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No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection.

ABSTRACT: Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (n = 866) or TDF (n = 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse transcriptase (Pol/RT) were assessed using INNO-LiPA Multi-DR v2/v3. Resistance surveillance was conducted for patients with viremia (HBV DNA ? 69IU/ml) by HBV Pol/RT sequencing at week 96 or at discontinuation. In vitro phenotypic analysis was performed for patients with conserved site substitutions or virologic breakthrough while adherent to the study drug. At baseline, the majority of patients harbored virus with wild-type Pol/RT (89.2%), with 10.8% harboring resistance associated mutations. A similar percentage of patients in the TAF or TDF groups qualified for sequence analysis through week 96 (TAF, 11.1%; TDF, 10.9%). Of these, a small percentage of patients experienced virologic breakthrough (TAF, 2.8%; TDF, 3.2%) that was often associated with drug nonadherence (TAF, 30%; TDF, 50%). Across treatment groups, 132 patients qualified for sequence analysis through week 96, with nearly half having no sequence changes from baseline (43.2%). Most sequence changes occurred at polymorphic positions, and no isolates showed a reduction in susceptibility in vitro After 96 weeks, the proportion of patients achieving virus suppression (HBV DNA < 69 IU/ml) was similar across treatment groups, and no substitutions associated with resistance to TAF or TDF were detected. (These studies have been registered at ClinicalTrials.gov under identifiers NCT01940471 and NCT01940341.).

SUBMITTER: Cathcart AL

PROVIDER: S-EPMC6153810 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection.

Cathcart Andrea L AL Chan Henry Lik-Yuen HL Bhardwaj Neeru N Liu Yang Y Marcellin Patrick P Pan Calvin Q CQ Shalimar Buti Maria M Cox Stephanie S Parhy Bandita B Zhou Eric E Martin Ross R Chang Silvia S Lin Lanjia L Flaherty John F JF Kitrinos Kathryn M KM Gaggar Anuj A Izumi Namiki N Lim Young-Suk YS

Antimicrobial agents and chemotherapy 20180924 10

Tenofovir alafenamide (TAF) has shown equivalent efficacy and improved safety profiles for patients with chronic hepatitis B (CHB) compared to tenofovir disoproxil fumarate (TDF). However, limited data are available for its resistance profiles. In two clinical trials, 1,298 hepatitis E antigen-positive and -negative patients with CHB were randomized 2:1 and treated with TAF (<i>n</i> = 866) or TDF (<i>n</i> = 432). Baseline nucleos(t)ide analog resistance substitutions in HBV polymerase/reverse ...[more]

PMID: 30038044

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Project description:BackgroundTenofovir disoproxil fumarate (TDF) is a prodrug of a nucleotide analogue. As an antiviral drug, TDF has been proposed in the first-line treatment of chronic hepatitis B (CHB). Qingzhong, a brand name of TDF, commercialized by Jiangsu Chia-tai Tianqing Pharmaceutical Co Ltd., and Viread, another brand name of TDF, commercialized by GlaxoSmithKline, have both been approved by the State Food and Drug Administration, China.AimTo investigate the efficacy and safety of the two TDF agents in the treatment of Chinese CHB patients.MethodsThis trial was registered at ClinicalTrials.gov with the identifier number of NCT02287857. A total of 330 Chinese CHB patients, among which 232 were hepatitis B e antigen (HBeAg)-positive, were included in this 5-year-long, multicenter, double-blinded, double-dummy, randomized-controlled, non-inferiority phase III trial. The participants were initially randomized into two groups: Group A (n = 161), in which the participants received 300 mg Qingzhong once a day for 48 wk; and Group B, in which the participants received 300 mg Viread once a day for 48 wk. Starting from week 49, all the participants in Groups A and B received 300 mg Qingzhong once a day until the 96th week. In this study, the primary endpoint was the decrease in plasma level of hepatitis B virus (HBV) DNA at the 96th week, while the secondary endpoints were suppression of HBV replication, alanine aminotransferase (ALT) normalization, HBeAg loss, and HBeAg seroconversion rates.ResultsFor the participants with HBeAg-positive CHB, the decrease in mean HBV DNA level relative to the baseline value was comparable between Groups A and B (5.77 vs 5.73 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-positive participants in the two groups exhibited undetectable levels of HBV DNA, HBeAg loss, and HBeAg seroconversion (71.05% vs 77.97%, 31.00% vs 27.27%, and 20.22% vs 15.79%, respectively, in Group A vs Group B; P > 0.05). For the participants with HBeAg-negative CHB, the decrease in mean HBV DNA level relative to the baseline value was also comparable between Groups A and B (4.46 vs 4.70 log10 IU/mL, P > 0.05) at the 96th week. In addition, similar percentages of HBeAg-negative participants in the two groups exhibited undetectable levels of HBV DNA (87.23% vs 94.12% in Group A vs Group B, respectively; P > 0.05). Finally, similar percentages of CHB patients (HBeAg-positive or HBeAg-negative) in the two groups exhibited normalization of ALT (80.14% vs 84.57% in Group A vs Group B, respectively; P > 0.05), and similar incidences of adverse events were observed (106 vs 104 in Group A vs Group B, respectively; P > 0.05).ConclusionBoth Qingzhong and Viread are effective and safe in the treatment of Chinese CHB patients according to the results of our clinical trial.

Project description:BackgroundTenofovir alafenamide (TAF) has good viral suppression efficacy and less adverse effect than tenofovir disoproxil fumarate (TDF). Real-world studies on the antiviral efficacy and safety of switching from TDF to TAF in patients with chronic hepatitis B (CHB) are limited.MethodsThis retrospective study included 167 nucleos(t)ide analogue (NA)-naive patients with CHB. All the patients received TDF at least 12 months before switching and TAF at least 12 months after switching at a single medical center. The Friedman test with Dunn-Bonferroni post hoc tests and repeated-measures analysis of variance was used to analyze the effect of complete viral suppression, alanine aminotransferase (ALT) level normalization, renal function changes, body weight, and body mass index in the periods before and after switching.ResultsThe mean age and TDF treatment duration were 52 ± 11 years and 2.8 years (interquartile range, 1.51-5.15 years), respectively. The complete viral suppression rate was similar between the time of switching and 48 weeks after switching to TAF (77.8% vs 76%, P = 1.000). The percentage of alanine aminotransferase (ALT) normalization increased from 26.3% at TDF start to 81.4% (P < 0.001) at time of switching and 89.2% at 48 weeks after switching to TAF (P = 0.428). The median estimated glomerular filtration rate decreased from 100.09 mL/min/1.73 m² at TDF start to 91.97 mL/min/1.73 m² (P < 0.001) at the time of switching and stabilized at 48 weeks after switching to TAF (93.47 mL/min/1.73m², P = 1.000). The body weight decreased from 69.2 ± 12.2 kg at TDF start to 67.4 ± 12.1 kg (P < 0.001) at the time of switching to TAF and returned to 68.7 ± 12.7 kg (P < 0.001) 48 weeks thereafter. The body mass index (BMI) decreased from 25 ± 3.3 kg/m² at TDF start to 24.5 ± 3.3 kg/m² (P = 0.002) at the time of switching to TAF and returned to 25.1 ± 3.6 kg/m² (P < 0.001) 48 weeks thereafter.ConclusionsOur study showed that switching to TAF from TDF had good antiviral effectiveness and stabilized renal function. The body weight and BMI decreased during TDF therapy and regained after switching to TAF.

Project description:Tenofovir alafenamide fumarate (TAF) is a first-line drug for the antiviral treatment of patients with chronic hepatitis B (CHB) in China. In the present study, the efficacy and renal safety of TAF were evaluated in treatment-naive patients with CHB. Patients with CHB who had not been previously treated with nucleoside analogues (NAs) were recruited before TAF treatment was initiated. Changes in the levels of hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) were analyzed at 24 and 48 weeks using immunoassays. In addition, liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were analyzed using transient elastography, while alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels, calcium (Ca) and inorganic phosphorus (IP) levels were measured using biochemistry assay. In addition, the estimated glomerular filtration rate (eGFR) was calculated. After 48 weeks, the ALT normalization rate was 95.24% (40/42), the complete virological response (HBV DNA <20 IU/ml) rate was 69.05% (29/42) and the HBeAg seroconversion rate was 8.57% (3/35). The levels of HBV DNA and HBsAg were significantly decreased from the baseline at 5.49±1.95 to 1.26±0.66 log10 IU/ml and from 3.59±0.81 to 3.32±0.55 log10 IU/ml after 48 weeks of treatment, respectively. Compared with that in the baseline measurements, LSM at 48 weeks was significantly decreased from 13.00±8.15 to 8.66±4.45 kPa. No significant differences were observed in the TG, TC, LDL-C, CAP, eGFR, Ca and IP measurements. According to the baseline ALT levels, patients were divided into group A [ALT ≤1 x upper limit of normal (ULN); ULN=50 U/l; n=21], group B (1 x ULN < ALT <2 x ULN; n=22) and group C (ALT ≥2 x ULN; n=18). A significant decrease in HBsAg levels was observed in group B (3.63±0.68 vs. 3.53±0.63 log10 IU/ml) and group C (4.15±0.57 vs. 3.66±0.48 log10 IU/ml) at 24 weeks compared with the baseline. In conclusion, TAF was found to be effective and safe in NA treatment-naive patients with CHB. Moreover, the higher the ALT levels, the more prominent the curative effect from TAF treatment. Therefore, NA treatment-naive CHB patients could benefit from TAF treatment in real world.

Project description:Abstract Background Ritonavir boosted protease inhibitors have been associated with GI intolerance. A post hoc analysis was conducted to assess the GI profile of D/C/F/TAF in treatment naïve patients. Methods The phase 3 AMBER trial (ClinicalTrials.gov: NCT02431247) enrolled treatment naïve patients randomized 1:1 to receive once daily D/C/F/TAF 800/150/200/10 mg or D/C + F/tenofovir disoproxil fumarate (TDF). This post hoc analysis evaluated the incidence, prevalence and duration of GI adverse events of interest (AEOIs) through Wk 96. Related GI AEOIs were defined as diarrhea, nausea, abdominal pain and flatulence (by preferred term using MedDRAv21) deemed very likely, probable, or possibly related to study drug by the investigator. Incidence and prevalence were examined at weekly intervals during the first month of treatment and monthly thereafter. Duration of an AE was calculated for patients whose AEs had start and stop dates. Results In AMBER (N = 725), 362 patients were randomized to D/C/F/TAF and 363 to D/C + F/TDF (Table). Through Wk 48, 14% of D/C/F/TAF patients had a study drug–related GI AEOI vs 19% of D/C + F/TDF patients; of these, all were grade 1/2 and none were serious. Incidence and prevalence of D/C/F/TAF-related GI AEOIs remained low through 96 wks (Figure 1 & 2). Incidence of D/C/F/TAF-related diarrhea and nausea were each 5% in Wk 1 and ≤1% after Wk 2; prevalence of each decreased to < 5% at Wk 2. There was 1 case of D/C/F/TAF-related abdominal discomfort at Wk 1 and none thereafter. Incidence of D/C/F/TAF-related flatulence was < 1% from Wk 1 through Wk 96. Only 2 (1%) patients discontinued before Wk 96 due to a D/C/F/TAF-related GI AEOI (both diarrhea). Through Wk 96, < 3% of patients required treatment with concomitant medication for a D/C/F/TAF-related GI AEOI. Among patients with a D/C/F/TAF-related GI AEOI, the median duration was 16.5 days. Conclusion In AMBER, incidences and prevalences of D/C/F/TAF-related GI AEOIs were low and tended to present early in the study. Combined with rapid decreases in prevalence, these finding suggest that GI AEOIs were transient. Overall, the GI profile of D/C/F/TAF was favorable, and to a greater extent than D/C + F/TDF, suggesting improved tolerance vs an older formulation. Table. Baseline Demographic and Clinical Characteristics Figure 1. Incidence of study drug–related GI AEOIs over time among patients randomized to D/C/F/TAF (n = 362). Figure 2. Prevalence of study drug–related GI AEOIs over time among patients randomized to D/C/F/TAF (n = 362). Disclosures Keith Dunn, PharmD, J&J (Employee, Shareholder) Yangxin Huang, PhD, MS, J&J (Employee) Bryan Baugh, MD, J&J (Employee, Shareholder) Nika Bejou, PharmD, BCIDP, AAHIVP, J&J (Employee, Shareholder) Donghan Luo, PhD, J&J (Employee, Shareholder) Jennifer Campbell, PhD, J&J (Employee, Shareholder) David Anderson, MD, J&J (Employee, Shareholder)

Dataset Information

No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection.

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No Resistance to Tenofovir Alafenamide Detected through 96 Weeks of Treatment in Patients with Chronic Hepatitis B Infection.

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