Introduction
Hepatitis B virus (HBV) infection is a global public health problem affecting an estimated 292 million people worldwide [
1]. In the USA, 3.1 million people are affected by chronic hepatitis B (CHB) virus infection [
1], and nearly 40% of patients with CHB die annually as a result of complications such as cirrhosis and hepatocellular carcinoma (HCC) [
2,
3]. Despite the availability of a prophylactic vaccine, the number of people diagnosed with CHB continues to rise primarily because of the asymptomatic nature of the first stages of the disease [
4]. Moreover, 31.6% of adults with chronic conditions have HBV vaccine coverage (at least three doses) per the Centers for Disease Control and Prevention (CDC) [
5].
The American Association for the Study of Liver Disease (AASLD) and European Association for the Liver (EASL) guidelines define functional cure as the induction of sustained, undetectable hepatitis B surface antigen loss (HBsAg) and hepatitis B virus (HBV) DNA in serum with or without seroconversion to hepatitis B surface antibody (anti-HBs) after completion of a finite course of treatment [
6]. Functional cure is the optimal CHB treatment endpoint; however, it is rarely achieved with current antiviral treatments [
7,
8]. In fact, functional cure during long-term nucleos(t)ide analogue (NA) therapy may occur in only 1–3% of cases [
9‐
11]. Treatment with interferon and its pegylated forms offers a slightly higher rate of functional cure (5–7%); however, these therapies are rarely used given their suboptimal safety and tolerability profile [
8].
Similarly, other current CHB treatments, such as NAs, rarely lead to functional cure (e.g., sustained HBsAg loss and undetectable HBV DNA), leading patients to require a chronic treatment duration (often lifetime) to achieve desired benefits. Consequently, life-long treatment represents a clinical and economic burden for patients with CHB that includes liver disease progression, negative effects on quality of life, increased medical resource utilization and poor outcomes associated with suboptimal adherence, and increased health care visits and hospitalizations [
12‐
14]. Current guidelines underscore that optimal medication adherence to CHB treatment is required to attain the best (clinical) results. Non-adherence to treatment is the main driver for suboptimal treatment response among patients with CHB resulting in virological failure, HBV flares, and increased risk of mortality [
15‐
17]. Currently there is a need to better understand the medication-taking behavior of patients with CHB. However, assessing adherence using real-world databases is challenging because there is limited information on daily dosing and medication-taking behavior. Therefore, treatment persistence, which measures the duration of a prescribed treatment, might allow for the evaluation of patients’ health outcomes using real-world evidence.
Treatment persistence to NAs among patients with CHB is not well documented. Furthermore, there is a lack of evidence regarding the economic burden among persistent patients with CHB versus those who are not. The primary objectives of this study were to describe the patient characteristics, utilization, and costs among a cohort of CHB-infected US veterans treated with NAs (stratified by the co-infection and persistence). The secondary objectives included describing the medical resource utilization costs among persistent and non-persistent CHB-infected patients using an inception cohort with no prior NAs use. The inception cohort was created to mitigate the risk of misclassifying NA-treated patients with HIV co-infection and prior NA use.
Discussion
This study was conducted to better characterize CHB-infected patients and quantify the relationship between NA persistence and economic outcomes using real-world data from the VHA database. CHB was observed to be associated with considerable clinical and economic burden. About 60% of the overall cohort of NA-treated patients were CHB mono-infected, whereas 32% of the sample was co-infected with HIV. Similarly, Moorman et al. [
25] found that 31.7% of patients with CHB analyzed from electronic medical records of an integrated health care system in the USA were co-infected with HIV. In the current analysis, patients treated with NAs had a greater proportion of complications and infections including hypertension, diabetes mellitus, chronic kidney disease, malignancy, and alcohol abuse/dependence, particularly in the CHB mono-infected patients vs HIV co-infected patients. One possible explanation for these findings is that our study may have captured a cohort of patients with CHB with longer disease duration. However, the exact disease duration was unknown given that the study sample included a prevalent CHB cohort. In addition, HIV co-infected patients may seek care more frequently as part of their HIV management which may result in additional preventative care compared to CHB mono-infected patients.
To explore the disease burden of CHB, baseline characteristics of mono-infected CHB treated patients were examined. These patients had fewer comorbidities and incurred lower all-cause heath costs compared to overall NA-treated patients. The subgroup of HIV co-infected patients had higher CCI scores and higher disease severity compared to the overall NA-treated patients, resulting in higher baseline heath care costs which could be as a result of receiving care for HIV infection.
HBV DNA quantification is a useful marker for diagnosis of CHB and the presence of HBsAg for at least 6 months is used to define chronic vs acute conditions. The AASLD recommends that ALT and HBsAg levels are measured at least every 6 months for patients with CHB. In our study, the frequency of testing was much lower, and only 52.4%, 89.1%, 35.6%, and 32.2% of patients were found to have had at least one HBV DNA, ALT, HBsAg, and HBeAg test, respectively, during the 6-month baseline period. Previous studies have shown that patients had laboratory tests at lower frequency than the recommended guidelines which might result in underdiagnosis of CHB [
26]. This may delay initiation of antiviral therapy, leaving patients at risk for disease progression and potentially leading to higher economic burden associated with the disease. Among patients with CHB who had available laboratory tests, the number of patients with CHB that had an undetectable viral load was relatively low in our study which could be an indication of limited effectiveness of NAs in the real-world settings or persistence concerns that could have led to non-occurrence of HBV DNA suppression. However, caution should be exercised when interpreting these data given that only one laboratory test value recorded within 90 days of the index date was used to capture HBV DNA values.
Most studies in the literature have evaluated the cost-effectiveness of immunization or treatment interventions for CHB [
27,
28]. Yuan et al. [
29] reported the annual costs associated with various liver outcomes among patients prescribed LAM and ETV. Estimates in 2006 were $1130 ($1408 in 2018) for compensated cirrhosis, $15,085 ($18,790 in 2018) for decompensated cirrhosis, and $9923 ($12,359 in 2018) for HCC in the USA. In our study, the unadjusted costs among overall NA-treated patients were $39,240 PPPY. Expenditures were lower among mono-infected patients with CHB ($29,957 PPPY) and higher among those co-infected with HIV ($55,220 PPPY). Patients co-infected with HIV had greater disease severity and CCI scores compared to the mono-infected CHB population, which may have contributed to the higher costs among these patients.
Overall, we observed suboptimal persistence to NA current standard of care and a decrease in persistence over time. Our data demonstrated a 29% NA persistence level during year 1 of follow-up, which decreased to 14% during year 2 of follow-up. Although most of the published literature on CHB treatment has evaluated adherence [
30‐
32], and indicated trends similar to those observed in our study with suboptimal adherence and a decrease in adherence overtime, Chotiyaputta, et al. reported that persistence decreased to 94.2% after 3 months, 77.6% after 6 months, 74.7% after 9 months, and 73.4% after 12 months on medication among patients with CHB with no prior exposure to NAs [
33].
Current guidelines for CHB therapy recommend continued treatment with NAs to achieve better outcomes [
34]. Chronic lifelong treatments may lead to a drop in persistence over time as observed in our study (decreased NA persistence after the 2-year follow-up period). These results are consistent with previous results reported in other chronic conditions which have reported a decrease in the rate of patients who persistently adhere to the prescribed medication for a chronic condition, particularly within the first 6 months of therapy [
35‐
38]. Further research is needed to confirm this trend in patients with longer follow-up time.
In the current study, multiple factors may be associated with non-persistence or discontinuation including occurrence of adverse events, death, or receipt of care outside the VHA system. In addition, approximately 27–32% of patients in this analysis were at least 65 years of age. There is a possibility that these patients received care through Medicare and hence their complete medical and treatment history may not have been captured.
This study demonstrated that maintaining persistence to NAs for at least 2 years is associated with fewer inpatient admissions, lower hospital LOS, and lower overall health care costs compared to patients with CHB who were non-persistent to NAs in the first 2 years of follow-up. After adjustment for potential confounders, the results of this study suggest that savings could be generated for patients with CHB who remain persistent to their index NA for at least 2 years, particularly for inpatient costs ($7889). This could also represent a significant clinical and economic burden for those patients that require lifelong treatment with the current standard of care. The reduced inpatient costs were offset by the higher pharmacy costs among NA-persistent patients resulting in a net overall cost savings of $851 compared to non-persistent patients. The difference in cumulative overall total costs in 2 years did not meet statistical significance most likely because of the small sample size, particularly in persistent patients and limited follow-up time.
The unadjusted health care cost among persistent patients during the first 2 years was lower by $8781 (non-significant) compared to non-persistent patients. Furthermore, persistent patients incurred significantly lower inpatient costs compared to those who were non-persistent. Non-persistent patients captured in this study incurred nearly double the inpatient costs of persistent patients. They also had a higher frequency of malignancies and mental health disorders (results not shown). The costs of comorbid conditions among non-persistent patients with CHB may explain the inpatient cost differences compared to persistent patients.
It is well documented in the literature that for many chronic diseases, treatment non-adherence is associated with increased morbidity, mortality (5.9%), and substantial increased costs (ranging from $5271 to $52,341) [
39,
40]. However, published literature regarding CHB is systematic reviews; direct comparisons to our study results are challenging because of differences in the study populations, study design, and/or varying definitions of persistence and adherence [
41‐
43].
NAs have been the mainstay of treatment among patients with CHB. However, proper treatment with NAs is long term, and optimal persistence to treatment may be required to reach appropriate and desired treatment outcomes. As previously reported, many patients with CHB have difficulty with current long-term treatment persistence. These patients may benefit by having access to finite novel treatments that have the potential to provide a functional cure for CHB in a shorter period of time. Several treatment options are currently in clinical development with the goal of providing patients the ability to achieve a functional cure and sustained off-treatment response [
44,
45]. Functional cure may also lead to additional benefits of further reducing long-term liver complications as well as reducing the overall health care utilization and costs associated with CHB. Consequently, new innovative technologies, with higher rates of functional cure and favorable safety and tolerability profiles, are needed to address the current unmet need among patients with CHB.
Strengths and Limitations
To the best of our knowledge, this is the first real-world analysis of US veterans with CHB that highlights the unmet treatment need using standard of care and evaluates the impact of persistence to NAs on economic outcomes. In addition, the VHA is a closed centralized system and is the largest health care provider for hepatitis care in the USA, providing an opportunity to examine economic burden among patients with CHB using a large data set. However, this study has several limitations. Only 5 years of VHA data was available for this analysis, which limits our ability to evaluate long-term outcomes (such as HBsAg loss and seroconversion, remission, HCC, liver failure, liver transplantation, cirrhosis) as well as complete patient history, date of first diagnosis, duration of CHB infection, or previous treatment prior to start date of available data. In addition, critical variables could increase the economic burden of CHB including factors associated with the response to treatment, burden associated with NA side effects, or CHB disease progression. These factors could not have been concluded with certainty as a result of the nature of the claims databases. Cumulative persistence to NAs was assessed during a 2-year follow-up period, which is a short duration for this purpose; therefore, a larger sample size and longer follow-up duration are necessary to more convincingly assess persistence over time. However, there is limited evidence of cumulative NA persistence from 2 years; future research should validate this data.
Laboratory data was limited which restricted our ability to assess variables such as disease severity or treatment response. These variables may have impacted the decision to continue treatment and consequently have substantial impact on the outcomes. Also, lab values were recorded within 90 days of the index date. Therefore, not all patients that were included in our analysis had a lab value for HBV DNA, ALT level, HBsAg, or fibrosis level. Medications dispensed over the counter, samples provided by a physician, and pharmacy claims in the inpatient setting cannot be observed in claims data. Hence, we could not evaluate the true cost associated with treating side effects of antiviral treatment. Moreover, since this analysis was conducted within the VHA system, which includes predominantly older white men in the USA with unique care delivery and reimbursement mechanisms, the findings may not be generalizable to other patients with CHB receiving care in different health care delivery systems, such as commercial managed care plans, Medicare, or Medicaid plans. In addition, the study does not reflect the costs for any health care services that were received outside of the VHA system and therefore may be another reason our study is not generalizable to the overall CHB population.