Comorbidities and co-medications in populations with and without chronic hepatitis C virus infection in Japan between 2015 and 2016

The advent of direct-acting anti-viral agents (DAAs) has dramatically improved the treatment of hepatitis C virus (HCV) infection. Treatment with these agents can achieve high sustained virologic response rates with a favourable tolerability and shortened treatment duration [1, 2]. However, DAA treatment is challenging for patients who use co-medications, especially drugs metabolised by cytochrome P450 CYP3A4, because of potential drug–drug interactions (DDIs) [3].

Chronic HCV infection causes persistent inflammation, which can result in the development of both liver diseases (e.g. cirrhosis, hepatocellular carcinoma) and extrahepatic diseases [4, 5]. Chronic HCV patients therefore tend to have various comorbidities. Some comorbidities such as HIV or hepatitis B virus (HBV) co-infection, obesity, and insulin resistance can contribute to the progression of liver fibrosis, which can lead to advanced liver diseases [6, 7]. Moreover, it has been reported that chronic HCV patients also have an increased risk of death from extrahepatic diseases such as circulatory diseases, renal diseases, and non-liver cancers compared with non-HCV patients [8]. Thus, management of these comorbidities is important to prevent disease progression and reduce mortality from both liver diseases and extrahepatic diseases. However, the use of co-medication to treat comorbidities, regardless of whether it is long- or short-term, can complicate HCV treatment because of the risk of DDIs with DAAs [3, 9]. The situation is even more challenging when treating older patients because they tend to have more comorbidities and use more co-medications [10].

Physicians therefore need to understand the comorbidities and co-medication profiles of chronic HCV patients to appropriately manage chronic HCV infection along with their comorbidities. In the US, studies have examined the comorbidities and co-medications of chronic HCV patients [9, 11]. However, to our knowledge, no such studies have been conducted in Japan, although the profile of chronic HCV patients there may differ from elsewhere. In Japan, the prevalence of HCV infection is higher in older people [12, 13]. HCV started to spread in the 1930s through intravenous drug abuse or medical procedures such as blood transfusion and the use of contaminated needles. However, transmission through blood transfusion has dramatically decreased over the past 50 years thanks to the discovery of HCV and the introduction of HCV antibody screening of donor blood [14], resulting in a low prevalence of HCV infection among younger people [15]. Because of the age distribution of the patient population and potential international differences in treatment patterns, it is important to obtain real-world data about comorbidities and co-medications in chronic HCV patients in Japan.

The aim of this study was therefore to describe the prevalence of comorbidities and the use of co-medications in chronic HCV patients in Japan by age group, compared with an age-, sex-, and hospital-matched non-HCV patient population, using a large-scale medical claims database. This study will create new data that are not yet available in Japan, which will provide physicians with the better understanding of chronic HCV patients in Japan.

To our knowledge, this is the first study to examine comorbidities and co-medications in chronic HCV patients in Japan. We found that chronic HCV patients had more comorbidities and used more co-medications than non-HCV patients. Older chronic HCV patients, who constitute the majority of the HCV patient population in Japan, commonly had multiple comorbidities and used more co-medications, suggesting the difficulty of appropriate management of this patient population.

In this study, older chronic HCV patients were more likely than younger patients to have comorbidities. Interestingly, however, the proportion of patients with comorbidities decreased in patients aged ≥75 years. This may be because those with fewer comorbidities tended to survive longer. It is also noteworthy that 16.0% of chronic HCV patients aged 18–24 years had four or more comorbidities, showing the relatively common presence of multiple comorbidities in young patients. Given that intravenous drug abuse is an important route of HCV transmission among young people [15], some of these young patients may be injecting drug users and are therefore more vulnerable to developing other diseases. However, these details could not be investigated in this study because of an absence of relevant data within the database.

The patterns of comorbidity distribution among chronic HCV patients were comparable to those of non-HCV patients who were 30 years older. The percentage of patients with no comorbidities decreased across the age groups in a very similar way in the two groups, although the proportion with no comorbidities was lower from a younger age in the chronic HCV group (see Fig. 1). A similar trend has been described for patients with ongoing HIV infection and it has been hypothesised that this might imply premature aging in those patients, possibly caused by persistent inflammatory and immune changes [18, 19]. Unfortunately, however, we did not examine whether similar changes occurred in chronic HCV patients.

The most common comorbidities in chronic HCV patients were diseases of oesophagus, stomach and duodenum (41.7%), hypertensive diseases (31.4%), and metabolic disorders (28.2%). A US study reported similar findings among chronic HCV patients: gastrointestinal disorders (24.4%), oesophageal disorders (20.5%), essential hypertension (32.6%), and disorders of lipid metabolism (25.9%) [11]. We also found that all ten systemic diseases were more common in chronic HCV patients than non-HCV patients, and that the prevalence of most systemic diseases tended to become higher in older chronic HCV patients. Our findings underscore the importance of age-related comorbidities such as hypertensive diseases, metabolic disorders, cardiovascular diseases and malignancies in older chronic HCV patients.

Chronic HCV patients used more co-medications than non-HCV patients, and more than one in five chronic HCV patients (22.9%) used at least four co-medications. Although direct comparisons of our results with previous findings are not appropriate because of different study methods, German studies have previously reported that 31–34% of HCV patients took at least four regular out-patient medications [3, 20]. An Italian study showed that 31.0% of chronic HCV patients with liver diseases used at least four co-medications, and estimated that 30–44% of chronic HCV patients receiving DAAs and using co-medications were at risk of DDIs [21]. The proportion in our study was slightly smaller than reported in these countries, but this may be because of our strict definition of co-medications. The common use of multiple co-medications in our study implies that chronic HCV patients in Japan may be at similarly high risk of potential DDIs.

The five most common co-medications used by chronic HCV patients were proton pump inhibitors, calcium antagonists, angiotensin-II antagonists, non-barbiturates, and antacids. This is similar to a German study reporting that the five most common co-medications included beta-blockers, proton pump inhibitors, thyroid hormones, angiotensin-II antagonists, and dihydropyridine calcium channel blockers [3]. The common use of gastric acid suppressants and hypertensive agents in our study might be attributed to our finding of a high prevalence of gastric diseases and hypertension in chronic HCV patients in Japan.

Gastric acid suppressants (e.g. proton pump inhibitors, antacids) have potential DDIs with DAAs [20‐23]. These medications alter the acid environment, which can result in reduced absorption of certain drugs such as ledipasvir [22, 23]. Calcium antagonists also have potential DDIs with DAAs; plasma concentration of these medications can be increased by the concomitant use of CYP3A inhibitors such as telaprevir and simeprevir [22‐24]. In this study, both these co-medications were common, especially in older chronic HCV patients. Although our chronic HCV population included a large proportion of untreated patients, examination of co-medication profiles in treated patients revealed that proton pump inhibitors and calcium antagonist were commonly prescribed to patients treated with DAAs (13.5 and 13.3%, respectively), roughly corresponding to the results of the overall chronic HCV population [see Table 3 & Additional file 1: Table S1]. Because of our strict definition of co-medications, our results probably reflect the medications used for chronic conditions, meaning that these medications may be difficult to stop or substitute. To select the optimal DAA treatment for chronic HCV patients, physicians should pay careful attention to the long-term use of these medications in their patients.

Even short-term use of other medications can influence DAA treatment. However, patients may not always inform their physicians about short-term use of medications, probably because they are not aware of the risks for DDIs. This study also examined short-term use of medications, and found that proton pump inhibitors, antacids, and calcium antagonists were used by about 25–30% of chronic HCV patients. Other classes of medications with potential DDIs with DAAs, such as analgesics, diuretics, and sedatives were also used by many chronic HCV patients [see Additional file 2: Table S2] [24, 25]. These results reinforce the need for physicians to have an exact knowledge of medication profiles of chronic HCV patients to avoid or manage DDIs. When initiating a DAA treatment, physicians may need to consider appropriate action for the management of DDIs, such as discontinuation, dose change, use of alternative medications, and increased monitoring of patients [23].

This study has several limitations. First, the generalisability of its results may be limited because the hospitals included in the database are only those with advanced medical care capabilities (e.g., acute care hospitals, general hospitals). The chronic HCV patients studied may therefore be “sicker” than other patients such as those treated at clinics. Likewise, the non-HCV patients may have severe medical conditions, which would influence the results. Second, the study has limitations inherent in the use of a pre-existing hospital claims database, such as misclassification owing to incorrectly recorded or missing data. For example, the diagnosis of chronic HCV infection was based on the diagnosis record and its accuracy might vary from hospital to hospital. Patients may have received other medications for other comorbidities at different hospitals, but this could not be traced. The lack of data on the time of HCV clearance in patients may have resulted in under- or overestimation of comorbidities. The low prevalence of HCV-related cirrhosis among chronic HCV patients may also be attributed in part to underestimation stemming from limitations of the database (i.e., miscoding, lack of data). However, this may also be explained by the difficulty of correct diagnosis of cirrhosis, which requires biopsy. Whereas patients usually undergo biopsy when they start HCV treatment, most of our chronic HCV patients were untreated, implying that not many patients who were likely to receive a correct diagnosis of HCV-related cirrhosis were included. Third, we set strict definitions to identify the chronic comorbidities and co-medications most likely to have been used to treat chronic conditions, which may have resulted in underestimation of both comorbidities and co-medications because patients may not constantly visit the hospital. Fourth, we examined ten relevant systemic diseases, but these are not comprehensive. Investigation of other extrahepatic manifestations is needed for a more comprehensive understanding of systemic manifestations in chronic HCV patients in Japan [see Additional file 3: Table S3 for additional data of additional extrahepatic manifestations of chronic HCV infection]. Finally, this study was unable to investigate any causal relationships between the results and chronic HCV infection or DAA treatment because the comorbidities and co-medications were not examined against the timing of diagnosis or treatment. Further studies may shed light on these relationships.

In the present study in Japan, patients with chronic HCV had more comorbidities than those without HCV regardless of age. In particular, older chronic HCV patients commonly had multiple comorbidities and used more co-medications. The results suggest the difficulty of managing chronic HCV patients in Japan, especially older patients constituting the majority of the HCV patient population in Japan, because of the potential for DDIs. To provide optimal DAA treatment for this older patient population, it is important for physicians to closely monitor their medication profiles and take appropriate action to manage DDIs.