Sustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: A systematic review and meta-analysis

doi:10.1016/j.jhep.2019.04.017

Journal of Hepatology

Volume 71, Issue 3, September 2019, Pages 473-485

https://doi.org/10.1016/j.jhep.2019.04.017 Get rights and content

Highlights

•
The present study summarizes the SVR rate in patients with/without liver cancer treated with all oral DAAs.
•
The cure rate was lower in patients with liver cancer, especially those with active cancer.
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Additional controlled studies are needed to study the impact of liver cancer on HCV cure rate in DAA-treated patients.

Background & Aims

The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC) infection remains unclear. Using a systematic review and meta-analysis approach, we aimed to investigate the effect of DAA therapy on sustained virologic response (SVR) among patients with CHC and either active, inactive or no HCC.

Methods

PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from 1/1/2013 to 9/24/2018. The pooled SVR rates were computed using DerSimonian-Laird random-effects models.

Results

We included 49 studies from 15 countries, comprised of 3,341 patients with HCC and 35,701 without HCC. Overall, the pooled SVR was lower in patients with HCC than in those without HCC (89.6%, 95% CI 86.8–92.1%, I² = 79.1% vs. 93.3%, 95% CI 91.9–94.7%, I² = 95.0%, p = 0.0012), translating to a 4.8% (95% CI 0.2–7.4%) SVR reduction by meta-regression analysis. The largest SVR reduction (18.8%) occurred in patients with active/residual HCC vs. inactive/ablated HCC (SVR 73.1% vs. 92.6%, p = 0.002). Meanwhile, patients with HCC who received a prior liver transplant had higher SVR rates than those who did not (p <0.001). Regarding specific DAA regimens, patients with HCC treated with ledipasvir/sofosbuvir had lower SVR rates than patients without HCC (92.6%, n = 884 vs. 97.8%, n = 13,141, p = 0.026), but heterogeneity was high (I² = 84.7%, p <0.001). The SVR rate was similar in patients with/without HCC who were treated with ombitasvir/paritaprevir/ritonavir ± dasabuvir (n = 101) (97.2% vs. 94.8%, p = 0.79), or daclatasvir/asunaprevir (91.7% vs. 89.8%, p = 0.66).

Conclusion

Overall, SVR rates were lower in patients with HCC, especially with active HCC, compared to those without HCC, though heterogeneity was high. Continued efforts are needed to aggressively screen, diagnose, and treat HCC to ensure higher CHC cure rates.

Lay summary

There are now medications (direct-acting antivirals or “DAAs”) that can “cure” hepatitis C virus, but patients with hepatitis C and liver cancer may be less likely to achieve cure than those without liver cancer. However, patients with liver cancer are also more likely to have advanced liver disease and risk factors that can decrease cure rates, so better controlled studies are needed to confirm these findings.

Graphical abstract

Introduction

Chronic hepatitis C virus (HCV) infection affected an estimated 71.1 million patients worldwide in 2015 and is a leading cause of liver cirrhosis and hepatocellular carcinoma (HCC).¹ Among patients who have undergone treatment with curative intent for HCC, early hepatic decompensation and HCC recurrence were the major drivers of mortality.² In recent studies of chronic hepatitis B-related HCC, antiviral therapy was shown to significantly reduce overall long-term mortality even in patients with very advanced HCC or decompensated cirrhosis, including those who were only receiving palliative treatment for HCC.[3], [4], [5], [6] Prior to the advent of interferon (IFN)-free direct-acting antiviral (DAA) therapy, patients with HCV-related HCC were often excluded from anti-HCV therapy as they tended to be older and had multiple non-liver and liver comorbidities, many of which rendered them unsuitable candidates for IFN-based therapy. Since 2014, many of these patients with HCC became treatment candidates for their chronic hepatitis C (CHC), despite the presence of advanced liver disease and comorbidities, as DAA therapy is not only highly efficacious but well tolerated.⁷ Individual real-world studies to date have included patients with HCC from both the East and West, and some have reported significantly lower cure rates.[8], [9], [10], [11], [12], [13], [14] However, most studies had small sample sizes and heterogeneous patient demographic and clinical characteristics.

Therefore, we performed a systematic review and meta-analysis to evaluate the effect of HCC on cure rates in DAA-treated patients with CHC, taking into account various viral, host and tumor factors.

Section snippets

Search strategy and selection criteria

This study was performed based on a pre-defined and registered protocol (PROSPERO: CRD42017079155). We searched PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1, 2013 to September 24, 2018 without language restrictions. The search strategy, developed by a medical librarian (MBB), included (“direct-acting antiviral” OR “DAA”) AND (“hepatocellular carcinoma” OR “HCC” OR “carcinoma, hepatocellular” OR “liver

Results

Of the 6,249 citations identified from PubMed, Embase, Web of Science, Cochrane Databases, and an additional 44 studies identified via manual bibliography review, 49 full-text studies, comprising 3,341 patients with HCC and 35,701 without HCC were included in the final analysis (Fig. 1).[8], [9], [10], [11], [12], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53]

Discussion

In this study, we pooled 49 articles (3,341 patients with HCC and 35,701 without HCC) and compared the pooled SVR rates in patients with or without HCC. To determine the source of heterogeneity and obtain more clinically relevant data, we categorized patients by several viral and host factors (e.g. HCV GT, HCC activity, prior HCV treatment status, presence of cirrhosis) as well as types of DAA treatment and study location to assess predictors for the lower SVR rates seen in patients with HCC

Financial support

The authors received no financial support to produce this manuscript.

Conflict of interest

Yee Hui Yeo, Mike Tzuhen Wei, Eiichi Ogawa, Masaru Enomoto, Dong Hyun Lee, Etsuko Iio, Wenjun Wang, Bin Wei, Tatsuya Ide, Michelle B Bass, Carmen Monica Preda, Fabio Conti, Rob Bielen, Hitomi Sezaki, Michele Barone, Po-sung Chu, Victor Virlogeux, Dennis Eurich, Takanori Kanai, Shuangsuo Dang, Zongfang Li, Akihiro Tamori: None to disclose. Fanpu Ji: Speaker Gilead Sciences, MSD and Ascletis. John Lubel: Research support (Institutional support only) Abbvie, BMS, MSD; consulting/advisory board

Authors’ contribution

All authors: Data contribution, data interpretation, and critical review of the manuscript for important content. FPJ, MTW, BW, YHY, MBB: Literature search and data extraction. FPJ, YHY, EO, ME, DHL, WJW, MB, SSD, ZFL, AT: Study quality assessment. FPJ, YHY, MTW, MHN: Study design and data analysis. FPJ, YHY, MHN: Drafting of the manuscript. MTW, MB, LH, RC: Critical revision of the paper. MHN: Study conception and study supervision.

Acknowledgment

We would like to thank Dr. Guido Schwarzer, PhD for his kind guidance with the R-programming for our meta-regression analysis.

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Research ArticleSustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: A systematic review and meta-analysis

Highlights

Background & Aims

Methods

Results

Conclusion

Lay summary

Graphical abstract

Introduction

Section snippets

Search strategy and selection criteria

Results

Discussion

Financial support

Conflict of interest

Authors’ contribution

Acknowledgment

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Research Article
Sustained virologic response to direct-acting antiviral therapy in patients with chronic hepatitis C and hepatocellular carcinoma: A systematic review and meta-analysis