- Email: [email protected]
Pharmacokinetics, safety and antiviral activity of CMX157, a novel prodrug of tenofovir, administered as ascending multiple doses to healthy volunteers and Hepatitis B virus-infected subjects
ORAL PRESENTATIONS V. Di Marco1 and RESIST-HCV (Rete Sicilia Selezione Terapia – HCV). 1 RESIST-HCV and Palermo; 2RESIST-HCV, Messina; 3RESIST-HCV, Catania; 4RESIST-HCV, Siracusa; 5RESIST-HCV, Agrigento; 6RESIST-HCV, Modica; 7RESIST-HCV, Comiso; 8RESIST-HCV, Enna; 9RESIST-HCV, Castelvetrano; 10RESIST-HCV, Trapani; 11RESIST-HCV, Messina, Italy E-mail: [email protected] Background and Aims: Direct-acting antivirals (DAAs) therapy induces the clearance of hepatitis C virus (HCV) in the majority of patients with chronic liver disease. The risk developing hepatocellular carcinoma (HCC) decreases after Sustained Virological Response (SVR). However, the risk of HCC occurrence during and after DAA based treatment and the clinical pattern is still debated. With this aim we analysed the on-going dataset from RESIST-HCV, which includes all HCV patients who started DAAs treatment in 22 Centres of Sicily. Methods: Between March 2015 and October 2016, 10,123 patients with HCV chronic liver disease were included in the RESIST-HCV and 5130 started the treatment. Each physician established DAA regimen and use of RBV. Patients performed surveillance of HCC as indicate by guidelines before and after treatment. We evaluated the HCC occurrence in 3447 patients who concluded DAA treatment. The primary endpoints of this analysis were the time to HCC occurrence from start of DAA and the pattern of HCC at the diagnosis. Results: Patients had a mean age of 64.3 years, 58% were males and 47% were naïve to antiviral therapy. The diagnosis of chronic hepatitis was performed in 764 patients (22.2%), while 2363 patients (68.6%) had Child-Pugh A cirrhosis and 320 patients (9.2%) had Child-Pugh B cirrhosis. Diabetes was present in 802 patients (23%). The Ribavirin was associated to DAA regimes in 1577 patients (45.7%), 2197 patients (63.7%) received a 12 weeks DAA regimen and 1250 patients (36.3%) received a 24 weeks regimen. During the observation (mean 34.2 weeks, range 8–72) 55 patients developed HCC with an overall rate of 1.44%. The occurrence of HCC was 0.13%, 1.69% and 4.37% in chronic hepatitis, Child-Pugh A cirrhosis and Child-Pugh B cirrhosis, respectively (p < 0.001). At the time of HCC diagnosis 49 patients (89.1%) meet Milan criteria and 6 patients (10.9%) were Milan-out. The evaluation of SVR was available in 2001 patients. By intention to treat analysis, 1752 patients (87.5%) achieved a SVR and 249 (12.5%) patients remained HCV-RNA positive. The rate of HCC occurrence was 1.48% (26/1752) in patients who achieved SVR and 4.0% (10/249) in patients who maintained HCV viremia ( p = 0.0089). Conclusions: The occurrence of ‘de novo’ HCC in patients treated with DAAs was similar to that observed in historical cohorts of patients who obtained SVR after interferon-based therapy. Patients with virological response to DAA and who achieved SVR had a lower risk to develop HCC than patients who maintained HCV viremia.
Hepatitis B and D: Emerging treatment options PS-039 A phase 2 dose-escalation study of lonafarnib plus ritonavir in patients with chronic hepatitis D: final results from the Lonafarnib with ritonavir in HDV-4 (LOWR HDV-4) study H. Wedemeyer1, K. Port1, K. Deterding1, A. Wranke1, J. Kirschner1, B. Bruno, B. Martins2, J.S. Glenn3, M. Kornberg1, M.P. Manns1. 1 Hannover University Medical School, Hannover, Germany; 2Eiger BioPharmaceuticals; 3Stanford University School of Medicine, Palo Alto, United States E-mail: [email protected] Background and Aims: Globally 15–20 million people are coinfected with hepatitis delta (HDV) and hepatitis B (HBV) viruses. Lonafarnib (LNF) is an oral prenylation inhibitor (PI) that has been shown to reduce levels of HDV RNA in a dose-dependent manner. Prenylation inhibitors are associated with gastrointestinal (GI) S24
adverse effects (AE) at higher doses, but a slow step-wise increase in dose has been shown to be well-tolerated in a pediatric population. LOWR HDV-4 is an open-label, dose-escalation study of LNF + ritonavir (RTV) in patients with HDV to investigate if rapid step-wise increases in LNF dose can allow more patients to achieve higher doses. Methods: Inclusion criteria: positive HDV RNA by qPCR, ALT < 10 × ULN, compensated liver disease, platelets > 90.000/µL. All patients were started on LNF/RTV (50 mg/100 mg bid). If well tolerated, LNF could be increased to 75 mg bid after a minimum of 4 wks, and next to 100 mg bid after a minimum of 2 weeks since the last escalation. RTV was maintained at 100 mg bid. Treatment was administered for 24 wks, followed by 24 wks of treatment-free follow-up (FU). HDV RNA (Robogene 2.0, LLOQ 14 IU/mL) and ALT were assessed at each visit. Results: 15 patients (11 male) were enrolled. At baseline (BL), mean HDV RNA was 4.60 ± 1.05 log10 IU/mL; mean ALT 118 IU/mL (54– 362 IU/mL), mean Fibroscan 14.6 kPA (3.6–35.3 kPA). 12 patients were on a HBV nucleos(t)ide (NUC) at BL, and 3 added a NUC during treatment in response to increasing HBV DNA associated with HDV RNA decline. A dose-escalation to LNF 100 mg bid + RTV was possible in 10 patients (66%), 5 of which remained at this dose until EOT. 13/15 patients completed 24 weeks of therapy. At EOT, mean HDV RNA decline from BL was −1.58 ± 1.38 log10 IU/mL; one patient became PCR-negative and one patient had HDV RNA < LLOQ. ALT normalized in 53% of patients. In FU visits to date, one patient remains
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ORAL PRESENTATIONS to investigate safety, pharmacokinetics and HBV antiviral effects of CMX157. Methods: In the phase 1 study, multiple ascending oral doses of 5, 10, 25, 50, and 100 mg CMX157 were administered sequentially to cohorts of 10 healthy subjects randomized 8:2, active: placebo for 14 days. In the proof of concept study, multiple ascending oral doses of 5, 10, 25, 50, and 100 mg CMX157 were administered sequentially to cohorts of 12 HBV-infected subjects randomized 10:2, CMX157: 300 mg Viread® for 28 days. Plasma levels of CMX157 and TFV were quantitated using a validated LC-MS/MS assay. Serum levels of HBV DNA were quantitated using the COBAS® AmpliPrep/COBAS® Taqman® HBV Test v2. Results: Data from day 1 single dose of the 5, 10, 25, 50, and 100 mg cohorts in the healthy volunteer study shows CMX157 was rapidly absorbed and eliminated. Tmax and t1/2 ranged across the cohorts as follows: 2.0–3.1 hr and 1.1–2.1 hr. Plasma exposure, AUC0-∞ and Cmax, of CMX157 was dose-proportional. AUC0-∞ and Cmax ranges were 10.0–261 hr*ng/mL and 3.1–110 ng/mL across the five cohorts. Data from the day 1 single dose of 5, 10, 25, and 50 mg cohorts in the HBVinfected subject study shows CMX157 was rapidly absorbed and eliminated similar to healthy volunteers. Tmax and t1/2 ranged across the cohorts were as follows: 2.0–2.5 hr and 1.0–1.3 hr. Plasma exposure, AUC0-∞ and Cmax, of CMX157 was dose-related. AUC0-∞ and Cmax ranges were 2.3–112 hr*ng/mL and 2.5–52.2 ng/mL across the four cohorts. CMX157 100 mg HBV-infected cohort data, steady state PK parameters for CMX157 and TFV, safety, and HBV DNA data will also be presented. Conclusions: CMX157 appeared to be safe and well tolerated in these studies. Consistent with a liver targeted approach, systemic exposure of parent drug and metabolite was low. The favorable safety profiles, PK profiles and in vitro anti-viral results warrant further clinical development of CMX157 in HBV-infected patients. PS-041 Improved bone and renal safety of switching from tenofovir disoproxil fumarate to tenofovir alafenamide: preliminary results from 2 phase 3 studies in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B H.L. Chan1, S. Fung2, W.K. Seto3, E. Gane4, J.F. Flaherty5, V. Suri5, L. Lin5, A. Gaggar5, G.M. Subramanian5, W.L. Chuang6, K. Agarwal7, H.L. Janssen8,9, M. Buti10. 1The Chinese University of Hong Kong, Hong Kong, Hong Kong, China; 2Toronto General Hospital, Toronto, Canada; 3 Queen Mary Hospital, Hong Kong, Hong Kong, China; 4Auckland Clinical Studies, Auckland, New Zealand; 5Gilead Sciences, Foster City, United States; 6Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 7Kings College Hospital, London, United Kingdom; 8Toronto Western Hospital, Toronto, Canada; 9Erasmus Medical Center, Rotterdam, The Netherlands; 10Hospital General Universitari Vall d’Hebron, Barcelona, Spain E-mail: [email protected] Background and Aims: Treatment with tenofovir alafenamide (TAF) has shown less bone and renal effects with similar efficacy rates compared to tenofovir disoproxil fumarate (TDF) in two large multinational Phase 3 studies after 48 weeks of therapy. Here, we evaluate patients who have completed 96 weeks of double blind treatment with TAF or TDF and have switched to open label treatment with TAF to determine changes in bone mineral density, creatinine clearance, and the maintenance of viral suppression. Methods: In two identically-designed Phase 3 studies, immune active chronic hepatitis B (CHB) patients who were HBeAg negative (GS-US-320-0108; N = 425) or HBeAg positive (GS-US-320-0110; N = 873) were randomized to and treated with TAF 25 mg QD or TDF 300 mg QD. A subset of patients (N = 200 in Study 0108 and N = 340 in Study 0110) in these ongoing 8 year studies had completed 96 weeks of double-blind (DB) treatment with TAF or TDF and switched to open-label (OL) TAF 25 mg QD at the time of the Week 96 analysis. Dual energy X-ray absorptiometry (DXA) scans were evaluated every
24 weeks as were serial assessments of creatinine clearance and viral suppression. Analyses included subjects with values at Week 96 and Week 120 for creatinine clearance (n = 362), spine BMD (n = 228) or hip BMD (n = 222). Results: A total of 540 subjects had entered the OL TAF phase after 96 weeks of blinded therapy across both studies. Creatinine clearance improved significantly in patients switched from DB TDF to OL TAF at Week 120 compared to Week 96 (N = 117, mean (SD) change = +2.43 (12.81) ml/min, p = 0.04); and remained stable in those previously receiving TAF (Figure A). BMD also showed improvement at Week 120 from Week 96 among patients switched from DB TDF to OL TAF (hip: N = 58, mean (SD) % change = +0.71% (1.43), p = 0.0004; spine: N = 60, mean (SD) % change = +1.41% (2.30), p < 0.0001). BMD changes in hip and spine for DB TAF patients entering the OL TAF period were relatively stable (Figure B). Compared to results at Week 96, high rates of virologic control were maintained across subjects in both studies during the OL period (97–99% and 80–83% in Studies 0108 and 0110, respectively).
Conclusions: Patients who switched from TDF to TAF treatment demonstrated rapid improvements in BMD and creatinine clearance within the first 24 weeks of treatment, and virologic control was maintained. Longer term data is required to establish the benefits of switching to TAF for treatment of CHB. PS-042 A phase 3 study comparing tenofovir alafenamide to tenofovir disoproxil fumarate in patients with HBeAg-negative, chronic hepatitis B: efficacy and safety results at week 96 M. Brunetto1, Y.S. Lim2, E. Gane3, W.K. Seto4, M. Osipenko5, S.H. Ahn6, H.L. Janssen7,8, A. Shukla9, W.L. Chuang10, H. Trinh11, M.K. Celen12, J.F. Flaherty13, A.H. Lau14, A. Gaggar13, V. Suri13, N. Bhardwaj13, K. Kim13, G.M. Subramanian13, C. Pan15, N. Izumi16, P. Marcellin17, H. Chan18, M. Buti19. 1University Hospital of Pisa, Pisa, Italy; 2Asan Medical Centre, Seoul, South Korea; 3Auckland Clinical Studies, Auckland, New Zealand; 4Queen Mary Hospital, Hong Kong, Hong Kong, China; 5Novosibirsk State Medical University, Novosibirsk, Russia; 6 Yonsei University, Seoul, South Korea; 7Toronto Western Hospital, Toronto, Canada; 8Erasmus Medical Center, Rotterdam, The Netherlands; 9 KEM Hospital, Mumbai, India; 10Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 11Silicon Valley Research Institute, San Jose, United States; 12Dicle Üniversitesi Hastanesi Enfeksiyon Hastaliklari Anabilim Dali, Diyarbakir, Turkey; 13Gilead Sciences, Foster City; 14 Gilead Sciences, Inc., Foster City, CA; 15New Discovery, LLC, Flushing, United States; 16Musashino Red Cross Hospital, Tokyo, Japan; 17Hôpital Beaujon, Clichy, France; 18The Chinese University of Hong Kong, Hong Kong, Hong Kong, China; 19Hospital General Universitari Vall d’Hebron, Barcelona, Spain E-mail: [email protected] Background and Aims: Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), is more stable in plasma and enhances delivery of TFV into hepatocytes with reduced circulating levels of TFV relative to tenofovir disoproxil fumarate (TDF). In this randomized, double blind study in HBeAg-negative patients comparing TAF to TDF, the efficacy of TAF was demonstrated to be noninferior to that of TDF at Week 48 in the proportion with HBV DNA < 29 IU/mL with improved bone and renal effects. Here we present the results after two years of treatment.
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Hepatitis B and D: Emerging treatment options PS-039 A phase 2 dose-escalation study of lonafarnib plus ritonavir in patients with chronic hepatitis D: final results from the Lonafarnib with ritonavir in HDV-4 (LOWR HDV-4) study H. Wedemeyer1, K. Port1, K. Deterding1, A. Wranke1, J. Kirschner1, B. Bruno, B. Martins2, J.S. Glenn3, M. Kornberg1, M.P. Manns1. 1 Hannover University Medical School, Hannover, Germany; 2Eiger BioPharmaceuticals; 3Stanford University School of Medicine, Palo Alto, United States E-mail: [email protected] Background and Aims: Globally 15–20 million people are coinfected with hepatitis delta (HDV) and hepatitis B (HBV) viruses. Lonafarnib (LNF) is an oral prenylation inhibitor (PI) that has been shown to reduce levels of HDV RNA in a dose-dependent manner. Prenylation inhibitors are associated with gastrointestinal (GI) S24
adverse effects (AE) at higher doses, but a slow step-wise increase in dose has been shown to be well-tolerated in a pediatric population. LOWR HDV-4 is an open-label, dose-escalation study of LNF + ritonavir (RTV) in patients with HDV to investigate if rapid step-wise increases in LNF dose can allow more patients to achieve higher doses. Methods: Inclusion criteria: positive HDV RNA by qPCR, ALT < 10 × ULN, compensated liver disease, platelets > 90.000/µL. All patients were started on LNF/RTV (50 mg/100 mg bid). If well tolerated, LNF could be increased to 75 mg bid after a minimum of 4 wks, and next to 100 mg bid after a minimum of 2 weeks since the last escalation. RTV was maintained at 100 mg bid. Treatment was administered for 24 wks, followed by 24 wks of treatment-free follow-up (FU). HDV RNA (Robogene 2.0, LLOQ 14 IU/mL) and ALT were assessed at each visit. Results: 15 patients (11 male) were enrolled. At baseline (BL), mean HDV RNA was 4.60 ± 1.05 log10 IU/mL; mean ALT 118 IU/mL (54– 362 IU/mL), mean Fibroscan 14.6 kPA (3.6–35.3 kPA). 12 patients were on a HBV nucleos(t)ide (NUC) at BL, and 3 added a NUC during treatment in response to increasing HBV DNA associated with HDV RNA decline. A dose-escalation to LNF 100 mg bid + RTV was possible in 10 patients (66%), 5 of which remained at this dose until EOT. 13/15 patients completed 24 weeks of therapy. At EOT, mean HDV RNA decline from BL was −1.58 ± 1.38 log10 IU/mL; one patient became PCR-negative and one patient had HDV RNA < LLOQ. ALT normalized in 53% of patients. In FU visits to date, one patient remains
Journal of Hepatology 2017 vol. 66 | S1–S32
ORAL PRESENTATIONS to investigate safety, pharmacokinetics and HBV antiviral effects of CMX157. Methods: In the phase 1 study, multiple ascending oral doses of 5, 10, 25, 50, and 100 mg CMX157 were administered sequentially to cohorts of 10 healthy subjects randomized 8:2, active: placebo for 14 days. In the proof of concept study, multiple ascending oral doses of 5, 10, 25, 50, and 100 mg CMX157 were administered sequentially to cohorts of 12 HBV-infected subjects randomized 10:2, CMX157: 300 mg Viread® for 28 days. Plasma levels of CMX157 and TFV were quantitated using a validated LC-MS/MS assay. Serum levels of HBV DNA were quantitated using the COBAS® AmpliPrep/COBAS® Taqman® HBV Test v2. Results: Data from day 1 single dose of the 5, 10, 25, 50, and 100 mg cohorts in the healthy volunteer study shows CMX157 was rapidly absorbed and eliminated. Tmax and t1/2 ranged across the cohorts as follows: 2.0–3.1 hr and 1.1–2.1 hr. Plasma exposure, AUC0-∞ and Cmax, of CMX157 was dose-proportional. AUC0-∞ and Cmax ranges were 10.0–261 hr*ng/mL and 3.1–110 ng/mL across the five cohorts. Data from the day 1 single dose of 5, 10, 25, and 50 mg cohorts in the HBVinfected subject study shows CMX157 was rapidly absorbed and eliminated similar to healthy volunteers. Tmax and t1/2 ranged across the cohorts were as follows: 2.0–2.5 hr and 1.0–1.3 hr. Plasma exposure, AUC0-∞ and Cmax, of CMX157 was dose-related. AUC0-∞ and Cmax ranges were 2.3–112 hr*ng/mL and 2.5–52.2 ng/mL across the four cohorts. CMX157 100 mg HBV-infected cohort data, steady state PK parameters for CMX157 and TFV, safety, and HBV DNA data will also be presented. Conclusions: CMX157 appeared to be safe and well tolerated in these studies. Consistent with a liver targeted approach, systemic exposure of parent drug and metabolite was low. The favorable safety profiles, PK profiles and in vitro anti-viral results warrant further clinical development of CMX157 in HBV-infected patients. PS-041 Improved bone and renal safety of switching from tenofovir disoproxil fumarate to tenofovir alafenamide: preliminary results from 2 phase 3 studies in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B H.L. Chan1, S. Fung2, W.K. Seto3, E. Gane4, J.F. Flaherty5, V. Suri5, L. Lin5, A. Gaggar5, G.M. Subramanian5, W.L. Chuang6, K. Agarwal7, H.L. Janssen8,9, M. Buti10. 1The Chinese University of Hong Kong, Hong Kong, Hong Kong, China; 2Toronto General Hospital, Toronto, Canada; 3 Queen Mary Hospital, Hong Kong, Hong Kong, China; 4Auckland Clinical Studies, Auckland, New Zealand; 5Gilead Sciences, Foster City, United States; 6Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 7Kings College Hospital, London, United Kingdom; 8Toronto Western Hospital, Toronto, Canada; 9Erasmus Medical Center, Rotterdam, The Netherlands; 10Hospital General Universitari Vall d’Hebron, Barcelona, Spain E-mail: [email protected] Background and Aims: Treatment with tenofovir alafenamide (TAF) has shown less bone and renal effects with similar efficacy rates compared to tenofovir disoproxil fumarate (TDF) in two large multinational Phase 3 studies after 48 weeks of therapy. Here, we evaluate patients who have completed 96 weeks of double blind treatment with TAF or TDF and have switched to open label treatment with TAF to determine changes in bone mineral density, creatinine clearance, and the maintenance of viral suppression. Methods: In two identically-designed Phase 3 studies, immune active chronic hepatitis B (CHB) patients who were HBeAg negative (GS-US-320-0108; N = 425) or HBeAg positive (GS-US-320-0110; N = 873) were randomized to and treated with TAF 25 mg QD or TDF 300 mg QD. A subset of patients (N = 200 in Study 0108 and N = 340 in Study 0110) in these ongoing 8 year studies had completed 96 weeks of double-blind (DB) treatment with TAF or TDF and switched to open-label (OL) TAF 25 mg QD at the time of the Week 96 analysis. Dual energy X-ray absorptiometry (DXA) scans were evaluated every
24 weeks as were serial assessments of creatinine clearance and viral suppression. Analyses included subjects with values at Week 96 and Week 120 for creatinine clearance (n = 362), spine BMD (n = 228) or hip BMD (n = 222). Results: A total of 540 subjects had entered the OL TAF phase after 96 weeks of blinded therapy across both studies. Creatinine clearance improved significantly in patients switched from DB TDF to OL TAF at Week 120 compared to Week 96 (N = 117, mean (SD) change = +2.43 (12.81) ml/min, p = 0.04); and remained stable in those previously receiving TAF (Figure A). BMD also showed improvement at Week 120 from Week 96 among patients switched from DB TDF to OL TAF (hip: N = 58, mean (SD) % change = +0.71% (1.43), p = 0.0004; spine: N = 60, mean (SD) % change = +1.41% (2.30), p < 0.0001). BMD changes in hip and spine for DB TAF patients entering the OL TAF period were relatively stable (Figure B). Compared to results at Week 96, high rates of virologic control were maintained across subjects in both studies during the OL period (97–99% and 80–83% in Studies 0108 and 0110, respectively).
Conclusions: Patients who switched from TDF to TAF treatment demonstrated rapid improvements in BMD and creatinine clearance within the first 24 weeks of treatment, and virologic control was maintained. Longer term data is required to establish the benefits of switching to TAF for treatment of CHB. PS-042 A phase 3 study comparing tenofovir alafenamide to tenofovir disoproxil fumarate in patients with HBeAg-negative, chronic hepatitis B: efficacy and safety results at week 96 M. Brunetto1, Y.S. Lim2, E. Gane3, W.K. Seto4, M. Osipenko5, S.H. Ahn6, H.L. Janssen7,8, A. Shukla9, W.L. Chuang10, H. Trinh11, M.K. Celen12, J.F. Flaherty13, A.H. Lau14, A. Gaggar13, V. Suri13, N. Bhardwaj13, K. Kim13, G.M. Subramanian13, C. Pan15, N. Izumi16, P. Marcellin17, H. Chan18, M. Buti19. 1University Hospital of Pisa, Pisa, Italy; 2Asan Medical Centre, Seoul, South Korea; 3Auckland Clinical Studies, Auckland, New Zealand; 4Queen Mary Hospital, Hong Kong, Hong Kong, China; 5Novosibirsk State Medical University, Novosibirsk, Russia; 6 Yonsei University, Seoul, South Korea; 7Toronto Western Hospital, Toronto, Canada; 8Erasmus Medical Center, Rotterdam, The Netherlands; 9 KEM Hospital, Mumbai, India; 10Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 11Silicon Valley Research Institute, San Jose, United States; 12Dicle Üniversitesi Hastanesi Enfeksiyon Hastaliklari Anabilim Dali, Diyarbakir, Turkey; 13Gilead Sciences, Foster City; 14 Gilead Sciences, Inc., Foster City, CA; 15New Discovery, LLC, Flushing, United States; 16Musashino Red Cross Hospital, Tokyo, Japan; 17Hôpital Beaujon, Clichy, France; 18The Chinese University of Hong Kong, Hong Kong, Hong Kong, China; 19Hospital General Universitari Vall d’Hebron, Barcelona, Spain E-mail: [email protected] Background and Aims: Tenofovir alafenamide (TAF), a novel prodrug of tenofovir (TFV), is more stable in plasma and enhances delivery of TFV into hepatocytes with reduced circulating levels of TFV relative to tenofovir disoproxil fumarate (TDF). In this randomized, double blind study in HBeAg-negative patients comparing TAF to TDF, the efficacy of TAF was demonstrated to be noninferior to that of TDF at Week 48 in the proportion with HBV DNA < 29 IU/mL with improved bone and renal effects. Here we present the results after two years of treatment.
Journal of Hepatology 2017 vol. 66 | S1–S32
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