Discussion
The approval of SOF, the novel nucleotide analogue NS5B polymerase inhibitor, represents a breakthrough in the treatment of chronic HCV and has become the backbone of current therapy regimes. SOF-based therapies are the novel standard of care with high antiviral activity, broad genotypic coverage and a high barrier to resistance. During therapy with SOF, no virological breakthrough has been reported so far.
However, many difficult-to-treat patient populations hitherto have been understudied. Thus, we included a high number of patients with cirrhosis in our study, since HCV treatment represents a high priority particularly in this patient group. As HCV recurrence after liver transplantation is universal and bears a high risk of premature graft failure, we also analyzed patients after liver transplantation in our study. Previously, in the abovementioned patient groups, IFN-based HCV therapies were limited because of toxicity and poor efficacy. Additionally, many patients in our study were treatment experienced and several of those had received a protease inhibitor in a previous therapy. The study population further comprised patients co-infected with human immunodeficiency virus (HIV). Recent data has shown that the outcome of DAA-based therapies in HCV/HIV co-infected patients is comparable to the HCV cure rates in HCV mono-infected patients and indication and drug choice should follow the general guidelines for HCV mono-infected subjects. Therefore, HCV/HIV co-infected individuals are no longer regarded as a special patient population by major guidelines. Instead, with current DAA-based therapies, genotype 3 infected patients or special populations, including patients with renal insufficiency or decompensated cirrhosis, have shifted into the focus as difficult-to-treat populations.
Considering overall SVR 12 rates, patients with HCV genotype 1 infection, which historically have been difficult to treat, still seem to be the population hardest to cure, as also reflected by our study results. In the NEUTRINO trial, a phase 3 study in previously untreated patients with HCV genotype 1, a 12-week regimen of SOF plus RBV and peg-IFN-alfa-2a was administered. Total SVR 12 rates were 90 % and SVR 12 rates for patients with cirrhosis were 80 %.. In a further small study involving treatment-naive patients with HCV genotype 1 infection and a high prevalence of advanced fibrosis and cirrhosis, a 24-week regimen of SOF and RBV resulted in SVR rates of 68 %. In our study population total SVR 12 rates were 74 % and SVR 12 rates for patients with cirrhosis were 57 %. While overall virological response rates are encouraging, the relative high relapse rate in genotype 1 patients may suggest that dual DAA combinations should be favored at least for patients with negative predictors for a successful treatment outcome.
Surprisingly, total SVR 12 rates for patients with genotype 2 were lower than expected. In contrast to the results in our study population, the combination of SOF plus RBV has yielded very favorable results in previous studies. In the FISSION trial, a phase 3 study involving previously untreated patients with HCV genotype 2 infection, a 12-week regimen of SOF and RBV showed total SVR 12 rates of 95 % and SVR 12 rates of 83 % for patients with cirrhosis. In comparison, total SVR 12 rates for patients with genotype 2 in our collective was 79 % and was only 50 % regarding patients with cirrhosis.
Furthermore, in genotype 3 infected HCV patients, which have previously emerged as a particularly difficult to treat patient group, total SVR 12 rates in our study turned out to be higher than projected. The VALENCE trial yielded for previously treated and untreated patients with HCV genotype 3 infection total SVR 12 rates of 77–93 % after a 24-week regime of SOF and RBV, while the subgroup of previously treated cirrhotic patients displayed only SVR 12 rates of 61 %. With the addition of peg-IFN-alfa-2a to 12 weeks of SOF plus RBV in the LONESTAR-2 trial SVR 12 rates of 83 % were achieved in this unfavorable subgroup of previously treated cirrhotics. It can be speculated that these positive results may reflect a selection of patients with early stage cirrhosis with only minimally lowered thrombocyte counts, which were therefore regarded to be eligible to receive IFN. The patients in our collective showed total SVR 12 rates of 92 % and even treatment-experienced cirrhotics showed a SVR 12 rate of 87 % despite an interferon-free treatment regime in most of the cases. Eventually these data suggest that besides SOF plus RBV for 24 weeks, a SOF plus RBV and IFN treatment for 12 weeks should still be considered for IFN-eligible genotype 3 patients.
The NEUTRINO trial, a study of SOF plus RBV and peg-IFN-alfa-2a in previously untreated patients with HCV genotype 4, presented total SVR 12 rates of 97 % and for patients with cirrhosis of 50 %. Corresponding rates in our study population were 80 and 50 %.
However, it has to be noted that a comparison of the data of the aforementioned trials with the results of our study population is limited due to differences regarding the inclusion of treatment experienced patients and the treatment of patients with either one of two available treatment options and variable treatment duration.
Interestingly, besides the presence of cirrhosis, we observed that a level of HCV-RNA ≥ 12 IU ml-1 by week 4 of treatment was a predictor for treatment failure in genotype 1 patients, despite the fact that early virological response appeared to be of limited value as a prognostic marker in previously published DAA-based studies. Regarding the subgroup of cirrhotics, SVR 12 rates were only 25 % when HCV-RNA levels were ≥ 12 IU ml-1 after 4 weeks of treatment. Notably, the predictive value of early virological response was only evident in genotype 1 patients receiving an IFN-containing regime, but not in patients on SOF + RBV. Taken into account that SOF + peg-IFN-alfa-2a + RBV may still remain the standard of care in many regions of the world, because of the high costs of IFN-free treatment regimes, analysis of early virological response may be helpful to establish response-guided therapy regimes in the future. However, the sensitivity of HCV RNA quantification can differ between different tests. Patients who may have tested HCV RNA negative during antiviral therapy by older assays with a LLOQ of ≥ 50 IU/ml may test HCV RNA positive by highly sensitive HCV RNA assays. In our study the highly sensitive Abbott RealTime (ART) HCV assay (Abbott Molecular, Des Plaines, IL, USA) with the LLOQ of 12 IU/ml was used. Therefore, it might be reasonably assumed that different assays may have an influence on the predictive value of the early treatment response.
Change in clinical chemistry from baseline to SVR 12 in patients with genotype 1 HCV infection showed a statistically significant decline in total bilirubin. It might be speculated that the observed change in total bilirubin under successful HCV therapy in genotype 1 patients could be translated into an improvement of the MELD score of patients with advanced stages of liver cirrhosis and therefore treatment may lead to a delay or permanent prevention of liver transplantation.
As a limitation of the study, there is no data on the interleukin 28B haplotype of the patients in our cohort available. An association of viral clearance with this polymorphism was shown for antiviral treatment with peg-IFN-alfa and RBV, but not for SOF so far.
In our patient cohort no data is available on baseline and post-treatment resistance–associated variants (RAVs) representing a further limitation of our study. However, SOF exhibits a high barrier to resistance and among patients who did not achieve SVR in recent trials, including the FISSION, POSITRON and VALENCE trials, SOF resistance–associated variants (RAVs) were not detected. On the other hand, the Q80K variant conferring resistance to the NS3 protease inhibitor simeprevir has been observed in 9–48 % of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Although patients with baseline RAVs still exhibit high SVR rates, screening for variants conferring resistance may help to reduce treatment failures with respect to cost intensive treatment regimes.
Consistent with the safety profile of IFN, adverse events and laboratory abnormalities were more common in the SOF, RBV and peg-IFN-alfa-2a group. As seen in our study, adverse event profiles improve substantially in the absence of IFN. In view of the inconvenience and high rate of significant side effects of IFN, all-oral, IFN-free DAA therapies will become the first choice for treatment of patients with chronic HCV.
However, even though great strides have been made since the approval of the first DAAs in 2011, future research needs to address the current limitations in the antiviral efficacy of available therapies in the increasing number of patients with advanced liver disease and previous DAA treatment failure. With a growing number of patients who have failed under DAA-based therapy, there is still an emerging demand for further novel antiviral agents.