Clinical Therapeutics/Volume ], Number ], 2015
Efficacy of Tenofovir-Based Rescue Therapy in Lamivudine-Resistant Chronic Hepatitis B Patients With Failure of Lamivudine and Adefovir Combination Jae Ho Park, MD1; Seok Won Jung, MD, PhD1; Neung Hwa Park, MD, PhD1,2; Bo Ryung Park, MS2; Min-Ho Kim, PhD2; Chang Jae Kim, PhD2; Byung Uk Lee, MD1; In Du Jeong, MD, PhD1; Byung Gyu Kim, MD, PhD1; Sung-Jo Bang, MD, PhD1; and Jung Woo Shin, MD, PhD1 1
Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea; and 2Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
ABSTRACT Purpose: In chronic hepatitis B patients, lamivudine (LAM) and adefovir (ADV) combination therapy is commonly used as a rescue therapy for LAM resistance, but it often results in incomplete viral suppression. We investigated the antiviral efficacy of tenofovir (TDF)/LAM combination therapy versus TDF monotherapy in LAM-resistant chronic hepatitis B (CHB) patients who failed to respond to LAM plus ADV rescue therapy. Methods: Among 108 patients with LAM-resistant CHB who had a partial virologic response (VR) to LAM and ADV combination therapy, Eighty one patients were finally included in this study. Findings: Resistance to ADV (ADV-R) was present in 32 patients (39.5%), and the remaining 49 patients (60.5%) had a partial virologic response to LAM/ ADV combination (ADV-P). The study subjects were treated with TDF alone (n=15) or TDF/LAM combination (n=66). VR was achieved in 61 patients (75.3%). The rates of VR at 6 and 12 months were not significantly different between TDF monotherapy and TDF/LAM combination therapy groups (46.7 vs. 68.2% at 6 months, and 66.7 vs. 75.9% at 12 months, log-rank P=0.357). Treatment efficacy of TDF alone or TDF/LAM combination was not statistically different according to pre-existing ADV or LAM resistant strains. In multivariate analysis, absolute HBV DNA levels at the start of TDF rescue treatment (Po0.001; OR, 0.556; 95% CI, 0.422-0.731) were the only significantly associated with VR. Implications: TDF monotherapy was as effective as TDF/LAM combination therapy in maintaining viral
] 2015
suppression in patients with LAM-resistant patients who failed to respond to LAM/ADV combination therapy. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: adefovir resistance, chronic hepatitis B, lamivudine resistance, tenofovir.
INTRODUCTION Lamivudine (LAM), the first oral antiviral agent approved for the treatment of chronic hepatitis B (CHB), is safe and well tolerated, including in patients with decompensated liver cirrhosis. However, resistance to LAM emerges in 20% of patients after 1 year of treatment and in 70% of patients after 5 years.1 Development of LAM resistance is associated with viral relapse, biochemical breakthrough, clinical deterioration, and loss of the favorable effects obtained with LAM treatment.2 Adefovir (ADV) has been shown to potently suppress LAM-resistant hepatitis B virus (HBV).3,4 Early studies have found that adding ADV to LAM therapy or switching to ADV can suppress viral replication and provide significant histologic improvement in patients with LAM resistance.3,5 However, according to results of a comparative study, adding ADV to ongoing LAM therapy was preferable to switching to ADV monotherapy in terms
Accepted for publication April 13, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.04.007 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics of potent antiviral effects and a lower rate of resistance.6 Previous treatment guidelines therefore recommended the use of a combination of LAM and ADV as salvage therapy to treat LAM resistance in patients with CHB. In addition, higher rates of viral suppression, particularly when it is introduced early, as well as fewer hepatic flares and a reduced potential for the development of ADV resistance have been reported.7–10 Other studies reported insufficient virologic responses after administration of ADV add-on LAM therapy in patients with higher baseline HBV DNA levels.10–12 Seto et al12 reported that among patients with higher baseline HBV DNA levels (Z8 log10 copies/mL), up to 25% of patients treated with LAM and ADV combination therapy failed to achieve a satisfactory virologic response. Tenofovir disoproxil fumarate (TDF) is a potent, once-daily nucleotide analogue anti-HBV medication recommended as a first-line therapy in CHB.8,13 TDF partially suppresses ADV-resistant HBV, and it is also highly effective against LAM-resistant virus, suggesting that this drug may be an effective treatment for patients who have previously failed to respond to treatment with LAM and ADV.14 Several studies also reported that TDF alone or in combination with entecavir or LAM has been evaluated as a rescue strategy for patients with suboptimal responses or virologic breakthrough during ADV therapy.14–17 However, patients in these studies had genotypic resistance or suboptimal response to ADV, and they were either ADV-naive or received ADV monotherapy as salvage therapy for LAM resistance. Therefore, data on TDF use in LAM-resistant CHB patients who failed to respond to LAM plus ADV rescue therapy are rare. In addition, there is debate about whether TDF is an effective choice as monotherapy for patients with previous suboptimal response or virologic breakthrough on LAM and ADV combination therapy for LAM-resistant CHB. The objective of the present study was to evaluate the efficacy and safety of TDF-based rescue therapy in patients with LAM-resistant CHB who had an incomplete virologic response after receiving ADV and LAM combination therapy for at least 12 months. TDF monotherapy versus TDF/LAM combination therapy was also compared in these patients.
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PATIENTS AND METHODS Patient Population The electronic medical records of patients with CHB who had developed LAM resistance were reviewed. A total of 447 patients with CHB and genotypic evidence of LAM-resistant HBV were treated with LAM and ADV from August 2003 to April 2012. Among these 447 patients, 329 received LAM (100 mg/d) and ADV (10 mg/d) combination therapy for 412 months. The remaining 118 patients were excluded from the study: 37 patients received combination therapy for o12 months, 35 patients had irregular treatment due to poor compliance, and 46 patients were lost to follow-up. A total of 108 (32.8%) patients had a partial virologic response (PVR). Among these 108 patients with a PVR, 81 who had been treated with TDF (300 mg/d) based rescue therapy for 46 months were included in this study. The remaining 27 patients were excluded: 7 patients received TDF-based rescue therapy for o6 months, 11 patients received continuous LAM and ADV combination therapy without TDF-based rescue therapy, and 9 patients were switched to entecavir (1 mg/d) and ADV combination therapy. All patients had detectable hepatitis B surface antigen, and HBV DNA in serum was documented for at least 6 months before the start of LAM therapy. Patients with impaired renal function (serum creatinine 41.5 mg/dL), antibodies to hepatitis C virus, antibodies to HIV, or autoimmune hepatitis were excluded. Additional criteria for exclusion were pregnancy, lactation, and alcohol abuse (440 g/d of ethanol). Diagnoses of chronic hepatitis and liver cirrhosis were based on results of liver biopsy (n = 6 [7.4%]) or, if these were unavailable, diagnoses were based on clinical, laboratory, and ultrasound data. Written informed consent was obtained from all patients participating in the study. This research was approved by the institutional review board at the Ulsan University Hospital.
Laboratory Measurements Liver and kidney function tests were performed every 3 months during TDF-based rescue therapy. HBV DNA levels were quantified by using the COBAS TaqMan HBV test (Roche Molecular Systems Inc, Branchburg, New Jersey), which has a lower detection limit of 12 IU/mL (60 copies/mL). Genotypic resistance to LAM or ADV was tested by restriction fragment mass polymorphism (GeneMatrix Inc, Yongin, Republic of Korea) assay, which can
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J.H. Park et al. detect 100 copies of HBV genome per milliliter. The specific HBV genotypes were identified by using the polymerase chain reaction–restriction fragment length polymorphism of the surface gene of the HBV genome. The 2 fragments of the HBV genome between the nucleotide positions 2823 and 2845 and between 61 and 80 were amplified by using polymerase chain reaction, and the products were treated with restriction enzymes. Patients underwent surveillance for hepatocellular carcinoma every 6 months; serial abdominal ultrasound and serum α-fetoprotein measurements were performed.
Definitions A virologic response was defined as the absence of serum HBV DNA according to polymerase chain reaction assay (o12 IU/mL) on 2 consecutive measurements during TDF-based rescue treatment. Hepatitis B e antigen (HBeAg) seroconversion was defined as the loss of HBeAg accompanied by the detection of anti-HBe and the absence of serum HBV DNA during treatment. PVR was defined as a decrease in HBV DNA of 41 log10 IU/mL but detectable HBV DNA after 12 months of antiviral therapy. Failure of LAM and ADV combination therapy included PVR or the development of ADV resistance. Virologic breakthrough was defined as an increase of 41 log10 IU/mL in the serum HBV DNA level from the nadir on 2 consecutive measurements or at the last available measurement.
Statistical Methods Serum HBV DNA levels were logarithmically transformed for analysis. Continuous variables were compared by using the Student’s t test, and categorical variables were compared by using the χ2 test. The Kaplan-Meier method was used to calculate the cumulative probabilities of clinical outcomes. To identify the factors predictive of outcome among the baseline variables, the variables for clinical outcomes were compared by using the χ2 test or univariate logistic regression. Multivariate analysis was conducted with the use of a stepwise logistic regression model. To determine the predictive value of baseline serum HBV DNA level for predicting the virologic response to TDF treatment, the odds ratio and receiver-operating characteristic curves were evaluated, with overall accuracy assessed according to the AUC. The AUCs and the corresponding 95% CIs were measured to assess the degree of discrimination provided by these variables.
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All data were analyzed by using SPSS for Windows version 19.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). In all cases, a 2-tailed P value o 0.05 was considered statistically significant.
RESULTS Overall Clinical Outcomes of TDF-Based Therapy The baseline characteristics of the 81 patients with CHB are shown in Table I. All patients belonged to genotype C2. All patients had been treated with LAM as a first-line oral antiviral agent and had genotypic resistance to LAM. The median duration of LAM therapy was 29 months (range, 13–110 months). Before undergoing TDF-based rescue therapy, all patients were treated with the LAM and ADV combination for 412 months as salvage therapy for LAM resistance. The median duration of LAM and ADV combination treatment was 45.5 months (range, 13–87 months). Among these 81 patients, resistance to ADV (ADV-R) occurred in 32 patients (39.5%) after a median of 35 months (range, 13–66 months) of LAM and ADV combination treatment, and the remaining 49 patients (60.5%) had a PVR to LAM and ADV combination treatment (ADV-P). The known genotypic ADV mutations rtA181T, rtA181V, rtN236T, rtA181T rtN236T, and rtA181V rtN236T were detected in 11, 4, 3, 8, and 6 patients, respectively. Study patients were treated with TDF alone (n ¼ 15) or TDF/LAM combination (n ¼ 66) therapy according to clinician or patient choice. The median follow-up during TDF or TDF/LAM combination treatment was 15 months (range, 8–22 months). Of the 81 study patients, 73 received TDFbased rescue therapy for 412 months. Twenty-four (29.6%) of the 81 patients had liver cirrhosis, and 70 (86.4%) patients were HBeAg positive. The mean HBV DNA level before TDF-based treatment was 4.11 (1.43) log10 IU/mL. Twenty-one (25.9%) patients had abnormal alanine aminotransferase (ALT) levels. The mean pretreatment HBV DNA levels were 4.11 (1.46) log10 IU/mL in HBeAg-positive CHB patients and 4.14 (1.25) log10 IU/mL in HBeAgnegative CHB patients. The mean pretreatment HBV DNA levels were similar between HBeAg-positive and HBeAg-negative patients with CHB (P ¼ 0.940). Among the 21 patients with elevated ALT levels at baseline, 17 (81.0%) achieved ALT normalization during TDF-based treatment. During TDF-based therapy, virologic response was achieved in 61 patients
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Clinical Therapeutics
Table I. Baseline characteristics of the 81 study patients. Continuous variables are expressed as median (range) or mean (SD). Characteristic Age, y Sex (male/female) Diagnosis (chronic hepatitis/cirrhosis) AST, IU/L* ALT, IU/L† HBV DNA, log10 IU/mL HBeAg positive Duration of LAM therapy, mo Duration of LAM and ADV therapy, mo Genotypic resistance to ADV (n ¼ 32) rtA181T rtA181V rtN236T rtA181T rtN236T rtA181V rtN236T
Value 51.0 (26–67) 64/17 57/24 43.5 (69.0) 67.0 (159.5) 4.11 (1.43) 70 (86.4%) 29 (13–110) 45.5 (13–87) n ¼ 11 n¼4 n¼3 n¼8 n¼6
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBV ¼ hepatitis B virus; HBeAg ¼ hepatitis B e antigen; LAM ¼ lamivudine; ADV ¼ adefovir. * AST upper limit of normal was defined as 40 IU/L. † ALT upper limit of normal was defined as 41 IU/L.
(75.3%). The cumulative rates of virologic response at 6, 12, and 15 months were 64.2%, 74.3%, and 75.9%, respectively. During the follow-up visits, 7 patients (8.6%) were found to be nonadherent to the TDF-based rescue therapy. Among the 73 patients who received TDF-based rescue therapy for 412 months, 15 (20.6%) patients experienced a PVR. Among these 15 patients, 6 (40%) had an rtN236T mutation of ADV before TDF-based rescue therapy, and 2 patients had poor adherence to TDF-based rescue therapy. Virologic breakthrough was observed in 3 (3.7%) patients at 9 to 11 months after starting TDF therapy; medical review revealed that these 3 patients had poor adherence to TDF. In HBeAg-positive patients (n ¼ 70), the cumulative probability of achieving a virologic response at 6, 12, and 15 months was 63.7%, 71.4%, and 73.5%, respectively. Among HBeAg-negative patients (n ¼ 11), 10 (90.9%) had achieved a virologic response. There was no statistically significant difference between HBeAgpositive and HBeAg-negative patients (P ¼ 0.305). Five (7.1%) of the 70 HBeAg-positive patients underwent
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HBeAg seroconversion during TDF-based rescue treatment. However, none of the patients experienced loss of serum hepatitis B surface antigen during treatment. No significant clinical adverse events occurred during the TDF-based treatment. Mean creatinine levels and estimated glomerular filtration rate revealed no significant change during the treatment period. Two patients (3.1%) had an increase in serum creatinine level. However, none of the patients had an increase in serum creatinine level 40.5 mg/dL above the baseline value. Mild hypophosphatemia (a serum phosphorus level of o2.7 mg/dL) was detected in 1 patient, with no change in serum creatinine level. One patient developed hepatocellular carcinoma during the follow-up period.
Comparison of Virologic Response between the TDF/LAM Combination Therapy and TDF Monotherapy Groups The virologic response rates were compared by using a log-rank test to define whether there was any difference in the virologic response rates between the
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J.H. Park et al. TDF/LAM and TDF monotherapy groups. The baseline characteristics of patients in the TDF monotherapy (n ¼ 15) and the TDF/LAM combination therapy (n ¼ 66) groups are shown in Table II. There was no significant difference between the TDF group and the TDF/LAM group except for HBeAg positivity and the duration of previous LAM and ADV combination treatment. The mean rates of reduction in the HBV DNA level from baseline between the TDF monotherapy and TDF/LAM combination therapy groups were nearly identical. The rates of virologic response at 6 and 12 months were not significantly different between the TDF monotherapy and TDF/ LAM combination therapy groups (46.7% vs 68.2% at 6 months and 66.7% vs 75.9% at 12 months; logrank test, P ¼ 0.357).
are shown in Table III. The ADV-R group had significantly higher baseline levels of aspartate aminotransferase, ALT (P o 0.05, respectively), and HBV DNA (P o 0.001) than the ADV-P group. The mean reduction in serum HBV DNA levels in the ADV-P group was significantly greater than that in the ADV-R group. A higher proportion of patients in the ADV-P group achieved a virologic response at 6 months (74.5% vs 46.9 %) and 12 months (86.2% vs 56.2%) compared with patients in the ADV-R group (log-rank test, P ¼ 0.008); however, the former subgroup had lower baseline HBV DNA values (mean, 3.49 [1.04] vs 5.07 [1.43] log10 IU/mL for the ADV-P and ADV-R groups, respectively).
Comparison of Virologic Response between the ADV-R and ADV-P Groups
We sought to determine the impact of clinical and virologic factors on virologic response. To determine whether there was any difference in the rates of virologic response according to clinical and virologic factors such as genotypic resistance profile, or TDF monotherapy versus combination therapy with LAM, the virologic response rates were compared according to these variables by using a logistic regression analysis. Table IV presents the predictors of
To determine whether there was any difference in the rates of virologic response according to the presence or absence of genotypic ADV resistance (ADV-R vs ADV-P), the virologic response rates were compared according to these variables by using the log-rank test. The baseline characteristics of patients in the ADV-R (n ¼ 32) and ADV-P (n ¼ 49) groups
Predictors of Virologic Response in Patients Treated With TDF
Table II. The baseline characteristics of patients in the tenofovir disoproxil fumarate (TDF) monotherapy and TDF/lamivudine (LAM) combination groups. Continuous variables are expressed as mean (SD). Characteristic Age, y Sex (male/female) Diagnosis (chronic hepatitis/cirrhosis) AST, IU/L* ALT, IU/L† HBV DNA, log10 IU/mL HBeAg positive Duration of LAM therapy, mo Duration of LAM and ADV therapy, mo Duration of TDF therapy, mo
TDF Monotherapy (n ¼ 15)
TDF þ LAM (n ¼ 66)
P
52.3 (10.9) 14/1 10/5 40.8 (34.3) 70.7 (90.7) 4.67 (1.86) 10 (66.7%) 35.9 (18.5) 54.1 (15.5) 14.6 (3.3)
49.7 (9.2) 50/16 47/19 44.1 (74.9) 66.1 (171.8) 3.99 (1.29) 60 (90.9%) 33.8 (19.5) 42.8 (15.1) 14.9 (2.8)
0.344 0.131 0.728 0.869 0.921 0.097 0.013 0.746 0.017 0.745
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBV ¼ hepatitis B virus; HBeAg ¼ hepatitis B e antigen; ADV ¼ adefovir. * AST upper limit of normal was defined as 40 IU/L. † ALT upper limit of normal was defined as 41 IU/L.
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Clinical Therapeutics
Table III. The baseline characteristics of patients in the following groups: resistance to adefovir (ADV-R) and partial virologic response to adefovir and lamivudine combination therapy (ADV-P). Continuous variables are expressed as mean (SD). ADV-R (n ¼ 32)
ADV-P (n ¼ 49)
P
50.4 (9.4) 26/6 19/13 70.6 (104.6) 121.9 (244.2) 5.07 (1.43) 27 (84.4%) 30.5 (13.3) 43.5 (14.6) 16.1 (3.03)
50.0 (9.7) 38/11 38/11 25.8 (8.6) 31.0 (23.5) 3.49 (1.04) 43 (87.8%) 36.5 (21.7) 45.5 (16.4) 14.1 (2.5)
0.845 0.689 0.080 0.022 0.044 o0.001 0.664 0.267 0.580 0.004
Characteristic Age, y Sex (male/female) Diagnosis (chronic hepatitis/cirrhosis) AST, IU/L* ALT, IU/L† HBV DNA, log10 IU/mL HBeAg positive Duration of LAM therapy, mo Duration of LAM and ADV therapy, mo Duration of TDF therapy, mo
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBV ¼ hepatitis B virus; HBeAg ¼ hepatitis B e antigen; LAM ¼ lamivudine; ADV ¼ adefovir; TDF ¼ tenofovir disoproxil fumarate. * AST upper limit of normal was defined as 40 IU/L. † ALT upper limit of normal was defined as 41 IU/L.
virologic response. Univariate analysis revealed that absolute HBV DNA levels at the start of TDF-based rescue treatment (P o 0.001) and ADV-P (P ¼ 0.009) were significantly related to virologic response. TDF monotherapy, or in combination with LAM, was not related to the achievement of a virologic response (P ¼ 0.357). In the multivariate analysis, the absolute HBV DNA level at the start of TDF rescue treatment (odds ratio, 0.556 [95% CI, 0.422–0.731]; P o 0.001) was the only variable significantly associated with virologic response. However, the presence or absence of genotypic ADV resistance did not affect the virologic response rates (P ¼ 0.693). To determine whether an optimal cutoff level of HBV DNA at baseline for TDF-based rescue treatment predicted a virologic response, the HBV DNA cutoff values that provided maximal predictive efficacy were analyzed. In our study, the best cutoff value of HBV DNA level for the prediction of virologic response was 5.0 log10 IU/mL at the start of TDF-based rescue therapy, with a sensitivity and specificity of 85.0% and 75.0%, respectively. Using the cutoff value of HBV DNA at the start of TDF-based rescue therapy, the cumulative virologic response rates in patients (n ¼ 24) with HBV DNA levels Z5.0 log10 IU/mL and
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in those (n ¼ 57) with HBV DNA levels o5.0 log10 IU/mL were 20.8% versus 82.5% at 6 months, and 34.0% versus 91.1% at 12 months, respectively (logrank test, P o 0.001) (Figure).
DISCUSSION Limited data are available regarding the comparison between efficacy of TDF monotherapy and TDF/LAM combination therapy in patients who had an incomplete virologic response after receiving ADV and LAM combination as salvage therapy for LAM resistance. In the present study, TDF-based rescue therapy produced a strong viral suppression in these patients. In addition, TDF monotherapy was as effective as TDF/ LAM combination therapy in maintaining viral suppression in our patients. We also found that treatment efficacy of TDF or TDF/LAM combination therapy was not statistically different according to the presence of ADV resistance. Moreover, multivariate analysis revealed that HBV DNA level at the start of TDF-based rescue therapy was the only predictor of subsequent virologic response. For patients with LAM resistance, ADV add-on therapy is highly effective in maintaining viral suppression and preventing the emergence of ADV
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J.H. Park et al.
Table IV. Analysis for predictive factors of virologic response. Univariate Analysis Variable Age Sex Diagnosis (chronic hepatitis/cirrhosis) Duration of TDF therapy AST ALT HBeAg positive HBV DNA at the start of rescue therapy TDF vs TDF þ LAM ADV-R vs ADV-P Duration of previous therapy
Multivariate Analysis
HR
95% CI
P
HR
95% CI
P
0.994 0.905 0.844 0.938 0.998 0.999 0.753 0.563 0.997 0.478 0.773
0.968–1.020 0.490–1.672 0.494–1.442 0.854–1.029 0.993–1.003 0.997–1.001 0.382–1.485 0.446–0.709 0.992–1.004 0.275–0.831 0.392–1.525
0.635 0.750 0.535 0.175 0.382 0.535 0.413 o 0.001 0.357 0.009 0.458
0.990 0.822 0.789 1.003 0.994 1.003 0.662 0.556 0.745 0.619 0.949
0.956–1.026 0.423–1.599 0.388–1.603 0.909–1.107 0.978–1.010 0.997–1.010 0.285–1.541 0.422–0.731 0.074–7.449 0.057–6.695 0.442–2.042
0.587 0.564 0.512 0.952 0.486 0.320 0.339 o0.001 0.802 0.693 0.894
HR ¼ hazard ratio; TDF ¼ tenofovir disoproxil fumarate; AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBeAg ¼ hepatitis B e antigen; HBV ¼ hepatitis B virus; LAM ¼ lamivudine; ADV-R ¼ resistance to adefovir; ADV-P ¼ partial virologic response to adefovir and lamivudine combination therapy.
resistance.6,10 However, recent studies have shown the existence of a virus resistant to both these drugs.12,18 All of the patients assessed in the present study developed virologic breakthrough and genotypic resistance after LAM treatment, and they were treated with ADV and LAM combination as salvage therapy for LAM resistance. In our study, failure of LAM and ADV combination therapy occurred in 108 (32.8%) of the 329 patients. Therefore, the antiviral efficacy of ADV and LAM combination was not satisfactory. Currently, for patients with LAM-resistant CHB infection, switching to or adding TDF are considered therapeutic options.12,18 Recent studies on the efficacy of TDF or TDF and emtricitabine combination therapy found that TDF treatment is highly effective in maintaining viral suppression in patients with ADVresistant HBV or suboptimal response to ADV.14,16,17 Van Bommel et al14 have reported that TDF rescue therapy strongly suppressed HBV DNA level in patients with CHB who failed to achieve a virologic response to sequential ADV treatment for LAM resistance. Another study by Patterson et al16 analyzed the efficacy of TDF in patients with CHB who had previously failed to respond with LAM therapy, and these patients exhibited significant viral replication despite at least 24 weeks of treatment with
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ADV. At 48 and 96 weeks, 46% and 64% of patients, respectively, achieved undetectable HBV DNA levels (o15 IU/ml). However, data on TDF use in LAMresistant CHB patients who failed to respond to LAM plus ADV rescue therapy are rare. In their study, van Bommel et al17 reported that TDF rescue therapy strongly suppressed HBV DNA levels in 29 patients who failed to achieve a virologic response to LAM and ADV combination treatment for LAM resistance. However, all of the patients received TDF alone. A prospective study by Patterson et al16 included 22 patients who failed to respond to LAM and ADV therapy for LAM-resistant CHB. All patients were switched from ADV/LAM to TDF/LAM. In our study, the cumulative rates of virologic response at 6, 12, and 15 months were 64.2%, 74.3%, and 75.9%, respectively. This observation is consistent with the data reported by Patterson et al.16 Our data confirmed that TDF-based rescue therapy demonstrated strong viral suppression in patients who failed to produce a virologic response after receiving ADV and LAM combination as salvage therapy for LAM resistance. Few data are available on the comparison between the efficacy of TDF monotherapy and TDF/LAM combination therapy in LAM-resistant patients with CHB who had failed to respond to treatment with
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Cumulative Rate of Virologic Response (%)
Clinical Therapeutics Log-rank P < 0.001
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HBV DNA
Efficacy of Tenofovir-Based Rescue Therapy in Lamivudine-Resistant Chronic Hepatitis B Patients With Failure of Lamivudine and Adefovir Combination Jae Ho Park, MD1; Seok Won Jung, MD, PhD1; Neung Hwa Park, MD, PhD1,2; Bo Ryung Park, MS2; Min-Ho Kim, PhD2; Chang Jae Kim, PhD2; Byung Uk Lee, MD1; In Du Jeong, MD, PhD1; Byung Gyu Kim, MD, PhD1; Sung-Jo Bang, MD, PhD1; and Jung Woo Shin, MD, PhD1 1
Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea; and 2Biomedical Research Center, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Republic of Korea
ABSTRACT Purpose: In chronic hepatitis B patients, lamivudine (LAM) and adefovir (ADV) combination therapy is commonly used as a rescue therapy for LAM resistance, but it often results in incomplete viral suppression. We investigated the antiviral efficacy of tenofovir (TDF)/LAM combination therapy versus TDF monotherapy in LAM-resistant chronic hepatitis B (CHB) patients who failed to respond to LAM plus ADV rescue therapy. Methods: Among 108 patients with LAM-resistant CHB who had a partial virologic response (VR) to LAM and ADV combination therapy, Eighty one patients were finally included in this study. Findings: Resistance to ADV (ADV-R) was present in 32 patients (39.5%), and the remaining 49 patients (60.5%) had a partial virologic response to LAM/ ADV combination (ADV-P). The study subjects were treated with TDF alone (n=15) or TDF/LAM combination (n=66). VR was achieved in 61 patients (75.3%). The rates of VR at 6 and 12 months were not significantly different between TDF monotherapy and TDF/LAM combination therapy groups (46.7 vs. 68.2% at 6 months, and 66.7 vs. 75.9% at 12 months, log-rank P=0.357). Treatment efficacy of TDF alone or TDF/LAM combination was not statistically different according to pre-existing ADV or LAM resistant strains. In multivariate analysis, absolute HBV DNA levels at the start of TDF rescue treatment (Po0.001; OR, 0.556; 95% CI, 0.422-0.731) were the only significantly associated with VR. Implications: TDF monotherapy was as effective as TDF/LAM combination therapy in maintaining viral
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suppression in patients with LAM-resistant patients who failed to respond to LAM/ADV combination therapy. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: adefovir resistance, chronic hepatitis B, lamivudine resistance, tenofovir.
INTRODUCTION Lamivudine (LAM), the first oral antiviral agent approved for the treatment of chronic hepatitis B (CHB), is safe and well tolerated, including in patients with decompensated liver cirrhosis. However, resistance to LAM emerges in 20% of patients after 1 year of treatment and in 70% of patients after 5 years.1 Development of LAM resistance is associated with viral relapse, biochemical breakthrough, clinical deterioration, and loss of the favorable effects obtained with LAM treatment.2 Adefovir (ADV) has been shown to potently suppress LAM-resistant hepatitis B virus (HBV).3,4 Early studies have found that adding ADV to LAM therapy or switching to ADV can suppress viral replication and provide significant histologic improvement in patients with LAM resistance.3,5 However, according to results of a comparative study, adding ADV to ongoing LAM therapy was preferable to switching to ADV monotherapy in terms
Accepted for publication April 13, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.04.007 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics of potent antiviral effects and a lower rate of resistance.6 Previous treatment guidelines therefore recommended the use of a combination of LAM and ADV as salvage therapy to treat LAM resistance in patients with CHB. In addition, higher rates of viral suppression, particularly when it is introduced early, as well as fewer hepatic flares and a reduced potential for the development of ADV resistance have been reported.7–10 Other studies reported insufficient virologic responses after administration of ADV add-on LAM therapy in patients with higher baseline HBV DNA levels.10–12 Seto et al12 reported that among patients with higher baseline HBV DNA levels (Z8 log10 copies/mL), up to 25% of patients treated with LAM and ADV combination therapy failed to achieve a satisfactory virologic response. Tenofovir disoproxil fumarate (TDF) is a potent, once-daily nucleotide analogue anti-HBV medication recommended as a first-line therapy in CHB.8,13 TDF partially suppresses ADV-resistant HBV, and it is also highly effective against LAM-resistant virus, suggesting that this drug may be an effective treatment for patients who have previously failed to respond to treatment with LAM and ADV.14 Several studies also reported that TDF alone or in combination with entecavir or LAM has been evaluated as a rescue strategy for patients with suboptimal responses or virologic breakthrough during ADV therapy.14–17 However, patients in these studies had genotypic resistance or suboptimal response to ADV, and they were either ADV-naive or received ADV monotherapy as salvage therapy for LAM resistance. Therefore, data on TDF use in LAM-resistant CHB patients who failed to respond to LAM plus ADV rescue therapy are rare. In addition, there is debate about whether TDF is an effective choice as monotherapy for patients with previous suboptimal response or virologic breakthrough on LAM and ADV combination therapy for LAM-resistant CHB. The objective of the present study was to evaluate the efficacy and safety of TDF-based rescue therapy in patients with LAM-resistant CHB who had an incomplete virologic response after receiving ADV and LAM combination therapy for at least 12 months. TDF monotherapy versus TDF/LAM combination therapy was also compared in these patients.
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PATIENTS AND METHODS Patient Population The electronic medical records of patients with CHB who had developed LAM resistance were reviewed. A total of 447 patients with CHB and genotypic evidence of LAM-resistant HBV were treated with LAM and ADV from August 2003 to April 2012. Among these 447 patients, 329 received LAM (100 mg/d) and ADV (10 mg/d) combination therapy for 412 months. The remaining 118 patients were excluded from the study: 37 patients received combination therapy for o12 months, 35 patients had irregular treatment due to poor compliance, and 46 patients were lost to follow-up. A total of 108 (32.8%) patients had a partial virologic response (PVR). Among these 108 patients with a PVR, 81 who had been treated with TDF (300 mg/d) based rescue therapy for 46 months were included in this study. The remaining 27 patients were excluded: 7 patients received TDF-based rescue therapy for o6 months, 11 patients received continuous LAM and ADV combination therapy without TDF-based rescue therapy, and 9 patients were switched to entecavir (1 mg/d) and ADV combination therapy. All patients had detectable hepatitis B surface antigen, and HBV DNA in serum was documented for at least 6 months before the start of LAM therapy. Patients with impaired renal function (serum creatinine 41.5 mg/dL), antibodies to hepatitis C virus, antibodies to HIV, or autoimmune hepatitis were excluded. Additional criteria for exclusion were pregnancy, lactation, and alcohol abuse (440 g/d of ethanol). Diagnoses of chronic hepatitis and liver cirrhosis were based on results of liver biopsy (n = 6 [7.4%]) or, if these were unavailable, diagnoses were based on clinical, laboratory, and ultrasound data. Written informed consent was obtained from all patients participating in the study. This research was approved by the institutional review board at the Ulsan University Hospital.
Laboratory Measurements Liver and kidney function tests were performed every 3 months during TDF-based rescue therapy. HBV DNA levels were quantified by using the COBAS TaqMan HBV test (Roche Molecular Systems Inc, Branchburg, New Jersey), which has a lower detection limit of 12 IU/mL (60 copies/mL). Genotypic resistance to LAM or ADV was tested by restriction fragment mass polymorphism (GeneMatrix Inc, Yongin, Republic of Korea) assay, which can
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J.H. Park et al. detect 100 copies of HBV genome per milliliter. The specific HBV genotypes were identified by using the polymerase chain reaction–restriction fragment length polymorphism of the surface gene of the HBV genome. The 2 fragments of the HBV genome between the nucleotide positions 2823 and 2845 and between 61 and 80 were amplified by using polymerase chain reaction, and the products were treated with restriction enzymes. Patients underwent surveillance for hepatocellular carcinoma every 6 months; serial abdominal ultrasound and serum α-fetoprotein measurements were performed.
Definitions A virologic response was defined as the absence of serum HBV DNA according to polymerase chain reaction assay (o12 IU/mL) on 2 consecutive measurements during TDF-based rescue treatment. Hepatitis B e antigen (HBeAg) seroconversion was defined as the loss of HBeAg accompanied by the detection of anti-HBe and the absence of serum HBV DNA during treatment. PVR was defined as a decrease in HBV DNA of 41 log10 IU/mL but detectable HBV DNA after 12 months of antiviral therapy. Failure of LAM and ADV combination therapy included PVR or the development of ADV resistance. Virologic breakthrough was defined as an increase of 41 log10 IU/mL in the serum HBV DNA level from the nadir on 2 consecutive measurements or at the last available measurement.
Statistical Methods Serum HBV DNA levels were logarithmically transformed for analysis. Continuous variables were compared by using the Student’s t test, and categorical variables were compared by using the χ2 test. The Kaplan-Meier method was used to calculate the cumulative probabilities of clinical outcomes. To identify the factors predictive of outcome among the baseline variables, the variables for clinical outcomes were compared by using the χ2 test or univariate logistic regression. Multivariate analysis was conducted with the use of a stepwise logistic regression model. To determine the predictive value of baseline serum HBV DNA level for predicting the virologic response to TDF treatment, the odds ratio and receiver-operating characteristic curves were evaluated, with overall accuracy assessed according to the AUC. The AUCs and the corresponding 95% CIs were measured to assess the degree of discrimination provided by these variables.
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All data were analyzed by using SPSS for Windows version 19.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). In all cases, a 2-tailed P value o 0.05 was considered statistically significant.
RESULTS Overall Clinical Outcomes of TDF-Based Therapy The baseline characteristics of the 81 patients with CHB are shown in Table I. All patients belonged to genotype C2. All patients had been treated with LAM as a first-line oral antiviral agent and had genotypic resistance to LAM. The median duration of LAM therapy was 29 months (range, 13–110 months). Before undergoing TDF-based rescue therapy, all patients were treated with the LAM and ADV combination for 412 months as salvage therapy for LAM resistance. The median duration of LAM and ADV combination treatment was 45.5 months (range, 13–87 months). Among these 81 patients, resistance to ADV (ADV-R) occurred in 32 patients (39.5%) after a median of 35 months (range, 13–66 months) of LAM and ADV combination treatment, and the remaining 49 patients (60.5%) had a PVR to LAM and ADV combination treatment (ADV-P). The known genotypic ADV mutations rtA181T, rtA181V, rtN236T, rtA181T rtN236T, and rtA181V rtN236T were detected in 11, 4, 3, 8, and 6 patients, respectively. Study patients were treated with TDF alone (n ¼ 15) or TDF/LAM combination (n ¼ 66) therapy according to clinician or patient choice. The median follow-up during TDF or TDF/LAM combination treatment was 15 months (range, 8–22 months). Of the 81 study patients, 73 received TDFbased rescue therapy for 412 months. Twenty-four (29.6%) of the 81 patients had liver cirrhosis, and 70 (86.4%) patients were HBeAg positive. The mean HBV DNA level before TDF-based treatment was 4.11 (1.43) log10 IU/mL. Twenty-one (25.9%) patients had abnormal alanine aminotransferase (ALT) levels. The mean pretreatment HBV DNA levels were 4.11 (1.46) log10 IU/mL in HBeAg-positive CHB patients and 4.14 (1.25) log10 IU/mL in HBeAgnegative CHB patients. The mean pretreatment HBV DNA levels were similar between HBeAg-positive and HBeAg-negative patients with CHB (P ¼ 0.940). Among the 21 patients with elevated ALT levels at baseline, 17 (81.0%) achieved ALT normalization during TDF-based treatment. During TDF-based therapy, virologic response was achieved in 61 patients
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Clinical Therapeutics
Table I. Baseline characteristics of the 81 study patients. Continuous variables are expressed as median (range) or mean (SD). Characteristic Age, y Sex (male/female) Diagnosis (chronic hepatitis/cirrhosis) AST, IU/L* ALT, IU/L† HBV DNA, log10 IU/mL HBeAg positive Duration of LAM therapy, mo Duration of LAM and ADV therapy, mo Genotypic resistance to ADV (n ¼ 32) rtA181T rtA181V rtN236T rtA181T rtN236T rtA181V rtN236T
Value 51.0 (26–67) 64/17 57/24 43.5 (69.0) 67.0 (159.5) 4.11 (1.43) 70 (86.4%) 29 (13–110) 45.5 (13–87) n ¼ 11 n¼4 n¼3 n¼8 n¼6
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBV ¼ hepatitis B virus; HBeAg ¼ hepatitis B e antigen; LAM ¼ lamivudine; ADV ¼ adefovir. * AST upper limit of normal was defined as 40 IU/L. † ALT upper limit of normal was defined as 41 IU/L.
(75.3%). The cumulative rates of virologic response at 6, 12, and 15 months were 64.2%, 74.3%, and 75.9%, respectively. During the follow-up visits, 7 patients (8.6%) were found to be nonadherent to the TDF-based rescue therapy. Among the 73 patients who received TDF-based rescue therapy for 412 months, 15 (20.6%) patients experienced a PVR. Among these 15 patients, 6 (40%) had an rtN236T mutation of ADV before TDF-based rescue therapy, and 2 patients had poor adherence to TDF-based rescue therapy. Virologic breakthrough was observed in 3 (3.7%) patients at 9 to 11 months after starting TDF therapy; medical review revealed that these 3 patients had poor adherence to TDF. In HBeAg-positive patients (n ¼ 70), the cumulative probability of achieving a virologic response at 6, 12, and 15 months was 63.7%, 71.4%, and 73.5%, respectively. Among HBeAg-negative patients (n ¼ 11), 10 (90.9%) had achieved a virologic response. There was no statistically significant difference between HBeAgpositive and HBeAg-negative patients (P ¼ 0.305). Five (7.1%) of the 70 HBeAg-positive patients underwent
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HBeAg seroconversion during TDF-based rescue treatment. However, none of the patients experienced loss of serum hepatitis B surface antigen during treatment. No significant clinical adverse events occurred during the TDF-based treatment. Mean creatinine levels and estimated glomerular filtration rate revealed no significant change during the treatment period. Two patients (3.1%) had an increase in serum creatinine level. However, none of the patients had an increase in serum creatinine level 40.5 mg/dL above the baseline value. Mild hypophosphatemia (a serum phosphorus level of o2.7 mg/dL) was detected in 1 patient, with no change in serum creatinine level. One patient developed hepatocellular carcinoma during the follow-up period.
Comparison of Virologic Response between the TDF/LAM Combination Therapy and TDF Monotherapy Groups The virologic response rates were compared by using a log-rank test to define whether there was any difference in the virologic response rates between the
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J.H. Park et al. TDF/LAM and TDF monotherapy groups. The baseline characteristics of patients in the TDF monotherapy (n ¼ 15) and the TDF/LAM combination therapy (n ¼ 66) groups are shown in Table II. There was no significant difference between the TDF group and the TDF/LAM group except for HBeAg positivity and the duration of previous LAM and ADV combination treatment. The mean rates of reduction in the HBV DNA level from baseline between the TDF monotherapy and TDF/LAM combination therapy groups were nearly identical. The rates of virologic response at 6 and 12 months were not significantly different between the TDF monotherapy and TDF/ LAM combination therapy groups (46.7% vs 68.2% at 6 months and 66.7% vs 75.9% at 12 months; logrank test, P ¼ 0.357).
are shown in Table III. The ADV-R group had significantly higher baseline levels of aspartate aminotransferase, ALT (P o 0.05, respectively), and HBV DNA (P o 0.001) than the ADV-P group. The mean reduction in serum HBV DNA levels in the ADV-P group was significantly greater than that in the ADV-R group. A higher proportion of patients in the ADV-P group achieved a virologic response at 6 months (74.5% vs 46.9 %) and 12 months (86.2% vs 56.2%) compared with patients in the ADV-R group (log-rank test, P ¼ 0.008); however, the former subgroup had lower baseline HBV DNA values (mean, 3.49 [1.04] vs 5.07 [1.43] log10 IU/mL for the ADV-P and ADV-R groups, respectively).
Comparison of Virologic Response between the ADV-R and ADV-P Groups
We sought to determine the impact of clinical and virologic factors on virologic response. To determine whether there was any difference in the rates of virologic response according to clinical and virologic factors such as genotypic resistance profile, or TDF monotherapy versus combination therapy with LAM, the virologic response rates were compared according to these variables by using a logistic regression analysis. Table IV presents the predictors of
To determine whether there was any difference in the rates of virologic response according to the presence or absence of genotypic ADV resistance (ADV-R vs ADV-P), the virologic response rates were compared according to these variables by using the log-rank test. The baseline characteristics of patients in the ADV-R (n ¼ 32) and ADV-P (n ¼ 49) groups
Predictors of Virologic Response in Patients Treated With TDF
Table II. The baseline characteristics of patients in the tenofovir disoproxil fumarate (TDF) monotherapy and TDF/lamivudine (LAM) combination groups. Continuous variables are expressed as mean (SD). Characteristic Age, y Sex (male/female) Diagnosis (chronic hepatitis/cirrhosis) AST, IU/L* ALT, IU/L† HBV DNA, log10 IU/mL HBeAg positive Duration of LAM therapy, mo Duration of LAM and ADV therapy, mo Duration of TDF therapy, mo
TDF Monotherapy (n ¼ 15)
TDF þ LAM (n ¼ 66)
P
52.3 (10.9) 14/1 10/5 40.8 (34.3) 70.7 (90.7) 4.67 (1.86) 10 (66.7%) 35.9 (18.5) 54.1 (15.5) 14.6 (3.3)
49.7 (9.2) 50/16 47/19 44.1 (74.9) 66.1 (171.8) 3.99 (1.29) 60 (90.9%) 33.8 (19.5) 42.8 (15.1) 14.9 (2.8)
0.344 0.131 0.728 0.869 0.921 0.097 0.013 0.746 0.017 0.745
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBV ¼ hepatitis B virus; HBeAg ¼ hepatitis B e antigen; ADV ¼ adefovir. * AST upper limit of normal was defined as 40 IU/L. † ALT upper limit of normal was defined as 41 IU/L.
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Clinical Therapeutics
Table III. The baseline characteristics of patients in the following groups: resistance to adefovir (ADV-R) and partial virologic response to adefovir and lamivudine combination therapy (ADV-P). Continuous variables are expressed as mean (SD). ADV-R (n ¼ 32)
ADV-P (n ¼ 49)
P
50.4 (9.4) 26/6 19/13 70.6 (104.6) 121.9 (244.2) 5.07 (1.43) 27 (84.4%) 30.5 (13.3) 43.5 (14.6) 16.1 (3.03)
50.0 (9.7) 38/11 38/11 25.8 (8.6) 31.0 (23.5) 3.49 (1.04) 43 (87.8%) 36.5 (21.7) 45.5 (16.4) 14.1 (2.5)
0.845 0.689 0.080 0.022 0.044 o0.001 0.664 0.267 0.580 0.004
Characteristic Age, y Sex (male/female) Diagnosis (chronic hepatitis/cirrhosis) AST, IU/L* ALT, IU/L† HBV DNA, log10 IU/mL HBeAg positive Duration of LAM therapy, mo Duration of LAM and ADV therapy, mo Duration of TDF therapy, mo
AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBV ¼ hepatitis B virus; HBeAg ¼ hepatitis B e antigen; LAM ¼ lamivudine; ADV ¼ adefovir; TDF ¼ tenofovir disoproxil fumarate. * AST upper limit of normal was defined as 40 IU/L. † ALT upper limit of normal was defined as 41 IU/L.
virologic response. Univariate analysis revealed that absolute HBV DNA levels at the start of TDF-based rescue treatment (P o 0.001) and ADV-P (P ¼ 0.009) were significantly related to virologic response. TDF monotherapy, or in combination with LAM, was not related to the achievement of a virologic response (P ¼ 0.357). In the multivariate analysis, the absolute HBV DNA level at the start of TDF rescue treatment (odds ratio, 0.556 [95% CI, 0.422–0.731]; P o 0.001) was the only variable significantly associated with virologic response. However, the presence or absence of genotypic ADV resistance did not affect the virologic response rates (P ¼ 0.693). To determine whether an optimal cutoff level of HBV DNA at baseline for TDF-based rescue treatment predicted a virologic response, the HBV DNA cutoff values that provided maximal predictive efficacy were analyzed. In our study, the best cutoff value of HBV DNA level for the prediction of virologic response was 5.0 log10 IU/mL at the start of TDF-based rescue therapy, with a sensitivity and specificity of 85.0% and 75.0%, respectively. Using the cutoff value of HBV DNA at the start of TDF-based rescue therapy, the cumulative virologic response rates in patients (n ¼ 24) with HBV DNA levels Z5.0 log10 IU/mL and
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in those (n ¼ 57) with HBV DNA levels o5.0 log10 IU/mL were 20.8% versus 82.5% at 6 months, and 34.0% versus 91.1% at 12 months, respectively (logrank test, P o 0.001) (Figure).
DISCUSSION Limited data are available regarding the comparison between efficacy of TDF monotherapy and TDF/LAM combination therapy in patients who had an incomplete virologic response after receiving ADV and LAM combination as salvage therapy for LAM resistance. In the present study, TDF-based rescue therapy produced a strong viral suppression in these patients. In addition, TDF monotherapy was as effective as TDF/ LAM combination therapy in maintaining viral suppression in our patients. We also found that treatment efficacy of TDF or TDF/LAM combination therapy was not statistically different according to the presence of ADV resistance. Moreover, multivariate analysis revealed that HBV DNA level at the start of TDF-based rescue therapy was the only predictor of subsequent virologic response. For patients with LAM resistance, ADV add-on therapy is highly effective in maintaining viral suppression and preventing the emergence of ADV
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J.H. Park et al.
Table IV. Analysis for predictive factors of virologic response. Univariate Analysis Variable Age Sex Diagnosis (chronic hepatitis/cirrhosis) Duration of TDF therapy AST ALT HBeAg positive HBV DNA at the start of rescue therapy TDF vs TDF þ LAM ADV-R vs ADV-P Duration of previous therapy
Multivariate Analysis
HR
95% CI
P
HR
95% CI
P
0.994 0.905 0.844 0.938 0.998 0.999 0.753 0.563 0.997 0.478 0.773
0.968–1.020 0.490–1.672 0.494–1.442 0.854–1.029 0.993–1.003 0.997–1.001 0.382–1.485 0.446–0.709 0.992–1.004 0.275–0.831 0.392–1.525
0.635 0.750 0.535 0.175 0.382 0.535 0.413 o 0.001 0.357 0.009 0.458
0.990 0.822 0.789 1.003 0.994 1.003 0.662 0.556 0.745 0.619 0.949
0.956–1.026 0.423–1.599 0.388–1.603 0.909–1.107 0.978–1.010 0.997–1.010 0.285–1.541 0.422–0.731 0.074–7.449 0.057–6.695 0.442–2.042
0.587 0.564 0.512 0.952 0.486 0.320 0.339 o0.001 0.802 0.693 0.894
HR ¼ hazard ratio; TDF ¼ tenofovir disoproxil fumarate; AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase; HBeAg ¼ hepatitis B e antigen; HBV ¼ hepatitis B virus; LAM ¼ lamivudine; ADV-R ¼ resistance to adefovir; ADV-P ¼ partial virologic response to adefovir and lamivudine combination therapy.
resistance.6,10 However, recent studies have shown the existence of a virus resistant to both these drugs.12,18 All of the patients assessed in the present study developed virologic breakthrough and genotypic resistance after LAM treatment, and they were treated with ADV and LAM combination as salvage therapy for LAM resistance. In our study, failure of LAM and ADV combination therapy occurred in 108 (32.8%) of the 329 patients. Therefore, the antiviral efficacy of ADV and LAM combination was not satisfactory. Currently, for patients with LAM-resistant CHB infection, switching to or adding TDF are considered therapeutic options.12,18 Recent studies on the efficacy of TDF or TDF and emtricitabine combination therapy found that TDF treatment is highly effective in maintaining viral suppression in patients with ADVresistant HBV or suboptimal response to ADV.14,16,17 Van Bommel et al14 have reported that TDF rescue therapy strongly suppressed HBV DNA level in patients with CHB who failed to achieve a virologic response to sequential ADV treatment for LAM resistance. Another study by Patterson et al16 analyzed the efficacy of TDF in patients with CHB who had previously failed to respond with LAM therapy, and these patients exhibited significant viral replication despite at least 24 weeks of treatment with
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ADV. At 48 and 96 weeks, 46% and 64% of patients, respectively, achieved undetectable HBV DNA levels (o15 IU/ml). However, data on TDF use in LAMresistant CHB patients who failed to respond to LAM plus ADV rescue therapy are rare. In their study, van Bommel et al17 reported that TDF rescue therapy strongly suppressed HBV DNA levels in 29 patients who failed to achieve a virologic response to LAM and ADV combination treatment for LAM resistance. However, all of the patients received TDF alone. A prospective study by Patterson et al16 included 22 patients who failed to respond to LAM and ADV therapy for LAM-resistant CHB. All patients were switched from ADV/LAM to TDF/LAM. In our study, the cumulative rates of virologic response at 6, 12, and 15 months were 64.2%, 74.3%, and 75.9%, respectively. This observation is consistent with the data reported by Patterson et al.16 Our data confirmed that TDF-based rescue therapy demonstrated strong viral suppression in patients who failed to produce a virologic response after receiving ADV and LAM combination as salvage therapy for LAM resistance. Few data are available on the comparison between the efficacy of TDF monotherapy and TDF/LAM combination therapy in LAM-resistant patients with CHB who had failed to respond to treatment with
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Cumulative Rate of Virologic Response (%)
Clinical Therapeutics Log-rank P < 0.001
100
HBV DNA
