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Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24

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Abstract

Purpose

This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment.

Methods

We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients.

Results

Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05).

Conclusions

The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes.

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Acknowledgments

This work was supported by the Coordination for the Improvement of Higher Level Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPq).

Author contributions

All coauthors listed contributed to the final manuscript in the following manner: RP conceived the study; RP, AW, FFL and HHB participated in its design; HHB, CMP and LMS participated in the systematic review and data extraction; FST assisted HHB in the statistical analysis for Bayesian meta-analysis; FFL assisted HHB in the manuscript preparation, including analysis of results; MLAP provided a clinical view on the subject and assistance for additional analyses. All authors provided revisions and approved the final manuscript submitted.

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Authors and Affiliations

  1. Department of Pharmacy, Pharmaceutical Sciences Postgraduate Research Program, Federal University of Paraná, Campus III, Av. Pref. Lothário Meissner, 632, Jardim Botânico, Curitiba, PR, 80210-170, Brazil

    Helena H. Borba, Astrid Wiens, Laiza M. Steimbach, Cassio M. Perlin, Fernanda S. Tonin & Roberto Pontarolo

  2. Gastroenterology Service, Hospital de Clínicas, Federal University of Paraná, Curitiba, Brazil

    Maria L. A. Pedroso

  3. Research Institute for Medicines (iMed.ULisboa), Department of Social Pharmacy, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal

    Fernando Fernandez-Llimos

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  2. Astrid Wiens
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  3. Laiza M. Steimbach
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  4. Cassio M. Perlin
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  5. Fernanda S. Tonin
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  6. Maria L. A. Pedroso
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  7. Fernando Fernandez-Llimos
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  8. Roberto Pontarolo
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Corresponding author

Correspondence to Roberto Pontarolo.

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Electronic supplementary material

Figure S1

PRISMA 2009 flow diagram. (DOCX 45 kb)

Table S1

Characteristics of the studies included in the meta-analyses. Peg-IFN, pegylated interferon; RBV, ribavirin; RCT, randomized clinical trial; w, weeks; BOC, boceprevir; DCV, daclatasvir; SMV, simeprevir; TVR, telaprevir. (DOCX 239 kb)

Table S2

Search strategies. (DOCX 16 kb)

Table S3

Benefit-risk analysis. (DOCX 75 kb)

Table S4a

Node splitting analysis of inconsistency - RVR (DOCX 27 kb)

Table S4b

Node splitting analysis of inconsistency - SVR (DOCX 22 kb)

Table S5a

Model fit - RVR (DOCX 28 kb)

Table S5b

Model fit - SVR (DOCX 28 kb)

Table S6

List of excluded studies (DOCX 33 kb)

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Borba, H.H., Wiens, A., Steimbach, L.M. et al. Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24. Eur J Clin Pharmacol 73, 1–14 (2017). https://doi.org/10.1007/s00228-016-2146-6

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  • DOI: https://doi.org/10.1007/s00228-016-2146-6

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