Dig Dis Sci (2015) 60:260–268 DOI 10.1007/s10620-014-3336-7

ORIGINAL ARTICLE

Viral Suppression and Cirrhosis Regression with Tenofovir Disoproxil Fumarate in Asians with Chronic Hepatitis B Naoky C. Tsai • Patrick Marcellin • Maria Buti • Mary Kay Washington • Samuel S. Lee • Sing Chan • Huy Trinh • John F. Flaherty • Kathryn M. Kitrinos Phillip Dinh • Prista Charuworn • G. Mani Subramanian • Edward Gane



Received: 19 June 2014 / Accepted: 12 August 2014 / Published online: 2 September 2014 Ó Springer Science+Business Media New York 2014

Abstract Background Chronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia– Pacific. Sustained virologic suppression correlates with regression of histologic fibrosis and cirrhosis. Aim This study evaluated efficacy and safety of tenofovir disoproxil fumarate (TDF) in Asian patients through 240 weeks of treatment. Methods Post hoc analysis of the Asian subpopulation from two phase 3 clinical studies was performed. Following a 48-week randomized, double-blind evaluation of once-daily TDF versus once-daily adefovir dipivoxil, openlabel TDF for up to 240 weeks was evaluated. Patients with

both baseline and week 240 liver biopsies were evaluated for histologic changes. Results At baseline, 189/641 (29 %) patients randomized were Asian. Sixty-eight percent of Asian patients were male; 50 % were hepatitis B e antigen (HBeAg)-positive. At week 240, similar proportions of Asian (88 %) and nonAsian (87 %) patients demonstrated improvement in liver histology, and 19/22 (86 %) Asian patients with baseline cirrhosis were no longer cirrhotic. By modified intent-totreat analysis, 74 % of Asian patients and 76 % of nonAsian patients had HBV DNA \400 copies/mL at the end of week 240 (P = 0.602). No differences were seen in HBeAg loss or seroconversion in Asian versus non-Asian

N. C. Tsai (&) Department of Medicine, Queens Medical Center, University of Hawaii at Manoa, 550 S. Beretania Street, POB III #405, Honolulu, HI 96734, USA e-mail: [email protected]

S. S. Lee Department of Medicine, University of Calgary, 2500 University Dr NW, Calgary, AB T2N1N4, Canada e-mail: [email protected]

P. Marcellin Service d’He´patologie, Viral Hepatitis Research Centre, Hoˆpital Beaujon, 100 Boulevard du General Leclerc, 92110 Clichy, France e-mail: [email protected] M. Buti Department of Hepatology, Hospital General Universitari Vall d’Hebron and Networked Biomedical Research Center: Hepatic and Digestive Diseases (CIBERehd), Pg. Vall d’Hebron, 119-129, 08035 Barcelona, Spain e-mail: [email protected] M. K. Washington Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, 1161 21st Ave S, Nashville, TN 37232, USA e-mail: [email protected]

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S. Chan Private Practice, 14241 41st Ave, Flushing, NY 11355, USA e-mail: [email protected] H. Trinh San Jose Gastroenterology, 2340 Montpelier Dr, San Jose, CA 45116, USA e-mail: [email protected] J. F. Flaherty  K. M. Kitrinos  P. Dinh  P. Charuworn  G. M. Subramanian Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA e-mail: [email protected] K. M. Kitrinos e-mail: [email protected] P. Dinh e-mail: [email protected]

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patients. No Asian patient experienced hepatitis B surface antigen loss. Safety and tolerability of TDF through week 240, including changes in renal function and in hip/spine bone mineral density (from weeks 192 to 240), were comparable between Asian and non-Asian patients. Conclusions Long-term virologic and histologic efficacy and safety of TDF are comparable in Asian and non-Asian CHB patients. Keywords Antiviral agent  Asian  Chronic hepatitis B  Liver cirrhosis  Tenofovir disoproxil fumarate

Introduction Hepatitis B is a serious global healthcare problem of particular concern in the Asia–Pacific region, where the disease is endemic [1, 2]. In these highly endemic areas, hepatitis B virus (HBV) is most commonly transmitted from mother to child at birth or from person to person during early childhood [2]. Exposure to HBV at an early age carries a high risk of chronicity: 80–90 % of those infected during the first year of life and 30–50 % of those infected before age 6 years develop chronic hepatitis B (CHB) infection [2]. As a result, and because large-scale vaccination programs were not implemented until relatively recently, approximately 5–10 % of the adult population in East Asia have CHB infection [2]. Natural history studies have revealed that, in the absence of effective treatment, up to 40 % of patients with CHB infection will develop cirrhosis, liver failure, or hepatocellular carcinoma (HCC) during their lifetime [3, 4], and approximately 25 % of adults who become chronically infected with HBV in childhood will die as a consequence of cirrhosis or HCC [2]. One of the most important risk factors associated with developing progressive liver complications in CHB patients is serum HBV DNA level [5]. The seminal Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study, conducted in Asian patients, has demonstrated that elevated HBV DNA is associated with an increased risk of both cirrhosis and HCC [6–8]. In addition, several other studies

P. Charuworn e-mail: [email protected] G. M. Subramanian e-mail: [email protected] E. Gane Department of Gastroenterology and Hepatology, Auckland City Hospital, 2 Park Road, Auckland 1142, New Zealand e-mail: [email protected]

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have demonstrated that effective suppression of HBV viral replication is associated with significant regression in liver fibrosis and a decreased rate of clinical progression of liver disease [3, 9–11]. Data from two prospective, long-term clinical studies have demonstrated that tenofovir disoproxil fumarate (TDF) is effective at achieving long-term suppression of viral replication in patients with CHB without development of resistance. Once-daily treatment with TDF was shown to be superior to adefovir dipivoxil (ADV) at week 48 [12], and in the intent-to-treat analysis at week 240, TDF reduced HBV DNA levels below 400 copies/mL in 83 % of hepatitis B e antigen (HBeAg)-negative patients and 65 % of HBeAg-positive patients. Among patients who remained on treatment at 240 weeks, rates of virologic response were 97 % or higher [11]. Furthermore, no evidence of viral resistance to TDF was observed [11]. Moreover, a pooled analysis of liver biopsies obtained at baseline and week 240 found a high rate of histologic improvement (87 %), fibrosis regression (51 %), and reversal of cirrhosis (74 %) associated with TDF treatment [11]. Morphometric quantification of collagen similarly documented a positive effect of long-term TDF treatment on the regression of fibrosis [13]. Given that patients of Asian descent represented a substantial proportion of the overall treatment population in these two studies, the purpose of the present analysis was to evaluate the effect of long-term TDF treatment on virologic and histologic responses among the Asian subpopulation, and to compare the overall response in this subpopulation with that of non-Asian patients.

Patients and Methods The protocol, study design, patient enrollment criteria, and analysis methods for the two clinical studies (GS-US-1740102 and GS-US-174-0103) have been described previously [12, 14]. The studies are registered as NCT00117676 and NCT00116805, respectively, at http://www.clin icaltrials.gov. In brief, these two international, multicenter, prospective phase 3 clinical trials, enrolling predominantly treatment-naive patients, were designed to evaluate the safety and efficacy of once-daily TDF in patients with CHB and consisted of a 48-week, randomized, double-blind evaluation of once-daily TDF versus once-daily ADV, followed by open-label treatment with TDF for up to a total of 384 weeks. Patients were enrolled from sites in North America, Europe, and Australia/New Zealand. At the discretion of the investigator, emtricitabine (FTC) could be added to TDF as a fixed-dose combination tablet (FTC/ TDF) from week 72 onward in patients with confirmed HBV DNA C400 copies/mL on two consecutive visits.

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Both studies were conducted in compliance with all regulatory obligations and with the institutional review board and informed consent regulations at each investigational site. The Asian subpopulation included any patient who self-identified as being of Asian descent regardless of the study site location. Although the present analysis was post hoc, all the endpoints were predefined for the overall population and were summarized for this Asian subpopulation analysis in a manner consistent with the overall analysis [11]. Liver biopsies were performed on all patients at baseline and week 48 during the double-blind study, and an optional biopsy was obtained at week 240 during the open-label phase. Patients who had both baseline and week 240 liver biopsies were evaluated for long-term histologic changes. The procedure for evaluation of liver biopsies has been previously described [11]. Biopsy slides were assessed by the Knodell scoring system, and fibrosis was staged using the Ishak Modified Histologic Activity Index grading scale [15, 16]. An independent, central pathologist, blinded to treatment outcome, reviewed all biopsy samples to minimize the potential for interobserver variability. Cirrhosis was defined as an Ishak fibrosis score C5, and regression of liver fibrosis was defined as a C1-point decrease in Ishak score. Histologic improvement was defined as a reduction in Knodell necroinflammation score of C2 points with no worsening of Knodell fibrosis at week 240. Other outcome measures included the proportion of patients with plasma HBV DNA \400 copies/mL (69 IU/ mL) (virologic response), the proportion of patients with normalized alanine aminotransferase (ALT) levels (defined in women as ALT B34 U/L for patients aged 18 to \69 years and B32 U/L for those aged C69 years, and in men as B 43 U/L for patients aged 18 to \69 years and B 35 U/L for those aged C69 years), serum HBeAg loss and seroconversion to anti-HBe (in HBeAg-positive patients), and serum hepatitis B surface antigen (HBsAg) loss and seroconversion to anti-HBs. Viral resistance testing for genotypic changes within the HBV polymerase/ reverse transcriptase was assessed annually for patients with HBV DNA C400 copies/mL who experienced virologic breakthrough or persistent viremia and those who discontinued the study with HBV DNA C400 copies/mL. Conserved site changes or any polymorphic site change observed in [1 patient by genotypic analysis was confirmed by phenotyping, as previously described [17, 18]. Descriptive statistics were used to summarize data (mean and standard deviation for continuous data; frequency and percentage for categorical data). Comparisons between groups were done using Wilcoxon rank sum test and Fisher’s exact test for continuous and categorical data, respectively. The proportion of patients with virologic response was evaluated by a modified intent-to-treat

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analysis [11], in which missing data were considered equal to treatment failure. Patients who added FTC were considered failures at all time points following addition. Any patient with HBsAg loss who discontinued study drug and met the endpoint criteria at the last on-study visit had the last value carried forward and was included in the HBV DNA analysis as a success. An on-treatment analysis was also performed, whereby all patients on study with nonmissing data were included and patients with missing data were excluded. Biochemical and serological responses were evaluated using an on-treatment analysis. Proportions of patients with HBsAg loss/seroconversion were estimated using the Kaplan–Meier method, and comparisons between groups were done using the log-rank test, with patients adding FTC included. Histologic improvements were compared using on-treatment data using Fisher’s exact test, or the signed-rank test for patients who had paired biopsies at baseline and week 240.

Results Patient Population Twenty-nine percent (189/641) of patients enrolled in the two studies were of Asian descent. Of these, 94 % (178/ 189) completed the 48-week double-blind phase, 86 % (163/189) entered the open-label phase, and 74 % (139/ 189) completed 240 weeks of study treatment (Fig. 1). Baseline characteristics of Asian and non-Asian patients are presented in Table 1. The two groups differed significantly in several areas: compared with non-Asian patients, Asian patients were more likely to be female and had lower mean body mass index (BMI), higher baseline Knodell necroinflammatory score, and were more likely to be HBeAg-positive (38 vs. 50 %, P = 0.004). Geographic distribution also differed significantly between the two groups: most Asian patients were enrolled from study sites in North America (62 %; 117/189) or Australia/New Zealand (26 %; 49/189), whereas most non-Asian subjects were enrolled from sites in Europe (79 %; 357/452). As expected, Asian patients were more likely to have HBV genotypes C (52 %) or B (38 %), and non-Asian patients were more likely to have HBV genotype D (70 %) or A (21 %). Liver Histology Eighty-eight of 189 (47 %) Asian patients had paired liver biopsy data available at baseline and at week 240: of those, 22 (25 %) had baseline cirrhosis. Compared with baseline, histologic improvement in liver biopsies at week 240 was observed in 77/88 (88 %) Asian and 227/260 (87 %) non-

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Fig. 1 Disposition of Asian patients. ADV adefovir dipivoxil, TDF tenofovir disoproxil fumarate

Asian patients (Table 2). Improvements in liver fibrosis among Asian patients after 240 weeks of treatment with TDF are illustrated in Fig. 2. Among 66 Asian patients who were non-cirrhotic at baseline, 30 (46 %) improved, 32 (49 %) remained unchanged, and 4 (6 %) had a worsening of fibrosis. Among 22 Asian patients who were cirrhotic at baseline, 19 (86 %) had reversal of histologic cirrhosis and C2-point improvement in Ishak fibrosis score from baseline. Of each of the remaining three patients, Ishak fibrosis score was 6 at both baseline and week 240. In terms of BMI, one of these three patients had BMI between 18.5 and 24.9 kg/m2, one between 25 and 29.9 kg/m2, and one C30 kg/m2. Compared with week 48, histologic improvements at week 240 were observed in 38/87 (43.7 %) of Asian patients and 123/258 (47.7 %) of non-Asian patients. Thus, the majority of Asians and non-Asian patients either maintained or demonstrated further histologic improvement from week 48 to week 240.

at the end of week 240 (Table 2). Using on-treatment analysis, the rate of virologic response was lower for Asian patients compared with non-Asian patients (96 vs. 99 %, P = 0.047). Overall, 22 Asian patients qualified for genotypic analysis during the open-label period, but no TDF resistanceassociated mutations were detected through 5 years of treatment. Seven of these patients had confirmed virologic breakthrough. Genotypic analysis demonstrated no sequence change in 6 of 7 patients experiencing virologic breakthrough and a unique polymorphic site change in 1 patient. Furthermore, nonadherence to study medication was confirmed in 6 of 7 Asian patients who experienced virologic breakthrough. Phenotypic analysis was conducted for 6 patients with virologic breakthrough, including the patient harboring a polymorphic site change, and none showed evidence of reduced susceptibility to TDF in vitro. Additional Outcomes

HBV DNA Levels Mean [standard deviation (SD)] HBV DNA levels were similar in Asian patients [7.7 (1.43) log10 copies/mL] and non-Asian patients [7.7 (1.52) log10 copies/mL] at baseline (Table 1). Mean HBV DNA declines through 240 weeks of treatment in both groups were comparable. In both patient populations, the percentage of patients achieving a virologic response increased steadily during the first 72 weeks of the study and remained high through 240 weeks of continuous treatment (Fig. 3). In the modified intent-totreat analysis, virologic response was seen in 74 % of Asian patients and 76 % of non-Asian patients (P = 0.602)

At week 240, the proportions of patients with ALT normalization [ALT B the upper limit of normal (ULN) for those with ALT [ ULN at baseline] were similar between the two groups (82 % for Asians and 80 % for non-Asians, P = 0.693). The mean changes from baseline in ALT were also comparable (-116 U/L for Asians and -111 U/L for non-Asians, P = 0.372) (Table 2). At week 240, the percentage of patients with HBeAg loss (47 vs. 50 %, P = 0.871) or seroconversion (40 vs. 41 %, P = 1.000) was not significantly different among Asian and non-Asian patients (Table 2). No Asian patient experienced HBsAg loss or seroconversion, compared with

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Table 1 Baseline characteristics of Asian and non-Asian patients Asian patients (n = 189)

Non-Asian patients (n = 452)

P value

Age [years, mean (SD)]

40.0 (10.90)

39.9 (12.36)

0.968

Male [n (%)]

129 (68.3)

344 (76.1)

0.049

BMI [kg/m2, mean (SD)]

23.8 (3.88)

26.1 (4.84)

\0.001

European Union

23 (12.2)

357 (79.0)

North America

117 (61.9)

36 (8.0)

Australia/New Zealand

49 (25.9)

59 (13.1)

11.7 (12.03)

9.0 (9.65)

0.024

7.7 (1.43)

7.7 (1.52)

0.980

\0.001

Region [n (%)]

Years positive for HBV [mean (SD)] HBV DNA [log10 copies/mL, mean (SD)] ALT [U/L, mean (SD)] HBeAg? [n (%)]

a

141.6 (133.54)

142.9 (106.67)

0.105

95 (50.3)

171 (37.8)

0.004 \0.001

Genotype [n (%)]

Table 2 Summary of efficacy results at week 240 for Asian and nonAsian patients NonAsian patients (n = 452)

HBV DNA \400 copies/ mLb, modified intent to treat [n (%)]

128/173 (74.0)

323/425 (76.0)

0.602

HBV DNA \400 copies/ mLc, on treatment [n (%)]

130/135 (96.3)

332/335 (99.1)

0.047

Normalized ALTc, on treatment [n (%)]

105/128 (82.0)

255/318 (80.2)

0.693

ALT [U/L, mean (SD)]

32.5 (19.0)

33.8 (27.0)

0.429

ALT [U/L, mean change (SD)]

-115.6 (148.2)

-110.6 (116.3)

0.372

HBeAg lossc,d, on treatment [n (%)]

28/59 (47.5)

53/106 (50.0)

0.871

HBeAg seroconversionc,d, on treatment [n (%)] HBsAg loss/seroconversion, Kaplan–Meier intent to treat (%)d,e

23/58 (39.7) 0/0

43/106 (40.6) 15.3/12.3

1.000

Histologic improvementf (on treatment)

77/88 (87.5)

227/260 (87.3)

A B

11 (6.0) 70 (38.3)

92 (20.7) 4 (0.9)

C

96 (52.5)

16 (3.6)

D

5 (2.7)

310 (69.7)

Otherb

1 (0.6)

23 (5.2)

Prior lamivudine experience [12 weeks [n (%)]

16 (8.5)

59 (13.1)

0.107

Knodell necroinflammatory score [mean (SD)]

8.5 (2.10)

7.8 (2.34)

\0.001

Ishak fibrosis score [median (IQR)]

3 (2, 4)

3 (2, 5)

0.911

d

39 (20.9)

113 (25.3)

0.262

e

Cirrhosis (Ishak fibrosis score C5) [n (%)]

P valuea

Asian patients (n = 189)

\0.001/0.002

1.000

ALT alanine aminotransferase, HBeAg hepatitis B e antigen, HBsAg hepatitis B surface antigen, SD standard deviation a

By Wilcoxon rank sum test for continuous data and Fisher’s exact test for categorical data

b

Patients with missing data or who were taking FTC were counted as treatment failures

c

BMI body mass index, HBeAg hepatitis B e antigen, HBV hepatitis B virus, IQR interquartile range, SD standard deviation

Patients with missing data were excluded from the analysis; patients taking FTC were included

Includes only HBeAg-positive patients; P values are from log-rank tests P values between groups were calculated using log-rank test; patients adding FTC were included

f

Defined as reduction in Knodell necroinflammation score of C2 points with no worsening of Knodell fibrosis

a

By Wilcoxon rank sum test for continuous data and Fisher’s exact test for categorical data

b

Other genotypes (E–H) or unevaluable

15 % of non-Asian HBeAg-positive patients who had HBsAg loss (P \ 0.001) and 12 % who had HBsAg seroconversion (P = 0.002) (Table 2). Seven of 189 (3.7 %) Asian patients and 31 of 452 (6.9 %) non-Asian patients had FTC added to their regimen; the difference in FTC use between the two groups was not statistically significant (P = 0.144). Safety Treatment with TDF was safe and well tolerated in Asian patients, and safety results were similar to those seen in

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non-Asian patients (Table 3). Two Asian patients (1.2 %) discontinued TDF because of an adverse event during the open-label period, including one patient with septic shock and one patient with osteoporosis reported at week 195 that was considered to be study drug related. The incidence of treatment-emergent grade 3–4 adverse events reported during the open-label period was similar for Asian and non-Asian patients (12.3 vs. 13.7 %, P = 0.686). No occurrences of liver decompensation or liver failure were observed during the study. Up to week 240, 4/189 (2.1 %) Asian patients and 8/452 (1.8 %) non-Asian patients developed HCC; incidence rates were not significantly different between groups (P = 0.7551).

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Fig. 2 Changes in liver fibrosis in Asian and non-Asian patients. a Distribution of Ishak fibrosis scores at baseline and week 240. a P value calculated by signedrank test. bP value calculated by Fisher’s exact test. b Response to TDF treatment at week 240, based on baseline Ishak fibrosis category (cirrhotic or noncirrhotic) at baseline. P value calculated by Fisher’s exact test

One Asian patient (0.6 %) had a confirmed increase of C0.5 mg/dL from baseline in serum creatinine (grade 1), and another (0.6 %) had a confirmed decrease of \2.0 mg/ dL in serum PO4 (grade 2). No Asian patient had a confirmed decrease in creatinine clearance to below 50 mL/ min using Cockcroft–Gault method for calculation. Bone mineral density (BMD) was not assessed at baseline in either cohort. At week 192, BMD, as assessed by dual-energy X-ray absorptiometry, was similar between Asian and non-Asian patients [mean (SD) hip BMD: 0.9 (0.12) vs. 1.0 (0.16) g/cm2, respectively, P = 0.698; mean (SD) lumbar spine BMD: 1.0 (0.14) vs. 1.1 (0.17) g/cm2, respectively, P = 0.057]. There was no significant change

in mean BMD results from week 192 to week 240 in either Asian or non-Asian patients.

Discussion The availability of safe and effective antiviral therapies for Asians with CHB is important because of the high prevalence of this viral infection among people of Asian descent, including those living outside Asia, and the high lifetime risk of liver-related complications [2, 19]. The present analysis demonstrates that the long-term virologic and histologic efficacy and safety profiles of TDF are

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Fig. 3 On-treatment analysis of the percentage (95 % confidence interval) of patients with HBV DNA \400 copies/ mL (69 IU/mL) among Asian and non-Asian patients by visit

Table 3 Safety summary during the open-label phasea Parameter [n (%)]

Asian patients (n = 163)

NonAsian patients (n = 422)

Patients with TEAE

150 (92.0)

336 (79.6)

Patients with TESAE

13 (8.0)

76 (18.0)

2 (1.2)

6 (1.4)

20 (12.3)

58 (13.7)

Confirmed increase in creatinine of C0.5 mg/dL from baseline

1 (0.6)

4 (0.9)

Confirmed phosphorous \2.0 mg/dL

1 (0.6)

6 (1.4)

0 (0.0)

1 (0.2)

Patients with TEAE leading to study drug discontinuation Patients with treatment-emergent grade 3/4 AE

Confirmed creatinine clearance \50 mL/min

b

AE adverse event, TEAE treatment-emergent adverse event, TESAE treatment-emergent serious adverse event a

The analysis set includes only subjects who entered the open-label phase

b

By the Cockcroft–Gault equation

comparable in Asian and non-Asian patients with CHB infection. None of the differences in baseline patient and disease characteristics between Asian and non-Asian patients, including male:female ratio, HBV genotype distribution, and BMI had a clinically meaningful effect on the efficacy and safety of TDF. In this analysis, 96 and 99 % of Asian and non-Asian patients, respectively, who remained on study maintained undetectable HBV DNA levels over 240 weeks of continuous treatment with TDF without development of resistance [17]. Rates of histologic improvement at 240 weeks were also comparable between Asian and non-Asian patients (88 vs. 87 %). Among patients with baseline

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cirrhosis, 86 % of Asian patients and 70 % of non-Asian patients had a reduction in fibrosis to below 5 on the Ishak scale. The histology results for patients without baseline cirrhosis were also similar for Asian and non-Asian patients; approximately 95 % of both groups were improved or unchanged by week 240. This suggests that, consistent with the overall patient cohort and the non-Asian cohort, long-term treatment with TDF in Asian patients with CHB results in viral suppression leading to regression of fibrosis and reversal of cirrhosis in a considerable proportion of patients. Given the high probability of CHB infection progressing to cirrhosis and the likelihood of liver-related mortality, the ability of long-term TDF treatment to halt and/or reverse disease progression carries important implications for the clinical outcomes of patients with CHB infection. It is noteworthy that the Asian cohort in our analysis was considerably larger than those in past studies of HBV antiviral therapy, such as entecavir and lamivudine, evaluating liver histology [20, 21]. Our Asian cohort was comprised of 92 patients (88 with paired liver biopsies) who completed 240 weeks of follow-up on TDF treatment. By comparison, a study of entecavir treatment (C3 years) on liver histology included a total of 57 patients, 38 of whom were Asian [20]. Thus, our analysis of TDF in Asian patients represents a substantial contribution to our understanding of HBV antiviral therapy in this key patient population. At present, however, a larger trial with longterm follow-up in Asian patients will be needed to evaluate an effect of TDF treatment on overall survival. As previously reported for studies 102 and 103, as well as other patient populations [11, 12, 22, 23], the rate of serious adverse events was low among Asian patients, and very few patients discontinued from the study because of adverse events. Renal events were uncommon, and no

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consistent trends in BMD change were observed from year 4 to year 5. Although the Asian group comprised more women and had a lower BMI at baseline, compared with the non-Asian group, there is no suggestion of accelerated bone loss. Additional longer term data through 8 years, however, will be required to more fully appreciate the effects of TDF on bone metabolism in these studies. The current analysis was post hoc, which may limit its generalizability. However, although this subgroup analysis was performed post hoc, all the endpoints and analytical methods were preplanned for the entire study population. In addition, the current analysis does not evaluate outcomes for patients who are mixed race. Additional information on the efficacy and safety of TDF in Asian patients is forthcoming from a large, randomized, controlled phase 3 study currently ongoing in China [24]. The results of the present analysis suggest that TDF is a valuable treatment option for viral suppression of HBV and is associated with long-term histologic improvement, including reversal of cirrhosis, in the Asian population. Acknowledgments This study was sponsored by Gilead Sciences, Inc. Anna Lau, PhD, and Evelyn Albu, PhD, of Percolation Communications LLC provided editorial assistance during manuscript development. Gilead Sciences, Inc. provided financial support for manuscript development. Conflict of interest Naoky C. Tsai reports research grants (AbbVie, BMS, Gilead, Genentech, Janssen, Vertex, Beckman); advisory board membership (Gilead, BMS, AbbVie); speakers bureau (Gilead, Genentech, Janssen, Salix, Bayer, Kadman, Vertex, Merck, AbbVie). Patrick Marcellin reports research grants (Roche, Gilead, BMS, Novartis, Janssen, MSD, Alios Biopharma); investigator role (Roche, Gilead, BMS; Vertex, Novartis, Janssen, MSD, Boehringer, AbbVie, Pfizer, Alios BioPharma); speaker and/or consultant (Roche, Gilead, BMS, Vertex, Novartis, Janssen, MSD, AbbVie, Alios BioPharma, Idenix, Akron). Maria Buti reports research grants (Gilead Sciences); advisory board membership (Gilead, BMS). Samuel S. Lee reports consulting and research support (Abbott, Boehringer Ingelheim, BMS, Gilead, Janssen, Merck, Novartis, Roche, Vertex); speaking fees (BMS, Gilead, Merck, Roche, Vertex). Huy Trinh reports research grants (Gilead); speaking fees (BMS, Gilead, Vertex); advisory board membership (BMS, Gilead, Vertex); personal stock (Gilead). John F. Flaherty, Kathryn M. Kitrinos, Phillip Dinh, Prista Charuworn, and G. Mani Subramanian report employment/stock (Gilead). Edward Gane reports advisory board membership (Gilead, Achillon, Merck, Roche, Idenix, Novira, Novartis, Janssen); speakers bureau (Gilead, Achillon, Novartis, Janssen). Mary Kay Washington and Sing Chan have nothing to declare.

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Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B.

Chronic hepatitis B (CHB) is a major public health concern, particularly in endemic areas like Asia-Pacific. Sustained virologic suppression correlate...
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