Clinical-demographical features of the study population
A total of 1,199 HCV-infected patients (1,081 HCV-monoinfected and 118 HIV/HCV-coinfected) initiated DAAs during the study period. A total of 144/1199 subjects (12.0%) presented psychiatric comorbidities and were included in the study, of whom 101 (70.1%) were on anxiolytic/antidepressant therapy (group A) and the remaining 43 (29.9%) were treated with antipsychotic drugs (group B). In Figure 1 is represented the study diagram.
The clinical characteristics of patients at baseline, are summarized in Table 1.
Patients were 49.3% males with a mean age of 60 years (SD ±13.5), and 31.9% of them were cirrhotic. Patients in treatment with antipsychotic drugs were younger (50.6 vs. 64.9 years, p<0.001), mostly males (67.4% vs. 41.6%, p=0.006), the main route of transmission was intravenous drug use (46.5% vs. 16.9%, p<0.001) and were more frequently infected with HCV genotype 1a (34.9% vs. 16.8%, p=0.020), and genotype 3 (30.2% vs. 4.9%, p<0.001).
Most patients (70.1% of the study population) had at least one comorbidity (other than psychiatric). Group A individuals were more likely to have at least one additional comorbidity before starting DAA-treatment (78.2% vs. 51.2%, p=0.002). Arterial hypertension was the most common reported comorbidity (42.4%), mainly diagnosed in patients belonging to group A (52.5% vs. 18.6%, p<0.001).
Failure to a previous anti-HCV treatment was reported in 32 patients (22.2%), the majority among patients in treatment with anxiolitycs and antidepressant (28.7% vs. 7.0%, p=0.004). Among the HCV treatment-experienced subjects, one had experienced failure with a previous DAA-based regimen.
All patients had compensated liver disease according to the Child–Pugh classification. Group A subjects showed a higher FIB-4 score (2.2 vs. 1.6, p=0.009). No differences in liver stiffness and fibrosis stage distribution, APRI/MELD score, and HCV-RNA at baseline were observed between the two groups.
Furthermore, 125 (86.8%) were HCV-monoinfected and 19 (13.2%) were HIV/HCV-coinfected. Coinfected patients were mostly represented among subjects in treatment with antipsychotic drugs (23.3% vs. 8.9%, p=0.030). Two patients had HBsAg positivity, both in the Group B.
DAA-regimens were chosen by treating clinicians based on clinical criteria and viral genotype. The most frequently prescribed DAA-regimen was SOF+VEL±RBV (25.7% overall), especially in subjects in treatment with antipsychotic (51.2% vs. 14.9%, p<0.001). The regimen including OMB+PTV/r± DAS ±RBV was never prescribed in group B patients (p=0.006).
In Table 2 the characteristics of the psychiatric disorder are detailed for both groups. Subjects belonging to group B, which included a higher percentage of former drug users, were mostly on substitution treatment with opioids at the time of inclusion in the study. The psychiatric illness’ duration was longer in group B (p=0.011) No statistically significant differences between the two groups were found regarding the referred alcohol consumption.
Change of psychiatric and antiretroviral treatment before DAAs-initiation
Among the entire study population, a total of 20 patients (13.8%) required a modification of psychiatric therapy based on DDIs in according to the psychiatrist’ judgment before the beginning of the DAA-regimen: a dose adjustment of psychiatric drugs was observed in two patients whereas in the remaining 18 patients (10 in group A 9.9% and 8 in group B, 18.6 % p=0.172) a complete therapeutic change was adopted. In seven cases (7/20, 35%) a therapeutic change was mandatory due to drug-drug interactions.
Regimens more likely to require a change of psychiatric drugs before starting DAA-treatment were SOF+DCV±RBV (3/13 patients, 23.1%); GRZ+EBR±RBV (4/20, 20%), SOF+VEL±RBV (7/37, 18.9%), and GLE+PIB (3/24, 12.5%).
Among the 19 HIV/HCV-coinfected individuals, all patients were on ART at the initiation of DAA-treatment and were aviremic. A total of 6/19 patients (31.6%) required a change of ART because of DDIs, of whom 4 patients from group A and two from group B (p=0.349). Before the change of ART, 5/6 (83.3%) patients were in treatment with protease inhibitors: one with atazanavir unboosted, two with lopinavir/ritonavir, two with darunavir/ritonavir. Of the 6 patients who changed ART, only one returned to his previous ART regimen after the end of DAA-treatment. No virological failure for HIV was observed.
Outcome
Among the 144 patients enrolled, 140/144 (97.2%) completed the prescribed DAA-regimen accomplishing EOT, while four patients prematurely interrupted their therapy: in one case due to imprisonment, and in the remaining three cases due to the occurrence of AEs (see the following paragraph).
Overall, according to an ITT-analysis, SVR-12 was achieved in 127/144 subjects (88.2%) of the study population, 93/101 (92.1%) in group A versus 34/43 (79.1%) in group B, respectively (p=0.045). Clinical characteristics of psychiatric patients stratified by achieving SVR-12 are detailed in Table 3.
Among the patients achieving EOT but not SVR-12, twelve were lost to follow-up (6 from group A and 6 from group B), and only one (belonging to group B) had a relapse. This patient was a non-cirrhotic subject infected with HCV genotype 3, who had received the SOF+DCV+RBV combination for 12 weeks; he had resistance testing performed at failure which demonstrated a resistance pattern against NS5A (Y93H).
A lower SVR rate (79%), was observed in psychotic patients (group B) compared to group A (92%) which was mostly due to a higher prevalence of patients lost to follow-up (6/43, 14% vs. 6/101, 6% respectively, p=0.183). The proportion of patients not achieving SVR-12 was higher among patients who underwent to a change of the psychiatric regimen before anti-HCV treatment (6/20 patients, 30%) compared to those who maintained the same psychiatric therapy (11/124, 8.8%) (p=0.015). On the contrary, no differences were observed according to ART change before anti-HCV treatment (no patient failed among those changing ART before baseline while only two failures were evidenced among the remaining subjects).
Safety profile of DAAs
The safety profile was evaluated for the 144 enrolled subjects, and is described in Table 4. Treatment discontinuation was observed in 4 (2.7%) individuals of the study population and were due to: seizures incoming, syncopal episode, severe headache; the fourth patient was detained and interrupted the treatment. A total of 60 patients (41.6%) experienced at least one AE. Most AEs in course of DAAs occurred in patients in treatment with anxiolytics and antidepressant (48.5% vs. 25.6%, p=0.015). The most common AEs were represented by neurological symptoms (18.0%), skin reactions (7.6%), and gastrointestinal disorders (7.6%). Patients receiving RBV more frequently showed AEs during treatment in comparison with subjects treated with RBV-sparing regimens. Erythropoietin use and a RBV dose reduction were reported in 2 (1.3%) and 4 (2.7%) patients, respectively. No statistically significant differences in terms of occurrence of AEs were observed between the two groups. Psychiatric symptoms such as anxiety episodes and mood disorders were reported only among group A patients.
Serious AEs were generally uncommon (6.9%). The most common SAE was severe anaemia in 3 patients (2.1%). Three hospitalizations (not leading to treatment discontinuation) were reported due to: angina episode, hyperammonaemic encephalopathy and hematemesis. No death was reported.