The purpose of treatment for chronic hepatitis B (CHB) is to repress the replication of hepatitis B virus (HBV) and prevent liver disease progression. Patients with CHB require long-term oral nucleotide analogs (NAs) to obtain remission and/or serologic response. However, the 5-year resistance rates of lamivudine (LAM) and adefovir dipivoxil (ADV) are 66% and 29%, respectively. For telbivudine (LDT), 4-year resistance rate is 10%. In patients with CHB, liver failure and hepatocellular carcinoma readily occur after virologic breakthrough. Increasing evidence shows that ADV-based combined antiviral therapy has become a good option for treatment of CHB. In recent year, more and more patients have received such combined treatment. These oral antiviral NAs are metabolized and excreted by kidneys. The long-term NA combination therapy exhibits good therapeutic effects and at the same time, useful clinical experience has been accumulated, but there still are some problems. Previous studies have shown that ADV alone can decrease estimated glomerular filtration rate (eGFR), but LDT alone can increase eGFR in the patients with CHB.[4,5,8] However, few studies have addressed the impact of ADV-based combination therapy on the renal function of patients with CHB who received ADV-based combination therapy after HBV resistance or no serologic response. This study evaluated the effects of ADV combined with other antiviral NAs on renal function of patients with CHB, and analyzed the risk factors for more than 20% reduction of baseline eGFR.
2 Materials and methods
All study methods were approved by the Ethics Committee of the Second Affiliated Hospital of Dalian Medical University. All the subjects enrolled into the study gave written informed consents to participate.
From February 2007 to October 2015, a total of 223 patients with CHB were diagnosed and treated in liver clinic of our hospital. The inclusion criteria were consistent with diagnostic criteria from the Guidelines of Prevention and Treatment for Chronic Hepatitis B ; baseline eGFR > 60 mL/min/1.73 m2; baseline serum creatinine (SCr) < 130 μmol/L; and follow-up time of more than 104 weeks. The exclusion criteria were a history of ADV usage; abnormal urine routine results; having edema, pleural effusion, celiac effusion, or severe cardiac insufficiency; and having tumor, hypertension, liver cirrhosis, diabetes, or kidney disease. Finally, 164 patients consistent with inclusion and exclusion criteria were enrolled in this study. The data of 164 patients with CHB were retrospectively analyzed. Of the 164 patients, 117 were man and 47 women with a mean age of 34 ± 6 years.
2.2 Treatment protocols
Combination therapy of ADV (10 mg/d) and LAM (100 mg/d) was given to the 68 patients that had showed resistance or poor serologic response during LAM monotherapy. Combination therapy of ADV (10 mg/d) and LDT (600 mg/d) was given to the 54 patients that had showed resistance or poor serologic response during LDT monotherapy. In addition, combination therapy of ADV (10 mg/d) and entecavir (ETV; 0.5 mg/d) was given to the 42 patients that had showed resistance or poor serologic response during LAM and ETV sequential monotherapies.
The SCr was determined using MODULP800 automatic biochemistry analyzer (Roche, Manheim, Germany) 52 and 104 weeks after combination therapy, respectively. And then eGFR was calculated according to the formula of modified diet in renal disease: eGFR = 186 × SCr−1.154 × age (year) −0.203 × (female × 0.742) × (black people 1.212). eGFR was graded as normal: eGFR ≥ 90 mL/min/1.73 m2; mild renal impairment: 60 ≤ eGFR < 90 mL/min/1.73 m2; and moderate renal impairment 30 ≤ eGFR < 60 mL/min/1.73 m2.
2.4 Statistical analysis
Statistical treatment was performed using SPSS 20.0 software. Measurement data were expressed as median (interquartile range). Wilcoxon rank sum test was used to compare the data between pre- and posttreatment within each group. Kruskal–Wallish rank sum test was used in the comparison among multiple groups. In univariate and multivariate analyses, logistic formula was used to calculate odds ratio of each factor for eGFR. Chi-squared test or continuity correction test was used in the analysis of enumeration data. Statistical significance was established at P < .05.
3.1 General data in the 3 groups
There were no statistical differences in age, sex, HBV DNA, alanine transaminase (ALT), SCr, eGFR, and HBeAg positive rate among the 3 groups (all P > .05, Table 1).
3.2 SCr in the 3 groups 52 and 104 weeks after combination therapy
After 52- and 104-week combination therapy, compared with the baseline level, SCr levels were significantly increased in the ETV + ADV group (67 μmol/L vs 69 μmol/L, P = .053; and 67 μmol/L vs 73 μmol/L, P = .012) and LAM + ADV group (68 μmol/L vs 72 μmol/L, P = .041; and 68 μmol/L vs 79 μmol/L, P = .008, but it was significantly decreased in the LDT + ADV group (69 μmol/L vs 67 μmol/L, P = .062; and 69 μmol/L vs 64 μmol/L, P = .023) (Fig. 1).
3.3 eGFR in the 3 groups 52 and 104 weeks after combination therapy
After 52- and 104-week combination therapy, compared with the baseline level, eGFR was significantly decreased in the ETV + ADV group (107.8 mL/min/1.73 m2 vs 103.6 mL/min/1.73 m2, P = .028; and 107.8 mL/min/1.73 m2 vs 96.1 mL/min/1.73 m2, P = .004) and LAM + ADV group (105.4 mL/min/1.73 m2 vs 97.2 mL/min/1.73 m2, P = .024; and 105.4 mL/min/1.73 m2 vs 87.3 mL/min/1.73 m2 , P = .000), but it was significantly increased in the LDT + ADV group (104.1 mL/min/1.73 m2 vs 109.8 mL/min/1.73 m2, P = .031; and 104.1 mL/min/1.73 m2 vs 116.2 mL/min/1.73 m2 , P = .005) (Fig. 2).
3.4 Injury degree of eGFR in the 3 groups 104 weeks after combination therapy
The proportion of patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) was significantly higher in the LDT + ADV group than in the ETV + ADV group (P = .002) and LAM + ADV group (P = .001) 104 weeks after combination therapy. However, there was no statistical difference in the proportion of patients with normal renal function between the LAM + ADV group and ETV + ADV group (P = .988) (Table 2).
Compared with baseline level, eGFR increased by 20% or more in 15 patients 104 weeks after combination therapy. Of the 15 patients, 2 were from the ETV + ADV group, 1 from the LAM + ADV group, and 12 from the LDT + ADV group. Compared with baseline level, eGFR decreased by 20% or more in 37 patients 104 weeks after combination therapy. Of the 37 patients, 11 were from the ETV + ADV group, 25 from the LAM + ADV group, and 1 from the LDT + ADV group.
3.5 Analysis of independent risk factors for more than 20% reduction of baseline eGFR
Univariate analysis showed that age (P = .003), male (P = .007), baseline eGFR (P < .001), LAM combined with ADV (P = .002), and LDT combined with ADV (P = .005) were correlated with 20% or more reduction of baseline eGFR. Multivariate analysis showed that age (P = .035), male (P = .005), baseline eGFR (P < .001), LAM combined with ADV (P < .008), and ETV combined with ADV (P = .03) were independent risk factors for more than 20% reduction of baseline eGFR (Table 3).
The NAs can reduce HBV replication through inhibiting its DNA polymerase activity, but cannot eradicate HBV, thus long-term NA treatment has become a recognized effective anti-HBV strategy. Although previous studies have reported that NAs monotherapy affects renal function, ADV and tenofovir could potentially cause renal injury,[12,13] LAM and ETV treatment do not produced obvious renal toxicity, while LDT then shows protective effects on kidney. It is necessary to determine that the changes of renal function in patients with CHB treated with ADV combined with LDT. The serum SCr level is associated with muscle metabolism, dietary intake, renal tubular secretion, and renal clearance, so serum Scr level varies greatly, which limits its application in evaluating mild impairment of renal function.[14,15] Therefore, we used eGFR to evaluate renal function in comparison of the effects of 3 different NA combination therapies on renal function of patients with CHB in this study.
Lee et al observed 831 patients with CHB who received different NAs for 96 weeks, and found that eGFR levels were significantly increased in ADV + LDT group and ADV + LAM group, but it was significantly decreased in ADV + ETV group as compared with baseline level. Our results showed that the changes of Scr and eGFR were smaller in 52-week therapy than in 104-week therapy, suggesting that longer ADV and LDT combination therapy can produce better renal function improvement. LAM and ADV, as well as ETV and ADV combination therapies could increase Scr and decrease eGFR levels, while LDT and ADV combination therapy could decrease Scr and increase eGFR levels as compared to the baseline levels, which are similar to previous research results.
Qi et al found that eGFR level was increased by 12.52 mL/min/1.73 m2 in the patients with mild baseline renal impairment and by 1.39 mL/min/1.73 m2 in the patients with normal baseline renal function after LDT and ADV combination therapy; while after LAM and ADV combination therapy, eGFR level was decreased by 10.81 mL/min/1.73 m2 in the patients with mild baseline renal impairment and by 20.46 mL/min/1.73 m2 in the patients with normal baseline renal function. In these results,[16,17,18] the change over 20% baseline eGFR was regarded as obvious change of renal function. This study indicated that the numbers of patients with more than 20% reduction of baseline eGFR were significantly higher in the ETV + ADV (11 cases, 26.19%) and LAM + ADV (25 cases, 43.10%) groups than in the LDT + ADV group (1 case, 1.86%) 104 weeks after combination therapy; in contrast, the number of patients with more than 20% elevation of eGFR level was significantly higher in LDT + ADV group than in other 2 groups. These results suggest that the combination therapy of LDT and ADV can improve renal function, and can also allow the eGFR under the baseline to become normal. The combination therapy of ETV and ADV or LAM and ADV induced a reduction of eGFR level. For patients with CHB requiring long-term combination therapy, the security for eGFR has important clinical significance. Renal function is an important safety issue because in the patients with advanced liver disease, especially in the patients with decompensated liver cirrhosis caused by hepatitis B, renal insufficiency is associated with high mortality. This study indicated that baseline eGFR level was a factor for more than 20% reduction of eGFR. Among 13 patients with mild eGFR impairment of LDT + ADV group, the eGFR in 9 patients returned to normal after ADV and LDT combination therapy, showing that ADV and LDT combination therapy was suitable for the patients with mild eGFR impairment. Considering that most patients showing over 20% reduction of eGFR level were from the patients treated by ETV and ADV or LAM and ADV combination therapy, and multivariate analysis showed that age, male, baseline eGFR, LAM combined with ADV, and ETV combined with ADV were independent risk factors for more than 20% reduction of baseline eGFR, so ETV and ADV or LAM and ADV combination therapy was not recommended for the elderly patients, male patients and the patients with renal impairment.
Previous studies showed the ADV decreases eGFR through inhibiting the replication and synthesis of mitochondrial DNA (mtDNA).[19,20] However, LDT and ADV combination therapy could elevate eGFR level, indicating the protective role of LDT on the kidney which might help to counteract the renal toxicity of ADV. The mechanism that LDT improves renal function has been unclear. The LDT excretion in the kidney may be mediated by passive diffusion that cannot cause mtDNA depletion or toxic effects on renal tubular epithelial cell function. LDT improves tubular dysfunction probably by increasing glomerular blood flow. LDT-based combination therapy has protective effects on kidneys, so for the patients with potential renal impairment, LDT-based combination therapy may be used as rescue therapy.
This is a retrospective small-sample study with relatively short follow-up, and also the changes of urine protein, urine glucose, blood pressure, serum phosphorus, and calcium were not determined during treatment. The influence of NA combination treatment on the renal function of patients with CHB remains to be further confirmed by the studies with larger sample and longer follow-up.
Writing – original draft: Yong Xu.
Writing – review & editing: Zhen-wang Nie.
. Kumada H, Okanoue T, Onji M, et al. Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan. Hepatol Res 2010;40:1–7.
. European Association for the Study of the Liver EASL Clinical Practice Guidelines: management of chronic hepatitis, B, virus, infection. Hepatology 2012;57:167–85.
. Scott DR, Levy MT. Liver transient elastography (Fibroscan): a place in the management algorithms of chronic viral hepatitis. Antivir Ther 2010;15:1.
. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil
for HBeAg-negative chronic hepatitis B
for up to 5 years. Gastroenterology 2006;131:1743–51.
. Wang Y, Thongsawat S, Gane EJ, et al. Efficacy and safety of continuous 4-year telbivudine
treatment in patients with chronic hepatitis B
. J Viral Hepat 2013;20:e37–46.
. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B
and advanced liver disease. N Engl J Med 2004;351:1521–31.
. Kim S, Cheong J, Lee D, et al. Adefovir-based combination therapy with entecavir or lamivudine for patients with entecavir-refractory chronic hepatitis B
. J Med Virol 2012;84:18–25.
. Belcher JM, Garcia-Tsao G, Sanyal AJ, et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753–62.
. Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical AssociationThe guideline of prevention and treatment for chronic hepatitis B
. Clin Hepatol 2011;27:1–6.
. Ceca SG, Yalavatthy R, Coneato J, et al. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 2008;73:1008–16.
. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137–47.
. Qi X, Wang JY, Mao RC, et al. Impact of nucleos (t)ide analogues on the estimated glomerular filtration rate
in patients with chronic hepatitis B
: a prospective cohort study in China. J Viral Hepat 2015;22:46–54.
. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil
for chronic hepatitis B
. N Engl J Med 2008;359:2442–55.
. Van Rompay KK, Durand-Gasselin L, Brignolo LL, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological effects. Antimicrob Agents Chemother 2008;52:3144–60.
. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil
for the treatment of hepatitis B e antigen-positive chronic hepatitis B
. N Engl J Med 2003;348:808–16.
. Lee M, Oh S, Lee HJ, et al. Telbivudine
protects renal function in patients with chronic hepatitis B
infection in conjunction with adefovir-based combination therapy. J Viral Hepatitis 2014;21:873–81.
. Qi X, Wang J, Chen L, et al. Impact of nucleos (t)ide analogue combination therapy on the estimated glomerular filtration rate
in patients with chronic hepatitis B
. Medicine (Baltimore) 2015;94:e646.
. Kim YJ, Cho HC, Sinn DH, et al. Frequency and risk factors of renal impairment during long-term adefovir dipivoxil
treatment in chronic hepatitis B
patients. J Gastroenterol Hepatol 2012;27:306–12.
. Stankov MV, Lucke T, Das AM, et al. Mitochondrial DNA depletion and respiratory chain activity in primary human subcutaneous adipocytes treated with nucleoside analogue reverse transcriptase inhibitors. Antimicrob Agents Chemother 2010;54:280–7.
. Zhang L, Chan SS, Wolff DJ. Mitochondnal disorders of DNA polymerase γ dysfunction: from anatomic to molecular pathology diagnosis. Arch Pathol Lab Med 2011;135:925–34.
. McKeage K, Keam SJ. Telbivudine
: a review of its use in compensated chronic hepatitis B
. Drugs 2010;70:1857–83.
. Chan HL, Chen YC, Gane EJ, et al. Randomized clinical trial: efficacy and safety of telbivudine
and lamivudine in treatment-naive patients with HBV-related decompensated cirrhosis. J Viral Hepat 2012;19:732–43.