-
Annals of Medicine Dec 2022Glecaprevir/pibrentasvir (G/P; 300 mg/120 mg) is a new direct-acting antiviral (DAA) that exhibits anti-hepatitis C virus (HCV) pan-genotype (GT) activity for 8,... (Meta-Analysis)
Meta-Analysis
Glecaprevir/pibrentasvir (G/P; 300 mg/120 mg) is a new direct-acting antiviral (DAA) that exhibits anti-hepatitis C virus (HCV) pan-genotype (GT) activity for 8, 12, or 16 weeks. However, the U.S. Food and Drug Administration have received reports that using G/P causes moderate to severe liver impairment. In some cases, isolated hyperbilirubinemia and jaundice have been reported without concomitant evidence of increased transaminase levels or other hepatic decompensation events. This study aimed to analyze the incidence of drug-induced liver injury of G/P for chronic hepatitis C virus. We searched databases from the inception of each database until March 2021. Data were pooled using a random-effects model. The Cochrane Risk of Bias Tool (RoB 2.0) and the OpenMeta [Analyst] software were performed for quality assessment and quantitative studies, respectively. The primary outcome was grade 3 level of drug-induced liver injury (DILI). The nine studies included in the meta-analysis involved a total of 7,650 participants, and the overall sustained virologic response rate was above 95%. The most frequent drug-related laboratory abnormalities in DILI involved total bilirubin, alanine aminotransferase, aspartate aminotransferase, and hemoglobin, but these abnormalities were minimal. The cirrhosis-without cirrhosis incidence risk ratio (IRR) was 2.724 (95% confidence interval: 1.182-6.276) in the grade 3 hyperbilirubinemia subgroup analysis. No significant differences were found within the other subgroups, in HCV GTs, and in treatment duration. DILI was found to occur frequently with G/P treatment. Hyperbilirubinemia occurred most frequently, especially, in patients with cirrhosis. However, G/P is still the primary therapy of choice for CKD and end-stage renal disease (ESRD) patients due to a superior safety rate.
Topics: Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Chemical and Drug Induced Liver Injury; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Proline; Pyrrolidines; Quinoxalines; Sulfonamides
PubMed: 34969349
DOI: 10.1080/07853890.2021.2012589 -
Journal of Hepatology Sep 2019The effect of hepatocellular carcinoma (HCC) on the response to interferon-free direct-acting antiviral (DAA) therapy in patients with chronic hepatitis C (CHC)... (Meta-Analysis)
Meta-Analysis
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%, I = 79.1% vs. 93.3%, 95% CI 91.9-94.7%, I = 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 (I = 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.
Topics: 2-Naphthylamine; Adolescent; Adult; Anilides; Antiviral Agents; Benzimidazoles; Carbamates; Carcinoma, Hepatocellular; Cyclopropanes; Female; Fluorenes; Hepacivirus; Hepatitis C, Chronic; Humans; Isoquinolines; Lactams, Macrocyclic; Liver Neoplasms; Liver Transplantation; Macrocyclic Compounds; Male; Proline; Ritonavir; Sofosbuvir; Sulfonamides; Sustained Virologic Response; Uracil; Valine; Young Adult
PubMed: 31096005
DOI: 10.1016/j.jhep.2019.04.017 -
Parasitology Jun 2019Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma...
Although leucocytes are targets of renin-angiotensin system (RAS) effector molecules and RAS-modulating drugs exert immunomodulatory effects, their impact on Trypanosoma cruzi infection remains poorly understood. By using the framework of a systematic review, we integrated the preclinical and clinical evidence to investigate the relevance of angiotensin-inhibiting drugs on T. cruzi infections. From a comprehensive and structured search in biomedical databases, only original studies were analysed. In preclinical and clinical studies, captopril, enalapril and losartan were RAS-modulating drugs used. The main in vitro findings indicated that these drugs increased parasite uptake per host cells, IL-12 expression by infected dendritic cells and IFN-γ by T lymphocytes, in addition to attenuating IL-10 and IL-17 production by CD8 + T cells. In animal models, reduced parasitaemia, tissue parasitism, leucocytes infiltration and mortality were often observed in T. cruzi-infected animals receiving RAS-modulating drugs. In patients with Chagas' disease, these drugs exerted a controversial impact on cytokine and hormone levels, and a limited effect on cardiovascular function. Considering a detailed evaluation of reporting and methodological quality, the current preclinical and clinical evidence is at high risk of bias, and we hope that our critical analysis will be useful in mitigating the risk of bias in further studies.
Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; CD8-Positive T-Lymphocytes; Captopril; Chagas Cardiomyopathy; Chagas Disease; Clinical Studies as Topic; Cytokines; Drug Evaluation, Preclinical; Enalapril; Humans; Losartan; Mice; Trypanosoma cruzi
PubMed: 30782223
DOI: 10.1017/S003118201900009X -
The American Journal of Clinical... Jul 2017Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently... (Meta-Analysis)
Meta-Analysis
Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct.
Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study. We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study ( = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and -interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Thirteen observational studies met the eligibility criteria ( < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (), gastric inhibitory polypeptide receptor (), caveolin 2 (), and peptidase D () (-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.
Topics: Case-Control Studies; Caveolin 2; Diabetes Mellitus; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Fiber; Dipeptidases; Energy Intake; Europe; Feeding Behavior; Female; Gene-Environment Interaction; Humans; Male; Middle Aged; Models, Biological; Receptors, Gastrointestinal Hormone; Risk Factors; Transcription Factor 7-Like 2 Protein
PubMed: 28592605
DOI: 10.3945/ajcn.116.150094 -
Frontiers in Pediatrics 2021Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA...
Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.
PubMed: 34041209
DOI: 10.3389/fped.2021.672004 -
Pharmacological Research Jan 2021Phase 2 and phase 3 clinical studies showed that hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) efficiently increased hemoglobin levels in both... (Meta-Analysis)
Meta-Analysis
Effects of hypoxia-inducible factor prolyl hydroxylase inhibitors on iron regulation in non-dialysis-dependent chronic kidney disease patients with anemia: A systematic review and meta-analysis.
Phase 2 and phase 3 clinical studies showed that hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) efficiently increased hemoglobin levels in both dialysis-dependent and non-dialysis-dependent chronic kidney disease (CKD) patients. However, the effects of HIF-PHIs on iron regulation have not been consistent among clinical trials. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the effects of six HIF-PHIs on iron regulation in non-dialysis CKD patients. Electronic databases were searched from inception to April 20, 2020, for eligible studies. Changes from baseline in transferrin saturation (TSAT), total iron-binding capacity (TIBC), iron, ferritin, and hepcidin levels were pooled using the inverse-variance method and presented as the mean difference (MD) or standardized MD (SMD) with 95 % confidence intervals (CIs). Meta-analysis of the included studies showed that, in non-dialysis-dependent CKD patients, HIF-PHIs decreased TSAT (MD, -4.51; 95 % CI, -5.81 to -3.21), ferritin (MD, -47.29; 95 % CI, -54.59 to -40.00) and hepcidin (SMD, -0.94; 95 % CI, -1.25 to -0.62), increased TIBC (MD, 9.15; 95 % CI, 7.08-11.22), and did not affect serum iron (MD, -0.31; 95 % CI, -2.05 to 1.42) despite enhanced erythropoiesis. This systematic review suggests that HIF-PHIs promote iron utilization in non-dialysis-dependent CKD patients. Importantly, HIF-PHIs are associated with increased transferrin levels (and TIBC), leading to reduced TSAT. Therefore, the reduction of TSAT after HIF-PHIs should not be interpreted as iron deficiency.
Topics: Anemia; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Prolyl-Hydroxylase Inhibitors; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic
PubMed: 33086081
DOI: 10.1016/j.phrs.2020.105256 -
European Journal of Clinical... Apr 2021To meta-statistically compare the efficiency of hypoxia-induced factor prolyl hydroxylase inhibitor on hemoglobin, ferritin, hepcidin rate, and adverse events. (Meta-Analysis)
Meta-Analysis
PURPOSE
To meta-statistically compare the efficiency of hypoxia-induced factor prolyl hydroxylase inhibitor on hemoglobin, ferritin, hepcidin rate, and adverse events.
METHODS
A systematic identification of literature was performed according to PRISMA guidelines on 4 academic databases: MEDLINE, Scopus, EMBASE, and CENTRAL. A meta-analysis evaluating the influence of hypoxia-induced factors was performed for patients undergoing/not undergoing hemodialysis. The analysis evaluated the efficacy of hypoxia-induced factors on hemoglobin, ferritin, hepcidin rate, and the number of adverse events.
RESULTS
Out of 1052 records, 15 articles including 2045 patients (mean age 62.1 ± 5.4 years) were included in this review. The systematic review presents a 1a level of evidence supporting the use of hypoxia-induced factor for mediating anemia in patients with chronic kidney disease. The meta-analysis reveals medium to large beneficial effects of the hypoxia-induced factor on hemoglobin rate for patients receiving (0.72) and not receiving (1.04) hemodialysis. Moreover, the administration of hypoxia-induced factors was reported to reduce ferritin rate and the hepcidin rate, and the number of adverse events in patients with chronic kidney disease.
CONCLUSION
The current meta-analysis recommends the use of hypoxia-induced factor prolyl hydroxylase inhibitor for managing anemia in chronic kidney disease.
Topics: Anemia; Controlled Clinical Trials as Topic; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 33161463
DOI: 10.1007/s00228-020-03037-1 -
Molecules (Basel, Switzerland) Jun 2021The Angiotensin-I-converting enzyme (ACE) is a peptidase with a significant role in the regulation of blood pressure. Within this work, a systematic review on the...
The Angiotensin-I-converting enzyme (ACE) is a peptidase with a significant role in the regulation of blood pressure. Within this work, a systematic review on the enzymatic preparation of Angiotensin-I-Converting Enzyme inhibitory (ACEi) peptides is presented. The systematic review is conducted by following PRISMA guidelines. Soybeans and velvet beans are known to have high protein contents that make them suitable as sources of parent proteins for the production of ACEi peptides. Endopeptidase is commonly used in the preparation of soybean-based ACEi peptides, whereas for velvet bean, a combination of both endo- and exopeptidase is frequently used. Soybean glycinin is the preferred substrate for the preparation of ACEi peptides. It contains proline as one of its major amino acids, which exhibits a potent significance in inhibiting ACE. The best enzymatic treatments for producing ACEi peptides from soybean are as follows: proteolytic activity by Protease P (Amano-P from sp.), a temperature of 37 °C, a reaction time of 18 h, pH 8.2, and an E/S ratio of 2%. On the other hand, the best enzymatic conditions for producing peptide hydrolysates with high ACEi activity are through sequential hydrolytic activity by the combination of pepsin-pancreatic, an E/S ratio for each enzyme is 10%, the temperature and reaction time for each proteolysis are 37 °C and 0.74 h, respectively, pH for pepsin is 2.0, whereas for pancreatin it is 7.0. As an underutilized pulse, the studies on the enzymatic hydrolysis of velvet bean proteins in producing ACEi peptides are limited. Conclusively, the activity of soybean-based ACEi peptides is found to depend on their molecular sizes, the amino acid residues, and positions. Hydrophobic amino acids with nonpolar side chains, positively charged, branched, and cyclic or aromatic residues are generally preferred for ACEi peptides.
Topics: Amino Acids; Angiotensin-Converting Enzyme Inhibitors; Aspergillus; Endopeptidases; Exopeptidases; Globulins; Hydrolysis; Hydrophobic and Hydrophilic Interactions; Mucuna; Pancreatin; Peptide Hydrolases; Peptides; Proline; Soybean Proteins; Glycine max; Temperature
PubMed: 34201554
DOI: 10.3390/molecules26133822 -
Alimentary Pharmacology & Therapeutics Mar 2020The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients... (Meta-Analysis)
Meta-Analysis
Systematic review with meta-analysis: impact of baseline resistance-associated substitutions on the efficacy of glecaprevir/pibrentasvir among chronic hepatitis C patients.
BACKGROUND
The effect of baseline resistance-associated substitutions (RAS) on the sustained virologic response at 12 weeks (SVR12) among chronic hepatitis C (CHC) patients receiving the second generation, pan-genotypic glecaprevir/pibrentasvir (G/P) regimen is unclear.
AIM
To assess the effect of RAS on the SVR12 in CHC patients treated with G/P regimen.
METHODS
The EMBASE, MEDLINE and Cochrane central register of controlled trials databases were searched for relevant studies published before 1 March 2019. The principal outcome was to compare the SVR12 in CHC patients with and without baseline RAS, particularly in genotype-1, genotype-3 and direct-acting anti-virals (DAAs) failure patients. The outcomes were pooled using a random-effects model and odds ratio (OR) was calculated. The risk of bias was assessed using the Cochrane risk of bias tools for randomised and nonrandomised interventional studies.
RESULTS
After initially identifying 410 studies, 3302 patients from 17 studies were included. Among 50 cases of virologic failures, 48% had genotype-3 infection, 44% genotype-1 infection and 36% DAA-failure patients. Baseline RAS were present in 44(88%) patients. The most common NS5a and NS3 mutations were Y93H and A166S respectively. The odds of SVR12 were significantly reduced in patients with any baseline RAS (NS3 and/or NS5a) (OR 0.32, 95%C I[0.15, 0.65], I = 0%) and NS5a substitutions (OR 0.36, 95%CI [0.18,0.73]). The impact of RAS on SVR12 was significant among genotype-3 patients, but not among genotype-1 or DAA-failure cases. The presence of Y93H and A30K mutations significantly impacted SVR12 rates in genotype-3 patients.
CONCLUSION
Baseline NS3 or NS5a RAS, especially the NS5a substitutions-A30K, Y93H, decrease the odds of achieving SVR12 in genotype-3 CHC patients.
Topics: Amino Acid Substitution; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Genotype; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Non-Randomized Controlled Trials as Topic; Proline; Pyrrolidines; Quinoxalines; Randomized Controlled Trials as Topic; Sulfonamides; Sustained Virologic Response; Treatment Outcome; Viral Nonstructural Proteins
PubMed: 31943236
DOI: 10.1111/apt.15633 -
Indian Journal of Pediatrics Oct 2018To summarize the available randomized controlled trials (RCTs) to evaluate the effect of taurine supplementation on growth in low birth weight infants (LBW). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To summarize the available randomized controlled trials (RCTs) to evaluate the effect of taurine supplementation on growth in low birth weight infants (LBW).
METHODS
PubMed, EmBase, and Cochrane Library electronic databases were searched for published articles through March 2017. Analysis was done to examine the effect of taurine supplementation on growth, and sensitivity analysis was performed by removing each individual study from meta-analysis.
RESULTS
Results of 9 trials totaling 216 LBW infants in the present meta-analysis were collected and analyzed. The conclusion of included studies demonstrated that taurine supplementation significantly reduced length gain (WMD:-0.18; P < 0.001), plasma glycine (WMD:-106.71; P = 0.033), alanine (WMD:-229.30; P = 0.002), leucine (WMD:-64.76; P < 0.001), tyrosine (WMD:-118.11; P < 0.001), histidine (WMD:-52.16; P < 0.001), proline (WMD: -84.29; P = 0.033), and asparagine-glutamine (WMD:-356.30; P < 0.001). However, taurine supplementation was associated with higher levels of acidic sterols (WMD:0.61; P = 0.024), total fatty acids (WMD:7.94; P = 0.050), total saturated fatty acids (WMD:9.70; P < 0.001), and unsaturated fatty acids (WMD:6.63; P < 0.001). Finally, taurine supplementation had little or no significant effect on weight gain, head circumference gain, plasma taurine, threonine, serine, citrulline, valine, methionine, isoleucine, phenylalanine, ornithine, lysine, arginine, glutamate, hydroxyproline, aspartate, dietary cholesterol, endogenous neutral sterols, cholesterol synthesis, and medium-chain triglycerides.
CONCLUSIONS
The findings suggest that although there are several significant differences in plasma indeces, no significant effect on growth in LBW infants was observed with taurine supplementation.
Topics: Body Height; Cephalometry; Food, Fortified; Humans; Infant Formula; Infant, Low Birth Weight; Infant, Newborn; Taurine; Weight Gain
PubMed: 29368111
DOI: 10.1007/s12098-018-2609-0