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PegIntron+Lamivudine vs LAM for HBV
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"A Randomized, Controlled Trial of Combination Therapy for Chronic Hepatitis B: Comparing Pegylated Interferon-{alpha}2b and Lamivudine with Lamivudine Alone"
Annals of Internal Medicine
15 February 2005
...Conventional interferon treatment with injections given up to 3 times per week for 12 to 24 weeks may lead to HBeAg seroconversion in 33% of treated patients compared with 12% of untreated controls... Studies suggest that only 16% to 18% of patients treated with lamivudine for 1 year develop HBeAg seroconversion... The durability of HBeAg seroconversion is estimated to be 46% to 64% up to 3 years after the cessation of lamivudine treatment... Since extending interferon treatment from 16 to 32 weeks is associated with higher rates of HBeAg seroconversion (21), combination therapy includes pegylated interferon-{alpha}2b given for 32 weeks... Our rationale for staggered treatment was that initial treatment with pegylated interferon-{alpha}2b probably enhances the immune clearance of intrahepatic HBV, including the closed covalent circular DNA, and that adding lamivudine at a later phase theoretically suppresses HBV replication and prevents reinfection of the hepatocytes. This particular hypothesis requires confirmation with studies of viral kinetics...
End Points
We defined virologic response as HBeAg seroconversion (that is, loss of HBeAg), detection of antibody to HBeAg, and HBV DNA level less than 500 000 copies/mL and biochemical response as normalization of ALT level. We assessed both the virologic and biochemical end-of-treatment responses (week 52 for monotherapy and week 60 for combination therapy) and the sustained responses at 24 weeks after the end of treatment.
The primary end point was sustained virologic response. Secondary end points included sustained biochemical response, end-of-treatment virologic and biochemical responses, reduction in HBV DNA levels, and histologic improvement. We scored histologic necroinflammation by using the Knodell scoring system (score range, 0 to 18) and liver fibrosis by using the Ishak scoring system (score range, 0 to 6). The necroinflammation score was the sum of 3 histologic components: severity of periportal necrosis (score range, 0 to 10), intralobular necrosis (score range, 0 to 4), and portal inflammation (score range, 0 to 4). We considered a reduction of at least 2 points to be a clinically meaningful indicator of histologic changes. We regarded liver biopsy results with at least 3 portal tracts as sufficient for histologic scoring. One histopathologist, who was blinded to treatment assignments or the times at which the specimens were obtained, assessed all histologic specimens. The proportion of patients developing lamivudine-resistant mutant in the 2 treatment groups was also compared.
AUTHOR DISCUSSION
The antiviral effect of lamivudine, a nucleoside analogue, for treating chronic HBV infection is suboptimal. The drug is associated with a low HBeAg seroconversion rate, frequent post-treatment relapses, and development of drug resistance with extended treatment. Combination therapy with lamivudine and other nucleoside analogues (for example, adefovir dipivoxil and telbivudine) may not improve virologic response (28, 29), and combination therapy with lamivudine and interferon shows conflicting results. In our study, we administered a combination of pegylated interferon-{alpha}2b and lamivudine in a staggered manner. Our rationale for staggered treatment was that initial treatment with pegylated interferon-{alpha}2b probably enhances the immune clearance of intrahepatic HBV, including the closed covalent circular DNA, and that adding lamivudine at a later phase theoretically suppresses HBV replication and prevents reinfection of the hepatocytes. This particular hypothesis requires confirmation with studies of viral kinetics.
We found that patients with HBeAg-positive chronic hepatitis B and moderately elevated ALT levels had a higher rate of virologic response at the end of treatment with the staggered combination regimen (60%) than with monotherapy (28%). The rate of sustained HBeAg seroconversion 24 weeks after cessation of treatment was also higher with the staggered combination regimen (36%) than with monotherapy (14%). The end-of-treatment seroconversion rate for the staggered combination regimen was better than that reported for other antiviral treatment regimens (9-11, 17, 28-30). Although a previous study had suggested that pegylated interferon might lead to higher rates of sustained seroconversion than conventional interferon (31), we found a rate of sustained post-treatment seroconversion similar to that reported in patients using either a conventional interferon and lamivudine combination (Table 4) or conventional monotherapy (34). Because these studies involved various patient populations with different HBV genotypes and used varying treatment regimens and definitions of virologic response, head-to-head comparisons are still needed to establish whether combination therapy with pegylated interferon and lamivudine leads to similar or higher rates of sustained response than either pegylated interferon alone or conventional interferon with or without lamivudine.
We also found a relatively high rate (40%) of post-treatment viral relapse among patients with initial end-of-treatment responses. The high relapse rate could be related to short durations of either pegylated interferon-{alpha}2b or lamivudine treatment. Extended lamivudine treatment after HBeAg seroconversion might improve the sustainability of virologic response (15, 35). However, despite suppression of HBV DNA in most patients and HBeAg seroconversion in almost half of the cases, we found lamivudine-resistant mutations in 21% of patients receiving combination treatment and 40% of patients receiving lamivudine monotherapy. The amount of lamivudine resistance that we found is higher than that reported in some series of Asian patients, perhaps because we used a highly sensitive line probe assay that could detect very low levels of mutants in a mixture with wild type (9-11, 27).
We found that patients in both treatment groups had biochemical and histologic improvements similar to those shown in previous studies with lamivudine treatment (9-11). We based histologic measurements on results of repeated liver biopsies that were performed in a sample of patients at the end of treatment. Histologic measurements taken several months after treatment might differ, particularly since patients in the lamivudine monotherapy group had higher post-treatment relapse rates than those in the combination therapy group.
Our trial has several limitations. First, we compared a staggered regimen of 60-week combination treatment with pegylated interferon and lamivudine versus 52-week treatment of lamivudine monotherapy. Under this study design, patients receiving combination treatment received a longer duration of antiviral treatment, which might affect the difference in clinical outcome. However, the antiviral effect of combination treatment at week 48 was still superior to that of lamivudine monotherapy and was similar to that of combination treatment at week 60. The extended therapy duration to 60 weeks did not seem to be a major factor affecting the virologic and clinical responses.
Second, since we did not include a pegylated interferon-{alpha}2b monotherapy group, we did not evaluate the additive benefit of lamivudine over pegylated interferon alone. The final results of a multicenter trial that compares the pegylated interferon and lamivudine combination with pegylated interferon monotherapy will shed light on this important issue (36). Third, the trial was not double-blinded since we did not use a placebo. However, no patients received antiviral or immunomodulator therapy other than the assigned drugs, and the end points were laboratory values that were probably not affected by patients' perceptions. Fourth, patients assigned to combination treatment had higher median ALT levels at baseline than patients assigned to monotherapy. We thought it unlikely that these relatively small differences in ALT levels accounted for the differences between groups in clinical outcomes, particularly since we confirmed a beneficial effect of combination treatment among the subgroup of patients with baseline ALT levels less than 5 times the upper limit of normal. Fifth, although we evaluated virologic response 24 weeks after treatment, chronic hepatitis B is a persistent disease. Studies with even longer follow-ups are needed to assess clinical outcomes and the durability of response to treatment.
In conclusion, we found that, in patients with HBeAg-positive chronic hepatitis B and moderately elevated ALT levels, combination treatment with pegylated interferon-{alpha}2b and lamivudine was associated with higher rates of end-of-treatment and post-treatment HBeAg seroconversion, an increased potency of HBV suppression, and a lower incidence of lamivudine resistance than lamivudine monotherapy. We now need head-to-head comparisons to see whether this combination treatment leads to similar or higher rates of sustained response compared with either pegylated interferon alone or conventional interferon with or without lamivudine.
ABSTRACT
Background: Conventional interferon and lamivudine monotherapy are unsatisfactory in treating hepatitis B virus (HBV) infection.
Objective: To evaluate the efficacy and safety of pegylatedinterferon-{alpha}2b and lamivudine combination therapy for chronic hepatitis B.
Design: Randomized, controlled, open-label trial.
Setting: Outpatient clinic in a referral center.
Participants: 100 treatment-naive patients with hepatitis B e antigen (HBeAg)--positive chronic hepatitis B and moderately elevated alanine aminotransferase levels.
Measurement: The primary end point was sustained virologic response (HBeAg seroconversion and HBV DNA level < 500,000 copies/mL) at 24 weeks after cessation of treatment.
Intervention: A staggered regimen of combination therapy with pegylated interferon-{alpha}2b (1.5 µg/kg of body weight per week; maximum, 100 µg) given for 32 weeks plus lamivudine (100 mg daily) given for 52 weeks versus lamivudine (100 mg daily) monotherapy given for 52 weeks. Of the 100 participants, 96% completed treatment and 80% completed post-treatment follow-up.
Results: The rate of sustained virologic response was 36% for the combination treatment group and 14% for the lamivudine monotherapy group (absolute difference, 22 percentage points [95% CI, 6 to 38 percentage points]). End-of-treatment outcomes showed that, compared with monotherapy, patients receiving combination therapy more often had virologic response (60% vs. 28% [absolute difference, 32 percentage points (CI, 14 to 50 percentage points)]); had more substantial reductions of HBV DNA (3.91 log10 copies/mL vs. 2.83 log10 copies/mL); and less often had lamivudine-resistant mutants (21% vs. 40%). The percentages of patients with normalization of alanine aminotransferase levels and histologic improvement did not differ. Adverse effects, such as transient influenza-like symptoms, alopecia, and local erythematous reactions, were more common with combination therapy.
Limitations: This study lacked a double-blind design and was conducted at 1 institution. Because of the staggered pegylated interferon--lamivudine regimen, patients assigned to combination therapy received treatment for 8 weeks longer than those assigned to monotherapy.
Conclusions: In patients with HBeAg-positive chronic hepatitis B, staggered combination treatment with pegylated interferon-{alpha}2b and lamivudine may lead to a higher rate of virologic response than lamivudine monotherapy.
Role of Funding Source
Schering-Plough Corp. supplied pegylated interferon-{alpha}2b, and GlaxoSmithKline supplied lamivudine. The authors developed the study protocol and were responsible for data collection and progress of the study. The authors had full access to all of the study's data files and were responsible for statistical analysis, reporting of data, and manuscript submission. Representatives of the pharmaceutical companies that supplied the drugs did not comment on the manuscript before submission.
INTRODUCTION
Chronic hepatitis B virus (HBV) infection affects more than 300 million people globally (1). Patients who have HBV infection with positivity for hepatitis B e antigen (HBeAg) and persistently active disease have increased risks for progressive disease leading to liver cirrhosis and hepatocellular carcinoma (2). Conventional interferon treatment with injections given up to 3 times per week for 12 to 24 weeks may lead to HBeAg seroconversion in 33% of treated patients compared with 12% of untreated controls (3). The treatment response to conventional interferon treatment among Asian patients seems less satisfactory (4, 5). Pegylated interferon-{alpha}2b is synthesized by bonding recombinant interferon-{alpha}2b to polyethylene glycol and is given once weekly rather than 3 times weekly (6). The antiviral efficacy of pegylated interferon-{alpha}2b for treating chronic hepatitis C is superior to that of conventional interferon (7, 8), but few studies have evaluated pegylated interferon in patients with chronic hepatitis B.
Lamivudine is an oral nucleoside analogue that effectively suppresses HBV replication (9, 10). Studies suggest that only 16% to 18% of patients treated with lamivudine for 1 year develop HBeAg seroconversion (9-11). Extending lamivudine treatment for up to 4 years is associated with development of drug-resistant viral mutants in about 70% of patients (12). The durability of HBeAg seroconversion is estimated to be 46% to 64% up to 3 years after the cessation of lamivudine treatment (13-15).
Successful elimination of HBV depends on a durable immune clearance of the existing pool of intrahepatic HBV, particularly the closed covalent circular DNA (16). Combining an immunomodulator (such as interferon) and an antiviral agent (such as lamivudine) is an appealing approach for treating chronic hepatitis B. However, past studies in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B showed conflicting results about the superiority of combination therapy over lamivudine monotherapy (11, 17-20). We evaluated whether the combination of pegylated interferon-{alpha}2b and lamivudine improves antiviral efficacy and increases HBeAg seroconversion rates more than lamivudine monotherapy in patients with HBeAg-positive chronic hepatitis B and moderately elevated alanine aminotransferase (ALT) levels. Since extending interferon treatment from 16 to 32 weeks is associated with higher rates of HBeAg seroconversion (21), combination therapy includes pegylated interferon-{alpha}2b given for 32 weeks.
SUMMARIES FOR PATIENTS
Combination Therapy for Chronic Hepatitis B
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The summary below is from the full report titled "A Randomized, Controlled Trial of Combination Therapy for Chronic Hepatitis B: Comparing Pegylated Interferon-{alpha}2b and Lamivudine with Lamivudine Alone." It is in the 15 February 2005 issue of Annals of Internal Medicine (volume 142, pages 240-250). The authors are H.L.-Y. Chan, N.W.-Y. Leung, A.Y. Hui, V.W.-S. Wong, C.-T. Liew, A.M.-L. Chim, F.K.-L. Chan, L.C.-T. Hung, Y.-T. Lee, J.S.-L. Tam, C.W.-K. Lam, and J.J.-Y. Sung.
What is the problem and what is known about it so far?
Hepatitis B is an inflammation of the liver that is caused by a virus. The virus spreads through contact with infected body fluids. Most people who get hepatitis B recover within a few months, but some develop chronic infection. Chronic infection increases risk for liver failure and liver cancer. Persons with chronic infection often have virus-related protein substances in their blood (called hepatitis B surface antigens and e antigens) for many years. Persons with hepatitis B e antigens may have very active liver disease and a high level of hepatitis B virus. Doctors often treat these patients with powerful antiviral drugs. However, some patients develop viral forms (mutants) that are resistant to 1 or more antiviral drugs. To help prevent resistance and improve outcomes, doctors sometimes combine 2 different types of antiviral drugs. Few studies have assessed the benefits and harms of these combination therapies for chronic hepatitis B.
Why did the researchers do this particular study?
To see whether combining pegylated interferon-{alpha}2b with lamivudine reduces the amount of hepatitis B virus in the body and liver inflammation more than lamivudine alone.
Who was studied?
100 adults with chronic hepatitis B who had hepatitis B e antigens. The average age was about 33 years, and about two thirds of the patients were men. All patients had abnormal liver test results that suggested inflammation.
How was the study done?
The researchers recruited patients with chronic hepatitis B and elevated liver test results (an alanine transaminase level 1.3 to 5 times the upper limit of normal) from a single hospital in Hong Kong. They randomly assigned patients to receive pegylated interferon-{alpha}2b for 32 weeks plus lamivudine for 52 weeks or lamivudine alone for 52 weeks. In the first group, interferon was given for 8 weeks before the lamivudine was started. Interferon was injected under the skin once weekly, and lamivudine was taken as a daily pill. The researchers asked patients about side effects and tested blood for evidence of virus, resistant mutants, and liver inflammation routinely during treatment and also 24 weeks after treatment ended.
What did the researchers find?
Tests at the end of treatment and 24 weeks after treatment showed that viral amounts were reduced more with combination therapy than with single therapy. Also, at the end of treatment, more patients who received single therapy had viral mutants resistant to lamivudine than patient who received combination therapy. Liver inflammation did not differ between the 2 groups. Patients who received combination therapy had more side effects, such as brief influenza-like symptoms and swelling at injection sites, than those who received single therapy.
What were the limitations of the study?
Patients assigned to combination therapy received treatment for 8 weeks longer than those assigned to single therapy. Both the researchers and the patients knew who received combination therapy.
What are the implications of the study?
Combining pegylated interferon with lamivudine may reduce viral amounts and viral resistance more than lamivudine alone in some patients with chronic hepatitis B who have hepatitis B e antigens.
Patients
We recruited consecutive patients 18 to 65 years of age with chronic hepatitis B from the Hepatitis Clinic of the Prince of Wales Hospital, Hong Kong, China, a secondary referral center serving around 1 million people. All patients had been positive for hepatitis B surface antigen (HBsAg) for at least 6 months, were HBeAg-positive, and had a serum HBV DNA level of at least 500 000 copies/mL and an ALT level that was 1.3 to 5 times the upper limit of normal. We excluded patients who had decompensated liver disease or a history of interferon or antiviral agent use. Other exclusion criteria were co-infection with hepatitis C virus, hepatitis D virus, or HIV; history of hepatocellular carcinoma; other causes of liver disease, including autoimmune hepatitis; Wilson disease; hemochromatosis and {alpha}1-antitrypsin deficiency; serious medical or psychiatric illness; concurrent use of corticosteroid or immunosuppressive agents; and pregnancy. We conducted the study in accordance with the guidelines of the Declaration of Helsinki. The ethics committee of The Chinese University of Hong Kong approved the protocol, and all patients gave witnessed, written informed consent.
Study Design
The study was a phase III, open-label, randomized trial. Within 4 weeks of screening for eligibility criteria, patients were randomly assigned to either combination therapy with pegylated interferon-{alpha}2b (PegIntron, Shering-Plough Corp., Kenilworth, New Jersey) and lamivudine (Zeffix, GlaxoSmithKline, Middlesex, United Kingdom) or lamivudine monotherapy in a ratio of 1:1. We based study group assignment on a computer-generated list, and research staff who were not involved in patient management placed the random numbers in opaque envelopes. A research nurse prescribed study drugs after receiving the information about treatment allocation at the baseline visit.
Pegylated interferon-{alpha}2b was given as a subcutaneous injection at a dosage of 1.5 µg/kg of body weight per week for patients who weighed less than 65 kg or 100 µg per week for patients who weighed more than 65 kg for 32 weeks (6). Lamivudine was administered as 100 mg orally daily for 52 weeks in both groups of patients. In patients receiving combination therapy, pegylated interferon-{alpha}2b was administered 8 weeks before lamivudine was administered. Then both treatments were given in combination for 24 weeks, followed by lamivudine monotherapy for a further 28 weeks. Patients in the combination group were asked to return at weeks 1, 2, 4, 8, 12, 16, 20, 24, 32, 40, 52, and 60 (end of treatment). Patients in the lamivudine monotherapy group received lamivudine for 52 weeks and were asked to return for follow-up at weeks 4, 8, 12, 16, 24, 32, 40, 48, and 52 (end of treatment). We followed patients in both groups every 8 weeks in the post-treatment period for 24 more weeks. We gave open-label lamivudine treatment to patients who experienced severe post-treatment relapse of chronic hepatitis B (defined as an ALT level > 10 times the upper limit of normal and HBV DNA level > 500 000 copies/mL).
Safety
The investigators interviewed patients for symptomatic adverse effects and closely monitored laboratory tests at each follow-up visit. They recorded symptoms and events that patients reported spontaneously, symptoms and events elicited in response to open-ended questions, and adverse effects observed at the follow-up visits. They assessed all adverse events on the likelihood of causality by the study drug or drugs. They assessed the severity of adverse events according to a preset table and classified the event as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4).
The dosage of pegylated interferon was reduced, as necessary, according to the severity of the adverse events. The dosage was reduced from 100 µg per week (or 1.5 µg/kg per week if body weight < 65 kg) to 50 µg per week (or 1.0 µg/kg per week if body weight < 65 kg) for grade 3 adverse events (or sometimes grade 2 adverse events at the discretion of the investigator). The dosage could be further reduced to 25 µg per week (or 0.5 µg/kg per week if body weight < 65 kg) if the adverse recurred despite initial dosage reduction. Pegylated interferon therapy was stopped in case of grade 4 adverse events. Patients receiving combination treatment were allowed to continue lamivudine if investigators thought that the adverse effect was related to pegylated interferon use. Lamivudine therapy was stopped if the adverse event persisted despite cessation of pegylated interferon therapy.
We tested serum for HBV DNA levels, HBeAg, and antibody to HBeAg (at baseline, then 8 weekly until the end of treatment, and weeks 8, 16, and 24 after treatment) and HBsAg and antibody to HBsAg (at baseline, end of treatment, and 24 weeks after treatment). We determined the presence of lamivudine-resistant mutations in the serum sample at the end of treatment. Liver biopsy was performed within 4 weeks before treatment began and at the end of treatment.
Results
Study Sample
We screened 182 patients between April 2000 and March 2002 and enrolled 100 eligible patients. Most baseline characteristics were well matched between the 2 groups. However, although all studied patients met inclusion criteria at the screening visit, several patients had either normal ALT levels or levels that were greater than 5 times the upper limit of normal at the baseline randomization visit. The median ALT levels of the combination group were higher than those of the lamivudine group (P = 0.02), but the proportion of patients (P > 0.2) in the different ALT categories (1 to 2 times, 2 to 5 times, or >5 times the upper limit of normal) did not differ between groups.
Virologic Response
On intention-to-treat analysis, 30 of 50 patients (60%) in the combination treatment group and 14 of 50 patients (28%) in the lamivudine monotherapy group showed virologic response at the end of treatment (absolute difference, 32 percentage points [95% CI, 14 to 50 percentage points]; P = 0.001). After adjustment for baseline ALT levels, the absolute difference in predicted probabilities of combination treatment and lamivudine monotherapy for end-of-treatment response was 31 percentage points (CI, 10 to 49 percentage points; P = 0.003). All patients who had lost HBeAg developed antibodies to HBeAg. One patient receiving combination treatment had lost HBsAg by the end of treatment. No patient receiving lamivudine monotherapy became HBsAg-negative. Five patients receiving combination therapy and 2 patients receiving lamivudine monotherapy became HBV DNA--negative by polymerase chain reaction assay. Among patients with baseline ALT levels less than 5 times the upper limit of normal, the end-of-treatment virologic response of the combination treatment group was still statistically significantly higher than the response of the lamivudine monotherapy group (25 of 42 [60%] patients vs. 12 of 44 [27%] patients [absolute difference, 32 percentage points (CI, 12 to 52 percentage points)]).
At the end of treatment, the median reduction in HBV DNA of patients who completed combination treatment and lamivudine monotherapy was 3.89 log10 copies/mL (range, 1.59 to 6.35 log10 copies/mL) and 2.74 log10 copies/mL (range, --0.10 to 5.68 log10 copies/mL), respectively (median difference, 1.24 log10 copies/mL [CI, 0.78 to 1.66 log10 copies/mL]). Since the treatment duration in the combination treatment group was 8 weeks longer than the duration of treatment in the lamivudine monotherapy group, we also compared the changes in HBV DNA levels when patients in both groups finished 48 weeks of treatment. At 48 weeks, the reduction in HBV DNA level among patients receiving combination treatment and lamivudine monotherapy was 4.65 log10 copies/mL (range, --0.84 to 7.83 log10 copies/mL) and 3.62 log10 copies/mL (range, 1.32 to 7.33 log10 copies/mL), respectively (median difference, 1.10 log10 copies/mL [CI, 0.55 to 1.65 log10 copies/mL]). Fifty percent of the patients receiving combination treatment and 28% of those receiving lamivudine monotherapy had virologic response at week 48 (absolute difference, 22 percentage points [CI, 3 to 41 percentage points]), although all HBeAg seroconversion in lamivudine monotherapy group occurred on or before week 40.
Nine patients in the combination treatment group had HBeAg seroconversion at week 8 before the commencement of lamivudine therapy. After 24 weeks of lamivudine treatment in both groups, 11 additional patients receiving combination treatment and 11 patients receiving lamivudine monotherapy had HBeAg seroconversion. More patients in the combination treatment group had HBeAg seroconversion in the last 28 weeks of extended lamivudine treatment (10 of 30 [33%] remaining patients) than in the lamivudine monotherapy group (3 of 39 [8%] remaining patients) (absolute difference, 25 percentage points [CI, 7 to 45 percentage points]). Among patients who developed HBeAg seroconversion during treatment, the median time for HBeAg seroconversion after commencement of treatment was 24 weeks (range, 8 to 60 weeks) in the combination treatment group and 24 weeks (range, 0 to 40 weeks) in the lamivudine monotherapy group (P = 0.13).
At 24 weeks after treatment, 18 patients (36%) in the combination treatment group and 7 patients (14%) in the lamivudine monotherapy group had sustained virologic response (absolute difference, 22 percentage points [CI, 6 to 38 percentage points]; P = 0.011). After adjustment for the baseline ALT levels, the absolute difference in predicted probabilities of combination treatment and lamivudine monotherapy for sustained virologic response was 22 percentage points (CI, 3 to 47 percentage points; P = 0.015). Among the subgroup of patients with baseline ALT levels less than 5 times the upper limit of normal, the predicted probability for sustained virologic response was still higher in the combination treatment group (15 of 42 patients [36% (CI, 21% to 50%)]) than in the lamivudine monotherapy group (6 of 44 patients [14% (CI, 4% to 24%)]) (absolute difference, 22 percentage points [CI, 4 to 40 percentage points]). Twelve of 30 (40%) patients who received combination treatment and 7 of 14 (50%) patients who received lamivudine monotherapy developed post-treatment viral relapse after an initial end-of-treatment response. Three patients receiving combination treatment and 2 patients receiving lamivudine treatment were negative for HBV DNA by polymerase chain reaction assay at 24 weeks after treatment.
Biochemical Response
At the end of treatment, 45 patients (90%) receiving combination treatment and 39 patients (78%) receiving lamivudine monotherapy had normalization of ALT levels (absolute difference, 12 percentage points [CI, --2 to 26 percentage points]). At 24 weeks after treatment, more patients receiving combination treatment had sustained ALT level normalization compared with those receiving lamivudine monotherapy (50% vs. 30% [absolute difference, 20 percentage points (CI, 1 to 39 percentage points)]). Among those with sustained virologic response, all except 1 patient who received combination treatment had sustained normalization of ALT levels (ALT level 1.1 times the upper limit of normal).
Histologic Response
Paired liver biopsy specimens were available in 40 patients receiving combination treatment and 44 patients receiving lamivudine monotherapy. Eight patients had insufficient liver tissue for accurate grading in 1 of the paired biopsy specimens (7 patients at baseline and 1 patient at week 52), 3 patients declined liver biopsy after treatment because of personal reasons, 4 patients withdrew prematurely from the study (1 patient also had insufficient liver tissue at baseline biopsy), and 2 post-treatment liver biopsies were cancelled because of the hospital outbreak of severe acute respiratory syndrome in March 2003. Among the 16 patients without evaluable paired liver biopsy specimens, 6 patients (4 receiving combination treatment and 2 receiving lamivudine monotherapy) had end-of-treatment virologic response and 2 patients (both receiving combination treatment) had sustained virologic response.
Twenty-four (60%) patients receiving combination treatment and 26 (59%) patients receiving lamivudine monotherapy had at least a 2-point increase in necroinflammatory score (absolute difference, 1 percentage point [CI, --20 to 22 percentage points]). Four (10%) patients receiving combination treatment and 4 (9%) receiving lamivudine monotherapy had at least a 2-point decrease in necroinflammatory score. Six (15%) and 4 (9%) patients receiving combination therapy and lamivudine monotherapy, respectively, had at least a 2-point increase in fibrosis scores (absolute difference, 6 percentage points [CI, --8 to 20 percentage points]), while 4 (10%) and 2 (5%) patients, respectively, had at least a 2-point decrease in fibrosis scores (absolute difference, 5 percentage points [CI, --6 to 17 percentage points]).
Drug-Resistant Mutants
At the end of treatment, a higher proportion of patients receiving lamivudine monotherapy developed a lamivudine-resistant mutant (19 of 48 [40%] patients) than did those receiving combination treatment (10 of 48 [21%] patients) (absolute difference, 19 percentage points [CI, 8 to 37 percentage points]). Among patients receiving monotherapy, 7 had a lamivudine-resistant mutant and 12 had both wide-type and lamivudine-resistant mutants. Among patients receiving combination therapy, 5 had a resistant mutant and 5 had mixed wide-type and resistant mutants. Patients who developed lamivudine resistance tended to have higher pretreatment HBV DNA (Table 2). A higher proportion of patients who developed lamivudine resistance (9 of 29 [31%] patients) had HBV DNA greater than 500 000 copies/mL at the end of treatment than those who did not develop lamivudine resistance (7 of 67 [10%] patients) (absolute difference, 21 percentage points [CI, 2 to 39 percentage points]). However, the development of lamivudine resistance did not seem to mitigate the virologic, biochemical, and histologic response.
Safety
Most adverse symptoms and events were transient and were related to the use of pegylated interferon-{alpha}2b. Four (8%) patients receiving combination treatment had serious adverse events. One patient developed bipolar disorder requiring antidepressant therapy (week 21), 1 developed pulmonary tuberculosis with right pleural effusion requiring antituberculosis treatment (week 11), 1 developed thyrotoxicosis requiring propyluracil treatment (week 17), and 1 developed severe local reaction at the injection sites (week 8) that resolved spontaneously. Pegylated interferon-{alpha}2b treatment was stopped in all 4 cases. Lamivudine treatment was continued in the first 3 cases until week 60, and we evaluated the treatment responses as per protocol. The fourth patient, who had received only 7 doses of pegylated interferon, withdrew from the study and was considered to have treatment failure. Five (10%) patients required reduction of dosage of pegylated interferon-{alpha}2b to 50 µg per week (if body weight > 65 kg) or 1.0 µg/kg per week (if body weight < 65 kg) as per protocol because of anemia (1 patient), neutropenia (3 patients), and/or thrombocytopenia (4 patients). One patient had pegylated interferon withheld for 2 doses at weeks 4 and 5 because of severe hepatitis flare-up (ALT level, 1762 U/L) and resumed at full dose at week 6 when ALT level decreased to a lower level (242 U/L). No patient who received lamivudine monotherapy developed serious adverse event during treatment, and no patient had dosage adjustment for lamivudine.
Five (10%) patients in the combination group and 11 (23%) patients in the lamivudine monotherapy group developed severe post-treatment relapse of chronic hepatitis B (absolute difference, --13 percentage points [CI, --27 to 2 percentage points]). Two patients in lamivudine monotherapy group had post-treatment relapse leading to elevation of serum bilirubin levels to 82 µmol/L (4.8 mg/dL) and 153 µmol/L (9.0 mg/dL), respectively. Lamivudine treatment was resumed, and all patients responded. No patient died or required liver transplantation.
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