Sofosbuvir‐based therapies in genotype 2 hepatitis C virus cirrhosis: A real‐life experience with focus on ribavirin dose

1. INTRODUCTION

Hepatitis C is one of the most common causes of chronic liver disease, with >185 million infected subjects and nearly 400,000 deaths per year in the world. ¹ In Europe, Italy is one of the countries with the greatest burden of hepatitis C virus (HCV) infection among the general population and has one of the highest mortality rates from HCV‐related cirrhosis and hepatocellular carcinoma. The prevalence of infection is approximately 1%, though a rate as high as 7% has been reported among persons born between 1935 and 1944; generally, prevalence is lowest among persons aged 30 or less without apparent risk factors. ²

Sofosbuvir (SOF), combined with ribavirin (RBV), has been widely used to treat genotype (GT) 2 HCV infection. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Although newer pangenotypic direct‐acting antiviral agents (DAA) such as sofosbuvir plus velpatasvir and glecaprevir plus pibrentasvir have now emerged, ⁹ SOF plus RBV was the only approved therapy for Italian GT2 subjects until May 2017, and continued to be used at a lesser extent even afterwards. With regard to GT2, phase 3 trials showed very promising sustained virological response (SVR) rates for this regimen, but with lower performances—as low as 60%—in cirrhotic subjects, especially if treatment‐experienced (TE). ¹⁰

Moreover, concomitant administration of RBV typically resulted in common adverse events (AE), of which the most relevant is undoubtedly anemia. In the pegylated interferon (PEG‐IFN)‐era, RBV‐induced anemia was reported with a varying incidence of 35.3% to 52.2% in Caucasian and Asian patients, respectively. ¹¹ , ¹² However, the individual effect of RBV dosage on the anemia development could not be properly investigated because of the concomitant bone marrow suppression caused by PEG‐IFN. In the present DAA era, the role of RBV dose on SVR and anemia development can be better analyzed, but comprehensive researches on RBV dose modifications are mainly restricted, to the best of our knowledge, to Asian patients. Limiting to the most recent evidence, RBV dosage reduction occurred more frequently at dosages >15 mg/kg/day ¹³ but was generally not a determinant of a lower SVR. ¹⁰ In all studies, RBV‐induced anemia was described as the most common AE, occurring in 15%–40% of subjects, with higher prevalences in patients ≥70 years, with liver cirrhosis, or with female gender. In any case, severe forms of anemia with consequent treatment discontinuations were reported only in a small proportion of patients. ¹⁰ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶

However, taking into consideration that anemia can represent a relevant problem especially for the most frail categories of subjects and that there are patients who are not eligible for RBV mostly due to baseline anemia, an alternative strategy to reducing RBV on treatment is represented by RBV‐free DAA regimens, the first of which historically available was the association of SOF plus the NS5A inhibitor daclatasvir (DCV). This regimen is obviously burdened with fewer side effects, but the optimal duration of treatment in GT2 is still object of debate. ¹⁶ , ¹⁷ , ¹⁸

An important further consideration is that the reported percentage of cirrhotic subjects in the aforementioned studies was quite modest (between 20% and 30%), ¹⁰ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ like almost all the previous ones, starting from clinical trials. ¹⁹ , ²⁰ , ²¹ , ²² So, in our opinion, the current literature is still not conclusive for the very specific subset of cirrhotic GT2 patients in defining the optimal RBV dose and the correct therapy duration, the latter one concerning specifically SOF plus RBV treatment, for which Italian (and European) clinicians could lawfully‐in accordance with the guidelines available at that time‐administer four different treatment schedules, namely 12, 16, 20, or 24 weeks. ³ , ⁴ , ⁵ , ⁶

Therefore, in the present study we decided to share our experience and to analyze the efficacy and safety of SOF‐based treatment regimens, and the consequences of RBV dosing modifications, for HCV GT2 infected cirrhotic subjects in a real‐world scenario in Italy.

2. MATERIALS AND METHODS

3. RESULTS

4. DISCUSSION

Our analysis confirmed previous recent reports on high real‐life efficacy and sufficient tolerability of SOF plus RBV therapy for HCV GT2 patients with well‐compensated cirrhosis. ¹⁰ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ The same considerations can be made for DCV‐based regimens, though resulting less studied in the recent literature. ¹⁰ , ¹⁶ , ³⁴ , ³⁶ , ³⁷ , ³⁸ , ³⁹ However, some important issues have to be addressed. First of all, the aforementioned studies, although providing a detailed overview of the performance of these treatment regimens, did not focus, like also almost all the other ones available in the previous literature, on the very specific subset of patients with cirrhosis, which remains, in our opinion, with unresolved issues. As a matter of fact, in all the above‐cited researches, only a minority of patients (generally ranging from 20% to 45%) had a diagnosis of cirrhosis. Our study, on the contrary, was centered only on patients with confirmed cirrhosis. Secondly, most of the recent researches studied Asian populations (mainly Far East), ¹⁰ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ²⁹ , ³¹ , ³³ , ³⁴ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ so Caucasian patients were not extensively analyzed. ¹⁷ , ³⁰ , ⁴⁵ , ⁴⁶ , ⁴⁷ Instead, in our case series all subjects were Caucasian. This is relevant, as GT2 has a major prevalence (≥10%) also for what concerns this ethnicity, mainly in Western Europe (where the present study was conducted) and white North Americans. ¹ , ⁴⁸ Finally, an explanation why—in contrast to the situation we detailed in our real‐life study—SOF plus DCV represented only a minority of the total reported prescriptions for the GT2 subpopulation, probably lies not only in different national prescribing policies but above all in the fact that, again, ours was a casuistry entirely of cirrhotic subjects (thus making this RBV‐free treatment preferable in the most frail patients because potentially burdened by fewer side effects).

Another key point that differentiates, in our view, our study is that RBV detailed prescription was not analyzed in detail in most previous researches. This, probably, is due to the fact that available guidelines recommended a fixed dosage of 1200 mg/day for patients ≥75 kg and 1000 mg/day for those <75 kg. ³ , ⁴ , ⁵ , ⁶ Nevertheless, our study revealed that about 1/5 of the prescribers initiated RBV at 800 mg/day, possibly based on their previous experience with PEG‐IFN. In addition, the weight‐based dosages had to be adjusted throughout therapy in 45.4% of cases. The pathophysiological mechanism for this resides in hemolysis, which is a common side effect of RBV and the major reason for its dose reduction. Age, baseline hemoglobin and platelet levels, chronic kidney disease, and RBV dose have all been reported to contribute to this RBV‐induced anemia and consequent dose reduction, as confirmed in our casuistry. ⁴⁹ , ⁵⁰ More in detail, for what concerns Caucasian patients, anemia caused by RBV was frequently reported (around 35%) in the era of PEG‐IFN and RBV combination therapies, with even higher incidences in cirrhotic subjects (about 70%). ¹² , ⁵¹ , ⁵² Similar reports were also made in Asian patients. ⁵³ , ⁵⁴ Most of these studies were related to inosine triphosphatase (ITPA) polymorphisms. ⁵⁵ As a consequence of drug‐induced anemia, the recorded RBV dose reduction rates were quite substantial (generally more than 33%), again with higher frequencies in the subjects with more advanced disease. ⁵³ The same report that ITPA polymorphisms are implicated in RBV‐induced anemia was subsequently provided also with regard to SOF/RBV combination therapies, as in the case of the present study, without evidence of association with the clinical outcome. ⁵⁶

With regard to the latter point, our data, although not including a genetic analysis, provided indirect evidence in favor, since the SVR rate in individuals who were given a reduced RBV dose was not lower than in those treated with the standard weight‐based dose, similarly to previous reports in Asian subjects. ¹⁰ Moreover, no differences amongst SVR rates could be found between subjects weighted <75 and ≥75 kg, and the same occurred when the patients were further stratified according to all different RBV dosages (data not shown). Therefore, the significant reduction in RBV dosing likely yielded improved treatment compliance and consequent SVR. In ultimate end, this study confirmed that RBV may still have a role in the therapy of HCV patients for its added value to achieve SVR in combination with a SOF monotherapy. We could also speculate that, as suggested by others, in this cohort of subjects with compensated cirrhosis RBV contributed to the shortening of therapy, with acceptable side effects in most cases and without loss of efficacy or real treatment disruption urgencies. ⁵⁷ However, larger multicenter trails are mandated for better configuration of final decisions on which exact doses are required for such patients on an individual basis, beyond the previously reported fixed start doses based merely on body weight. In this respect, RBV steady‐state plasma levels would seem promising for both predicting SVR and preventing significant anemia, and may be used as a tool in addition to simple RBV toxicity monitoring for a more rational average drug dose adjusting in the case of patients with difficult‐to‐cure characteristics such as impaired renal function and/or cirrhosis. ⁵⁸ In this regard, it must be said that most published studies showed contradictory results, possibly due to their small sample sizes and retrospective nature; it should also be noted that none of these studies was focused on cirrhotic patients. ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² Among other things, this methodology—as well as the systematic baseline research at the ITPA genotype—remains currently the prerogative of a few research laboratories and would be difficult to use in clinical practice, also taking into account that these are outpatient patients.

A further noteworthy consideration with regard to RBV use—and that at least partially could question the above considerations—is that, at least in our experience, there may have been a possible bias in favor of the efficacy of the RBV reducing strategy due to the fact that the most frail subjects (in particular those with contraindications to the use of RBV) were offered an alternative all‐oral therapy based on SOF and DCV. This may have allowed the treatment (and consequent cure) of subjects that otherwise would likely have experienced an even higher incidence of RBV‐related complications, primarily anemia, with the need for significant RBV dose reductions—or even full discontinuation‐ and consequent potential lower viral eradication rates. Obviously, being the SOF/DCV arm RBV‐free, anemia was not a documented side effect in that subpopulation.

For what concerns SVR rates of SOF plus RBV treatments, they were very convincing, and even slightly higher than most clinical trial and real‐life records. These results were obtained regardless of previous antiviral treatments, reduced RBV dosing (taking into account all the above considerations) and treatment duration (provided it was >12 weeks). As regarding the latter point, an interesting remark is that the 12 week schedule, representing initially the most widely studied regimen, was adopted in our local experience only by a small minority (1%) of clinicians, probably because they feared a possible suboptimal efficacy in patients with advanced fibrosis. As a matter of fact, the main five phase III SOF clinical trials (known as the FISSION, POSITRON, FUSION, VALENCE, and BOSON trials)—none of which, however, was focused specifically on the subpopulation of HCV GT2‐infected cirrhotic patients—globally showed average SVR12 rates around 83% for the 12 week schedule (investigated in 49 of the 90 cirrhotic GT2 subjects collectively studied). ¹⁹ , ²⁰ , ²¹ , ²² The same trials suggested that the 12 week schedule—despite having many advantages—was suboptimal in the cirrhotic setting, and that more prolonged durations (i.e., 16 and 24 weeks) were associated to higher SVR rates (up to 100% in TN subjects). This evidence was further confirmed in the much more numerous real‐life studies that subsequently became available. ¹⁴ , ¹⁵ , ¹⁶ , ²⁹ , ⁴⁵ , ⁴⁶ , ⁶³ Coming back to our study, it is also noteworthy that the second choice in order of preference (51%) was 20 weeks (similarly to what happened in other European countries), although, for what concerns GT2 cirrhotic subjects, it was not formally tested in the aforementioned clinical trials, but—to the best of our knowledge—in only one major clinical study. ³⁰ So, in our opinion, the best possible therapy duration for this very specific subset of patients (i.e., 16, 20, or 24 weeks) remains not completely defined in the available clinical literature and should probably deserve some more additional research. In any case, at least in our casuistry, we could not demonstrate a possible propension to treat the more severe subjects with a longer duration (i.e., ≥20 weeks). This may be due also to the fact that our case series was very homogeneous, that is, it consisted only of cirrhotic patients, in the vast majority compensated (94% Child A, only 6% Child B, no Child C subjects).

Moreover, the most common AE of SOF/RBV, including anemia which has been discussed above, were similar to other reports, and in any case they were generally mild/moderate. ⁴⁷ , ⁶⁴ , ⁶⁵ Incidentally, all the few dropouts were attributable to reasons not related to the prescribed therapy. We also consider the safety data of particular significance since this was a frail mostly elderly population, like typical cohorts of cirrhotic patients in the Western world. ⁵² , ⁶⁶ , ⁶⁷ , ⁶⁸

However, this research reveals also many possible shortcomings. First, the frequency and severity of AE were estimated on the basis of clinical charts and may partially have been classified in an inaccurate way due to the different individual tolerance. Nonetheless, the most relevant occurrence (i.e., anemia) did not lead to treatment discontinuations. Second, the rationale for the RBV dose choice was not formally explored as this was a retrospective study. In any case, what emerged is that higher RBV doses were generally related to higher body weight (obviously, the main determinant of RBV dosage), male sex, higher MELD score and TE status. Other well‐known predictive factors of RBV‐induced anemia—such as advanced age, lower baseline hemoglobin values, and impaired renal function—were not correlated with the starting dose of RBV. This may suggest that RBV dosing was not primarily based on the patient predicted tolerability and concomitant diseases—as in the PEG‐IFN era—and that the clinicians preferred to follow as closely as possible the label indications, especially in those subjects with unfavorable predictors of SVR (such as previous treatment failure or more severe liver damage), probably taking into account that this advanced fibrosis‐population had a lower probability of response. From this point of view it is paradigmatic that this clinical approach was not a prerogative only of experienced physicians, as no significant differences in initial RBV dosage were observed between clinicians with work experience greater or less than 10 years (p = .437, data not shown).

In conclusion, SOF‐based therapies proved to be highly effective and tolerable in a big cohort of Italian cirrhotic patients with GT2 HCV infection, regardless of past antiviral experience and current treatment duration (provided it was longer than 12 weeks). Moreover, a low RBV dosage was as effective as the standard dose, confirming previous Asian experiences. ¹⁰ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ³³ , ⁴⁴ , ⁵⁰

DISCLOSURE

All authors declare they have no financial support or relationships that may pose conflict of interest.

ETHICS STATEMENT

The study protocol was approved by a centralized institutional review board (Comitato Etico Interaziendale Novara, Novara, Italy, IRB code CE 34/17) for all hospitals, and was therefore performed in accordance with the ethical standards set up in the Declaration of Helsinki 7th revision (2013).

PATIENT CONSENT STATEMENT

All persons had given their informed consent to the processing of personal data before starting antiviral treatments.

PERMISSION TO REPRODUCE MATERIAL FROM OTHER SOURCES

N/A.

CLINICAL TRIAL REGISTRATION

N/A.

Smirne C, D'Avolio A, Bellan M, Gualerzi A, Crobu MG, Pirisi M. Sofosbuvir‐based therapies in genotype 2 hepatitis C virus cirrhosis: A real‐life experience with focus on ribavirin dose. Pharmacol Res Perspect. 2021;9:e00811. 10.1002/prp2.811

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.