Study population
Between March 2016-February 2017 forty patients with HCV GT1 and past PI treatment failure were screened. One patient failed screening due to potential drug-drug interactions (clopidogrel) and 39 patients initiated treatment according to the study protocol. Thirty-seven patients completed treatment and 12 weeks of follow-up and were analysed for SVR12 (treatment was discontinued prematurely in two patients). Clinical and demographic characteristics are presented in Table 1. Out of 39 patients included, 59% were male. Average age and body mass index (BMI) were 54.0±8.7 years and 28.7±4.5 kg/m2, respectively. The average baseline viral load was 24.41*105±29.26*105IU/ml. Advanced fibrosis (F3-4) (by FibroScan®) was present in 18 patients (46.2%) while cirrhosis (F4) was present in 11 patients (28.2%). The majority of patients were previously treated with telaprevir (53.8%), 43.6% with boceprevir and only one patient with simeprevir.
Primary outcome, treatment efficacy
There were 4 parallel groups of treatment according to the patient’s genotype and the presence/absence of cirrhosis. Four patients had GT1a (2 cirrhotics) and 35 patients had GT1b (9 cirrhotics) (Table 1). Virologic response was observed among 36/37 patients who completed the treatment (97.3%) while one patient (2.7%, G1b- non-cirrhotic, serial no. 28) had a viral breakthrough after 12 weeks of treatment [2055IU/ml after 12 weeks (EOT) and 554,847 IU/ml at 24 weeks, (EOS)] (Figure 1). There was no virologic relapse among patients that completed the study, thus the per-protocol SVR12 rate was 97.3% and comparable to 97% SVR12 described in historical cohorts (P=1.000, Chi-square test). There were two early treatment terminations both did not achieve SVR12. Thus, according to the intention-to-treat protocol, the SVR12 rate was 36/39 (92.3%) and comparable to the historical cohort SVR12 (92.3% vs. 97%, P=0.349, Chi-square test). Intention-to-treat and per-protocol SVR12 according to treatment groups are shown in Figure 2.
Secondary outcomes, clinical and laboratory
Baseline median FibroScan® score was 9.3 kPa (min-max 3.7-34.0 kPa). By EOS there was a statistically significant decrease to 7.8 kPa (min-max 3.7-34.8kPa) (P=0.007). The prevalence of advanced fibrosis (F3-F4) markedly declined from baseline 46.2% to EOS 25.7%, (P=0.016) (Figure 3). Seven patients (43.8%) had advanced fibrosis at baseline and markedly improved during treatment and follow-up (in 4 patients with F3 and 3 patients with F4 the score declined to F2). Furthermore, within the advanced fibrosis category, 2 patients with F4 at baseline improved to F3 at EOS.
Baseline ALT levels were abnormal in 84.6% of patients (higher than twofold the upper limit of normal (ULN) in 35.9%) while at the EOS, ALT levels were within normal range in 91.4% of the patients and none exceeded 1.5-fold of the ULN (Figure 4).
Patient Reported Outcomes
The prevalence of a better health perception (answers 1+2) as opposed to all other answers was comparable (39.5% vs. 41.2%, respectively, P=1.000). As a continuous variable, the mean scores at baseline and at EOS were comparable as well (2.76±1.0 vs. 2.64±1.03, respectively, P=0.513).
According to the Work Productivity and Activity Impairment Questionnaire, the prevalence of patients with a steady job at baseline and EOS was similar (74.4% vs. 71.4%, respectively, P=0.625). No overall work impairment due to HCV (0% impairment) was reported by 69% of patients at baseline and 80.8% of patients at the EOS. Significant overall work impairment (≥50% impairment) was reported by 6.9% of patients at baseline and 11.5% at EOS. No impairment to general activity (0% impairment) was reported by 59.5% of patients at baseline and 64.7% at EOS. Significant impairment to general activity (≥50% impairment) was stated by 18.9% of patients at baseline and 23.5% of patients at EOS.
Adverse events
Out of 39 patients, two patients had an early drop-out – one after a few days because of palpitations, leg oedema and general weakness and another after 6 weeks because of an acute psychotic episode and admission to a psychiatric ward. Weight-based RBV was administrated to 12/39 (30.8%) patients (1000mg/d for 2 patients and 1200mg/d for 10 patients). In 4 patients RBV dose had to be reduced due to side effects but none required discontinuation of the drug. The total number of any adverse events was 25 events, and 7/25 (28%) were serious adverse events (Table 2). The number of patients experiencing at least one adverse event was higher among patients treated with RBV compared to those without RBV [8 (66.7%) vs. 7(25.9%), respectively, P=0.031].
Resistance-associated substitutions (RASs)
There were 30 pre-treatment valid samples for amplification and analysis (supplementary 1). NS3 RASs were detected in 15 patients (50%) and NS5A RASs in 9 patients (30%). Six patients (20%) had both NS3 and NS5A RASs. Fourteen patients were previously treated with boceprevir and in two patients, resistance to boceprevir was detected (174F and 55A). One patient (patient no. 28) had resistance to boceprevir but was previously treated with telaprevir (54S, 168V). This patient had resistance to telaprevir as well (54S, 117C). None of the other 15 patients previously treated with telaprevir had evidence of resistance. Aside from patient no. 28, four more patients had baseline resistance to telaprevir without any previous exposure. As for the current treatment, two patients had pre-treatment resistance to ombitasvir, one achieved SVR12 and the other one, patient no. 28, had dual resistance to paritaprevir as well. Post-treatment analysis was performed only to patient no. 28, which was similar to the pre-treatment pattern and showed resistance to all NS3 protease inhibitors and to all NS5A inhibitors except pibrentasvir.