A randomized, open-label study comparing low-dose clevudine plus adefovir combination therapy with clevudine monotherapy in naive chronic hepatitis B patients.
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ABSTRACT: Purpose
Clevudine 30 mg showed potent antiviral activity with a marked post-treatment antiviral effect. However, long-term treatment with clevudine monotherapy induced resistance and myopathy in some cases. The objective of this study is to evaluate the preliminary efficacy and safety of the combination of clevudine 20 mg and adefovir compared to clevudine monotherapy.Methods
Seventy-four patients were randomized to either a combination of clevudine 20 mg and adefovir or clevudine 20 or 30 mg and were treated for 2 years. The viral kinetics for 24 weeks, virological response [VR; hepatitis B virus (HBV) DNA less than 300 copies/ml], and the biochemical response [BR; normal alanine aminotransferase (ALT)] were assessed.Results
There was no difference in baseline characteristics among the three groups. Viral kinetics study showed no statistically significant difference among them during 24 weeks. The combination group showed 95 % virological response with a statistically significant difference compared to the clevudine 30 mg (67 %) and 20 mg (71 %) groups (p = 0.0376). Biochemical response rates were similar in all groups (78-94 %). No resistance was reported in the combination group, while 20 % of patients treated with clevudine 30 mg or 20 mg reported resistance during 2 years. Muscle-related symptoms such as myalgia (1 in clevudine 30 mg, 1 in the combination group) and muscle weakness (1 in clevudine 30 mg, 2 in clevudine 20 mg) were reported in five patients (7 %); of these, three patients discontinued the study.Conclusion
We concluded that the combination of clevudine 20 mg and adefovir produced a potent antiviral response together with a good resistance profile compared to clevudine monotherapy at 96 weeks in this pilot study.
SUBMITTER: Tak WY
PROVIDER: S-EPMC4116600 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background/aimAcute-on-chronic liver failure (ACLF-B) in spontaneous reactivation of chronic hepatitis B (SR-CHB) has high mortality. Tenofovir disoproxil fumarate (TDF) improves survival by ~40% in ACLF-B but is potentially nephrotoxic. Combining telbivudine (LDT) with TDF may negate this risk and could boost rapid viral clearance and improve clinical outcomes.Patients and methodsSeventy consecutive patients with SR-CHB were randomized to TDF (300 mg/day, n = 35) or TDF plus LDT (600 mg/day; n = 35). In all, 25 had ACLF-B and none had option for liver transplantation. Primary endpoint was survival at 3 months. Secondary endpoints were survival at 3 months in ACLF-B, serial reduction in hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg) loss and liver-related complications.ResultsOverall baseline clinical and laboratory parameters in the two groups were comparable. Reduction in HBV DNA at weeks 2, 4 and 12 was independent of treatment groups and presence of ACLF-B (P < 0.01). All six patients with HBsAg loss at 12 weeks had lower HBV DNA at baseline and none had ACLF-B. Patients with no ACLF-B had more rapid decline in bilirubin and alanine aminotraminase at week 2 compared with ACLF-B. Patients on TDF plus LDT showed significant improvement in AKI on follow-up (five of six patients) compared with TDF monotherapy (none of six patients) and had less reduction in estimated glomerular filtration rate at week 12. Eight of 10 patients with liver-related deaths received TDF monotherapy (P = 0.02). New-onset septic shock, TDF monotherapy, e-antibody positivity, and higher baseline model for end-stage liver disease score were predictors of mortality in ACLF-B. None had treatment-related severe adverse effects.ConclusionAddition of LDT to tenofovir is safe and may be renoprotective in spontaneous reactivation of hepatitis B. Combination therapy improves survival in ACLF-B despite comparable HBV DNA suppression to tenofovir monotherapy.
| S-EPMC6784432 | biostudies-literature
Project description:BackgroundThe efficacy of switching to tenofovir disoproxil fumarate (TDF) monotherapy from lamivudine (LAM) plus adefovir dipivoxil (ADV) combination therapy (stable switching) in patients with LAM-resistant chronic hepatitis B (CHB) and undetectable hepatitis B virus (HBV) DNA is not clear.MethodsIn this non-inferiority trial, patients with LAM-resistant CHB and undetectable serum HBV DNA (<20 IU/mL) for >6 months after initiating LAM+ADV combination therapy were randomized (1:2) either to continue the combination therapy (LAM+ADV group, n = 58) or switched to TDF monotherapy (TDF group, n = 111). They were followed-up with serum biochemistry tests and HBV DNA measurement at 12-week intervals for 96 weeks. The primary endpoint of this study was the proportion of patients with viral reactivation at week 96.ResultsPatients with CHB enrolled in this study (n = 169) included 74 patients with compensated liver cirrhosis. In total, 9 patients (4 in the LAM+ADV group and 5 in the TDF group) dropped-out from the study. After a mean follow-up period of 96 weeks, the proportion of HBV reactivation observed was 6.8% (4/58) in the LAM+ADV group and 4.5% (5/111) in the TDF group by using intention-to-treat analysis (difference, -2.3%; 95% CI, -9.84-5.24%). None of the subjects in either group experienced viral reactivation based on per protocol analysis. No serious adverse reactions were observed. In the subgroup analysis for estimated glomerular filtration rate (eGFR) before and after treatment, decreased eGFR was observed only in the TDF group with cirrhosis (85.22 vs. 79.83 mL/min/1.73 m2, p = 0.000).ConclusionsStable switching to TDF monotherapy yielded non-inferior results at 96 weeks compared to the results obtained with LAM+ADV combination therapy in patients with LAM-resistant CHB and undetectable HBV DNA. However, TDF monotherapy in patients with cirrhosis requires close attention with respect to renal function.Trial registrationClinicalTrials.gov NCT01732367.
| S-EPMC5766122 | biostudies-literature
Project description:A substantial proportion of patients with lamivudine-resistant hepatitis B virus (HBV) show suboptimal virologic response during rescue combination treatment with lamivudine plus adefovir. In this randomized active-control trial, 90 patients with serum HBV DNA levels of >2,000 IU/ml after at least 24 weeks of treatment with lamivudine-plus-adefovir therapy for lamivudine-resistant HBV were randomized to combination treatment with entecavir plus adefovir (ETV+ADV, n = 45) or continuation of lamivudine plus adefovir (LAM+ADV, n = 45) for 52 weeks. At baseline, patients' mean serum HBV DNA level was 4.60 log(10) IU/ml (standard deviation [SD], 1.03). All 90 patients completed 52 weeks of treatment. At week 52, the proportion of patients with serum HBV DNA levels of <60 IU/ml, the primary endpoint, was significantly higher in the ETV+ADV group than in the LAM+ADV group (n = 13, 29%, versus n = 2, 4%, respectively; P = 0.004). The mean reduction in serum HBV DNA levels from baseline was significantly greater in the ETV+ADV group than in the LAM+ADV group (-2.2 log(10) IU/ml versus -0.6 log(10) IU/ml, respectively; P < 0.001). At week 52, additional mutations causing resistance to adefovir or entecavir were analyzed in all patients with detectable HBV DNA by restriction fragment mass polymorphism assays and detected in none of the ETV+ADV group but in 15% of patients in the LAM+ADV group (P = 0.018). Safety and adverse event profiles were similar in the two groups. In conclusion, entecavir-plus-adefovir combination therapy provides superior virologic response and favorable resistance profiles, compared with the continuing lamivudine-plus-adefovir combination, in patients with lamivudine-resistant HBV who fail to respond to lamivudine-plus-adefovir combination therapy.
| S-EPMC3370750 | biostudies-literature
Project description:BackgroundShortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.MethodsIn this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0-F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression.ResultsOf 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0-F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen.ConclusionsOverall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.Trial registrationClinicalTrials.gov NCT01846832.
| S-EPMC4948848 | biostudies-literature
Project description:To examine the efficacy of telbivudine (LdT) + adefovir (ADV) vs continuation of lamivudine (LAM) + ADV in patients with LAM-resistant chronic hepatitis B (CHB) who show a suboptimal response to LAM + ADV.This was a randomized, active-control, open-label, single-center, parallel trial. All eligible patients were enrolled in this study in Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, between March 2010 and March 2011. Hepatitis Be antigen (HBeAg)-positive CHB patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM + ADV therapy were included. Enrolled patients were randomized to either switching to LdT (600 mg/d orally) plus ADV (10 mg/d orally) (LdT + ADV group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally) (LAM + ADV group), and were followed for 48 wk. One hundred and six patients completed the 48-wk treatment period. Serum HBV DNA, HBeAg status, liver biochemistry and safety were monitored at baseline and week 12, 24, 36 and 48.The duration of prior LAM + ADV treatment was 18.3 (LdT + ADV) and 14.9 mo (LAM + ADV), respectively (P = 0.131). No difference was seen in baseline serum HBV DNA between the two groups [3.66 (LdT + ADV) vs 3.76 (LAM + ADV) log10 IU/mL, P = 0.729]. At week 48, although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT + ADV group and LAM + ADV group (-0.81 vs -0.47 log10 IU/mL, P = 0.167), more patients in the LdT + ADV group had undetectable HBV DNA levels compared to those in the LAM + ADV group (30.2% vs 11.5%, P = 0.019). Three patients with LdT + ADV treatment and 2 patients with LAM + ADV treatment achieved HBeAg loss. The patients in both groups tolerated the treatment well without serious adverse events. The proportion of patients with estimated glomerular filtration rate ? 90 mL/min per 1.73 m(2) in the LdT + ADV group increased from 49.1% (26/53) at baseline to 58.5% (31/53) at week 48, while that in the LAM + ADV group decreased from 37.7% (20/53) at baseline to 30.2% (16/53) at week 48.The switch to LdT + ADV in suboptimal responders to LAM + ADV showed a significantly higher rate of virologic response at week 48. These results suggest that LdT + ADV could be a therapeutic option for patients who are unable to use enofovir disoproxil fumarate for any reason.
| S-EPMC3837266 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma.MethodsIn this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed.FindingsBetween Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab.InterpretationPerioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma.FundingBristol Myers Squibb and the US National Institutes of Health.
| S-EPMC8840977 | biostudies-literature
Project description:Background:De novo combination of lamivudine (Lam) and adefovir (Adv) was not rarely used in clinical practice. However, head-to-head comparisons of entecavir (Etv) monotherapy with this combination in hepatitis B virus (HBV)-related compensated cirrhosis patients are unavailable. This study aimed to compare the efficacy and safety of Etv monotherapy with combination therapy in patients with HBV-related compensated liver cirrhosis. Methods:Treatment-naïve patients with HBV-related compensated liver cirrhosis were recruited to receive either Etv monotherapy or a de novo combination of Lam and Adv. Data were collected at baseline and every 6 months thereafter. Results:A total of 578 patients (485 in Etv group, 93 in combination group) were included. Baseline characteristics were comparable between the two groups. At the end of 1, 2, and 3 years, HBV DNA was undetectable in 82.7%, 96.2%, and 94.3% of patients in the Etv group and 88.9%, 81.7%, and 84.6% in the combination group, respectively (all P>0.05). The cumulative virological breakthrough rate at 1, 2, and 3 years was 2.7%, 6.7%, and 9.8% in the Etv group and 2.9%, 13.3%, and 32.2% in the combination group, respectively (P=0.003). After propensity-score adjustment for age, sex, and baseline HBeAg, ALT, and total bilirubin, virological breakthrough was higher in the de novo combination of Lam and Adv (HR 2.83, 95% CI 1.37-5.86; P<0.01). The cumulative rate of liver-related events, including decompensation and hepatocellular carcinoma, at 1, 2, and 3 years was 2.9%, 4.2%, and 6.1% in the Etv group and 2.2%, 2.2%, and 6.7% in combination group, respectively (P=0.83). Biochemical response and serological response were similar between the groups. Conclusion:Etv treatment had less virological breakthrough and potentially higher HBV-DNA suppression than de novo combination of Lam and Adv during 3 years in treatment-naïve HBV-related compensated liver cirrhosis.
| S-EPMC6448536 | biostudies-literature
Project description:INTRODUCTION:Dapagliflozin is a selective sodium glucose co-transporter 2 inhibitor that improves glycemic control and reduces body weight and systolic blood pressure in patients with type 2 diabetes mellitus (T2DM). Dapagliflozin is effective and well tolerated over 12-24 weeks in Japanese patients with T2DM. In this study, the safety and efficacy of dapagliflozin administered as monotherapy and combination therapy were assessed over 52 weeks in Japanese patients with T2DM. METHODS:This was a 52-week open-label Phase 3 study consisting of a single treatment arm with no comparator. Dapagliflozin was administered as monotherapy (n = 249) or combination therapy (n = 479) with existing antihyperglycemic agents (sulfonylurea, glinides, metformin, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or glucagon-like peptide-1 receptor agonists) to Japanese patients with T2DM and inadequate glycemic control for 52 weeks. Treatment with dapagliflozin was initiated at 5 mg/day and titrated to 10 mg/day as required. RESULTS:Dapagliflozin administered as monotherapy or combination therapy was well tolerated. The frequency of adverse events (AEs) over 52 weeks was similar between monotherapy (79.1%) and combination therapy (72.4%) groups, and AEs were mostly mild or moderate. The incidence of hypoglycemia at 52 weeks was 2.4% in the monotherapy group and 4.0% in the combination therapy group. In patients receiving dapagliflozin as monotherapy or combination therapy, reductions from baseline to week 52 were observed in glycosylated hemoglobin (HbA1c) (-0.7% in both groups), weight (-2.6 and -2.1 kg, respectively), and systolic blood pressure (-5.2 mmHg and -3.9 mmHg). In patients with insufficient response to 5 mg/day, dapagliflozin was increased to 10 mg/day, and a further decrease in HbA1c from the pre-titration value was observed in both groups. CONCLUSION:Dapagliflozin was well tolerated and effective as monotherapy or combination therapy in Japanese patients with T2DM over 52 weeks.
| S-EPMC4269643 | biostudies-literature
Project description:IntroductionThe present phase 3, randomized, open-label study compared the efficacy and safety of basal insulin peglispro with insulin glargine after 26 weeks of treatment when added to oral antihyperglycemic medications in insulin-naïve Asian patients with type 2 diabetes.Materials and methodsThe primary objective was to show non-inferiority of the change in glycated hemoglobin from baseline to 26 weeks.ResultsAt 26 weeks, insulin peglispro was non-inferior to glargine, meeting the primary objective. Patients receiving insulin peglispro (n = 192) showed a greater reduction in glycated hemoglobin from baseline compared with glargine (n = 196); -1.6 vs -1.4%, P = 0.005) and in fasting serum glucose (-61.2 vs -54.8 mg/dL, P = 0.02). A significantly higher proportion of patients receiving insulin peglispro achieved glycated hemoglobin <7% (57 vs 44%, P = 0.012). Insulin peglispro patients showed significantly less weight gain from baseline (1.1 vs 1.6 kg, P = 0.03). Relative rates (insulin peglispro/glargine) of total and nocturnal hypoglycemia through 26 weeks were 1.06 (P = 0.67) and 0.7 (P = 0.10), respectively. Significantly more insulin peglispro-treated patients experienced adverse events compared with glargine-treated patients (P = 0.042). Alanine aminotransferase and aspartate aminotransferase were significantly increased from baseline with insulin peglispro compared with glargine at week 26 (3.5 vs -4.6 IU/L and 2.8 vs -1.5 IU/L, respectively; P < 0.001). The incidence of injection site reactions was low and did not differ between the treatments.DiscussionInsulin peglispro provided better glycemic control vs glargine with no differences in hypoglycemia and increased aminotransferases in insulin-naïve Asian patients with type 2 diabetes.
| S-EPMC5754544 | biostudies-literature
Project description:Tenofovir disoproxil fumarate (TDF) monotherapy is a therapeutic option for chronic hepatitis B (CHB) patients infected with hepatitis B virus (HBV) variants resistant to lamivudine (LAM). We evaluated the antiviral efficacy and safety of TDF alone compared to those of TDF plus LAM or telbivudine (LdT) combination in patients harboring HBV variants with genotypic resistance to LAM. This multicenter retrospective study included consecutive patients who had LAM-resistant HBV variants and were treated with TDF alone (monotherapy group) or TDF combined with LAM or LdT (combination therapy group) for at least 6 months. Inverse probability of treatment weighting (IPTW) for the entire cohort was applied to control for treatment selection bias. Overall, 153 patients (33 in the monotherapy group and 120 in the combination therapy group) were analyzed. The overall probability of achieving complete virologic suppression at month 12 was 91.6%: 88.6% in the monotherapy group and 92.6% in the combination therapy group. Combination therapy was not superior to monotherapy in viral suppression before and after IPTW (P=0.562 and P=0.194, respectively). Hepatitis B e antigen (HBeAg) loss, biochemical response, and virologic breakthrough did not differ between treatment groups. The probabilities of complete virologic suppression were comparable between treatment groups in the subsets according to HBeAg status and HBV DNA levels at baseline. No patient experienced any significant renal dysfunction during the treatment period. In conclusion, TDF monotherapy has antiviral efficacy comparable to that of TDF plus LAM or LdT combination therapy, with a favorable safety profile in CHB patients with LAM-resistant HBV variants.
| S-EPMC4335865 | biostudies-literature