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1. Efficacy and Safety of Adding Ribavirin for Genotype 3 HCV Compensated Cirrhosis Patients
Receiving 12 weeks of Sofosbuvir/Velpatasvir: A Meta-analysis
JH Loo1, FWX Xu1, JT Low1, WX Tay1, LS Ang1, YC Tam2, PH Thurairajah1,3, R Kumar4,5, YJ Wong1,4,5
1Yong Loo Lin School of Medicine, National University of Singapore, 2Education Resource Centre, Medical Board, Singapore General Hospital , 3Division of Gastroenterology & Hepatology, National University Hospital,
Singapore, 4Department of Gastroenterology & Hepatology, Changi General Hospital, Singapore, 5Duke-NUS Medicine Academic Clinical Program, SingHealth
Methodology
Results
Introduction
Hepatitis C virus (HCV) remains a leading cause of liver cirrhosis and
hepatocellular carcinoma globally. Sofosbuvir/velpatasvir (SOF/VEL)
is an effective pan-genotypic direct-acting antiviral combination for
treatment of chronic HCV infections.
While the addition of ribavirin (RBV) to SOF/VEL improved sustained
virological response (SVR12) in genotype 3 (GT3) decompensated
cirrhosis patients, the benefits of RBV in GT3 compensated cirrhosis
patients receiving SOF/VEL remains unclear.
Aim
To evaluate the efficacy and safety of SOF/VEL, with or without RBV
in GT3 compensated cirrhosis patients.
Eligibility and search strategy
• By PRISMA guidelines
• 4 electronic databases: PubMed/Medline, Embase, Cochrane and
Web of Science searched from initiation to 1 June 2021
• Inclusion criteria:
1. Studies on patients with hepatitis C GT3 compensated cirrhosis
2. Evaluated efficacy or safety of SOF/VEL for 12 weeks, with or
without RBV
3. Reported SVR12, and/or treatment-related adverse events as
study outcomes
Study outcomes
• Primary outcome: SVR12
• Secondary outcome: Treatment-related adverse events, defined by
symptomatic anemia requiring transfusion or a drop in hemoglobin
beyond 2 g/dL
Data synthesis and analysis
• Review Manager Software used to estimate relative risk ratios (RR)
and 95% confidence intervals (CI)
• Cochran’s Q test and I2 statistics to assess statistical heterogeneity
Risk of bias assessment
• Cochrane Risk of Bias 2.0 for randomized cohort trials (RCT) based
on sequence generation, allocation concealment, performance bias,
detection bias and reporting bias
• Newcastle–Ottawa Scale to assess cohort studies based on
selection, comparability and exposure
Characteristics and quality of studies
• 1752 search results → 69 full texts reviewed → 7 studies included
• Total of 1088 subjects: 506 in SOF/VEL+RBV group versus 582 in SOF/VEL group
• Baseline proportions of GT3a and GT3b subtypes were 99.5% and 0.5%
• Pooled rate of HIV coinfection was 13.0% (35/269)
• 4 studies with low risk of bias, 3 studies with moderate risk of bias due to
concerns over differing severity of liver disease in intervention and control groups
Sustained Virologic Response at 12 weeks (SVR12)
• SVR12 similar regardless of RBV addition, in both intention-to-treat and per
protocol analysis [(RR: 1.03, 95% CI: 0.99–1.07; I2 = 0%) (Figure 1) versus (RR:
1.03, 95% CI: 0.99–1.07; I2 = 48%) (Figure 2)]
• SVR12 remained comparable following subgroup analysis by study design, with
less heterogeneity observed among RCTs than cohort studies (RR: 1.06, 95% CI:
1.00–1.13; I2 = 0%).
Figure 1. Sustained virological response by intention-to-treat analysis
from SOF/VEL with or without RBV
Figure 2. Sustained virological response by per-protocol analysis
from SOF/VEL with or without RBV
Treatment-related adverse events
• Overall pooled rate of treatment-related adverse events was 7.2%
(95% CI: 4.4%–11.0%)
• Addition of RBV to SOF/VEL increased the pooled risk of treatment-
related adverse events, when compared to SOV/VEL without RBV
(RR: 4.20, 95% CI: 1.29–13.68; I2 = 0%)
Figure 3 Severe adverse events from SOF/VEL with or without RBV
Subgroup analysis
• Treatment-experienced: RBV use did not result in a higher SVR12 among
treatment-experienced GT3 compensated cirrhosis patients (96% vs 96%).
• Baseline RAS mutation: Baseline RAS testing was performed in 17.0% of subjects,
from two studies. Among those with baseline RAS mutation, addition of RBV was
associated with a numerically higher SVR12 (96% vs 87%, P = 0.12).
Conclusion
Among GT3 compensated cirrhosis patients, adding RBV to 12-
weeks of SOF/VEL did not significantly increase SVR12. As RBV was
associated with a higher risk of treatment-related adverse events,
routine addition of RBV among GT3 compensated cirrhosis patients
receiving SOF/VEL should be reconsidered.
RBV has a limited role as routine add-on therapy in GT3
compensated cirrhosis treated with SOF/VEL. Overall SVR12 was
similar, regardless of the use of RBV. This finding remained robust
when subgroup analysis was performed based on study design and
prior treatment experience.
In terms of safety, addition of RBV increased the pooled risk of
treatment-related adverse events, defined as symptomatic
anemia requiring transfusion or a drop in hemoglobin > 2 g/dL. Five
studies reported severe adverse events, defined as the need for
hospitalization, intensive care unit, permanent disability, death and
treatment cessation. Overall, severe treatment-related adverse
events were rare (0.8%) and were comparable regardless of RBV
use. The most common minor adverse events were asthenia and
headache.
Discussion