New Anti-viral Agent : Combination Therapy of Interferon Alpha and Lamivudine for HBeAg-positive Chronic Hepatitis B

( Harry L. A. Janssen ) 대한간학회 2004 Clinical and Molecular Hepatology(대한간학회지) Vol.10 No.1(S)

SYMPOSIUM 2 : Clinical Significance of HBV DNA and HBsAg Quantitative Testing as Biomarkers in Chronic HBV Natural History and Treatment

( Harry L A Janssen ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Monitoring HBV DNA in combination with quantitative HBsAg will likely help us to decide when an HBV patient is in remission of disease. Both markers have also been associated with the likelihood of developing hepatocellular carcinoma. Low HBV DNA and HBsAg levels appear to give a lower risk for liver cancer. ^ Monitoring response early during nucleos(t)ide analogs (NAs) and pegylated interferon (PEG-IFN) therapy potentially allows early differentiation between responders and non-responders, and raises the possibility of individualized, response-guided therapy in CHB. ^ Responders: Early favorable results demonstrating on-treatment decline in HBsAg could motivate patients to continue NA or to complete therapy with PEG-IFN and achieve sustained immune control. - Sustained immune control is a key step towards HBsAg clearance ^ Non-responders: Early indications of failing therapy could allow alterations to treatment regimen. ^ Individualizing therapy: - Nucleos(t)ide analogs (NAs): An increasingly common question encountered in the clinic is ‘when can therapy be stopped?’ HBsAg quantification could have a role in identifying those patients who may be able to stop treatment with a low risk for relapse. - PEG-IFN: In HBeAg-negative disease, an early stopping rule at week 12 based on quantitative HBsAg and HBV DNA decline has been validated in HBV genotypes. In HBeAg-positive disease, HBsAg decline and actual HBsAg values at week 12 and 24 are being investigated as a guide to management decisions. ^ Given the valuable information it provides, HBsAg monitoring is, in combination with HBV DNA measurement, likely to play a role in future studies undertaken to improve the management of CHB and in developing a responseguided therapy approach for individual patients.

Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis

Boni, Carolina,Janssen, Harry L.A.,Rossi, Marzia,Yoon, Seung Kew,Vecchi, Andrea,Barili, Valeria,Yoshida, Eric M.,Trinh, Huy,Rodell, Timothy C.,Laccabue, Diletta,Alfieri, Arianna,Brillo, Federica,Fisic W.B. Saunders Co. 2019 Gastroenterology Vol.157 No.1

<P><B>Background & Aims</B></P> <P>One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection.</P> <P><B>Methods</B></P> <P>We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients.</P> <P><B>Results</B></P> <P>GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells.</P> <P><B>Conclusions</B></P> <P>In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF) in Virally Suppressed Chronic Hepatitis B (CHB) Patients with Moderate or Severe Renal Impairment, or in End-Stage Renal Disease (ESRD) Patients on Hemodialysis (HD): Week 2

( Jeong Heo ),( Harry L.A. Janssen ),( Young-suk Lim ),( Edward J. Gane ),( Claire Fournier ),( Sang Hoon Ahn ),( Owen Tsang ),( Wan-long Chuang ),( Aric Josun Hui ),( Magdy Elkhashab ),( Chi-yi Chen 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: TAF, a novel tenofovir prodrug, has demonstrated noninferior efficacy to TDF with superior bone and renal safety in virally suppressed CHB patients with eGFR (by Cockcroft-Gault; eGFR_CG) ³50 mL/min when switched from TDF. The efficacy and safety of virally suppressed patients on TDF with renal impairment who were switched to TAF were evaluated in this Phase 2 study. Methods: CHB patients with renal impairment taking TDF for ³48 weeks and virally suppressed for ³6 months with HBV DNA <20 IU/mL at screening were enrolled into 2 cohorts: 1) moderate-severe renal impairment (eGFR_CG 15 to <60mL/min) and 2) ESRD (eGFR_CG <15 mL/min) patients on chronic HD. All patients were switched to TAF 25 mg QD for 96 weeks. Co-primary endpoints were proportion with HBV DNA <20 IU/mL and graded adverse events (AEs)/lab abnormalities at Week 24. Results: 93 patients (Mod-severe impairment 78; ESRD 15) were enrolled from 26 sites in 8 countries. Median age was 65 years, 74% male, 77% Asian, 83% HBeAg-negative, up to 60% had low BMD at hip and/or spine, and 60% and 24% had a history of HTN and/or diabetes, respectively. Key efficacy/safety results at Week 24 are summarized in the Table. All patients on treatment at Week 24 maintained HBV DNA <20 IU/mL and a high proportion had normal ALT levels. Relative to baseline levels, switching to TAF from TDF resulted in increases in hip/spine BMD, decreases in bone turnover markers, as well as increases in eGFR_CG and decreases in renal tubular markers. TAF was well tolerated with few having Grade 3 or 4 AEs (8%) and no discontinuations due to AEs. Conclusions: In renally-impaired CHB patients, including ESRD patients on HD, viral suppression was well maintained and the bone and renal safety were improved 24 weeks after switching from TDF to TAF.

A Phase 3 Study Comparing Tenofovir Alafenamide (TAF) to Tenofovir Disoproxil Fumarate (TDF) in HBeAg-Negative CHB Patients at Week 96

( Seung Kew Yoon ),( Maurizia Brunetto ),( Young Suk Lim ),( Ed Gane ),( Wai Kay Seto ),( Marina Osipenko ),( Sang Hoon Ahn ),( Harry L. Janssen ),( Akash Shukla ),( Wan Long Chuang ),( Huy Trinh ),( 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: 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. Methods: 425 patients were randomized to receive TAF 25 mg QD (n=285) or TDF 300 mg QD (n=140) and treated for 144 weeks.. Efficacy analyses at Week 96 included virologic (HBV DNA <29 IU/mL), and biochemical (ALT normalization) responses; key secondary safety endpoints were changes in hip and spine bone mineral density (BMD), and changes in serum creatinine and estimated GFR by Cockcroft- Gault method (eGFRCG). Serum markers of bone turnover and urine markers of renal tubular function were also assessed. Results: Baseline characteristics included: mean age 46 years, 61% males, 72% Asians, genotypes A through D (5%, 24%, 38%, 31%); 19% had HBV DNA ≥ 7 log10 IU/mL, and 21% were previously treated with nucleos(t)ides. Efficacy and safety results are summarized in the Table. At Week 96, virologic response rates were similar in the TAF and TDF groups.A greater percentage of TAF patients achieved normalization of serum ALT valuesPatients receiving TAF showed smaller declines in hip and spine BMD compared with TDF patients through Week 96. The smaller decline in eGFRCG and smaller changes in renal tubular markers observed with TAF. The rates of treatment discontinuations for adverse events (<2%) and serious adverse events were (≤11%) were similar. Conclusions: At Week 96, high rates of virologic suppression were maintained with a higher rate of ALT normalization seen in TAF patients relative to TDF and continued improved bone and renal safety with TAF compared with TDF.

A Phase 3 Study Comparing Tenofovir Alafenamide (TAF) to Tenofovir Disoproxil Fumarate (TDF) in Patients with HBeAg-positive CHB patients

( Sang Hoon Ahn ),( Kosh Agarwal ),( Scott Fung ),( Wai Kay Seto ),( Young Suk Lim ),( Ed Gane ),( Harry L. Janssen ),( Manoj Sharma ),( Wan Long Chuang ),( Ho Bae ),( Ki Tae Yoon ),( John F. Flaherty 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1

Aims: In this randomized, double blind study in HBeAg- positive patients, 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. Methods: 873 patients were randomized to receive TAF 25 mg QD (n=581) or TDF 300 mg QD (n=292) and treated for 144 weeks. Efficacy analyses included virologic (HBV DNA <29 IU/mL), biochemical, and serologic responses; key secondary safety endpoints Results: Baseline characteristics included: mean age 38 years, 64% males, 82% Asians, 52% genotypes C, 47% had HBV DNA ≥ 8 log10 IU/mL, and 26% were treated previously with nucleos(t)ides. Efficacy and safety end points are summarized in the Table. At Week 96, virologic response rates were similer between TAF and TDF groups. A greater percentage of TAF patients achieved normalization of serum ALT values with similar proportions of TAF and TDF patients experiencing HBeAg loss. Patients on TAF experienced smaller changes in hip and spine BMD than TDF patients through 96 weeks. The smaller decline in eGFRCG and smaller changes in renal tubular markers observed with TAF through Week 96. The rates of treatment discontinuations for adverse events (<1.5%) and serious adverse events (≤6%) were low and similar in the two arms. Conclusions: At Week 96, similar rates of virologic suppression were seen with a higher rate of ALT normalization seen in TAF patients relative to TDF and continued improved bone and renal safety with TAF compared with TDF.

Impact of Treatment with Tenofovir Alafenamide (TAF) or Tenofovir Disoproxil Fumarate (TDF) on Hepatocellular Carcinoma (HCC) Incidence in Patients with Chronic Hepatitis B (CHB)

( Young-Suk Lim ),( Henry Lik Yuen Chan ),( Wai-Kay Seto ),( Qing Ning ),( Kosh Agarwal ),( Harry L. A. Janssen ),( Calvin Q. Pan ),( Wan Long Chuang ),( Namiki Izumi ),( Scott K Fung ),( Dr Shalimar 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Potent antiviral treatment can reduce HCC incidence in CHB patients. TAF has shown antiviral efficacy similar to TDF, with higher rates of ALT normalization and no resistance in Phase 3 studies. We evaluated the impact of TAF or TDF on HCC in the ongoing Phase 3 studies. Methods: HBeAg-positive (n=1039) and -negative (n=593) patients with HBV DNA≥20,000 IU/mL and ALT >60 U/L (males) or >38 U/L (females) were recruited from 190 sites in 20 countries and randomized (2:1) to TAF or TDF. HCC was assessed at 6-monthly intervals by hepatic ultrasonography introduced after Week 96 and throughout by local standards of care. The standardized incidence ratio (SIR) for HCC was calculated for observed cases relative to predicted risk using the REACH-B model. Results: Through 5 years of follow-up, HCC occurred in 21 patients (1.0% [11/1,093] with TAF, 1.9% [10/539] with TDF). Median (Q1, Q3) time to HCC onset was 104 (55, 191) weeks. At baseline, relative to those without HCC, patients with HCC were more likely to be older (median age 53 vs 39y; P<0.001), male (90% vs 65%; P=0.014), and cirrhotic (FibroTest ³0.75; 33% vs 9%; P<0.001). The overall SIR was significantly reduced with TAF or TDF (SIR 0.42, 95% CI 0.27-0.64). HCC incidence was significantly reduced in noncirrhotic patients (SIR 0.37, 95% CI 0.22 to 0.63), and in patients receiving TAF (SIR 0.35, 95% CI 0.19-0.62). Lack of ALT normalization at Week 24 (HR 6.90; P=0.011), cirrhosis (HR 4.18; P=0.006), baseline HBsAg level (HR 0.53; P=0.006), and baseline hypertension (HR 5.55; P<0.001) were significant predictors of HCC development by multivariable analysis. Conclusions: In CHB patients receiving TAF or TDF, the incidence of HCC was reduced comparing with expected HCC incidence from REACH-B model. In patients treated with TAF, a significant reduction in SIR was seen, whereas those treated with TDF showed a trend toward a reduction.