Summary
Background
Grey Zone (GZ) is an ill‐defined situation including patients falling between inactive carrier (IC) state and HBeAg‐negative chronic hepatitis B (HBeAg‐negative CHB).
Aims
To ...assess the long‐term outcomes of GZ patients compared to IC in the absence of treatment.
Methods
Retrospective analysis of 287 IC and GZ HBeAg‐negative patients. Patients were classified into 4 groups at baseline: HBV‐DNA <2000 IU/mL and ALT <40 U/L (IC), HBV‐DNA <2000 IU/mL and ALT 40‐80 U/L (GZ‐1), HBV‐DNA 2000‐20 000 IU/mL and ALT <40 U/L (GZ‐2) or ALT 40‐80 U/L (GZ‐3). Data were also analysed using AASLD ALT criteria.
Results
After a median follow‐up of 8.2 (5‐19) years, HBsAg loss occurred in about 15% ICs or GZ patients. Transition into IC state occurred in 40% of GZ patients. DNA fluctuations >2000 IU/mL correlated inversely with transition into IC and HBsAg loss. HBsAg levels were significantly lower in ICs than in GZ patients (338 IU/mL 20‐3269 vs 5763 IU/mL 2172‐17 754; P < 0.05). Among the latter group, there was an increasing gradient of HBsAg levels from GZ‐1 to GZ‐3 patients (P < 0.05). HBeAg‐negative CHB occurred in only 18 (6.3%) GZ patients. No patient developed cirrhosis nor advanced fibrosis. ALT/HBV‐DNA fluctuations and HBeAg‐negative CHB development were more frequent in genotype B/C patients, whereas HBsAg loss occurred only in genotype A/D patients.
Conclusions
Most Caucasian GZ patients present excellent long‐term outcomes in the absence of treatment, with a high rate of HBsAg loss and low rate of progression to HBeAg‐negative CHB. HBV‐genotyping and HBsAg levels could help to predict outcomes and better classify GZ patients.
Linked ContentThis article is linked to Ridruejo paper. To view this article visit https://doi.org/10.1111/apt.14644.
Summary
Background
A few cases of hepatitis B virus (HBV) reactivation during anti‐viral therapy against hepatitis C (HCV) have been reported. However, the information regarding the real impact of ...this phenomenon is scarce.
Aim
To evaluate the risk of HBV reactivation during anti‐viral therapy against HCV with an interferon‐free regimen with direct‐acting anti‐virals (DAAs).
Methods
Observational and prospective study of 352 patients receiving DAAs therapy between September 2015 and May 2016. HBV‐DNA and ALT levels were monitored at baseline, at week 4 of anti‐viral therapy, at end of treatment and 12 weeks after treatment discontinuation in patients with HBV surface antigen (HBsAg) positive or HBV core antibody (anti‐HBc) positive before starting anti‐viral therapy.
Results
Ten (2.8%) and 64 (18%) patients were HBsAg and anti‐HBc positive at baseline, respectively. Five (50%) of 10 HBsAg positive and one (1.6%) of 64 anti‐HBc positive patients presented HBV virological reactivation (>1log increase in HBV‐DNA levels). None of these patients presented clinical reactivation (increase in ALT levels).
Conclusions
HBV virological reactivation is frequent in HBsAg+ patients receiving anti‐viral therapy against HCV. However, HBV‐DNA elevations were modest (<20 000 IU/mL) and without clinical impact (no ALT elevation).
Linked ContentThis article is linked to Londoño et al, Huang et al, Chen, Wang and Kao, Hsu et al papers. To view these articles visit https://doi.org/10.1111/apt.14104, https://doi.org/10.1111/apt.14080, https://doi.org/10.1111/apt.14051, https://doi.org/10.1111/apt.14116 and https://doi.org/10.1111/apt.14127.
IL28B gene polymorphisms are associated with the response to antiviral therapy in hepatitis C patients. We investigated the influence of IL28B polymorphisms on the response to therapy before and ...after liver transplantation (LT). Genotyping of SNPs rs8099917 and rs12979860 was performed in 128 HCV‐infected liver transplant recipients and in their donors; all patients underwent antiviral treatment after LT. The prevalence of genotypes rs12979860CC and rs8099917TT was higher in donors than in recipients (50% vs.19%, p < 0.001 and 67% vs. 38%, p < 0.001, respectively). Response to antiviral therapy was significantly higher for recipient genotype rs12979860CC as compared to rs12979860CT/TT both before (100% vs. 48% p = 0.013) and after LT (59% vs. 25% p = 0.002). The figures were almost identical for SNP rs8099917. Sustained virological response after LT was particularly high in patients with favorable recipient and donor genotypes (p < 0.01 for both SNPs). In a subgroup of 34 patients treated while awaiting LT, a favorable donor IL28B genotype was associated with an improved virological response after LT. Our results support a major role of recipient IL28B genotype in the response to antiviral treatment for hepatitis C recurrence. Interestingly, donor genotype also seems to influence the response pattern, especially in recipients who have a favorable IL28B genotype.
These results support a major role for the recipient IL28B genotype in the response to antiviral treatment for hepatitis C recurrence after liver transplantation, while the donor genotype seems to exert a positive effect in recipients who have a favorable IL28B genotype.
Neutralizing antibody (nAb) activity during the course of natural infection is believed to be crucial to combating virus propagation. The aim of this study was to measure the impact of nAb response ...on HCV early kinetics and genetic evolution in the liver transplantation (LT) setting. A cohort of 28 patients undergoing LT for HCV‐related cirrhosis was included in the study. Viral load, nAb titers and hypervariable region 1 (HVR1) sequences were determined in serum samples obtained before and at different time points after LT. Serum nAb titers were assessed using HCV pseudoparticles (HCVpp). HVR1 sequences were obtained by direct sequencing. Patients were classified according to viral kinetic patterns (plateau or increasing), during the first week after LT. All patients demonstrated high titers of nAbs before LT, although this was not associated with early kinetic patterns or HVR1 evolution during the first week after LT. We found that in patients with plateau HCV early kinetics, the virus required adaptive mutations, while in those with increasing viral loads, the HVR1 region remained largely conserved (p = 0.015). These data suggest that HCV adaptation via selection of the best‐fitted variants may account for early viral kinetics following LT.
This study of liver allograft recipients with hepatitis C virus suggests that viral adaptation may account for early viral kinetics following liver transplantation.
Aims/hypothesis Decreased sensing of the innate immune system may lead to chronic activation of the inflammatory cascade. We hypothesised that mannan-binding lectin (MBL) deficiency may confer risk ...of obesity and insulin resistance. Materials and methods We performed a cross-sectional study of MBL protein concentration (n=434) and MBL2 gene mutations (exon 1) (n=759) in association with obesity, markers of inflammation and insulin action (euglycaemic clamp, n=113), and a longitudinal study of MBL protein before and after weight loss in obese patients (n=10). We also studied the effects of MBL in vitro in muscle cells and circulating MBL-A (mouse equivalent of human MBL) in a mouse model. Results Among 434 consecutive non-diabetic men, the age-adjusted serum MBL concentration was lower in obese subjects than in lean subjects (median: 959 μg/ml interquartile range: 116.8-2,044 μg/ml vs 1,365 467-2,513 μg/ml; p=0.01) and was accompanied by increased serum inflammatory markers. Insulin action correlated significantly with serum MBL (r=0.49, p<0.0001). Serum MBL concentration increased by a median of 110.2% after weight loss. The change in serum concentration of MBL was positively associated with the increase in insulin sensitivity (r=0.713, p=0.021). At least one MBL2 gene mutation was present in 48.2% of obese vs 39.3% of non-obese subjects (p=0.037). The plasma concentration of MBL-A was lower in insulin-resistant obese ob/ob mice, as was the glucose/insulin ratio. Incubation of rat soleus muscle with human MBL markedly increased fatty acid oxidation. Conclusions/interpretation These findings suggest that MBL, previously thought only to be involved in inflammation and immune system function, affects metabolic pathways.
Background and purpose:
Highly selective M
3
muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of ...non‐selective antimuscarinics have been associated with activity at M
2
receptors as these receptors are mainly responsible for muscarinic receptor‐dependent bradycardia. We have investigated a novel antimuscarinic, SVT‐40776, highly selective for M
3
over M
2
receptors (Ki = 0.19 nmol·L
−1
for M
3
receptor affinity). This study reports the functional activity of SVT‐40776 in the bladder, relative to its activity in atria.
Experimental approach:
In vitro
and
ex vivo
(oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT‐40776. The
in vivo
efficacy of SVT‐40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration.
Key results:
SVT‐40776 was the most potent in inhibiting carbachol‐induced bladder contractions of the anti‐cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT‐40776 exhibited the highest urinary versus cardiac selectivity (199‐fold). In the guinea pig
in vivo
model, SVT‐40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 µg·kg
−1
i.v), without affecting arterial blood pressure.
Conclusions and implications:
SVT‐40776 is a potent inhibitor of M
3
receptor‐related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT‐40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients.
British Journal of Pharmacology
(2009) doi:10.1111/j.1476‐5381.2008.00082.x
Hepatitis C virus (HCV) compartmentalization may have important implications in the pathogenesis of HCV infection. The aim of this study was to investigate the presence and relevance of HCV ...compartmentalization in the setting of liver transplantation (LT). We collected samples of serum, peripheral blood mononuclear cells (PBMC), perihepatic lymph nodes (PLN) and liver explant at the time of LT, and serum and PBMC after transplantation from 57 HCV‐infected cirrhotic patients undergoing LT: 38 individuals received antiviral treatment before LT and 19 were untreated controls. HCV‐RNA levels were determined by real‐time PCR and the hypervariable region 1 (HVR‐1) was sequenced. HCV‐RNA was detected in all samples from control patients. In virological responders, recurrence after LT was associated with residual HCV‐RNA in the liver explant. Within the entire cohort, 47% of patients harbored differences in direct sequences from distinct compartments. Quasispecies analysis revealed that in most cases, HVR‐1 sequences recovered after infection recurrence were identical or closely related to those isolated from the liver explant and serum at the time of LT. Our study shows that a significant proportion of HCV‐infected cirrhotic patients exhibit compartmentalization. Viral variants originating within the liver appear to be the main cause of HCV recurrence after LT.
Our results show that HCV compartmentalization is frequent in HCV‐infected liver transplant patients, but do not support a contribution of extrahepatic compartments to HCV infection recurrence after liver transplantation.
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