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


To the best of our knowledge, this is the first systematic review to examine the neurocognitive effects of the DAAs treatment in HCV subjects. The current review included 12 studies with HCV-monoinfected subjects with and without severe liver damage, HCV/HIV subjects and healthy control groups. Our results point to the scarcity of neuropsychological data related to DAAs treatment, even considering HCV infection as associated with modified cerebral metabolism and neurocognitive dysfunction.[3,5,41]

The studies included in this review assessed different cognitive functions. Attention, memory and executive functions were the most frequently observed neuropsychological functions; processing speed and intelligence were assessed in six studies, whilst motor skills were assessed in four studies. Although these studies assessed the key functions generally impaired in chronic HCV patients,[42,43] the significant variation between each investigation hindered the precise measurement of treatment effects.

Most of the studies, with the exception of the two articles by Kleefeld and colleagues,[29,31] used the same neuropsychological tests at baseline and follow-up assessments. It should be observed that practise effects as a confounding factor cannot be excluded, especially for the studies that reported cognitive improvements after treatment.[32–35,37,39] Participants can learn not only the required answers to a given test but also an effective strategy of response, despite the time between assessments being as large as a year.[44,45] Future studies should mitigate this confounder by using different sets of the same tests at follow-up assessments.

Some studies showed positive changes in brain structures[33,34] and an increase of monocytes activation[38] associated with neurocognitive improvement in most cases. Evidence suggests that endogenous cytokine levels are related to poorer cognitive functioning, due to immune system activation related to the cerebral alterations.[46,47] The only study that reported reduced cognitive performance following DAAs treatment, specifically for processing speed and immediate and delayed visual memory, did so from a sample of subjects with psychiatric comorbidities.[35] Whilst this finding is important from a naturalistic sampling point-of-view, the inclusion of clinically depressed and/or anxious patients in their sample was a limiting confounder.

Some of the studies included in this systematic review also assessed health-related quality of life, depression and fatigue.[29,31,38] The findings are consistently positive, all pointing towards an increase in quality of life and less fatigue in self-reported scales after SVR. The data presented in this review are in accordance with previously reported results[23,48] and further strengthen the benefits of DAAs in the HRQoL and well-being dimensions.

An important point to emphasize in this review is the HCV/HIV coinfection. Although Kleefeld et al. (2018)[31] included a sample of patients coinfected with HIV; the authors did not perform comparative analysis with HCV-monoinfected patients. Sun et al.,[38] in contrast, showed that HCV/HIV patients performed better in visual learning/memory after DAAs treatment when compared to the monoinfected HCV group, suggesting that the eradication of HCV has a beneficial effect in other pathological conditions. HIV and HCV are both associated with cognitive impairment and have been found in cerebrospinal fluid and brain matter.[4,49] Rempel et al.[50] indicate that coinfection is associated with a type 1 IFN monocyte activation profile that was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection.

The results from this systematic review must be viewed considering its limitations. Most studies have small sample sizes, which makes it difficult to generalize the results. In addition to this, there is heterogeneity regarding the HCV sample between the controlled studies. Another limitation is related to neuropsychological assessment. The studies used heterogeneous neuropsychological measures amongst themselves, probably due to aspects of validity and standardization for their samples, making it difficult to generalize the results on the pro-cognitive effect of DAAs treatment.

This systematic review points towards cognitive improvement after DAAs treatment in HCV-monoinfected and coinfected subjects, as well as the general safety of this treatment from a neurocognitive perspective. The findings suggest that patients undergoing DAAs therapy can reach SVR without any major adverse impact on their cognitive functioning, whilst attaining higher HRQoL levels and reducing fatigue. The neuropsychological effects of DAAs treatment for HCV are still understudied. Future studies need to confirm these findings.