This study was conducted in compliance with all regulatory obligations as well as the institutional review board and informed consent regulations at each investigational site.
Lewis W. Teperman and Thomas Schiano have received research grants from Gilead Sciences, Inc.; Lewis W. Teperman has served as a speaker. Fred Poordad has served on advisory boards and as a speaker and has received research grants and unrestricted grants from Gilead Sciences. Natalie Bzowej has served in an advisory capacity for Gilead Sciences. Paul Martin has received unrestricted grants from Gilead Sciences. John Flaherty, Phillip Dinh, Stephen Rossi, and G. Mani Subramanian are employees of Gilead Sciences. Surakit Pungpapong and James Spivey have nothing to disclose.
This study was sponsored by Gilead Sciences, Inc. In collaboration with the investigators, Gilead Sciences designed the study, conducted statistical analyses, and interpreted the data, which Gilead Sciences holds. The authors had unrestricted access to the primary data and were not limited by Gilead Sciences in the writing of this article. The corresponding author (Lewis W. Teperman) takes full responsibility for the veracity of the data and the statistical analysis.
Address reprint requests to Lewis W. Teperman, M.D., Mary Lea Johnson Richards Organ Transplant Center, New York University Langone Medical Center, 403 East 34th Street, New York, NY 10016. Telephone: 212-263-8134; FAX: 212-263-8157; E-mail: email@example.com
The prognosis after orthotopic liver transplantation (OLT) for patients with chronic hepatitis B virus (HBV) infection was poor until the introduction, 20 years ago, of high-dose, long-term prophylaxis with hepatitis B immunoglobulin (HBIG) to prevent HBV recurrence.[1-3] Pioneering studies by Samuel et al.[2, 3] demonstrated that the 3-year HBV recurrence rate was 30% to 36% overall for patients receiving long-term HBIG monotherapy and 75% to 89% for those not receiving treatment.[2, 3] In addition, HBIG prophylaxis confers significant survival benefits[4, 5] and is now considered routine therapy for preventing HBV recurrence after OLT. However, HBIG is expensive, with annual costs ranging from $10,000 to more than $100,000 depending on the regimen employed.[6-8] The use of HBIG also requires parenteral administration, which is inconvenient and requires monitoring. Furthermore, although a major advance, HBIG monotherapy does not universally prevent HBV recurrence.[5, 9, 10]
The addition of the oral nucleoside analogue lamivudine to high-dose HBIG prophylaxis subsequently reduced the early rate of HBV recurrence to 5% to 10%. This prompted the investigation of modified HBIG protocols aimed at reducing the HBIG dose or eliminating it altogether. The replacement of HBIG with lamivudine was not successful and resulted in high rates of HBV recurrence with the development of lamivudine resistance. Similarly, studies examining lamivudine maintenance after HBIG withdrawal have shown mixed results; this approach appears to be most successful in patients at lower risk for recurrence (ie, those who are HBV DNA–negative before transplantation). When lamivudine is combined with HBIG, it is possible to reduce the HBIG dose[14, 15]; however, resistance to lamivudine can arise and necessitate the addition of a second oral antiviral agent.[16, 17]
The current standard of care for the prevention of HBV recurrence after OLT remains indefinite treatment with HBIG plus oral antiviral therapy. With the introduction of newer and more potent antiviral agents such as tenofovir disoproxil fumarate (TDF) and entecavir, questions have arisen regarding the role of HBIG prophylaxis and combination oral antiviral therapy.
Fixed-dose emtricitabine (FTC)/TDF is a combination product containing FTC, a nucleoside analogue reverse-transcriptase inhibitor, and TDF, an oral prodrug of the nucleotide analogue reverse-transcriptase inhibitor tenofovir. The fixed-dose combination of FTC and TDF is licensed, in combination with other antiretroviral agents, for the treatment of human immunodeficiency virus 1 (HIV-1) infection.[16, 17] Although not approved for the treatment of chronic HBV infection, FTC has in vitro activity comparable to that of lamivudine as well as a similar resistance profile. TDF is approved for the treatment of chronic HBV in adults and, in combination with other antiretroviral agents, for the treatment of HIV1 infection in adults and children. TDF is recommended in the guidelines of the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver as a preferred therapy for patients with chronic HBV infection.[14, 20]
Oral antiviral regimens containing 2 reverse-transcriptase inhibitors (eg, TDF and FTC) that are active against HBV are recommended as first-line therapy for patients coinfected with HIV and HBV.[21, 22] Although data are somewhat limited on the use of FTC/TDF in patients with chronic HBV infection, the combination has been used successfully in clinical practice.[23, 24] Recently, a Food and Drug Administration advisory panel recommended FTC/TDF for reducing the risk of acquiring an HIV-1 infection. There are only limited data on the efficacy and safety of FTC/TDF when it is used as prophylaxis against HBV recurrence after OLT.[25, 26]
Previous studies investigating HBIG combined with antiviral agents were frequently retrospective, nonrandomized, and uncontrolled. The purpose of this study was to prospectively compare FTC/TDF plus HBIG to FTC/TDF alone after HBIG withdrawal as strategies for preventing HBV recurrence in patients who had undergone OLT.
PATIENTS AND METHODS
This was a prospective, phase 2, 96-week study (NCT00507689) conducted at 7 transplant centers in the United States. The study had 2 distinct study periods (Fig. 1). In the first open-label (OL), prerandomization phase, patients who were clinically stable and had received at least 12 weeks of post-OLT HBIG prophylaxis were enrolled and treated with FTC/TDF plus HBIG for 24 weeks. In the second phase, patients who had maintained confirmed viral suppression were randomized (1:1) to continue FTC/TDF plus HBIG or receive FTC/TDF alone for an additional 72 weeks. This study was conducted in compliance with all regulatory obligations and the institutional review board and informed consent regulations at each investigational site.
Eligible patients were adults who were 18 to 75 years old and had chronic HBV [either hepatitis B e antigen (HBeAg)–positive or HBeAg-negative] before OLT and antibodies to hepatitis B s antigen within 30 days of screening. All patients had to have received at least 12 weeks of prophylactic therapy after liver transplantation (including HBIG) according to the standard protocol at each participating site. Patients must have been clinically stable after transplantation and could not have had 2 or more of the following findings associated with decompensated liver disease: a conjugated bilirubin level > 1.5 times the upper limit of normal, a prothrombin time > 1.5 times the upper limit of normal, a platelet count < 60,000/mm3, and a serum albumin level < 3.0 g/dL. Patients must have had a calculated creatinine clearance (CLcr) value ≥ 40 mL/minute. Patients were excluded if they had a history of variceal bleeding or hepatic encephalopathy after OLT, experienced a recurrence of chronic HBV (confirmed HBV DNA level ≥ 400 copies/mL after OLT), or had evidence of hepatocellular carcinoma, which was defined by an alpha-fetoprotein level > 50 ng/mL, by any other standard of care measure, or by the presence of multifocal hepatocellular carcinoma (exceeding the Milan criteria) at the time of transplantation. Coinfection with HIV, hepatitis C virus, or hepatitis D virus before transplantation or at screening was a cause for exclusion, as was prior treatment with TDF or FTC/TDF after OLT or >12 months of treatment with TDF or FTC/TDF before OLT. Patients who were likely to receive systemic drugs with nephrotoxic potential during the study other than immunosuppressive agents (eg, cyclosporine and tacrolimus) were excluded.
HBIG was administered according to each participating center's protocol. The fixed-dose combination of FTC and TDF (200 and 300 mg, respectively) was taken once daily without regard to food. The dosing interval was adjusted in patients with an altered CLcr after trial entry. If the CLcr value was 30 to 49 mL/minute, patients were to receive 1 FTC/TDF tablet every 48 hours. Patients with a CLcr value < 30 mL/minute (and those requiring hemodialysis) were not to be administered FTC/TDF.
Patients who achieved a sustained viral response (ie, they had an HBV DNA level < 400 copies/mL by polymerase chain reaction and were hepatitis B s antigen–negative) after 24 weeks of OL FTC/TDF plus HBIG were eligible for randomization. Patients were centrally randomized in a 1:1 ratio to receive OL FTC/TDF plus HBIG (the FTC/TDF+HBIG group) or FTC/TDF alone (the FTC/TDF group); those receiving HBIG continued according to the site-specific protocol. Patients received immunosuppressant regimens per institution-specific guidelines. Prohibited medications included medications with activity against HBV (lamivudine, adefovir dipivoxil, and entecavir), interferon and pegylated interferon, hepatotoxic and nephrotoxic agents, and interleukin-2.
Patients were evaluated at the time of screening, at study baseline, every 8 weeks through week 24, and every 12 weeks thereafter during the randomized phase through week 96. The primary efficacy measure was the proportion of patients with recurrence of chronic HBV viremia, which was defined as a confirmed HBV DNA level ≥ 400 copies/mL at 2 consecutive visits before week 72 or an HBV DNA level ≥ 400 copies/mL at the week 72 visit while the patient was on randomized treatment. HBV DNA was measured with the Roche COBAS TaqMan assay, which has a lower limit of quantification (LLOQ) of 169 copies/mL. Secondary efficacy measures included HBV recurrence, which was defined as 2 consecutive visits with an HBV DNA level ≥ 400 copies/mL, up to week 96; the proportion of patients with an HBV DNA level < 169 copies/mL (below the LLOQ) by visit; and the alanine aminotransferase (ALT) value and the mean change from the study baseline by visit.
Safety outcomes included adverse events (AEs), laboratory assessments, body weight, and vital signs. AEs were coded with Medical Dictionary for Regulatory Activities version 10. AE summaries included grade 3/4 AEs, serious AEs, deaths, and AE-related discontinuations. Renal endpoints were serum creatinine (mg/dL), CLcr (mL/minute), and phosphorus (mg/dL). In addition, the proportion of patients with confirmed CLcr values < 50 mL/minute and the number with confirmed CLcr values < 50 mL/minute by treatment and study period were analyzed. Adherence to FTC/TDF treatment was assessed via pill counts. Adherence was categorized according to the percentage of medication taken: <75% or ≥75%.
Formal sample size calculations were not performed. Efficacy and safety were analyzed in all randomized patients who received 1 or more doses of the study medication according to the randomized treatment that they received. No formal statistical hypothesis for the primary efficacy endpoint was tested because the objective of this study was to explore whether the withdrawal of HBIG after the addition of FTC/TDF resulted in a recurrence of HBV in patients previously maintained on HBIG alone. Treatment comparisons were performed with a 95% confidence interval (CI) to describe the difference between randomized treatment groups in the proportions of HBV recurrence. Missing data were not imputed. An analysis of secondary endpoints comprised descriptive summaries for categorical and continuous outcomes and used 95% CIs to describe differences between the randomized treatment groups.
Patient screening began in September 2007, and the last patient observation occurred in April 2011. Forty of the 51 patients who were screened enrolled and began 24 weeks of OL FTC/TDF plus HBIG (Fig. 1). There were 11 screen failures: the most common reason was a low CLcr value (<40 mL/minute; n = 5); for 2 patients, the reason was unknown; and for the others, the reasons were prior use of TDF (n = 1), a coinfection with hepatitis C virus (n = 1), loss to follow-up (n = 1), and an inability to meet the study requirements (n = 1). Thirty-seven of the 40 enrolled patients (92%) completed 24 weeks of OL treatment; all 37 patients maintained viral suppression and were randomized to receive FTC/TDF plus HBIG (n = 19) or FTC/TDF alone (n = 18) for an additional 72 weeks. A total of 35 patients [19/19 (100%) in the FTC/TDF+HBIG group and 16/18 (89%) in the FTC/TDF group] completed 48 weeks of randomized treatment up to the week 72 visit of the study. Two patients in the FTC/TDF group discontinued treatment before week 72: 1 patient withdrew consent, and 1 experienced a serious AE (a cerebrovascular accident considered to be unrelated to the study drug). Thirty-four patients [18/19 (95%) in the FTC/TDF+HBIG group and 16/18 (89%) in the FTC/TDF group] completed the entire 96 weeks of the study. One patient in the FTC/TDF+HBIG group discontinued treatment after week 72 because of elevated hepatic enzymes (considered to be unrelated to the study drug).
The demographics and the clinical characteristics at the baseline were generally similar across the randomized treatment groups (Table 1). Overall, the median age was 59 years, and 80% of the patients were male. Thirty-eight percent were Asian, 33% were Caucasian, and 25% were African American. Patients had an HBV infection for a median of 9 years (interquartile range = 5-16 years), the majority of the patients (70%) were HBeAg-negative before transplantation, and the median time since OLT was 3.4 years (interquartile range = 1.9-5.6 years). Before OLT, HBV DNA was undetectable in 17 of the 33 patients (52%) with available data, and the distribution was equal in the treatment groups. At the baseline, the median ALT value was 21 U/L (interquartile range = 16-28 U/L). Patients received immunosuppressive regimens that included tacrolimus (93%), mycophenolate (53%), prednisone (38%), sirolimus (13%), and/or azathioprine (3%). Almost all patients had prior exposure to at least 1 antiviral agent. Approximately 85% of the patients had previously received lamivudine, and 45% had previously received adefovir. Patients previously treated with lamivudine or adefovir were approximately evenly distributed between the treatment groups. All enrolled patients were virally suppressed at study entry; therefore, resistance testing was not performed at the baseline or at any time during the study after treatment with FTC/TDF.
Table 1. Demographics and Disease Characteristics at the Baseline
No patient experienced HBV recurrence through 72 weeks (the primary endpoint) or at 96 weeks. All patients had HBV DNA levels below the LLOQ at weeks 24, 72, and 96. One patient in the FTC/TDF group showed an HBV DNA level above the LLOQ at week 84 (314 copies/mL) with a single measurement of hepatitis B s antigen positivity that was not confirmed. This result may have been spurious because all HBV DNA values were undetectable at every other measured time point.
Ninety-five percent of the patients (38/40) had normal ALT values at the baseline. After the week 24 randomization, the mean values (with standard deviations) increased slightly and then remained stable through the end of the study. The median change from the baseline to week 96 was 2 U/L (interquartile range = −14 to 26 U/L) in the FTC/TDF+HBIG group and 5 U/L (interquartile range = −10 to 24 U/L) in the FTC/TDF group. The mean FTC/TDF adherence rates were similar in the randomized groups (73.3% ± 26.15% in the FTC/TDF+HBIG group and 75.9% ± 23.07% in the FTC/TDF group).
Few drug-related AEs occurred during the study. In the 24-week prerandomization, OL phase, 6 of 40 patients (15%) experienced a drug-related AE; all AEs were mild to moderate in severity, and none were serious. The most frequently reported drug-related AE was decreased creatinine renal clearance (2 patients). One patient discontinued treatment because of moderate worsening of ulcerative colitis, an AE that was attributed to the study drug by the investigator.
During the randomized phase, no patients experienced grade 3/4 AEs or serious AEs that were judged by the investigator to be related to the study drug (FTC/TDF). One patient in the FTC/TDF group experienced a mild study drug–related rash that did not lead to discontinuation, and 1 patient (FTC/TDF group) died from a cerebrovascular accident that was considered to be unrelated to the study drug.
Grade 3/4 laboratory abnormalities were infrequently observed. Only hyperglycemia and glycosuria were observed in more than 2 patients (3 patients each in the prerandomization phase). During the randomized phase, more grade 3/4 laboratory abnormalities occurred in the FTC/TDF+HBIG group (n = 7) versus the FTC/TDF group (n = 2; Supporting Table 1).
Although the majority of the patients had mild renal impairment (CLcr values between 50 and 80 mL/minute) at the baseline, it is notable that a substantial percentage of the patients [23% (9/40) in the initial prerandomization phase] had moderate impairment (CLcr < 50 mL/minute), and only 18% (7/40) had normal renal function (CLcr > 80 mL/minute). The mean CLcr values (with 95% CIs) remained relatively stable over time (Fig. 2). At the baseline, the mean serum creatinine values for patients in the CLcr categories of <50, 50 to 80, and >80 mL/minute were 1.42 ± 0.38, 1.19 ± 0.22, and 1.04 ± 0.17 mg/dL, respectively. The serum creatinine levels generally remained stable within each CLcr category over the course of the study. No patients experienced a grade 3 or 4 increase in serum creatinine in either the prerandomized or randomized phase of the study, nor were there any cases of renal failure or severe renal impairment. Only 2 patients had an AE leading to a change in dose in the prerandomized phase (1 mild decrease and 1 moderate decrease in CLcr), and 1 patient did in the randomized phase. No patients discontinued the study for a renal-related event. Among the 15 patients who had CLcr values of less than 50 mL/min or less during the study, all but 5 had such levels at the screening or baseline. No on-treatment hepatic flares occurred during the study. One patient had increased CLcr on the study drug.
The observation 20 years ago that HBIG prophylaxis could prevent HBV recurrence enabled patients with decompensated liver disease due to HBV infection to successfully undergo liver transplantation. The introduction of potent oral antivirals has allowed the further evolution of HBV treatment for liver transplant recipients. In this study, which prospectively evaluated the safety and efficacy of FTC/TDF with or without HBIG in patients with chronic HBV infection who underwent OLT, no patient experienced HBV recurrence after HBIG withdrawal over 72 weeks of evaluation. Furthermore, treatment with FTC/TDF alone or the combination of FTC/TDF with HBIG was well tolerated, with few patients discontinuing for AEs. On the basis of these data, treatment with FTC/TDF plus HBIG followed by the withdrawal of HBIG at 6 months should be considered as a treatment strategy for preventing chronic HBV recurrence after OLT.
Our findings confirm and build upon results from smaller, mostly retrospective and nonrandomized studies,[25, 26, 28] including 1 nonrandomized study that reported the successful use of FTC/TDF with a low recurrence of HBV infection after HBIG discontinuation in patients after OLT. A recent study of entecavir monotherapy without HBIG in a heterogeneous patient population reported hepatitis B surface antigenemia in 22.5% of patients within a 2-year time frame even though 94% of the patients had undetectable HBV DNA levels at the time of their last follow-up.
Importantly, both treatment arms were found to be safe and well tolerated. Study drug–related AEs were all mild to moderate in severity, and there was only 1 AE leading to study drug discontinuation (worsening of ulcerative colitis), which occurred during the initial prerandomization phase of the study; this AE was considered by the investigator to be study drug–related. Overall, the AEs and laboratory abnormalities observed were representative of those expected in a posttransplant patient population.
Renal dysfunction is common after OLT and is often due to the nephrotoxicity of the immunosuppressive agents used in this patient population.[28, 30] In this study, more than 80% of the patients had renal dysfunction at the baseline, and despite this, the glomerular filtration rates (as estimated by CLcr) remained remarkably stable over the course of 96 weeks in the majority of the patients. Dose adjustments for renal AEs were infrequently required. No patient experienced renal failure or progressive deterioration in renal function over the course of the study. Importantly, patients with moderate to severe renal insufficiency (CLcr < 40 mL/minute) were excluded from this trial, and it is recommended that FTC/TDF be used cautiously in such instances.
Patients were HBV-positive for a median of 9 years and underwent OLT a median of 3.4 years before study entry; 30% of the patients were HBeAg-positive at study entry. In this population, HBV DNA levels remained below the LLOQ during the entire study period in all patients, and no patients had confirmed detection of HBsAg in serum; importantly, the majority of the patients in both randomized treatment groups were adherent to the study drug. Each institution was allowed to follow its site-specific HBIG protocol; however, efficacy data were consistent between institutions, and this suggests that the results are applicable across a range of site-specific HBIG protocols. Several limitations must be noted. This was a small study that demonstrated equivalence in the 2 arms. Although we followed randomized patients for 72 weeks, longer term follow-up is necessary and is ongoing. Because of the entry requirements of complete HBV DNA suppression and no posttransplant history of HBV recurrence and the relatively extended period between OLT and enrollment, the population that we studied likely represents those at lower risk for recurrence. Lastly, the study was conducted in the United States, so it is conceivable that the results may not be directly applicable to other countries.
Although this study supports the safe and effective withdrawal of HBIG after 6 months, at our individual institutions, we are investigating whether HBIG can be withdrawn earlier. It may be possible, if renal function is adequate, to successfully withdraw HBIG as soon as 1 month after transplantation. TDF alone has not been studied and may also show efficacy in the posttransplant setting. Further studies to examine all these issues will be required to assess the optimal regimen for HBIG withdrawal to ensure successful OLT in the setting of chronic HBV infection.
The authors thank Mariana Ovnic, Ph.D., and Evelyn Albu, Ph.D., of Percolation Communications LLC for providing medical editorial assistance during manuscript development. Gilead Sciences, Inc., provided financial support for manuscript development.