Abstract
BACKGROUND:
Chronic hepatitis B (CHB) can lead to serious health complications. Patients with CHB often have a higher burden of extrahepatic comorbidities such as chronic kidney disease (CKD) and osteopenia/osteoporosis (OP) compared with the general population. Understanding the burden of these comorbidities in those with CHB may facilitate the development of strategies to better support patients and guide treatment decisions.
OBJECTIVE:
To evaluate demographic characteristics and prevalence of CKD, OP, and established risk factors for CKD and OP in patients with a confirmed diagnosis of CHB and assess prevalence of nucleos(t)ide analogue (NA) use in the United States.
METHODS:
This study evaluated retrospective claims data from Optum’s deidentified Clinformatics® Data Mart database between January 1, 2016, and March 31, 2025. Commercially and Medicare-insured adults (aged ≥18 years) with a confirmed diagnosis of CHB (≥1 inpatient or ≥2 outpatient diagnostic codes ≥30 days apart) who met continuous enrollment criteria and had no evidence of HIV infection were included. Descriptive analyses were carried out to estimate the prevalence of CKD, OP, related established risk factors, and NA treatment experience.
RESULTS:
A total of 19,176 patients with CHB meeting eligibility were identified; 73% were older than 50 years, and 53% were male. Twenty-seven percent received NA treatment during the observation period: tenofovir disoproxil fumarate was most commonly used (14%), followed by entecavir (12%) and tenofovir alafenamide (7%). More than one-quarter (30%) of patients had CKD, including 9% with stage 4 or 5 CKD. Among patients with CHB, renal risk factors were prevalent, with 80% and 27%, respectively, having risk factors for CKD related to a comorbidity or medication use. More than one-quarter (29%) of the patients had a diagnosis of OP. Risk factors for OP were also prevalent, with 72% and 60% of patients, respectively, having a risk factor for OP-driven comorbidities or medication use. The overall prevalence of renal- and bone-related comorbidities and risk factors was similar among patients treated with NAs.
CONCLUSIONS:
This study demonstrates the high burden of comorbidities among patients with CHB, with established risk factors for CKD and OP present among most individuals. Although NAs are the mainstay therapy for CHB, different safety considerations exist for each therapy, and this analysis found that fewer than one-third of patients had a history of NA use. These findings highlight the importance of considering the renal and bone safety profiles of CHB treatment options to help mitigate comorbidities and prevent complications.
Plain language summary
People with chronic hepatitis B often need long-term treatment. In this US study, fewer than 1 in 3 people with chronic hepatitis B received antiviral medicines to control the virus. Kidney and bone problems were common in this group, whether or not people received treatment. Treatment choices for chronic hepatitis B should consider kidney and bone health.
Implications for managed care pharmacy
Renal and bone comorbidities were prevalent among individuals with chronic hepatitis B, particularly those aged 60 years and older, in a US claims database. Most individuals had not received guideline-recommended nucleos(t)ide analogue treatment. This highlights the need for benefit design and formulary decisions that encourage guideline-recommended treatments and clinical programs that mitigate comorbidity risks to improve outcomes, especially in populations with, or at risk for, comorbid renal and bone diseases.
Hepatitis B virus (HBV) remains a major global and US public health concern: an estimated 254 million people worldwide, including approximately 1.6 million in the United States, are living with chronic hepatitis B (CHB).1,2 Progression of CHB can lead to complications including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and death.1,3 Guidelines from the Centers for Disease Control and Prevention (CDC) recommend HBV screening for all adults at least once in their lifetime,4 and the US Preventive Services Task Force recommends periodic screening for all asymptomatic, nonpregnant adolescents and adults at increased risk for HBV infection.3 Despite these guidelines, between 880,000 and 1.89 million people in the United States are living with CHB.5 An estimated one-third to one-half of these individuals are aware of their infection based on data from 2017 to 2020, suggesting that although the Viral Hepatitis National Strategic Health Plan’s 2025 awareness goal of 50% may not have been met, meaningful progress has been made, with continued gains needed to reach the 90% target by 2030.5–7
The average age for prevalent people with CHB in the United States has increased during the past 2 decades as those with CHB have aged.8,9 In 2022, the CDC reported 16,729 newly identified cases of CHB, with adults aged 40 years and older, 50 years and older, and 60 years and older accounting for 66%, 42%, and 23% of cases, respectively.10 HBV infection has been associated with elevated risk of chronic kidney disease (CKD)11,12 as well as osteoporosis and bone fractures.13,14 Among the aging population of people with CHB, renal, bone, metabolic, and cardiovascular comorbid conditions are common.8,9
Antiviral therapies such as the nucleos(t)ide analogues (NAs) entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are recommended first-line treatments for CHB.15–17 These agents were approved in the United States in 2005, 2008, and 2015, respectively.18,19 NAs have demonstrated efficacy, are generally well tolerated, and provide a barrier to genetic resistance, although the extent of this barrier varies among different NAs.15,17 NA treatment is also associated with a decreased risk of cirrhosis20 and incidence of hepatocellular carcinoma in people with CHB.21,22 As most available treatments for CHB rarely result in functional cure and typically require lifelong therapy, careful consideration and evaluation of comorbid conditions and associated risk factors remain essential.23–26
Treatment guidelines for managing CHB differ according to patient characteristics such as age, alanine aminotransferase levels, HBV DNA levels, the presence of cirrhosis, hepatitis B e antigen status, and comorbidities (Supplementary Table 1 (354.9KB, pdf) , available in online article).15,17,27,28 Although NA treatment has been related to lower risk of disease-specific CHB,12 this relationship differs by NA treatment. For patients who are at risk of renal or bone diseases, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend TAF or ETV,15,17,27,28 given that some patients with CHB treated with TDF have experienced declines in renal function26,29,30 and reductions in bone mineral density (BMD).29,31,32 A recent network meta-analysis found that TAF and ETV have less impact on renal function than does TDF, and TAF has also shown a smaller effect on BMD than TDF.33 Furthermore, switching from TDF to TAF has been associated with improvements in both renal and bone parameters.23,34–36
Given the need for long-term NA therapy, patient comorbidities, concurrent medications, and other risk factors must be carefully considered when choosing an appropriate treatment to manage the long-term outcomes associated with CHB. Although studies using claims databases and medical record reviews have observed increasing comorbidity levels and aging of the CHB population, these studies used data from 2015 and earlier,8,9 prior to the US approval of TAF and not necessarily reflective of current prevalence. Using data from a US-payer database, we report demographic characteristics and the prevalence of CKD, osteopenia/osteoporosis (OP), and risk factors for CKD and OP among people with CHB. We also examine patterns of NA use in relation to the presence of bone and renal risk factors in patients with CHB.
Methods
STUDY DESIGN AND DATA SOURCE
This was a retrospective, descriptive study using deidentified data obtained from the Optum Clinformatics® Data Mart database during the study period of January 1, 2016, through March 31, 2025 (Supplementary Figure 1 (354.9KB, pdf) ). Optum’s deidentified Clinformatics® Data Mart (Optum CDM or Optum Clinformatics®) is derived from a database of administrative health claims for members of large commercial and Medicare Advantage health plans.
INCLUSION CRITERIA
The cohort for this analysis included commercially or Medicare Advantage–insured adults aged 18 years or older in the United States who met continuous enrollment criteria and had a confirmed diagnosis of CHB. CHB index date was defined as the first observed CHB diagnosis in the study period, and continuous enrollment was required for at least 12 months prior to an individual’s index date. No follow-up or minimum enrollment was required after the index date. Individuals with CHB were identified using a claims-based algorithm, defined as at least 1 inpatient or 2 outpatient International Classification of Diseases, Ninth and Tenth Revision (ICD-9/10) codes for HBV at least 30 days apart, similar to prior analyses.37–39 Demographic characteristics were assessed at the time of the first CHB diagnosis within the study period. Patients with any evidence of HIV infection were excluded from the analysis because both TDF and TAF are common components in HIV therapies.
BONE AND RENAL IDENTIFICATION
Subgroup analyses for this study were performed for patients with CHB and comorbid CKD or OP, or with CHB and established risk factors for these conditions. Patients were identified as having the condition if they had 1 inpatient or 1 outpatient ICD-9/10 code for that condition or risk factor. Renal and bone risk factors were identified based on a previous study (Supplementary Table 2 (354.9KB, pdf) ); codes for comorbidity-related renal and bone risk factors included age, comorbidities, medication use, renal function, and body mass index (Supplementary Table 3 (354.9KB, pdf) for comorbidities and Supplementary Table 4 (354.9KB, pdf) for medication-related risk factors).40 Diagnosis of patients with CKD, OP, or related risk factors could occur at any time prior to or after their first claim for HBV infection. Additional subgroup analyses included patients with CHB who received treatment with TDF, TAF, and/or ETV at any time after CHB diagnosis. Prescribed NA treatment was identified using at least 1 national drug code for each of these treatments. Patients could contribute to multiple groups if they had evidence of multiple NAs during the study period.
DATA ANALYSIS
Descriptive analyses were carried out to estimate the prevalence of CKD and OP, as well as the prevalence of established risk factors for these conditions, among the cohort of patients with CHB. Demographic and clinical characteristics were presented as counts and proportions. The numbers and proportions of patients in the primary cohort with CHB, as well as among each of the subgroups, who were exposed to TDF, TAF, and/or ETV during the study period were summarized. A subgroup analysis capturing TDF, TAF, or ETV use during the last year of data collection (2024-2025) was also performed to provide updated estimates of NA treatment use. Missing data were not imputed.
Results
PATIENT DEMOGRAPHICS
In total, 19,176 patients with CHB met eligibility criteria, of whom a majority were male (53%) (Table 1; Supplementary Figure 2 (354.9KB, pdf) ). Most patients were aged 50 years or older (73%), and 47% were older than 64 years. Overall, 48% of patients were commercially insured and 52% were insured by Medicare; among patients older than 64 years, 94% were insured by Medicare.
TABLE 1.
Characteristics of Patients With CHB Overall and of Those With Concurrent CKD or OP
| CHB | CHB and CKD | CHB and OP | |
|---|---|---|---|
| N = 19,176 | n = 5,813 | n = 5,601 | |
| Age, years a | |||
| <25 | 108 (1) | <5 (<1) | 0 (0) |
| 25-29 | 257 (1) | <5 (<1) | <5 (<1) |
| 30-39 | 1,912 (10) | 59 (1) | 37 (1) |
| 40-49 | 2,928 (15) | 248 (4) | 174 (3) |
| 50-59 | 3,298 (17) | 619 (11) | 621 (11) |
| 60-64 | 1,595 (8) | 521 (9) | 510 (9) |
| >64 | 9,078 (47) | 4,360 (75) | 4,256 (76) |
| Sex a | |||
| Female | 9,030 (47) | 2,469 (42) | 4,091 (73) |
| Male | 10,142 (53) | 3,342 (57) | 1,510 (27) |
| Unknownb | 4 (<1) | 2 (<1) | 0 (0) |
| Race | |||
| Asian | 8,804 (46) | 1,846 (32) | 2,468 (44) |
| Black | 2,253 (12) | 931 (16) | 546 (10) |
| Hispanic | 1,331 (7) | 591 (10) | 448 (8) |
| White | 5,276 (28) | 2,039 (35) | 1,777 (32) |
| Unknownb | 1,512 (8) | 406 (7) | 362 (6) |
| Insurance type c | |||
| Commercial | 9,259 (48) | 1,010 (17) | 1,104 (20) |
| Medicare | 9,918 (52) | 4,805 (83) | 4,500 (80) |
| Insurance typec (age >64 years) | |||
| Commercial | 523 (6) | 163 (4) | 170 (4) |
| Medicare | 8,557 (94) | 4,197 (96) | 4,088 (96) |
| CKD | |||
| Any CKD | 5,813 (30) | 5,813 (100) | — |
| CKD, stage 1 | 454 (2) | 454 (8) | — |
| CKD, stage 2 | 1,724 (9) | 1,724 (30) | — |
| CKD, stage 3 | 2,457 (13) | 2,457 (42) | — |
| CKD, stage 4 | 1,130 (6) | 1,130 (19) | — |
| CKD, stage 5 (end-stage kidney disease) | 573 (3) | 573 (10) | — |
| Unspecified CKD | 2,991 (16) | 2,991 (51) | — |
| OP d | |||
| OP | 5,601 (29) | — | 5,601 (100) |
| Osteopenia | 3,999 (21) | — | 3,999 (71) |
| Osteoporosis | 3,452 (18) | — | 3,452 (62) |
| Treated for OP | 1,209 (6) | — | 1,209 (22) |
Values in table reflect n (%). Patients may appear in more than 1 category.
Age and sex were assessed at the time of initial HBV diagnosis.
Sex or race not recorded or not provided.
Insurance groups are not mutually exclusive.
Osteopenia/osteoporosis includes any diagnosis and/or treatment for these conditions.
CHB = chronic hepatitis B; CKD = chronic kidney disease; HBV = hepatitis B virus; OP = osteopenia/osteoporosis.
More than one-quarter (30%) of patients with CHB also had CKD. Among those with CKD, the majority were diagnosed with stage 2 (30%) or stage 3 (42%), while 19% had stage 4, and 10% had end-stage renal disease (stage 5). Compared with the overall CHB population, patients with both CHB and CKD tended to be older; 75% were older than 64 years. The majority were male (57%), most were either White (35%) or Asian (32%), and 83% were covered by Medicare.
Twenty-nine percent of patients with CHB had a diagnosis of, or received treatment for, OP. Patients with both CHB and OP were generally older than the overall CHB population, with 76% older than 64 years. In contrast to the overall CHB cohort, the majority of patients with OP were female (73%). Most patients with CHB and OP were Asian (44%) or White (32%), and 80% were insured by Medicare.
NA TREATMENT AMONG PATIENTS WITH CHB OVERALL AND WITH COMORBID CKD, OP, OR RELATED RISK FACTORS
Twenty-seven percent of patients with CHB received NA treatment (TDF, TAF, or ETV) at any time during the observation period (Table 2). Throughout the study period, of 19,176 patients, 14%, 12%, and 7% received TDF, ETV, and TAF, respectively. Compared with the overall population, patients with commercial insurance had a higher prevalence of treatment with NAs, whereas those insured by Medicare Advantage had lower prevalence of treatment.
TABLE 2.
Treatment Among Patients With CHB Overall and With Comorbid CKD, OP, or Related Risk Factors, Overall and for Those Insured With Commercial Insurance and Medicare Advantage
| CHB | CHB and CKD | CHB and OP | CHB and risk factor for CKD | CHB and risk factor for OP | CHB and any renal condition, bone disorder, or risk factor for either condition | |
|---|---|---|---|---|---|---|
| N = 19,176 | n = 5,813 | n = 5,601 | n = 17,937 | n = 16,752 | n = 18,378 | |
| Any TDF, TAF, ETV | 5,238 (27) | 1,487 (26) | 1,494 (27) | 4,885 (27) | 4,490 (27) | 5,009 (27) |
| Any TDF | 2,750 (14) | 632 (11) | 687 (12) | 2,511 (14) | 2,251 (13) | 2,601 (14) |
| Any TAF | 1,380 (7) | 477 (8) | 473 (8) | 1,315 (7) | 1,219 (7) | 1,343 (7) |
| Any ETV | 2,289 (12) | 766 (13) | 735 (13) | 2,175 (12) | 2,044 (12) | 2,205 (12) |
| Treatment in the final 12 months of the study period (03/2024-03/2025) | ||||||
| Patients with ≥1 day of eligibility | n = 8,854 | n = 3,053 | n = 3,159 | n = 8,528 | n = 8,195 | n = 8,672 |
| TDF | 575 (6) | 136 (4) | 144 (5) | 544 (6) | 505 (6) | 560 (6) |
| TAF | 392 (4) | 174 (6) | 173 (5) | 381 (4) | 368 (4) | 386 (4) |
| ETV | 675 (8) | 247 (8) | 255 (8) | 648 (8) | 620 (8) | 654 (8) |
| Patients with commercial insurance | n = 9,251 | n = 1,005 | n = 1,101 | n = 8,015 | n = 6,836 | n = 8,455 |
| Any TDF, TAF, ETV | 3,022 (33) | 395 (39) | 428 (39) | 2,672 (33) | 2,277 (33) | 2,795 (33) |
| Any TDF | 1,806 (20) | 209 (21) | 245 (22) | 1,569 (20) | 1,308 (19) | 1,658 (20) |
| Any TAF | 733 (8) | 120 (12) | 146 (13) | 668 (8) | 573 (8) | 696 (8) |
| Any ETV | 1,207 (13) | 193 (19) | 191 (17) | 1,094 (14) | 963 (14) | 1,124 (13) |
| Patients with Medicare Advantage | N = 9,918 | N = 4,805 | N = 4,500 | N = 9,915 | N = 9,909 | N = 9,916 |
| Any TDF, TAF, ETV | 2,216 (22) | 1,092 (23) | 1,066 (24) | 2,213 (22) | 2,213 (22) | 2,214 (22) |
| Any TDF | 944 (10) | 423 (9) | 442 (10) | 942 (10) | 943 (10) | 943 (10) |
| Any TAF | 647 (7) | 357 (7) | 327 (7) | 647 (7) | 646 (7) | 647 (7) |
| Any ETV | 1,082 (11) | 573 (12) | 544 (12) | 1,081 (11) | 1,081 (11) | 1,081 (11) |
Values in table reflect n (%). Patients may appear in more than 1 category.
CHB = chronic hepatitis B; CKD = chronic kidney disease; ETV = entecavir; OP = osteopenia/osteoporosis; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
Consistent with the overall population, only 26% of patients with both CHB and CKD received NA treatment during the study period. Among the 5,813 patients with CHB and CKD, 13%, 11%, and 8% received ETV, TDF, and TAF, respectively. A total of 17,937 patients had CHB and risk factors for CKD, such as hypertension, vitamin D deficiency, and chronic nonsteroidal anti-inflammatory drug (NSAID) use. Among these patients, TDF treatment was the most frequently prescribed (14%), followed by ETV (12%) and TAF (7%).
Comparable to the overall CHB population, 27% of patients with CHB and OP received NA treatment during the study period. Of the 5,601 patients with CHB and OP, 13% and 12% were treated with ETV and TDF, respectively, whereas 8% received TAF. A total of 16,752 patients were identified as having CHB and OP risk factors, such as statin use, diabetes mellitus, and hypogonadism. Throughout the study period, 13% of patients with CHB and a risk factor for OP were treated with TDF, whereas 12% received ETV and 7% received TAF.
Among patients with CHB who were treated with NAs in the final 12 months of the study period, ETV was the most commonly used (8%), followed by TDF (6%) and TAF (4%). Among patients with CHB overall, as well as in those with CHB and CKD or OP, or CHB and risk factors for either CKD or OP, 8% of patients received ETV, whereas 4% to 6% were treated with TDF or TAF.
RENAL AND BONE RISK FACTOR SUMMARY
Many patients with CHB had renal and bone risk factors related to comorbidities or concomitant medications (Figure 1). When considering NA treatment at any point during the study period, patients who received TDF had a lower prevalence of risk factors than the overall CHB population. Patients who were treated with TAF or ETV had a similar prevalence of risk factors compared with the overall CHB cohort. The overall prevalence of risk factors among these treatment groups was similar in patients who received treatment during the final 12 months of the study (March 2024 to March 2025). The exception to this was medication-related renal risk factors, which were most prevalent among patients who received TAF and least prevalent among patients treated with ETV.
FIGURE 1.
Renal and Bone Risk Factor Prevalence Among Patients With CHB
Data for patients with CHB overall were not available for the 03/2024-03/2025 subgroup.
CHB = chronic hepatitis B; ETV = entecavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
RENAL RISK FACTORS IN THE OVERALL COHORT OF PATIENTS WITH CHB AND AMONG THOSE TREATED WITH NAS
Comorbidity- or medication-related renal risk factors were prevalent among patients with CHB, with 17,943 (94%) patients experiencing a renal risk factor or receiving a diagnosis of a renal disease (Table 3). The most prevalent comorbidity-related risk factors were hypertension (65%), vitamin D deficiency (45%), acute kidney injury (20%), tobacco abuse (15%), and alcohol abuse (10%). The only medication-related renal risk factor with greater than 3% prevalence was chronic NSAID use (27%).
TABLE 3.
Renal Risk Factors Among Patients With CHB Overall and Among Those Treated With NAs
| Treatment in the final 12 months of the study period (03/2024-03/2025) | |||||||
|---|---|---|---|---|---|---|---|
| Overall | TDF at any time | TAF at any time | ETV at any time | TDF | TAF | ETV | |
| N = 19,176 | n = 2,750 | n = 1,380 | n = 2,289 | n = 575 | n = 392 | n = 675 | |
| Age-related renal risk factors | |||||||
| Age >40 y | 16,658 (87) | 2,271 (83) | 1,219 (88) | 2,062 (90) | 490 (85) | 365 (93) | 615 (91) |
| Comorbidity-related renal risk factors | |||||||
| Acute kidney injury | 3,885 (20) | 351 (13) | 282 (20) | 570 (25) | 57 (10) | 88 (22) | 190 (28) |
| Acute tubular necrosis | 872 (5) | 77 (3) | 51 (4) | 141 (6) | 11 (2) | 14 (4) | 41 (6) |
| Alcohol abuse | 1,852 (10) | 175 (6) | 111 (8) | 214 (9) | 47 (8) | 36 (9) | 67 (10) |
| CKD, stage 1 | 454 (2) | 52 (2) | 32 (2) | 50 (2) | 14 (2) | 10 (3) | 18 (3) |
| Hydronephrosis | 981 (5) | 118 (4) | 70 (5) | 154 (7) | 24 (4) | 26 (7) | 52 (8) |
| Hypertension | 12,557 (65) | 1,525 (55) | 892 (65) | 1,556 (68) | 357 (62) | 301 (77) | 500 (74) |
| Opioid abuse | 1,028 (5) | 69 (3) | 50 (4) | 78 (3) | 22 (4) | 18 (5) | 27 (4) |
| Pyelonephritis | 608 (3) | 58 (2) | 38 (3) | 82 (4) | 11 (2) | 14 (4) | 28 (4) |
| Tobacco abuse | 2,954 (15) | 340 (12) | 180 (13) | 317 (14) | 78 (14) | 71 (18) | 98 (15) |
| Vitamin D deficiency | 8,558 (45) | 1,086 (39) | 689 (50) | 982 (43) | 258 (45) | 220 (56) | 348 (52) |
| Any comorbidity-related renal risk factora | 15,275 (80) | 1,986 (72) | 1,110 (80) | 1,845 (81) | 445 (77) | 343 (88) | 590 (87) |
| Medication-related renal risk factors | |||||||
| Chronic NSAID use | 5,106 (27) | 701 (25) | 416 (30) | 602 (26) | 181 (31) | 156 (40) | 200 (30) |
| Any medication-related renal risk factora | 5,154 (27) | 703 (26) | 416 (30) | 607 (27) | 182 (32) | 156 (40) | 203 (30) |
| Renal summarya | |||||||
| Any risk factor or diagnosis | 17,943 (94) | 2,511 (91) | 1,315 (95) | 2,176 (95) | 544 (95) | 381 (97) | 648 (96) |
Values in table reflect n (%). Patients may appear in more than 1 category.
Represents the full dataset, including risk factors with less than 3% prevalence.
CHB = chronic hepatitis B; CKD = chronic kidney disease; ETV = entecavir; NA = nucleos(t)ide analogue; NSAID = nonsteroidal anti-inflammatory drug; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
In total, 15,275 (80%) patients with CHB had a comorbidity-related renal risk factor. Among patients treated with ETV, TAF, or TDF, the prevalence of these risk factors was 81%, 80%, and 72%, respectively. Almost all comorbidity-related renal risk factors were most prevalent among patients receiving ETV; one exception was vitamin D deficiency, which was more common among those treated with TAF (50%) compared with ETV (43%) or TDF (39%). Among patients treated with ETV, TAF, or TDF, the prevalence of medication-related renal risk factors was 27%, 30%, and 26%, respectively. Among patients who received treatment in the final 12 months of the study period, comorbidity-related renal risk factors were more prevalent in patients treated with ETV or TAF than in those who received TDF, and medication-related renal risk factors were most prevalent in patients treated with TAF.
BONE RISK FACTORS AMONG PATIENTS WITH CHB OVERALL AND AMONG THOSE TREATED WITH NAS
Of the 19,176 patients with CHB, 16,808 (88%) had a bone risk factor or diagnosis (Table 4). The most common comorbidity-related bone risk factors were diabetes mellitus (36%), hypogonadism (33%), hypothyroidism (23%), fracture (21%), tobacco abuse (15%), and alcohol abuse (10%). The most common medication-related bone risk factors were use of statins (40%), opioids (28%), corticosteroids (23%), and antiepileptics (19%).
TABLE 4.
Bone Risk Factors Among Patients With CHB Overall and Among Those Treated With NAs
| Treatment in the final 12 months of the study period (03/2024–03/2025) | |||||||
|---|---|---|---|---|---|---|---|
| Overall | TDF at any time | TAF at any time | ETV at any time | TDF | TAF | ETV | |
| N = 19,176 | n = 2,750 | n = 1,380 | n = 2,289 | n = 575 | n = 392 | n = 675 | |
| Age-related bone risk factors | |||||||
| Age >50 years | 13,638 (71) | 1,649 (60) | 933 (68) | 1,651 (72) | 369 (64) | 307 (78) | 505 (75) |
| Comorbidity-related bone risk factors | |||||||
| Alcohol abuse | 1,852 (10) | 175 (6) | 111 (8) | 214 (9) | 47 (8) | 36 (9) | 67 (10) |
| Ankylosing spondylitis | 1,271 (7) | 110 (4) | 94 (7) | 142 (6) | 30 (5) | 29 (7) | 47 (7) |
| Diabetes mellitus | 6,928 (36) | 809 (29) | 511 (37) | 860 (38) | 194 (34) | 176 (45) | 279 (41) |
| Fracture | 3,989 (21) | 398 (14) | 258 (19) | 441 (19) | 92 (16) | 83 (21) | 161 (24) |
| Hemochromatosis | 285 (1) | 40 (1) | 32 (2) | 52 (2) | 9 (2) | 10 (3) | 18 (3) |
| Hyperparathyroidism | 1,158 (6) | 79 (3) | 79 (6) | 147 (6) | 11 (2) | 31 (8) | 57 (8) |
| Hyperthyroidism | 506 (3) | 61 (2) | 41 (3) | 63 (3) | 14 (2) | 15 (4) | 15 (2) |
| Hypogonadism | 6,327 (33) | 709 (26) | 484 (35) | 866 (38) | 179 (31) | 171 (44) | 293 (43) |
| Hypothyroidism | 4,382 (23) | 451 (16) | 276 (20) | 486 (21) | 115 (20) | 82 (21) | 168 (25) |
| Monoclonal gammopathy of uncertain significance | 439 (2) | 32 (1) | 43 (3) | 82 (4) | 10 (2) | 18 (5) | 30 (4) |
| Multiple myeloma | 242 (1) | 29 (1) | 23 (2) | 65 (3) | 8 (1) | <5 (1) | 27 (4) |
| Psoriasis | 652 (3) | 78 (3) | 51 (4) | 76 (3) | 22 (4) | 24 (6) | 24 (4) |
| Rheumatoid arthritis | 1,545 (8) | 130 (5) | 106 (8) | 157 (7) | 27 (5) | 42 (11) | 57 (8) |
| Tobacco abuse | 2,954 (15) | 340 (12) | 180 (13) | 317 (14) | 78 (14) | 71 (18) | 98 (15) |
| Ulcerative colitis | 438 (2) | 50 (2) | 39 (3) | 65 (3) | 16 (3) | 12 (3) | 14 (2) |
| Any comorbidity-related bone risk factora | 13,841 (72) | 1,716 (62) | 1,002 (73) | 1,711 (75) | 394 (69) | 322 (82) | 552 (82) |
| Medication-related bone risk factors | |||||||
| Antiepileptics | 3,691 (19) | 380 (14) | 243 (18) | 454 (20) | 93 (16) | 99 (25) | 153 (23) |
| Corticosteroids | 4,494 (23) | 547 (20) | 379 (27) | 728 (32) | 155 (27) | 137 (35) | 260 (39) |
| Statins | 7,608 (40) | 800 (29) | 511 (37) | 964 (42) | 213 (37) | 190 (48) | 333 (49) |
| Opioids | 5,312 (28) | 580 (21) | 365 (26) | 717 (31) | 139 (24) | 113 (29) | 227 (34) |
| H2 blockers | 1,337 (7) | 157 (6) | 124 (9) | 185 (8) | 36 (6) | 51 (13) | 75 (11) |
| Any medication-related bone risk factora | 11,499 (60) | 1,427 (52) | 865 (63) | 1,522 (66) | 355 (62) | 286 (73) | 478 (71) |
| Bone summarya | |||||||
| Any bone risk factor or diagnosis | 16,808 (88) | 2,269 (83) | 1,233 (89) | 2,053 (90) | 505 (88) | 373 (95) | 623 (92) |
Values in table reflect n (%). Patients may appear in more than 1 category.
Represents the full dataset, including risk factors with less than 3% prevalence.
CHB = chronic hepatitis B; ETV = entecavir; H2 = histamine H2 receptor; NA = nucleos(t)ide analogue; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
In total, 13,841 (72%) patients with CHB had a comorbidity-related bone risk factor. Among patients treated with ETV, TAF, or TDF, the prevalence of comorbidity-related bone risk factors was 75%, 73%, and 62%. The prevalence of medication-related bone risk factors was 66% among patients treated with ETV, 63% among those treated with TAF, and 52% among those treated with TDF. Among the subset of patients who received treatment during the final 12 months of the study period (March 2024 to March 2025), most comorbidity-related bone risk factors and all medication-related bone risk factors were less prevalent among patients who received TDF compared with those treated with ETV or TAF.
Discussion
This analysis characterizes the prevalence of renal and bone comorbidities, along with related risk factors, among US patients diagnosed with CHB. In this real-world dataset, more than one-quarter of patients with CHB had comorbid CKD or OP. Most of these patients also had comorbidity- or medication-related risk factors for CKD or bone disease, including hypertension, diabetes, vitamin D deficiency, opioid use, and statin use. These findings are intended to inform population health decision-makers for potential disease education programs to optimize treatment of CHB.
The majority (56%) of patients with CHB were aged 60 years or older, and those with CHB and comorbid CKD or OP were generally older than the overall CHB population. This finding aligns with recent studies from the United States, Middle East, Europe, and China, which highlight an aging population with CHB and an increasing burden of comorbidities.9,38–40 Although this analysis focused on renal- and bone-related conditions, other studies have shown that the prevalence of comorbidities such as HCC and other cancers, metabolic disease, and cardiovascular disease also increased over time in patients with CHB.9,41–43
Current guidelines from AASLD and EASL recommend the use of TAF or ETV over TDF for patients with renal or bone disease or risk factors, as well as for those older than 60 years,15,17,27,28 because of the known association of TDF with declines in renal function and reductions in BMD.26,29–32 In meta-analyses, TDF therapy resulted in a decreased estimated glomerular filtration rate compared with ETV or TAF, whereas ETV treatment had less effect on serum creatinine levels than TDF or TAF.33,44,45 In clinical studies, patients who switched to TAF after previously receiving TDF for up to 3 years experienced improvements in estimated glomerular filtration rate by the Cockcroft-Gault equation and increased BMD.23,46
Despite guideline recommendations, TDF was the most commonly prescribed NA therapy in the overall cohort, with 2,750 (14%) patients receiving TDF, and TAF was the least common, with only 1,380 (7%) patients treated with TAF. This could be due, in part, to TAF only receiving approval in the United States in 2015,18 or to insurance policies that require failed treatment with ETV or TDF prior to prescription of TAF, thereby limiting its use.47–49,50 The prevalence of comorbidity- and medication-related risk factors for CKD and OP was lower among patients treated with TDF than among those treated with TAF or ETV. These risk factors were also generally less common among patients treated with TDF than in the overall CHB population. This suggests that some US clinicians may be preferentially prescribing TAF or ETV for patients at higher risk for CKD or OP, in accordance with current clinical guidelines.
Although alcohol and tobacco abuse were not among the most prevalent comorbidity-related contributors to renal and bone risk factors in this study, they stand out as modifiable, unlike many of the other identified risks. A recent study found that 34% of age-standardized hepatitis B deaths were attributable to tobacco use, alcohol use, and high body mass index.51 In 2019 alone, tobacco use was linked to more than 38,000 hepatitis B–related deaths, whereas alcohol use accounted for more than 125,000. Although selecting an appropriate NA treatment based on a patient’s comorbidities and risk factors remains essential, it is also important for clinicians to address modifiable lifestyle factors in patients with CHB to improve long-term outcomes. Risk factors used in this study were based on prior research,40 and it is important to consider that not all risk factors are equally associated with risk of CKD or OP (eg, some research has found that statin use is associated with decreased rather than increased risk of OP).52
The World Health Organization (WHO) has set a goal to eliminate viral hepatitis as a public health threat by 2030.53 Although NAs are the preferred treatment for CHB, less than one-third of patients in this study had a history of NA treatment. This low treatment rate may be partly due to the restrictive eligibility criteria outlined in current AASLD guidelines, which render as few as 7% of US patients with CHB eligible for treatment.54 In 2024, the WHO published updated recommendations aimed at expanding access and reducing barriers that prevent more widespread use of NAs.55 These revised guidelines introduced more flexible treatment eligibility criteria, including a recommendation to consider coinfections, comorbidities, extrahepatic manifestations, and family history of HCC or cirrhosis as indications for NA therapy.
LIMITATIONS
This study was based on administrative claims data. Use of health care claims data is subject to coding errors and may lead to underreporting or overreporting of comorbidities. Furthermore, the data provide limited clinical information to confirm diagnoses, introducing the risk of misclassification and information bias. To mitigate this, at least 1 inpatient or 2 or more outpatient claims at least 30 days apart for CHB were required. This method of identifying individuals with CHB in claims data is widely used in administrative claims data and has been previously validated. Although alternative spacing intervals between claims are possible, a separation of at least 30 days was selected in order to retain sample size but reduce the possibility of misclassification, duplicate billing, or the use of a code by a provider for a differential diagnosis when ordering screening tests. Additionally, the use of a 12-month look-back period prior to an individual’s index was used because it allowed for adequate capture of baseline conditions and characteristics while minimizing misclassification. Requiring continuous enrollment for more than this time period may have resulted in a significant attrition of the study cohort. For the outcomes of CKD and OP, to prevent underreporting, only 1 inpatient or 1 outpatient claim was required, which may have resulted in overreporting for these conditions. Comorbidity and medication-related risk factors for CKD and OP were based on a prior study within a healthy population,37 which may not reflect the CHB population risk adequately. This study included only commercially and Medicare-insured individuals, which may limit the generalizability of the findings to Medicaid-insured and uninsured populations. Finally, patients could have received treatment at any point between January 1, 2016, and March 31, 2025, limiting our ability to assess temporal associations between NA treatment and comorbidities.
Conclusions
This analysis of a US claims dataset demonstrated the high burden of comorbidities among patients with CHB. Most patients exhibited 1 or more risk factors for CKD or bone disease, including hypertension, diabetes, vitamin D deficiency, opioid use, and/or statin use. A high proportion of patients treated with NA therapy also had renal- and bone-related comorbidities or risk factors. When selecting a treatment for CHB, clinicians should consider patients’ comorbid conditions. Optimizing NA treatment with attention to renal and bone risk factors may help minimize complications and improve short- and long-term outcomes. These findings highlight the importance of considering comorbidity risks for patients with CHB when designing benefits and making formulary decisions within managed care settings.
Disclosures
Alice E. Stead, Mary J. Christoph, Amanda W. Singer, Wenyi Wang, Alice Hsiao, Sunil Majethia, Sean Byrne, Woodie Zachry are employees of Gilead Sciences, Inc., and may own stock or stock options in Gilead Sciences, Inc.
Acknowledgments
This study was funded by Gilead Sciences, Inc. Medical writing and editorial support were provided by Stephanie Biedka, PhD, of Red Nucleus and were funded by Gilead Sciences, Inc.
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