Martín Bonacci

Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus–Associated Cryoglobulinemia Treated With Direct-Acting Antivirals

BACKGROUND & AIMS Cryoglobulins (circulating immune complexes of polyclonal IgG, monoclonal IgM, and rheumatoid factor) are detected in the circulation of 40% to 60% of patients with chronic hepatitis C virus infection, and cryoglobulinemic vasculitis (CV) is observed in approximately 10% of patients. We aimed to assess the clinical and immune effects of direct‐acting antiviral treatment. METHODS We performed a prospective study of 64 patients with HCV infection with circulating cryoglobulins receiving direct‐acting antiviral therapy at a single center in Barcelona, Spain, from January 2014 through April 2016. Patients were classified as having CV (n = 35) or asymptomatic circulating cryoglobulins (ACC, n = 29). Clinical response was considered complete if a patient’s Birmingham Vasculitis Activity Score (version 3) was 0, or if all affected organs improved 12 weeks after the end of therapy. A complete immunologic response (CIR) was defined as no detection of circulating cryoglobulins and normalized levels of complement and/or rheumatoid factor. RESULTS Clinical manifestations of CV included purpura (65%), weakness (70%), arthralgia (31%), myalgia (20%), peripheral neuropathy (50%), and renal involvement (20%). At baseline, patients with CV had significantly higher levels of rheumatoid factor and lower levels of C4 complement than patients with ACC, whereas cryocrits were similar between groups (3.2% vs 2.6%). Overall, 60 patients (94%) had a sustained viral response 12 weeks after therapy. Among patients with CV, the median Birmingham Vasculitis Activity Score (version 3) decreased from 9 (range, 2–31) to 3 (range, 0–12) (P < .001). Twenty‐five patients with CV (71%) achieved a complete clinical response. Immune‐suppressive therapy was reduced for 4 of 13 patients and withdrawn for 6 of 13. Overall, 48% of patients achieved a CIR. A low baseline cryocrit level (<2.7%) was the only factor associated with CIR (odds ratio, 9.8; 95% confidence interval, 2.2–44; P = .03). CONCLUSIONS Viral eradication was associated with clinical improvement in most patients with CV. Markers of immune activation, including circulating cryoglobulins, persisted in 52% of patients with CV or ACC, despite a sustained viral response 12 weeks after therapy. A longer follow‐up period after viral eradication might be necessary to ensure a normal immune response.

Hepatitis B reactivation in patients with chronic hepatitis C undergoing anti-viral therapy with an interferon-free regimen.

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.

Antiviral treatment with sofosbuvir and simeprevir in a kidney transplant recipient with HCV-decompensated cirrhosis: viral eradication and removal from the liver transplant waiting list.

Hepatitis C positive kidney transplant (KT) recipients are a difficult‐to‐treat subpopulation. Interferon‐based therapies are contraindicated (or at least not used) in KT patients, due to the risk of allograft rejection, its poor tolerability and the low rates of sustained virological response (SVR) achieved with these therapies. Nevertheless, the use of direct‐acting antiviral drugs (DAAs) will certainly provide new opportunities for hepatitis C treatment in the KT setting. Here, we report the case of a KT recipient with decompensated cirrhosis who received antiviral therapy with sofosbuvir, simeprevir, and ribavirin during 24 weeks while awaiting liver transplantation. Hepatitis C was eradicated, and the patient was removed from the transplant list. Although there is no safety and efficacy data regarding the use of DAAs in the KT setting, this case suggests that KT recipients may benefit from the use of new antiviral drugs with high SVR rates and an excellent safety profile.

Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the Grey Zone

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).

Editorial: STAT-4 polymorphism - a tool to personalise clinical practice in chronic HBV infection

Chronic hepatitis B (CHB) infection is a dynamic process reflecting the interaction between hepatitis B virus (HBV) replication and host immune response. Intrahepatic inflammation during HBV infection is the result of a noncytopathic process initiated by the immune response towards eliminating the virus. Intensive efforts have revealed several host genetic factors leading to liver fibrosis progression in CHB. Signal transducers and activators of transcription (STATs) are members of a well conserved family of transcription factors that play integral roles in various cellular processes. Generally, STAT proteins regulate cytokine‐mediated cell proliferation and play crucial roles in the pathology of liver diseases; STAT4 is regarded as a transducer of interleukin‐12 and interferons signalling for IFN‐γ production. However, neither its activation in the hepatocytes nor its role in liver injury and fibrosis is well understood. A single nucleotide polymorphism, the rs7574865 in the third intron of STAT4, specifically the GG genotype, has been associated with an increased risk of HBV‐ related cirrhosis and hepatocarcinogenesis. However, most of these data derived from Asiatic populations might not be universally applicable; in addition, this genetic predisposition was not evaluated in earlier stages of CHB. In a recent issue of AP&T, El Sharkawy et al presented an intriguing hypothesis about the role of STAT4 rs7574865 variation in the development of liver injury in a large cohort of Caucasian patients with CHB. The authors reported the results of 830 histologically characterised CHB patients in the absence of antiviral treatment. A relevant finding of the study was the association of the rs7574865 GG genotype with severity of liver histology outcomes. In a refined analysis of the data adjusted by age, gender, presence of diabetes, and viral load, GG genotype was associated with hepatic inflammation (Metavir A0‐1 vs A2‐A3, OR: 1.42, P = 0.02) and of fibrosis (Metavir F0‐F2 vs F3‐F4 OR: 1.71, P = 0.01), suggesting that genetic variation in STAT4 may play an important role in the progression of liver fibrosis. What are the possible immunopathogenic mechanisms by which STAT4 rs7574865 variation drives progression of liver disease during CHB? The authors extended knowledge in this scenario by studying STAT4 mRNA expression in PBMCs and natural killer (NK) cells. Despite the small numbers, they observed that STAT4 mRNA expression was significantly reduced in subjects with rs7574865 GG (minor allele). Consistent with the in vivo data, INF‐γ production by NK cells after stimulation with interleukin‐12 and interleukin‐18 was also decreased among patients with the GG genotype. Finally, the observation of the highest expression of STAT4 in Kupffer cells followed by hepatocytes suggested that immune cells, rather than direct effects on stellate cells, probably mediate the effect of STAT4 on liver inflammation. Although there is a vast area of research ahead in CHB, this study enhances our current understanding of HBV‐related liver damage, showing that STAT4 variation at rs7574865 is associated with greater hepatic inflammation and fibrosis among Caucasians. These results may encourage the scientific community to assess host genetic factors, including STAT4 variation, to personalise clinical practice for CHB patients.

Shorter hepatitis B immunoglobulin administration is not associated to hepatitis B virus recurrence when receiving combined prophylaxis after liver transplantation

The combination of hepatitis B immunoglobulin and a nucleos(t)ide analogues has markedly reduced the rate of hepatitis B virus recurrence after liver transplantation; however, the optimal duration of hepatitis B immunoglobulin has not been clarified. This lack of consensus perpetuates the use of different strategies. The aim of this study was to evaluate the risk factors associated to hepatitis B virus recurrence after liver transplantation in a large cohort of patients under different hepatitis B immunoglobulin regimens.

Effectiveness and safety of elbasvir/grazoprevir therapy in patients with chronic HCV infection: Results from the Spanish HEPA-C real-world cohort

In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real‐world HCV patient cohort. HEPA‐C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA‐C between December 2016 and May 2017, and treated with EBR/GZR with at least end‐of‐treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19‐92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post‐treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real‐world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.

Long-Term Outcomes of Patients With HCV-Associated Cryoglobulinemic Vasculitis After Virologic Cure

Patients with hepatitis C virus-associated cryoglobulinemic vasculitis (HCV-CV) have high rates of clinical remission after treatment with direct-acting antivirals (DAAs), but circulating cryoglobulins persist, and vascular disorders reappear in some patients shortly after DAA treatment ends. We performed a prospective study to assess the long-term clinical and immune system effects of HCV eradication with DAAs in 46 patients with HCV-CV and 42 asymptomatic patients with circulating cryoglobulins. A median of 24 months after DAA treatment (range, 17-41 months), 66% of patients with HCV-CV and 70% of asymptomatic patients with circulating cryoglobulins had an immunologic response, with comparable reductions in cryocrit from 2.6% to 0% (P < .05). However, 20% of patients still had positive test results for cryoglobulins after DAA therapy. Among patients with HCV-CV, 42 (91%) had a clinical response, in that their Birmingham Vasculitis Activity Score (version 3) decreased from 7 to 0 (P < .01). Nevertheless, within 2 years after a sustained viral response to DAA therapy, 5 patients with HCV-CV (11%, 4 with cirrhosis) had relapses of vasculitis that included severe organ damage and death.

Impact of comorbidities on patient outcomes after interferon-free therapy-induced viral eradication in hepatitis C

BACKGROUND & AIMS Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of direct-acting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model. METHODS This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes. RESULTS A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29-1.86; p = 0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; p = 0.004), age (HR 1.06 95% CI 1.02-1.11; p = 0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; p = 0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; p = 0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, Child-Pugh 0.72, CirCom 0.68) regarding one- and two-year mortality. HepCom score identified low- (≤5.7 points: 2%-3%) and high-risk (≥25 points: 56%-59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups. CONCLUSIONS The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one- and two-year mortality, and relevant clinical events, after starting direct-acting antiviral therapy. LAY SUMMARY The prognosis of patients with severe comorbidities may not benefit from HCV viral clearance. An algorithm to decide who will benefit from the treatment is needed to manage the chronic HCV infection better.