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February 14, 2017; 88 (7) Clinical/Scientific NotesOpen Access

Effect of interferon-free therapy on cognition in HCV and HCV/HIV infection: A pilot study

Felix Kleefeld, Sophie Heller, Heiko Jessen, Patrick Ingiliz, Antje Kraft, Katrin Hahn
First published December 21, 2016, DOI: https://doi.org/10.1212/WNL.0000000000003575
Felix Kleefeld
From Universitätsmedizin Charité (F.K., S.H., A.K., K.H.); Praxis Jessen2+Kollegen Berlin (H.J.); and Medizinisches Infektiologiezentrum Berlin (P.I.), Germany.
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Sophie Heller
From Universitätsmedizin Charité (F.K., S.H., A.K., K.H.); Praxis Jessen2+Kollegen Berlin (H.J.); and Medizinisches Infektiologiezentrum Berlin (P.I.), Germany.
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Heiko Jessen
From Universitätsmedizin Charité (F.K., S.H., A.K., K.H.); Praxis Jessen2+Kollegen Berlin (H.J.); and Medizinisches Infektiologiezentrum Berlin (P.I.), Germany.
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Patrick Ingiliz
From Universitätsmedizin Charité (F.K., S.H., A.K., K.H.); Praxis Jessen2+Kollegen Berlin (H.J.); and Medizinisches Infektiologiezentrum Berlin (P.I.), Germany.
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Antje Kraft
From Universitätsmedizin Charité (F.K., S.H., A.K., K.H.); Praxis Jessen2+Kollegen Berlin (H.J.); and Medizinisches Infektiologiezentrum Berlin (P.I.), Germany.
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Katrin Hahn
From Universitätsmedizin Charité (F.K., S.H., A.K., K.H.); Praxis Jessen2+Kollegen Berlin (H.J.); and Medizinisches Infektiologiezentrum Berlin (P.I.), Germany.
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Effect of interferon-free therapy on cognition in HCV and HCV/HIV infection: A pilot study
Felix Kleefeld, Sophie Heller, Heiko Jessen, Patrick Ingiliz, Antje Kraft, Katrin Hahn
Neurology Feb 2017, 88 (7) 713-715; DOI: 10.1212/WNL.0000000000003575

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Approval of direct-acting antivirals against the hepatitis C virus (HCV) has dramatically changed the management of HCV infection due to high cure rates and a favorable safety profile. Their influence on neurologic aspects is notably relevant, as studies demonstrated active HCV replication within the CNS1 and alterations in cerebral metabolism consistent with neuroinflammatory conditions.2 These findings may be causative for cognitive deficits in HCV-infected patients.3 Similar impairment has been demonstrated in patients coinfected with HIV, with a prevalence as high as 60%.4 Therefore, these patients may particularly benefit from HCV eradication. To date, studies addressing the issue of reversibility of cognitive deficits after HCV therapy are based on interferon treatment, which itself can cause continuing cognitive impairment.5 The important question whether these deficits are indeed reversible after HCV eradication remains unsolved to date.

Methods.

We conducted an open observational trial with HCV and HCV/HIV coinfected patients and planned HCV treatment. Patients with liver cirrhosis (defined as fibroscan >12.5 kPa), a history of substance dependence, or cerebral diseases were excluded. HIV-infected patients had to have undetectable plasma HIV levels for at least 6 months. We assessed a comparison group of healthy controls (n = 30) for baseline, but not for follow-up. The neuropsychological test battery included standardized tests and—to minimize practice effects—alternate versions for follow-up testing, covering 7 domains (table). We used age-corrected norms. To test for baseline and longitudinal differences, we used t tests for dependent and independent samples, respectively. Participants completed self-report assessments of cognitive symptoms, instrumental activities of daily living, fatigue, depression, and quality of life. Testing sessions took place at baseline and at the earliest 12 weeks after the end of HCV treatment.

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Table

Cognitive performance at baseline before therapy

Results.

We have seen 25 HCV-positive outpatients between 2015 and 2016 before treatment. Fifteen were coinfected with HIV. All but one participant were male. Groups did not differ significantly in age or years of education (patients [mean age 43.8 years (SD 11.7); mean education 15.1 years (SD 2.1)]; controls [mean age 39.5 years (SD 9.9); mean education 16.1 years (SD 2.0)]). Mean nadir CD4 of the coinfected group was 328 cells/μL (SD 215); baseline CD4 cell count was 846 cells/μL (SD 242) and remained stable over time. At baseline, the patient group showed significantly poorer performance in the domains of visual and working memory, processing speed, attention, and executive functioning (table). We did not observe a difference between monoinfected and coinfected patients.

To date, 12 participants have completed therapy and undergone follow-up. Treatment regimens were well-tolerated and included the following: ombitasvir/paritaprevir/ritonavir + ribavirin (n = 2), ledipasvir/sofosbuvir (n = 9), or sofosbuvir + ribavirin (n = 1). Mean therapy duration was 10 weeks (8–12 weeks); all patients were HCV-RNA-negative at week 12 after treatment completion.

At follow-up assessment, patients did not show cognitive decline in any domains compared to baseline; neither did any patient report subjective impairment during or after the therapy. On the contrary, 2-tailed t tests indicate a significant (p < 0.05) improvement in the domains visual memory, processing speed, attention, and executive functioning. In addition, we observed a significant (p = 0.022) decline in self-reported fatigue severity. There was no significant change in the level of depression, but an increase in self-reported quality of life.

Discussion.

In this study, we investigate the effect of an interferon-free treatment on cognitive function in HCV-monoinfected and HCV/HIV coinfected patients. Our data show that HCV-infected patients without comorbidities had significantly poorer cognitive performance than controls. Against our expectations, HIV coinfection did not increase the extent of cognitive deficits. These findings partially contradict conclusions made by other studies. A recent study6 showed that HCV coinfection did not have an effect on cognitive function in a cohort of HIV-infected patients, which led the authors to question an influence of HCV on cognition per se.

In contrast, our data suggest a significant influence of HCV infection on cognitive function, which seems to outweigh that caused by HIV infection. Our first follow-up data support this assumption, showing an improvement in those cognitive domains that were impaired before HCV eradication. Our study was explicitly designed to detect differences attributable to HCV eradication. In contrast to the cross-sectional approach of most previous studies, we therefore chose a longitudinal approach.

Nevertheless, these first data have to be interpreted carefully due to small sample size. Practice effects might partially contribute to the observed improvements. However, reported effect sizes are relatively small (Cohen d = 0.00–0.24)7 compared to the ones seen in our cohort (d = 0.20–1.79). To verify an improvement, more follow-up data need to be considered using a reliable change index approach8 to differentiate between practice effects and treatment-related cognitive changes.

Acknowledgments

Acknowledgment: The authors thank Ute Kopp for neuropsychological advice.

Footnotes

  • Author contributions: Felix Kleefeld: acquisition of data, analysis and interpretation of data, drafting the manuscript. Sophie Heller: acquisition of data, analysis and interpretation of data, revision of the manuscript. Heiko Jessen and Patrick Ingiliz: study concept and design, patient recruiting, revision of the manuscript. Antje Kraft: study concept and design, revision of the manuscript. Katrin Hahn: study concept and design, study supervision, critical revision of the manuscript for intellectual content.

  • Study funding: No targeted funding reported.

  • Disclosure: F. Kleefeld and S. Heller report no disclosures relevant to the manuscript. H. Jessen has received payment for study cost from Gilead Sciences GmbH; for Board membership from Gilead Sciences GmbH, Bioscientia-Institut für Medizinische Diagnostik GmbH, and ViiV Healthcare GmbH; for speaker activities from ViiV Healthcare GmbH, Abbvie Deutschland GmbH & Co. KG, Bristol-Myers Squib GmbH & Co KGaA, Gilead Sciences GmbH, and Gilead Sciences Ltd.; and for travel/accommodation/meeting expenses from ViiV Healthcare GmbH, Abbvie Deutschland GmbH & Co. KG, Bristol-Myers Squib GmbH & Co KGaA, Gilead Sciences GmbH, and Gilead Sciences Ltd. P. Ingiliz has received lecture or consultancy fees from AbbVie, BMS, Gilead, Janssen, and MSD. A. Kraft reports no disclosures relevant to the manuscript. K. Hahn has received lecture fees from AbbVie, Astellas, CSL Behring, Gilead, Pfizer, and ViiV. Go to Neurology.org for full disclosures. The Article Processing Charge was paid by the authors.

  • Received May 16, 2016.
  • Accepted in final form November 22, 2016.
  • Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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