96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection

JOURNAL OF HEPATOLOGY

Research Article Viral Hepatitis

96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection Kosh Agarwal1,⇑, Maurizia Brunetto2, Wai Kay Seto3, Young-Suk Lim4, Scott Fung5, Patrick Marcellin6, Sang Hoon Ahn7, Namiki Izumi8, Wan–Long Chuang9, Ho Bae10, Manoj Sharma11, Harry L.A. Janssen12,13, Calvin Q. Pan14, Mustafa Kemal Çelen15, Norihiro Furusyo16, Dr. Shalimar17, Ki Tae Yoon18, Huy Trinh19, John F. Flaherty20, Anuj Gaggar20, Audrey H. Lau20, Andrea L. Cathcart20, Lanjia Lin20, Neeru Bhardwaj20, Vithika Suri20, G. Mani Subramanian20, Edward J. Gane21, Maria Buti22, Henry L.Y. Chan23,⇑, and the GS-US-320-0108 Investigators 1 Kings College Hospital, London, United Kingdom; 2University of Pisa, Pisa, Italy; 3University of Hong Kong, Hong Kong; 4Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 5Toronto General Hospital, Toronto, ON, Canada; 6Hôpital Beaujon, Clichy, France; 7 Yonsei University, Seoul, South Korea; 8Musashino Red Cross Hospital, Tokyo, Japan; 9Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 10Asian Pacific Liver Center, St. Vincent Medical Center, Los Angeles, USA; 11Institute of Liver and Biliary Sciences, New Delhi, India; 12Toronto Western Hospital, Toronto, ON, Canada; 13Erasmus Medical Center, Rotterdam, The Netherlands; 14 NYU Langone Medical Center, NYU School of Medicine, New York, USA; 15Dicle University Hospital Infectious Diseases, Diyarbakir, Turkey; 16 Kyushu University Hospital, Fukuoka, Japan; 17All India Institute of Medical Sciences, New Delhi, Delhi, India; 18Pusan National University Yangsan Hospital, Yangsan, South Korea; 19San Jose Gastroenterology, San Jose, USA; 20Gilead Sciences, Foster City, CA, USA; 21Auckland Clinical Studies, Auckland, New Zealand; 22Hospital Universitario Valle Hebron, Barcelona, Spain; 23The Chinese University of Hong Kong, Hong Kong

Background & Aims: Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double-blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. Methods: In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAgpositive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. Results: At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference
2.2% (95% CI
8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference
0.6% (95% CI
7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change
0.33% vs.
2.51%; Keywords: Chronic hepatitis B virus; Bone safety; Renal safety. Received 3 August 2017; received in revised form 13 October 2017; accepted 12 November 2017 ⇑ Corresponding authors. Addresses: Kings College Hospital, London, United Kingdom (K. Agarwal), or The Chinese University of Hong Kong, Hong Kong (H.L.Y. Chan). E-mail addresses: [email protected] (K. Agarwal), [email protected] (H.L.Y. Chan).

p <0.001) and lumbar spine (mean % change
0.75% vs.
2.57%; p <0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by CockcroftGault method (
1.2 vs.
4.8 mg/dl; p <0.001). Conclusion: In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. Lay summary: At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341. Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction The World Health Organization estimates that approximately 240 million people worldwide are chronically infected with the hepatitis B virus (HBV).1 Without treatment, chronic HBV infection can cause progressive liver fibrosis, which may lead to cirrhosis, decompensation, and hepatocellular carcinoma.2–4 Suppressive antiviral treatment has been shown to reduce the risk of liver-related complications, and can halt or even reverse disease progression.5–7 However, since few patients achieve seroclearance of the hepatitis B surface antigen (HBsAg), which is considered the hallmark of functional cure, treatment is generally life-long.6–9 In an aging population with comorbidities, side effects of treatment such as renal and bone complications can be problematic with long-term treatment.9–13

Journal of Hepatology 2018 vol. xxx j xxx–xxx Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

Research Article

Viral Hepatitis

Tenofovir alafenamide (TAF) is an orally bioavailable prodrug of tenofovir (TFV), a nucleotide analog that inhibits reverse transcription of HIV and HBV.14–16 TAF was designed to have greater plasma stability than tenofovir disoproxil fumarate (TDF) allowing delivery of the active metabolite, tenofovir diphosphate, to hepatocytes more efficiently than TDF, which must be dosed at relatively high levels to achieve a therapeutic concentration in hepatic cells.17,18 Because of this high systemic exposure of tenofovir (TFV), the long-term use of TDF has been be associated with bone and renal toxicity in some patients.10,13,19–21 When TAF is administered at a dose of 25 mg to patients with HBV or HIV infection, circulating levels of TFV were approximately 90% lower than levels with the standard 300 mg dose of TDF.22,23 GS-US-320-0110 and GS-US-320-0108 are large, ongoing, randomized, double-blind, international phase III trials designed to compare the efficacy and safety of TAF with that of TDF in treatment-naïve and treatment-experienced patients with chronic HBV infection, including those with compensated cirrhosis. The studies were identical in design except that GS-US-320-0110 enrolled only patients with HBeAg-positive HBV infection and GS-US-320-0108 enrolled only patients with HBeAg-negative HBV infection. After 48 weeks, TAF was shown in both studies to be statistically non-inferior to TDF in antiviral efficacy, as measured by rates of suppression of HBV DNA to <29 IU/ml.24,25 Moreover, patients receiving TAF in both trials had significantly smaller decreases in bone mineral density (BMD) in the lumbar spine and hip, smaller increases in serum creatinine and smaller decreases in estimated creatinine clearance, as well as other biomarkers of bone and renal safety than TDF. In the current report, we present 96-week results from both trials.

Patients and methods Patients and study design The designs of these two randomized, double-blind, activecontrolled international phase III trials have been described previously.24,25 Briefly, patients were at least 18 years of age with chronic HBV infection (with HBV DNA levels of at least 20,000 IU/ml), alanine transaminase (ALT) levels of >60 U/L in men or >38 U/L in women, and estimated creatinine clearance of at least 50 ml/min (by the Cockcroft-Gault method). We excluded patients with platelet count ≤50,000 cells/ll, hemoglobin <10 g/dl, albumin <3 g/dl, direct bilirubin of >2.5 times the upper limit of normal (ULN), and aspartate transaminase or ALT >10 times the ULN. Patients with evidence of decompensation (i.e. clinical ascites, encephalopathy, or variceal hemorrhage) and those with hepatocellular carcinoma were not enrolled. Full eligibility criteria are provided in the supplementary information. Patients in both trials were randomly assigned in a 2:1 ratio to receive TAF 25 mg orally once daily or TDF 300 mg orally once daily. All patients received placebo tablets matching the alternative treatment (i.e. patients assigned to receive TAF also received a matching TDF placebo tablet, and vice versa). Patients and investigators were blinded to treatment assignment throughout the 96 weeks of the double-blind phase. Members of the clinical research and biometrics departments of the sponsor were unblinded at the 48-week timepoint for the assessments related to the primary analysis. Randomization was stratified by screening HBV DNA levels (≥8 log10 IU/ml vs. 7 to 8 log10 IU/ml vs. <7 log10 IU/ml in Study GS-US-320-0108, and 2

≥8 log10 IU/ml vs. <8 log10 IU/ml in Study GS-US-320-0110) and prior oral antiviral treatment (naïve vs. previously treated). Before enrollment, written informed consent was obtained from all patients. The study was approved by the institutional review board or independent ethics committees at all participating sites and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. All authors had access to the study data and had reviewed and approved the final manuscript. Procedures Study visits occurred every four weeks starting at treatment week four until treatment week 48, after which study visits occurred every eight weeks. Laboratory assessments included hematologic analysis, serum chemistry tests, fasting lipid parameters, and measures of renal function (serum creatinine, estimated glomerular filtration rate, proteinuria by dipstick), as well as quantitative markers of proteinuria (protein to creatinine ratio, albumin to creatinine ratio, retinol-binding protein to creatinine ratio, b2-microglobulin to creatinine ratio; Covance Laboratories, Indianapolis, IN, USA). Percentage change in BMD was assessed in all patients by dual energy x-ray absorptiometry scans of the lumbar spine and hip at screening, and every 24 weeks thereafter. Biomarkers of bone turnover were also assessed, including C-type collagen sequence, which is associated with bone resorption, and bone-specific alkaline phosphatase, osteocalcin, and procollagen type 1 N-terminal propeptide, which are all associated with bone formation. Outcomes Efficacy endpoints for this week 96 analysis were the proportion of patients with HBV DNA <29 IU/ml, proportions of patients with HBsAg loss and seroconversion to anti-HBs, and, in the HBeAg-positive patients, proportions of patients HBeAg loss and seroconversion to anti-HBe. Other prespecified week 96 efficacy endpoints include proportion of patients with ALT normalization (defined as ALT above the ULN at baseline but within the normal range at week 96) and the incidence of drugresistant mutations. We assessed ALT using normal ranges set by the central laboratory (Covance), and those set forth in the American Association for the Study of the Liver Diseases (AASLD) guidelines.8 Resistance analyses included population or deep sequencing of the HBV polymerase/reverse transcriptase region in all patients with HBV DNA ≥69 IU/ml at week 96 or those who discontinued the study early with viremia (HBV DNA ≥69 IU/ml) after a minimum of 24 weeks of treatment. Safety endpoints at week 96 included percentage change in hip BMD, percentage change in spine BMD, and changes in renal function, as measured by serum creatinine and estimated glomerular filtration rate (eGFRCG) determined by the Cockcroft-Gault method. Statistical analysis For the primary efficacy analysis, the difference in proportions between treatment groups and its 95% CI was calculated based on the Mantel-Haenszel proportions adjusted by baseline HBV DNA categories and oral antiviral treatment status (naïve vs. experienced) strata. P values were from the Cochran-MantelHaenszel tests stratified by baseline HBV DNA categories and oral antiviral treatment status strata. For further details regarding the materials used, please refer to the CTAT table and supplementary information.

Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

JOURNAL OF HEPATOLOGY Role of the funding source The study sponsor oversaw trial management, data collection, and statistical analyses. The first draft of the report was prepared by a medical writer employed by the sponsor. The corresponding authors had full access to all data in the study and had final responsibility for the decision to submit for publication.

Results Patient disposition Of the 873 HBeAg-positive patients originally randomized and treated in the GS-US-320-0110 study (581 to TAF and 292 to receive TDF), 792 (91%; 530 TAF and 262 TDF) completed two years of double-blind treatment. Of the 425 HBeAg-negative patients originally randomized and treated in the GS-US-3200108 trial, 395 (93%; 266 TAF and 129 TDF) completed two years double-blind treatment at the time of this analysis. Further details on patient disposition are provided (Figs. S1 and S2), as well as details regarding treatment-emergent adverse events leading to treatment discontinuation (Table S1). The baseline demographic characteristics of the patients for the individual studies were described in the 48-week reports.24,25 The patients characteristics of the pooled population are shown (Table 1). The characteristics of patients receiving TAF and TDF were similar. Most patients were male (63%) and Asian (79%), with a mean age of 41 years. Mean HBV DNA and median ALT at baseline were 7.0 log10 IU/ml and 80 U/L, respectively. Two-thirds of patients were HBeAg-positive and the most common HBV genotype was C, observed in about half (48%) of patients, followed by genotype D (25%), genotype B (19%), and genotype A (7%). Median estimated glomerular filtration rate estimated by the Cockcroft-Gault method (eGFRCG) for patients at baseline was 106 ml/min. Comorbidities (hypertension, diabetes mellitus, cardiovascular disease, and hyperlipidemia) were present in a small percentage (<13%) of the overall study population with a similar distribution between the TAF and TDF groups. Efficacy Antiviral efficacy The proportion of HBeAg-positive patients receiving TAF who had HBV DNA <29 IU/ml at week 96 was 73% (423 of 581 patients), compared to 75% (218 of 292 patients) of those receiving TDF (Fig. 1A and Table 2). The adjusted difference was
2.2% (95% CI
8.3% to 3.9%; p = 0.47). At week 96, the lower bound of the two-sided 95% CI of the adjusted difference (TAF – TDF) in the response rate was greater than the prespecified
10% margin used to determine noninferiority for the primary efficacy endpoint (proportion of patients with HBV DNA <29 IU/ml) at week 48. In patients with HBV DNA <29 IU/ml, the proportion of patients with HBV DNA ‘‘target not detected” was 14% (81 of 581 patients) in patients receiving TAF compared to 9% (25 of 292 patients) of patients receiving TDF. Of the 873 patients randomized and treated, 232 did not have HBV DNA <29 IU/ml at week 96. Of these, 148 had observed treatment failure (HBV DNA ≥29 IU/ml) at the week-96 visit: 106 patients (18%) receiving TAF and 42 patients (14%) receiving TDF. Of those with observed treatment failure there was a higher proportion of patients in the TAF group (n = 28; 5%) compared with the TDF group (n = 6; 2%) with HBV DNA values ≥29 IU/ml and <69 IU/ml. There were 84 patients who were considered treatment failures at week 96 for nonvirologic reasons: 52 patients

(9%) receiving TAF and 32 patients (11%) receiving TDF; the reasons for treatment failure (lack of efficacy, early discontinuations for an adverse event or death, other reasons [e.g. withdrawal of consent or lost to follow-up], or those having missing data within the analysis window but remaining on study) were similar between groups. The proportion of HBeAg-negative patients receiving TAF who had HBV DNA <29 IU/ml at week 96 was 90% (257 of 285 patients), compared to 91% (127 of 140 patients) of those receiving TDF (Fig. 1B and Table 2). The adjusted difference was
0.6% (95% CI
7.0% to 5.8%; p = 0.84). At week 96, the lower bound of the two-sided 95% CI of the adjusted difference (TAF – TDF) in the response rate was greater than the prespecified
10% margin used to determine noninferiority for the primary efficacy endpoint (proportion of patients with HBV DNA <29 IU/ml) at week 48. In patients with HBV DNA <29 IU/ml, the proportion of patients with HBV DNA ‘‘target not detected” was 33% (93 of 285 patients) in patients receiving TAF compared to 31% (44 of 140 patients) of patients receiving TDF. Of the 425 patients randomized and treated, 41 were considered treatment failures at week 96. Of these, eight had observed treatment failure (HBV DNA ≥29 IU/ml) at the week-96 visit: five patients (2%) receiving TAF and three patients (2%) receiving TDF. There were 33 patients who failed treatment at week 96 for nonvirologic reasons: 23 patients (8%) in the TAF group and 10 patients (7%) in the TDF group; the reasons for nonvirologic failure were similar between treatment groups. ALT normalization The proportion of HBeAg-positive patients receiving TAF with ALT above the ULN at baseline who had normal ALT at week 96 of treatment by central laboratory criteria was 75%, compared to 68% among patients receiving TDF; the difference of 8.0% was statistically significant (95% CI 1.2% to 14.7%; p = 0.017) (Table 2). The same was true using laboratory criteria recommended by the AASLD (≤30 U/L for men and ≤19 U/L for women), a significantly higher proportion of patients receiving TAF achieved normalized ALT than those receiving TDF (52% vs. 42%, a difference in proportions of 10.6% (95% CI 3.6% to 17.6%; p = 0.003). Patients receiving TAF had higher rates of ALT normalization than patients receiving TDF at every study visit after week 8 (Fig. 2). The proportion of HBeAg-negative patients receiving TAF, with ALT above the ULN at baseline, who had normal ALT at week 96 of treatment by central laboratory criteria was 81%, compared to 71% among patients receiving TDF; the difference of 9.8% was statistically significant (95% CI 0.2% to 19.3%; p = 0.038) (Table 2). When assessed using laboratory criteria recommended by the AASLD, a significantly higher proportion of patients receiving TAF than those receiving TDF achieved normalized ALT (50% vs. 40%, a difference in proportions of 10.9% [95% CI 0.8% to 21.0%]; p = 0.035). Moreover, patients receiving TAF had higher rates of ALT normalization than patients receiving TDF at every study visit after week 4 (Fig. 2). HBeAg and HBsAg loss and seroconversion The rate of HBeAg loss among HBeAg-positive patients receiving TAF was 22% (123/565) at week 96, which was not statistically different from the rate of 18% (51/285) among patients receiving TDF; the rate of HBeAg seroconversion was also numerically higher among patients receiving TAF than among those receiving TDF, but the difference did not achieve statistical

Journal of Hepatology 2018 vol. xxx j xxx–xxx

3

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

Research Article

Viral Hepatitis

Table 1. Patient characteristics in the pooled population.

Mean age, years (range) Male sex, n (%) Race Asian White Black Pacific Islander Other Mean HBV DNA, log10 IU/ml (range) Median ALT (Q1, Q3) HBeAg status Positive Negative HBV genotype A B C D E F H Unknown Patients with known cirrhosis Mean Fibrotest score (range) Fibrotest score ≥0.75 Median eGFR by Cockcroft-Gault (Q1, Q3) Diabetes mellitus Cardiovascular disease Hypertension Hyperlipidemia Total hip bone mineral density clinical status Normal (T-score ≥
1.0) Osteopenia (
2.5 ≤T-score <
1.0) Osteoporosis (T-score <
2.5) Not determined Lumbar spine bone mineral density clinical status Normal (T-score ≥
1.0) Osteopenia (
2.5 ≤T-score <
1.0) Osteoporosis (T-score <
2.5) Not determined 25-hydroxy vitamin D, ng/ml Median (Q1, Q3) <20 ng/ml

TAF 25 mg (n = 866)

TDF 300 mg (n = 432)

Total (N = 1,298)

40 (18–80) 544 (63)

41 (18–72) 275 (64)

41 (18–80) 819 (63)

687 (79) 167 (19) 7 (1) 3 (<1) 2 (<1) 7.0 (1.8–9.9) 80 (56, 123)

333 (77) 87 (20) 6 (1) 3 (1) 3 (1) 7.0 (1.4–9.9) 80 (53, 130)

1,020 (79) 254 (20) 13 (1) 6 (<1) 5 (<1) 7.0 (1.4–9.9) 80 (54, 125)

569 (66) 297 (34)

290 (67) 142 (33)

859 (66) 439 (34)

54 (6) 160 (18) 418 (48) 224 (26) 7 (1) 3 (<1) 0 0 65/636 (10) 0.37 (0.04–0.98) 76/846 (9) 106 (91, 125) 57 (7) 28 (3) 98 (11) 76 (9)

31 (7) 88 (20) 200 (46) 105 (24) 3 (1) 2 (<1) 2 (<1) 1 (<1) 38/326 (12) 0.37 (0.03–0.99) 42/421 (10) 105 (90, 124) 29 (7) 14 (3) 61 (14) 42 (10)

85 (7) 248 (19) 618 (48) 329 (25) 10 (1) 5 (<1) 2 (<1) 1 (<1) 103/962 (11) 0.37 (0.03–0.99) 118/1267 (9) 106 (91, 125) 86 (7) 42 (3) 159 (12) 118 (9)

570 (67) 256 (30) 12 (1) 13 (2)

285 (67) 131 (31) 2 (<1) 8 (2)

855 (67) 387 (30) 14 (1) 21 (2)

477 (56) 309 (36) 57 (7) 13 (2) n = 861 17.2 (12.8, 22.4) 546 (63)

237 (56) 152 (36) 29 (7) 8 (2) n = 429 17.2 (12.4, 22.4) 276 (64)

714 (56) 461 (36) 86 (7) 21 (2) n = 1,290 17.2 (12.8, 22.4) 822 (64)

ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; HBeAg, Hepatitis B e antigen; HBV, hepatitis B virus; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.

significance (18% [99/565] vs. 12% [35/285], respectively, p = 0.05). In both groups, the rate of HBsAg loss at week 96 was 1%: 7 of 576 of patients receiving TAF, and 4 of 288 patients receiving TDF. HBsAg seroconversion at week 96 was experienced by 6 of 576 patients (1%) receiving TAF and no patients receiving TDF. At baseline, mean levels of HBsAg were similar between treatment groups (4.0 and 4.1 log10 IU/ml, for the TAF and TDF groups, respectively), and similar mean declines were observed at week 96 (
0.51 and
0.64 log10 IU/ml for the TAF and TDF groups, respectively; p = 0.13). One patient in the study in HBeAg-negative patients experienced loss of HBsAg: a 44-year-old Asian woman with genotype A infection who was receiving TAF tested negative for HBsAg at week 64 and achieved seroconversion to anti-HBs at week 80 which persisted through week 96. At baseline, mean HBsAg levels were similar between treatment groups (3.4 log10 IU/ml in both groups); small and similar mean declines in HBsAg 4

levels were observed at week 96 (
0.14 and
0.10, for the TAF and TDF groups, respectively; p = 0.50). Response in subgroups Among patients with HBeAg-positive infection, differences in the proportion of patients with HBV DNA <29 IU/ml at week 96 were not significantly different between treatment groups in predefined subgroups according to age (<50 years or ≥50 years), sex, race (Asian or non-Asian), baseline HBV DNA level or ≥8 log10 IU/ml), treatment status (<8 log10 IU/ml (treatment-experienced or treatment naïve), genotype (A/D or B/C), baseline ALT level (≤ULN or >ULN by central laboratory normal range), and baseline FibroTest score (<0.75 or ≥0.75) (Fig. S3). In the small subgroup of patients with <95% adherence by pill count, a lower response rate was seen in the TAF group (40% or 8/20 patients) compared with the TDF group (82% or 9 of 11 patients); however, this difference is due in a large part

Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

JOURNAL OF HEPATOLOGY Proportion of HBeAg-positive patients with HBV DNA <29 IU/ml by study visit

A Proportions of patients (%)

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

100 80 60

p = 0.47

40 20 0 0

16

32 48 64 Time (weeks)

80

96

Proportion of HBeAg-negative patients with HBV DNA <29 IU/ml by study visit

B

Proportions of patients (%)

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

100 80

p = 0.84

60 40 20 0 0

16

32 48 64 Time (weeks)

80

96

Fig. 1. Viral suppression by visit week. (A) shows proportion of HBeAgpositive patients with HBV DNA <29 IU/ml by study visit. (B) Shows proportion of HBeAg-negative patients with HBV DNA <29 IU/ml by study visit. p value by Cochran-Mantel-Haenszel tests stratified by baseline HBV DNA categories and oral antiviral treatment status. HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

to a high proportion of TAF patients (7 of the 12 treatment failures) having missing data (i.e. early study drug discontinuation) at week 96. The proportion of HBeAg-negative patients with HBV DNA <29 IU/ml at week 96 was not significantly different between the two treatments in predefined subgroups, including age (≥50 or <50), sex, race (Asian or non-Asian), HBV genotype (A/D or B/C), treatment status (naïve or experienced), baseline HBV DNA (<7, or ≥7 log10 IU/ml), baseline ALT (> or ≤ULN by central laboratory), baseline FibroTest score (≥ or <0.75), and study drug adherence (<95% or ≥95%) (Fig. S3). Resistance surveillance Of the 1,298 patients who were randomized and treated in both studies, 1,242 entered year two of the study. Of these, 132 (11%) met the criteria for resistance testing at week 96, 87 patients receiving TAF and 45 receiving TDF. The types of sequence changes observed were similar for the TAF and TDF groups, with the majority of patients having virus that was unable to sequence, due to low viral load, or having no sequence changes from baseline at the consensus sequence level (59%). Most patients who qualified had viremia in the absence of virologic

breakthrough (i.e. persistent viremia above 69 IU/ml), with 36 patients qualifying with virologic breakthrough (confirmed HBV DNA ≥69 IU/ml after achieving <69 IU/ml, or >1 log10 IU/ ml increase in HBV DNA from nadir). Of these, 11 of 36 (31%) experienced virologic breakthrough associated with nonadherence to study medication. Overall, no HBV pol/RT amino acid substitutions associated with resistance to tenofovir were detected through week 96 in the TAF or TDF groups in either study. Safety The pooled safety analysis populations included 866 patients receiving TAF and 432 receiving TDF. Both treatments were well tolerated; the majority of patients experienced only adverse events that were mild to moderate in severity (Table 3). The proportion of patients who discontinued treatment due to adverse events was low in both groups: 13 patients (2%) receiving TAF and four patients (1%) receiving TDF. The types and frequencies of adverse events did not differ from those previously reported at week 48.24,25 The most common adverse events were headache, nasopharyngitis, and upper respiratory tract infection (Table 3). Seven percent of patients in both groups, 60 patients receiving TAF and 29 receiving TDF experienced serious adverse events, none of which were deemed by the investigator to be related to study treatment. No patient died during treatment, but five patients (two TAF and three TDF) died while off treatment (two deaths were due to HCC, 1 TAF patient and 1 TDF patient, at weeks 66 and 56, respectively; 1 TAF patient due to H1NI influenza at week 14; 1 TDF patient due to bilateral bronchopneumonia at week 59; 1 TDF patient due to presumed cardiopulmonary arrest at week 64). Similar percentages of patients receiving both drugs experienced grade 3 or 4 laboratory abnormalities, 36% of patients receiving TAF and 34% of patients receiving TDF. The most common grade 3 and 4 laboratory abnormalities were elevations in ALT (8% and 10% of patients receiving TAF and TDF, respectively) and AST (3% and 5% of patients, respectively). Five (1%) patients receiving TAF and 4 (1%) patients receiving TDF experienced an ALT flare (elevation in serum ALT value of >2 x baseline and >10 x ULN and confirmed upon retesting) during treatment; these events occurred early in treatment (within the first one to two months) and all resolved without sequelae. In the TAF group, 50 patients (6%) experienced grade 3 elevations in fasting LDL cholesterol (no patients had a grade 4 elevation) which were mostly isolated events seen in individuals with a history of dyslipidemia, an elevated LDL level at baseline, or both. Three patients (1%) receiving TDF had grade 3 elevations in fasting LDL cholesterol. For fasting glucose, 11 patients (1%) in the TAF group experienced grade 3 elevations compared to none in the TDF group; no patients had a grade 4 elevation. These elevations were mostly isolated events seen in individuals with a history of diabetes mellitus, an elevated fasting glucose level at baseline, or both. No clinically meaningful differences were detected in median (Q1, Q3) changes from baseline in fasting glucose levels at week 96 between TAF and TDF groups in both HBeAg-positive and HBeAg-negative patients. The mean percentage decrease in hip BMD from baseline to week 96 was
0.33% (95% CI
0.51 to
0.14) for patients receiving TAF, which was significantly less than the reduction of
2.51% (95% CI
2.82 to
2.21) for patients receiving TDF (p <0.001) (Fig. 3A). Similarly, the mean percentage decrease in spine BMD from baseline to week 96 was
0.75% (95% CI

Journal of Hepatology 2018 vol. xxx j xxx–xxx

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Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

Research Article

Viral Hepatitis

Table 2. Efficacy outcomes at week 96. HBeAg-positive patients

HBeAg-negative patients

TAF 25 mg (n = 581)

TDF 300 mg (n = 292)

Difference in proportions (95% CI)

HBV DNA <29 IU/ml

423 (73%)

218 (75%)

HBeAg loss, n/N (%)*

123/565 (22%)

51/285 (18%)

99/565 (18%)

35/285 (12%)

7/576 (1%)

4/288 (1%)

6/576 (1%)

0

405/537 (75%)

181/268 (68%)


2.2% (
8.3% to 3.9%) 3.7% (
1.9% to 9.4%) 5.1% (0.2% to 10.1%)
0.1% (
2.0% to 1.8%) 1.1% (
0.3% to 2.4%) 8.0% (1.2% to 14.7%)

299/572 (52%)

121/290 (42%)

HBeAg seroconversion, n/N (%)* HBsAg loss, n/N (%)y HBsAg seroconversion, n/N (%)y Normalized ALT by Central Lab Normal Range, n/N (%)à Normalized ALT by AASLD Normal Range, n/N (%)§

10.6% (3.6% to 17.6%)

p value

p value

TAF 25 mg (n = 285)

TDF 300 mg (n = 140)

Difference in proportions (95% CI)

0.47

257 (90%)

127 (91%)

0.20

—

—


0.6% (
7.0% to 5.8%) —

—

0.05

—

—

—

—

0.88

1/281 (<1%)

0

0.078

1/281 (<1%)

0

0.017

191/236 (81%)

86/121 (71%)

0.1% (
2.5% to 2.7%) 0.1% (
2.5% to 2.7%) 9.8% (0.2% to 19.3%)

0.003

139/276 (50%)

55/138 (40%)

10.9% (0.8% to 21.0%)

0.84

0.72 0.72 0.038

0.035

AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. * Among patients who were seropositive for HBeAg and negative for anti-HBe at baseline. y Among patients who were seropositive for HBsAg and negative for anti-HBs at baseline. à Among patients with ALT at baseline above the central lab normal range. § Among patients with ALT at baseline above AASLD defined normal range.


1.01 to
0.49) for patients receiving TAF, which was significantly less than the mean percentage change of
2.57% (95% CI
2.97 to
2.18) in patients receiving TDF (p <0.001) (Fig. 3B). Moreover, the magnitude of the difference in BMD decreases between the TAF and TDF groups was significantly greater at week 96 compared to the difference in decline observed at week 48 (p <0.001; from mixed-model repeated measures) when assessed at hip but not at spine (Fig. 3A and B). These data, at least for hip, suggest that the gap in difference in bone loss between the TDF and TAF groups continues to widen over time. When categorical percentage changes in hip and spine BMD are evaluated, decreases of 7% or greater for hip and 5% or greater for spine are considered clinically relevant. At week 96, 1.1% (8 of 740 patients) of the TAF group vs. 6% (21 of 369 patients) TDF patients demonstrated a ≥7% decrease in hip BMD; for spine, 11% (82 of 746 patients) in the TAF group compared to 25% (93 of 371 patients) in the TDF group were observed to have a ≥5% decline in BMD (Table S2). Clinically, a T-score is used to diagnose osteopenia (T-score ≥
2.5 to <
1.0) or osteoporosis (<
2.5). At baseline, 570 patients in the TAF group had a normal T-score (≥
1.0) and 285 patients were normal in the TDF group with regard to hip BMD (Table 1). At week 96, in the TAF group, 6% (28 patients) with available data developed osteopenia whereas 16% (39 patients) developed osteopenia in the TDF group; no patients with a normal T-score at baseline in either group developed osteoporosis. Of the 256 TAF-treated patients with osteopenia at baseline, two patients (1%) with available data at week 96 shifted to osteoporosis, compared with 4 of 131 (4%) of TDF-treated patients (Table S3). Biomarkers associated with bone resorption (Ctype collagen sequence), formation (procollagen type 1 Nterminal propeptide, bone-specific alkaline phosphatase, and osteocalcin), and metabolism (parathyroid hormone) either showed significantly smaller median percentage increases or 6

larger median percentage decreases at week 96 in patients receiving TAF than those receiving TDF (Table S4). Fracture events were uncommon in both groups and were generally the result of trauma: nine patients (1%) receiving TAF and seven patients (2%) receiving TDF experienced a fracture event. None of the fractures were deemed related to the study drugs by the investigators, and none resulted in discontinuation of study drugs. Patients in both groups had small mean increases in serum creatinine from baseline to week 96; the mean increase of 0.003 mg/dl in patients receiving TAF was significantly smaller than the increase of 0.019 mg/dl in patients receiving TDF (p = 0.001). Patients receiving TAF had a significantly smaller median decrease in estimated glomerular filtration rate (by Cockcroft-Gault equation; eGFRCG) than patients receiving TDF (
1.2 ml/min vs.
4.8 ml/min, p <0.001) (Fig. 4). When assessed as the percentage of patients experiencing a 25% or greater decline in eGFRCG, a significantly smaller proportion of patients receiving TAF compared with TDF met this endpoint (10% vs. 18%; p <0.001), and a smaller proportion of TAF patients experienced a confirmed decline in eGFRCG below 50 ml/min compared to TDF patients (0.1% TAF [1 patient] and 1.2% TDF [5 patients], respectively; p = 0.017). Independent predictors of eGFRCG decline of ≥25% from baseline were identified by multivariate analysis and included the following characteristics: diabetes mellitus, treatment with TDF, vitamin D level below the lower limit of the normal range, and baseline ALT value >5 times ULN by AASLD criteria (Tables S5 and S6). A similar proportion of patients in each group experienced a confirmed decrease in serum phosphorus level below 2.0 mg/dl (0.5% each group), and the median (Q1, Q3) change from baseline at week 96 in serum phosphorus levels was also similar for the TAF and TDF groups (
0.1 [
0.4, 0.2] vs.
0.1 [
0.4, 0.3]). The percentage of patients in each group with at least one graded event of proteinuria by dipstick during the study

Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

JOURNAL OF HEPATOLOGY HBeAg-positive patients Proportions of patients (%)

B

Central Lab criteria

80

80

60

60

HBeAg-positive patients

p = 0.038

40

20

20 0

0 16

32 48 64 80 Time (weeks)

96

0

16

32 48 64 80 Time (weeks)

96

HBeAg-negative patients

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

100

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

p = 0.017

40

0

AASLD criteria

HBeAg-negative patients 100

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

100

Proportions of patients (%)

A

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

100

80

80

60

60 40

40 p = 0.003

20

p = 0.035

20 0

0 0

16

32

48 64 80 Time (weeks)

96

0

16

32

48 64 80 Time (weeks)

96

Fig. 2. ALT Normalization by visit week. (A) shows proportion of patients achieving ALT normalization by central laboratory (Covance) criteria (≤34 U/L for women <69 years or ≤32 for women ≥69 years; ≤43 U/L for men <69 years or ≤35 U/L for men ≥69 years) by study visit. (B) Shows proportion of patients achieving ALT normalization by AASLD criteria (≤19 U/L for women and ≤30 U/L for men) by study visit. p value by Cochran-Mantel-Haenszel tests stratified by baseline HBV DNA categories and oral antiviral treatment status. AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.

Table 3. Safety data.

Patients with any adverse event Adverse event leading to study drug discontinuation Deaths Patients with grade 3 or 4 adverse events Patients with serious adverse event Adverse events occurring in ≥5% of patients in any treatment group Headache Nasopharyngitis Upper respiratory tract infection Cough Back pain Fatigue Nausea Dyspepsia Diarrhea Grade 3 or 4 laboratory abnormalities in ≥1% of patients in any treatment group* Alanine aminotransferase >5 ULN Aspartate aminotransferase >5 ULN Amylase >2ULN Creatine kinase ≥10 ULN Fasting cholesterol >300 mg/dl Fasting LDL cholesterol >190 mg/dl Gamma glutamyl transferase >5x ULN Hemoglobin <9.0 g/dl Segmented neutrophils <750/mm3 Fasting glucose >250 mg/dl Nonfasting glucose >250 mg/dl Occult blood Urine erythrocytes Urine glucose

TAF 25 mg (n = 866)

TDF 300 mg (n = 432)

670 (77%) 13 (2%)

327 (76%) 4 (1%)

0 58 (7%) 60 (7%)

0 22 (5%) 29 (7%)

104 (12%) 105 (12%) 98 (11%) 70 (8%) 54 (6%) 52 (6%) 52 (6%) 43 (5%) 47 (5%)

43 (10%) 44 (10%) 45 (10%) 34 (8%) 27 (6%) 23 (5%) 24 (6%) 22 (5%) 22 (5%)

72 (8%) 30 (3%) 28 (3%) 28 (3%) 10/857 (1%) 50/843 (6%) 4 (<1%) 7 (1%) 9 (1%) 11 (1%) 31/856 (4%) 81 (9%) 75/798 (9%) 44/859 (5%)

41 (10%) 23 (5%) 13/427 (3%) 13 (3%) 0 3/418 (1%) 6 (1%) 9/426 (2%) 3 (1%) 0 7/426 (2%) 39/426 (9%) 39/397 (10%) 7/426 (2%)

LDL, low-density lipoprotein; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ULN, upper limit of normal. * Laboratory results are based on 859 patients for TAF 25 mg, and 428 patients for TDF 300 mg, unless otherwise noted.

was 72% (620 of 859) for patients receiving TAF and 75% (319 of 426) for patients receiving TDF; the difference was not statistically significant (p = 0.41). In contrast median percentage

increases from baseline to week 96 in the markers of proximal tubular dysfunction urine retinol-binding protein to creatinine ratio and urine beta-2-microglobulin to creatinine ratio were significantly smaller among patients receiving TAF than among those receiving TDF (p <0.001 for the differences at every timepoint through week 96) (Table S7). No patient in either group experienced a renal serious adverse event, a renal adverse event resulting in discontinuation of study drugs, an event of proximal tubulopathy (including Fanconi syndrome), or an adverse event of renal failure.

Discussion In reporting the 48-week outcomes for these large, randomized, phase III clinical trials, we noted that the interpretation of the results was limited by the relatively short follow-up and that the durability of the favorable effects of TAF over TDF treatment would need confirmation at a later timepoint. The present 96-week findings confirm these earlier results. Efficacy and safety outcomes were consistent with those at week 48 for both HBeAg-positive and HBeAg-negative patients, confirming that treatment with TAF resulted in a similar rate of viral suppression compared to that of TDF. Consistent with week 48 results, treatment effects between TAF and TDF did not differ statistically in prespecified subgroups including age, race, region, HBV genotype, baseline HBV DNA level and prior oral antiviral treatment status. Through 96 weeks of double-blind treatment, no resistance development was seen in either treatment group. Further, the superior safety profile of TAF relative to TDF with regard to bone and renal parameters seen at week 48 is confirmed through 96 weeks of double-blind treatment. Another effect seen at both weeks 48 and 96 was that more patients in the TAF groups who had elevated ALT levels at baseline achieved ALT normalization than those in the TDF groups. At week 48, the difference was only significant when using the normal ranges for men and women proposed by AASLD. In the current week 96 analysis, the rate of ALT normalization was also significantly higher in both HBeAg-negative and HBeAg-positive patients receiving TAF when using the normal ranges of the central laboratory which conducted the testing (Covance). Given the consistency of this effect over time – the rate of ALT normalization was higher for TAF than TDF patients at every visit after week 8 in both studies – there can be little doubt that it is a treatment effect and not due to some

Journal of Hepatology 2018 vol. xxx j xxx–xxx

7

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

Research Article

B

4

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg p <0.001

2 -0.15

0

-0.33

p <0.001

-2

p <0.001

-1.86

-2.51

-4 -6 -8

10

Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

5 0 -1.2 p <0.001

-5

24

48 Time (weeks)

72

96

24

48 Time (weeks)

72

96

Fig. 4. Median change from baseline in eGFR (Cockcroft-Gault). The figure shows median (Q1, Q3) change from baseline in estimated glomerular filtration rate (ml/min, by Cockcroft-Gault) by study visit. p value calculated by two-sided Wilcoxon rank sum test to compare the two treatment groups. eGFR, estimated glomerular filtration rate.

SPINE Tenofovir alafenamide 25 mg Tenofovir disoproxil fumarate 300 mg

4

-4.8

-10 -15

p = 0.80

2 0

-0.57

-0.75

p <0.001

-2

p <0.001 -2.57

-2.38

-4 -6 -8

24

48 Time (weeks)

72

96

Fig. 3. Changes in bone mineral density. (A) shows mean percentage change in hip bone mineral density at weeks 24, 48, 72, and 96 of treatment. (B) shows mean percentage change in spine bone mineral density at weeks 24, 48, 72, and 96 of treatment. p value to compare percent change from baseline between treatment groups was calculated by ANOVA model including treatment as a fixed effect. P value to compare the magnitude of the difference in percent BMD decline between treatment groups at week 48 vs. Week 96 was calculated by mixed-model repeated measures. BMD, bone mineral density.

undetected bias in the randomized populations. Several hypotheses about the cause of this unexpected effect have been considered, and while exploratory investigations are currently underway, the mechanism of this effect remains unknown. TDF treatment is known to have a ‘‘lipid lowering effect” as previously described in HIV infected patients wherein levels of fasting total cholesterol, LDL cholesterol, and HDL cholesterol, are all significantly reduced in patients who initiate or are switched to TDF-containing therapy.26,27 However, the ratio of total cholesterol to HDL is not significantly different following TDF treatment; therefore, the clinical relevance of this lipid lowering effect is unclear and a precise mechanism for these changes has not been ascertained. In the integrated analysis of these two phase III studies, median changes in fasting lipid parameters were small in the TAF group while declines in all three fasting lipid parameters and triglycerides were observed in the TDF group, consistent with results seen in HIV patients (Table S8). Thus, compared to TDF, TAF seems to demonstrate a ‘‘lipid neutral” effect. As previously reported, at week 48, a higher proportion of TAF-treated patients experienced grade 3 or higher levels of fasting LDL (≥300 mg/dl) compared with the TDF group.25,28 Integrated analysis at week 48 of available data from both studies for 1,254 patients (data on file, Gilead Sciences) showed rates of ≥grade 3 fasting LDL levels were 4% with TAF and 1% with TDF. At week 96 (Table 3), the rates were 6% with TAF and 1% with TDF treatment, representing a small change after two years of treatment. 8

Median change from baseline, ml/min (Q1, Q3)

Mean change from baseline, % (SD)

HIP

Mean change from baseline, % (SD)

A

Viral Hepatitis

Serologic responses were similar for TAF compared with TDF, albeit among patients positive for HBeAg, the rates of HBeAg loss and anti-HBe seroconversion were numerically higher in patients receiving TAF than in those receiving TDF and in both groups these rates increased from week 48 to week 96 and are consistent with results from previous studies of TDF, particularly those in which treatment-experienced patients were included.26,29 Also consistent with prior studies the rates of HBsAg loss were low (approximately 1% in HBeAg-positive patients) through two years of treatment, and mean declines in HBsAg levels were small in both patient populations. Safety outcomes at week 96 were also consistent with those of week 48. Overall, both treatments were well tolerated with the same rate of serious adverse events (7%) and low rates of discontinuations due to adverse events (1–2%). There were, however, significant differences between the groups in favor of TAF in renal and bone safety. As noted, TAF was specifically designed to substantially reduce systemic exposure to tenofovir, which was thought to be causing these known abnormalities associated with long-term TDF use.10,19–21 Regarding bone loss, over two years minimal declines in hip and spine BMD were observed with TAF treatment compared with progressive declines in BMD with TDF. This difference is particularly evident at the hip, which continues to demonstrate ongoing significant BMD decline with TDF therapy compared to TAF from week 48 to week 96. While the overall clinical implications of these data will require longer term studies and follow-up, preventing further BMD decline in patients is a meaningful clinical goal as it is known that fracture risk increases exponentially as BMD decreases.30 Similar to BMD findings, over two years of treatment, the significant differences in declines in estimated glomerular filtration rate and smaller changes in biomarkers of proximal tubular function support that TAF has less of an impact on renal function than TDF. A limitation of this renal analysis is that the patients were all relatively healthy from a renal perspective – all patients enrolled had creatinine clearances ≥50 ml/min and most patients were ≤65 years old and without comorbidities. While longer term follow-up will be needed to fully characterize the renal safety profile of TAF, these findings of lower renal impact compared to TDF are important given the reports that link TDF use to kidney injury.19,31,32,20 This analysis has several limitations; while 96 weeks of treatment has yielded similar findings to the week 48 analysis, longer term data are required to better determine differences in clinical outcomes. In both of these studies, double-blind treatment will be

Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039

JOURNAL OF HEPATOLOGY continued through three years (week 144) in a substantial subset of patients (approximately 58%) who had signed informed consent for a recently enacted amendment to the study protocol which allows another year of blinded therapy. Further, in both studies all patients who roll over to open-label TAF treatment (at either week 96 or week 144) will have the ability to continue this therapy through eight years (week 384). Across both study populations the proportion of patients considered to be at higher risk of TDF-associated bone and renal complications (i.e. age over 60 years, history of clinically significant bone and/or renal disease)9 is relatively small (estimated to be less than 20%) and additional studies in these populations are warranted. Further, our studies enrolled only viremic patients with elevated levels of serum ALT at screening who are considered candidates for initiating antiviral treatment by all current guidelines.8,9,33 Whether the safety advantages and comparable antiviral efficacy we observed for TAF relative to TDF in these studies can be duplicated in virally suppressed patients who switch treatment from TDF to TAF remains to be determined. A preliminary analysis of 541 patients enrolled in these two trials who switched from double-blind TDF to open-label TAF at week 96 has shown significant improvements in bone and renal parameters as early as 24 weeks following switch.34 Of note, a large randomized, controlled trial to evaluate the efficacy and safety of switching chronic HBV patients who are suppressed on long-term TDF 300 mg once daily to TAF 25 mg once daily has been recently initiated (NCT02979613). In conclusion, after two years of treatment, TAF remained as effective in suppressing HBV replication as TDF with no virologic resistance, and was associated with significantly less bone and renal toxicity. The mechanism behind the superior rates of ALT normalization for TAF over TDF remains to be elucidated.

Board – Gilead, BMS, AbbVie; Research – Gilead, Merck. Employees and stockholders of Gilead Sciences: John F. Flaherty, Anuj Gaggar, Audrey H. Lau, Vithika Suri, Andrea L. Cathcart, Neeru Bhardwaj, Lanjia Lin, and G. Mani Subramanian. Huy Trinh: Research—Gilead, Intercept; Advisory Board and Speaker—Gilead. Edward J. Gane: Advisory Board – AbbVie, ALIOS, Gilead, Janssen, Roche; Speaker—Gilead, AbbVie. Maria Buti: Advisory Board and Speaker – Gilead, MSD, BMS, Janssen, AbbVie. Henry L.Y. Chan: Advisor and speaker for AbbVie, BMS, Gilead and Roche; Advisor for Janssen; Speaker for MSD. No relevant conflicts of interest to disclose: Scott Fung, Patrick Marcellin, Manoj Sharma, Mustafa Kemal Çelen, Norihiro Furusyo, Dr. Shalimar, Ki Tae Yoon. Please refer to the accompanying ICMJE disclosure forms for further details.

Authors’ contributions John F. Flaherty, Anuj Gaggar, G. and Mani Subramanian contributed to the study concept and design. Kosh Agarwal, Maurizia Brunetto, Young-Suk Lim, Calvin Q. Pan, Maria Buti, Wai Kay Seto, Scott Fung, Patrick Marcellin, Sang Hoon Ahn, Namiki Izumi, Wan Long Chuang, Ho Bae, Manoj Sharma, Harry L.A. Janssen Mustafa Kemal Çelen, Norihiro Furusyo, Dr. Shalimar, Ki Tae Yoon, Huy Trinh, Edward Gane, and Henry L.Y. Chan contributed to the acquisition of data. Lanjia Lin contributed to the statistical analysis. All authors contributed to the analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content.

Acknowledgements This study was sponsored by Gilead Sciences. Writing assistance was provided by David McNeel of Gilead Sciences.

Financial support The study sponsor (Gilead Sciences) was involved with the study design, collection, analysis, and interpretation of data.

Supplementary data

Conflict of interest

Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.jhep.2017.11. 039.

Kosh Agarwal: Advisory Board and Speaker – AbbVie, Achillion, BMS, GSK, Gilead, Intercept, Janssen, Merck, Novartis, Roche; Consultant – AbbVie, Achillion, BMS, GSK, Gilead, Intercept, Janssen, Merck, Novartis, Roche. Grant – BMS, Gilead, Roche. Maurizia Brunetto: Advisory Board – Gilead, Merck, AbbVie, Janssen; Speaker – AbbVie, BMS, Gilead, Janssen, Merck, Roche. Wai Kay Seto: Advisory Board-Gilead, AbbVie, Bristol-Myers Squibb; Speaker’s Bureau-Gilead, AbbVie, Bristol-Myers Squibb, Novartis, AstraZeneca, Alfa Wassermann. Young-Suk Lim: Advisory Board – Bayer, Bristol-Myers Squibb, Gilead; Research – Bayer, Bristol-Myers Squibb, Gilead Sciences, Novartis; Speaker – Bayer, Gilead. Sang Hoon Ahn: Advisory Board – Bristol-Myers Squibb, Gilead, AbbVie, MSD; Research – Bristol-Myers Squibb, Gilead Sciences, Roche. Namiki Izumi: Advisory Board-Gilead; Speaker-Gilead, AbbVie, Shionogi, Otsuka, Bayer, MSD. WanLong Chuang: Advisory board–Gilead, AbbVie, BMS, MSD, PharmaEssentia; Speaker–Gilead, AbbVie, BMS, MSD, PharmaEssentia, Roche. Ho Bae: Speaker and research grant for Gilead. Harry L.A. Janssen: Grants – AbbVie, Bristol-Myers Squibb, Gilead Sciences, Innogenetics, Janssen, MedImmune, Medronic, Merck, Roche; Consultant – AbbVie, Benitec, Bristol-Myers Squibb, Gilead Sciences, Janssen, MedImmune, Merck, Roche, Arbutus. Calvin Q. Pan: Consultant – Gilead, AbbVie; Advisory

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Journal of Hepatology 2018 vol. xxx j xxx–xxx

Please cite this article in press as: Agarwal K et al. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol (2018), https://doi.org/ 10.1016/j.jhep.2017.11.039