Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B
January 2004, Volume 126, Number 1
Marion G. Peters* *, H.W. Hann‡, Paul Martin§, E. Jenny Heathcote||
P. Buggisch, R. Rubin, M. Bourliere, K. Kowdley, C. Trepo, D.F. Gray
M. Sullivan, K. Kleber, R. Ebrahimi, S. Xiong, Carol L. Brosgart
Division of Gastroenterology, University of California, San Francisco, San Francisco, California, USA, ‡Jefferson Medical College, Philadelphia, Pennsylvania, USA, §Cedars-Sinai Medical Center, Los Angeles, California, USA, ||Toronto Western Hospital, Toronto, Ontario, Canada, ¶Universitaetsklinikum Eppendorf, Hamburg, Germany, #Digestive Healthcare of Georgia, Atlanta, Georgia, USA, **Hopital Saint Joseph, Marseille, France, ‡‡University of Washington Hepatology Center, Seattle, Washington, USA, §§Hopital Hôtel Dieu, Lyon, France, ¶¶GlaxoSmithKline, Greenford, Middlesex, England UK, ||||Gilead Sciences, Inc., Foster City, California, USA
Background & Aims: Adefovir dipivoxil possesses potent in vitro and in vivo antiviral activity in wild-type hepatitis B. This study assessed the safety and efficacy of adefovir dipivoxil alone and in combination with lamivudine compared with ongoing lamivudine therapy in patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant hepatitis B virus (HBV).
Methods: Fifty-nine hepatitis B e antigen (HBeAg)-positive patients with genotypic evidence of lamivudine-resistant HBV, serum alanine aminotransferase (ALT) level 1.2 times the upper limit of normal, and serum HBV DNA level 6 log10 copies/mL despite ongoing treatment with lamivudine were randomized to adefovir dipivoxil 10 mg, lamivudine 100 mg, or addition of adefovir dipivoxil to ongoing lamivudine daily. The primary end point was the time-weighted average change from baseline in serum HBV DNA level (DAVG) up to week 16.
Results: Rapid reductions in serum HBV DNA level were seen by 4 weeks in all recipients of adefovir dipivoxil; DAVG16 was --0.07 in the lamivudine group compared with --2.45 and --2.46 log10 copies/mL in the adefovir dipivoxil/lamivudine and adefovir dipivoxil monotherapy groups, respectively (P < 0.001).
Median change from baseline in serum HBV DNA level at week 48 was 0.0, --3.59, and --4.04 log10 copies/mL in the lamivudine, adefovir dipivoxil/lamivudine, and adefovir dipivoxil groups, respectively.
ALT level normalized in 10 of 19 (53%) and 9 of 18 (47%) recipients of adefovir dipivoxil/lamivudine and adefovir dipivoxil, respectively, compared with 1 of 19 (5%) recipients of lamivudine.
Three patients receiving adefovir dipivoxil or adefovir dipivoxil/lamivudine and none receiving lamivudine monotherapy were HBeAg negative at week 48 and one became hepatitis B surface antigen negative.
Conclusions: These data, limited to patients with compensated liver disease, indicate that adefovir dipivoxil alone or in combination with ongoing lamivudine therapy provides effective antiviral therapy in patients with lamivudine-resistant HBV.
(see discussion of ALT flares and resistance below)
Chronic hepatitis B is an important cause of morbidity and mortality, with continuing new infections worldwide. The goals of therapy in patients with hepatitis B virus (HBV) are to limit or reverse progression of the disease through sustained suppression of HBV replication. This is usually achieved through treatment-induced suppression of HBV DNA and through hepatitis B e antigen (HBeAg) seroconversion to antibody to hepatitis B e antigen (anti-HBe) in HBeAg-positive patients. Lamivudine, a nucleoside analogue of cytosine, and adefovir dipivoxil, a nucleotide analogue of adenosine monophosphate, suppress viral replication through inhibition of HBV DNA polymerase and chain termination. Both agents consistently result in improved liver histology, including reduced fibrosis, enhanced HBeAg seroconversion, normalization of alanine aminotransferase (ALT) levels, and clinical improvement in patients with advanced liver disease following 1 year of therapy.
However, suppression of HBV DNA is not sustained in a proportion of lamivudine-treated patients. After at least 6 months of continuous lamivudine therapy, substitutions (methionine to valine or isoleucine) at position 204 in the tyrosine-methionine-aspartate-aspartate (YMDD) locus of HBV DNA polymerase can be detected. The incidence increases with increasing duration of treatment (from 16% to 32% at 1 year to 38%, 53%, 66%, and 69% after 2, 3, 4, and 5 years, respectively).
Discontinuation of lamivudine therapy in patients with lamivudine-resistant HBV has resulted in the return of wild-type HBV as the predominant detectable species in serum within 1--6 weeks, although the mutation may be noted for more than 1 year after discontinuation of lamivudine. This observation suggests that during treatment with lamivudine, such patients have both wild-type and lamivudine-resistant HBV but the wild-type species remains largely suppressed until lamivudine is discontinued. Adefovir dipivoxil has been shown in vitro to potently suppress both wild-type and lamivudine-resistant HBV and in vivo to suppress wild-type HBV. Studies in liver transplantation recipients with lamivudine-resistant HBV have reported that adefovir dipivoxil therapy results in sustained reductions in serum HBV DNA level and is associated with improvement of liver function. This study was designed to address the role of adefovir dipivoxil alone or in combination with lamivudine compared with ongoing continued lamivudine therapy in the management of patients with chronic hepatitis B with compensated liver disease and lamivudine-resistant HBV.
Patients eligible for the study were 16--65 years of age with serum hepatitis B surface antigen (HBsAg) present for at least 6 months, positive for HBeAg, and had an elevated serum ALT level (1.2--10 times the upper limit of normal [ULN] on at least 2 occasions at least 1 month apart within the preceding 6 months). All patients had received treatment with lamivudine for at least 6 months that was ongoing at the time of randomization with confirmed HBV polymerase gene mutation within the YMDD motif by sequencing and serum HBV DNA level 6 log10 copies/mL (Roche Amplicor Monitor polymerase chain reaction; Roche, Indianapolis, IN).
Patients had well-preserved liver function (Child-Pugh-Turcotte [CPT] score 7) with prothrombin time <1 second above the ULN, serum albumin level >3 g/dL, total bilirubin level <2.5 mg/dL (<43 µmol/L), and no history of variceal bleeding, ascites, or encephalopathy. The exclusion criteria were as follows: serum phosphorus level 2.4 mg/dL (0.77 mmol/L); serum creatinine level 1.5 mg/dL (130 µmol/L); creatinine clearance <50 mL/min; absolute neutrophil count 1000 cells/mL; hemoglobin 10 or 9 g/dL (males or females, respectively); serum -fetoprotein level >50 ng/mL; prior use of adefovir dipivoxil or treatment with interferon or other immunomodulatory therapies within the 6 months preceding study screening; treatment with nephrotoxic drugs, competitors of renal excretion, and/or hepatotoxic drugs within 2 months before study screening or during the study period; prior organ transplantation; serious concurrent medical conditions, including other concurrent liver diseases; coinfection with human immunodeficiency virus (HIV); current alcohol or substance use; and pregnancy and/or lactation.
Clinical study design
This was a double-blind, randomized, active-controlled, multicenter, international study. Patients were randomly assigned to receive adefovir dipivoxil 10 mg and lamivudine placebo once daily, ongoing lamivudine monotherapy 100 mg and adefovir dipivoxil placebo once daily, or combination therapy with adefovir dipivoxil 10 mg once daily plus ongoing lamivudine 100 mg once daily for 48 weeks in a 1:1:1 ratio. There was no interruption in lamivudine therapy before randomization.
After week 48, patients completing the requirements of this study were eligible to receive continued treatment with adefovir dipivoxil 10 mg daily through open-label continued access protocols until adefovir dipivoxil was available commercially. Patients who showed HBeAg seroconversion or durable HBeAg loss in conjunction with a serum HBV DNA level <1000 copies/mL at week 48 were eligible to enroll in a long-term follow-up protocol designed to evaluate the durability of HBeAg seroconversion. After the planned 16-week interim analysis, the protocol was amended to allow access to open-label adefovir dipivoxil 10 mg for patients experiencing a severe exacerbation of chronic hepatitis B either during or after the 48-week treatment period.
A total of 59 patients were enrolled in the study from 20 centers in Australia, Canada, France, Germany, the United Kingdom, and the United States. One patient from the adefovir dipivoxil monotherapy group discontinued the study before receiving any treatment and is not included in the analysis. Two patients who prematurely discontinued treatment are included; one patient in the adefovir dipivoxil monotherapy group discontinued at week 32 due to noncompliance, and 1 patient receiving lamivudine discontinued at week 44 due to progression of disease.
The 3 treatment groups had similar demographic and baseline characteristics, with the exception of slightly higher serum ALT levels in the adefovir dipivoxil monotherapy group and a somewhat higher percentage of Asian patients in the adefovir dipivoxil/lamivudine group. Patients randomized to adefovir dipivoxil monotherapy had received prior lamivudine therapy for a median of 6--12 months longer than the other 2 groups. Two patients in the adefovir dipivoxil/lamivudine group were HBeAg positive at screening and negative at baseline. One of these patients was anti-HBe positive at baseline. In addition, one patient in the combination group had a serum ALT level within the reference range at baseline.
Serum HBV DNA levels (DAVG16) significantly decreased in patients receiving adefovir dipivoxil alone or in combination with lamivudine by week 16 that continued to week 48.
There is an initial rapid reduction of 2 log10 copies/mL in serum HBV DNA level at 4 weeks in both the adefovir dipivoxil monotherapy and adefovir dipivoxil/lamivudine groups, with continued reduction over 48 weeks. Serum HBV DNA level did not change significantly from baseline in the lamivudine monotherapy group. Although the median baseline serum HBV DNA level was higher for the adefovir dipivoxil group (8.42 log10 copies/mL) than for the adefovir dipivoxil/lamivudine and lamivudine groups (7.94 and 8.20 log10 copies/mL, respectively), the median change in serum HBV DNA level from baseline to week 48 was not significantly different between the adefovir dipivoxil monotherapy and adefovir dipivoxil/lamivudine groups (--4.04 and --3.59 log10 copies/mL, respectively).
At week 48, serum HBV DNA level was <1000 copies/mL in 26% of patients receiving adefovir dipivoxil monotherapy and 35% of patients receiving adefovir dipivoxil/lamivudine compared with no patients receiving lamivudine monotherapy (P < 0.05).
Serum ALT level decreased over 48 weeks in patients receiving adefovir dipivoxil monotherapy. A significantly larger number of patients receiving adefovir dipivoxil monotherapy (47%) and adefovir dipivoxil/lamivudine (53%) had normalized serum ALT levels by week 48 compared with patients receiving lamivudine monotherapy (5%) (P < 0.005).
Of those patients who were HBeAg positive at baseline, 16% of patients receiving adefovir dipivoxil monotherapy and 11% of patients receiving adefovir dipivoxil/lamivudine were HBeAg negative at week 48, whereas no patients receiving lamivudine monotherapy lost HBeAg.
One patient receiving adefovir dipivoxil/lamivudine was HBeAg positive at screening, negative at baseline, and fluctuated from borderline HBeAg positive to negative but was negative after week 40. Of the 5 patients with HBeAg loss, 3 regained HBeAg while off treatment during the posttreatment follow-up phase, one of whom received open-label adefovir dipivoxil and subsequently lost HBeAg once again. One patient in the adefovir dipivoxil/lamivudine group regained HBeAg while still on randomized treatment. A further 5 patients became HBeAg negative at their last available assessment in the study (range, week 52--64), all while receiving open-label adefovir dipivoxil monotherapy. Two of 18 patients (11%) and 1 of 18 patients (6%) in the adefovir dipivoxil monotherapy and adefovir dipivoxil/lamivudine groups, respectively, developed anti-HBe by week 48. One patient in the adefovir dipivoxil/lamivudine group became HBsAg negative at week 44 and was antibody to hepatitis B surface antigen positive at the last available visit, after 27 months on continuous adefovir dipivoxil.
There was no significant change from baseline in CPT scores among the 3 treatment groups. All patients were Child class A (CPT score 5--7) at baseline and week 48.
The nature of adverse events reported was similar across treatment groups. No patients discontinued study treatment due to an adverse event.
There were 5 serious adverse events. Two patients in the adefovir dipivoxil monotherapy group became HIV positive during the study; one patient in the adefovir dipivoxil monotherapy group was hospitalized for renal colic, with the event lasting 1 day and resolving on continued treatment; one patient in the lamivudine group was hospitalized for cholelithiasis for 1 day; and one patient receiving open-label adefovir dipivoxil after week 48 experienced diverticulitis lasting 3 days. All adverse events were considered unrelated to study medication.
The adefovir dipivoxil monotherapy group reported 7 events (37%) of grade 3 ALT (>5--10 times the ULN) elevations. None of the elevations in ALT level were accompanied by increases in serum HBV DNA level and/or signs of reduced hepatic function. Most of the patients receiving adefovir dipivoxil (monotherapy or combination) who experienced grade 3 or 4 toxicity in serum ALT experienced the maximum toxicity grade during the first 12 weeks after initiation of study treatment. Elevations in ALT level were not associated with reversion to wild-type HBV.
There was 1 (5%) grade 3 ALT (>5-10 times the ULN) in tht patients (n=20) receiving adefovir+lamivudine; there were no grade 3 ALT events in patients receiving lamivudine. Regarding grade 4 ALT events (>10 times the ULN): 3 (16%) in patients receiving lamivudine (n=19); 0 in patients receiving adefovir (n=19); 1 (5%) in patients receibfadefovir+lamivudine.
One of the 7 patients receiving adefovir dipivoxil monotherapy who reverted to wild type had a transient ALT elevation at week 4 that decreased at all subsequent visits.
Three patients receiving lamivudine monotherapy experienced grade 4 ALT flares (>10 times the ULN), 2 of whom had concurrent changes in serum bilirubin and/or serum albumin level. One patient with a baseline ALT level of 201 IU/L and CPT score of 5 experienced a peak ALT level of 692 IU/L at week 44 with a corresponding CPT score of 8 (serum bilirubin, 2.6 mg/dL; serum albumin, 2.7 g/dL). This patient started open-label adefovir dipivoxil at week 48; at the last assessment (week 64), his CPT score was 7 and ALT level was normal. The second patient had a baseline ALT level of 128 IU/L and CPT score of 5 and experienced a peak ALT level of 480 IU/L at week 44 with a concurrent decrease in albumin level to 3.4 g/dL (CPT score of 6). The patient discontinued all therapy at week 48, and the CPT score was 5 and ALT level was 115 IU/L at the last available assessment (week 64). The third patient with a persistently elevated ALT level (peak, 578 IU/L at week 16) was withdrawn from randomized treatment at week 44 for nonresponse and received open-label adefovir dipivoxil. There was no laboratory evidence of reduced hepatic function in this patient. Of the 12 patients who experienced an ALT level >5 times the ULN, 4 became HBeAg negative, 2 of whom acquired anti-HBe at week 48. All 4 patients also had confirmed HBV DNA levels <1000 copies/mL at week 48.
All patients discontinued blinded treatment at week 48 per protocol. Some patients received open-label adefovir dipivoxil, and some discontinued all therapy. During the posttreatment phase, 5 patients off therapy in the adefovir dipivoxil monotherapy group experienced an elevation of ALT level at least 5 times the ULN, 4 of who resumed open-label treatment with adefovir dipivoxil per protocol. Three patients receiving adefovir dipivoxil/lamivudine showed an elevation in ALT level after treatment, 2 of who then received open-label adefovir dipivoxil. In the 6 patients treated with open-label adefovir dipivoxil for an elevation in ALT level after treatment, all had resolution of ALT elevations by the last assessment (median, 44 IU/L; range, 23--108 IU/L). However, the 2 patients with posttreatment ALT flares who did not receive open-label adefovir dipivoxil continued to have elevated serum ALT levels (730 and 815 IU/L on the last assessment, respectively). None of the posttreatment elevations in ALT level were associated with signs of hepatic decompensation.
There was no evidence of abnormal changes in renal function. At week 48, the median change from baseline in serum creatinine level was 0.1 mg/dL in the adefovir dipivoxil monotherapy group and 0.0 mg/dL in both the adefovir dipivoxil/lamivudine and lamivudine groups. No patient had an increase in serum creatinine level 0.5 mg/dL above baseline or a serum phosphorus level <1.5 mg/dL, as confirmed by 2 consecutive laboratory assessments. Two patients receiving adefovir dipivoxil monotherapy had a confirmed increase in creatinine level of 0.3 mg/dL but <0.5 mg/dL. One resolved while continuing on therapy during the 48-week treatment period, and the other was reported at week 48 and resolved at week 52 while off treatment in the follow-up period. No patients required dose interruptions or discontinued treatment due to renal laboratory abnormalities.
Genotypic analyses of HBV polymerase performed on all 58 patients had lamivudine resistance mutations by sequencing at baseline. All 4 major patterns of lamivudine resistance mutations were observed in these patients. The L180M + M204V double mutation occurred most frequently (in 52% of these patients); M204I (21%), L180M+M204I (17%), V173L+L180M+M204V (9%), L180M+M240V/I (2%).
The effect of adefovir dipivoxil therapy on persistence of lamivudine-associated resistance mutations was evaluated at weeks 16, 32, and 48. Sequencing of the HBV polymerase in the 19 patients receiving adefovir dipivoxil monotherapy showed reversion to wild type at position M204 in 4 (21%), 6 (32%), and 7 (37%) patients after 16, 32, and 48 weeks, respectively. No patients in the lamivudine monotherapy group and one patient in the adefovir dipivoxil/lamivudine group lost lamivudine-associated mutations through week 48. The compensatory mutations (L180M and V173L) also reverted to wild-type sequence in 7 of the 8 patients who showed reversion of YMDD mutations through week 48. Reversion to wild-type HBV was not limited to a single mutational pattern. Of the patients who lost mutations, 2 lost the M204I mutation, 5 lost the M204V mutation, and one lost a M204I/V mixture. Adefovir dipivoxil therapy continued to suppress HBV DNA level (without viral rebound or increase in serum ALT level) in patients whose HBV reverted to wild-type HBV following cessation of treatment with lamivudine. To evaluate the potential development of adefovir dipivoxil-resistant mutations, serum HBV DNA levels were analyzed in all patients who received adefovir dipivoxil in this study. None of the 39 patients treated with either adefovir dipivoxil monotherapy or adefovir dipivoxil/lamivudine combination therapy experienced a rebound in serum HBV DNA level on treatment (i.e., a confirmed increase in serum HBV DNA level 1.0 log10 copies/mL from the on-treatment nadir).
DISCUSSION by authors
This randomized, double-blind, active-controlled study shows that treatment with adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant HBV results in significant suppression of HBV replication after 48 weeks. The antiviral response seen between the combination of adefovir dipivoxil plus lamivudine compared with adefovir dipivoxil monotherapy was similar, suggesting that lamivudine provides little or no antiviral benefit in patients with lamivudine resistance and confirming the activity of adefovir dipivoxil against both wild-type and lamivudine-resistant HBV. Our study did not include liver biopsy, but previous studies have shown histologic improvement in those who responded to adefovir dipivoxil therapy.
Patients enrolled in this trial had compensated liver function with serum HBV DNA level 106 copies/mL despite more than 6 months of continuous lamivudine therapy. Following the initiation of adefovir dipivoxil monotherapy or the combination of adefovir dipivoxil/lamivudine, both groups exhibited rapid responses to treatment with decreases in serum HBV DNA level by week 4 of approximately 2 log10 copies/mL. In contrast, no change was seen in patients receiving lamivudine monotherapy. These decreases in serum HBV DNA level were approximately 3 logs at 16 weeks and approximately 4 logs at 48 weeks of treatment with adefovir dipivoxil monotherapy or adefovir dipivoxil/lamivudine. The initial and longer-term treatment response observed in this study is consistent with early evidence that adefovir dipivoxil is active against wild-type and lamivudine-resistant HBV at a dose of 10 mg once daily.
Lamivudine-resistant HBV emerges in patients on prolonged lamivudine therapy, increases in frequency over time, and is associated with loss of clinical and virologic benefit. Treatment options for these patients with lamivudine-resistant HBV have been limited to continuation or cessation of lamivudine therapy or initiation of interferon alfa therapy. The continuation of lamivudine therapy in lamivudine-resistant HBV has been associated with worsening of liver histology in some patients. Cessation of therapy results in reemergence of wild-type HBV, and patients remain at risk of the consequences of progressive liver disease. Furthermore, the reintroduction of lamivudine therapy leads to a more rapid reappearance of the mutant virus than in treatment-naive patients. There are few studies evaluating the role of interferon alfa in the treatment of lamivudine-resistant HBV. Interferon alfa is associated with significant side effects, and the risk/benefit ratio has not been established for the treatment of patients with lamivudine-resistant HBV. Consequently, there is a need for a safe and effective treatment regimen for patients with lamivudine-resistant HBV.
The benefit of adefovir dipivoxil in treatment-naive patients with HBeAg-positive and HBeAg-positive chronic hepatitis B has been shown in randomized controlled trials. In addition, adefovir dipivoxil was used for the treatment of lamivudine-resistant HBV and HIV coinfection in an open-label, single-center study. The development of lamivudine-resistant HBV is even more rapid in patients coinfected with HIV, with up to 90% of patients developing HBV resistance to lamivudine by 4 years. In these HBV/HIV-infected patients, the decrease in HBV DNA level was similar to that seen in our study, with a decline of 4.07 log10 copies/mL at week 48. Another open-label study of 324 pretransplantation and posttransplantation patients with HBV with lamivudine-resistant HBV showed a median change in serum HBV DNA level from baseline of --4.1 and --4.3 log10 copies/mL, respectively, following 48 weeks of treatment with adefovir dipivoxil 10 mg in addition to ongoing lamivudine therapy. Therefore, the independent contribution of adefovir dipivoxil therapy in suppressing lamivudine-resistant HBV remained to be evaluated in these patients.
HBeAg seroconversion has been reported in patients who have developed lamivudine-resistant mutations, but it is less common than in those with wild-type HBV. In our study, HBeAg seroconversion was only seen in patients receiving adefovir dipivoxil either as monotherapy or in combination with lamivudine, although the rates were low and there was no significant difference between the treatment groups. These results suggest that long-term continuous therapy with adefovir dipivoxil may be needed. The efficacy and safety of long-term therapy with adefovir dipivoxil in patients with compensated liver disease and lamivudine-resistant HBV requires further study.
Lamivudine-resistant and wild-type HBV likely coexist as viral quasi-species in patients with lamivudine-resistant HBV. Both adefovir dipivoxil and lamivudine exert potent antiviral activity against wild-type HBV, whereas only adefovir dipivoxil is active against lamivudine-resistant HBV. Therefore, maintaining lamivudine therapy provided a selective advantage to lamivudine mutations over wild-type HBV and thus delayed or prevented the reversion to wild-type HBV. Wild-type viruses were observed to emerge over lamivudine mutants after lamivudine-resistant patients were switched to adefovir dipivoxil monotherapy. This phenomenon may be due to hypersensitivity of lamivudine mutants to adefovir dipivoxil or to better replication fitness of wild-type versus lamivudine mutant viruses. HBV expressing lamivudine-resistant polymerases with mutations including lamivudine (204I, 204V, L180M, and V173L) remain susceptible to adefovir in cell-based assays of HBV replication. Similarly, enzymatic assays indicate that adefovir diphosphate is active against HBV polymerases containing these lamivudine resistance mutations. However, the clinical significance of the loss of lamivudine mutations in patients receiving adefovir dipivoxil needs further study.
In this study, it appears safe to transition patients immediately to adefovir dipivoxil from lamivudine. Although one third of patients receiving adefovir dipivoxil monotherapy experienced a flare with serum ALT level 5--10 times the ULN (grade 3), none had elevations >10 times the ULN (grade 4), concurrent elevations in HBV DNA level, or signs of hepatic decompensation. The increases in ALT level were between 1.2 and 3.3 times the baseline values (see Table 5). Only 3 patients had an elevation of serum ALT level of more than one grade, of whom 2 were on lamivudine monotherapy and one on adefovir dipivoxil monotherapy. However, the effect of such elevations was not evaluated in patients with biopsy-documented cirrhosis or decompensated liver disease. Whether a shorter overlapping period of combination therapy in patients with more advanced liver disease might be an appropriate treatment strategy before discontinuing treatment with lamivudine has not been assessed.
Adefovir dipivoxil alone or in combination with lamivudine was generally well tolerated during the 48-week treatment period in the current study, as has been shown in other studies. No patients discontinued study treatment due to an adverse event. No serious adverse events were considered by the investigators to be related to the study drug. There was no evidence of nephrotoxicity in this study. Changes in serum creatinine and serum phosphorus levels are the most sensitive and specific markers for adefovir-related nephrotoxicity when treatment with adefovir dipivoxil is administered at doses of at least 30 mg daily. However, to date, nephrotoxicity at the 10-mg dose of adefovir dipivoxil in patients with HBV and compensated liver function has not been observed. In patients with creatinine clearance <50 mL/min, dose interval modification is recommended as noted in the prescribing information for adefovir dipivoxil. This 48-week treatment study shows significant and sustained antiviral efficacy of adefovir dipivoxil in patients with chronic hepatitis B and lamivudine-resistant HBV. Treatment with adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant HBV results in significant suppression of HBV replication (starting at week 4 and continuing at every time point thereafter), normalization of ALT levels, and HBeAg seroconversion after 48 weeks. The antiviral response of the 2 adefovir dipivoxil-containing regimens was similar, suggesting that continuation of lamivudine following the introduction of adefovir dipivoxil may not confer any further antiviral benefit.
Adefovir dipivoxil has been shown to be clinically active against wild-type HBV infection. This study confirms that it is also highly active against lamivudine-resistant HBV.