Nonliver Comorbidities in Patients With Chronic Hepatitis B

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Abbreviations

CHB

chronic hepatitis B virus

CI

confidence interval

CKD

chronic kidney disease

eGFR

estimated glomerular filtration rate

ETV

entecavir

FRAX

fracture risk assessment tool

HR

hazard ratio

IRR

incidence rate ratio

OR

odds ratio

TAF

tenofovir alafenamide

TDF

tenofovir disoproxil fumarate

Chronic hepatitis B virus (CHB) infection affects approximately 250 million people around the world.1 The annual incidence rate of cirrhosis among those with CHB is 1% to 2%, whereas among those with cirrhosis, the annual incidence rate of hepatocellular carcinoma is 3% to 5%.2, 3 In addition to the high clinical burden with disease progression for those with CHB, there is also higher health care cost and resource utilization.4

Beyond its impact on the liver, CHB classically has been associated with several extrahepatic manifestations, including nonspecific autoantibodies, glomerulonephritis, essential mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, vasculitis, uveitis, and other autoimmune conditions.5, 6, 7, 8, 9 However, beyond extrahepatic manifestations, CHB has also been associated with many nonliver comorbidities.

Nonliver Comorbidities of CHB

Several population studies on patients with CHB have found associations to nonliver comorbidities such as osteoporosis, chronic kidney disease (CKD), end‐stage renal disease, carotid atherosclerosis, alcoholism, cardiovascular disease, diabetes, hepatitis C virus, and human immunodeficiency virus.10, 11, 12, 13 In a study based in Japan, Ishizaka et al.12 found via ultrasound visualization of carotid plaques that CHB was associated with carotid atherosclerosis. Within the US population, patients with CHB were found to have a higher Deyo‐Charlson Comorbidity Index compared with a nonmatched CHB group. Patients with CHB had a higher prevalence of alcoholism, cardiovascular disease, diabetes, hepatitis C virus, human immunodeficiency virus, and renal impairment.13 Interestingly, in a Taiwan‐based study, CHB was found to be associated with decreased risk for ischemic stroke, although this claims‐based study was unable to account for variables such as toxic habits and laboratory data.14

CHB has also been associated with a higher prevalence of malignancy, including colorectal, pancreatic, gallbladder and biliary duct, kidney, and ovarian cancer, as well as Hodgkin's lymphoma, non‐Hodgkin's lymphoma, and multiple myeloma.13, 15, 16, 17, 18, 19 There has been some debate regarding the association of CHB and lymphoma.19, 20, 21, 22 In a Danish national registry–based study, Andersen et al.21 found that compared with patients without HBV, patients with HBV did not demonstrate statistically significant increased risk for all‐type cancer (incidence rate ratio [IRR] 1.10 [95% confidence interval (CI): 0.92‐1.31]) and non‐Hodgkin's lymphoma (IRR 1.22 [95% CI: 0.42‐3.55]). However, in 2002, Kim et al.20 performed a case‐control study in Korea and found that the risk for B cell non‐Hodgkin's lymphoma was increased among patients with CHB, with an adjusted odds ratio (OR) of 3.30 (95% CI: 1.69‐6.45). Further, in a claims‐based study conducted in Taiwan comparing patients with CHB against those without, Su et al.19 found HBV to be a risk factor for both lymphoma (hazard ratio [HR] 2.07 [95% CI: 1.76‐2.43]) and non‐Hodgkin's lymphoma (HR 2.18 [95% CI: 1.80‐2.65]), as well as for multiple myeloma. Several other studies have also corroborated the finding that CHB is linked to development of lymphoma.16, 22 This link has led authors such as Wang et al.23 to raise the hypothesis that hepatitis B may be involved in malignant B cell transformation.

Beyond medical illness, CHB appears to impact mental health. Findings in a Taiwan‐based study by Chong et al.24 reported that HBV infection may be associated with the development of bipolar disorder. Interestingly, patients receiving treatment for CHB did not convey an increased risk for bipolar disorder. In a related study, Zhu et al.25 found that the higher the Child‐Pugh rating, the higher patients scored on two widely used depression and anxiety scales (Hamilton Depression Scale and Hamilton Anxiety Scale). In another China‐based study, controlled for socioeconomic factors, awareness of having hepatitis B increased odds of major depression (OR 1.84 [95% CI: 1.16‐2.90]) compared with patients without hepatitis B.26 However, these findings may be confounded by social stigma. For patients who had CHB but were unaware of their status, there was no statistically significant difference in having major depression.26 Although development of mental illness may be attributable, at least in part, to discrimination or fear of discrimination, this perception carries significant consequences for patients with CHB.27, 28, 29

Adverse Effects of Antiviral Therapy

Currently, there is no cure for CHB, so the emphasis of management is on prevention through vaccination. In fact, since 1991, when the United States adopted childhood vaccination programs, there has been a 68% decrease in the prevalence of HBV infection.4, 30, 31

However, for those with CHB, viral suppression is the goal of therapy.32, 33 Among first‐line therapies, entecavir (ETV) was introduced in 2005, followed by tenofovir disoproxil fumarate (TDF) in 2008 and tenofovir alafenamide (TAF) in 2016.13 Successful viral suppression results in normalization of alanine aminotransferase, improvement in liver histology, the delay of disease progression, and ultimately, improved mortality.33, 34

But there are concerns that the use of first‐line nucleos(t)ide analogues may increase the risk for osteoporosis and renal disease. Nevertheless, there are conflicting results as to whether these medications are the actual causative agents.35, 36 In our work comparing patients with CHB who received TDF, received ETV, or remained untreated, we did not find a statistically significant difference between groups in the incidence of osteopenia/osteoporosis.37 These findings have been corroborated by several other studies.10, 38, 39, 40, 41, 42

In the meantime, TAF was recently approved for treatment of CHB because it was found to be noninferior to TDF in terms of efficacy in two large registration clinical trials.35, 43, 44 Overall, when TAF was compared with TDF, TAF was associated with a milder decrease in both bone mineral density and estimated glomerular filtration rate (eGFR) after a follow‐up of 48 weeks.43, 44 In a follow‐up study at 96 weeks, TAF was found to also have smaller decreases in hip and spine bone mineral density compared with TDF. Given these findings, TAF and ETV have been recommended as a switch from TDF for patients with underlying bone or renal disease.45

There has been concern that preexisting disease may worsen with antiviral therapy. In a Hong Kong–based retrospective study examining patients with CHB and also CKD, Wong et al.46 found that relative to untreated patients, patients receiving ETV had no statistically significant mean annual change in eGFR, but patients taking TDF had a significant decrease (−1.21 mL/min/1.73 m² [95% CI: −0.81 to −0.22]). In a separate analysis, Wong46 found that higher baseline CKD stage translated to increased likelihood of development of worsening disease, with stage 2 disease experiencing mean change of eGFR of –0.9 mL/min/1.73 m² (95% CI: −1.19 to −0.60) and stage 4 disease demonstrating eGFR change of −5.81 mL/min/1.73 m² (95% CI: −7.54 to −4.08) relative to stage 1 disease. However, in this analysis, TDF, ETV, and untreated subjects were grouped together, making it difficult to parse out whether TDF, ETV, or no therapy impacted deterioration of kidney function at specific stages of kidney disease.46 Separately, in a study by Trinh et al.,39 among patients with moderate renal impairment, patients taking TDF had higher baseline eGFR (not statistically significant) compared with patients taking ETV, and at the end of follow‐up, eGFR was significantly lower for patients taking TDF compared with ETV (44.7 versus 50.8 mL/min/1.73 m²; P < 0.0001). Unfortunately, neither of these studies made a direct comparison with untreated patients, and as such, conclusion on deterioration beyond the natural course of kidney disease is difficult.

Similarly, with respect to bone disease, the presence of osteopenia/osteoporosis appears to worsen more rapidly relative to patients with CHB without osteopenia/osteoporosis. Few studies examine this, likely because of the logistical difficulty of studying osteopenia/osteoporosis, which requires regular bone densitometry scans. In Seto et al.'s47 96‐week follow‐up study, in multivariate logistic regression, having baseline hip (OR 0.576 [95% CI: 0.406‐0.818] or spine (OR 0.663 [95% CI: 0.440‐0.999]) osteopenia/osteoporosis was found to be a significant factor for losing more than 3% hip and spine bone mineral density at week 96. When dividing up patients by hip fracture risk assessment tool (FRAX) score quartiles, at week 96, the proportion of patients who had bone mineral density greater than 3% increased with each FRAX score quartile for TDF, but for TAF this remained relatively similar. Unfortunately, there is no direct comparison for patients with CHB who are not taking any antiviral therapy, making it difficult to determine whether the loss of bone mineral density is more rapid than natural progression.47

At this point, current recommendations advise caution when prescribing the antiviral, especially for those with risk factors for development of or worsening of renal or bone disease. However, further study is needed to better understand the impact of antivirals on bone disease.

Conclusion

Despite the availability of vaccinations for the prevention of HBV, the incidence of CHB continues to increase. Viral suppression is key to treating CHB, but there are concerns that CHB antiviral therapy has adverse effects on renal and bone disease. However, thus far, these data remain largely inconclusive, so caution is warranted with the administration of first‐line nucleos(t)ide analogues, although with the recent introduction of TAF, many of the concerns may at least be attenuated. CHB is also associated with a higher prevalence of nonliver comorbidities, so vaccination, screening, diagnosing, and treating CHB are essential components to managing CHB.48