HCV New Drugs

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Information on the therapeutic response of patients with CPT class C cirrhosis to DAAs is fragmentary, as safety concerns regarding DAA use has limited their enrollment in registered trials [[4], [5], [6]]. Data are numerically more consistent for CPT class B, but the characteristics of patients in this subgroup are very heterogeneous. Indeed, CPT class C patients with decompensated cirrhosis (ascites, bleeding, encephalopathy, jaundice) may be reclassified into class B following successful treatment of the event. In addition, CPT class B can include both patients with a past decompensated event and minimal alteration in biochemical parameters (INR, bilirubin, albumin) and patients who have never decompensated but have larger changes in hepatic indices. There is a confusing relationship between CPT class and impairment of liver function. CPT classification considers five variables, of which two are clinical events consequent to portal hypertension (ascites and encephalopathy) and three are laboratory tests likely reflecting impaired liver function. Although the laboratory parameters are only marginally affected by therapeutic interventions, ascites and encephalopathy may resolve following treatment but recur during follow-up. This variability means an individual patient may be classified differently over time, with a likely transition from one class to another one during CPT staging. In contrast, the D’Amico staging system [8][8] only considers the status of cirrhosis in relation to portal hypertension, the most important consequence of liver fibrosis and a harbinger of episodes of decompensation. Adoption of this system means a patient with cirrhosis and ascites remains in the same stage even after successful treatment of the event. In our investigation, SVR rates ranged from 96.5% in the absence of portal hypertension, to 95.1% in the presence of varices (stage 2), 100% and 95.7% in the event of past decompensation (stages 3 and 4, respectively), and 93.6% in patients with multiple events (stage 5). Our findings suggest the use of DAAs for previously decompensated (stages 3–5) patients urgently needing for a cure of their HCV infection could be expanded.

As there are no head-to-head randomized controlled trials comparing DAA regimes, and our data were sufficient to conduct supplemental analyses, we undertook indirect treatment comparisons of the efficacy of the different DAA schedules. The analysis provided comparable SVR rates for all regimens: 95.4% for sofosbuvir/simeprevir ± ribavirin, 97.4% for sofosbuvir/ledipasvir ± ribavirin, and 96.4% for dasabuvir/ombitasvir/paritaprevir/ritonavir ± ribavirin. For countries with budget constraints, our results would allow therapeutic choice to be governed only by the cost of the drug(s).

In general, patients with cirrhosis who received treatment with the new DAAs whether or not in registered trials [10][10] had lower rates of SVR compared to patients in the present cohort. A likely explanation may be the exclusion from our analysis of patients treated with sofosbuvir/ribavirin, a regimen considered of limited efficacy for GT1 and GT4 patients with cirrhosis. A further reason could be the meticulous checking for potential drug interactions between the DAAs and other agents co-administered to the patient [13][13].

Benefit from therapy in this fragile population should not obscure the safety issue. Weker et al. have recently documented the frequency of hepatic decompensation during the course of DAA treatment for hepatitis C [17][17]. Gray et al. have also reported a 6% rate of on-treatment mortality in patients who were in CPT class B at baseline, and of 21% in those in CPT class C [18][18]. This high frequency of serious adverse events has been reported with virtually all oral regimens [19][19]. However, the alternative view that these events may be unrelated and coincidental to therapy, representing progression of the disease despite antiviral therapy, has been discussed [20][20]. The safety profile in our real-world cohort was excellent: adverse events occurred in a few patients but the majority of events were mild to moderate and aggravated by ribavirin co-administration. It should be remembered that a consistent proportion of our patients with cirrhosis received off-label therapy with simeprevir-containing schedules and a dasabuvir/ombitasvir/paritaprevir/ritonavir combination, regimens that are not recommended in CPT B and C cirrhosis [15][15]. Despite this, only three life-threatening events were seen in the 27 patients in these classes.

A favorable outcome following DAA administration has been consistently documented in previous studies [[1], [2], [10]]: in general, improvements in CPT classes and/or MELD scores have been noted in about one third of treated patients, and are usually thought to reflect better liver function. However, these two staging systems do not only reflect hepatic synthetic function, as two portal hypertension adverse events are included in the CPT classification, and creatinine value in the MELD scoring. Our data in previously decompensated patients revealed improvements in two liver synthetic indices, in platelets counts, and in creatinine values.

In conclusion, the main finding after treating 2612 HCV-infected patients with advanced fibrosis or cirrhosis in a real-world setting is that the treatment is safe and efficacious even for patients with previously decompensated disease. With the recommendation to check for drug interactions between DAAs and other co-administered agents, this subgroup of patients may benefit the most from DAA treatment: following a positive therapeutic outcome, parameters of liver synthetic capability are improved and the number of hepatic decompensation events is reduced.
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