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Clinical Drug Investigation May 2018Hepatitis C treatment has changed considerably in recent years, and many interferon (IFN)-free therapies are now available. Considering the high rates of sustained... (Meta-Analysis)
Meta-Analysis Review
Sustained Virological Response in Special Populations with Chronic Hepatitis C Using Interferon-Free Treatments: A Systematic Review and Meta-analysis of Observational Cohort Studies.
BACKGROUND AND OBJECTIVES
Hepatitis C treatment has changed considerably in recent years, and many interferon (IFN)-free therapies are now available. Considering the high rates of sustained virological response (SVR) presented by clinical trials for these treatments, high rates of effectiveness are also expected in real-world clinical practice. Hence, this study aimed to conduct a systematic review and meta-analysis of observational cohort studies to evaluate the clinical effectiveness and safety of IFN-free therapies for hepatitis C.
METHODS
The search was performed in four electronic databases and included cohort studies that evaluated IFN-free schemes and provided data on SVR at 12 weeks after the end of treatment (SVR12) as the primary outcome. Overall and subgroup meta-analyses of patients' clinical conditions (e.g. co-infection with human immunodeficiency virus (HIV), cirrhosis, liver transplant, specific genotypes, and other conditions) were performed.
RESULTS
Sixty-eight studies encompassing a total of 24,151 patients were included for quantitative and qualitative analyses, evaluating six treatments: sofosbuvir with ledipasvir, daclatasvir, or simeprevir; daclatasvir with asunaprevir; paritaprevir/ritonavir in combination with ombitasvir and dasabuvir; and sofosbuvir with ribavirin. The overall analysis showed SVR rates of 88-96% for all treatments except sofosbuvir combined with ribavirin, which had SVR rates of approximately 80%. The results of subgroup analyses showed that the genotype 3 virus appears to be the most difficult to treat.
CONCLUSION
In order to choose the best treatment option, it is necessary to consider the patients' conditions and characteristics. In conclusion, the use of IFN-free therapies meets the high expectations created by clinical trials, including patients in special clinical conditions.
Topics: 2-Naphthylamine; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Ribavirin; Ritonavir; Simeprevir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Uracil; Valine
PubMed: 29435907
DOI: 10.1007/s40261-018-0624-6 -
Expert Review of Gastroenterology &... Nov 2016Sofosbuvir (SOF) with simeprevir (SIM) combination was the first interferon-free regimen that reached optimal results in terms of sustained viral response (SVR). Areas... (Review)
Review
Sofosbuvir (SOF) with simeprevir (SIM) combination was the first interferon-free regimen that reached optimal results in terms of sustained viral response (SVR). Areas covered: A systematic review of the scientific literature concerning the effects that the SOF/SIM combination had on hepatitis C genotype 1 patients yielded 771 references. After the revision process, four clinical trials and 15 observational studies met the inclusion criteria; in total, these studies involved 5,766 patients. The SVR ranged from 67% to 100% depending on the patients' viral subtype and cirrhosis status. Adverse effects were common, but treatment discontinuation related to drug toxicity occurred in less than 5% of cases. Expert commentary: The SOF/SIM combination exhibits efficacy and tolerability profiles that are similar to those of the other available interferon-free combinations used for non-cirrhotic genotype 1b patients. Meanwhile, for patients with advanced cirrhosis or genotype 1a, this approach cannot be considered a routine treatment option due to the unsatisfactory results.
Topics: Antiviral Agents; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Patient Selection; Risk Factors; Simeprevir; Sofosbuvir; Treatment Outcome
PubMed: 27626505
DOI: 10.1080/17474124.2016.1236682 -
Journal of Gastroenterology and... Sep 2020Various all-oral direct-acting antiviral (DAA) regimens are being widely used in the treatment of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Various all-oral direct-acting antiviral (DAA) regimens are being widely used in the treatment of human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients; however, the comparative efficacy and safety of different types and combinations of DAAs are not completely clear. There is still a lack of integration of evidence for optimized therapies for HIV/HCV co-infection.
METHODS
We conducted a systematic literature search in several databases up to January 1, 2020. All the studies that reported the sustained virologic response (SVR) and adverse events of DAAs in HIV/HCV co-infected patients were included. The Bayesian Markov Chain Monte Carlo method was used for the pooled estimates of network meta-analysis.
RESULTS
We identified 33 eligible articles with 7 combinations of all-oral DAAs for the analyses of efficacy and safety. Grazoprevir-elbasvir ± ribavirin (GZR/EBR ± RBV: 95.6%; 95% CrI, 91.7-98.1%), ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin (3D ± RBV: 95.3%; 95% CrI, 93.4-96.9%), sofosbuvir-ledipasvir ± ribavirin (SOF/LDV ± RBV: 95.2%; 95% CrI, 93.7-96.6%), and sofosbuvir-daclatasvir ± ribavirin (SOF/DCV ± RBV: 94.8%; 95% CrI, 92.5-96.6%) were the most effective combinations for HIV/HCV co-infected patients, with SVR rates of approximately 94% and above while severe adverse events were rare. However, the SVR rates of sofosbuvir-ribavirin (SOF/RBV) and sofosbuvir-simeprevir ± ribavirin (SOF/SMV ± RBV) both failed to reach 90%, and the incidences of adverse events were higher than 5%.
CONCLUSIONS
Efficacy and safety of all-oral DAAs were in prospect for HIV/HCV co-infection patients. GZR/EBR ± RBV was the optimal combination recommended for HIV/HCV co-infected patients based on the excellent treatment effects and insignificant adverse events.
Topics: Administration, Oral; Adult; Aged; Amides; Antiviral Agents; Benzofurans; Carbamates; Coinfection; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; Hepatitis C, Chronic; Humans; Imidazoles; Male; Middle Aged; Quinoxalines; Ribavirin; Safety; Sulfonamides; Sustained Virologic Response; Treatment Outcome
PubMed: 32246857
DOI: 10.1111/jgh.15051 -
PloS One 2015The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs.
AIM
Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1.
METHODS
Medline and Scopus were searched up to 25th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using 'pmeta' command in STATA program.
RESULTS
Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens without PR, i.e. SOF plus LDV with/without ribavirin, SOF plus SMV with/without ribavirin, SOF plus DCV with/without ribavirin, and PrOD with/without ribavirin, (pooled incidence of SVR12 ranging from 93% to 100%, and pooled incidence of SVR24 ranging from 89% to 96%) were much higher than the pooled incidence rates of SVR12 (51%) and SVR24 (48%) in PR alone. In comparing SOF plus LDV with ribavirin and SOF plus LDV without ribavirin, the chance of having SVR12 was not significantly different between these two regimens, with the pooled RR of 0.99 (95% CI: 0.97, 1.01). Regarding adverse drug events, risk of serious adverse drug events, anemia and fatigue were relatively higher in treatment regimens with PR than the treatment regimens without PR. The main limitation of our study is that a subgroup analysis according to dosages and duration of treatment could not be performed. Therefore, the dose and duration of recommended treatment have been suggested in range and not in definite value.
CONCLUSIONS
Both DAA plus PR and dual DAA regimens should be included in the first line drug for treatment naïve HCV genotype 1 because of the significant clinical benefits over PR alone. However, due to high drug costs, an economic evaluation should be conducted in order to assess the value of the investment when making coverage decisions.
Topics: Antiviral Agents; Drug Therapy, Combination; Fatigue; Genotype; Hepacivirus; Hepatitis C; Humans; Odds Ratio; Publication Bias; Time Factors; Treatment Outcome; Viral Load
PubMed: 26720298
DOI: 10.1371/journal.pone.0145953 -
European Journal of Clinical... Jan 2017This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with... (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Antiviral Agents; Genotype; Hepatitis C, Chronic; Humans; Interferons; Network Meta-Analysis; Polyethylene Glycols; Protease Inhibitors; Ribavirin; Sustained Virologic Response
PubMed: 27757504
DOI: 10.1007/s00228-016-2146-6 -
BMJ Open Gastroenterology 2016Outcome data on simeprevir and sofosbuvir (SMV+SOF) in patients with liver transplantation (LT) with hepatitis C virus genotype 1 (HCV-1) are limited with individual...
BACKGROUND
Outcome data on simeprevir and sofosbuvir (SMV+SOF) in patients with liver transplantation (LT) with hepatitis C virus genotype 1 (HCV-1) are limited with individual studies having a small sample size and limited SVR12 (sustained virological response) data. Our goal was to perform a meta-analysis to study the outcome of SMV+SOF±ribavirin (RBV) in recipients with LT.
METHODS
In April 2015, we conducted a literature search for 'simeprevir' in MEDLINE/EMBASE and five major liver meetings. We included studies with SVR12 data in ≥5 post-LT mono-infected HCV-1 patients treated with SMV+SOF±RBV. We used random-effects models to estimate effect sizes, and the Cochrane Q-test (p value <0.10) with I(2) (>50%) to assess study heterogeneity.
RESULTS
We included nine studies with a total of 325 patients with post-LT. Studies included mostly men (59-81%). Pooled SVR12 was 88.0% (95% CI 83.4% to 91.5%). In two studies, HCV-1a patients with mild fibrosis (n=108) had an SVR12 rate of 95.0% (95% CI 82.4% to 98.7%), which was significantly higher than that of HCV-1a patients with advanced fibrosis (n=49) with an SVR12 rate of 81.7% (95% CI 69.8% to 89.5%), OR 4.2 (95% CI 1.1 to 16.1, p=0.03). The most common pooled side effects were: fatigue 21% (n=48/237), headache 9% (n=23/254), dermatological symptoms 15% (n=38/254), and gastrointestinal symptoms 6% (12/193).
CONCLUSIONS
SMV+SOF±RBV is safe and effective in recipients with LT with HCV-1 infection.
PubMed: 26966549
DOI: 10.1136/bmjgast-2015-000066 -
Transplant Infectious Disease : An... Apr 2019Comprehensive evaluation of safety and efficacy of different combinations of direct-acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Comprehensive evaluation of safety and efficacy of different combinations of direct-acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1) hepatitis C virus (HCV) recurrence remains limited. Therefore, we performed this systematic review and meta-analysis in order to evaluate the clinical outcome of DAA treatment in liver transplant patients with HCV GT1 recurrence.
METHODS
Studies were included if they contained information of 12 weeks sustained virologic response (SVR12) after DAA treatment completion as well as treatment related complications for liver transplant recipients with GT1 HCV recurrence.
RESULTS
We identified 16 studies comprising 885 patients. The overall pooled estimate proportion of SVR12 was 93% (95% confidence interval (CI): 0.89, 0.96), with moderate heterogeneity observed (τ = 0.01, P < 0.01, I =75%). High tolerability was observed in liver transplant recipients reflected by serious adverse events (sAEs) with pooled estimate proportion of 4% (95% CI: 0.01, 0.07; τ = 0.02, P < 0.01, I = 81%). For subgroup analysis, a total of five different DAA regimens were applied for treating these patients. Sofosbuvir/Ledipasvir (SOF/LDV) led the highest pooled estimate SVR12 proportion, followed by Paritaprevir/Ritonavir/Ombitasivir/Dasabuvir (PrOD), Daclatasvir (DCV)/Simeprevir (SMV) ± Ribavirin (RBV), and SOF/SMV ± RBV, Asunaprevir (ASV)/DCV. There was a tendency for favoring a higher pooled SVR12 proportion in patients with METAVIR Stage F0-F2 of 97% (95% CI: 0.93, 0.99) compared to 85% (95% CI: 0.79, 0.90) for stage F3-F4 (P < 0.01). There was no significant difference between LT recipients treated with or without RBV (P = 0.23).
CONCLUSIONS
Direct-acting antiviral treatment is highly effective and well-tolerated in liver transplant recipients with recurrent GT1 HCV infection.
Topics: Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Liver Transplantation; Recurrence; Sustained Virologic Response; Transplant Recipients; Treatment Outcome
PubMed: 30615227
DOI: 10.1111/tid.13047 -
Clinical Drug Investigation Nov 2020Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C...
BACKGROUND
Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs.
METHODS
Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website.
RESULTS
Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration-time curve (AUC) by 138%, 103%, and 161%, respectively.
CONCLUSIONS
DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.
Topics: Anticoagulants; Antiviral Agents; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Hepatitis C; Humans
PubMed: 32809123
DOI: 10.1007/s40261-020-00962-y -
Expert Review of Gastroenterology &... Dec 2018High prices of second-generation direct-acting antivirals (DAAs) in the treatment of chronic hepatitis C virus (HCV) patients led to reimbursement decisions based on...
High prices of second-generation direct-acting antivirals (DAAs) in the treatment of chronic hepatitis C virus (HCV) patients led to reimbursement decisions based on cost per quality-adjusted life year (QALY). Areas covered: We performed a systematic review of cost-utility analyses (CUA) comparing interventions with second-generation DAA therapies with no treatment, and with previous therapies for chronic HCV patients until July 2017. A total of 36 studies were included: 30 studies from the perspective of the healthcare payer, 3 from the societal perspective, and 3 did not report the perspective. For genotype 1, the highest number of ICER comparison corresponds to sofosbuvir (SOF) triple therapy and SOF-based combinations which reported a cost per QALY systematically ranging from negative to lower than US$100,000 when compared with no treatment or dual therapy or Simeprevir triple therapy. Expert commentary: Selected studies may be overestimating the true cost per QALY of second-generation DAAs in the treatment of HCV, mainly because of neglecting non-healthcare costs, using official list prices which are higher than actual transaction prices and not adopting the long run drug price in a dynamic approach. In addition, the impact of important price reductions of several DAAs in recent years on cost per QALY should be considered.
Topics: Antiviral Agents; Cost-Benefit Analysis; Drug Costs; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Models, Economic; Quality of Life; Sustained Virologic Response; Treatment Outcome
PubMed: 30791790
DOI: 10.1080/17474124.2018.1540929