. Islam Abdelmawla Emran Ammar
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  6. Mohamed Mahmoud Abdel-Halim Mahmoud
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  7. Ghada M. Salum
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  8. Ahmed Mohamed Abdulhamid Altanbouly
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  9. Mai A. El Meguid
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  10. Mostafa K. El Awady
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Contributions

The second and last two authors executed the virologic investigation and helped in writing the manuscript. The corresponding author took care of study design, case management, data analysis, and writing the manuscript; other co-authors helped in recruiting and management of patients and revised the manuscript.

Corresponding author

Correspondence to Mohamed Darwish Ahmed Abd Alla.

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Human and animal rights

All procedures performed in the current study that involved human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the current study. This article does not contain any studies with animals performed by any of the authors.

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Trop.Med._13Med.Research_Inf.GIT.Liv.Dis._0000013.

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Abd Alla, M.D.A., Dawood, R.M., Rashed, H.A.EH. et al. Treatment of hepatitis C virus infection with direct-acting antivirals plus ribavirin eliminates viral RNA from peripheral blood mononuclear cells and reduces virologic relapse in diverse hepatic parenchymal changes. Arch Virol 166, 1071–1081 (2021). https://doi.org/10.1007/s00705-021-04969-4

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