In our study of a clinical cohort linked to health administrative data with validated chronic disease ascertainment algorithms, we found individual comorbidity burden to be greater among people with HCV than the general population. This was especially true for substance use, mental health, and liver-related diseases. In addition, we found that the multimorbidity of these conditions was significantly greater for people with HCV, including both physical and combined physical and mental health multimorbidity. This finding was most significant among younger age groups and persisted up until age 66 years for both men and women. We also found that multimorbidity was not associated with receiving interferon-containing or DAA treatment, nor with achieving cure with DAA treatment. However, people with substance use disorder in their middle age were less likely to receive treatment even with DAA. As there is no known validated algorithm for HCV ascertainment using administrative data, our study is the first to our knowledge to use combined cohort and population-based data to determine multimorbidity among a cohort of people living with HCV and to compare this to a general, representative population.
We found an increase in the prevalence of several chronic conditions among people living with HCV. Substance use is a well-established risk factor for HCV exposure and the prevalence of concomitant mental health conditions is recognized as being very high in those with HCV infection.[59] However, we found even higher prevalence of these conditions in our cohort than other populations. For example, we found substance use disorders among nearly one-third of the HCV patients in our cohort, whereas other studies found 4-25% prevalence. Similarly we found mood and anxiety disorders among one-third of HCV patients, compared to 13.9-23.7% for depression in other studies.[26, 27, 30] One reason for this could be that our setting has universal access to care, which could have facilitated patient access for these conditions. In addition, the consequences of chronic HCV infection include liver failure, hepatocellular carcinoma, and the need for liver transplantation.[60] As such, our finding that liver-related disease is higher in those living with HCV compared to the general population is not surprising.
We also found that the prevalence of several non-hepatic conditions was greater among people with HCV. This was true for conditions known to have causal relationships with HCV, including diabetes, some cancers, and chronic renal failure,[5-10, 15-19] although our estimates for these conditions were generally lower than those in other studies with less stringent, unvalidated methods of chronic disease ascertainment [26, 27, 29, 30] or from clinical charts.[25] For example, we found the prevalence of diabetes in our cohort was 13.27%, compared to 13.8-26.1% in other studies. [25-27, 29, 30] We also found greater prevalence of lung conditions including asthma and COPD, which were, when combined, higher than some [26, 29] and lower[27] than prevalences reported in studies with less robust definitions, likely due to overlap between these conditions and their relationship with smoking. We also did not find evidence of increased prevalence of any cardiovascular conditions among people with HCV compared to the general population, including both acute (myocardial infarction, stroke) or chronic (hypertension, chronic coronary syndrome, congestive heart failure, arrhythmia) conditions. This is in contrast to other studies that found increased prevalences of these conditions among people with HCV [26-29], although, again, our condition ascertainment was more rigorous. For example, we found hypertension among one quarter of our HCV patients, whereas other studies reported prevalence of 31.4-40.1%. [26, 27, 29, 30] Again, we note that the comparator studies used a variety of ascertainment methods for defining comorbidity, the majority of which have not been validated, or included symptom-based diagnoses such as pain, making comparisons challenging.
Importantly, we also found that the multimorbidity of these conditions, including combined physical and mental health multimorbidity, was also particularly high in those living with HCV infection. To our knowledge, only one other study has quantified this burden [30]: these authors found slightly greater proportions of multiple conditions. However, ascertainment of these conditions was not validated and many of those conditions, including those at greatest prevalence contributing to multimorbidity counts, were symptom-based, such as abdominal pain, back problems, and fatigue, thus may not have the same implications for engaging people in care and treatment.
In our study, multimorbidity was not associated with initiation of either interferon or DAA regimens. This result was surprising, as interferon is well known for producing and/or exacerbating underlying medical and mental health conditions, many of which have been considered relative or absolute contraindications to initiating interferon-based therapy.[61] We suspect this reflects our practice of reserving interferon-based treatment to those with more advanced liver fibrosis, who would have been older and more likely to have multimorbidity as demonstrated by our analysis. A major advantage of DAA therapy is that there are few contraindications, even in those with advanced liver disease or other comorbidities [62], which supports our finding that multimorbidity was not associated DAA-based treatment initiation. While, in at least one study, early discontinuation of interferon-free therapy was predicted in part by comorbidity burden [38], in our analysis the proportion of DAA-treated patients achieving a SVR was unrelated to prevalence of multimorbidity. Finally, when we restricted our analyses to people with substance use disorders, those who were middle-aged were less likely to receive DAA, although these individuals were equally likely to achieve cure. Others in similar settings have also noted this disparity.[63] This finding is of concern given that DAA therapy is reimbursed by our provincial formulary for nearly all patients and that the average age of people with HCV who use drugs in Canada is in the mid to late forties range.[63, 64] It is critical to develop policies and strategies that facilitate DAA uptake and completion in those facing barriers to treatment.[65, 66]
A strength of our study is that we used a combination of rich data from a diverse cohort of people living with HCV in a broad geographic region combined with robust population-level data for comorbidity ascertainment. In addition, recognizing that mental health comorbidity, in particular substance use disorder, may be particularly high among people living with HCV, we stratified our findings to include those with and without these conditions so as not to overestimate the impact of their prevalence on all people living with HCV. Nevertheless, there are limitations. Although we used validated algorithms to identify comorbidities, our estimates are restricted to people who are diagnosed and receiving care. We also could not ascertain treatment outcomes among people who were lost to follow-up from care, and in particular among interferon-based treatment recipients for whom treatment outcomes were incomplete. This would introduce bias in our results if the multimorbidity of those lost to follow up had significantly different morbidity from those who were retained for analysis. Evaluation of comorbidity as a function of liver fibrosis stage would have been revealing. However, our dataset did not allow for this analysis. Finally, our study setting is one of single payer, universal care, which likely optimizes disease ascertainment based on diagnosis codes but may not be generalizable to other settings. Given the retrospective nature of this analysis we were able to identify associations but not establish causality.
People living with HCV have a higher prevalence of many comorbidities as well as both physical and physical-mental health multimorbidity compared to the Ontario population. Middle-aged individuals with substance use disorder were less likely to receive treatment, even in the DAA era. In addition to well-known reductions in mortality and liver-specific comorbidity, HCV treatment has also been shown to reduce future comorbidity, including diabetes, renal disease, cardiovascular disease, mental and cognitive health, and quality of life.[67-73] As such, our findings support current calls for taking a broad, inclusive approach to offering HCV antiviral therapy regardless of physical and mental health comorbidity and mode of HCV transmission, including injection drug use. With the evidence that the management of chronic diseases is most effectively and economically provided in well-supported primary care settings [74, 75], our findings call for integrated, comprehensive, community-oriented approaches to HCV care delivery. Specific strategies may include involving peers in care, case management, integration of HCV care with substance use, social service delivery, primary care services [76], use of telehealth services [77], and self-management strategies.[78-80]