Neuropsychological Effects of Direct-acting Antiviral Treatment for Hepatitis C Virus Subjects

A Systematic Review

Cassio Santos-Lima, Breno Souza-Marques, Flávia Vieira, Maria Isabel Schinoni, Lucas C. Quarantini and Neander Abreu


J Viral Hepat. 2021;28(12):1672-1682. 

In This Article


Search Results and Study Characteristics

A total of 182 hits were retrieved from the databases (21 in PubMed/Medline, 06 in Embase, 07 in Lilacs and 166 in Scopus) as potential papers for inclusion. Of those articles, nine studies fulfilled the selection criteria. In addition to the studies found in the search for descriptors, we identified and included three other articles that met the eligibility criteria for this investigation (Figure 1). A complete summary of study characteristics and quality assessment of the 12[29–40] included studies are presented in Table 2. Two of them were considered high quality, whilst the remaining ten others had ratings ranging from 4 to 6 stars, suggesting moderate quality. All studies, with the exception of one case series, were prospective cohort studies.

Measurements of Neuropsychological Outcomes Across Studies and Control Groups

The number of neuropsychological assessments over time varied between studies. Nine of the studies only evaluated it at the end of DAAs treatment.[29,31–35,38–40] The other studies evaluated it twice—during, soon after the end, or after the end of DAAs treatment.[30,36,37] Amongst the results related to the cognitive effect of DAAs treatment, some studies had one or two control groups of healthy subjects, subjects coinfected with HIV and/or subjects with another clinical condition.[29,31,34,38]

Clinical Conditions of Hepatitis C Virus Patients

Three studies investigated patients with severe clinical conditions to HCV infection—cirrhosis, advanced liver disease and post-transplant patients. Volpato et al.[30] showed that patients with cirrhosis all Child-Pugh A, with an average model for end-stage liver disease, exhibited a significant slowing in choice reaction times at the end of the course of DAAs treatment when compared with other patients post-liver transplantation. The authors report mild, transient worsening in cognitive and neurophysiological performance in patients with cirrhosis at the end of a course of treatment with Sofosbuvir-based regimens, with or without ribavirin. The study conducted by Hamdy et al.[32] assessed the neuropsychological performance of patients with compensated liver disease, all Child-Pugh A, using the Montreal Cognitive Assessment test (MoCA). The results showed no significant differences between baseline and the evaluation at the end of DAAs treatment. However, the mean MoCA scores were higher after twelve weeks from the end of treatment (p < 0.001). Laursen et al.[36] compared the neuropsychological performance with the continuous reaction time (CRT) test of HCV patients with advanced liver disease at baseline (Child-Pugh A and B), 12 weeks, and one year after DAAs treatment; the reaction time improved at one-year follow-up. These authors highlight that patients had a mean CRT index suggestive of minimal hepatic encephalopathy at baseline and that CRT index improved after DAAs treatment.

Main Neuropsychological Outcomes Related to Direct-acting Antivirals Treatment

Regarding DAAs treatment, the neurocognitive performance of HCV and HCV/HIV subjects improved for processing speed, verbal fluency and verbal/visual episodic memory.[29,31,33–35,37,39] It is noteworthy that most studies used the Rey Complex Figure to assess immediate and delayed visual episodic memory, but not all of them had an improved score following DAAs treatment. Lower scores in immediate and delayed visual memory were also reported, evaluated with the Brief Visuospatial Memory Test-Revised (BVMT-R), and processing speed, in HCV monoinfected with comorbidities such as anxiety and depression.[35] The main studies outcomes and their neuropsychological findings related to DAAs treatment are presented in Table 3.

Neuropsychological Outcomes Associated With Neuroimaging and Neurophysiological Measures

Two studies explored the association of neuropsychological functions and neuroimage before and after DAAs treatment. Bladowska et al.[33] submitted eleven HCV-monoinfected patients with either advanced liver fibrosis or cirrhosis to magnetic resonance, diffusion tensor, perfusion-weighted imaging and to a comprehensive battery of neuropsychological assessment. When compared to baseline, patients performed significantly better for visual-spatial constructional ability/visual memory and for the executive function measure after treatment. These cognitive improvements were positively associated with better white matter integrity of the inferior fronto-occipital fascicle following treatment. Marciniewicza et al.[34] reported, within this same sample, brain volume alterations, in comparison with a control group of 18 healthy subjects. At baseline, there were no significant differences between the HCV patient group and healthy controls for the total grey and white matter volumes. After DAAs treatment, the HCV patient group showed significant volume loss in the cingulate and frontopolar gyri, anterior circular sulcus of the insula and anterior segment of the lateral sulcus. The authors reinforced Bladowska's findings of improvements in neuropsychological scores and indicated that brain atrophy following the DAAs treatment might be a consequence of reduced HCV-dependent oedema and inflammation.

The study conducted by Vaghi et al.[39] assesses perceptual and cognitive activity through an 'endogenous' brain wave, using the Mini-Mental State Examination (MMSE), the Psychometric Hepatic Encephalopathy Score (PHES) and a neuropsychological battery associated with a neurophysiology measure—the P300. At baseline, the HCV group, who did not meet the criteria for a minimal hepatic encephalopathy, had significantly worse mean scores on the MMSE, RAVLT, Digit Backward Span, Rey Figure—Copy and verbal judgement tests, when compared with control groups. After DAAs treatment, the HCV group had a significant improvement in the RAVLT, semantic and phonemic verbal fluency scores, and a shortening of about 15 ms for P300, suggesting a direct effect on the brain.

Bar et al.[40] did not find significant differences between baseline and the evaluation three months after the end of DAAs treatment for the neuropsychological outcome, evaluated with Trail Making Test A and the Digit symbols test. The results for the critical flicker frequency (CFF) test—a neurophysiological measure of visual discrimination and general arousal, were positively significant. All patients effectively achieved viral eradication, but the HCV neurotoxicity group—with high viral load and abnormal baseline CFF results, had a more prominent improvement after treatment.

Neuropsychological Outcomes Associated With Neurotransmitters, Cytokines and Monocyte Measures

One open-label study investigated the relationship between neurotransmitters, cytokines and cognition.[35] HCV subjects without cirrhosis and with psychiatric comorbidities were assessed at baseline and 24 weeks after the completion of DAAs treatment. All participants reached sustained virological response (SVR) and the results showed a significant correlation between cognitive performance and serum measures at baseline and 24 weeks post-treatment.

Sun et al.[38] measured monocyte immune activation to determine the impact of mono-infection or coinfection of HCV/HIV on cognitive performance. The study longitudinally compared 7 HCV subjects and 12 HCV/HIV subjects before and after DAAs treatment with 12 HIV subjects and 9 healthy controls who followed the same protocol but did not receive HCV treatment. The results showed less monocyte activation post-DAAs and an increase in cognition performance for HCV coinfected patients. A significant improvement in overall cognition, defined by a global deficit score of 25% after HCV therapy, in coinfected subjects was reported, especially for visual learning/memory. The study also showed decreased markers associated with liver damage.