Summary
Background and Aim
Bulevirtide (BLV) blocks the uptake of the hepatitis D virus (HDV) into hepatocytes via the sodium/bile acid cotransporter NTCP. BLV was conditionally approved by the EMA ...but real‐life data on BLV efficacy are limited.
Methods
Patients were treated with BLV monotherapy. Patients who did not achieve further decreases in HDV‐RNA after 24 weeks were offered PEG‐IFN as an add‐on therapy in a response‐guided manner.
Results
Twenty‐three patients (m: 10, f: 13; mean age: 47.9 years, cirrhosis: 16; median ALT: 71 IU/ml; median HDV‐RNA: 2.1 × 105copies/ml) started BLV monotherapy (2 mg/day: 22; 10 mg/day: 1). Twenty‐two completed ≥24 weeks of treatment (24–137 weeks): Ten (45%) were classified as BLV responders at week 24. BLV was stopped in two patients with >6 months HDV‐RNA undetectability, but both became HDV‐RNA positive again. One patient was transplanted at week 25. One patient terminated treatment because of side effects at week 60. Ten patients are still on BLV monotherapy. Adding PEG‐IFN in eight patients induced an HDV‐RNA decrease in all (1.29 ± 0.19 SD log within 12 weeks). HDV‐RNA decreased by >2log or became undetectable in 45%(10/22), 55%(11/20), 65% (13/20) and 69% (9/13); and ALT levels normalised in 64% (14/22), 85% (17/20), 90% (18/20) and in 92% (12/13) patients at weeks 24, 36, 48 and 60, respectively. Portal pressure decreased in 40% (2/5) of patients undergoing repeated measurement under BLV therapy.
Conclusion
Long‐term BLV monotherapy is safe and effectively decreases HDV‐RNA and ALT—even in patients with cirrhosis. The optimal duration of BLV treatment alone or in combination with PEG‐IFN remains to be established. An algorithm for a response‐guided BLV treatment approach is proposed.
The novel antiviral drug Bulevirtide (BLV) was studied in 23 patients (70% had cirrhosis) with hepatitis D virus infection. At week 24 (W24), 45% (10/22, one dropped out) were classified as virologic responders (2‐log decline or HDV‐RNA undetectablity) to BLV monotherapy. Interferon treatment was added in eight patients who achieved no further decline in HDV‐RNA after W24, inducing a synergistic antiviral effect. The proportion of patients who achieved virologic response and normalisation of ALT continuously increased from W24 to W60. No clinically relevant side effects were attributed to BLV treatment, despite marked increases in bile acid levels.
Background and Aims
Sustained virologic response (SVR) to interferon (IFN)‐free therapies ameliorates portal hypertension (PH); however, it remains unclear whether a decrease in hepatic venous ...pressure gradient (HVPG) after cure of hepatitis C translates into a clinical benefit. We assessed the impact of pretreatment HVPG, changes in HVPG, and posttreatment HVPG on the development of hepatic decompensation in patients with PH who achieved SVR to IFN‐free therapy. Moreover, we evaluated transient elastography (TE) and von Willebrand factor to platelet count ratio (VITRO) as noninvasive methods for monitoring the evolution of PH.
Approach and Results
The study comprised 90 patients with HVPG ≥ 6 mm Hg who underwent paired HVPG, TE, and VITRO assessments before (baseline BL) and after (follow‐up FU) IFN‐free therapy. FU HVPG but not BL HVPG predicted hepatic decompensation (per mm Hg, hazard ratio, 1.18; 95% confidence interval, 1.08‐1.28; P < 0.001). Patients with BL HVPG ≤ 9 mm Hg or patients who resolved clinically significant PH (CSPH) were protected from hepatic decompensation. In patients with CSPH, an HVPG decrease ≥ 10% was similarly protective (36 months, 2.5% vs. 40.5%; P < 0.001) but was observed in a substantially higher proportion of patients (60% vs. 24%; P < 0.001). Importantly, the performance of noninvasive methods such as TE/VITRO for diagnosing an HVPG reduction ≥ 10% was inadequate for clinical use (area under the receiver operating characteristic curve AUROC, < 0.8), emphasizing the need for HVPG measurements. However, TE/VITRO were able to rule in or rule out FU CSPH (AUROC, 0.86‐0.92) in most patients, especially if assessed in a sequential manner.
Conclusions
Reassessment of HVPG after SVR improved prognostication in patients with pretreatment CSPH. An “immediate” HVPG decrease ≥ 10% was observed in the majority of these patients and was associated with a clinical benefit, as it prevented hepatic decompensation. These results support the use of HVPG as a surrogate endpoint for interventions that lower portal pressure by decreasing intrahepatic resistance.
Systemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment ...initiation impacts biomarkers of systemic inflammation and (2) whether these changes in systemic inflammation predict complications and mortality.
Biomarkers of systemic inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB and under stable NSBB intake. The influence of NSBB-related changes in systemic inflammation on the risk of decompensation and liver-related death was analysed using competing risk regression.
Our study comprised 307 stable patients with ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17-24) mm Hg) including 231 (75.2%) with decompensated disease.WBC significantly decreased upon NSBB therapy initiation (median: -2 (IQR -19;+13)%, p=0.011) in the overall cohort. NSBB-related reductions of WBC (Child-C: -16 (-30;+3)% vs Child-B: -2 (-16;+16)% vs Child-A: +3 (-7;+13)%, p<0.001) and of CRP (Child-C: -26 (-56,+8)% vs Child-B: -16 (-46;+13)% vs Child-A: ±0 (-33;+33)%, p<0.001) were more pronounced in advanced stages of cirrhosis. The NSBB-associated changes in WBC correlated with changes in CRP (Spearman's ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) and IL-6 (ρ=0.501, p=0.001), but not with changes in HVPG (ρ=0.097, p=0.088).An NSBB-related decrease in systemic inflammation (ie, WBC reduction ≥15%) was achieved by n=91 (29.6%) patients and was found to be an independent protective factor of further decompensation (subdistribution HR, sHR: 0.694 (0.49-0.98), p=0.038) in decompensated patients and of liver-related mortality in the overall patient cohort (sHR: 0.561 (0.356-0.883), p=0.013).
NSBB therapy seems to exert systemic anti-inflammatory activity as evidenced by reductions of WBC and CRP levels. Interestingly, this effect was most pronounced in Child-C and independent of HVPG response. An NSBB-related WBC reduction by ≥15% was associated with a decreased risk of further decompensation and death.
Nonselective beta blockers (NSBBs) exert beneficial effects beyond lowering hepatic venous pressure gradient (HVPG), which may be particularly relevant in patients with decompensated cirrhosis (DC), ...in whom bacterial translocation and bacterial-induced systemic inflammation drive the development of complications such as acute-on-chronic liver failure (ACLF). We evaluated whether NSBB-related changes in von Willebrand factor (VWF) may serve as a biomarker for these effects.
In this retrospective analysis, 159 prospectively characterized patients with clinically stable DC (ie, without acute decompensation) who underwent paired HVPG/VWF assessments before/on NSBB therapy were classified as ‘VWF-responders’ (as defined by a ≥5% decrease in VWF) versus ‘VWF-non-responders.’
There were no major differences in baseline characteristics between VWF-responders (61%) and VWF-non-responders. VWF-responders showed more pronounced decreases in inflammation (procalcitonin), whereas rates of HVPG-response were similar. In line, NSBB-related changes in VWF correlated with the dynamics of bacterial translocation/inflammation (lipopolysaccharide-binding protein, C-reactive protein, and procalcitonin), rather than those of HVPG. Interestingly, VWF-responders also showed less pronounced NSBB-related decreases in mean arterial pressure, suggesting an amelioration of systemic vasodilatation. Finally, VWF-response was associated with decreased risks of further decompensation (adjusted hazard ratio aHR, 0.555; 95% confidence interval CI, 0.337-0.912; P = .020), ACLF (aHR, 0.302; 95% CI, 0.126-0.721; P = .007), and liver-related death (aHR, 0.332; 95% CI, 0.179-0.616; P < .001) in Cox regression models adjusted for prognostic factors including changes in HVPG.
Decreases in VWF upon NSBB therapy reflect their anti-inflammatory activity, are accompanied by less pronounced adverse effects on systemic hemodynamics, and are independently associated with a decreased risk of further decompensation, ACLF, and death. VWF-response may discriminate between decompensated patients who benefit from NSBB treatment and have a favorable prognosis versus patients with poor outcomes.
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Background & Aims
Experimental evidence indicates that systemic inflammation (SI) promotes liver fibrogenesis. This study investigated the potential link between SI and fibrogenesis in patients with ...advanced chronic liver disease (ACLD).
Methods
Serum biomarkers of SI (CRP, IL‐6, procalcitonin PCT) and extracellular matrix (ECM) turnover (i.e., fibrogenesis/fibrolysis) were analysed in 215 prospectively recruited patients with ACLD (hepatic venous pressure gradient HVPG ≥6 mm Hg) undergoing hepatic vein catheterization. Patients with non‐elective hospitalization or bacterial infection were excluded. Histological alpha‐smooth muscle actin (α‐SMA) area was quantified on full biopsy scans by automated morphometric quantification in a subset of 34 patients who underwent concomitant transjugular liver biopsy.
Results
Histological α‐SMA proportionate area correlated with enhanced liver fibrosis (ELF) score (Spearman's ρ = 0.660, p < .001), markers of collagen formation (PRO‐C3, ρ = 0.717, p < .001; PRO‐C6, ρ = 0.526, p = .002) and tissue inhibitor of metalloproteinases‐1 (TIMP1; ρ = 0.547, p < .001), indicating that these blood biomarkers are capable of reflecting the dynamic process of ECM turnover. CRP, IL‐6 and PCT levels correlated with ELF, biomarkers of collagen synthesis/degradation and TIMP1, both in compensated and decompensated patients. Multivariate linear regression models (adjusted for HVPG) confirmed that CRP, IL‐6 and PCT were independently linked to markers of liver fibrogenesis and ECM turnover.
Conclusion
Systemic inflammation is linked to both liver fibrogenesis and ECM turnover in ACLD and this association is not confounded by the severity of liver disease, as evaluated by HVPG. Our study confirms experimental data on the detrimental impact of SI on ECM deposition and fibrosis progression in a thoroughly characterized cohort of patients with ACLD.
Carvedilol induces stronger decreases in hepatic venous pressure gradient (HVPG) than conventional nonselective β-blockers (ie, propranolol). Limited data exist on the efficacy of carvedilol in ...secondary prophylaxis of variceal bleeding.
Patients undergoing paired HVPG measurements for guiding secondary prophylaxis with either carvedilol or propranolol were included in this retrospective analysis. All patients also underwent band ligation. Changes in HVPG and systemic hemodynamics were compared between the 2 groups. Long-term follow-up data on rebleeding, acute kidney injury, nonbleeding decompensation, and liver-related death were analyzed applying competing risk regression.
Eighty-seven patients (carvedilol/propranolol, n = 45/42) were included in our study. The median baseline HVPG was 21 mm Hg (interquartile range, 18–24 mm Hg), and 39.1%/48.3%/12.6% had Child–Turcotte–Pugh A/B/C cirrhosis, respectively. Upon nonselective β-blocker initiation, HVPG decreased more strongly in carvedilol users (median relative decrease, -20% interquartile range: -29% to -10% vs -11% -22% to -5% for propranolol; P = .027), who also achieved chronic HVPG response more often (53.3% vs 28.6%; P = .034). Cumulative incidences for rebleeding (Gray test, P = .027) and liver-related death (P = .036) were significantly lower in patients taking carvedilol compared with propranolol. Notably, ascites development/worsening also was observed less commonly in carvedilol patients (P = .012). Meanwhile, acute kidney injury rates did not differ between the 2 groups (P = .255). Stratifying patients by HVPG response status yielded similar results. The prognostic value of carvedilol intake was confirmed in competing risk regression models.
Carvedilol induces more marked reductions in HVPG than propranolol in secondary prophylaxis of variceal bleeding, and thus is associated with lower rates of rebleeding, liver-related death, and further nonbleeding decompensation.
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Background and Aims
Risk stratification after cure from hepatitis C virus (HCV) infection remains a clinical challenge. We investigated the predictive value of noninvasive surrogates of portal ...hypertension (liver stiffness measurement LSM by vibration‐controlled transient elastography and von Willebrand factor/platelet count ratio VITRO) for development of hepatic decompensation and hepatocellular carcinoma in patients with pretreatment advanced chronic liver disease (ACLD) who achieved HCV cure.
Approach and Results
A total of 276 patients with pretreatment ACLD and information on pretreatment and posttreatment follow‐up (FU)‐LSM and FU‐VITRO were followed for a median of 36.6 months after the end of interferon‐free therapy. FU‐LSM (area under the receiver operating characteristic curve AUROC: 0.875 95% confidence interval CI: 0.796‐0.954) and FU‐VITRO (AUROC: 0.925 95% CI: 0.874‐0.977) showed an excellent predictive performance for hepatic decompensation. Both parameters provided incremental information and were significantly associated with hepatic decompensation in adjusted models. A previously proposed combined approach (FU‐LSM < 12.4 kPa and/or FU‐VITRO < 0.95) to rule out clinically significant portal hypertension (CSPH, hepatic venous pressure gradient ≥10 mm Hg) at FU assigned most (57.3%) of the patients to the low‐risk group; none of these patients developed hepatic decompensation. In contrast, in patients in whom FU‐CSPH was ruled in (FU‐LSM > 25.3 kPa and/or FU‐VITRO > 3.3; 25.0% of patients), the risk of hepatic decompensation at 3 years following treatment was high (17.4%). Patients within the diagnostic gray‐zone for FU‐CSPH (17.8% of patients) had a very low risk of hepatic decompensation during FU (2.6%). The prognostic value of this algorithm was validated in an internal (n = 86) and external (n = 162) cohort.
Conclusion
FU‐LSM/FU‐VITRO are strongly and independently predictive of posttreatment hepatic decompensation in HCV‐induced ACLD. An algorithm combining these noninvasive markers not only rules in or rules out FU‐CSPH, but also identifies populations at negligible versus high risk for hepatic decompensation. FU‐LSM/FU‐VITRO are readily accessible and enable risk stratification after sustained virological response, and thus facilitate personalized management.
Objective
Several single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). ...However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.
Design
Patients with biopsy-proven NAFLD were genotyped for the
PNPLA3
-
rs738409
(minor allele:G),
TM6SF2
-
rs58542926
(minor allele:T) and
HSD17B13
-
rs72613567
(minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0–F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.
Results
703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3–4:81(11.5%).
PNPLA3
G/G genotype was associated with a NAS ≥ 5(aOR 2.23,
p
= 0.007) and advanced fibrosis (aOR-3.48,
p
< 0.001).
TM6SF2
T/- was associated with advanced fibrosis (aOR 1.99,
p
= 0.023).
HSD17B13
TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65,
p
= 0.041, TA/TA: aOR 0.40,
p
= 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of
PNPLA3
(AUC 0.766),
HSB17B13
(AUC 0.766), and their combination(AUC 0.775), but not of
TM6SF2
(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if
PNPLA3
(AUC 0.789), and TM6SF2(AUC 0.786) but not if
HSD17B13
(0.777) were added.
Conclusion
In biopsy-proven NAFLD,
PNPLA3
G/-,
TM6SF2
T/- and
HSD17B13
TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.
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