Efficacy of 8-Week Daclatasvir-Sofosbuvir Regimen in Chronic Hepatitis C: A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-4928226/v1

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Research Article

Efficacy of 8-Week Daclatasvir-Sofosbuvir Regimen in Chronic Hepatitis C: A Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-4928226/v1

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Background: The high rates of the sustained virologic response 12 weeks after treatment (SVR12) in real world settings provoked the adoption of shortened courses of the costly direct-acting antivirals (DAAs) regimens. This study provides, to our knowledge, the first systematic review and meta-analysis for the efficacy of the shortened 8-week course of sofosbuvir (SOF) plus daclatasvir (DCV), the most accessible DAAs in the low-middle income countries (LMICs).

Methods: We performed a proportion meta-analysis to determine a reliable rate of SVR12 by pooling all studies that evaluated the results of the 8-week regimen of DCV+SOF. In addition, we applied two imputation paradigms a conservative approach, and a pragmatic approach to avoid overestimating the efficacy of the 8-week regimen in studies that followed a Response-Guided Treatment (RGT) approach.

Results: The pooled SVR12 rate ranged from 91% to 97% in the included scenarios. The pragmatic scenario showed that the pooled SVR12 was 97% (95% CI 91%; 100%) with lower variability as assessed by the prediction interval. The conservative approach revealed an SVR12 of 93% (95% CI 84%; 95%).

Conclusion: The 8-week course of 60 mg DCV with SOF provided a comparable SVR12 to the standard 12-week regimen in treatment-naïve, non-HIV co-infected patients with a minimum estimated efficacy of 90%.

Hepatitis C Virus

Daclatasvir

Efficacy

Shortened

8-week

The Hepatitis C virus (HCV) has been a significant global health issue for decades. In 2019, there were 58 million cases and 1.5 million new infections, with over 250,000 deaths reported by the World Health Organization (WHO) [1, 2]. WHO guidelines for HCV have evolved since 2017 to accelerate the elimination of HCV by 2030 and reduce the economic burden of treatment, particularly with costly Direct-Acting Antivirals (DAAs) [2–12]. Shortened DAA regimens, supported by high sustained virologic response (SVR) rates in real-world settings, have been a key strategy [4, 14–22].

Among the DAAs currently available is the combination of sofosbuvir plus daclatasvir (SOF + DCV). SOF + DCV is approved by the European Medicines Agency (EMA) and FDA, and is recommended by WHO as a pan-genotypic treatment for HCV, irrespective of viral genotype [4, 13]. Real-world evidence supports the efficacy and safety of SOF + DCV in managing HCV in various patient populations [14–16]. Since 2020, SOF + DCV regimen has become the preferred DAA treatment for HCV in low- and middle-income countries (LMICs) that constitute over two thirds of the global disease prevalence [17], and became one of the WHO Model List of Essential Medicines (EML) [5].

Recent studies that investigated the efficacy of the 8-week course of DCV plus SOF showed that the shortened 8-week course of DCV + SOF emerges as a promising shortcut to the approved and the currently in-use 12-week course [18–20].

This study aims to provide an up-to-date literature evaluation and, to our knowledge, the first systematic review and meta-analysis for the efficacy of the shortened 8-week course of DCV + SOF for the management of HCV infection.

Search Strategy

This meta-analysis was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement (Appendix A). The protocol was registered with the PROSPERO registry (CRD42023413487). Two independent researchers (A.K. and A.N.) searched PubMed, Scopus, and Web of Sciences for studies published before April 2023. The search strategy in each database is available in table S1 (Appendix B). All studies were exported to Mendeley (version 1.19.8, Clarivate, Philadelphia, USA). The references cited in these studies were reviewed to identify additional eligible studies. Studies included in the meta-analysis: 1) described patients with HCV treated with SOF + DCV regimen for eight weeks; 2) reported the success rate defined as SVR12 or provided sufficient data for such calculation; 3) were published in English.

The following studies were excluded: 1) case reports, letters, reviews, in vitro investigations, animal studies, and technical reports; 2) did not disclose the data necessary for the meta-analysis; 3) had duplicated samples; 4) were not written in English; and 5) were methodologically faulty (Table S2 and Figure S1). A.K. and A.N. independently assessed the study titles and abstracts to determine eligibility. The listed studies' full texts were retrieved and evaluated.

Quality Assessment

The quality of the included studies was assessed by A.K. and A.N. using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for case series. The JBI checklist for case series includes ten items that evaluate the inclusion criteria, method of condition measurement, the validity of the diagnostic methods, consecutive enrollment of participants, adequacy of participants' inclusion, the presentation of the demographic characteristics, clinical information, outcomes, presenting clinic demographic information and the appropriateness of the statistical methods [21].

Data Extraction

Data extraction and cross-checking were conducted by A.K. and A.N. independently. The following data were extracted: first author, publication year, age, study design, study population, prior treatment experience, cirrhosis state, baseline log₁₀ HCV, the GT of the infected patients, SOF, and DCV doses, HCV assay technique applied with its Lower Limit Of Detection (LLOD) and Lower Limit Of Quantification (LLOQ), retreatment outcome in case of SVR12 failures. The primary outcome of the current study was the SVR12, defined as HCV RNA below LLOD 12 weeks following the eight weeks course of SOF + DCV.

Data synthesis

A meta-analysis of proportions using the random-effects model was used to pool the SVR12 estimates from different studies. Without appropriate data transformation, the accompanying meta-analyses experience threats to statistical conclusion validity [22], such as the confidence limits falling outside of the established zero-to-one range and variance instability [23]. While the logit transformation solves the problem of confidence interval estimates falling outside the zero to one range, it does not necessarily resolve the issues regarding variance from extreme proportional datasets. As the double arcsine transformation (Freeman-Tukey transformation) addresses both problems listed above, it is the preferred transformation method and was implemented in the current analysis. Once the meta-analysis had been performed on the transformed proportions, a back-transformation was performed. There is still no consensus about the back-transformation method that should be used with the Freeman-Tukey double arcsine method, although the harmonic mean was suggested for back-transformation [24].

Heterogeneity between studies

The I² statistic was used to explore the percentage of heterogeneity attributed to variation in true-effect sizes secondary to inter-population variation. Estimates from subgroups within the same study were pooled using a fixed-effects model and used in the meta-analysis. The 95% confidence interval (CI) and Z-statistic were calculated and used for hypothesis testing.

Prediction Interval

The prediction interval was used to assess the treatment effect that may be predicted in future analyses, considering the different settings across different studies. It captures the variability in the true treatment effect across different settings. With substantial heterogeneity, prediction intervals will be broader than confidence intervals and might be considered a more conservative technique to integrate uncertainty in the analysis [25].

Subgroup analysis

Subgroup analysis was performed based on GT, HIV status, DCV dose, prior HCV treatment, presence of cirrhosis, and risk of bias to explore possible sources of heterogeneity between studies.

Publication bias

Funnel plots were used to assess publication bias. Egger’s test was used to test the asymmetry of funnel plots [26]. The trim-and-fill method was not used to detect and adjust for publication bias [27]. However, it has been shown that the trim and fill method can underestimate the true effect when the between-study heterogeneity (variability in the true effect size) is large, even in the absence of publication bias [28]. Funnel plots were used to assess publication bias. Egger’s test was used to test the asymmetry of funnel plots [26]. The trim-and-fill method was also used to detect and adjust for publication bias [27].

Sensitivity analysis

The leave-one-out sensitivity analysis was used to assess the effect of individual studies on the observed effect size and heterogeneity. Leave-one-out sensitivity analysis was also used to assess the effect size and between-study heterogeneity after the exclusion of individual studies.

For studies that adopted the RGT approach and used the rapid virological response (RVR) to assess whether respondents would receive an 8-week course or a standard 12-week regimen, we proposed two imputation scenarios for the SVR12 rate under the 8-week regimen for those who were received the 12-week course. In one scenario, we assumed that these respondents were SVR12 failures under the 8-week regimen (worst-case scenario or conservative approach) [29, 30]. In the second scenario, we used the lower confidence interval limit for the SVR12 (80%) from Flower’s study (where RVR achievers were assigned to the 4-week arm while RVR non-achievers were assigned to the 8-week arm). The later aims to provide a more prudent estimate for the SVR12 rate for those who failed to reach a RVR and were accordingly assigned to the 12-week regimen instead of the 8-week one (pragmatic approach).

Statistical Analysis

Statistical analysis was performed using R v 3.6.3 (R Core Team, Vienna, Austria). The random-effects model (using the maximum likelihood estimator for tau) was used to pool the effect sizes from the included studies. The underlying hypothesis for adopting the random-effects model is that heterogeneity or observed variance of effect is a sum of sampling error and variation in true-effect sizes stemming from inter-population variability. The generic inverse variance method was used for weighing using the per-protocol population of each trial. The Hartung-Knapp adjustment was used to prevent counterintuitive effects and to yield more conservative inferences, as the heterogeneity variance estimate is commonly associated with substantial uncertainty, especially in contexts where only a few studies are available. Forest plots were used to visualize the results. P values < 0.05 were considered statistically significant.

3.1. Study selection.

After duplicates removal, eighty-four results were obtained. A.N. and A. K. screened the abstracts for clinical studies that investigated the 8-week regimen of SOF+DCV (Figure. 1). Forty-six studies were selected for further full-text assessment. After a critical appraisal of the articles, six studies were included in the qualitative and quantitative data synthesis.

A summary of the publications excluded and a full list of these publications are provided in Tables S2 and S3, respectively. Four out of the six studies included in the qualitative and quantitative analysis showed a case-series design [24]. Two studies - [19] and [20] - followed a RGT approach where patients were assigned to the shortened 8-week course if they achieved a RVR on days 2, 14, and 28 [29,30]. Study designs and patient characteristics for the included studies are summarized in Table 1.

3.2. Risk of Bias Assessment

One study was unclear regarding the statistical analysis used [32] . Two studies showed bias in terms of including patients, where only those who developed RVR were assigned to the shortened regimen of DCV+SOF (8-week regimen) [19,20]. However, these studies adhered to our inclusion/exclusion criteria, reporting the SVR12 rate following an 8-week treatment with the dual SOF+DCV, along with patient demographics and characteristics. Both reviewers agreed to include all six studies that passed the initial inclusion/exclusion criteria screening (Table 2).

The pooled SVR12 rate ranged from 91% to 97% in the included scenarios (Figure 2). When all studies were included (Figure 1a), the pooled SVR12 rate was 91% (95% CI 81%; 98%) with an I² of 55%. When patients who received 30 mg DCV were excluded, the heterogeneity decreased to 43%. When the lower limit of success was used for the study conducted by Yakoot rather than considering all patients who did not achieve RVR as failures, minimal change in heterogeneity and SVR12 estimates were observed. Interestingly, in the fourth scenario in which patients who received DCV 30 mg were excluded, and an 80% SVR12 was assumed in patients who were not assigned to the 8-week course, no heterogeneity was observed between studies (I² = 0), and a more precise estimate was obtained (Pooled SVR12 = 97%, 95% CI 91%; 100%) with lower variability as assessed by the prediction interval.

3.3. Study Outcomes

No publication bias was observed (small studies with high effect size and standard error). Moreover, the studies conducted by Yakoot, and a subgroup of Wyle’s study (patients who received 30 mg) had small effect sizes and lower standard errors in scenarios (a) and (b). In scenario (c), only the subgroup that received DCV 30 was identified as a possible source of heterogeneity. A symmetric funnel plot was observed in scenario (d). Egger’s test was not statistically significant in any of the scenarios indicating the absence of publication bias, although the number of studies is low to derive a robust conclusion (Figure 3).

Leave one out sensitivity analysis showed that the study conducted by Yakoot had the biggest influence on heterogeneity (Figure 4). Omitting either study conducted by Yakoot or Wyles (only patients who received 30 mg) resulted in a pooled SVR12 of 93%, a more precise estimate, and a reduction in between-study heterogeneity to 43% and 50%, respectively.

Subgroup analysis showed that HIV status was significantly associated with the pooled estimate for SVR12 (P interaction < 0.01) as shown in Figure S1. The pooled estimate for HIV-positive patients was lower than that observed in HIV-negative patients (97% vs. 80%). Similarly, DCV was significantly associated with the pooled estimate for SVR12 (P < 0.01). The pooled SVR12 in patients who received 60 mg of DCV daily was higher than that in patients who received 30mg (97% vs. 72%), with no heterogeneity observed between studies that used 60 mg of DCV. No interaction was observed between GT and the pooled SVR12 estimate (P _interaction = 0.21). Prior treatment status was not significantly associated with the pooled SVR12 estimate (P interaction = 0.17). Cirrhosis was associated with a lower pooled SVR12 estimate (73% vs. 95% in cirrhotic and non-cirrhotic patients, respectively, P interaction = 0.03). It should be noted that only one study included a subgroup of patients with cirrhosis.

The revolutionary introduction of the novel DAAs to the battle of HCV combat made the elimination of HCV a much more attainable pursuit than before. Since its first release in 2011, DAAs resulted in considerably higher SVR12 cure rates at shorter duration and much more desirable safety profiles than classical interferon-based regimens [34]. The accumulated data on the high efficacy of the shortened regimen of Glecaprevir + Pibrentasvir prompted the FDA to expand its licensed regimen from 12 weeks to only eight weeks in candidate HCV patients [35]. Recent reports on the SOF-based regimens provided more evidence on the efficacy of the shortened eight-week course of many of its dual combinations, including SOF+LDV, SOF+Velpatasvir, and SOF+DCV [36–42].

The efficacy of the shortened 8-week course of DCV+SOF was first questioned in the ALLY-2 trial in 2015 [33]. Although it highlighted a low SVR12 of the pooled 8-week regimen (76%), it implicitly outlined a promising efficacy for the 8-week course of the standard 60 mg dose of DCV. This efficacy is reflected by the fact that the fraction of patients who received the regular 60 mg DCV dose for eight weeks and achieved SVR12 is 9/10 (90%). The remaining SVR12 failures in this arm were observed with the reduced DCV dose (30 mg), and only one failure was linked to the 90 mg dose. The 30 mg dose of DCV in the 8-week arm was primarily attributed to the previously expected pharmacokinetic drug-drug interaction between DCV and the ritonavir-augmented anti-HIV medications. Notably, this dose was later found to be of no clinical relevance and became no longer recommended [43].

The efficacy of the 60 mg dose of DCV in an 8-week regimen was later scrutinized by Hezode et al., 2017 in chronic HCV infection with GT-3. The two-month regimen resulted in an SVR12 of 92% (24/26), comparable to 89% (797/895) by the 12 weeks course in GT-3 [44]. This efficacy is further investigated in adolescents infected with HCV GT-4 by El-Shabrawi, M., 2018, where an SVR12 of 100% (9/9) [19] is achieved compared to 97% (178/183) by the standard regimen [44]. In another aspect, Flower B. et al., 2023 reported that the two-month regimen of SOF+DCV resulted in an SVR12 of 100% (17/17) in GTs 1 and 6 [18,42,44]. Furthermore, an SVR12 of 100% (15/15) is achieved following the shortened 8-week course of DCV (60 mg) plus half of the regular dose of SOF (200 mg) in patients with acute HCV infection and renal impairment. This efficacy is comparable to that achieved by the standard DCV course in hemodialysis patients, which reached an SVR12 of 97.2% (35/36) [31,45].

Mathematically, the extrapolation of the time-to-cure (TTC) using the HCV kinetic modeling generated estimates similar to the reported clinical efficacy for the 8-week regimen [46]. The TTC is the time needed to reach less than one virion in the whole extracellular fluid so that the risk of insidious viral replication and disease relapse after the end of therapy is theoretically cut down to zero [47]. Using the mathematical modeling of viral kinetics, the TTC is predicted to be less than eight weeks in non-cirrhotic patients treated with SOF+DCV (mean: 6.4 weeks; 95% CI: 5.2-7.6 weeks; 99% CI: 4.8-8) [48]. These estimates were also consistent with those predicted in compensated cirrhosis patients treated with SOF, which showed a mean TTC of 6.8 weeks (95% CI: 6.1 – 7.4 weeks) with a median of 5.6 weeks and IQR (4-8 weeks) [49].

In another aspect, and regarding the treatment failures entailed by the shortened course of DCV+SOF, Flower B. et al., 2023 revealed that all of the SVR12 failures by the 4-week regimen were cured when retreated for 12 weeks using the same DAA combo of DCV+SOF (13/13) [18]. This finding is further supported by the real-world reports on the efficacy of the retreatment outcome in SOF-DCV relapsers or non-responders that reached an SVR12 success rate of 92.7% with other courses of DAAs [50].

An important remark is that two out of the six studies in this review followed a RGT approach, where only patients who showed a RVR on days 2, 14, or 28 after treatment initiation were assigned to the shortened regimen. Nonetheless, recent studies suggest that RVR, especially that estimated using only one HCV-RNA measurement, as in our studies, is not a sensitive predictor of achieving SVR12 [40,51–53]. Nevertheless, as an attempt to circumvent this source of heterogeneity and to draw a more careful and unbiased inference about the outcome of the shortened course of the anti-HCV regimen, we applied a sensitivity analysis using two imputation paradigms, a conservative approach and a pragmatic approach, to estimate the SVR12 rates that could have been achieved under the 8-week regimen in those who did not achieve RVR (12 patients) in the RGT arms and received the standard 12 weeks regimen.

Accordingly, the SVR12 rates under the 8-week regimen by Yakoot M were estimated as either 78% (46/59) or 97% (57/59) per the conservative and pragmatic approaches. The imputed SVR12 rate under the 8-week course by the other RGT study in this review (El-Shabrawi, M. et al., 2018) remained unchanged since no patients failed to reach an RVR in this study.

Applying the two scenarios (conservative- and pragmatic-based imputation) for SVR12 rates by Yakoot’s study resulted in minimal deviation in the pooled SVR12 estimate. A minimal reduction in the heterogeneity score I² (from 55% to 51) was also observed when applying the pragmatic approach, which is more realistic and clinically relevant. This observation is further supported by the publication bias analysis using the Freeman-Tukey double arcsine transformation, which showed that the imputed SVR12 rate by Yakoot M. et al. 2017 under the pragmatic assumption was more unbiased and less anomalous concerning those reported by other studies in this review. Similarly, the sensitivity analysis showed that Wyles D. et al. 2015-30 mg subgroup conferred much heterogeneity to the source of the effect of interest (SVR12) as reflected by a remarkable lowering of I² from 51% to 0% following the exclusion of this subgroup from the meta-analysis. The postulation that the Wyles D. et al. 30 mg subgroup conveyed a biased source of SVR12 is also clearly observed through the diagrammatic presentation of the publication bias analysis, where a symmetric funnel plot is obtained following this subgroup's exclusion of the SVR12 rate. Furthermore, and coinciding with clinical practice, the exclusion of the 30 mg arm by Wyles D. et al. 2015 can be clinically reasoned since this altered dosing became obsolete in HCV patients with no HIV co-infection and not receiving concurrent ritonavir-boosted protease inhibitors.

To recap, scenario-4 for the 8-week regimen of DCV (60 mg) + SOF, which precludes the 30 mg arm by [33] and imputes the SVR12 by [20] at the lowest reported margin, shows the most plausible and unbiased picture that reflects the efficacy of the 8-weeks course of 60 mg DCV+SOF in treatment-naïve patients without HIV coinfection. This scenario had a mean SVR12 of 97% (95% CI: 93-100%) offered a remarkable reduction in heterogeneity score. This is mainly attributed to minimizing the source and the established SVR12 of DAAs in clinical practice.

In another field, and looking through the lens of Pharmacoeconomics, the cost-effectiveness analysis for the shortened courses of different DAAs regimens (including SOF+DCV) versus the standard 12-week regimens provided a robust recommendation to adopt the 8-week regimens [54]. This cost-effectiveness is calculated after considering the monetary savings to one-third versus the expected added cost by the SVR12 failures and subsequent retreatment protocols.

This meta-analysis, however, had some limitations. First, although the heterogeneity inherited by scenario-4 is reduced to almost null, the number of studies included in the meta-analysis is relatively small to derive a wider perspective for the 8-week safety and efficacy. Second, a direct head-to-head comparison of the shortened versus the standard regimens, independent of the RVR, is lacking. Although our meta-analysis used the arcsine transformation to account for the single-arm design followed by four studies in this review, a randomized controlled trial (RCT) in which HCV patients are randomly assigned to either the 8-week regimen or the standard 12-week course, irrespective of their baseline viral load or the early virological response, is strongly needed. Third, no study in this review investigated the shortened course of DCV+SOF in HCV GT-5 or decompensated cirrhotic patients, which limits the generalizability of our results, especially in these two subpopulations. Fourth, only one study in this review [18] reported the DAAs retreatment regimen in case of SVR12 failure. Finally, real world studies would be encouraged to derive more realistic estimates for the efficacy and pharmacoeconomic effectiveness for the 8-weeks course and its associated retreatment policies. Along that domain, McCabe, L. and colleagues are currently investigating both the safety and the efficacy of shortened regimens of DAAs including SOF+DCV[55].

In conclusion, our results show that the 8-week course of 60 mg DCV+SOF provided a comparable alternative to the standard 12-week regimen in treatment-naïve, non-HIV co-infected HCV patients with a minimum estimated efficacy of 90%.

AASLD	American Association for the Study of Liver Diseases
CI	Confidence Interval
DAA	Direct-Acting Antiviral
DCV	Daclatasvir
EASL	European Association for the Study of Liver
EMA	European Medicines Agency
EML	WHO Model List of Essential Medicines
FDA	U.S. Food and Drug Administration
GT	Genotype
HIV	Human Immunodeficiency Virus
LDV	Ledipasvir
LMICs	Low-Middle Income Countries
LLOD	Lower Limit Of Detection
LLOQ	Lower Limit Of Quantification
MPP	Medicines Patent Pool
NICE	British National Institute for Health and Care Excellence
NS5A	Non-structural 5A
NS5B	Non-structural 5B
PRISMA	Preferred Reporting Items for Systematic Reviews and Meta-Analyses
RCT	Randomised Controlled Trial
RGT	Response-Guided Treatment
SOF	Sofosbuvir
SVR	Sustained Virologic Response
TTC	Time-To-Cure

Ethics approval and consent to participate:

Not applicable

Consent for publication:

Not applicable

Availability of data and materials:

Data that support research findings is available from the corresponding author upon request

Competing interests:

The authors declare no conflict of interest.

Funding:

This research received no external funding.

Authors' contributions:

A. F. conceptualization, data extraction, and manuscript drafting; A. K. data extraction, data analysis and manuscript revision for intellectual content; A. F. and A. K. final approval of the manuscript.

Acknowledgments

None

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Tables 1 to 2 are available in the Supplementary Files section

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Efficacy of 8-Week Daclatasvir-Sofosbuvir Regimen in Chronic Hepatitis C: A Systematic Review and Meta-Analysis

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1. Introduction

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3. Results

3.1. Study selection.

3.2. Risk of Bias Assessment

3.3. Study Outcomes

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