Tuesday, September 25, 2018

Editorial: interferon‐free DAAs are a great boon for patients with hepatitis C and cryoglobulinaemia

Aliment Pharmacol Ther. 2018 Oct;48(7):770-771. doi: 10.1111/apt.14899.

Editorial: interferon‐free DAAs are a great boon for patients with hepatitis C and cryoglobulinaemia
M. Atsukawa, A. Tsubota
Pages: 770-771
First Published: 23 September 2018 

Chronic hepatitis C is often accompanied by various extrahepatic manifestations that affect the health‐related quality of life (HRQoL) and mortality of patients.1, 2 In particular, mixed cryoglobulinaemia (MC) and MC syndrome (MCS) are closely associated with hepatitis C virus (HCV) infection. Thus, the most rational treatment strategy for HCV‐related MC/MCS is HCV eradication. As expected, interferon (IFN)‐based treatment can alleviate MC/MCS in patients with a sustained virological response (SVR).3 However, the SVR rate is low and drug adherence is frequently reduced due to adverse events.4 MCS patients exhibit systemic complications that may attenuate the efficacy of IFN‐based treatment. Moreover, MC is a negative, independent predictor of virological response.5 Currently, IFN‐free direct‐acting antiviral (DAA) combination therapy that yields a high SVR rate with high tolerability is the standard of care for chronic hepatitis C. DAA treatment for MC patients reportedly achieved a SVR rate of 74%‐100% and reduced or resolved the symptoms in 61%‐100% of the patients with SVR.6

To our knowledge, Gragnani and colleagues were the first to conduct a prospective, case‐control study to evaluate the virological/clinical/immunological response and the HRQoL score following IFN‐free, DAA‐based treatment for cryoglobulinaemic vasculitis (CV) patients, MC patients without vasculitis, and control patients without CV/MC.7 This comparative study reconfirmed the excellent efficacy/safety profile of DAA‐based treatment even in CV/MC patients. The SVR rate (89.9%) was almost twice that (48.6%) with pegylated IFN/ribavirin treatment.5, 7 It was noteworthy that SVR persistently improved the clinical indices at a high rate in CV patients. Immunological response progressively improved in CV patients with SVR. Moreover, the HRQoL score, including physical and mental components, was lower at baseline in CV patients than in MC/control patients, while it significantly improved in CV patients with SVR. Therefore, the highly effective and safe DAA treatment is a great boon for CV patients, because it consequently reduces their physical and/or mental burden future healthcare costs.

However, the SVR rates in CV/MC patients (90.6% and 88.9%, respectively) were lower (although not significantly) than those in control patients (95.3%).7 In fact, most patients with treatment failure had cryoglobulinaemia and some exhibited severe manifestations before treatment. Such patients failed to experience clinical improvement during the post‐treatment period. These outcomes suggest the importance of early treatment for CV/MC patients before disease progression to severe stages.

DAAs are rapidly developing, and treatment options are increasing; therefore, personalised medication by regimen optimisation is possible for cryoglobulinaemic patients with various complications. For instance, sofosbuvir/ribavirin is administered to CV patients.6 However, 8%‐58% of cryoglobulinaemic patients have renal impairment.8 Sofosbuvir and ribavirin are mainly excreted in the urine; thus, both are contraindicated for, or should be carefully administered to, patients with moderate/severe renal dysfunction. Currently, the AASLD guidelines specify elbasvir/grazoprevir or glecaprevir/pibrentasvir as the first‐line treatment.9 Moreover, the EASL guidelines recommend ribavirin‐free treatment for cryoglobulinaemic patients with renal dysfunction.10 Precision medicine is required, particularly for cryoglobulinaemic patients with severe complications and refractory features.

Declaration of personal interests: M Atsukawa has served as a speaker for AbbVie, MSD and Gilead Sciences, and has received research funding from AbbVie and MSD. 

Zignego AL, et al. Aliment Pharmacol Ther. 2018

We would like to express our gratitude to Drs Atsukawa and Tsubota for their comments and the correct interpretation of the main messages that may be deduced from our study,1, 2 especially concerning the future challenges in the treatment of cryoglobulinaemic vasculitis (mixed cryoglobulinaemia syndrome, MCS), a HCV‐related disease that is often under‐estimated and not sufficiently known.3

The occurrence of MCS represents a condition that justifies careful prioritization of Interferon‐free anti‐HCV treatment. This appears to be the most effective as soon as it is carried out, whereas, when the therapy is too late and the patients have already developed severe damage (especially renal), MCS requires careful evaluation and accurate tailoring of non‐aetiological therapies (e.g, anti‐inflammatory and immunosuppressant) to be performed before, but also after, and sometimes concomitantly with anti‐viral therapy.

The complex pathogenetic cascade that underlies this lymphoproliferative disorder, and that originates from the clonal expansion of specific B‐cells (RF‐B cells), may lead to the subsequent overcoming of points of no return whose identification would be important for the assessment of a rational approach to the patients. Above all, in case of the persistence of MCS symptoms and/or signs, it would be important to distinguish the causes indicating the risk of evolution of the lymphomagenetic process (the overcoming of points of no return), from those without this risk, such as the simple occurrence of irreversible tissue damage.4

In this light, it seems conceivable that a key factor for the correct interpretation of the persistence of MCS stigmata even after viral eradication, is the evaluation of the persistence of B cell clonal expansion. Various factors have been suggested as playing a key role in inducing clonal expansion, first the important and sustained activation of the B‐cell compartment by both viral and host factors. Among the latter, special emphasis was placed on the binding of the viral E2 protein and the CD81 molecule on the surface of the B cells5 and the effect of the B‐cell‐activating factor (BAFF)/B‐lymphocyte stimulator (BLyS), especially in subjects harbouring particular genetic variants.6 Such an important and persistent B‐cell activation would cooperate to the lymphomagenetic process with B‐cell anti‐apoptotic factors including, first, the t (14; 18) translocation7 and could possibly be correlated with an exhaustion of the B cells observed during MCS.8 Consequently, it seems conceivable that the detection of persistent B cell expanded clones through sensitive methods, after HCV eradication, could help in understanding the condition that we are facing; this would be helpful in deciding the best approach to the patient (more frequent follow‐ups and/or specific therapies).

In conclusion, following the demonstration of the positive effect of viral eradication in MCS patients, the most important future challenge is the identification of markers useful in assessing the best approach to patients that maintain clinical and/or immunological MCS stigmata after SVR.

The authors’ declarations of personal and financial interests are unchanged from those in the original article.2

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