Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients

Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or... Open Forum Infectious Diseases MAJOR ARTICLE Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients Chao-Wei Hsu, Yi-Cheng Chen, Ming-Ling Chang, Chen-Chun Lin, Shi-Ming Lin, Wei-Ting Chen, Yu-De Chu, and Chau-Ting Yeh Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan Background. Besides antiviral activities against hepatitis B virus (HBV), telbivudine has an extrahepatic pharmaceutical effect: to improve renal function assessed by estimated glomerular filtration rate (eGFR). However, the durability of this effect aer ft with- drawal of telbivudine or switching to other antivirals has never been investigated. Methods. We conducted a postmarketing, real-world observation study for telbivudine treatment. e Th durability of telbivu- dine-associated renal function improvement was examined following withdrawal/switching of antivirals. Results. Of 160 telbivudine-treated, chronic hepatitis B patients, 21, 6, and 2 patients were loss to follow-up, dead, and preg- nant during the study, respectively. Of the remaining 131 patients, 26, 47, 28, and 30 patients experienced telbivudine withdrawal, continuous use of telbivudine, switching to entecavir, or switching to tenofovir, respectively. During the first 2 years, eGFR in tel- bivudine-treated patients significantly improved before withdrawal/switching of antivirals (P  =  .009). Thereaer ft , eGFR remained unchanged for >1  year in the withdrawal (P  =  .100) and continuous use (P  =  .517) subgroups, but decreased significantly in the switching to entecavir (P = .002) and switching to tenofovir (P < .001) subgroups. Multivariate logistic regression analysis revealed that switching to tenofovir and poor liver functional reserve were predictors for eGFR deterioration. Conclusions. Telbivudine-associated renal function improvement was durable aer w ft ithdrawal or continuous use of telbivu- dine. However, renal function deteriorated if patients were switched to entecavir or tenofovir. Keywords. creatine kinase; telbivudine; virological breakthrough. Hepatitis B virus (HBV) chronically infects 350 million indi- antiviral therapy for chronic hepatitis B is to provide prolonged viduals, representing an estimated 5% of the worldwide popu- suppression of HBV replication to abrogate progression of liver lation [1]. In their lifetime, approximately 15%–40% of chronic injury [14–18]. hepatitis B patients develop life-threatening complications, Currently, interferon α-2b, pegylated interferon α-2a, and 5 such as liver cirrhosis and hepatocellular carcinoma (HCC) [2, oral agents—adefovir dipivoxil, entecavir (ETV), lamivudine, 3]. The prevalence of HBV infection varies in different parts of telbivudine, and tenofovir (TDF)—have been approved as the world. The highest prevalence is found in Asia, Africa, the therapeutic agents for chronic hepatitis B [19–30]. Telbivudine Middle East, the Mediterranean region, South America, and the has been approved for clinical use based on a phase III clin- Pacific Islands, where the disease is commonly acquired in early ical trial [31, 32]. It is a synthetic thymidine nucleoside ana- childhood [4–6]. The risk of developing chronic HBV infection log with a potent inhibitory effect on HBV DNA polymerase. aer ac ft ute exposure ranges from 90% in newborns of hepati- Interestingly, recent studies have indicated that this antiviral tis B e antigen (HBeAg)–positive mothers to <5% in immuno- drug could improve renal function during long-term usage [33]. The present study is a postmarketing, open-label, prospec- competent adults [7, 8]. There is strong evidence supporting the tive, and observational surveillance study for the clinical use of view that the risk of cirrhosis and liver failure increases with telbivudine in Taiwan. All patients were treated according to the higher serum levels of HBV DNA [9–13]. Hence, the goal of best judgments of their physicians in outpatient clinics without interference by this study. Treatment was continued, stopped, Received 6 September 2017; editorial decision 13 December 2017; accepted 20 December or switched to other antivirals at the physician’s discretion. e Th Correspondence: C. T. Yeh, MD, PhD, Liver Research Center, Chang Gung Memorial Hospital, clinical efficacies, virological suppression or breakthrough, side 199 Tung Hwa North Road, Taipei 105, Taiwan (chautingy@gmail.com). effects, and renal function changes were assessed. Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative METHODS Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Inclusion/Exclusion Criteria medium, provided the original work is not altered or transformed in any way, and that the work This study was approved by the Institutional Review Board at is properly cited. For commercial re-use, please contact journals.permissions@oup.com Chang Gung Medical Center (98-3808C, 98-3663B). Written DOI: 10.1093/ofid/ofx271 Durability of Ldt-Induced eGFR Elevation • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 informed consent was obtained from all enrolled patients. and P < .05 was considered statistically significant. Continuous Patients must have met all of the following criteria to be included variables were analyzed using the t test. The Wilcoxon rank- in this observational study: (1) male or female at least 18 years sum or sign-rank test was conducted if the data were not nor- of age; (2) documented chronic hepatitis B defined by all of mally distributed. Categorical variables were analyzed using the the following: clinical history compatible with chronic hepa- chi-square or Fisher exact test. titis B, detectable serum hepatitis B surface antigen (HBsAg) RESULTS >6  months at screening visit, with either HBeAg positive or negative; (3) willing and able to comply with the observational Patients Included drug regimen subscribed by the physicians and all other study Overall, 160 patients could be classified into 6 groups according requirements; (4) willing and able to provide written informed to their clinical presentations (Table S1). HBeAg was positive in consent to participate in the study. Patients were excluded from 39 patients. They were classified into 3 groups: group I, HBeAg- the study for any of the following reasons: (1) pregnancy, intent positive, treatment-naïve patients (n  =  16); group II, HBeAg- to become pregnant, or breastfeeding; (2) co-infection with hep- positive and ETV experienced patients (n = 15); and group III, atitis C virus, hepatitis D virus, or human immunodeficiency HBeAg-positive and HCC patients receiving chemotherapy virus; (3) 1 or more known primary or secondary causes of liver (n  =  8). None of these patients had taken nephrotoxic drugs. disease other than hepatitis B (eg, alcoholism, steatohepatitis, Other baseline characteristics were listed in Table S1. autoimmune hepatitis, malignancy with liver metastasis, hemo- e Th HBeAg-negative patients (n = 121) could also be divided chromatosis, alpha-1 antitrypsin deficiency, Wilson’s disease, into 3 groups: group IV, HBeAg-negative, treatment-naïve other congenital or metabolic conditions affecting the liver, patients (n  =  39); group V, HBeAg-negative, liver cirrhotic congestive heart failure or other severe cardiopulmonary dis- patients (n = 34); and group VI, HBeAg-negative, HCC or other ease); (4) enrolled or planning to be enrolled in another clinical cancer patients, receiving chemotherapy (n = 48). In this group trial of an investigational agent while participating in this study; of patients, 45, 2, and 1, respectively, had HCC, breast cancer, (5) unable to receive safety and tolerability assessments. and gastric cancer. Patients were considered lost to follow-up (ie, those patients Compliance, Withdrawal, Switching Antivirals, and Loss to Follow-up whose status was unclear because they failed to appear for study During the time of this study, antiviral therapy was covered by visits without stating an intention to withdraw) if no particular the National Health Insurance Policy of Taiwan for only a 2-year reason could be documented aer t ft he attempts were made to period. At the end of the second year of postmarketing obser- contact the patients. vation, 7 patients achieved a complete virological response with Duration of Observation Study complete virological suppression for more than 1 year (the stop- The term of prospective observation was 104 weeks ping rule), and the treatment was stopped. Six patients died of (24 months). Subsequent renal function data beyond 24 months HCC, 21 patients were lost to follow-up, and 2 had pregnancy were assessed in a retrospective manner. Dose adjustments, (Figure 1). Of 58 patients switching to other antivirals during or interruptions, or changes of medication were entirely clinically at the end of the 2-year period, 28 were switched to ETV and 30 judged by physicians. In the case of HBeAg seroconversion at to TDF. The decision of withdrawal/switching was made by the any point, treatment was continued or stopped at the clinician’s physicians after discussion with the patients. In the remaining discretion. Virological breakthrough (defined as an increase in 66 patients, telbivudine was still being used at the end of the HBV DNA load by 1 Log10 from nadir) was either continuously second year. Afterward, 19 met the stopping rule of treatment treated with telbivudine (patient remained in the observational and were withdrawn from antivirals. On the other hand, 38 study) or by the addition of other antiviral agents to the patient’s and 9 patients continued the telbivudine treatment for >1 year regimen or by switching to other treatments at the physician’s and <1 year, respectively, until the end of this study (Figure 1). discretion. Three of them received an adefovir add-on treatment due to de- Safety velopment of drug resistance. All of the adverse events contained in the medical chart were Therapeutic Responses extracted and recorded for the safety assessment. Table S2 summarizes the virological, biochemical, and serolog- Statistical Analysis ical responses of the patients. The virological response rates as For a surveillance study, descriptive statistics were used for assessed by HBV DNA copy number of fewer than 300 cop- presenting characteristics of efficacy variables. Mean, standard ies/mL were lower in the groups that were HBeAg-positive deviation, median, minimum, maximum, and 95% confidence (groups I and II) compared with the groups that were HBeAg- interval were presented for continuous variables. Categorical negative (groups IV, V, and VI) at week 48 of surveillance. The variables were summarized by counts and percentages in fre- response rates in group III were not assessed due to the small quency tables. All statistical assessments used were 2-sided, case number and the short patient survival time. At week 104, 2 • OFID • Hsu et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Total patients, n = 160 Loss to Follow-up Death (HCC) Pregnancy Complete response On Ltd throughout Switch to other Ldt stopped insurance period Treatment n = 21 n = 6 n = 2 n = 7 n = 66 n = 58 n = 19 Extended Ldt Switch to entecavir Switch to tenofovir Ldt withdrawal Treatment >1 y n = 28 n = 30 n = 26 n = 38 Additional Ldt <1 y n = 9 Figure 1. Distribution of patients enrolled who were either compliant with the treatment, lost to follow-up, or withdrew from the study. Abbreviation: HCC, hepatocellular carcinoma. the virological response rates increased slightly in group I and Muscle soreness could have been associated with a high creat- decreased in groups II and V; the rates increased in groups IV ine kinase (CK) level. We also examined the biochemical and and VI. hematological data during the follow-up visits. Table S4 shows ALT normalization rates were higher in the HBeAg-positive that a significant proportion of patients experienced a high CK groups (I and II) while the HBeAg-negative groups (IV, V, and level. The median CK levels were significantly higher at week VI) had lower rates at week 48. At week 104, the ALT normali- 104 than at baseline. The upper limit of normal in the central zation rates in HBeAg-positive groups I and II decreased while laboratory of the hospital was 200 IU/mL, suggesting that in rates increased in the HBeAg-negative groups (IV and V) but groups I and V, more than half of the patients had abnormal CK not in group VI. levels. Notably, the highest CK level reached greater than 1000 e HB Th eAg loss and seroconversion were the same for the IU/mL in group V patients. Univariate followed by multivariate HBeAg-positive groups. e Th y remained at 33.3% at weeks 48 analysis showed that liver cirrhosis (P = .008) and body height and 104 for group I patients. In group II patients, the serocon- (P  =  .0167) were independently associated with a high (>300 version rates were 14.3% at week 48 and 33.3% at week 104, IU/mL) CK level (Table S5). suggesting that in patients previously failing to achieve HBeAg Improvement of eGFR and Durability After Withdrawal/Switching seroconversion with ETV therapy, the addition of telbivudine Antivirals or switching to telbivudine monotherapy helped to achieve fur- We assessed the eGFR using both the Cockcraft-Gault and ther HBeAg seroconversion. the Modification of Diet in Renal Disease (MDRD) methods e acc Th umulative virological breakthrough rates during the (Table S6). The statistical analysis employed the paired t test 2-year follow-up assessments, defined by an increase of greater for all patients combined (calculated by the MDRD method) than 1 log10 of HBV DNA level, ranged from 0% to 33.3%. (Figure  2, B and C). For all patients who were followed until A Kaplan-Meier analysis was performed to evaluate the time to 24 months (n = 131), including those who had switched antivi- virological breakthrough (Figure 2A). HBeAg-positive patients rals during this period, a significant increase in the eGFR level in groups I and II had significantly shorter intervals of time to was found between baseline and week 104 (P  =  .024), and an breakthrough compared with all HCC patients (P  =  .047). In even more significant increase was observed between weeks 48 fact, no virological breakthrough was found in HCC or other and 104 (P < .001). cancer patients. Because the national insurance coverage period for antiviral Increased Serum Creatine Kinase Levels therapy was 2  years during our study period, another analysis No severe adverse events were associated with telbivudine use. was performed by comparing the baseline eGFRs with those Even in 2 pregnancies, both infants were delivered smoothly assessed at the time of withdrawal (n = 7) or the end of 2-year and without birth defects. Table S3 listed the adverse events of continuous telbivudine (n = 66), or the time of switching anti- grades 1 and 2.  Muscle soreness (11.25%) and abdominal dis- viral treatment (n = 58) (paired t test for all these patients com- tension (11.88%) were reported in more than 10% of patients. bined). In this analysis, all patients had received telbivudine Durability of Ldt-Induced eGFR Elevation • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 A 0.4 HBeAg-positive (n = 31) 0.2 HBeAg-negative (n = 73) P = .047 0 HCC (n = 56) 0306090 120 weeks BC 180 180 140 140 120 120 100 100 80 80 Naive, CH P = .024 HBeAg-positive ETV-treated 60 60 HCC Naive, CH P < .001 40 40 HBeAg-negative Naive, Cirr HCC 20 20 Baseline 48 weeks 104 weeks Baseline 48 weeks 104 weeks Figure 2. (A) Kaplan-Meier analysis of virological time-to-breakthrough between HBeAg-positive patients (blue), HBeAg-negative patients (green), and HCC patients (or- ange). (B) Changes in renal function (mean ± SD) assessed by eGFR (MDRD method) by group. Groups I to III are HBeAg-positive, light green, blue, black, respectively. Groups IV to VI are HBeAg-negative, red, deep green, and orange, respectively. (C) Changes in renal function assessed by eGFR (MDRD method) for all patients enrolled (paired t tests). Abbreviations: HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease. treatment only during the comparison period (Figure  3A). It the eGFRs did not change (P  =  .100 and .517, respectively) was found that eGFR increased significantly during the telbivu- (Figure 3C). dine treatment period (P  =  .009). However, when compared When analyzing eGFR improvement from the beginning with the final eGFRs assessed >1 year into the mid–time point, of treatment to the end of insurance coverage (Table S7), it the eGFRs decreased significantly (between initial eGFRs and was found that HCC, previous use of contrast medium, initial final eGFRs, P = .010; between mid–time point eGFRs and final eGFR, CKD-II, hemoglobin, prothrombin time, albumin, and eGFRs, P < .001) (Figure 3A). bilirubin (P < .001, .001, .013, .033, <.001, .003, <.001, and .008, To understand why the overall renal function deteriorated respectively) were predictors in univariate analysis; whereas only when compared with the initial level, we performed a sub- albumin (P = .011) remained an independent predictor in mul- group analysis (Figure 3B and C). It was found that in patients tivariate analysis, suggesting that liver functional reserve was switching to ETV or TDF, eGFR significantly deteriorated aer ft important for eGFR improvement. On the other hand, when switching (P = .002 and <.001, respectively) (Figure 3B). On the analyzing eGFR improvement from the beginning of treatment other hand, in patients who continued to use telbivudine for until >1  year aer t ft he end of insurance coverage (Table S8), it >1 year or in patients withdrawn from telbivudine treatment, was found that HCC, withdrawal of telbivudine, switching to 4 • OFID • Hsu et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 eGFR (MDRD) Proportion of virological breakthrough eGFR (MDRD) P = .010 P = .009 P < .001 Baseline End of insurance >1 year after switching/withdrawal end of insurance switching/withdrawal BC 180 180 P = .517 160 160 140 140 Withdraw (n = 26) P = .100 TDF (n = 30) 120 120 P < .001 LdT (n = 38) 100 100 ETV (n = 28) 80 80 P = .002 60 60 40 40 20 20 End of insurance >1 year after End of insurance >1 year after switching/withdrawal end of insurance switching/withdrawal end of insurance switching/withdrawal switching/withdrawal Figure 3. Renal function change assessed by eGFR (MDRD method). (A) eGFR was assessed at (1) the start of treatment (baseline), (2) end of insurance coverage (2 years) or at the time of switching or withdrawal before the end of second year, and (3) final follow-up, at least 1 year into the mid–time point. (B) eGFRs assessed at the aforemen- tioned mid–time point and the final follow-up were compared in patients switched to entecavir (brown) or tenofovir (green). (C) eGFRs assessed at the mid–time point and the final follow-up were compared in patients withdrawn from telbivudine (red) or continuously treated by telbivudine (LdT; blue). Abbreviations: eGFR, estimated glomerular filtration rate; ETV, entecavir; MDRD, Modification of Diet in Renal Disease; TDF, tenofovir. tenofovir, hemoglobin, prothrombin time, albumin, and biliru- end of insurance coverage (P = .084). When classified according bin (P = .009, .005, .048, .019, .012, <.001, and .008, respectively) to withdrawal, continuous use of telbivudine, switching to ente- were predictors in univariate analysis, whereas HCC (P = .048), cavir, and switching to tenofovir, none of the subgroups showed switching to tenofovir (P  =  .003) and bilirubin (P  =  .035) significant differential eGFR improvement between CKD-II vs remained independent predictors in multivariate analysis. non-II patients, possibly due to a small case number in each subgroup. However, if the latter 2 switching subgroups were Stages of Chronic Kidney Disease and eGFR Improvement combined (n  =  58), improvement of eGFR could be found in When classified by stages of CKD, 113, 38, 5, and 4 patients 10/17 (58.8%) vs 12/41 (29.3%) for CKD-II vs non-II patients were in CKD-I, II, III, and IV, respectively. When compared (P = .035). between patients in CKD-II vs other stages, 26/38 (68.4%) vs 59/122 (48.4%) patients showed improvement of eGFR at the DISCUSSION end of insurance coverage for telbivudine (P = .030). This ob- servation was consistent with those of previous studies. After This was a prospective, postmarketing surveillance study. No withdrawal or switching antivirals, when compared between intervention to the therapeutic decision was allowed during the patients in CKD-II vs non-II stages, 21/38 (55.3%) vs 48/122 follow-up assessments. As a result, about half of the patients (39.3%) patients showed improvement of eGFR >1 year after the enrolled did not continue the telbivudine antiviral treatment. Durability of Ldt-Induced eGFR Elevation • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 eGFR (MDRD) eGFR (MDRD) eGFR (MDRD) Virological breakthrough, noncompliance, and abnormal CK of tenofovir in the switching to tenofovir group. On the other levels with muscle soreness were the major known reasons for hand, telbivudine usage followed by withdrawal of telbivudine withdrawal or switching. Another limitation of this study was was in fact a beneficial factor for eGFR improvement in univar - the short survival time of the HCC or cancer patients receiving iate analysis (Table S8). From this point of view, nephrotoxicity chemotherapy. of entecavir might not be the cause of eGFR deterioration in As reported in previous global studies [18, 31, 32], the the switching to entecavir group. Instead, it was possible that virological suppression effect remained excellent in telbivu- these patients had hepatitis activities during the telbivudine dine-treated patients. e Th median HBV DNA levels were below treatment period, and thus required switching to entecavir. the detection limit in all HBeAg-negative groups and were Presumably, the liver function reserve in these patients was less 0.0051 and 0.0002 Meq/mL for HBeAg-positive (groups I  and well compared with those who could be withdrawn from tel- II) patients. Despite the excellent virological suppression effect, bivudine treatment, and good liver function was an independ- virological breakthrough due to resistant mutants remained a ent predictor for eGFR improvement in the analyses in Tables significant concern [18, 31, 32]. In non-HCC patients, the viro- S7 and S8. The observation that a limited period of telbivudine logical breakthrough rates ranged from 8.7% to 25.0% among treatment irreversibly improved eGFR raised the possibility that the different groups at week 104, which is compatible with other telbivudine might be used to improve renal function in mild reports [18, 31]. Surprisingly, no virological breakthrough was renal insufficient patients (CKD-II). observed in HCC patients receiving chemotherapy in this study. Finally, the mechanisms for renal function improvement by e diff Th erence was statistically significant when compared with telbivudine remained unclear. However, our previous cDNA the HBeAg-positive patients. The reason for this finding was microarray comparison study revealed a list of candidate not clear. We speculate that a low baseline viral load could be genes that were associated with kidney function and differen- a contributing factor. Additionally, the para-cancerous cirrhotic tially expressed in peripheral blood mononuclear cells between liver had already experienced many rounds of hepatocyte regen- patients with and without telbivudine treatment [35]. Of these eration, which might not have allowed rigorous HBV replica- gene products, we had verified that the angiotensin-converting tion, and thus was less favorable to the development of resistant enzyme gene was indeed differentially expressed between these mutants. 2 groups of patients. Searching through the list, other important When adverse events were investigated, we found that muscle candidate differentially expressed genes should also be verified, soreness was a major complaint from the patients. When such an including APOBEC3A, KLK8, PCNK18, etc. Persistence of event was combined with a high CK level, the physicians would eGFR improvement aer t ft elbivudine withdrawal implied that likely switch the patients to other oral antiviral agents. Logistic differential expression of some of these genes was irreversible. regression analysis showed that high CK levels were most likely In summary, this study showed that the efficacy, adverse re- associated with liver cirrhosis and taller body height. To our action, drug resistance, and renal function improvement of tel- knowledge, this finding has not been previously reported. bivudine usage in Taiwan were all consistent with those found Recent studies have indicated that long-term use of telbivu- in global studies. Additionally, we discovered that the renal dine was associated with an improvement in renal function [33]. function improvement attributed to telbivudine usage was quite In this study, we examined the eGFRs at baseline, week 48, and durable aer w ft ithdrawal, whereas the renal function could de- week 104. Improvement in the eGFR occurred mostly during the teriorate if switching to other drugs. second year of telbivudine treatment. Here we further analyzed Supplementary Data the changes of eGFR following different paths of antiviral treat- Supplementary materials are available online. Consisting of data provided ments. Strikingly, in 26 patients who withdrew from telbivudine by the authors to benefit the reader, the posted materials are not copyedited treatment, eGFR assessed >1  year later showed no significant and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. changes, indicating that telbivudine-associated renal function improvement was quite durable. In contrast, in patients switch- Acknowledgments ing to ETV or TDF, eGFRs deteriorated significantly. Recently, We thank all of the members of the Liver Research Center for help com- an independent study also showed that withdrawal of telbivu- pleting the study, including study coordinators, Ms. Yen-Ling Chuang, and dine did not result in reduction of eGFR to original levels [34]. Mr. Chien-Chih Wang. The authors also thank Liver Disease Prevention and Treatment Research Foundation, Taiwan, for the spiritual support. Our findings were consistent with the data in this report. We Author contributions. Chao-Wei Hsu and Chau-Ting Yeh contrib- further discovered that the persistence of improved eGFR was uted equally to the acquisition of the data, analysis, and interpretation of not limited to noncirrhotic patients. From analysis in Tables S7 the data, and statistical analysis and drafting of the manuscript. The other authors contributed to establishing the study concept, recruiting patients, and S8, it was found that switching to tenofovir and liver func- and revision of the manuscript. tional reserve were the most important deteriorating factors for Financial support. This study was supported by Chang Gung Memorial eGFR. Therefore, one major reason for renal function deteri- Hospital Medical Research Program (CMRPG392181, CMRPG3E0241, oration aer t ft he end of insurance coverage was renal toxicity AND CORPG3G0991). 6 • OFID • Hsu et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Potential conifl cts of interest. e a Th uthors have no financial or per - 19. Perrillo RP, Schiff ER, Davis GL, et  al. A randomized, controlled trial of inter- feron alfa-2b alone and after prednisone withdrawal for the treatment of chronic sonal relationships with other people or organizations that could inappro- hepatitis B.  The Hepatitis Interventional Therapy Group. N Engl J Med 1990; priately influence (bias) their work. All authors have submitted the ICMJE 323:295–301. Form for Disclosure of Potential Conflicts of Interest. Conflicts that the edi- 20. Wong DK, Cheung AM, O’Rourke K, et al. 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Report of an international workshop: change of off- treatment eGFR after 3 years of treatment in non-cirrhotic chronic roadmap for management of patients receiving oral therapy for chronic hepatitis hepatitis B patients. BMC Gastroenterol 2017; 17:22. B. Clin Gastroenterol Hepatol 2007; 5:890–7. 35. Liang KH, Chen YC, Hsu CW, et al. Decrease of serum Angiotensin converting 18. Zeuzem S, Gane E, Liaw YF, et al. Baseline characteristics and early on-treatment enzyme levels upon telbivudine treatment for chronic hepatitis B virus infection response predict the outcomes of 2 years of telbivudine treatment of chronic hep- and negative correlations between the enzyme levels and estimated glumerular atitis B. J Hepatol 2009; 51:11–20. filtration rates. Hepat Mon 2014; 14:e15074. 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Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients

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Abstract

Open Forum Infectious Diseases MAJOR ARTICLE Durability of Telbivudine-Associated Improvement of Renal Function Following Withdrawal or Switching of Antivirals in Chronic Hepatitis B Patients Chao-Wei Hsu, Yi-Cheng Chen, Ming-Ling Chang, Chen-Chun Lin, Shi-Ming Lin, Wei-Ting Chen, Yu-De Chu, and Chau-Ting Yeh Liver Research Center, Chang Gung Memorial Hospital-Lin Kou, Chang Gung University College of Medicine, Taipei, Taiwan Background. Besides antiviral activities against hepatitis B virus (HBV), telbivudine has an extrahepatic pharmaceutical effect: to improve renal function assessed by estimated glomerular filtration rate (eGFR). However, the durability of this effect aer ft with- drawal of telbivudine or switching to other antivirals has never been investigated. Methods. We conducted a postmarketing, real-world observation study for telbivudine treatment. e Th durability of telbivu- dine-associated renal function improvement was examined following withdrawal/switching of antivirals. Results. Of 160 telbivudine-treated, chronic hepatitis B patients, 21, 6, and 2 patients were loss to follow-up, dead, and preg- nant during the study, respectively. Of the remaining 131 patients, 26, 47, 28, and 30 patients experienced telbivudine withdrawal, continuous use of telbivudine, switching to entecavir, or switching to tenofovir, respectively. During the first 2 years, eGFR in tel- bivudine-treated patients significantly improved before withdrawal/switching of antivirals (P  =  .009). Thereaer ft , eGFR remained unchanged for >1  year in the withdrawal (P  =  .100) and continuous use (P  =  .517) subgroups, but decreased significantly in the switching to entecavir (P = .002) and switching to tenofovir (P < .001) subgroups. Multivariate logistic regression analysis revealed that switching to tenofovir and poor liver functional reserve were predictors for eGFR deterioration. Conclusions. Telbivudine-associated renal function improvement was durable aer w ft ithdrawal or continuous use of telbivu- dine. However, renal function deteriorated if patients were switched to entecavir or tenofovir. Keywords. creatine kinase; telbivudine; virological breakthrough. Hepatitis B virus (HBV) chronically infects 350 million indi- antiviral therapy for chronic hepatitis B is to provide prolonged viduals, representing an estimated 5% of the worldwide popu- suppression of HBV replication to abrogate progression of liver lation [1]. In their lifetime, approximately 15%–40% of chronic injury [14–18]. hepatitis B patients develop life-threatening complications, Currently, interferon α-2b, pegylated interferon α-2a, and 5 such as liver cirrhosis and hepatocellular carcinoma (HCC) [2, oral agents—adefovir dipivoxil, entecavir (ETV), lamivudine, 3]. The prevalence of HBV infection varies in different parts of telbivudine, and tenofovir (TDF)—have been approved as the world. The highest prevalence is found in Asia, Africa, the therapeutic agents for chronic hepatitis B [19–30]. Telbivudine Middle East, the Mediterranean region, South America, and the has been approved for clinical use based on a phase III clin- Pacific Islands, where the disease is commonly acquired in early ical trial [31, 32]. It is a synthetic thymidine nucleoside ana- childhood [4–6]. The risk of developing chronic HBV infection log with a potent inhibitory effect on HBV DNA polymerase. aer ac ft ute exposure ranges from 90% in newborns of hepati- Interestingly, recent studies have indicated that this antiviral tis B e antigen (HBeAg)–positive mothers to <5% in immuno- drug could improve renal function during long-term usage [33]. The present study is a postmarketing, open-label, prospec- competent adults [7, 8]. There is strong evidence supporting the tive, and observational surveillance study for the clinical use of view that the risk of cirrhosis and liver failure increases with telbivudine in Taiwan. All patients were treated according to the higher serum levels of HBV DNA [9–13]. Hence, the goal of best judgments of their physicians in outpatient clinics without interference by this study. Treatment was continued, stopped, Received 6 September 2017; editorial decision 13 December 2017; accepted 20 December or switched to other antivirals at the physician’s discretion. e Th Correspondence: C. T. Yeh, MD, PhD, Liver Research Center, Chang Gung Memorial Hospital, clinical efficacies, virological suppression or breakthrough, side 199 Tung Hwa North Road, Taipei 105, Taiwan (chautingy@gmail.com). effects, and renal function changes were assessed. Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative METHODS Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Inclusion/Exclusion Criteria medium, provided the original work is not altered or transformed in any way, and that the work This study was approved by the Institutional Review Board at is properly cited. For commercial re-use, please contact journals.permissions@oup.com Chang Gung Medical Center (98-3808C, 98-3663B). Written DOI: 10.1093/ofid/ofx271 Durability of Ldt-Induced eGFR Elevation • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 informed consent was obtained from all enrolled patients. and P < .05 was considered statistically significant. Continuous Patients must have met all of the following criteria to be included variables were analyzed using the t test. The Wilcoxon rank- in this observational study: (1) male or female at least 18 years sum or sign-rank test was conducted if the data were not nor- of age; (2) documented chronic hepatitis B defined by all of mally distributed. Categorical variables were analyzed using the the following: clinical history compatible with chronic hepa- chi-square or Fisher exact test. titis B, detectable serum hepatitis B surface antigen (HBsAg) RESULTS >6  months at screening visit, with either HBeAg positive or negative; (3) willing and able to comply with the observational Patients Included drug regimen subscribed by the physicians and all other study Overall, 160 patients could be classified into 6 groups according requirements; (4) willing and able to provide written informed to their clinical presentations (Table S1). HBeAg was positive in consent to participate in the study. Patients were excluded from 39 patients. They were classified into 3 groups: group I, HBeAg- the study for any of the following reasons: (1) pregnancy, intent positive, treatment-naïve patients (n  =  16); group II, HBeAg- to become pregnant, or breastfeeding; (2) co-infection with hep- positive and ETV experienced patients (n = 15); and group III, atitis C virus, hepatitis D virus, or human immunodeficiency HBeAg-positive and HCC patients receiving chemotherapy virus; (3) 1 or more known primary or secondary causes of liver (n  =  8). None of these patients had taken nephrotoxic drugs. disease other than hepatitis B (eg, alcoholism, steatohepatitis, Other baseline characteristics were listed in Table S1. autoimmune hepatitis, malignancy with liver metastasis, hemo- e Th HBeAg-negative patients (n = 121) could also be divided chromatosis, alpha-1 antitrypsin deficiency, Wilson’s disease, into 3 groups: group IV, HBeAg-negative, treatment-naïve other congenital or metabolic conditions affecting the liver, patients (n  =  39); group V, HBeAg-negative, liver cirrhotic congestive heart failure or other severe cardiopulmonary dis- patients (n = 34); and group VI, HBeAg-negative, HCC or other ease); (4) enrolled or planning to be enrolled in another clinical cancer patients, receiving chemotherapy (n = 48). In this group trial of an investigational agent while participating in this study; of patients, 45, 2, and 1, respectively, had HCC, breast cancer, (5) unable to receive safety and tolerability assessments. and gastric cancer. Patients were considered lost to follow-up (ie, those patients Compliance, Withdrawal, Switching Antivirals, and Loss to Follow-up whose status was unclear because they failed to appear for study During the time of this study, antiviral therapy was covered by visits without stating an intention to withdraw) if no particular the National Health Insurance Policy of Taiwan for only a 2-year reason could be documented aer t ft he attempts were made to period. At the end of the second year of postmarketing obser- contact the patients. vation, 7 patients achieved a complete virological response with Duration of Observation Study complete virological suppression for more than 1 year (the stop- The term of prospective observation was 104 weeks ping rule), and the treatment was stopped. Six patients died of (24 months). Subsequent renal function data beyond 24 months HCC, 21 patients were lost to follow-up, and 2 had pregnancy were assessed in a retrospective manner. Dose adjustments, (Figure 1). Of 58 patients switching to other antivirals during or interruptions, or changes of medication were entirely clinically at the end of the 2-year period, 28 were switched to ETV and 30 judged by physicians. In the case of HBeAg seroconversion at to TDF. The decision of withdrawal/switching was made by the any point, treatment was continued or stopped at the clinician’s physicians after discussion with the patients. In the remaining discretion. Virological breakthrough (defined as an increase in 66 patients, telbivudine was still being used at the end of the HBV DNA load by 1 Log10 from nadir) was either continuously second year. Afterward, 19 met the stopping rule of treatment treated with telbivudine (patient remained in the observational and were withdrawn from antivirals. On the other hand, 38 study) or by the addition of other antiviral agents to the patient’s and 9 patients continued the telbivudine treatment for >1 year regimen or by switching to other treatments at the physician’s and <1 year, respectively, until the end of this study (Figure 1). discretion. Three of them received an adefovir add-on treatment due to de- Safety velopment of drug resistance. All of the adverse events contained in the medical chart were Therapeutic Responses extracted and recorded for the safety assessment. Table S2 summarizes the virological, biochemical, and serolog- Statistical Analysis ical responses of the patients. The virological response rates as For a surveillance study, descriptive statistics were used for assessed by HBV DNA copy number of fewer than 300 cop- presenting characteristics of efficacy variables. Mean, standard ies/mL were lower in the groups that were HBeAg-positive deviation, median, minimum, maximum, and 95% confidence (groups I and II) compared with the groups that were HBeAg- interval were presented for continuous variables. Categorical negative (groups IV, V, and VI) at week 48 of surveillance. The variables were summarized by counts and percentages in fre- response rates in group III were not assessed due to the small quency tables. All statistical assessments used were 2-sided, case number and the short patient survival time. At week 104, 2 • OFID • Hsu et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Total patients, n = 160 Loss to Follow-up Death (HCC) Pregnancy Complete response On Ltd throughout Switch to other Ldt stopped insurance period Treatment n = 21 n = 6 n = 2 n = 7 n = 66 n = 58 n = 19 Extended Ldt Switch to entecavir Switch to tenofovir Ldt withdrawal Treatment >1 y n = 28 n = 30 n = 26 n = 38 Additional Ldt <1 y n = 9 Figure 1. Distribution of patients enrolled who were either compliant with the treatment, lost to follow-up, or withdrew from the study. Abbreviation: HCC, hepatocellular carcinoma. the virological response rates increased slightly in group I and Muscle soreness could have been associated with a high creat- decreased in groups II and V; the rates increased in groups IV ine kinase (CK) level. We also examined the biochemical and and VI. hematological data during the follow-up visits. Table S4 shows ALT normalization rates were higher in the HBeAg-positive that a significant proportion of patients experienced a high CK groups (I and II) while the HBeAg-negative groups (IV, V, and level. The median CK levels were significantly higher at week VI) had lower rates at week 48. At week 104, the ALT normali- 104 than at baseline. The upper limit of normal in the central zation rates in HBeAg-positive groups I and II decreased while laboratory of the hospital was 200 IU/mL, suggesting that in rates increased in the HBeAg-negative groups (IV and V) but groups I and V, more than half of the patients had abnormal CK not in group VI. levels. Notably, the highest CK level reached greater than 1000 e HB Th eAg loss and seroconversion were the same for the IU/mL in group V patients. Univariate followed by multivariate HBeAg-positive groups. e Th y remained at 33.3% at weeks 48 analysis showed that liver cirrhosis (P = .008) and body height and 104 for group I patients. In group II patients, the serocon- (P  =  .0167) were independently associated with a high (>300 version rates were 14.3% at week 48 and 33.3% at week 104, IU/mL) CK level (Table S5). suggesting that in patients previously failing to achieve HBeAg Improvement of eGFR and Durability After Withdrawal/Switching seroconversion with ETV therapy, the addition of telbivudine Antivirals or switching to telbivudine monotherapy helped to achieve fur- We assessed the eGFR using both the Cockcraft-Gault and ther HBeAg seroconversion. the Modification of Diet in Renal Disease (MDRD) methods e acc Th umulative virological breakthrough rates during the (Table S6). The statistical analysis employed the paired t test 2-year follow-up assessments, defined by an increase of greater for all patients combined (calculated by the MDRD method) than 1 log10 of HBV DNA level, ranged from 0% to 33.3%. (Figure  2, B and C). For all patients who were followed until A Kaplan-Meier analysis was performed to evaluate the time to 24 months (n = 131), including those who had switched antivi- virological breakthrough (Figure 2A). HBeAg-positive patients rals during this period, a significant increase in the eGFR level in groups I and II had significantly shorter intervals of time to was found between baseline and week 104 (P  =  .024), and an breakthrough compared with all HCC patients (P  =  .047). In even more significant increase was observed between weeks 48 fact, no virological breakthrough was found in HCC or other and 104 (P < .001). cancer patients. Because the national insurance coverage period for antiviral Increased Serum Creatine Kinase Levels therapy was 2  years during our study period, another analysis No severe adverse events were associated with telbivudine use. was performed by comparing the baseline eGFRs with those Even in 2 pregnancies, both infants were delivered smoothly assessed at the time of withdrawal (n = 7) or the end of 2-year and without birth defects. Table S3 listed the adverse events of continuous telbivudine (n = 66), or the time of switching anti- grades 1 and 2.  Muscle soreness (11.25%) and abdominal dis- viral treatment (n = 58) (paired t test for all these patients com- tension (11.88%) were reported in more than 10% of patients. bined). In this analysis, all patients had received telbivudine Durability of Ldt-Induced eGFR Elevation • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 A 0.4 HBeAg-positive (n = 31) 0.2 HBeAg-negative (n = 73) P = .047 0 HCC (n = 56) 0306090 120 weeks BC 180 180 140 140 120 120 100 100 80 80 Naive, CH P = .024 HBeAg-positive ETV-treated 60 60 HCC Naive, CH P < .001 40 40 HBeAg-negative Naive, Cirr HCC 20 20 Baseline 48 weeks 104 weeks Baseline 48 weeks 104 weeks Figure 2. (A) Kaplan-Meier analysis of virological time-to-breakthrough between HBeAg-positive patients (blue), HBeAg-negative patients (green), and HCC patients (or- ange). (B) Changes in renal function (mean ± SD) assessed by eGFR (MDRD method) by group. Groups I to III are HBeAg-positive, light green, blue, black, respectively. Groups IV to VI are HBeAg-negative, red, deep green, and orange, respectively. (C) Changes in renal function assessed by eGFR (MDRD method) for all patients enrolled (paired t tests). Abbreviations: HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease. treatment only during the comparison period (Figure  3A). It the eGFRs did not change (P  =  .100 and .517, respectively) was found that eGFR increased significantly during the telbivu- (Figure 3C). dine treatment period (P  =  .009). However, when compared When analyzing eGFR improvement from the beginning with the final eGFRs assessed >1 year into the mid–time point, of treatment to the end of insurance coverage (Table S7), it the eGFRs decreased significantly (between initial eGFRs and was found that HCC, previous use of contrast medium, initial final eGFRs, P = .010; between mid–time point eGFRs and final eGFR, CKD-II, hemoglobin, prothrombin time, albumin, and eGFRs, P < .001) (Figure 3A). bilirubin (P < .001, .001, .013, .033, <.001, .003, <.001, and .008, To understand why the overall renal function deteriorated respectively) were predictors in univariate analysis; whereas only when compared with the initial level, we performed a sub- albumin (P = .011) remained an independent predictor in mul- group analysis (Figure 3B and C). It was found that in patients tivariate analysis, suggesting that liver functional reserve was switching to ETV or TDF, eGFR significantly deteriorated aer ft important for eGFR improvement. On the other hand, when switching (P = .002 and <.001, respectively) (Figure 3B). On the analyzing eGFR improvement from the beginning of treatment other hand, in patients who continued to use telbivudine for until >1  year aer t ft he end of insurance coverage (Table S8), it >1 year or in patients withdrawn from telbivudine treatment, was found that HCC, withdrawal of telbivudine, switching to 4 • OFID • Hsu et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 eGFR (MDRD) Proportion of virological breakthrough eGFR (MDRD) P = .010 P = .009 P < .001 Baseline End of insurance >1 year after switching/withdrawal end of insurance switching/withdrawal BC 180 180 P = .517 160 160 140 140 Withdraw (n = 26) P = .100 TDF (n = 30) 120 120 P < .001 LdT (n = 38) 100 100 ETV (n = 28) 80 80 P = .002 60 60 40 40 20 20 End of insurance >1 year after End of insurance >1 year after switching/withdrawal end of insurance switching/withdrawal end of insurance switching/withdrawal switching/withdrawal Figure 3. Renal function change assessed by eGFR (MDRD method). (A) eGFR was assessed at (1) the start of treatment (baseline), (2) end of insurance coverage (2 years) or at the time of switching or withdrawal before the end of second year, and (3) final follow-up, at least 1 year into the mid–time point. (B) eGFRs assessed at the aforemen- tioned mid–time point and the final follow-up were compared in patients switched to entecavir (brown) or tenofovir (green). (C) eGFRs assessed at the mid–time point and the final follow-up were compared in patients withdrawn from telbivudine (red) or continuously treated by telbivudine (LdT; blue). Abbreviations: eGFR, estimated glomerular filtration rate; ETV, entecavir; MDRD, Modification of Diet in Renal Disease; TDF, tenofovir. tenofovir, hemoglobin, prothrombin time, albumin, and biliru- end of insurance coverage (P = .084). When classified according bin (P = .009, .005, .048, .019, .012, <.001, and .008, respectively) to withdrawal, continuous use of telbivudine, switching to ente- were predictors in univariate analysis, whereas HCC (P = .048), cavir, and switching to tenofovir, none of the subgroups showed switching to tenofovir (P  =  .003) and bilirubin (P  =  .035) significant differential eGFR improvement between CKD-II vs remained independent predictors in multivariate analysis. non-II patients, possibly due to a small case number in each subgroup. However, if the latter 2 switching subgroups were Stages of Chronic Kidney Disease and eGFR Improvement combined (n  =  58), improvement of eGFR could be found in When classified by stages of CKD, 113, 38, 5, and 4 patients 10/17 (58.8%) vs 12/41 (29.3%) for CKD-II vs non-II patients were in CKD-I, II, III, and IV, respectively. When compared (P = .035). between patients in CKD-II vs other stages, 26/38 (68.4%) vs 59/122 (48.4%) patients showed improvement of eGFR at the DISCUSSION end of insurance coverage for telbivudine (P = .030). This ob- servation was consistent with those of previous studies. After This was a prospective, postmarketing surveillance study. No withdrawal or switching antivirals, when compared between intervention to the therapeutic decision was allowed during the patients in CKD-II vs non-II stages, 21/38 (55.3%) vs 48/122 follow-up assessments. As a result, about half of the patients (39.3%) patients showed improvement of eGFR >1 year after the enrolled did not continue the telbivudine antiviral treatment. Durability of Ldt-Induced eGFR Elevation • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 eGFR (MDRD) eGFR (MDRD) eGFR (MDRD) Virological breakthrough, noncompliance, and abnormal CK of tenofovir in the switching to tenofovir group. On the other levels with muscle soreness were the major known reasons for hand, telbivudine usage followed by withdrawal of telbivudine withdrawal or switching. Another limitation of this study was was in fact a beneficial factor for eGFR improvement in univar - the short survival time of the HCC or cancer patients receiving iate analysis (Table S8). From this point of view, nephrotoxicity chemotherapy. of entecavir might not be the cause of eGFR deterioration in As reported in previous global studies [18, 31, 32], the the switching to entecavir group. Instead, it was possible that virological suppression effect remained excellent in telbivu- these patients had hepatitis activities during the telbivudine dine-treated patients. e Th median HBV DNA levels were below treatment period, and thus required switching to entecavir. the detection limit in all HBeAg-negative groups and were Presumably, the liver function reserve in these patients was less 0.0051 and 0.0002 Meq/mL for HBeAg-positive (groups I  and well compared with those who could be withdrawn from tel- II) patients. Despite the excellent virological suppression effect, bivudine treatment, and good liver function was an independ- virological breakthrough due to resistant mutants remained a ent predictor for eGFR improvement in the analyses in Tables significant concern [18, 31, 32]. In non-HCC patients, the viro- S7 and S8. The observation that a limited period of telbivudine logical breakthrough rates ranged from 8.7% to 25.0% among treatment irreversibly improved eGFR raised the possibility that the different groups at week 104, which is compatible with other telbivudine might be used to improve renal function in mild reports [18, 31]. Surprisingly, no virological breakthrough was renal insufficient patients (CKD-II). observed in HCC patients receiving chemotherapy in this study. Finally, the mechanisms for renal function improvement by e diff Th erence was statistically significant when compared with telbivudine remained unclear. However, our previous cDNA the HBeAg-positive patients. The reason for this finding was microarray comparison study revealed a list of candidate not clear. We speculate that a low baseline viral load could be genes that were associated with kidney function and differen- a contributing factor. Additionally, the para-cancerous cirrhotic tially expressed in peripheral blood mononuclear cells between liver had already experienced many rounds of hepatocyte regen- patients with and without telbivudine treatment [35]. Of these eration, which might not have allowed rigorous HBV replica- gene products, we had verified that the angiotensin-converting tion, and thus was less favorable to the development of resistant enzyme gene was indeed differentially expressed between these mutants. 2 groups of patients. Searching through the list, other important When adverse events were investigated, we found that muscle candidate differentially expressed genes should also be verified, soreness was a major complaint from the patients. When such an including APOBEC3A, KLK8, PCNK18, etc. Persistence of event was combined with a high CK level, the physicians would eGFR improvement aer t ft elbivudine withdrawal implied that likely switch the patients to other oral antiviral agents. Logistic differential expression of some of these genes was irreversible. regression analysis showed that high CK levels were most likely In summary, this study showed that the efficacy, adverse re- associated with liver cirrhosis and taller body height. To our action, drug resistance, and renal function improvement of tel- knowledge, this finding has not been previously reported. bivudine usage in Taiwan were all consistent with those found Recent studies have indicated that long-term use of telbivu- in global studies. Additionally, we discovered that the renal dine was associated with an improvement in renal function [33]. function improvement attributed to telbivudine usage was quite In this study, we examined the eGFRs at baseline, week 48, and durable aer w ft ithdrawal, whereas the renal function could de- week 104. Improvement in the eGFR occurred mostly during the teriorate if switching to other drugs. second year of telbivudine treatment. Here we further analyzed Supplementary Data the changes of eGFR following different paths of antiviral treat- Supplementary materials are available online. Consisting of data provided ments. Strikingly, in 26 patients who withdrew from telbivudine by the authors to benefit the reader, the posted materials are not copyedited treatment, eGFR assessed >1  year later showed no significant and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. changes, indicating that telbivudine-associated renal function improvement was quite durable. In contrast, in patients switch- Acknowledgments ing to ETV or TDF, eGFRs deteriorated significantly. Recently, We thank all of the members of the Liver Research Center for help com- an independent study also showed that withdrawal of telbivu- pleting the study, including study coordinators, Ms. Yen-Ling Chuang, and dine did not result in reduction of eGFR to original levels [34]. Mr. Chien-Chih Wang. The authors also thank Liver Disease Prevention and Treatment Research Foundation, Taiwan, for the spiritual support. Our findings were consistent with the data in this report. We Author contributions. Chao-Wei Hsu and Chau-Ting Yeh contrib- further discovered that the persistence of improved eGFR was uted equally to the acquisition of the data, analysis, and interpretation of not limited to noncirrhotic patients. From analysis in Tables S7 the data, and statistical analysis and drafting of the manuscript. The other authors contributed to establishing the study concept, recruiting patients, and S8, it was found that switching to tenofovir and liver func- and revision of the manuscript. tional reserve were the most important deteriorating factors for Financial support. This study was supported by Chang Gung Memorial eGFR. Therefore, one major reason for renal function deteri- Hospital Medical Research Program (CMRPG392181, CMRPG3E0241, oration aer t ft he end of insurance coverage was renal toxicity AND CORPG3G0991). 6 • OFID • Hsu et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx271/4770295 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Potential conifl cts of interest. e a Th uthors have no financial or per - 19. Perrillo RP, Schiff ER, Davis GL, et  al. A randomized, controlled trial of inter- feron alfa-2b alone and after prednisone withdrawal for the treatment of chronic sonal relationships with other people or organizations that could inappro- hepatitis B.  The Hepatitis Interventional Therapy Group. N Engl J Med 1990; priately influence (bias) their work. All authors have submitted the ICMJE 323:295–301. Form for Disclosure of Potential Conflicts of Interest. Conflicts that the edi- 20. Wong DK, Cheung AM, O’Rourke K, et al. 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Open Forum Infectious DiseasesOxford University Press

Published: Jan 1, 2018

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