Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

Background/Aims:

Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB.

Methods:

We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB.

Results:

The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR.

Conclusions:

TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary.     

Long-term outcomes of two rescue therapies in lamivudine-refractory patients with chronic hepatitis B: combined lamivudine and adefovir,and 1-mg entecavir

Background/Aims

Adefovir (ADV) and lamivudine (LAM) combination therapy (ADV+LAM) has been a useful option for patients with LAM-resistant (LAM-r) chronic hepatitis B (CHB). However, the long-term outcomes of LAM+ADV and 1-mg entecavir (ETV) rescue therapies have still been limited. The aim of this study was to determine the long-term outcomes of these two rescue therapies.

Methods

Sixty patients with LAM-r CHB underwent rescue therapy with LAM+ADV (n=36) or 1-mg ETV (n=24). We determined the duration of rescue therapy, timing and type of mutation, undetectable serum hepatitis B virus (HBV) DNA by PCR (lower limitation of detection, < 140 copies/mL), biochemical response (alanine aminotransferase < 40 IU/mL), and the incidence of hepatitis B virus e antigen (HBeAg) seroconversion and virologic breakthrough.

Results

Baseline characteristics did not differ between the two therapy groups. The duration of rescue therapy was 56 months (range, 14-100 months) in the ADV+LAM group and 42 months (range, 12-73 months) in the ETV group (P=0.036). The cumulative rates of HBV DNA undetectability and HBeAg seroconversion up to 6 years were 88.6% and 43.0%, respectively, in the ADV+LAM group, and 45.8% and 31.8% in the ETV group. The rate of virologic breakthrough and resistance was 14.4% in the ADV+LAM group and 71.9% in the ETV group (P=0.001).

Conclusions

Combination of LAM and ADV therapy for up to 6 years achieved modest rates of virological suppression and resistance. ETV is not an optimal therapy because the risk of viral breakthrough to ETV increases over time.     

Impact of prior lamivudine use on the antiviral efficacy and development of resistance to entecavir in chronic hepatitis B patients

Background/Aims

To determine the efficacies of entecavir (ETV) in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients and in those with prior lamivudine (LAM) use who did not develop resistance.

Methods

We retrospectively enrolled 337 patients with CHB who were treated with ETV (0.5 mg daily) for at least 30 months. The study included 270 (80.1%) NA-naïve patients and 67 (19.9%) LAM-use patients. Ten of the LAM-use patients were refractory to LAM therapy without developing resistance.

Results

Genotypic resistance to ETV developed more frequently in the LAM-use group (13.1%) than in the NA-naïve group (2.6%) at 60 months (P=0.009). In subgroup analysis, after excluding the 10 patients who were refractory to LAM therapy, the cumulative probability of ETV resistance did not differ significantly between the two groups (P=0.149). Prior LAM refractoriness and a higher hepatitis B virus DNA level at month 12 were independent predictive factors for the development of ETV resistance.

Conclusions

ETV resistance developed more frequently in LAM-use patients with CHB. However, prior LAM use without refractoriness did not affect the development of ETV resistance. The serum hepatitis B virus DNA level at month 12 was a major predictor for the development of ETV resistance.     

High efficacy of adefovir and entecavir combination therapy in patients with nucleoside-refractory hepatitis B

Background/Aims

Newly developed and potent antiviral agents suffer from the problem of drug resistance. Multidrug resistance is a major impediment in the treatment of patients with chronic hepatitis B (CHB). In line with American Association for the Study of Liver Diseases guidelines, adefovir dipivoxil (ADV) add-on therapy is recommended in the case of lamivudine resistance, while tenofovir disoproxil fumarate (TDF) is recommended for ADV or entecavir (ETV) resistance. TDF is currently not available in Korea. ADV+ETV combination therapy may be a viable alternative to TDF in patients with either ADV or ETV resistance. However, the efficacy of ADV+ETV combination therapy in patients with CHB and multidrug resistance is unclear. This study investigated the efficacy of ADV+ETV combination therapy in patients with multidrug resistance.

Methods

Twenty-five patients were enrolled and were administered ADV+ETV combination therapy for at least 6 months. Blood was drawn at baseline and at 3, 6, 9, and 12 months after commencing treatment, and the following blood parameters were analyzed: alanine transaminase, hepatitis B e-antigen (HBeAg), anti-hepatitis B e-antigen, and hepatitis B virus (HBV) DNA levels. The initial virological response (IVR) was defined as an HBV DNA level of <4 log₁₀ copies/mL after 6 months of combination therapy.

Results

The IVR rate was 76%. The proportion of patients with a high viral load (≥5.0 log) dropped from 76% at baseline to only 5% after 6 months of treatment. The biochemical response rate during the first 6 months was 71%. HBeAg was lost in 2 patients (10%).

Conclusions

ADV+ETV combination therapy induced a good IVR in CHB patients who were refractory to more than 2 antiviral agents. This regimen may be a good alternative to TDF in Korea, where that drug is not available.     

Lamivudine plus adefovir combination therapy for lamivudine resistance in hepatitis-B-related hepatocellular carcinoma patients

Background/Aims

Lamivudine (LAM) plus adefovir (ADV) combination therapy has been accepted as one of the best treatments for LAM-resistant chronic hepatitis B (CHB). The aim of this study was to determine the efficacy of this combination therapy in hepatocellular carcinoma (HCC) patients.

Methods

The medical records of CHB patients who developed LAM resistance and were treated with LAM plus ADV combination therapy for more than 6 months were reviewed. Their virological response (VR; undetectable HBV DNA) and biochemical response (BR; alanine aminotransferase normalization) were evaluated, and the findings of HCC and non-HCC patients were compared.

Results

The data from 104 patients (19 with HCC and 85 without HCC) were analyzed. The VR rates did not differ significantly between the HCC and non-HCC groups: 33.3% vs. 55.6% at 12 months (P=0.119), 58.3% vs. 67.2% at 24 months (P=0.742), 50% vs. 69.8% at 36 months (P=0.280), and 66.7% vs. 71.0% at 48 months (P=1.000). The BR rates also did not differ significantly between the groups: 55.6% vs. 84.0% at 12 months (P=0.021), 58.3% vs. 83.8% at 24 months (P=0.057), 70.0% vs. 77.8% at 36 months (P=0.687), and 66.7% vs. 80.6% at 48 months (P=0.591).

Conclusions

The efficacy of LAM plus ADV combination therapy is comparable in HCC and non-HCC patients.     

Adefovir-based combination therapy with entecavir or lamivudine for patients with entecavir-refractory chronic hepatitis B

This study evaluated the efficacy of adefovir (ADV) plus lamivudine (LAM) or ADV add‐on therapy for patients with entecavir (ETV)‐refractory hepatitis B infection. Twenty‐nine ETV‐resistant and 8 patients with suboptimal response to ETV were enrolled. Twenty‐seven patients received ADV + LAM therapy and 10 patients received ADV + ETV therapy for >24 weeks. In 29 patients who were ETV‐resistant, the mean reduction in HBV DNA levels at 24 weeks was not different between the ADV + LAM and ADV + ETV groups (?1.98 log₁₀ IU/ml vs. ?2.16 log₁₀ IU/ml; P = 0.792). Primary non‐response was observed in 52.2% (12/23) of ADV + LAM group and 33.3% (2/6) of ADV + ETV group (P = 0.651). Initial virologic response (IVR) was observed in 17.4% (4/23) of ADV + LAM group and 33.3% (2/6) of ETV + ADV group (P = 0.362). In eight patients with suboptimal response to ETV, the ADV + ETV group had a greater reduction in HBV DNA at 24 and 48 weeks than the ADV + LAM group (?2.29 log₁₀ IU/ml vs. ?0.09 log₁₀ IU/ml and ?2.04 log₁₀ IU/ml vs. ?0.72 log₁₀ IU/ml; P = 0.020 and P = 0.012, respectively). Primary non‐response and IVR did not significantly differ between the two groups [100% (4/4) vs. 50% (2/4) and 0% (0/4) vs. 50% (2/4); P = 0.429 and P = 0.429, respectively]. The antiviral efficacies of ADV‐based therapy with ETV or LAM for patients with ETV‐resistant hepatitis B were limited and did not differ between the two groups. However, adding ADV to ETV may be more effective than ADV + LAM therapy in patients with suboptimal virologic response to ETV. J. Med. Virol. 84:18–25, 2011. © 2011 Wiley Periodicals, Inc.     

Antiviral efficacy of combination therapy with entecavir and adefovir for entecavir/lamivudine-resistant hepatitis B virus with or without adefovir resistance

There is little clinical information on the management of hepatitis B virus (HBV) that is resistant to multiple drugs including entecavir (ETV). The present retrospective cohort study assessed the antiviral efficacy of ETV/adefovir dipivoxil (ADV) combination therapy for ETV-resistant HBV with prior lamivudine (LAM) resistance, and either with or without previous ADV resistance. The cumulative probability of achieving a virological response (undetectable serum HBV DNA) was compared by Kaplan-Meier analysis and the Breslow method. Seventeen patients with ETV-resistant HBV who were treated with ETV/ADV combination therapy for at least 6 months at a tertiary care center, were included; seven had dual resistance to ETV and LAM [ADV-r(-) group] and 10 had triple resistance to ETV, LAM, and ADV [ADV-r(+) group]. The median follow-up period was 9 months (range, 6-23). A virological response was noted in seven patients after a median of 3 months (range, 3-12) of treatment; five in the ADV-r(-) group and two in the ADV-r(+) group. The cumulative probability of a virological response was significantly higher in the ADV-r(-) group than in the ADV-r(+) group (6 months cumulative probability, 57.1% vs. 11.1%). In conclusion, ETV/ADV combination therapy led to virological responses in five of seven patients with resistance to ETV and LAM, but a significantly poorer response in patients with prior ADV resistance than in those without prior ADV resistance. Therefore, ETV/ADV combination therapy could be a useful therapeutic option for ETV- and LAM-resistant HBV without prior ADV resistance.     

Entecavir versus tenofovir in patients with chronic hepatitis B: Enemies or partners in the prevention of hepatocellular carcinoma

Over the past several decades, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have remained the first-line antiviral agents in several international guidelines. These two antiviral agents have shown similar short to intermediate-term efficacy, including virologic, biochemical, serologic, and histologic responses. However, huge controversies regarding the antiviral efficacy of ETV and TDF in preventing the development of hepatocellular carcinoma (HCC) still exist. In this review, we summarized recent studies that compared the treatment efficacy of ETV and TDF in terms of HCC development.     

Dynamics of lamivudine-resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapy

Adefovir dipivoxil has been used alone or together with lamivudine to suppress lamivudine-resistant hepatitis B virus (HBV). However, the dynamics of HBV populations under different selection pressures and their impact on treatment outcome are poorly understood. Pyrosequencing was applied to quantify longitudinally the evolution of wild type and lamivudine/adefovir-resistant HBV. Eight patients, with lamivudine-resistant HBV, were randomized to receive adefovir monotherapy or adefovir/lamivudine combination therapy for a median of 79 and 71 weeks, respectively. Pyrosequencing proved highly sensitive with a lower limit of quantitation of minor HBV populations of 2% irrespective of viraemia levels. Adefovir/lamivudine treatment resulted in greater viraemia reduction than adefovir monotherapy. During combination therapy, lamivudine-resistant HBV populations (codons 180 and 204) remained dominant (>90%) and no adefovir-resistance developed. During adefovir monotherapy, reversion to wild-type HBV was detected in two patients with one patient accumulating rapidly adefovir-resistant HBV along with increased viraemia. In conclusion, the dynamics of drug-resistant HBV strains vary under different selection pressures which have a significant impact on the success of rescue therapy, as well as for the selection of new mutations. The use of techniques such as Pyrosequencing provides an evidence-based approach for successful management of drug-resistant HBV.     

Virologic response is not durable after adefovir discontinuation in lamivudine-resistant chronic hepatitis B patients

Background/Aims

We investigated the durability of the biochemical and virologic responses after adefovir (ADV) discontinuation in lamivudine-resistant (LMV-R) chronic hepatitis B (CHB) patients, and the outcomes of ADV discontinuation compared to that of ADV maintenance.

Methods

The indication for ADV treatment cessation was an undetectable level of hepatitis B virus (HBV) DNA documented on two occasions at least 6 months apart. All patients received additional ADV for at least 12 months after the confirmation of undetectable HBV DNA (Cobas TaqMan PCR assay, <70 copies/mL). Of 36 patients who had a sufficient ADV therapeutic effect, 19 discontinued ADV treatment, while the others maintained it. A virologic rebound was arbitrarily defined as the redetection of HBV DNA at a level higher than 10⁵ copies/mL.

Results

In the ADV discontinuation group, ADV treatment and additional therapy were administered for medians of 33 months (range, 12-47 months) and 18 months, respectively. The patients were followed for a median of 12 months (range, 3-30 months) after ADV cessation. During that period, 18 of 19 patients (95%) experienced viral relapse. Viral rebound was observed in six patients (32%). However, 12 of 18 patients (67%) exhibited serum HBV DNA levels of less than 10⁵ copies/mL. Biochemical relapses were observed in four of the six patients with viral rebound. In the ADV maintenance group, patients were treated for a median of 53 months (range, 31-85 months), and 9 patients (53%) experienced viral breakthrough.

Conclusions

During short-term follow-up after ADV discontinuation, most patients (95%) exhibited viral relapse, whereas and viral breakthrough occurred in about half of patients (53%) maintained on ADV therapy. Therefore, the durability of virologic response after ADV discontinuation in LMV-R patients was unsatisfactory. In addition, and viral breakthrough was not infrequent in the ADV continuation group.     

恩替卡韦联合阿德福韦酯治疗拉米夫定耐药的慢性乙型肝炎的疗效

目的 探讨恩替卡韦(ETV)联合阿德福韦酯(ADV)治疗拉米夫定耐药的慢性乙型肝炎(CHB)的疗效.方法 以2012年4月至2013年4月本院收治的拉米夫定耐药的CHB患者90例为研究对象,按随机数字表法分为ETV联合ADV治疗组(A组,n=48)和ETV治疗组(B组,n=42).B组患者口服ETV(0.5 mg/d),每天1次;A组患者在此基础上,联合应用ADV口服(10 mg/d),每天1次,均持续用药48周.治疗前及治疗后12、24、48周检测HBV血清学标志物、血清HBV DNA、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST) 、IL-10水平,计算生物化学应答率、病毒学应答率、HBeAg转阴率、HBeAg血清学转换率.结果 治疗后12、24、48周,两组患者HBVDNA及ALT水平均显著下降(均P＜0.05),且上述各时点A组HBV DNA及ALT水平均显著低于B组(均P＜0.05).治疗后24、48周,A组的生物化学应答率、病毒学应答率均显著高于B组(均P＜ 0.05),但HBeAg转阴率及HBeAg血清学转换率差异无统计学意义(均P＞ 0.05).治疗后12、24、48周,A组IL-10水平均显著低于B组(均P＜0.05).结论 ETV联合ADV治疗拉米夫定耐药的CHB患者中期治疗效果较好.     

Multidrug‐resistant hepatitis B virus resulting from sequential monotherapy with lamivudine,adefovir, and entecavir: Clonal evolution during lamivudine plus adefovir therapy

Whether multidrug‐resistant (MDR) hepatitis B virus (HBV) harbors mutations co‐located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV‐resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETV‐resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV‐resistant mutations. The rtA181T/V mutation emerged after reversion from ETV‐resistant mutants to wild‐type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co‐localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV. J. Med. Virol. 85:55–64, 2012. © 2012 Wiley Periodicals, Inc.     

拉米夫定耐药后的抗乙型肝炎病毒治疗

目的探讨拉米夫定耐药后慢性乙型肝炎患者采用α2b干扰素或α2b干扰素加α1胸腺肽进行后续抗病毒的疗效。方法共66例拉米夫定耐药患者,分治疗组A、治疗组B和对照组。治疗组A26例,单用α2b干扰素治疗1个月后停用拉米夫定,然后继续单用α2b干扰素治疗5个月;治疗组B10例,α2b干扰素和α1胸腺肽联合治疗1个月后停用拉米夫定,然后继续两药联合治疗5个月;对照组30例,直接停用拉米夫定,不用其他任何抗病毒药。定期进行血清肝功和病毒学指标检测。结果治疗组A和治疗组B的HBVDNA阴转率和HBeAg/HBeAb转换率均明显高于对照组。结论慢性乙型肝炎患者拉米夫定耐药后采用α2b干扰素或α2b干扰素加α1胸腺肽进行后续抗病毒治疗可能是有益的。     

Clinical course and predictive factors of virological response in long-term lamivudine plus adefovir dipivoxil combination therapy for lamivudine-resistant chronic hepatitis B patients

The aims of this study were to assess the long‐term efficacy of lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy in patients with chronic hepatitis B resistant to LAM, to identify predictive factors of complete viral response (HBV‐DNA <2.6 log copies/ml at 12 months of combination therapy), and to analyze amino acid substitutions associated with treatment resistance in the hepatitis B virus (HBV) genome. Seventy‐two patients who received ADV in addition to LAM for breakthrough hepatitis were enrolled. Undetectable HBV‐DNA was observed in 61%, 74%, 81%, 84%, and 85% at 12, 24, 36, 48, and 60 months of combination therapy, respectively. On multivariate analysis, undetectable HBV‐DNA during the preceding LAM monotherapy (P < 0.0001), alanine aminotransferase value ≥ the upper limit of normal × 6 (P = 0.006) and HBV‐DNA level < 6.0 log copies/ml at the initiation of combination therapy (P = 0.007) were independent significant predictors of complete viral response. The cumulative rate of undetectable HBV‐DNA was significantly higher in patients with response to the preceding LAM monotherapy than in those with poor response to it. Breakthrough hepatitis occurred in three patients without complete viral response and with poor response to the preceding LAM monotherapy, and rtA181A/V substitution was detected in one of the three patients. In conclusion, undetectable HBV‐DNA during the LAM monotherapy was the strongest independent predictor of complete viral response to the following combination therapy. The efficacy of LAM plus ADV combination therapy may be determined by viral response to the preceding LAM monotherapy. J. Med. Virol. 83:953–961, 2011. © 2011 Wiley‐Liss, Inc.