Summary
Background
Chronic hepatitis delta is a severe liver disease with rapid progression to cirrhosis. The impact of hepatitis delta virus (HDV)‐RNA on disease progression and interferon treatment ...in a real‐world cohort has been barely explored.
Aim
To assess the development of clinical events in a cohort of chronic hepatitis delta patients according to the presence or absence of HDV‐RNA
Methods
Multicentre study at four academic hospitals in Spain included anti‐HDV‐positive patients with compensated liver disease with a follow‐up ≥12 months.
Results
Among 2888 HBsAg‐positive subjects, 151 (5.2%) tested positive for anti‐HDV, and 118 were included (58% men; median age, 49 years; 73% detectable HDV‐RNA and 30% cirrhosis, most often in subjects with HDV‐RNA). After a median follow‐up of 8 years, subjects with initially detectable HDV‐RNA were more prone to developing cirrhosis (31% vs 0%, P = .002) and/or liver decompensation (28% vs 3%, P = .019). Mortality rate was 0.44 per 1000 person‐months. The probability of a clinical event was 6%, 25%, and 80% according to initial baseline‐event‐anticipation score. HDV‐RNA became undetectable in 21 (24%) subjects either due to interferon or spontaneously (48% vs 52%, P = .29). Liver decompensation was reduced in interferon‐treated patients (13% vs 38%, P = .026).
Conclusions
Subjects with persistently positive HDV‐RNA had a worse prognosis in terms of clinical events. Baseline‐event‐anticipation score is useful in predicting the risk of developing liver decompensation and hepatocellular carcinoma. Interferon was beneficial in reducing liver decompensation, even in the absence of virological response.
LINKED CONTENTThis article is linked to Sonneveld and de Knegt and Palom et al papers. To view these articles, visit https://doi.org/10.1111/apt.15549 and https://doi.org/10.1111/apt.15558.
Summary
Background
Spontaneous HDV‐RNA fluctuations, assessed by nonstandardised in‐house assays, have been reported during the course of chronic hepatitis delta (CHD).
Aims
To evaluate changes in ...serum HDV‐RNA concentrations in untreated CHD patients and correlate these changes with other HBV markers.
Methods
A total of 323 consecutive serum samples from 56 CHD patients (detectable HDV‐RNA) followed for >3 years were retested for HDV‐RNA levels by a sensitive technique using the first WHO international HDV‐RNA standard. Quantitative HBsAg, HBV‐DNA, and HBV‐RNA were also determined.
Results
Most participants were male, middle‐aged, white European, and HBeAg‐negative (82%). Almost half had liver cirrhosis and 64% were receiving nucleos(t)ide analogues. At inclusion, median‐HDV‐RNA was 5.3 (4.2‐6.5) log10IU/mL, HBsAg 4.0 (3.5‐4.3) log10IU/mL, and HBV‐DNA 1.6 (1.0‐2.6) log10IU/mL; ALT values were normal in 13 (23%). During a mean follow‐up of 5.6 (3‐16) years, 14 (25%) showed ≥2log10 HDV‐RNA decline, including 11 (20%) who spontaneously achieved undetectable HDV‐RNA. Four patients (7%) lost HBsAg, with undetectable HDV‐RNA. The remaining 42 (75%) had persistently detectable HDV‐RNA. During follow‐up, patients with a ≥2log10 HDV‐RNA decline showed a greater HBsAg drop (−0.7 ± 1.1 vs −0.09 ± 0.9 log IU/mL; P = 0.039) than those with a <2 log10 HDV‐RNA decline. Overall, ALT and HBV‐DNA levels decreased over time. There were no differences in clinical outcomes between groups.
Conclusions
One‐quarter of untreated CHD patients showed a ≥2log10 decline in HDV‐RNA and 20% reached HDV‐RNA undetectability during a mean follow‐up of 5.6 years. The decline was associated with ALT decrease. These findings have implications for designing new therapies for CHD.
Patients with ≥2 log10 HDV‐RNA decline have a higher likelihood of achieving undetectable HDV‐RNA, HBsAg loss and normal ALT levels. No differences in clinical events were observed. These findings may have implications for the design of studies with new therapies for CHD.
Direct‐acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are ...available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa‐C registry investigated the effectiveness and safety of interferon‐free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child‐Turcotte‐Pugh CTP class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End‐Stage Liver Disease (MELD) score alone (cut‐off 18) was the best predictor of survival. Conclusion: Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810‐1822).
Summary
Background
Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is the recommended rescue therapy for patients with chronic hepatitis C infection who fail direct‐acting antivirals (DAAs). ...Data are limited on the effectiveness of this treatment after the current first‐line therapies. Our aim was to analyse the effectiveness and safety of SOF/VEL/VOX among patients failing sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB).
Methods
Retrospective multicentre study (26 Spanish hospitals), including chronic hepatitis C patients unsuccessfully treated with SOF/VEL or GLE/PIB, and retreated with SOF/VEL/VOX ± ribavirin for 12 weeks between December 2017 and December 2022.
Results
In total, 142 patients included: 100 (70.4%) had failed SOF/VEL and 42 (29.6%) GLE/PIB. Patients were mainly men (84.5%), White (93.9%), with hepatitis C virus genotype (GT) 3 (49.6%) and 47.2% had liver cirrhosis. Sustained virological response (SVR) was evaluated in 132 patients who completed SOF/VEL/VOX and were followed 12 weeks after end of treatment; 117 (88.6%) achieved SVR. There were no significant differences in SVR rates according to initial DAA treatment (SOF/VEL 87.9% vs. GLE/PIB 90.2%, p = 0.8), cirrhosis (no cirrhosis 90% vs. cirrhosis 87.1%, p = 0.6) or GT3 infection (non‐GT3 91.9% vs. GT3 85.5%, p = 0.3). However, when considering the concurrent presence of SOF/VEL treatment, cirrhosis and GT3 infection, SVR rates dropped to 82.8%. Ribavirin was added in 8 (6%) patients, all achieved SVR.
Conclusion
SOF/VEL/VOX is an effective rescue therapy for failures to SOF/VEL or GLE/PIB, with an SVR of 88.6%. Factors previously linked to lower SVR rates, such as GT3 infection, cirrhosis and first‐line therapy with SOF/VEL were not associated with lower SVRs.
Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is an effective rescue therapy for patients with chronic hepatitis C infection who have failed SOF/VEL and glecaprevir/pibrentasvir (GLE/PIB), achieving sustained virological response (SVR) in 89% of patients who completed treatment. There is a non‐significant trend towards lower SVR rates in patients with GT3 HCV infection, cirrhosis and prior therapy with SOF/VEL.
Non-alcoholic fatty liver disease (NAFLD) could play a catalytic role in the development of metabolic comorbidities, although the magnitude of this effect in metabolically healthy patients with NAFLD ...remains unclear. We assessed the role of biopsy-proven NAFLD on the risk of developing type 2 diabetes mellitus (T2DM) and other metabolic comorbidities (arterial hypertension AHT, and dyslipidemia) in metabolically healthy patients.
We included 178 metabolically healthy—defined by the absence of baseline T2DM, AHT, dyslipidemia—patients with biopsy-proven NAFLD from the HEPAmet Registry (N = 1,030). Hepamet fibrosis score (HFS), NAFLD fibrosis score, and Fibrosis-4 were calculated. Follow-up was computed from biopsy to the diagnosis of T2DM, AHT, or dyslipidemia.
During a follow-up of 5.6 ± 4.4 years, T2DM occurred in 9% (16/178), AHT in 8.4% (15/178), low HDL in 9.6% (17/178), and hypertriglyceridemia in 23.6% (42/178) of patients. In multivariate analysis, significant fibrosis predicted T2DM and AHT. Independent variables related to T2DM appearance were significant fibrosis (HR 2.95; 95% CI 1.19–7.31; p = 0.019), glucose levels (p = 0.008), age (p = 0.007) and BMI (p = 0.039). AHT was independently linked to significant fibrosis (HR 2.39; 95% CI 1.14–5.10; p = 0.028), age (p = 0.0001), BMI (p = 0.006), glucose (p = 0.021) and platelets (p = 0.050). The annual incidence rate of T2DM was higher in patients with significant fibrosis (4.4 vs. 1.2 cases per 100 person-years), and increased in the presence of obesity, similar to AHT (4.6 vs. 1.1 cases per 100 person-years). HFS >0.12 predicted the risk of T2DM (25% 4/16 vs. HFS <0.12 4.5% 4/88; logRank 6.658, p = 0.010).
Metabolically healthy patients with NAFLD-related significant fibrosis were at greater risk of developing T2DM and AHT. HFS >0.12, but not NAFLD fibrosis score or Fibrosis-4, predicted the occurrence of T2DM.
Patients with biopsy-proven non-alcoholic fatty liver disease and significant fibrosis were at risk of developing type 2 diabetes mellitus and arterial hypertension. The risk of metabolic outcomes in patients with significant fibrosis was increased in the presence of obesity. In addition to liver biopsy, patients at intermediate-to-high risk of significant fibrosis by Hepamet fibrosis score were at risk of type 2 diabetes mellitus.
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•NAFLD-related significant fibrosis predicts the occurrence of type 2 diabetes mellitus and arterial hypertension.•The annual incidence of metabolic outcomes is four-times higher in the presence of significant fibrosis.•Neither steatosis nor NASH predict the appearance of metabolic outcomes.•Hepamet fibrosis score >0.12 is associated with the risk of developing type 2 diabetes mellitus.
Insulin resistance affects sustained virological response (SVR) in chronic hepatitis C. To know whether adding metformin to standard antiviral treatment improves SVR, we conducted a prospective, ...multicentered, randomized, double‐blinded, placebo‐controlled trial in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insulin resistance. Patients were randomized to receive either metformin (arm A; n = 59) or placebo (arm B; n = 64) in addition to peginterferon alfa‐2a (180 μg/week) and ribavirin (1000–1200 mg/day). The primary end point was SVR, and secondary endpoints were viral clearance at weeks 12, 24, and 48, and changes in the homeostasis model assessment (HOMA) index over the first 24 weeks. There were no differences between arms at baseline. In the intent‐to‐treat analysis, SVR was observed in 53% versus 42% in arm A and arm B, respectively (P = NS). In the subgroup analyses, SVR was higher in females (n = 54) receiving metformin: arm A, 58% (15/26) versus 29% (8/28) arm B (P = 0.03). In the per protocol analysis (PPA; n = 101), SVR was 67% in arm A and 49% in arm B (P = 0.06). Viral decline during the first 12 weeks was greater in females receiving metformin: −4.88 (1.18) versus −4.0 (1.44) (P = 0.021), whereas no differences were seen in males. The triple therapy was well tolerated, but diarrhea was more often seen in arm A (34% versus 11%; P < 0.05). Conclusion: Adding metformin to peginterferon and ribavirin was safe and improved insulin sensitivity. Although the study failed to show a statistically significant difference between arms, it did show an improved SVR in females. (HEPATOLOGY 2009.)
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•Patients achieve high SVR12 rates with sofosbuvir/velpatasvir/voxilaprevir after prior DAA failures.•Sofosbuvir/velpatasvir/voxilaprevir is a very safe and well tolerated ...combination.•GT3 cirrhotic patients with previous treatment with NS5A-inhibitors are poor responders.•GT3 is the only factor that impacts SVR12 rates in retreatment with sofosbuvir/velpatasvir/voxilaprevir.
Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting.
This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded.
A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific.
Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group.
Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.
This article describes the event detection system of the NEXT-White detector, a 5 kg high pressure xenon TPC with electroluminescent amplification, located in the Laboratorio Subterráneo de Canfranc ...(LSC), Spain. The detector is based on a plane of photomultipliers (PMTs) for energy measurements and a silicon photomultiplier (SiPM) tracking plane for offline topological event filtering. The event detection system, based on the SRS-ATCA data acquisition system developed in the framework of the CERN RD51 collaboration, has been designed to detect multiple events based on online PMT signal energy measurements and a coincidence-detection algorithm. Implemented on FPGA, the system has been successfully running and evolving during NEXT-White operation. The event detection system brings some relevant and new functionalities in the field. A distributed double event processor has been implemented to detect simultaneously two different types of events thus allowing simultaneous calibration and physics runs. This special feature provides constant monitoring of the detector conditions, being especially relevant to the lifetime and geometrical map computations which are needed to correct high-energy physics events. Other features, like primary scintillation event rejection, or a double buffer associated with the type of event being searched, help reduce the unnecessary data throughput thus minimizing dead time and improving trigger efficiency.
There are several contributors to HIV-pathogenesis or insufficient control of the infection. However, whether HIV/HCV-coinfected population exhibits worst evolution of HIV-pathogenesis remains ...unclear. Recently, some markers of immune exhaustion have been proposed as preferentially upregulated on T-cells during HIV-infection. Herein, we have analyzed T-cell exhaustion together with several other contributors to HIV-pathogenesis that could be affected by HCV-coinfection.
Ninety-six patients with chronic HIV-infection (60 HIV-monoinfected and 36 HIV/HCV-coinfected), and 20 healthy controls were included in the study. All patients were untreated for both infections. Several CD4 and CD8 T-cell subsets involved in HIV-pathogenesis were investigated. Non-parametric tests were used to establish differences between groups and associations between variables. Multivariate linear regression was used to ascertain the variables independently associated with CD4 counts.
HIV-patients presented significant differences compared to healthy controls in most of the parameters analyzed. Both HIV and HIV/HCV groups were comparable in terms of age, CD4 counts and HIV-viremia. Compared to HIV group, HIV/HCV group presented significantly higher levels of exhaustion (Tim3+PD1- subset) in total CD8+ T-cells (p = 0.003), and higher levels of exhaustion in CD8+HLADR+CD38+ (p = 0.04), CD8+HLADR-CD38+ (p = 0.009) and CD8+HLADR-CD38- (p = 0.006) subsets of CD8+ T-cells. Interestingly these differences were maintained after adjusting by CD4 counts and HIV-viremia.
We show a significant impact of HCV-coinfection on CD8 T-cells exhaustion, an important parameter associated with CD8 T-cell dysfunction in the setting of chronic HIV-infection. The relevance of this phenomenon on immunological and/or clinical HIV progression prompts HCV treatment to improve management of coinfected patients.
Background
Long-term antiviral therapy has resulted in viral suppression and biochemical response in chronic hepatitis B, although the risk of hepatocellular carcinoma has not been abolished. The ...Page-B score could be useful to estimate the probability of HCC.
Aims
To analyze the effectiveness and safety of entecavir or tenofovir for more than 4 years and the usefulness of Page-B score in the real-world setting.
Methods
Analysis of Caucasian chronic hepatitis B subjects treated with entecavir or tenofovir from the prospective, multicenter database CIBERHEP.
Results
A total of 611 patients were enrolled: 187 received entecavir and 424 tenofovir. Most were men, mean age 50 years, 32% cirrhotic and 16.5% HBeAg-positive. Mean follow-up was 55 (entecavir) and 49 (tenofovir) months. >90% achieved HBV DNA <69 IU/mL and biochemical normalization by months 12 and 36, respectively. Cumulative HBeAg loss and anti-HBe seroconversion were achieved by 33.7 and 23.8%. Four patients lost HBsAg; three HBeAg-positive. Renal function remained stable on long-term follow-up. Fourteen (2.29%) developed HCC during follow-up all of them with baseline Page-B ≥10. Nine were diagnosed within the first 5 years of therapy. This contrasts with the 27 estimated by Page-B, a difference that highlights the importance of regular HCC surveillance even in patients with virological suppression.
Conclusions
Entecavir and tenofovir achieved high biochemical and virological response. Renal function remained stable with both drugs. A Page-B cut-off ≥10 selected all patients at risk of HCC development.
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