Published online Aug 21, 2026. doi: 10.3748/wjg.119706
Revised: March 16, 2026
Accepted: April 15, 2026
Published online: August 21, 2026
Processing time: 179 Days and 21.8 Hours
Patients diagnosed with chronic hepatitis B (CHB) complicated by advanced hepatic fibrosis/compensated cirrhosis face a significant risk of disease progre
To identify the high-risk factors linked to the occurrence of LLV among CHB pa
This retrospective study enrolled 141 CHB patients with advanced hepatic fi
A total of 141 patients were included in this study, among whom 17.0% (24/141) developed LLV. Significant differences were identified between the LLV and CVR groups regarding baseline HBV DNA, HBV RNA, hepatitis B e antigen positivity, HBV DNA ≥ 5.0 Log10 IU/mL, 6.0 Log10 IU/mL, 7.0 Log10 IU/mL, HBV RNA ≥ 5.0 Log10 copies/mL, and baseline alpha-fetoprotein. Multivariate logistic regression confirmed that that HBV DNA ≥ 7.0 Log10 IU/mL (OR = 18.824, 95%CI: 1.608-220.404, P = 0.019) at baseline was associated with the occurrence of LLV.
In TDF-treated CHB with advanced hepatic fibrosis/compensated liver cirrhosis, HBV DNA ≥ 7.0 Log10 IU/mL is a high-risk factor associated with LLV.
Core Tip: Our retrospective study enrolled 141 chronic hepatitis B (CHB) patients with advanced hepatic fibrosis/com
- Citation: Zhang RL, Zhang HY, Jia YY, Wang ZY, Liu F, Chen HS, Rao HY. Risk factors for low-level viremia in tenofovir disoproxil fumarate-treated chronic hepatitis B patients with advanced hepatic fibrosis/compensated cirrhosis. World J Gastroenterol 2026; 32(31): 119706
- URL: https://www.wjgnet.com/1007-9327/full/v32/i31/119706.htm
- DOI: https://dx.doi.org/10.3748/wjg.119706
Chronic hepatitis B (CHB) is a chronic inflammatory liver disorder induced by long-term hepatitis B virus (HBV) infection[1], has emerged as a major global public health challenge, exerting profound impacts on global morbidity and mortality. The core clinical concern of CHB lies in its potential progression to severe liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC)[2]. Approximately 40% of males and 15% of females with perinatal HBV infection eventually die of cirrhosis or HCC[2,3]. Liver cirrhosis is one of the leading causes of liver-related death worldwide, with patients suffering from decompensated cirrhosis showing a 5-year survival rate as low as 14%-35%. Consequently, managing the advancement of compensated cirrhosis is essential for enhancing patient survival.
Nucleos(t)ide analogues (NAs) are recognized as first-line therapy agents for CHB due to their efficacy in inhibiting HBV replication, decelerating disease development, reversing liver fibrosis, and diminishing the risk of HCC[4,5]. At present, antiviral therapy for CHB mainly includes NAs and pegylated interferon[6]. NAs demonstrate significant antiviral efficacy and robust safety characteristics. First-line NAs are widely recommended for CHB patients, given their potent antiviral effects and high resistance barrier[7]. Despite their proven therapeutic effects, only 50%-80% of patients achieve complete virological response (CVR; i.e., serum HBV DNA level below the lower limit of detection, typically 10-20 IU/mL) after 48 weeks of antiviral therapy[4,8]. Among patients receiving antiviral therapy, nearly 10%-40% develop persistent or intermittent low-level viremia (LLV). Meanwhile, an additional 10% of patients exhibit HBV DNA levels greater than 2000 IU/mL despite treatment with first-line antiviral agents[9,10]. Moreover, with the ongoing enhan
Existing studies have confirmed that LLV can promote the progression of liver fibrosis by persistently inducing low-grade inflammatory responses, increase the risk of HBV drug-resistant mutations, and is closely related to an increased risk of HCC[10,12,13]. However, the underlying mechanism of LLV is not well understood, potentially due to various factors including cccDNA reservoir size, host immunological state, limitations of pharmacotherapy, and patient adherence to medication[14-18]. Studies on patients with uncomplicated CHB have shown that baseline high HBV DNA levels (≥ 6.0 Log10 IU/mL), high quantitative hepatitis B surface antigen (HBsAg) levels (≥ 9000 IU/mL), hepatitis B e antigen (HBeAg) positivity, low platelet (PLT) count (< 100 × 109/L), and high liver stiffness measurement (LSM ≥ 13.0 kPa) are independent risk factors for LLV[19]. At now, the majority of studies on LLV risk factors have focused on patients with uncomplicated CHB, and there is a deficiency of pertinent research about the risk factors of antiviral therapy in CHB patients complicated by advanced hepatic fibrosis/compensated cirrhosis.
This study intends to identify risk factors for LLV in this specific population by examining the serological and imaging indicators of patients with CHB complicated by advanced hepatic fibrosis/compensated cirrhosis after tenofovir disoproxil fumarate (TDF) treatment. Identifying these risk factors provides a basis for the early clinical recognition of patients at high risk of LLV, thereby helping to reduce the occurrence of LLV, postponing the advancement of liver fibrosis, mitigating the risk of HCC and overall disease progression, and ultimately enhancing the prognosis of patients through prompt modification of personalized treatment regimens (such as drug replacement or combination therapy). This work offers scientific evidence for the prognosis stratified management of CHB patients complicated by advanced hepatic fibrosis/compensated cirrhosis, filling the gap in prognostic evaluation and intervention research in this field.
This study collected clinical data of CHB patients complicated by advanced hepatic fibrosis/compensated cirrhosis who received TDF therapy from January 2015 to December 2020. Fundamental patient information, encompassing gender and age (age at the initial TDF therapy), was obtained from the hospital’s electronic medical record system. Given the retrospective design using routinely collected clinical data, the Institutional Review Board exempted this study from obtaining written informed consent from participants. A total of 141 patients who met all the following criteria were enrolled.
Inclusion criteria: (1) Baseline age of 18-60 years before antiviral therapy; (2) Positive serum HBsAg for ≥ 6 months or a definite history of HBV infection; (3) Baseline pathological diagnosis of advanced hepatic fibrosis or compensated cirrhosis; (4) No prior history of NA treatment (i.e., treatment-naive patients); presence of indications for antiviral therapy [elevated alanine aminotransferase (ALT) and/or moderate to severe histological liver injury verified by liver biopsy or non-invasive examination]; and (5) Complete clinical data, including records of virological, serological, biochemical, and imaging indicators at baseline (before treatment) and after treatment (at least one follow-up visit).
Exclusion criteria: (1) Concurrent infection with other hepatitis viruses or human immunodeficiency virus; (2) Con
This was a retrospective study based on routine clinical follow-up data. Adherence to treatment denotes the degree to which a patient follows the prescribed pharmaceutical regimen and the agreed-upon duration of treatment established with the physician. Good adherence to medicine was defined as a cumulative adherence of ≥ 90% during the study period[18]. All participants in this study received the standard dosage of TDF consistently, without any dosage alterations.
All laboratory tests were performed at Peking University People’s Hospital in strict accordance with the kit instructions.
HBV DNA levels were quantified utilizing the Cobas AmpliPrep/Cobas TaqMan 96 automated nucleic acid extraction and real-time fluorescent PCR system (Roche Diagnostics, Switzerland). The required sample volume was 650 μL, and the titer was reported in IU/mL with a detection sensitivity of 20 IU/mL. The linear quantitative range of this assay was 20-1.7 × 108 IU/mL. The Cobas 8000 e801 automatic chemiluminescence immunoanalyzer (Roche Diagnostics, Switzerland) was employed, and the electrochemiluminescence method was utilized to detect HBsAg, HBeAg and alpha-fetoprotein (AFP). HBV RNA was detected using the ABI7500 real-time fluorescence quantitative PCR instrument (Thermo Fisher Scientific, United States). Serum HBV RNA was extracted by the magnetic bead method, and the conserved region of HBV RNA was specifically detected. Reagents were purchased from Beijing Hotgen Biotech Co., Ltd. The detection threshold was set at 300 copies/mL, and the linear range was 1 × 103 to 1 × 108 copies/mL. The AU5800 automatic biochemical analyzer (Beckman Coulter, United States) was used to detect serum ALT, aspartate aminotransferase (AST), direct bilirubin, total bilirubin, and creatinine. Reagents were supporting reagents from Beckman Coulter, United States. PLT was detected using the XN-2800 automatic hematology analyzer (Sysmex Corporation, Japan) by the impedance method. All operations were carried out in strict accordance with the kit instructions.
Liver elasticity was measured using the FibroScan transient elastography scanner (Echosens, France; distributed by Shenzhen Eko Medical Devices Co., Ltd.). The detection area was the 7th to 9th intercostal spaces on the right side from the anterior axillary line to the midaxillary line. Each patient recorded at least 10 valid measurements, and the system automatically calculated the median as the final LSM value. Measurements with a success rate of less than 60% or a deviation exceeding 30% were considered invalid.
Patients enrolled in this study were assigned to two groups based on their virological response after 48 weeks of antiviral treatment: The LLV group, in which HBV DNA remained detectable but below 2000 IU/mL, and the CVR group, in which HBV DNA less than 20 IU/mL.
Categorical variables were summarized as frequencies and percentages, and between-group comparisons were per
Following the exclusion of patients who ceased treatment, 141 patients who persisted with treatment were included (Table 1). The proportion of male patients was 74.5% (105/141), with a median age of 43 years; the mean baseline HBV DNA level was 5.7 Log10 IU/mL and the median baseline ALT was 47.0 U/L. Serum HBeAg was positive in 51.1% (72/141) patients. The median LSM was 13.0 kPa. Among them, 17.0% (24/141) experienced LLV, and 83.0% (117/141) patients experienced CVR. We identified two patients with intermediate or reduced susceptibility to TDF, neither of whom showed evidence of drug resistance. One of these two cases was categorized in the LLV group, while the other was assigned to the CVR group.
| Overall (n = 141) | CVR (n = 117) | LLV (n = 24) | P value | |
| Male sex | 105 (74.5) | 86 (73.5) | 19 (79.2) | 0.563 |
| Age (year) | 43.0 | 43.0 | 44.0 | 0.626 |
| HBV DNA (Log10 IU/mL) | 5.7 | 5.4 | 7.0 | < 0.001 |
| ≥ 7 | 30 (21.3) | 14 (12.0) | 16 (66.7) | < 0.001 |
| ≥ 6 | 59 (41.8) | 41 (35.0) | 18 (75.0) | 0.001 |
| ≥ 5 | 98 (69.5) | 75 (64.1) | 23 (95.8) | 0.014 |
| HBV RNA (Log10 copies/mL) | 5.4 | 5.2 | 6.7 | < 0.001 |
| ≥ 5 | 88 (62.4) | 65 (55.6) | 23 (95.8) | 0.005 |
| HBeAg positive | 72 (51.1) | 52 (44.4) | 20 (83.3) | 0.002 |
| ALT (U/L) | 47.0 | 45.0 | 58.5 | 0.083 |
| > ULN1 | 61 (43.3) | 47 (40.2) | 14 (58.3) | 0.106 |
| AST (U/L) | 38.0 | 37.8 | 43.0 | 0.096 |
| > ULN2 | 67 (47.5) | 54 (46.2) | 13 (54.2) | 0.474 |
| TBIL (μmol/L) | 16.1 | 16.1 | 16.9 | 0.632 |
| Outside the normal range | 35 (24.8) | 32 (27.4) | 3 (12.5) | 0.137 |
| DBIL (μmol/L) | 4.6 | 4.5 | 5.2 | 0.840 |
| Outside the normal range | 26 (18.4) | 18 (20.5) | 2 (8.3) | 0.177 |
| PLT (109/L) | 126.0 | 124.0 | 127.5 | 0.522 |
| Outside the normal range | 68 (48.2) | 59 (50.4) | 9 (37.5) | 0.252 |
| LSM (kPa) | 13.0 | 13.0 | 12.9 | 0.205 |
| ≥ 7.2 | 132 (93.6) | 109 (93.2) | 23 (95.8) | 0.629 |
| ≥ 13.0 | 70 (49.6) | 58 (49.6) | 12 (50.0) | 0.970 |
| AFP (ng/mL) | 4.4 | 4.2 | 4.8 | 0.032 |
| ≥ 7.0 | 39 (27.7) | 32 (27.4) | 7 (29.2) | 0.856 |
| Creatinine (μmol/L) | 68.0 | 67.2 | 70.0 | 0.692 |
| Outside the normal range | 35 (24.8) | 31 (26.5) | 4 (16.7) | 0.315 |
| FIB-4 | 1.9 | 1.9 | 1.9 | 0.919 |
| < 1.45 | 49 (34.8) | 39 (33.3) | 10 (41.7) | 0.272 |
| 1.45-3.25 | 62 (44.0) | 55 (47.0) | 7 (29.2) | |
| ≥ 3.25 | 30 (21.3) | 23 (19.7) | 7 (29.2) | |
| eGFR [mL/(minute × 1.73 m2)] | 109.2 | 109.9 | 106.9 | 0.805 |
| Medication adherence | 7 (5.0) | 7 (6.0) | 0 (0.0) | 0.999 |
The proportions of patients with high viral load (HBV DNA ≥ 7.0 Log10 IU/mL, ≥ 6.0 Log10 IU/mL, and ≥ 5.0 Log10 IU/mL) in the LLV group were 66.7% (16/24), 75.0% (18/24) and 95.8% (23/24), respectively, all of which were markedly higher than the corresponding rates in the CVR group [12.0% (14/117), 35.0% (41/117) and 64.1% (75/117); P < 0.05; Table 1]. The mean baseline HBV DNA level was 5.4 Log10 IU/mL in the CVR group and < 20 IU/mL at week 48. The mean reduction in HBV DNA level was significantly greater in the LLV group than in the CVR group (5.2 Log10 IU/mL vs 4.5 Log10 IU/mL, P < 0.05; Table 2).
| 48 weeks | |||
| CVR | LLV | P value | |
| HBV DNA decrease (Log10 IU/mL) | 4.5 | 5.2 | < 0.050 |
| HBeAg seroconversion | 3/117 (2.6) | 1/24 (4.2) | 0.670 |
| ALT 48 weeks | 35.0 | 41.0 | 0.013 |
| Normalized ALT | 37/47 (78.7) | 8/14 (57.1) | 0.870 |
| AST 48 weeks | 30.0 | 30.0 | 0.128 |
| Normalized AST | 44/54 (81.5) | 9/13 (69.2) | 0.992 |
| HBsAg loss, n (%) | 0 (0.0) | 1 (4.2) | > 0.999 |
| LSM (kPa) | 9.3 | 9.8 | 0.256 |
| FIB-4 | 1.8 | 2.2 | 0.478 |
| eGFR [mL/(minute × 1.73 m2)] | 108.2 | 104.1 | 0.611 |
| Creatinine (μmol/L) | 69.0 | 73.2 | 0.777 |
Furthermore, the proportion of HBeAg-positive patients in the LLV group was 83.3% (20/24), which was notably higher than the 44.4% (52/117) observed in the CVR group (P = 0.002). The HBeAg seroconversion rate was numerically higher in the LLV group, but the betweengroup difference did not reach statistical significance (4.2% vs 2.6%, P = 0.670).
At baseline, the median ALT levels were 58.5 U/L in the LLV group and 45.0 U/L in the CVR group, with no significant difference (P = 0.083). At week 48, the proportion of ALT normalization was 57.1% (8/14) in the LLV group and 78.7% (37/47) in the CVR group, with no statistically significant difference between the two groups (P = 0.870). The median baseline AST values were 43.0 U/L and 37.8 U/L in the LLV and CVR groups, respectively (P = 0.096). At week 48, the AST normalization rate was 69.2% (9/13) in the LLV group and 81.5% (44/54) in the CVR group, with no significant difference (P = 0.992). Similarly, no significant differences were observed in LSM and fibrosis-4 at week 48 between groups (P = 0.256 and P = 0.478). Additionally, no significant differences were observed in median creatinine levels and eGFR between the LLV and CVR groups at week 48 (P = 0.777 and P = 0.611).
Univariate analysis results revealed that HBeAg positivity status, HBV DNA levels, HBV DNA ≥ 7.0 Log10 IU/mL, 6.0 Log10 IU/mL and 5.0 Log10 IU/mL, HBV RNA levels, HBV RNA ≥ 5.0 Log10 copies/mL and baseline AFP were all statistically significant. Multivariate analysis demonstrated that baseline HBV DNA ≥ 7.0 Log10 IU/mL (OR = 18.824, 95%CI: 1.608-220.404, P = 0.019) was independently associated with the occurrence of LLV in CHB complicated by progressive hepatic fibrosis/compensated cirrhosis.
Owing to its potent antiviral activity and high genetic barrier to resistance, TDF is widely applied as a first-line NAs in the clinical treatment of CHB. Nonetheless, certain individuals continue to be unable to attain CVR after prolonged TDF monotherapy and subsequently exhibit LLV. The persistence of LLV may increase the risk of liver fibrosis advancement, decompensated cirrhosis, and HCC, along with the likelihood of viral drug-resistant mutations, jeopardizing the long-term prognosis of CHB patients. We conducted an analysis of baseline characteristics and 48-weeks treatment-related indices in CHB patients with advanced hepatic fibrosis or compensated cirrhosis treated with long-term TDF mo
Studies have shown that despite the widespread use of first-line antiviral drugs such as entecavir (ETV) and TDF, 20.0%-37.9% of CHB patients maintain low level viral replication, further confirming that LLV is a non-negligible clinical problem during long-term tenofovir treatment[12,20-22]. This study covered 141 patients, with an incidence of LLV of 17.0%. This value is marginally lower than the incidence of LLV documented in certain prior studies, indicating that the viral suppression effect may be comparatively more advantageous in the study population or treatment context, potentially linked to patient baseline characteristics, treatment protocols, and follow-up management. Baseline characteristic analysis revealed no significant differences in demographic factors, including gender distribution and median age, between LLV and CVR groups. However, significant between-group differences were detected in viral, biochemical, and hepatic fibrosis-related indicators, suggesting that viral replication, liver inflammation, and fibrosis stage may act as critical determinants affecting treatment efficacy of TDF. A study assessing the relationship between low viral load and adherence revealed that inadequate adherence to antiviral medications is significantly associated with low viral load[18]. However, medication adherence was evaluated in this study, and no significant difference was observed between the LLV and CVR groups. These findings suggest that poor medication adherence is unlikely to be a major contributor to the observed LLV in our study population.
The examination of virological indicators constitutes a principal finding of this work. Our results revealed that the proportions of patients with high baseline viral loads (HBV DNA ≥ 5.0 Log10 IU/mL, 6.0 Log10 IU/mL, 7.0 Log10 IU/mL) in the LLV group were significantly higher than those in the CVR group. In addition, the mean baseline HBV DNA level in the LLV group (7.0 Log10 IU/mL) was much higher than that in the CVR group (5.4 Log10 IU/mL). This result is consistent with the conclusions of multiple studies[19]. In Li et al’s study cohort[19], the proportion of patients with baseline HBV DNA ≥ 6.0 Log10 IU/mL in the LLV group (63.8%) was significantly higher than that in the CVR group (45.1%). The results indicate that high baseline HBV DNA load may be an important early warning indicator for the occurrence of LLV. Our study further demonstrated that baseline HBV DNA ≥ 7.0 Log10 IU/mL was an independent risk factor of LLV, which aligns with findings reported by Kim et al[10], who also identified high baseline HBV DNA load as a key risk factor for LLV. Extensive data has established that the baseline HBV DNA level is significantly associated with treatment response in CHB patients undergoing antiviral therapy: Lower HBV DNA levels correspond to a greater likelihood of attaining early virological response and HBeAg seroconversion[19]. A study by Lok et al[23] demonstrated that a baseline HBV DNA level ≥ 108 IU/mL significantly impairs the 48-week therapeutic efficacy of NAs. In these patients, the HBV DNA detection rate was 33% after week 52 of treatment and persisted at 23% after 3 years. The findings indicate that patients with a high baseline viral load should undergo extended treatment duration to diminish the occurrence of LLV and sustain therapeutic outcomes.
Notably, HBV DNA remained detectable in the LLV group after 48 weeks of treatment (1.8 Log10 IU/mL), but the mean reduction in HBV DNA levels (5.2 Log10 IU/mL) was significantly greater than that in the CVR group (4.5 Log10 IU/mL). This suggests that LLV patients exhibit some responsiveness to TDF; however, the extent of this response fails to satisfy the CVR criteria, indicating that these patients may require an extended treatment duration or regimen modification to enhance viral suppression. Han et al[21] reported that the incidence of LLV declines with prolonged treatment duration, and that LLV occurs more frequently in patients treated for less than 36 months than in those treated for more than 36 months.
In our investigation, HBsAg loss was seen in one LLV patient. Previous research indicates that the HBsAg level reflects the transcriptional activity of cccDNA, and seroclearance of HBsAg signifies the attainment of transcriptional silence or eradication of cccDNA[24]. It is important to note that HBsAg seroclearance does not signify total viral eradication; hence, prolonged vigilant surveillance may still be required, particularly in individuals with advanced liver disease[25]. Prior research has substantiated that, in contrast to uncured patients, individuals who attained functional cure (HBsAg loss) exhibited markedly diminished intrahepatic cccDNA levels, a reduced percentage of intrahepatic HBsAg-positive hepatocytes, decreased HBV DNA integration and transcription levels, and lower intrahepatic HBV RNA levels. Moreover, as many as 23.4% of patients with a functional cure may attain the clearance of both intrahepatic cccDNA and HBsAg[26], suggesting that the elimination of HBsAg alongside residual low-level cccDNA is biologically plausible. In our investigation, this patient was categorized into the LLV group with detectable HBV DNA at week 48. The patient attained complete viral response at later follow-up intervals, specifically at weeks 60, 72, 84, 96, 120, 144, 168, 180, 192, and 204. This signifies significant and prolonged inhibition of viral replication.
HBeAg serves as a major serological indicator that reflects active HBV replication and elevated viral infectivity[20]. Chang et al[27] evaluated the antiviral effect of lamivudine and found that HBeAg-positive individuals were more prone to developing drug resistance with long-term antiviral treatment relative to HBeAg-negative patients, thus carrying a higher risk of virological breakthrough and suboptimal virological response. Kim et al[10] and Chen et al[22] and other scholars pointed out that baseline HBeAg positivity acts as an independent risk factor for low-level viral replication among CHB patients receiving long-term ETV treatment. Nonetheless, our analysis identified a significant disparity in HBeAg status solely between the LLV and CVR groups, and did not establish that baseline HBeAg status is an independent risk factor for LLV. The connection with LLV warrants more validation in prospective cohort studies.
Alterations in liver function and fibrosis markers are critical for evaluating liver damage recovery and disease progression in patients with LLV. In this study, baseline ALT and AST levels tended to be higher in the LLV group than in the CVR group, suggesting a trend toward more severe hepatic inflammation in LLV patients. However, these differences were no longer statistically significant. Nevertheless, elevated liver function indicators may still reflect impaired liver metabolic capacity. Given that TDF metabolism is intricately linked to hepatic function, compromised liver metabolism may influence medication bioavailability and antiviral activity, thereby heightening the risk of LLV. Consequently, in clinical practice, alongside virological markers, it is imperative to consider patients' baseline liver metabolic function when evaluating the risk of LLV.
Despite the absence of a statistically significant difference in the ALT normalization rate between the two groups (78.7% vs 57.1%) at 48 weeks of treatment, the ALT normalization rate in the LLV group was still lower than that in the CVR group, suggesting that LLV may delay the repair process of liver inflammation. A cross-sectional study conducted by Wang et al[28] established that incomplete viral suppression, particularly intrahepatic viral transcriptional activity, correlates with abnormal liver histopathology. Additionally, Sun et al[12] discovered that in chronic HBV-infected patients undergoing 78 weeks of ETV treatment, persistently detectable low-level HBV DNA in serum is linked to the advancement of liver fibrosis. Furthermore, Li et al[19] reported that more advanced liver fibrosis (indicated by low PLT count, cirrhosis, or even subclinical cirrhosis) was closely linked to a higher risk of LLV development. Consequently, for patients with chronic HBV infection and severe baseline liver fibrosis, clinical practice must prioritize the selection of effective antiviral treatment regimens and promptly modify the treatment strategy upon detection of LLV during monitoring; concurrently, enhancing the dynamic monitoring of liver fibrosis in patients with LLV holds significant clinical guiding value.
NAs might substantially diminish liver inflammation, fibrosis progression, and the likelihood of cirrhosis and HCC by inhibiting the reverse transcription of pregenomic RNA into HBV DNA, thus enhancing long-term clinical outcomes[29]. Current research on HBV RNA predominantly examines the general CHB population, with insufficient targeted investigations into the risk factors for LLV following antiviral treatment in CHB patients complicated by progressive hepatic fibrosis/compensated cirrhosis. This study found that the proportion of patients with HBV RNA ≥ 5.0 Log10 copies /mL in the LLV group was significantly higher than those in the CVR group, and the mean baseline HBV RNA level in the LLV group (6.7 Log10 copies /mL) was significantly higher than that in the CVR group (5.2 Log10 copies /mL), which is an important innovative finding. Notably, in HBV patients with LLV, serum HBV RNA exhibits a stronger correlation with HBsAg compared with HBV DNA. During the early to mid-stages of disease progression, HBV RNA exhibits the capacity to function as an independent predictive marker, with its predictive efficacy markedly surpassing that of conventional liver function parameters; conversely, in the mid to advanced stages of the disease, it assumes a more ancillary role in prognostic evaluation[30]. These data demonstrate that monitoring HBV RNA levels is clinically significant, as it aids in assessing the effectiveness of antiviral medication in CHB patients with LLV and in forecasting disease progression and clinical outcomes for these patients. However, it has not yet been incorporated into the global standard surveillance protocol for CHB. Moreover, low-and middle-income countries face many limitations in accessing the resources and advanced technologies needed to diagnose HBV, as these require highly skilled personnel to operate[31]. Therefore, the clinical application of HBV RNA must be tailored to regional healthcare conditions.
After univariate and multivariate logistic regression analyses, this study confirmed that baseline HBV DNA ≥ 7.0 Log10 IU/mL was an independent risk factor for LLV in CHB patients with advanced hepatic fibrosis or compensated cirrhosis who received longterm TDF monotherapy. The OR value of baseline HBV DNA ≥ 7.0 Log10 IU/mL was 18.824, indicating that patients with this level of HBV DNA may find it challenging to attain CVR with TDF monotherapy; thus, early combination therapy or transitioning to a more potent treatment regimen should be contemplated.
This study has certain limitations. This study only followed up to 48 weeks of treatment, lacking long-term follow-up, which precludes an assessment of the enduring effects of LLV and the efficacy of various treatment adjustment strategies on prognosis. Additionally, this study did not evaluate other NAs apart from TDF, precluding comparisons of potential differences among various NAs; thus, the conclusions are exclusively relevant to the patient population undergoing TDF treatment. Concerning potential drug-drug interactions, all patients in this study received TDF monotherapy, we cannot assess the influence of other concomitant drugs. We intend to rectify this deficiency in future prospective studies through the careful gathering of concomitant drug data. Recent reports indicate the presence of primary TDF resistance-associated mutations in treatment-naïve CHB patients, including mutations in the RT region of HBV polymerase, such as A194T, which may facilitate the emergence of LLV[32]. Subsequent study will include HBV resistance mutation testing to enhance the analysis of LLV risk variables. This study did not measure the patient’s cccDNA level, making it unable to directly investigate the association between cccDNA and the occurrence of LLV. Future studies may conduct pertinent study to enhance the exploration of mechanisms.
In summary, the incidence of LLV is 17.0% in patients with CHB complicated by progressive hepatic fibrosis or compensated cirrhosis receiving long-term TDF monotherapy. Baseline HBV DNA ≥ 7.0 Log10 IU/mL is an independent high-risk factor for LLV. In clinical practice, for patients with the above high-risk factor, sole reliance on TDF monotherapy should be avoided. Early combination therapy or switching to a more optimized treatment regimen is recommended, and enhanced monitoring of virological, biochemical, and liver fibrosis indicators during treatment should be performed to effectively inhibit viral replication, reduce liver injury, and improve long-term prognosis.
We are thankful to all patients who took part in this study.
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