Effectiveness of Calcitonin Gene-Related Peptide Monoclonal Antibodies in the Prevention of Migraine: A Systematic Review and Meta-Analysis of Observational Cohort Studies.

BACKGROUND AND OBJECTIVE: Migraine is a neurological disorder characterized by episodes of moderate-to-severe headache. The emergence of drugs derived from monoclonal antibodies specific for the calcitonin gene has brought forth a therapeutic option for patients in whom the traditional treatments have failed. This study aimed to evaluate the clinical effectiveness of calcitonin gene-related peptide antibodies in the prevention of migraine through a systematic review and meta-analysis of observational cohort studies. METHODS: A literature search for evidence was performed in electronic databases for observational studies that evaluated adult patients with migraine receiving calcitonin gene-related peptide receptor antagonists (e.g. erenumab, fremanezumab, galcanezumab and eptinezumab) and reported effectiveness outcomes (mean reduction in monthly migraine/headache days, and proportion of patients with 50% or greater reduction in migraine/headache days). RESULTS: During the screening process, 47 records were included for data extraction and qualitative and quantitative analyses. The overall rate of patients with a reduction of at least 50% of mean monthly migraine days was 54% (95% CI 49-59%), and overall mean monthly migraine reduction was about 7.7 days (95% CI 8.4-7.0 days). Regarding the outcome ≥ 50% reduction in mean monthly headache reduction, the overall rate of patients with a reduction of at least 50% was 57% (95% CI 48-64%), and the overall mean monthly headache reduction was approximately 8.8 days (95% CI 10.1-7.5 days). Subgroup analyses considering the drug treatment used and type of migraine were consistent with previous results. CONCLUSIONS: The use of calcitonin gene-related peptide antibodies in real-world studies to prevent migraine demonstrates promising effectiveness outcomes, in agreement with those reported in previously published randomized clinical trial reports.

Cross-Cultural Translation into Brazilian Portuguese and Validation of the Oral Anticoagulation Knowledge Tool (AKT-Br)

ABSTRACT Introduction: Oral anticoagulants are the treatment of choice for diverse types of coagulation disorders. Warfarin is widely used by the Brazilian population, possibly due to its lower cost than other oral anticoagulants. However, it has a high risk of serious adverse effects if used incorrectly. The Anticoagulation Knowledge Tool (AKT) can assess a patient's knowledge about her/his oral anticoagulant therapy and can assist health professionals in identifying patients with difficulties in adherence. This study aimed to translate, culturally adapt, and validate the AKT into Brazilian Portuguese. Methods: After a standard forward-backward procedure to translate the AKT into Brazilian Portuguese (AKT-Br), a version of the instrument was applied in three groups (patients, pharmacists, and the general population). The reliability of the AKT-Br was tested using an internal consistency measure and test-retest. The validity of the instrument was confirmed with data from the contrasted groups. All statistical analyses were performed with RStudio. Results: The median scores obtained with the AKT-Br were 29.0, 17.0, and 7.5 for pharmacists, patients, and the general population, respectively (maximum score of 35 points). There was moderate internal consistency for the instrument and test-retest reliability was satisfactory. Analysis of variance for validity of the groups revealed a significant relationship between the total score and the evaluated groups. Conclusion: The ATK-Br is a reliable and valid tool to assess knowledge about oral anticoagulants. AKT-Br can be used in clinical practice as an auxiliary tool to improve patient care through personalised educational interventions.

Thromboprophylaxis of Patients Submitted to Total Hip and Knee Arthroplasty: A Cost-Effectiveness Assessment From the Perspective of the Brazilian National Health System.

OBJECTIVES: Venous thromboembolism (VTE) is a serious national and international public health issue. Major orthopedic surgeries, such as a total hip (THA) and knee (TKA) arthroplasties, are associated with an increased risk of VTE, long-term complications, functional disability, and death resulting from hypercoagulability by surgical trauma. This pharmacoeconomic analysis aimed to identify the most cost-effective anticoagulant alternative in preventing VTE in patients undergoing THA and TKA. METHODS: A decision tree model was developed, comparing direct oral anticoagulants (rivaroxaban, apixaban, and dabigatran) with enoxaparin, with separate THA and TKA models a 3-month time horizon from the perspective of the Brazilian National Health System. The results were presented as incremental cost-effectiveness ratio (ICER), and the outcomes analyzed were avoided complications (ACs) after thromboprophylaxis. Comparative effectiveness was obtained from a published meta-analysis. A willingness to pay value of approximately R$ 15 000.00 was used per AC, and a probabilistic sensitivity analysis with the Monte Carlo simulation was conducted. RESULTS: Apixaban was the anticoagulant that presented the best ICER for patients undergoing THA (R$ 207.52/AC) and TKA (R$ 133.59/AC), followed by rivaroxaban (R$ 347.21/AC), dabigatran (R$ 372.56/AC), and enoxaparin (R$ 711.44/AC) for THA and by dabigatran (R$ 194.07/AC), rivaroxaban (R$ 221.12/AC), and enoxaparin (R$ 747.25/AC) for TKA. After ICER analysis, apixaban prevails over the other technologies analyzed for both surgical procedures, confirmed after sensitivity analysis. CONCLUSION: Our model suggests that, in the Brazilian National Health System, apixaban is the most cost-effective alternative in preventing VTE after THA and TKA.

Cross-Cultural Translation into Brazilian Portuguese and Validation of the Oral Anticoagulation Knowledge Tool (AKT-Br).

INTRODUCTION: Oral anticoagulants are the treatment of choice for diverse types of coagulation disorders. Warfarin is widely used by the Brazilian population, possibly due to its lower cost than other oral anticoagulants. However, it has a high risk of serious adverse effects if used incorrectly. The Anticoagulation Knowledge Tool (AKT) can assess a patient's knowledge about her/his oral anticoagulant therapy and can assist health professionals in identifying patients with difficulties in adherence. This study aimed to translate, culturally adapt, and validate the AKT into Brazilian Portuguese. METHODS: After a standard forward-backward procedure to translate the AKT into Brazilian Portuguese (AKT-Br), a version of the instrument was applied in three groups (patients, pharmacists, and the general population). The reliability of the AKT-Br was tested using an internal consistency measure and test-retest. The validity of the instrument was confirmed with data from the contrasted groups. All statistical analyses were performed with RStudio. RESULTS: The median scores obtained with the AKT-Br were 29.0, 17.0, and 7.5 for pharmacists, patients, and the general population, respectively (maximum score of 35 points). There was moderate internal consistency for the instrument and test-retest reliability was satisfactory. Analysis of variance for validity of the groups revealed a significant relationship between the total score and the evaluated groups. CONCLUSION: The ATK-Br is a reliable and valid tool to assess knowledge about oral anticoagulants. AKT-Br can be used in clinical practice as an auxiliary tool to improve patient care through personalised educational interventions.

Lag times in the publication of network meta-analyses: a survey.

OBJECTIVE: We assessed the extent of lag times in the publication and indexing of network meta-analyses (NMAs). STUDY DESIGN: This was a survey of published NMAs on drug interventions. SETTING: NMAs indexed in PubMed (searches updated in May 2020). PRIMARY AND SECONDARY OUTCOME MEASURES: Lag times were measured as the time between the last systematic search and the article submission, acceptance, online publication, indexing and Medical Subject Headings (MeSH) allocation dates. Time-to-event analyses were performed considering independent variables (geographical origin, Journal Impact Factor, Scopus CiteScore, open access status) (SPSS V.24, R/RStudio). RESULTS: We included 1245 NMAs. The median time from last search to article submission was 6.8 months (204 days (IQR 95-381)), and to publication was 11.6 months. Only 5% of authors updated their search after first submission. There is a very slightly decreasing historical trend of acceptance (rho=-0.087; p=0.010), online publication (rho=-0.080; p=0.008) and indexing (rho=-0.080; p=0.007) lag times. Journal Impact Factor influenced the MeSH allocation process, but not the other lag times. The comparison between open access versus subscription journals confirmed meaningless differences in acceptance, online publication and indexing lag times. CONCLUSION: Efforts by authors to update their search before submission are needed to reduce evidence production time. Peer reviewers and editors should ensure authors' compliance with NMA standards. The accuracy of these findings depends on the accuracy of the metadata used; as we evaluated only NMA on drug interventions, results may not be generalisable to all types of studies.

Prognostic Factors, Survival Analyses and the Risk of Second Primary Cancer: A Population-Based Study on Burkitt Lymphoma/Leukemia.

Burkitt lymphoma/leukemia (BL/L) is an aggressive oncohematological disease. This study evaluated the population-based prognosis and survival on BL/L as well as if BL/L behaved as a risk factor for the development of second primary cancers (SPCs) and if other first tumors behaved as risk factors for the occurrence of BL/L as an SPC. A retrospective cohort using the Surveillance, Epidemiology and End Results (SEER) Program (2008-2016) was performed. Kaplan-Meier, time-dependent covariate Cox regression and Poisson regression models were conducted. Overall, 3094 patients were included (median, 45 years; IQR, 22-62). The estimated overall survival was 65.4 months (95% CI, 63.6-67.3). Significantly more deaths occurred for older patients, black race, disease at an advanced stage, patients without chemotherapy/surgery and patients who underwent radiotherapy. Hodgkin lymphomas (nodal) (RR, 7.6 (3.9-15.0; p < 0.001)), Kaposi sarcomas (34.0 (16.8-68.9; p < 0.001)), liver tumors (3.4 (1.2-9.3; p = 0.020)) and trachea, mediastinum and other respiratory cancers (15.8 (2.2-113.9; p = 0.006)) behaved as risk factors for the occurrence of BL/L as an SPC. BL/L was a risk factor for the occurrence of SPCs as acute myeloid leukemias (4.6 (2.1-10.4; p < 0.001)), Hodgkin lymphomas (extranodal) (74.3 (10.0-549.8; p < 0.001)) and Kaposi sarcomas (35.1 (12.1-101.4; p < 0.001)). These results may assist the development of diagnostic and clinical recommendations for BL/L.

Chemotherapy Treatments for Burkitt Lymphoma: Systematic Review of Interventional Studies.

BACKGROUND: Burkitt lymphoma (BL) is an aggressive hematologic cancer. This study synthetized the evidence about the efficacy and safety of chemotherapy treatments used in patients with BL using the World Health Organization classification. MATERIALS AND METHODS: A systematic review of interventional studies was performed. A search was carried out in PubMed, Scopus, and Web of Science, with additional manual and gray literature searches. The methodological quality of articles was assessed with the Newcastle-Ottawa scale. RESULTS: We identified 1358 studies; 9 nonrandomized studies satisfied the eligibility criteria (n = 544 patients). The BL epidemiologic variants were sporadic BL (44.5%), endemic BL (47.2%), and immunodeficiency-associated BL (8.3%). Regarding chemotherapy protocols, 4 groups were identified: based on CODOX-M/IVAC (n = 4), EPOCH (n = 1), BFM (n = 1), and simplified treatment schemes used in African countries (n = 3). Most studies had moderate quality. Empirically and qualitatively, the best options for adults with sporadic BL were 'DA-EPOCH-R' (7-year overall survival [OS], 100%; 95% confidence interval [CI], 82-100), 'HDR + LD into CODOX-M/IVAC' (2-year OS, 84%), and 'RD-CODOX-M/IVAC' (4-year progression-free survival, 92%; 95% CI, 77-100); in pediatric patients, the 'BFM-NHL-90-like' showed promising results (3-year OS, 90%). For immunodeficiency-associated BL, the 'SC-EPOCH-RR' demonstrated a good therapeutic profile (6-year OS, 90%; 95% CI, 60-98). The 'Malawi 2012-2014' (1-year OS, 73%; 95% CI, 61-85) could be the treatment choice in endemic BL (African countries). The main adverse events were hematologic. CONCLUSION: Selecting chemotherapy protocols for BL should be grounded in its epidemiologic variants. Further studies with greater methodological quality are needed to strengthen the evidence.

Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis.

PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

Safety and Efficacy of Oral Anticoagulants Therapies in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Network Meta-Analysis.

BACKGROUND: Different antithrombotic treatments, from vitamin K antagonists to direct oral anticoagulants (DOACs), are available to reduce ischemic risks in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). Objective: To synthetize evidence about the benefit-risk ratio of antithrombotic treatments and their combinations in patients with AF and PCI. METHODS: A network meta-analysis and a stochastic multicriteria acceptability analysis (SMAA) were performed including randomized controlled trials (RCT) that evaluate antithrombotic treatments in adults with AF and PCI. Searches were conducted in PubMed and Scopus (updated November-2019). Outcomes compared included bleeding, stroke, and death (Prospero registration: CRD42019146813). RESULTS: Five RCTs were included (11 532 patients). Vitamin K antagonists + dual antiplatelet therapy was associated with major bleeding (odds ratio: 0.52 [95% CI: 0.32-0.86]) compared to DOAC + P2Y12. No statistical differences were found among DOAC regimens for the main outcomes, including bleeding, stroke, and death. Surface under the cumulative ranking curve analysis (SUCRA) and SMAA demonstrated edoxaban 60 mg + P2Y12 inhibitor as the worst option (28%). Apixaban 5 mg + P2Y12 inhibitor was the safest alternative (63%) in all scenarios. CONCLUSIONS: Insufficient evidence on the clinical superiority among anticoagulant regimens exists, although apixaban slightly stands out. Edoxaban was associated with more adverse events. To strength this evidence, well-designed, low risk of bias clinical trials are needed. Cost-minimization analyses are required to provide further information for clinical decision-making.

Effectiveness and Cost-Effectiveness of Triple Therapy With Telaprevir and Boceprevir for Chronic Hepatitis C: A Decision Analysis From the Brazilian Public Health System Perspective.

OBJECTIVES: Because of the lack of evidence regarding long-term effectiveness and cost-effectiveness of first-generation direct-acting antivirals for chronic hepatitis C (CHC) treatment in Brazil, we performed a cost-utility analysis comparing standard dual therapy (peginterferon plus ribavirin [pegIFN/RBV]), boceprevir, and telaprevir for CHC patients. METHODS: We developed a state-transition Markov model simulating the progression of CHC. Long-term outcomes included remaining life expectancy in life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Short-term outcomes included sustained virological response rates (SVR). Direct medical costs were obtained from Brazilian databases. A lifelong time horizon was considered and a 5% annual discount rate was applied for costs and clinical outcomes. A willingness-to-pay threshold of approximately $20 000 per QALY was used. We performed multiple sensitivity analyses. RESULTS: For short- and long-term scenarios, therapy with boceprevir was dominated by telaprevir, which was more effective than standard dual therapy (75.0% vs 40.4% SVR rate, 13.47 vs 12.59 LYs, and 9.74 vs 8.49 QALYs, respectively) and was also more expensive ($15 742 vs $5413). The corresponding ICERs were $29 854/SVR, $11 803/LY, and $8277/QALY. Based on our model, triple therapy with telaprevir was the most cost-effective treatment for the Brazilian health system. Despite a lack of data regarding the Brazilian population, we incorporated as many applicable parameters as possible. CONCLUSIONS: Telaprevir is more effective and cost-effective than boceprevir. Our model may be applied for other settings with a few adjustments in the input parameters.

Effectiveness and safety of pegvisomant: a systematic review and meta-analysis of observational longitudinal studies.

PURPOSE: Acromegaly is a rare disease that often requires drug treatment to achieve control, with pegvisomant being one of the most widely used therapies. In the present paper, we aimed to obtain evidence regarding the effectiveness and safety of pegvisomant by reviewing real-world observational longitudinal studies. METHODS: A systematic review was performed with a meta-analysis of event rates (95% confidence interval (CI)) using a random effects model. Sensitivity and subgroup analyses were performed (comprehensive meta-analysis 2.0). The systematic review was performed in accordance to preferred reporting items for systematic reviews and meta-analyses, meta-analysis of observational studies in epidemiology, and Cochrane recommendations (PROSPERO register CRD 42017059880). PubMed, Scopus, Web of Science, and SciELO were used to search for literature. Observational studies in patients using pegvisomant for the treatment of acromegaly were included. RESULTS: Initially, 552 papers were retrieved from the databases; and 31 articles were included in the qualitative analysis and 14 in the quantitative analysis. Eight primary meta-analyses were performed. The overall rate of patients with disease control was of 60.9% (51.8-69.3%; 95% CI). When considering patients under monotherapy, the control rate was 71.7% (64.0-78.4%; 95% CI). Tumor growth was estimated in 7.3% (4.7-11.1%; 95% CI) and elevation of transaminases in 3.0% (1.7-5.2%; 95% CI). CONCLUSIONS: The real-world data showed that the effectiveness of pegvisomant is not as high as reported in interventional studies. Acromegaly appears to be better controlled when pegvisomant is used as a monotherapy. No serious adverse events were associated with the use of pegvisomant; however, given the high cost of this drug, further studies are required.

Cost-effectiveness of acromegaly treatments: a systematic review.

PURPOSE: Acromegaly is a rare disease that results in the enlargement of body extremities and in organomegaly. Treatments include surgery, drugs, and radiotherapy, which are all onerous. Therefore, well-conducted cost-analyses are crucial in the decision-making process. METHODS: A systematic review of cost-effectiveness studies on acromegaly therapies was performed following PRISMA and Cochrane recommendations. The search for records was conducted in PubMed, Scopus, and Web of Science (May 2018). The quality of the included studies was assessed using the Joana Briggs Institute Tool. RESULTS: From initial 547 records, 16 studies were included in the review. The studies could present more than one economic evaluation, and encompassed cost-effectiveness (n = 13), cost-utility (n = 5), and cost-consequence (n = 1) analyses. All studies were model-based and evaluated only direct medical costs. Eleven records did not mention discounting and only 10 performed sensitivity analyses. The characteristic of the studies, the cost-effectiveness results and the studies' conclusions are described and commented upon. The main limitation of the studies was discussed and aspects to improve in future studies were pointed out. CONCLUSIONS: Cost-effectiveness studies on acromegaly have been performed in several scenarios, evaluating different phases of treatment. However, the studies present limitations and, overall, were considered of moderate quality. Further economic models should be developed following health economics guidelines recommendations, and must improve transparency.

Medical Treatments for Acromegaly: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Acromegaly results from the hypersecretion of growth hormone. Because of the low incidence rates of this disease worldwide, few clinical trials evaluating drug treatments have been conducted. OBJECTIVES: To conduct the first network meta-analysis simultaneously comparing all available drugs used in acromegaly treatment so as to provide more robust evidence in this field. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration recommendations (PROSPERO database under the registration number CRD42017059880). The electronic searches were conducted in PubMed (MEDLINE), Scopus, and Web of Science databases. Randomized controlled trials comparing any drug for the treatment of acromegaly head-to-head or versus placebo were included. Outcomes concerning the efficacy and safety of treatments were evaluated. The statistical analyses were performed using Aggregate Data Drug Information System version 1.16.8 (drugis.org, Groningen, The Netherlands). RESULTS: The initial search retrieved 2059 articles. Of these, 10 randomized controlled trials were included in a qualitative analysis and 7 in a quantitative analysis. The network meta-analysis for the efficacy outcome (number of patients achieving insulinlike growth factor 1 control) showed that pegvisomant and lanreotide autogel were statistically superior to placebo (odds ratio [95% credible interval] 0.06 [0.00-0.55] and 0.09 [0.01-0.88]). No further differences were found. The probability rank indicated that pegvisomant and pasireotide have the highest probabilities (33% and 34%, respectively) of being the best therapeutic options. No major side effects were noted. CONCLUSIONS: Pegvisomant is still a good option for acromegaly treatment, but pasireotide seems to be a promising alternative. Nevertheless, other important key factors such as drug costs and effectiveness (real-world results) should be taken into account when selecting acromegaly treatment.

Discontinuation of non-anti-TNF drugs for rheumatoid arthritis in interventional versus observational studies: a systematic review and meta-analysis.

PURPOSE: Although randomized controlled trials (RCTs) are the gold standard for the assessment of clinical outcomes, long-term extension trials (LTEs) and observational cohorts may help generate evidence. Our goal was to compare the discontinuation rates of abatacept, rituximab, and tocilizumab in rheumatoid arthritis (RA) reported in different study designs. METHODS: A systematic review was conducted with searches in PubMed, Scopus, and the Cochrane Library, plus a manual search, for RCTs, LTEs, and observational cohorts reporting discontinuation rates by any of three causes (all-cause, inefficacy, adverse events). Meta-analyses with sensitivity analyses and meta-regressions were conducted. RESULTS: Of the 111 studies included, 74 were RCTs (n = 55) or LTEs (n = 17) reporting data on abatacept (n = 33), rituximab (n = 10), and tocilizumab (n = 31) and 37 were observational cohort studies (abatacept = 11, rituximab = 8, tocilizumab = 18). The follow-up duration did not differ among the study designs. Discontinuation rates were similar among the drugs but varied among the study designs. Discontinuation rates were significantly higher in cohort studies than those in interventional studies for the three drugs. Sensitivity analyses could not identify patient characteristics associated with these differences. Meta-regression analyses demonstrated no correlation between study follow-up duration and discontinuation rates. CONCLUSIONS: The discontinuation rates reported for non-anti-TNF drugs varied relative to the study design in which they were investigated. Regulatory agencies, price-setting entities, and evidence-gathering researchers should consider the effect of the real-life environment in their decisions and conclusions.

Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: A Network Meta-Analysis.

BACKGROUND: A broad range of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is available. However, the efficacy and safety of traditional DMTs compared with the recently developed DMTs remain unclear. OBJECTIVE: Therefore, we have synthesised available evidence of clinical outcomes for DMTs in adults with RRMS. METHODS: PubMed, Scopus and a manual search were performed. Bayesian network meta-analyses of randomised clinical trials assessing DMTs as monotherapies were conducted. SUCRA and GRADE were used to rank therapies and to assess quality of general evidence, respectively. RESULTS: Thirty-three studies were included in the meta-analyses. The most effective therapies for the outcome of annualised relapse rate were alemtuzumab (96% probability), natalizumab (96%) and ocrelizumab (85%), compared with all other therapies (hazard ratio versus placebo, 0.31, 0.31 and 0.37, respectively; p < 0.05 for all comparisons) (high-quality evidence). However, no significant differences among these three therapies were found. Discontinuation due to adverse events revealed similarity across all therapies, except for alemtuzumab, which showed less discontinuation when compared with interferon-1a intramuscular (relative risk 0.37; p < 0.05). CONCLUSION: High-quality evidence shows that alemtuzumab, natalizumab and ocrelizumab present the highest efficacy among DMTs, and other meta-analyses are required regarding adverse events frequency, to better understand the safety of therapies. Based on efficacy profile, guidelines should consider a three-category classification (i.e. high, intermediate and low efficacy).

Efficacy of Interferon-Free Therapies for Chronic Hepatitis C: A Systematic Review of All Randomized Clinical Trials.

BACKGROUND AND OBJECTIVES: Second-generation direct-acting antivirals (DAAs) have recently arisen as more effective and safer treatments for chronic hepatitis C. These drugs can be combined into treatments without interferon (IFN), and are therefore called IFN-free therapies. OBJECTIVE: The objective of this study systematic review was to evaluate the efficacy of IFN-free therapies for the treatment of chronic hepatitis C, and thus increase the clinical evidence for these therapies. METHODS: A systematic review was conducted in accordance with Cochrane Collaboration recommendations. A search was performed in six different electronic databases using 'clinical trials', 'hepatitis C' and 'interferon-free' as the main descriptors, and studies that conformed to the inclusion criteria had their data extracted, including study information, baseline characteristics, and efficacy outcomes (sustained virologic response, rapid virologic response, and virologic failure). RESULTS: Sixty-four randomized clinical trials including 15 different therapies were included in a total of 15,731 patients infected with the hepatitis C virus, mostly with genotype 1, and mainly treated for 12 or 24 weeks. The sustained virologic response rate after 12 weeks of treatment was approximately 89%, while the virologic failure rate was below 5%. CONCLUSIONS: Second-generation DAAs presented several advantages: virologic response values higher than the average achieved by previous IFN-based therapies, reduced treatment duration, and the possibility of different combinations of therapies to meet patient needs. Thus, IFN-free therapies appear to be valuable alternatives for the treatment of chronic hepatitis C.

Ledipasvir/sofosbuvir with or without ribavirin for the treatment of chronic hepatitis C genotype 1: A pairwise meta-analysis.

BACKGROUND AND AIM: Ledipasvir with sofosbuvir (LED/SOF) for the treatment of patients infected with genotype 1 hepatitis C virus can be used with or without ribavirin (RBV). RBV is well known to promote significant adverse events (AE). The aim of this study was to compare the efficacy and safety of treatment with LED/SOF, with or without RBV, in patients infected with hepatitis C virus genotype 1. METHODS: We performed a systematic review followed by a pairwise meta-analysis including randomized controlled trials that reported efficacy (rapid virological response, sustained virological response at 4 and 12 weeks post-treatment (SVR4 and 12), and viral relapse) and safety outcomes (any AE, serious AE, discontinuation owing to AE, anemia, and rash). It was performed a subgroup analysis evaluating the SVR12 including only cirrhotic patients. Results were reported as risk ratios (RR) and with 95% confidence intervals (95% CI). RESULTS: Seven randomized controlled trials were analyzed. LED/SOF with RBV showed a worse safety profile when compared with LED/SOF without RBV for the following outcomes: any AE (RR 0.56 [95% CI 0.46-0.69]), anemia (RR 0.08 [95% CI 0.04-0.17]), and rash (RR 0.35 [95% CI 0.19-0.65]). No significant differences were observed regarding serious AE, rapid virological response, SVR4, SVR12, or viral relapse. The subgroup analysis did not show significant differences between either treatment groups. CONCLUSION: Administration of LED/SOF + RBV to treatment-naïve patients with or without cirrhosis, and non-cirrhotic treatment-experienced patients, did not promote significant additional benefits. Furthermore, it is still unclear whether cirrhotic treatment-experienced patients could benefit from combined therapy.