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Potential Benefit of Telbivudine on Renal Function Does Not Outweigh Its High Rate of Antiviral Drug Resistance and Other Adverse Effects - Editorial
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Download the PDF here
Download the PDF here
Gastroenterology
January 2014
SUNA YAPALI
ANNA S. LOK
Division of Gastroenterology and Hepatology
University of Michigan Health System
Ann Arbor, Michigan
See "Telbivudine improves renal function in patients with chronic hepatitis B," by Gane EJ, Deray G, Liaw Y-F, below
Five nucleos(t)ide analogs (NUCs) are approved for the treatment of hepatitis B. NUC therapy had been shown to reverse fibrosis and cirrhosis, and to reduce the risk of hepatic decompensation and hepatocellular carcinoma.1, 2 Although NUCs are effective in suppressing hepatitis B virus (HBV) replication, they do not eradicate the virus; therefore, most patients require long-term treatment. Long-term efficacy, safety, drug resistance, and costs are the major considerations in determining which NUC should be considered as first-line treatment.
NUCs are generally safe and well-tolerated, but side effects have been reported including nephrotoxicity, neuropathy, myopathy, lactic acidosis, and decrease in bone mineral density.1, 3, 4, 5, 6 Of these, nephrotoxicity associated with adefovir or tenofovir has received the most attention. Nephrotoxicity manifesting as decrease in glomerular filtration rate (GFR) is more common in patients who are >50 years old, have baseline renal insufficiency, hypertension and/or diabetes mellitus.7 Proximal renal tubular injury-resembling Fanconi syndrome with hypophosphatemia, hypouricemia, aminoaciduria, and glycosuria-had also been reported.8 In most instances, nephrotoxicity is reversible after dose reduction or discontinuation of treatment. The postulated mechanisms of nephrotoxicity associated with adefovir and tenofovir treatment include increased intracellular influx through organic anion transporters and/or a defect in its luminal excretion through multidrug-resistance-associated proteins, or mitochondrial toxicity in the proximal tubular cells of the kidney.9 Lamivudine and entecavir have not been reported to be associated with nephrotoxicity. All NUCs approved for HBV are eliminated by the kidneys and dose adjustments are needed in patients with impaired renal function. Renal impairment is common in patients with decompensated cirrhosis and in liver transplant recipients. Therefore, renal safety is an important factor in deciding which NUC is most appropriate for patients with hepatitis B, particularly those who have other risk factors for renal impairment.
In this issue of the Gastroenterology, Gane et al10 reported the results of a comprehensive analysis of renal function in the telbivudine clinical trial database. This database included 1367 patients with compensated chronic hepatitis B randomized to receive telbivudine or lamivudine for 2 years in the GLOBE study, 655 patients in the GLOBE study and in a similar study in China (Study 015) who received telbivudine in the feeder study and in the extension study (A2303) for a total duration up to 4 years, 70 patients who continued to receive telbivudine in another extension study (CN04E1) for a total duration of 4-6 years, 66 patients who discontinued telbivudine treatment at the end of the GLOBE study or Study 015 owing to efficacy, 398 patients who received lamivudine in the GLOBE study and telbivudine for 2 years in the extension study (A2303), and 228 patients with decompensated cirrhosis randomized to receive telbivudine or lamivudine for 2 years in Study A2301.6, 11, 12, 13, 14
Renal function was assessed by 3 different calculations for estimated GFR (eGFR), Cockroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration. The authors showed that renal function assessed by serum creatinine and the 3 formulas for eGFR improved in patients who received telbivudine during the GLOBE trial, whereas those who received lamivudine had a decline in renal function. The changes in eGFR at the end of 2 years of treatment were +8.5% versus -0.5% for the entire cohort of patients who received telbivudine versus lamivudine, respectively; +11.4% versus -2.4% for patients age >50 years; +17.2% versus +4.3% for those with eGFR ≤90 mL/min/1.73 m2 at baseline; and +7.2% versus +2.3% for patients with cirrhosis. Multivariate analysis of baseline factors in the GLOBE study that predicted a shift in eGFR from baseline of 60-90 to ≥90 mL/min/1.73 m2 at year 2 were telbivudine treatment (odds ratio [OR], 2.51), younger age (OR, 0.94), and non-Caucasian race (OR, 0.34). Improvement in eGFR was maintained during long-term telbivudine treatment. At year 4, mean increase of eGFR was +14.9 mL/min/1.73 m2 and 74% (165/223) of the telbivudine-treated patients with baseline eGFR of 60-89 mL/min/1.73 m2 had eGFR of ≥90 mL/min/1.73 m2.
Among the patients who received lamivudine in the GLOBE/015 studies with no evidence of genotypic resistance at the end of the feeder studies, eGFR improved by 8.9% after 2 years of lamivudine and by 9.5% after 2 years of telbivudine treatment in the extension studies.
In patients with decompensated cirrhosis, eGFR at year 2 improved by 2.0 mL/min/1.73 m2 in the patients who received telbivudine but declined by 4.6 mL/min/1.73 m2 in those who received lamivudine.
The study by Gane et al10 showed that improvement in eGFR was observed in chronic hepatitis B patients treated with telbivudine. The improvement in eGFR was maintained during continuous treatment of telbivudine for up to 6 years and was observed in various subpopulations. Although the mechanism responsible for the improvement in renal function is unclear, the results are convincing.
What are the implications of these results? Is the improvement in renal function specific for telbivudine? Does the benefit on renal function outweigh the risk of antiviral resistance and other adverse effects of telbivudine? Should telbivudine be recommended as a first-line antiviral agent for hepatitis B?
Gane et al10 showed that improvement in eGFR was observed in the telbivudine group but not in the lamivudine group in the GLOBE study; however, in the subgroup of patients in GLOBE/015 studies who did not have genotypic resistance after 2 years of lamivudine, an improvement in eGFR was observed and the percentage of change in eGFR was similar to that observed after 2 years of telbivudine treatment in the extension studies. Thus, although the authors found that improvement in eGFR during telbivudine treatment was not related to virologic response, it is possible that a higher rate of virologic breakthrough in the lamivudine group in the GLOBE study might have contributed to the minor decline in eGFR in the entire lamivudine group.
Improvement in renal function has not been systematically examined in patients receiving other HBV NUCs. Registration trials and clinical studies have focused on the incidence of renal impairment (Table 1).1, 3, 5, 14, 15, 16, 17, 18, 19, 20, 21, 22 Renal impairment was reported in studies of other HBV NUCs, but not in studies of telbivudine. Reports of some telbivudine trials provided data on improvement in eGFR but did not specify whether any patient had deterioration in renal function.6, 11, 12, 13, 14 Renal impairment is more commonly associated with adefovir than with other HBV NUCs and more common in patients with decompensated cirrhosis than in those with compensated liver disease.5, 15, 16, 17, 18, 22 Despite their similarities in molecular structure, nephrotoxicity is less common with tenofovir treatment than with adefovir treatment, occurring in 1% of patients with HBV monoinfection and compensated liver disease after ≤5 years of tenofovir treatment.1 A retrospective, match-control study comparing 230 patients with chronic hepatitis B who had received 2 years of telbivudine or entecavir treatment showed that, compared with baseline, serum creatinine and eGFR improved significantly in both groups after 1 year of treatment but no significant difference was observed in either group at year 2.23 Similarly, a shift toward a better eGFR category was seen in both groups at year 1 but not at year 2.
The key question is whether improvement in renal function outweighs the risk of antiviral drug resistance and other adverse effects of telbivudine to justify its use as a first-line antiviral agent for hepatitis B. Despite its potent antiviral activity, telbivudine has a low barrier to antiviral drug resistance and shares similar resistance mutations as lamivudine. A phase III clinical trial of telbivudine found that viral resistance was observed in 25.1% and 39.5% of hepatitis B e antigen (HBeAg)-positive patients and in 10.8% and 25.9% of HBeAg-negative patients after 2 years of telbivudine and lamivudine, respectively.6 Of the patients who did not have genotypic resistance at year 2 and who continued to receive telbivudine in the extension study, the cumulative rate of antiviral resistance at 4 years was 10.6% in HBeAg-positive and 10.0% in HBeAg-negative patients.13 By contrast, phase III trials of entecavir and tenofovir in nucleoside-naïve patients showed genotypic resistance rates at 5 years of 1.2% and 0%, respectively.1, 24 In an attempt to decrease the rate of antiviral resistance, the roadmap approach was tested in a prospective study of 100 HBeAg-positive patients. Patients with detectable HBV DNA at week 24 were to receive add-on tenofovir and 45% did so.25 The high percentage of patients in whom tenofovir had to be added as a rescue therapy by week 24 negates its benefit of being a lower cost HBV NUC. Telbivudine has been associated with myopathy and peripheral neuropathy and these adverse events were more frequent and severe when telbivudine was used in combination with pegylated interferon, leading to early termination of that trial. In patients who received 4 years of telbivudine monotherapy, muscle symptoms (including myalgia, muscular weakness, musculoskeletal pain, myopathy, myositis, and musculoskeletal discomfort), peripheral neuropathy, and grade 3-4 increase in serum creatine kinase levels were observed in 6.1%, 1.2%, and 15.9% of patients, respectively.13
In summary, although Gane et al10 provided tantalizing data suggesting that telbivudine may be renal protective, it is not clear whether this protective effect is specific to telbivudine. This potential benefit does not outweigh the high rate of antiviral drug resistance and neuromuscular adverse effects. Therefore, these results, albeit being highly relevant from the clinical and safety profile perspectives, do not support the use of telbivudine as a first-line NUC in hepatitis B treatment and should not prompt revision to existing guidelines.
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Telbivudine Improves Renal Function in Patients With Chronic Hepatitis B
Edward J. Gane,1 Gilbert Deray,2 Yun-Fan Liaw,3 Seng Gee Lim,4 Ching-Lung Lai,5 Jens Rasenack,6 Yuming Wang,7 George Papatheodoridis,8 Adrian Di Bisceglie,9 Maria Buti,10 Didier Samuel,11 Alkaz Uddin,12 Sophie Bosset,13 and Aldo Trylesinski13
Methods
Patients From Telbivudine Clinical Trial Database Analyzed for Renal Function
GLOBE study
The GLOBE study (CLDT600A2302) was a randomized, double-blind, 104-week, phase III trial designed to compare the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) in adults with CHB and compensated liver disease.19 Patients with SCr >133 μmol/L at screening were excluded. In the intent-to-treat population (n = 1367; 921 hepatitis B e antigen [HBeAg]-positive and 446 HBeAg-negative), patients were randomized 1:1 to receive either telbivudine 600 mg daily for up to 104 weeks or lamivudine 100 mg daily for up to 104 weeks. HBeAg-positive patients were younger (32 years in the telbivudine group and 33 years in the lamivudine group) compared with HBeAg-negative patients (43 years in both treatment groups). At baseline, 37.6% (256 of 680) of patients in the telbivudine group and 34.1% (234 of 687) in the lamivudine group had CKD stage 2 (eGFR at 60-89 mL/min/1.73 m2; Modification of Diet in Renal Disease [MDRD]). In the telbivudine and lamivudine groups, 65.3% and 64.3% of patients were of Asian origin, respectively.
Long-term extension studies of GLOBE
The study A2301 (CLDT600A2303) was an extension study for CHB patients who had successfully completed either the GLOBE study (CLDT600A2302) or Study 015 (NV-02B-015), both of which were similar in design to the GLOBE trial, but were conducted entirely in China. In the A2303 study, 82.6% of patients were of Asian origin. In this extension study, patients received an additional 2 years of open-label telbivudine treatment.20, 21, 22 Patients who completed 2-year treatment with telbivudine or lamivudine in the GLOBE or 015 studies and who did not develop genotypic resistance to lamivudine or telbivudine and had undetectable serum HBV DNA at the end of the 2 years were enrolled in Study A2303, where they received open-labeled telbivudine treatment for an additional 2 years. At the end of Study A2303, patients were able to continue telbivudine treatment for an additional 2 years in extension studies CN04 and CN04E1. Of those patients who received 4-6 years of telbivudine treatment during these 4 studies (ie, GLOBE/015, A2303, CN04, and CN04+1), a total of 70 had evaluable paired liver biopsies at baseline and year 5.
Patients who switched from lamivudine in GLOBE study to telbivudine in study A2303
Of the 852 patients treated with lamivudine in the GLOBE and 015 studies, 398 without genotypic resistance at the end of the feeder studies rolled over to extension study 2303 to receive telbivudine for 2 additional years. Of these, 299 (171 HBeAg-positive and 128 HBeAg-negative) had undetectable HBV DNA at the time of switch. The effect of telbivudine switch on renal function was analyzed in this subgroup of patients.
Patients off treatment in the study A2303
At the end of the GLOBE and 015 studies, 66 patients met the per-protocol criteria for discontinuation of telbivudine treatment due to efficacy. Before treatment discontinuation, 98% of patients had undetectable HBV DNA (<300 copies/mL) and all had HBeAg seroconversion. Maintenance of eGFR improvement in patients off treatment was studied in these patients.
Decompensated CHB patients of the A2301 study
The study A2303 (CLDT600A2301) was a double-blind randomized controlled trial that compared telbivudine vs lamivudine in adult patients with decompensated CHB and evidence of cirrhosis.23 In telbivudine and lamivudine groups, 64.9% of patients were of Asian origin. Patients were randomized 1:1 to 104-week treatment with telbivudine 600 mg/d or lamivudine 100 mg/d (n = 114 in each treatment group of the intent-to-treat population).
Assessment of Renal Function
The GFR was estimated by the following formulas based on SCr.
1. Cockcroft-Gault calculation for eGFR (mL/min) = 0.85 if female (with weight in kg and SCr in mg/dL).24
2. MDRD calculation for eGFR (mL/min/1.73 m2) = 186 x creatinine (mg/dL)-1.154 x age-0.203 x 1.210 (if black) x 0.742 (if female).25
3. CKD-EPI calculation for eGFR (mL/min) = GFR = 141 x min(SCr/κ, 1)α x max(SCr/κ, 1)-1.209 x 0.993Age x 1.018 (if female) x 1.159 (if black) where SCr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of SCr/κ or 1, and max indicates the maximum of SCr/κ or 1.26
Statistical Analysis
For the GLOBE and 2301 studies, where an active comparator was present, analysis of covariance model was used to test if there was any significant difference in eGFR between the 2 treatment groups (telbivudine vs lamivudine). The analysis of covariance model included treatment, country, and baseline values as covariates; means were calculated using the least square method. The last observation carried forward method was used. For the other studies, where all patients were on telbivudine, change from baseline within treatment group was analyzed using Student t test.
The baseline eGFR was classified into 3 categories: <60 mL/min/1.73 m2, 60-89 mL/min/1.73 m2 (CKD stage 2), and ≥90 mL/min/1.73 m2 and a shift table allowed comparing changes of categories from baseline to end of study.
An exploratory analysis was performed to evidence the possible relationship between individual eGFR data from GLOBE Study and laboratory parameters (eg, alanine aminotransferase, total bilirubin, creatine kinase [CK]) or physiological parameters (eg, blood pressure, heart rate).
A multivariate analysis was performed to assess the factors predictive of shifting in eGFR (MDRD) to ≥90 mL/min/1.73 m2 at year 2 in GLOBE study in patients with eGFR at 60-89 mL/min/1.73 m2 at baseline. Stepwise regression methods were applied to select the variables in the logistic regression model (P ≤ .1 to enter, P ≤ .1 to stay).
Results
eGFR Changes in CHB Patients From the GLOBE Study (2 Years)
In the intent-to-treat population of the GLOBE study, 680 patients were randomized in the telbivudine treatment group and 687 patients in the lamivudine treatment group.19 The mean overall treatment exposure was 100.2 weeks in the telbivudine treatment group and 99.3 weeks in the lamivudine treatment group.
Results in Table 1 indicate that all markers of renal function (SCr and 3 SCr-based estimating equations for GFR) were improved at weeks 52 and 104 for patients in telbivudine group compared with the lamivudine group. Figure 1 shows that renal function declined over time in lamivudine-treated patients, and renal function steadily improved in telbivudine-treated patients, with the greatest improvement seen during the second year of treatment. Results with CKD-EPI and MDRD equations were comparable during the 2 years of treatment (Figure 1).
Maintenance of eGFR Improvement in Long-Term Studies in CHB
The extension studies of GLOBE showed that the eGFR improvement was maintained during long-term telbivudine therapy. Thus, in the 2-year GLOBE extension, eGFR increased from baseline and remained significantly elevated during the 4 years of the study. The mean increase in eGFR was +14.9 mL/min/1.73 m2 at week 208 (P < .0001) (Table 2). In 74% (165 of 223) of the telbivudine-treated patients with baseline eGFR of 60-89 mL/min/1.73 m2 (CKD stage 2), renal function improved to ≥90 mL/min/1.73 m2 after 4 years of treatment.
Long-term effect of telbivudine on eGFR was evaluated in patients who received overall 4 to 6 years of telbivudine treatment (extension study CN04E1). In this small study population, the absolute change in eGFR from baseline was statistically significant with +29.3 and +30.2 mL/min/1.73 m2 at weeks 104 and 208, respectively (n = 70) (mean, MDRD). In 37 of 39 (94.9%) of patients with baseline CKD stage 2, renal function improved to normal at week 312; meanwhile, no patient with baseline eGFR >90 mL/min/1.73 m2 shifted to 60-89 mL/min/1.73 m2 at week 312.
Maintenance of eGFR Improvement in Patients Off Treatment
Patients off treatment (telbivudine or lamivudine) at the end of studies GLOBE/015 were followed up during the 2-year extension study. At the end of GLOBE/015 studies, mean eGFR were 107.0 (n = 66) and 98.7 mL/min/1.73 m2 (n = 57) in patients from telbivudine and lamivudine groups, respectively (P = .037). After 2 years off treatment, eGFR remained stable compared with extension study baseline: -0.9% in patients of telbivudine group and -1.2% in lamivudine group (P = .8265), respectively.
eGFR Improvement in Patients Switching From Lamivudine to Telbivudine
The effect of switch from lamivudine to telbivudine on renal function was analyzed in patients who received 2 years of lamivudine in GLOBE/015 studies and rolled over to extension study to receive telbivudine for 2 additional years. After 104 weeks of lamivudine treatment, eGFR change from baseline was +5.5 mL/min/1.73m2 (P < .0001; n = 299), corresponding to +8.9%. At week 208 (2 years after switch to telbivudine), the change from baseline of extension study A2303 was +7.7 mL/min/1.73m2 (P <.0001; n = 260), corresponding to +9.6%.
eGFR Changes in Special Populations of GLOBE Study (>50 Years, Insufficiency Stage and Advance Liver Fibrosis)
A subanalysis of patients with baseline CKD stage 2 (60-89 mL/min/1.73 m2), demonstrated that 72.3% of patients receiving telbivudine, had eGFR improvement to ≥90 mL/min after 104 weeks of treatment in comparison to 52.6% of patients in the lamivudine-treated group (Table 3). In patients with baseline eGFR ≥90 mL/min, 91.2% (382 of 419) had stable eGFR, in comparison to 59.8% (266 of 445) of patients in the lamivudine-treated group. As shown in Figure 2, the eGFR increased in telbivudine-treated patients by 8.5% after 2 years. This improvement was even greater in those CHB subpopulations at greatest risk of renal dysfunction: patients with age older than 50 years (+11.4%) and patients with baseline CKD stage 2 (+17.2%). Lamivudine treatment was associated with decrease in eGFR or only modest increase.
Similar telbivudine-associated improvements in renal function were also observed in the subpopulation of GLOBE study with severe fibrosis or cirrhosis at baseline (Ishak fibrosis score [IF] ≥ 3). Mean changes of eGFR levels after 104 weeks of treatment with IF ≥ 3 were +6.1 mL/min/1.73 m2 (8.0%, n = 182) in telbivudine group and -5.0 mL/min/1.73 m2 (-4.6%; n = 255) in lamivudine group (P < .0001 for treatment groups comparisons); with IF ≥ 4, changes were +7.6 mL/min/1.73 m2 (+10.4%, n = 66) in telbivudine group and -1.4 mL/min/1.73 m2 (+0.1%, n = 80) in lamivudine group (P = .0004 for treatment groups comparison); with IF 5-6, changes were +5.2 mL/min/1.73 m2 (+7.2%, n = 33) in telbivudine group and -0.6 mL/min/1.73 m2 (+2.3%; n = 46) in lamivudine group (P = .1018 for treatment groups comparisons).
In patients with CKD stage 2 at baseline, 79.7% (55 of 69) with IF ≥ 3, 83.3% (20 of 24) with IF ≥ 4 and 75% (3 of 4) with IF 5-6 shifted to GFR >90 mL/min/1.73 m2 under telbivudine treatment and only 37.2% (35 of 94) with IF ≥ 3, 43.7% (14 of 32) with IF ≥ 4, and 41.1% (7 of 17) with IF 5-6 under lamivudine treatment.
The improvements in eGFR observed in this subpopulation of patients with severe fibrosis or cirrhosis were not related with virological response (either HBV DNA reduction from baseline or nondetectability after 104 weeks).
eGFR Changes in CHB Patients With Decompensated Cirrhosis
In the A2301 study, patients with decompensated CHB were randomized 1:1 to 104 weeks treatment with telbivudine or lamivudine.23 Although eGFR declined during lamivudine treatment (-4.6 mL/min/1.73 m2 at week 104; -4.6%), eGFR steadily improved in telbivudine-treated patients (+2.0 mL mL/min/1.73 m2; +2.0%; P = .0231). Among patients with CKD stage 2 at baseline, eGFR improved to >90 mL/min/1.73 m2 at week 104 in 40.7% (11 of 27) of telbivudine-treated patients compared with 31.4% (11 of 35) of lamivudine-treated patients.
Correlation of eGFR Improvement With Baseline Virological Characteristics and Efficacy Markers
Treatment-related changes in eGFR (MDRD) in patients of GLOBE study with CKD stage 2 (baseline GFR 60-89 mL/min/1.73 m2) were assessed according to virologic and serologic responses (undetectable HBV DNA at week 104, resistance, baseline HBeAg status and HBeAg seroconversion at week 104). Changes in eGFR were similar in telbivudine-treated patients with or without complete virologic response (<300 copies/mL) at week 104: +17.2% (n = 157) and +20.3% (n = 99), respectively (P = .28) (least-square mean, MDRD). Patients with and without genotypic resistance, developed during first 2 years, had similar eGFR increase of +22.8% ± 3.7% (n = 59) vs +17.0% ± 2.8% (n = 197) (P = .09). Changes in eGFR were also similar in telbivudine-treated patients with and without viral suppression (HBV DNA > 5 log10 HBV DNA) and HBeAg-positive patients with and without complete response (HBV DNA undetectable, alanine aminotransferase normalization, and HBeAg seroconversion) (data not shown). No significant correlation was observed between eGFR improvement and HBV DNA decline (P = .2771 for telbivudine group and P = .4435 for lamivudine group).
Improvement in eGFR change was greater in HBeAg-positive patients than in HBeAg-negative patients: +8.3% vs +4.6% (P = .0170) at week 52 and +9.6% vs +6.5% (P = .0607) at week 104, respectively. However, HBeAg-positive patients were younger (mean age 32 years) than HBeAg-negative patients (mean age 43 years) at baseline in the GLOBE study. The influence of HBeAg status on eGFR improvement was investigated further in a multivariate analysis.
HBeAg seroconversion in HBeAg-positive patients was not associated with improvement in eGFR. In fact, in patients with CKD stage 2 at baseline, the improvement in eGFR after 104 weeks of telbivudine treatment was greater in those patients who failed to achieve HBeAg seroconversion (n = 114) than in those who did (n = 44): 7.3% vs 17.6% (P = .022).
A multivariate analysis was performed on the GLOBE study patients, to assess which baseline factors could predict shifting from eGFR 60-90 mL/min/1.73 m2 (MDRD) at baseline to ≥90 mL/min/1.73 m2 at week 104 (Table 4). The independent predictors for improvement in eGFR were telbivudine treatment (telbivudine vs lamivudine, odds ratio = 2.509; P < .0001), younger age (odds ratio = 0.940; P < .0001) and non-Caucasian race (Caucasian vs non-Caucasian, odds ratio = .338; P = .0012). Baseline HBeAg status did not have an independent effect on eGFR change. The observed differences between HBeAg-positive and HBeAg-negative patients were most probably related to age differences at enrollment.
In patients with decompensated CHB (Study A2301), no significant correlation was evidenced between virological efficacy (HBV DNA < 4 log10 copies/mL or HBV DNA suppression) and improvement in eGFR.
Correlation of eGFR Improvement With Laboratory and Clinical Parameters
In an exploratory analysis, no correlation was reported between individual eGFR data from GLOBE study and laboratory parameters (eg, alanine aminotransferase, total bilirubin) and physiological parameters (eg, blood pressure, heart rate). In clinical studies, the incidence of CK elevations was increased in telbivudine-treated patients vs lamivudine-treated patients, although the clinical significance of this observation remains unclear. Therefore, the possible correlation between CK elevations and changes in renal function was determined in the subpopulation from the GLOBE study whose renal function shifted from eGFR 60-89 mL/min/1.73 m2 at baseline to ≥90 mL/min/1.73 m2 at 104 weeks. eGFR change was similar in patients with at least one documented elevation in CK level compared with those without (29.3% ± 3.6% vs 28.8% ± 6.2%; P = .93). Similarly, eGFR change was similar in patients with at least 2 documented elevated CK levels compared with those without (+23.6% ± 3.6% vs +18.4% ± 3.6%; P = .072).
Discussion
CKD is frequent in patients with chronic hepatitis B: 15%-30% have either baseline renal dysfunction or comorbidities associated with CKD, such as diabetes and hypertension.5, 6, 13 GFR is an important indicator of kidney function, which allows detection, assessment, and management of chronic kidney diseases. Because GFR cannot be practically measured for routine purposes, calculations for GFR have been adopted based on SCr levels and other patient factors that determine renal function. The most widely used calculation is the Cockcroft-Gault equation, which relies on weight, age, sex, and SCr. Because the Cockcroft-Gault equation underestimates the degree of renal impairment in patients with advanced chronic liver disease, the MDRD calculation was developed to incorporate markers of nutritional status, namely serum albumin and urea levels. This formula has become the accepted method for estimating GFR in patients with chronic liver disease. The CKD-EPI calculation has recently been adopted to improve accuracy in patients with mild renal dysfunction.24, 25, 26
In the pivotal GLOBE study, a steady improvement in mean eGFR was observed in patients treated with telbivudine for 2 years, but not in those treated with lamivudine. The subsequent extension studies demonstrated that this improvement was maintained throughout 4-6 years of continuous telbivudine therapy. Of note, concordance was observed when GFR was estimated by each of the 3 eGFR calculations.
Treatment with telbivudine was associated with improvement in eGFR in patients older than 50 years of age and those with CKD stage 2 at baseline. One third of patients in the GLOBE study had CKD stage 2 at baseline. In this subpopulation at greatest risk for progressive renal dysfunction, eGFR improved to normal values (eGFR ≥90 mL/min/1.73 m2) in 72.3% during 2 years of telbivudine therapy, a benefit that was maintained long term in the subsequent extension studies. It is intriguing whether this might provide similar benefit in patients with more severe renal dysfunction (eGFR <60 mL/min/1.73 m2), including those with advanced fibrosis or cirrhosis, those with decompensated CHB, and those who have undergone liver transplantation.
In patients with advanced liver fibrosis (IF ≥ 3) or cirrhosis (IF 5-6) in the GLOBE study, eGFR significantly improved during telbivudine treatment. This improvement was not related to antiviral efficacy. CHB patients with cirrhosis have a high risk for renal impairment. A recent large randomized trial in patients with decompensated HBV-cirrhosis patients (Study A2301) reported that telbivudine therapy was also associated with a significant increase in eGFR compared with lamivudine after 2 years.23
After transplantation for CHB, oral antiviral therapy is administered long term to prevent HBV recurrence. This patient population has a high risk for CKD because of the concomitant use of calcineurin inhibitors and other nephrotoxic drugs, and because of the high prevalence of the comorbidities of diabetes and hypertension. Telbivudine appears to be safe and antiviral prophylaxis has been effective in this population.27, 28
Telbivudine therapy has also been associated with improvement in renal function in other patient populations at high risk of renal impairment, including patients with acute-on-chronic liver failure, those receiving chemotherapy, and those with HBV-related nephritis.27, 29 Finally, it is of great interest to note that the combination of telbivudine with tenofovir, a potential nephrotoxic agent, was also associated with improvement in eGFR.30, 31, 32
The combined results from these studies containing >3500 patients with CHB suggest that long-term therapy with telbivudine leads to an improvement of renal function, in contrast to most other oral nucleo(t)sides against CHB.33, 34, 35, 36 The European Association for the Study of the Liver 2012 guidelines state that renal function decline has been reported with all nucleos(t)ides except perhaps for telbivudine, which seems to improve the creatinine clearance.37 Adefovir and tenofovir might both be associated with nephrotoxicity, particularly in those patients with other risk factors for renal dysfunction, such as human immunodeficiency virus infection or liver transplantation. In a retrospective cohort analysis of CHB patients rescued with tenofovir for lamivudine resistance, the 5-year tenofovir treatment was associated with a significant decrease of eGFR (-10.3 mL/min/1.73 m2 with MDRD equation; P = .01).17 In a recent "real-life" study comparing patients receiving long-term therapy with either tenofovir or entecavir, SCr elevations (>18 μmol/L) were common in both treatment groups with confirmed increases of SCr significantly more frequent on entecavir treatment than tenofovir treatment (11% vs 2%; P = .029). Reduction in renal function (>20% decrease in eGFR) was common in both treatment arms (43% and 45%, respectively).16
The potential adverse impact of long-term antiviral therapy on renal function is an important issue in those CHB patients at particular risk for CKD, especially those older than 50 years of age and with baseline renal impairment. Therefore, the results from this review of telbivudine studies would support the recommendation from the 2012 European Association for the Study of the Liver guidelines, that baseline SCr levels and eGFR should be measured in all patients with CHB before commencing nucleos(t)ide therapy.37 In addition, the baseline renal risk should be assessed for all patients at particular risk for CKD, including those with decompensated CHB, baseline moderate renal impairment (eGFR <60 mL/min), poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs, and those who have undergone solid organ transplantation. These guidelines also recommend appropriate on-treatment monitoring of eGFR and serum phosphate levels in all patients receiving nucleotide analogue therapy (adefovir or tenofovir) and monitoring of eGFR in high-risk patients receiving nucleoside analogue therapy (ie, lamivudine, telbivudine, and entecavir).
The mechanism responsible for the improvement of renal function during long-term telbivudine therapy is still under investigation. A recent study compared telbivudine, entecavir, tenofovir, and adefovir on renal function and toxicity in normal rats.38 Tenofovir showed renal histopathology changes (tubular-cell nuclear enlargement, intracellular accumulation of α-2 microglobulin) correlating with slight down-regulation of tubule-associated genes. Adefovir evidenced down-regulation of renal tubular-associated genes and autophagic vacuoles filled with mitochondria at different stages of degradation, which suggested involvement of mitochondrial toxicity.
The lack of improvement in eGFR within the first 24 weeks of telbivudine treatment during clinical studies would argue against interference by telbivudine on laboratory measurement of SCr or drug-induced glomerular hyperfiltration. The lack of association between change in eGFR and on-treatment virologic or serologic response would support a direct beneficial effect on the kidney rather than an indirect effect from HBV suppression. This hypothesis is further supported by lack of deterioration of renal function after virologic rebound due to emergence of telbivudine resistance. Even in patients who had achieved complete viral suppression (undetectable serum HBV DNA) on lamivudine therapy, switch to telbivudine resulted in improvement in eGFR. Finally, the improvement of eGFR during telbivudine therapy was maintained even after addition of a second, potentially nephrotoxic nucleos(t)ide. A possible effect of telbivudine could be on kidney structures or on inflammatory/fibrotic pathways. The mechanisms of nucleos(t)ide excretion in kidney should be also explored by studying the expression of transport pumps (eg, hOAT1, hOAT3, MRP4) in cells of proximal tubules.39, 40
In conclusion, in global trials in compensated and decompensated patients, telbivudine therapy was associated with consistent increase in renal function (eGFR) across different patient populations. This effect was maintained during long-term therapy and was also observed in patients at greatest risk of renal dysfunction (older than 50 years of age or with baseline renal dysfunction). The mechanism of the beneficial effect of telbivudine therapy on renal function remains to be determined.
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