Our study has demonstrated that CHC causes considerable cognitive impairment in patients with and without cirrhosis, which improves after treatment with DAAs and achievement of SVR. In patients who did not achieve cure, there was a reduced improvement in cognitive scores for reaction times, digit span, verbal memory and executive function (NCT and Stroop test) with persistently high anxiety and depression scores. We did not find any association of age, gender, presence of cirrhosis, route of transmission, substance abuse and rural practice as independent predictors of treatment failure. This study shows that the HCV-related neuropsychiatric syndrome is potentially reversible with DAA-based therapy with HCV cure rates exceeding 90% in a public health setting.[15,16]
The challenges of population-based therapy include accumulation of treatment failures, reinfection patterns in subsets like people who inject drugs (PWID), and gender and age-related differences in access to advanced care. The primary determinant of outcome in this study was adherence to the regimen. Therefore, PLHCV should be assigned a dedicated caregiver at home, who can supervise therapy and liaise with the integrated treating unit. The use of computer-based rapid, objective neurocognitive battery in the clinic is a useful iterative tool for pre- and post-therapy cognitive changes in PLHCV. Also, the use of DAAs in our cohort obviated IFN-α associated confounding depression, fatigue and poor HRQoL. Therefore our data provides a causal association for the HCV neurocognitive impairment, which is eliminated after achieving cure.
Older PLHCV and women scored lower on vitality, pain and social functioning on HRQoL domains in our study, which is comparable to prior studies. These gender differences need to be tackled to overcome microelimination in vulnerable subgroups in India, where small communities with unsafe injection practices contribute to new incidence of HCV, rather than PWID. The perceived social stigma in women and elderly due to HCV, colloquially called 'black jaundice', and lack of information about the availability of holistic care in the public health setting are a big challenge.[16,18] Moreover, depression and/or anxiety have been reported in about one-third of PLHCV. Navinés et al. reported an 18.2% prevalence of depression in 500 persons with HCV. In particular, major depressive disorder, generalized anxiety and panic were present in 6.4%, 7.0% and 5.8% of the patients, respectively.
Our data show that these scores improve after attaining SVR-12 and become comparable to healthy controls without cirrhosis. Our concern was that depression and poor cognition may affect adherence or cure rates. Paradoxically, baseline scores for BDI and GAD-7 were higher in patients who subsequently achieved SVR-12. This can be explained by the fact that the Punjab Model stresses on the involvement of a caregiver in the treatment, which ensures adherence even in patients with cognitive impairment. In prior studies, depression was independently associated with perceived barriers to accessing HCV care, thus creating a vicious circle.
The studies that have explored cognitive function in PLHCV were extremely heterogeneous in terms of patient characteristics, confounding factors (e.g. intravenous drug use and alcohol intake), lack of control groups or standard cognitive testing methodology[10,25–27]
Table S6 summarizes all the available data on the HCV-related neuropsychiatric syndrome, with a focus on newer studies on DAA-based therapy. Many of these studies are limited by the cross sectional design, small sample sizes, comparison of mixed populations with decompensated cirrhosis and MHE, injection drug use, HIV or HBV coinfection, treatment with IFN-α or psychoactive medications. The inclusion of even a few individuals with overt HE can skew results for attention-based tasks like vigilance or Stroop tests, and we were careful to exclude such persons. Weissenborn et al. reported a deficit in attention and higher executive function in PLHCV, in parallel with an increase in depression and anxiety. There was no correlation between baseline anxiety/depression and cognitive performance like our data. Kleefeld et al. reported poorer performance for visual memory, learning, working memory, processing speed, executive functions and motor skills at baseline in patients with HCV or HIV-HCV coinfection.
Despite being the largest prospective cohort till date, our study has few limitations. First, the number of women is only 23.9%, which may reflect on the gender differences in access to tertiary care in low- and middle-income countries like India. Second, SVR-12 rate in the larger Punjab programme is 92.6%, and even in the complicated PLHCV referred to the hub was 90.6%. Thus, only 36 cases of treatment failures were noted in the cohort of 385 individuals, which possibly limits a comparative analysis. This re-enforces the fact that DAAs are highly efficacious, even when provided by primary care providers. Despite these limitations, ours is the largest prospective real-world cohort on the neurocognitive impairment, depression and anxiety in PLHCV, including those with cirrhosis, which affects treatment outcomes in HCV elimination programmes.
Santos-Lima reported a systematic review on the effect on DAA-based therapy on the HCV-associated neuropsychiatric impairment. All 12 studies indicated an improved HRQoL after SVR, with only one study reporting worsening of cognitive outcomes. However, these were all small studies with 20–30 subjects only.[9,11] Our study used a combination of culturally adapted instruments for depression, anxiety, HRQoL and cognitive function, with objective assessment of these states before and after treatment. We also identified that the treatment access and integrated psychological support for women that needs to be improved. The neuropsychological evaluation in our study was conducted in a structured, comprehensive way, by cognitive domain, and test results scored against normative databases, rather than simply compared to small internal control groups. Mood, fatigue and quality of life should be assessed in PLHCV with focus on niche groups like women and older persons.
In conclusion, considering the large cohort size with details of the neuropsychiatric evaluation at two time points in a real-world setting, we confirm that PLHCV exhibits a subtle type of cognitive impairment, independent of liver derangement, as disclosed by the comparison with patients with NAFLD. Therefore, it must be ascribed to the direct or indirect effects of the viral infection on the brain. Viral clearance through DAAs ensured a cognitive improvement in given functional domains, with improved depression and anxiety scores, and HRQoL. Lastly, our findings emphasize that integrated care models with mental health professionals taking an active role in the HCV treatment of large populations is essential to improve adherence, manage psychological symptoms and remove social stigma, which remains a barrier to care in public health models.
The Indian Council of Medical Research (ICMR) partially supported the project via grant number ICMR 2018–0297. The sponsor did not have any role in the study design, analysis, interpretation of data, report writing and the decision to submit for publication.
ALT, alanine aminotransferase; BDI, Beck's Depression Inventory; CHC, chronic hepatitis C; CI, confidence interval; DAAs, direct-acting antiviral agents; DCV, daclatasvir; DH, District Hospital; G, Genotype; GAD-7, Generalized Anxiety Disorder-7; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HRQoL, health-related quality of life; IDU, injection drug use; LDV, ledipasvir; MMPHCRF, Mukh Mantri Punjab Hepatitis C Relief Fund; MoCA, Montreal Cognitive Assessment; NVHCP, National Viral Hepatitis Control Programme; PEG-IFN, peg-interferon; PLHCV, person living with HCV; PWID, People Who Inject Drugs; RBV, ribavirin; SF-36, Short Form Health Survey; SOF, sofosbuvir; SVR, sustained virological response; VEL, velpatasvir.
Mr. Vasu Mahesh M. Tech provided technical support for standardization of the Neurocognitive Battery for Customized Testing and automated data capture using the using Psychology Experiment Building Language version 2.1, an open-source software.
Consent to Participate
Written informed consent was obtained from all participants enrolled in the study.
Consent To Publish
All authors have read and approved the final version of the manuscript and gave consent to the study to be published in the present form.
Data Availability Statement
Limited access to data can be provided on request to the corresponding author.
J Viral Hepat. 2022;29(5):395-406. © 2022 Blackwell Publishing