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Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre– and post–liver transplantation patients
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Eugene R. Schiff (Center for Liver Diseases, University of Miami, Miami, FL) and colleagues; Gilead Sciences
December 2003, Volume 38, Number 6
ABSTRACT. Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily.
In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor MonitorTM polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of –4.1 log10 and –4.3 log10 copies/mL, respectively.
Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients.
The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV.
No adefovir resistance mutations were identified in patients after 48 weeks of therapy.
One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis).
Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity.
In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.
Below you’ll read about clinical improvement, safety, renal abnormalities and resistance in this advanced patient population.
BACKGROUND
Chronic hepatitis B (CHB) is a significant disease in pre- and post-liver transplantation (LT) patients. Elevated serum hepatitis B virus (HBV) DNA levels before transplantation increases the risk of recurrence of hepatitis B post-LT and may even prevent entry onto a transplantation waiting list. Recurrence of CHB post-LT results in increased risk for graft failure and death. Survival in LT recipients for CHB before available therapies was 50% 2 years post-LT. With the advent of hepatitis B immune globulin (HBIg) and lamivudine therapy, a significant reduction in recurrent HBV infection and improvement in survival was observed. A study from Europe reported a recurrent HBV infection rate of 36% at 3 years with long-term use of HBIg. Studies in the United States using higher doses of HBIg reported recurrent HBV infection rates of 11% to 19% at 2 years. Although lamivudine monotherapy decreased the recurrent HBV infection rate to 10% to 29% at year 1 post-LT, the reported incidence of lamivudine-resistant HBV in transplantation patients increases over time. Virological breakthroughs in transplantation recipients treated with lamivudine are observed in 25% (range, 10%-27%) after 11 to 18 months with increasing rates of 45% (range, 13%-65%) after 21 to 36 months.
In the absence of prophylactic or therapeutic intervention, HBV recurrence after orthotopic LT reduces both graft and patient survival to unacceptable levels. Until recently, the only effective strategies to allow patients with CHB to undergo LT to prevent or ameliorate HBV recurrence in orthotopic LT patients were long-term prophylaxis with HBIg and nucleoside analogs such as lamivudine. Although these measures have dramatically improved the results of transplantation, they are not completely successful.
Adefovir dipivoxil (Hepsera, Gilead Sciences) is a prodrug of adefovir, a nucleotide analog of adenosine monophosphate that has been shown to have in vivo and in vitro activity against both lamivudine-resistant HBV and wild-type HBV. To date, in 2 randomized, double-blind, placebo-controlled studies, 48 weeks of adefovir dipivoxil therapy in hepatitis B e antigen (HBeAg)+ and HBeAg– CHB resulted in histologic, biochemical, and virologic improvement. In HBeAg+ CHB patients, serologic improvements also were shown. The primary efficacy end point in both studies was histologic improvement as defined by a 2 point decrease in the Knodell necroinflammatory score with no worsening of the Knodell fibrosis score. Forty-eight weeks of adefovir dipivoxil showed histologic improvement in 53% (P < .001, compared with placebo) and 64% (P < .001, compared with placebo) in the HBeAg+ and HBeAg– CHB patients, respectively. In the HBeAg+ patients, serum HBV DNA decreased by a median of 3.52 log10 copies/mL (P< .001, compared with placebo) whereas a median reduction of 3.91 log10 copies/mL (P < .001, compared with placebo) was observed in the HBeAg– patients. In addition, 48% and 72% of HBeAg+ and HBeAg– patients, respectively, receiving adefovir dipivoxil had normalized alanine aminotransferase (ALT) (P < .001, compared with placebo). In HBeAg+ patients, loss of HBeAg occurred in 24% (P < .001) and seroconversion in 12% (P < .049) as compared with 11% and 6% in placebo, respectively. In a study of 35 CHB patients with lamivudine-resistant HBV and human immunodeficiency virus (HIV) coinfection receiving 150 mg lamivudine twice daily as part of their current HIV-1 antiretroviral regimen, the addition of 10 mg adefovir dipivoxil once daily resulted in a mean decrease at 48 weeks in serum HBV DNA of 4.01 log10 copies/mL (n = 29; P < .001; Roche Amplicor MonitorTM [Roche Diagnostics, Indianapolis, IN] polymerase chain reaction [PCR], lower limit of quantification [LLQ] < 400 copies/mL). Across all 3 patient populations, those with HBeAg+, HBeAg–, and HIV/HBV coinfection, adefovir dipivoxil therapy was well tolerated.
The study described here was initiated in 1999 to evaluate the safety and efficacy of adefovir dipivoxil as a treatment for lamivudine-resistant HBV in patients pre- and post-LT.
PATIENTS & METHODS
Study GS-98-435 was designed as an open-label, compassionate use study. The primary objective of this study was to evaluate the virological, biochemical, and clinical response after adefovir dipivoxil therapy in CHB patients pre- and post-LT with lamivudine-resistant HBV. No control group was included in the design of this study as it was considered unethical to withhold active treatment to this population, at risk for death or loss of graft, without alternative treatment options. Concomitant HBIg and ongoing lamivudine treatment were allowed at the discretion of the investigator. The analysis population included all patients with a baseline and 1 postbaseline visit. In the pre-LT group, patient data were not censored at the time of transplantation. Safety analysis was conducted on the entire population, 128 and 196 patients in the pre- and post-LT groups, respectively, whereas the efficacy data were based on available central laboratory results from centrally assessed patients.
To be eligible for enrollment, patients must have had a positive serum HBV DNA result (1,000,000 copies/mL by the Roche Amplicor MonitorTM PCR assay or the Digene Hybrid Capture II assay [Digene Corporation, Gaithersburg, MD] or positive by the Abbott Genostics assay [Abbott Diagnostics, Abbott Park, IL], Chiron Quantiplex bDNA assay [Chiron Corporation, Emeryville, CA], or the Digene Hybrid Capture assay) on at least one occasion within 2 months before study enrollment despite ongoing treatment with lamivudine, and either underwent LT or were wait-listed for LT. Other inclusion criteria included serum ALT 1.2 times the upper limit of normal (ULN), prothrombin time 3 seconds above the normal range (or international normalized ratio [INR] 1.3), serum albumin 2.8 g/dL, serum total bilirubin 5 mg/dL, absolute neutrophil count of 750/mm3, platelet count of 50,000 mm3, hemoglobin level in excess of 7.5 g/dL, no history of variceal bleeding or history of hepatic encephalopathy and adequate renal function (defined as serum creatinine <1.5 mg/dL and serum phosphorus 2.0 mg/dL). Patients likely to receive investigational agents with hepatitis B activity, systemic agents with nephrotoxic potential except immunosuppressive agents or competitors of renal excretion and those requiring chemotherapeutic agents during the course of the study were excluded. Any patients with an active medical or psychiatric illness or alcohol or drug use deemed by the study investigator to potentially interfere with patient treatment, assessment, or compliance also were excluded. Protocol exemptions were granted to patients with inadequate liver, renal, or hematologic function and those coinfected with hepatitis C, delta virus, or HIV-1.
RESULTS
BASELINE CHARACTERISTICS.
During the period from May, 1999, to February, 2002, 324 patients enrolled in the study had a baseline and at least 1 post-baseline visit evaluated in this study. One hundred twenty-eight patients were enrolled in the pre-LT cohort, and 196 patients were enrolled in the post-LT group. Patients had varying degrees of post-baseline follow-up with the median duration on adefovir dipivoxil therapy of 18.7 weeks and 56.1 weeks for the pre-LT and post-LT groups, respectively. Median Age: pre-LT-51, post-LT-54; 85% men; white: 63%-79%, Asian: 33%-21%; Black: 2%, 1%. HBV-DNA: 7.4 log c/ml in pre-LT, 8.2 million c/ml post-LT. Serum total bilirubin: 66% preLT, 30%, postLT; Serum albumin (g/dL)
The CPT score at baseline was higher for the pre-LT group than the post-LT group, showing the severity of liver disease and greater degree of decompensation of liver function in this group. At baseline, 37% of pre-LT patients were categorized as CPT class A (compared with 77% in post-LT cohort), 39% as class B (compared with 21%), and 24% as class C (compared with 3%). In the post-LT group, the median time from LT to study enrollment was 200 weeks. The median time on lamivudine therapy until loss of response was 68 weeks and 56 weeks for the pre- and post-LT groups, respectively.
Clinical improvements
Adefovir dipivoxil 10 mg once daily resulted in significant reductions in serum HBV DNA that was durable through 48 weeks. Through 24 weeks of adefovir dipivoxil treatment, the median DAVG of HBV DNA was –3.1 log10 copies/mL (DAVG24) for both pre- (n = 65) and post-LT (n = 144) groups.
A further reduction in serum HBV DNA was noted at week 48 (DAVG48), with the median DAVG of –3.4 log10 copies/mL (n = 30) and –3.3 log10 copies/mL (n = 110) for the pre- and post-LT groups, respectively. Similarly, when evaluating the absolute median change in HBV DNA from baseline, 48 weeks of adefovir dipivoxil resulted in a median reduction in serum HBV DNA of 4.1 (n = 13) and 4.3 log10 copies/mL (n = 57) for the pre- and post-LT groups, respectively.
After 48 weeks of therapy, normalization in serum ALT occurred in 76% of patients who had abnormal baseline ALT in the pre-LT group. Similarly, 49% of patients in the post-LT group achieved ALT normalization at week 48. Other indicators of synthetic or secretory liver function, such as albumin and bilirubin, normalized in the majority of patients who had abnormal values at baseline, whereas prothrombin time normalized in 83% and 20% of patients by week 48 in the pre- and post-LT groups, respectively. The CPT score stabilized or improved in over 90% of patients in both groups.
Genotypic analysis of HBV isolates
One hundred twenty-two baseline serum HBV samples in the post-LT cohort were analyzed genotypically for the presence of lamivudine-resistant HBV mutations. Of these, 119 patients (98%) had lamivudine-resistant mutations in the B and C domain of the HBV polymerase. Four major patterns of lamivudine mutations were identified: rtL180M + rtM204V (61%), rtV173L + rtL180M + rtM204V (19%), rtM204I (9%), and rtL180M + rtM204I (9%). Adefovir dipivoxil resulted in similar serum HBV DNA reduction in patients at week 48 regardless of patterns of lamivudine resistance mutations at baseline.
Genotypic analysis also was performed for 96 available pairs of baseline and week 48 samples by direct sequencing of HBV DNA amplified from serum by PCR to monitor for potential emergence of adefovir resistance mutations. Fifty-five samples with serum HBV DNA >400 copies/mL by PCR could be amplified and sequenced. The remaining 41 pairs were not sequenced because these were below the lower level of detection by PCR. Of the 55 paired samples with genotyping data, one conserved site substitution (rtS85P) in HBV polymerase was observed to develop at week 48 in one patient. However, the emergence of this substitution was not associated with rebound in serum HBV DNA, which remained suppressed below 400 copies/mL at week 96, suggesting that rtS85P mutation does not confer resistance to adefovir dipivoxil. In addition, none of the 55 genotyped patients displayed HBV DNA rebound after 48 weeks of adefovir dipivoxil therapy.
Safety
Adefovir dipivoxil 10 mg daily generally was well tolerated in this group of 324 severely medically compromised CHB patients pre- or post-LT for whom lamivudine therapy was failing. Patients had numerous comorbidities and varying degrees of hepatic and renal insufficiency, and many were taking concomitant nephrotoxic agents. A total of 42 (11%) deaths were reported. Causes of death were consistent with those observed in patients pre- and post-LT and/or with decompensated liver disease. Of the 128 patients in the pre-LT group, 13 (10%) of the patients were discontinued from the study, 7 (5%) died, and all but 1 death was considered unrelated to adefovir dipivoxil. The cause of death was diagnosed as hepatorenal syndrome secondary to end-stage decompensated liver disease based on preexisting medical conditions that included hepatic encephalopathy, esophageal varices, and elevated aminotransferase and total bilirubin at baseline. Three patients (2%) withdrew from the study because of an adverse event. Of these, hepatorenal syndrome, acute renal failure, and elevated liver enzymes were the causes of early study termination. Of 196 patients in the post-LT group, 17 (9%) discontinued the study, 13 (7%) died of causes unrelated to adefovir dipivoxil, and 4 (2%) withdrew from the study because of an adverse event. Causative factors for early withdrawal in these 4 patients, as assessed by the investigator, included increased liver enzymes, respiratory distress, elevated serum creatinine, and ascites. The most common adefovir dipivoxil treatment-related serious adverse events reported in the pre-LT patients with a 3% frequency included hepatic failure (7%), kidney failure (5%), sepsis (5%), encephalopathy (4%), and apnea (3%). Gastrointestinal hemorrhage, esophageal hemorrhage, hepatorenal syndrome, diarrhea, and pleural effusion occurred in 2%. All of the pre-LT patients with serious adverse events had evidence of decompensated liver disease as evident by CPT class B or C, and in each case, these events were assessed by the investigator to be caused by progression of the underlying liver disease. For the post-LT group, serious adverse events were reported in 49 patients (25%) with the most commonly reported treatment-related serious adverse events with a 2% frequency being fever, ascites, cellulitis, infection, hepatic failure, gastrointestinal hemorrhage, nausea, vomiting, abnormal liver function, dehydration, hyperkalemia, encephalopathy, pleural effusion, pneumonia, and kidney failure. Adverse events possibly or probably related to adefovir dipivoxil occurring in at least 2% or more of patients in the pre- and post-LT cohorts.
Renal laboratory abnormalities
After 48 weeks of adefovir dipivoxil therapy, there were a limited number of patients with elevated serum creatinine. Increase in serum creatinine ≥0.5 mg/dL above baseline, as confirmed by 2 consecutive laboratory assessments, was observed in 15 pre-LT and 26 post-LT patients. After initiation of adefovir dipivoxil and stabilization of clinical status, 11 of the 15 pre-LT patients underwent LT. Concomitant nephrotoxic and immunosuppressant agents were added to the therapeutic regimen after LT; immediately after, the increases in serum creatinine were observed. In 3 other patients, the changes in renal function were associated with fulminant decompensation of liver function. The remaining patient had a rise in serum creatinine 3 months after the last dose of adefovir dipivoxil and was not considered treatment emergent. In the 26 patients in the post-LT group with confirmed changes in serum creatinine, concomitant administration of cyclosporine or tacrolimus (n = 26), preexisting medical conditions (n = 11), pre-existing renal impairment (creatinine clearance <50 mL/min; n = 8), decompensated cirrhosis (n = 4), intercurrent illness (n = 13), and other concomitant nephrotoxic agents (n = 2) may have contributed to the increase in serum creatinine. No patients in the pre-LT group discontinued adefovir dipivoxil because of a renal event and only 2% of the post-LT group discontinued adefovir dipivoxil therapy with a renal event. The remainder of the patients in both groups with changes in serum creatinine were able to continue adefovir dipivoxil therapy with dose reduction and/or dosing interval modification. The extent to which adefovir dipivoxil contributed to the changes in serum creatinine is difficult to assess in the face of confounding factors such as concomitant nephrotoxic agents such as cyclosporine and tacrolimus, preexisting medical conditions, preexisting renal impairment, decompensated cirrhosis, and intercurrent illness present either at baseline and/or before the changes in serum creatinine.
Discussion By Authors
Efficacy in suppressing HBV viral replication in the transplantation setting is particularly important as patients who undergo LT for CHB are at risk for recurrent HBV infection in the liver graft. Reinfection may lead to rapid disease progression and has been associated with death within the first year after transplantation. Furthermore, by effectively suppressing HBV viral replication, patients previously unable to undergo LT because of high serum levels of HBV DNA after the emergence of lamivudine resistance are now able to undergo transplantation. Consistent with results from a 5-patient case series of adefovir dipivoxil-treated patients in the transplantation setting, the present study showed a similar reduction in serum HBV DNA after 48 weeks of adefovir dipivoxil treatment. The virologic response at 48 weeks also is similar to that seen in HBeAg+ and HBeAg– patients with compensated CHB and in patients with lamivudine-resistant HBV and HIV coinfection.
In this study, adefovir dipivoxil showed significant antiviral activity in pre- and post-LT patients with confirmed lamivudine resistance mutations at baseline, consistent with in vitro study results. Adefovir dipivoxil effectively suppressed replication of HBV DNA regardless of the pattern of lamivudine resistant mutations at baseline. Importantly, resistance to adefovir dipivoxil was not identified after 48 weeks of therapy in this population, thus providing a more durable response in contrast to the rates of resistance with lamivudine. This finding is consistent with a previous published reportshowing that adefovir dipivoxil does not lead to the emergence of resistant virus after 60 weeks of continuous therapy. Ongoing adefovir dipivoxil resistance surveillance to week 96 for all patients enrolled in this study will further characterize the resistance profile of adefovir dipivoxil in the pre- and post-LT setting. The incidence of resistance to adefovir dipivoxil appears to be delayed and infrequent in HBeAg+ and HBeAg– patients during phase 3 trials with 0% identified through 48 weeks and <2% through 96 weeks. A unique adefovir resistance mutation (the rtN236T in the D domain of the HBV polymerase) has been identified and is currently being characterized in vitro and in vivo.
The current study has shown that adefovir dipivoxil therapy not only results in significant suppression of viral replication markers in serum and an improved hepatic biochemical profile, but also results in clinical improvement. Survival in both pre- and post-LT after one year of adefovir dipivoxil treatment was 84% for the pre-LT and 93% for the post-LT patients (Kaplan-Meier analysis), which compares favorably to historical controls.
Treatment-related adverse events associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity, leading to discontinuation in 10% and 9% of pre- and post-LT patients, respectively. At the time of analysis, 26 post- and 15 pre-LT patients with changes in serum creatinine were evaluated individually to determine the potential contributory role of adefovir dipivoxil. Because confounding factors present either at baseline and/or prior changes in serum creatinine, it was difficult to assess the contributory role of adefovir dipivoxil. The results from a recent pharmacokinetic study of adefovir dipivoxil in patients with renal dysfunction demonstrated that patients with creatinine clearance less than 50 mL/min would have had increased adefovir levels comparable with levels observed with higher doses of adefovir dipivoxil that have been associated with nephrotoxicity.
Patients in this study were dosed before the availability of the dosing interval recommendations that have emerged from the pharmacokinetic study. Although many of the patients had renal impairment at baseline and confounding risk factors for renal dysfunction during therapy, only 2% of the post-LT group and none of the pre-LT group discontinued adefovir dipivoxil therapy for a renal event. Dosing interval modification is now recommended in all patients with creatinine clearance <50 mL/min. Patients with renal dysfunction or at risk of renal dysfunction must be monitored closely.
Treatment with adefovir dipivoxil provides an effective and safe treatment for CHB patients with lamivudine-resistant HBV pre- and post-LT who have no alternative treatment options. There was significant improvement in virological, biochemical, and clinical parameters in the pre- and post-LT patients with the addition of adefovir dipivoxil. Benefit was shown in this population through improvement in overall liver function, including normalization of serum albumin, serum bilirubin, and prothrombin time. The CPT scores in the pre- and post-LT groups showed stabilization or improvement and correlated with the improvements in albumin, prothrombin time, and bilirubin.
In this study, the post-LT group had failed lamivudine therapy, and in many cases had failed HBIg therapy also. The patients presented with elevated liver transaminases of greater than 1.2 times the ULN, evidence of high viral replication of greater than 6 log10 copies/mL in serum HBV DNA, and 28 percent of patients showed evidence of decompensated liver disease at baseline. Without therapeutic intervention, these patients were at high risk for disease progression. Historical data indicate LT for HBV-related liver disease has been associated with high viral recurrence rates and poor patient survival in the prelamivudine and HBIg era. Recurrence was noted to be highest among patients with markers of active viral replication. With the addition of adefovir dipivoxil therapy for these patients who had failed lamivudine therapy, HBV replication was reduced and survival greatly improved compared with historical cohorts. As such, the CPT scores in combination with liver function parameters such as serum albumin, serum bilirubin, and prothrombin time provided a useful, reliable, and generalizable tool to assess the global health for the individual patient and for the cohort.
Compared with historical data, the survival experience in pre- and post-LT patients, together with the biochemical, virological, and clinical improvements, show that adefovir dipivoxil provides a clinically meaningful benefit in this setting. The safety profile was consistent with the advanced stage of liver disease and the attendant comorbidities. Therefore, adefovir dipivoxil meets an urgent, unmet medical need and presents a potential life-saving treatment option for pre- and post-LT patients with lamivudine-resistant HBV who are at high risk for morbidity and mortality. Further studies are needed to evaluate adefovir dipivoxil as first-line therapy for patients with hepatitis B, both pre- and post-LT, alone and in combination with HBIg or lamivudine.
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