HCV study population characteristics
A total of 7411 chronic HCV patients were included in this analysis (Table ). The study population was predominantly male (62.9%) and the median age was 49 years. Almost half of the patients received interferon during the study period (46.8%) and 19.7% had advanced liver disease. Most patients were from the northeast region of the United States (63.8%) and 83.1% of patients had HMO (health maintenance organization) or PPO (preferred provider organization) insurance. When comparing HCV infected cases vs. HCV uninfected controls, reported drug use (14.9% vs. 3.2%) and alcohol use (6.5% vs. 0.85%) was much higher among cases. Also, both drug use and alcohol use were 1.3- and 1.7- fold higher among HCV untreated patients versus the treated population.
Characteristics of HCV study population
Overall frequency of HCV comorbidities
Comorbidities were common in this insured HCV population (Figure ). Almost all HCV patients (99.4%) reported ≥1 comorbidity and only 41 patients (0.6%) reported none. Fifteen percent reported ≤5 comorbidities, whereas 52% reported 6-15 comorbidities, and 5.5% reported ≥31 conditions. When comparing HCV-infected patients to uninfected controls, HCV-infected patients reported almost double the number of comorbidities (101,219 vs. 53,589, respectively). More uninfected control patients (37.4%) reported ≤5 comorbidities compared to case patients (14.8%). The HCV infected population was more likely to report ≥21 comorbidities than the uninfected, 13.5% vs. 3.7%, respectively.
The proportion of HCV infected cases and HCV uninfected controls reporting comorbidities.
Top 25 most common comorbidities
Table presents a ranked list of the top 25 most common comorbidities in the overall HCV population, and also presents the frequency of these conditions among the treated and untreated HCV populations. In addition, the association (odds ratios adjusted for age, sex, and advanced liver disease) of the comorbidity between HCV treated and untreated, and between the HCV-infected (all) compared to the uninfected controls are shown. For a number of conditions where the CCS category name is denoted with "other" or was considered not to be fully explanatory, we described the most common conditions that were classified within that comorbidity by ICD-9 codes as a table footnote. Eight symptoms (denoted by category C) and eighteen comorbid conditions were identified among the top 25 list.
25 most prevalent comorbidities and symptoms in the overall HCV population stratified and compared by antiviral treatment status and control patients without HCV
Among the top ranked conditions, the majority of the comorbidities were grouped into 7 wider body system classes as follows: diseases of the digestive system (liver diseases, other [rank 1], gastrointestinal disorders, other and unspecified [rank 13], esophageal disorders [rank 16]), disease of the musculoskeletal system and connective tissue (connective tissue disease, other [rank 2], back problems, other [rank 7], non-traumatic joint disorders, other [rank 8]), diseases of the respiratory system (upper respiratory infections, other [rank 4], unspecified lower respiratory disease, other [rank 5], upper respiratory disease, other [rank 17]), diseases of the circulatory system (essential hypertension [rank 6], non-specific chest pain [rank 10]), endocrine, nutritional and metabolic diseases and immunity disorders (disorders of lipid metabolism [rank 11] and diabetes mellitus without complication [rank 23]), mental disorders (alcohol and substance-related mental disorders [rank 20] and depressive disorders [rank 22]), and diseases of the nervous systems and sense organs (blindness and vision defects [rank 21], eye disorders, other [rank 25]). Symptoms and signs influencing health status (malaise and fatigue [rank 12] and allergic reactions [rank 18]) were also common in this HCV population.
Other liver diseases (37.5%) was the most common comorbidity (inclusive of symptoms) identified in this HCV population, and of these patients, 70% reported abnormal liver function, 26.7% elevated aminotransaminases, 13.8% abnormal serum enzyme levels, 10.7% ascites, and 9.0% hepatomegaly. In addition, these patients were more likely to have been treated during the study period (odds ratio, OR = 1.34, 95% CI: 1.21-1.47).
Comorbidities associated with HCV antiviral treatment
We note that several conditions associated with antiviral treatment (see Table ; A) were ranked among the top 25 comorbidities: muscle aches (denoted within connective tissues disease, 34.6% of those treated), sinusitis (within upper respiratory infections, 34.7%), skin irritation (within skin disorders, 28.8% and allergic reactions, which comprised mainly unspecified dermatitis, 17.8%), malaise and fatigue (26.9%), anemia (28.3%), visual disturbances (within blindness and vision defects, 14.8% and eye disorders, other, 14.4%) and depressive disorders (14.1%), however, only those reporting malaise and fatigue (OR = 1.18, 95% CI: 1.07-1.32), anemia deficiency (OR = 1.99, 95% CI: 1.77-2.23) and eye disorders, other (OR = 1.23, 95% CI: 1.08-1.41) were significantly more likely to be treated during the study period. Thyroid disorders, which are contraindicated for treatment, did not rank in the top 25 comorbid conditions (prevalence, 12.5%). However, upper respiratory disease (19.4%; rank 17), was comprised mainly of rhinintis, which is known to be associated with thyroid disorders [16
]. Therefore, the high prevalence of rhinitis may suggest the under-diagnosis of thyroid disorders in this HCV population. There was no difference in treatment status for patients with upper respiratory disease, although patients with thyroid disorders were more likely to be treated (OR = 1.60; 95% CI: 1.39-1.85) in our study population (data not shown).
Several conditions which preclude patients from treatment (see Table ; B) were also among the top comorbidities; diabetes mellitus without complications (13.8%), and depressive disorders (13.9%), however only those with diabetes mellitus without complications were less likely to be treated during the study period (OR = 0.74, 95% CI: 0.65-0.85). Non-specific chest pain (26.5%) could be a symptom of HCV disease or result as an adverse event from pegylated interferon treatment (mainly Pegasys [17
]), and it was identified in our ranked list of comorbidities. Although we cannot determine which condition chest pain is associated with, these patients were less likely to be treated (OR = 0.84; 95% CI: 0.76-0.94). We did not identify chronic obstructive pulmonary disease (COPD) in our top list of comorbidities, an antiviral treatment contraindication, however, it ranked only slightly lower than our top 25 (prevalence, 13%).
Although disorders of lipid metabolism [rank 11] was not defined by HCV management guidelines in Table , HCV infection is known to be associated with enhanced lipogenesis, reduced secretion, and β-oxidation of lipids; therefore, it was not surprising that it ranked in our most frequent list of comorbidities [18
Comorbidites associated with HCV disease
We also found that several conditions associated with HCV disease ranked among the top 25 comorbidities. Among the symptoms associated with HCV disease (see Table ; C), joint pain (including back problems (32.5%) and joint disorders (29.3%)) and abdominal pain (36.1%) were identified; and these patients were less likely to be treated. In addition, gastrointestinal disorders (24.4%) comprising mainly of diarrhea, splenomegaly, irritable bowel syndrome and unspecified site of abdominal/pelvic swelling may also result in abdominal pain.
Among the common extrahepatic manifestations seen among chronic HCV patients (see Table ; D), we identified rheumatoid symptoms (denoted within connective tissue disease and malaise/fatigue) and psychological disorders (within substance-related mental disorders and depressive disorders) to be the most prevalent in our study population.
Among the comorbidities known to be associated with liver disease progression (see Table ; E), substance-related mental disorders, (associated with drug and alcohol use) and essential hypertension ranked in our top list, and those with substance-related mental disorders were less likely to be treated (OR = 0.70, 95% CI: 0.61-0.80). Although HIV, HBV, obesity did not rank in our list, the prevalence of these comorbidities were 3.2%, 8.4%, and 3.8%, respectively. Approximately 20% of the HCV population had advanced liver disease (cirrhosis and HCC); and these patients are at risk of developing further complications from cirrhosis which occur as a result of portal hypertension and hyperdynamic circulation [19
]. This is evidenced by the high ranking of esophageal disorders (particularly esophageal varices) in our ranking of most common comorbidities.
Comorbidities not known to be associated with HCV antiviral treatment or disease
Of the top 25 ranked list of comorbidities, the conditions (n = 3) that were not known to be associated with antiviral treatment or disease, and hence were least expected, were benign neoplasms, upper respiratory disease, genitourinary symptoms and ill-defined conditions, and viral infections (which was defined mainly by unspecified viral infections, viral warts, and unspecified herpes simplex). These conditions were about 1.3- to 1.7-fold higher in the HCV-population compared to the HCV uninfected controls.
Ranking of top 25 comorbidities according to HCV status
The top ranking comorbidities among the overall HCV population were consistently identified in the top 25 comorbidities list of stratified groups of HCV treated, untreated, and controls populations, however with different prevalence and ranking orders (data not shown). There were a few exceptions. Specifically, diabetes mellitus without complication did not rank among the top-ranked list of comorbidities among HCV treated patients, whereas patients with thyroid disorders (13.4%; mainly hypothyroidism) were recorded. Among the HCV untreated patients, eye disorders and allergic reactions were not seen, whereas cardiac dysrhythmias (14.0%) and osteoarthritis (13.5%) ranked. Amongst the uninfected control group, other liver diseases, anemia deficiency, substance-related mental disorders, and depressive disorders were not present in the top 25 list, whereas bone disease and musculoskeletal deformities, other (9.1%), ear and sense organ disorders, other (8.8%), non-malignant breast conditions (8.7%), and cardiac dysrhythmias (8.3%) ranked.
Comorbidities in the HCV population (regardless of treatment status) were more prevalent than in the controls, except for disorders of lipid metabolism (32.2% among controls vs. 25.9% among cases; OR = 0.73; 95% CI: 0.68-0.79). Not surprising, HCV cases with other liver diseases (OR = 19.67; 95% CI: 16.57-23.36) had the highest OR compared to the HCV controls, followed by those with anemia deficiency (OR = 4.57; 95% CI: 4.06-5.14) and depressive disorder (OR = 3.72; 95% CI: 3.25-4.27).