Increased genomic instability following treatment with direct acting anti-hepatitis C virus drugs

Abstract

Mixed Cryoglobulinemic Vasculitis (MCV) is a prominent extra-hepatic manifestation of Hepatitis C virus (HCV) infection. HCV has been reported to cause B-cell disorders and genomic instability. Here, we investigated B-cell activation and genome stability in HCV-MCV patients receiving the direct antiviral agent, Sofosbuvir, at multiple centers in Egypt. Clinical manifestations in HCV-MCV patients were improved at the end of treatment (EOT), such as purpura (100%), articular manifestations (75%) and neuropathy (68%). Eighteen patients (56%) showed vasculitis relapse after EOT. BAFF and APRIL were higher at EOT and continued to increase one year following treatment onset. Chromosomal breaks were elevated at EOT compared to baseline levels and were sustained at 3 and 6 months post treatment. We report increased expression of DNA genome stability transcripts such as topoisomerase 1 and TDP1 in HCV-MCV patients after treatment, which continued to increase at 12 months from treatment onset. This data suggest that B-cell activation and DNA damage are important determinants of HCV-MCV treatment outcomes.

Relapse of Hepatitis C Virus Cryoglobulinemic Vasculitis After Sustained Viral Response After Interferon-Free Direct-Acting Antivirals

“…A recent study showed that an increased expression of both B-cell activating factor and a proliferation-inducing ligand in patients with HCV-CryoVas at EOT compared with their pretreatment levels, with these levels continuing to increase throughout the follow-up period. These cytokines may be the basis for further CryoVas relapse (17) and represent potential biomarkers in predicting CryoVas progression and/or relapse.…”

“…Although DAAs are successful in inducing SVR, CryoVas relapse still seems to be a challenge in clinical practice. Recent long-term studies have reported CryoVas relapse to range between 4% and 18% in HCV-cured patients treated with DAAs (4,5,16,17). A prospective cohort of 148 patients with a 15-month median follow-up found no relapse and reported 4 deaths (2.8%) unrelated to CryoVas (3).…”

Persistence of Cryoglobulinemic Vasculitis after DAA Induced HCV Cure

“…Two thousand articles were initially identified through database-searching on PubMed, Embase, Cochrane, Web of Science, and clinicaltrials.gov. Ultimately, 19 studies [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] meeting the prespecified inclusion criteria were selected (Figure 2).…”

“…Relapse after CR/PR was mentioned in eight studies and ranged from 0-18% of the treated patients. Genetics as predictive factors for persistence or relapse CryoVas and persistent B-cell clones were focused on in three [28][29][30] and two studies [26,31], respectively, without providing information about the overall response or relapse. Nephrology complications, neurology complications, and dermatological complications were discussed in four, another four, and six studies, respectively.…”

“…Hegazy et al [30] prospectively studied 32 patients with HCV-related CryoVac, 13 patients with HCV infection alone, and 8 healthy controls. Different DAA-based combination therapies were used.…”