Clinical-demographical features of the study population
A total of 1,199 HCV-infected patients (1,081 HCV-monoinfected and 118 HCV/HIV-coinfected) initiated DAAs during the study period. A total of 144/1,199 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 HCV/HIV-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 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 four patients from group A and two from group B (p=0.349). Before the ART change, 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).
Patients who did not achieve SVR-12 were mostly males (76.5% vs 45.7% in responders patient, p=0.020), younger (51.6 vs 61.8, p=0.038), more frequently intravenous drug users (52.9% vs 22%, p=0.014 ) and presented a higher rate of failure to a previous anti-HCV treatment (47.0% vs 18.9%, p=0.024 ). The proportion of patients not achieving SVR-12 was higher among patients who underwent 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).
Excluding lost to follow-up and non compliant patients, according to PP-analysis, SVR-12 was achieved in 93/95 (97.9%) in group A versus 34/36 (94.4%) in group B (p=0.30).
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.
Severe 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.