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发表于 2005-3-11 09:48
PEGYLATED INTERFERON IN CHRONIC HEPATITIS B
In a recent report of 194 HBeAg-positive patients with chronic hepatitis B, treatment with pegylated IFN alfa-2a (90, 180, or 270 mg/wk) for 24 weeks resulted in more rapid and greater decline in HBV DNA compared with standard IFN (4.5 MU three times a week) [26]. HBeAg seroconversion was observed in 37%, 33%, and 27% versus 25% in the pegylated IFN and standard IFN groups, respectively.
In a recent phase III study of HBeAg-positive chronic hepatitis B, 266 patients were randomized to receive pegylated IFN alfa-2b alone or in combination with lamivudine for 12 months [27]. At the end of 6-month follow-up after completion of therapy, HBeAg loss was seen in 36% and 35%, respectively. Loss of HBsAg was seen in approximately 5% in both groups.
Recently, the results of a randomized, placebo- controlled study of 48 weeks of pegylated IFN alfa-2a 180 mg once weekly (PEG-IFN) plus lamivudine (100 mg/d) versus placebo or lamivudine monotherapy in patients with HBeAg-negative chronic hepatitis B were reported (n: 177, 179, and 181 patients, respectively) [28*]. Sustained normalization of serum ALT or undetectable HBV DNA (levels to below 20,000 copies/mL) was significantly higher with PEG-IFN monotherapy (59% and 43%, respectively) and PEG-IFN plus lamivudine (60% and 44%), compared with lamivudine monotherapy (44%, P = 0.004 and P = 0.003, respectively; and 29%, P = 0.007 and P = 0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies/mL were 19% with PEG-IFN monotherapy, 20% with combination therapy, and 7% with lamivudine alone (P < 0.001 for PEG-IFN plus placebo vs with lamivudine alone). HBsAg loss was seen in 12 patients (3%) who received PEG-IFN and none of the patients who received lamivudine alone. As in patients with HBeAg- positive hepatitis, the addition of lamivudine to PEG-IFN does not appear to increase virologic response rates.
LAMIVUDINE (3TC)
Lamivudine (Epivir-HBV; GlaxoSmithKline, Research Triangle Park, NC) is the (-) enantiomer of 2',3'-dideoxy-3' -thiacytidine, which is phosphorylated to the triphosphate and competes with deoxycytidine triphosphate for incorporation into growing DNA chains causing chain termination.
HBeAg-positive chronic hepatitis B
Three large randomized clinical trials involving 731 patients from the U.S, Europe, and Asia have shown that lamivudine therapy for 1 year leads to HBeAg seroconversion in 16% to 18% of patients, compared with 4% to 6% of untreated control subjects [29, 30, 31, 32, 33]. Histologic improvement (defined as reduction in necroinflammatory score greater than 2 points) occurred in 49% to 56% of treated patients and in 23% to 25% of control subjects. In the Asian study, HBeAg seroconversion rates increased with duration of treatment, ranging from 17% at 1 year to 27%, 40%, 47%, and 50% at 2, 3, 4, and 5 years, respectively [34].
In a recent large multicenter controlled trial involving 286 patients aged 2 to 17 years with elevated ALT, patients were randomized to receive lamivudine (3 mg/kg/d up to 100 mg/d) or placebo for 52 weeks [35]. At the end of treatment, 23% of children treated with lamivudine lost HBeAg, compared with 13% on placebo. Drug-resistant HBV mutants were detected in 18% of treated children. As with IFN, pretreatment serum ALT is the strongest predictor of response in patients with HBeAg-positive chronic hepatitis [36, 37]. In a recent analysis of four phase III trials (where a total of 406 patients received lamivudine for 1 year) [37], HBeAg seroconversion occurred in 2%, 9%, 21%, and 47% of patients with pretreatment ALT levels within normal, one to two times normal, two to five times normal, and more than 5 times normal; whereas the corresponding figures for 196 patients in the placebo group were 0%, 5%, 9%, and 15%, respectively. In the large multicenter placebo-controlled study of lamivudine in children, HBeAg seroconversion rate was higher in those with pretreatment ALT greater than two times normal (34% vs 16%) [35].
HBeAg-negative chronic hepatitis B
In patients with HBeAg-negative chronic hepatitis B [38, 39], virologic and biochemical response has been seen in up to 70% to 96% of patients receiving 48 weeks of lamivudine therapy versus less than 10% among patients on placebo. Histologic improvement has been seen in 20% to 95% of cases [40]. The majority of patients, however, relapse once therapy is stopped [40, 41]. Continued treatment, however, results in the development of drug- resistant mutants and response is not maintained; in one study, complete response (biochemical and virologic) was seen in 81% of patients at 1 year--this was decreased to 69% during the second year. Lamivudine-resistant mutants increased from 19% at the end of year 1 to 44% at the end of year 2 [42].
Lamivudine has also been studied in previous nonresponders to IFN treatment. In one study of 238 IFN nonresponders, patients were randomized to receive lamivudine alone for 52 weeks, combination of lamivudine plus IFN for 24 weeks, or no treatment. Histologic response was significantly more common in patients treated with lamivudine (52% vs placebo 25%, P = 0.002) or the combination regimen (32%, P = 0.01). HBeAg loss was also more common with lamivudine (33% vs 13% vs 21%); HBeAg seroconversion was seen in 18%, 12%, and 13% of patients, respectively [43]. These data suggest that patients who failed IFN treatment have similar virologic response to lamivudine as treatment-naive patients and re-treatment with combination of IFN and lamivudine did not confer any added benefit compared with lamivudine monotherapy.
When lamivudine is stopped, the majority of patients maintain HBeAg seroconversion. In the Asian study, 83% of patients maintained seroconversion after 6 to 36 (median 19) months [44]. However, the duration of lamivudine treatment after HBeAg seroconversion may be important to prevent early relapse after stopping treatment [44]. In one study of 67 Korean patients treated with lamivudine, those who received lamivudine for at least 4 months after HBeAg seroconversion had a much lower rate of relapse compared with those who received treatment for less than 2 months after HBeAg seroconversion (32% vs 74% at 2 years) [45]. Based on these findings, it is recommended that lamivudine be continued for at least 4 to 6 months after HBeAg seroconversion to decrease the likelihood of relapse [46].
The initial controlled studies have shown that 1-year treatment with lamivudine is associated with histologic improvement in more than 50% of patients [29, 30, 31]. With longer duration of treatment, however, drug-resistant mutations may reverse this initial histologic benefit. In the Asian trial, 62 patients were evaluated with liver histology at 0, 1, and 3 years. Whereas necroinflammatory scores continued to improve at 1 and 3 years among patients without resistance, histologic scores worsened at 3 years after an initial improvement at 1 year in those with resistant mutations [47]. These data, along with other reports suggesting that patients with advanced disease who develop resistance can have further disease progression and decompensation, raise concerns over the continued use of lamivudine after development of drug resistance and the long-term clinical impact of lamivudine-resistant mutants.
The recommended dose of lamivudine for adults is 100 mg/d given orally, with dose reduction reserved for patients with renal insufficiency. The recommended dose for children is 3 mg/kg up to 100 mg. Patients who have HBV and HIV coinfection should be treated with 150-mg doses twice a day in addition to other antiretroviral therapies.
Lamivudine is generally well tolerated. In patients who do not achieve HBeAg seroconversion (among those who are HBeAg positive) or biochemical plus virologic response (in HBeAg-negative chronic hepatitis B), lamivudine can be continued as long as one is aware of the potential risks of developing resistance. If treatment is discontinued, patients should be closely monitored because acute exacerbations of hepatitis and hepatic decompensation have been reported even in patients with HBeAg seroconversion [34, 48, 49*, 50]. If this occurs, lamivudine can be reinstituted and is usually effective in controlling exacerbations if the patients have not developed a breakthrough infection. In patients with HBeAg-negative chronic hepatitis B, a longer course of treatment is recommended to prevent relapse; however, the optimal duration is unclear.
ADEFOVIR DIPIVOXIL
(ed note regarding tenofovir & coinfection: a recent study was presented at the 12th CROI meeting finding that in HBV/HIV coinfected patients tenofovir was at least as potent as adefovir in suppressing HBV in coinfected patients. This was a non-inferiority study so the study was stopped at week 24 when it was clear that tenofovir had equal efficacy. But HBV DNA reductions were greater for tenofovir than for adefovir (at week 48: -4.03 vs -3.12 log, ITT). Gilead Sciences is planning studies to show that tenofovir is superior to adefovir in mono and coinfected patients. In coinfection, often HAART therapy includes tenofovir plus 3TC or FTC when the clinician decides to treat the HIV & the HBV at once. The link to the CROI report is:
http://www.natap.org/2005/CROI/croi_24.htm
Adefovir dipivoxil is an orally bioavailable prodrug of adefovir, a nucleotide analogue of adenosine monophosphate [2**, 51, 52, 53*]. It effectively inhibits both the reverse transcriptase and DNA polymerase activity of HBV.
HBeAg-positive chronic hepatitis B
In the multicenter placebo-controlled phase III study, 515 patients were randomized to receive 10 or 30 mg of adefovir or placebo for 48 weeks. Histologic response (defined as greater than 2-point decrease in Knodell necroinflammatory score with no worsening of fibrosis) was seen more commonly with both doses of adefovir compared with placebo (53% to 59% vs 25%) [52]. HBeAg loss was seen in 11%, 24%, and 27% and HBeAg seroconversion in 6%, 12%, and 14% of patients receiving placebo, adefovir 10 and 30 mg, respectively. No adefovir-associated resistant mutations were identified at the end of 48 weeks of therapy. More recent data suggest that as with lamivudine, continued treatment with adefovir will also increase rates of HBeAg seroconversion, increasing from 12% at week 48 to 29% at week 96 and 43% at week 144 of therapy [53*].
HBeAg-negative chronic hepatitis B
In the multicenter phase III trial of HBeAg-negative chronic hepatitis B, 185 patients were randomized to receive 10 mg of adefovir versus placebo in a 2:1 ratio for 48 weeks. Histologic response was significantly higher among the treated patients, 64% versus 33% of control subjects (P < 0.001) [54*]. Normalization of serum ALT and undetectable HBV DNA by PCR was achieved in 72% versus 29% and 51% versus 0%, respectively (P < 0.001). In addition, no adefovir-resistant mutations were identified at 48 weeks.
Use of adefovir in lamivudine-resistant hepatitis B
Adefovir has been shown to be effective in suppressing HBV DNA in both wild-type and lamivudine-resistant HBV infection [51, 55, 56]. In cases of lamivudine resistance, it is generally recommended to start adefovir while continuing lamivudine until a biochemical and virologic response is achieved before stopping lamivudine. If such a response is not seen (~ after 3 months) and there is no evidence of any flare, lamivudine can be withdrawn but the clinical course should be carefully followed because adefovir-resistant strains of HBV appear to arise more frequently in patients with prior lamivudine resistance.
Adefovir is generally well tolerated but a potential toxicity with adefovir is the development of a dose-dependent type 4 renal tubular acidosis. The recommended dose of adefovir is 10 mg/d. Dosing intervals should be adjusted in patients with renal insufficiency. Increases in serum creatinine (> 0.5 mg/dL) have been observed in approximately 20% of patients with decompensated cirrhosis and post-liver transplant patients [57]. Therefore, close monitoring is required in these clinical settings when using adefovir.
Management of Patients with Chronic Hepatitis B and Advanced Liver Disease and Post-liver Transplantation
Interferon
Patients with compensated cirrhosis appear to tolerate IFN and respond as well as patients with precirrhotic chronic hepatitis B. However, IFN is associated with a wide spectrum of side effects and there is substantial risk of serious infections and potentially fatal exacerbations of hepatitis even with low doses of IFN among patients with decompensated cirrhosis [58, 59]. Therefore, standard or pegylated IFN should not be used in patients with decompensated HBV cirrhosis.
Lamivudine
Lamivudine is a safer treatment than IFN in patients with advanced liver disease, including those with decompensated cirrhosis [60]. Improvement in liver disease with decrease in Child-Turcotte-Pugh score, along with decreased need for liver transplantation, has been observed in patients who completed a minimum of 6 months of treatment [61]. In a recent large study of 651 patients with advanced fibrosis or cirrhosis, patients were randomized in a 2:1 ratio to receive lamivudine (100 mg/d) or placebo for a maximum of 5 years. The study was terminated after a median duration of 32.4 months of treatment due to a significant reduction in the time to disease progression among patients receiving lamivudine compared with placebo (17.7% vs 7.8%, hazard ratio 0.45, P = 0.02) [62**]. Genotypic resistance on lamivudine developed in 49% of patients and patients with these mutations were more likely to have disease progression as determined by Child-Turcotte-Pugh score. Some patients with advanced liver disease continue to have progression despite antiviral therapy. For example, in an analysis of 154 patients with decompensated liver disease, the benefit of lamivudine was evident only in the 84% of patients who survived the initial 6 months of treatment [63].
The combined prophylactic use of hepatitis B immune globulin and lamivudine has reduced the incidence of recurrent HBV infection after transplant to less than 10% [2**, 64]. A recent review of 166 patients transplanted for hepatitis B over a 17-year period at a single center showed that survival is significantly improved, with 1- and 5-year patient survival rates of 86% and 72% [65]. Lamivudine has also been used to treat patients with recurrent hepatitis B. In one multicenter study, 52 patients with recurrent hepatitis B were treated with open-label lamivudine for 52 weeks [66]. HBV DNA became undetectable in 60%, and 31% of HBeAg-positive patients lost HBeAg. Loss of HBsAg was seen in 6%. Virologic response was accompanied by biochemical and histologic improvement; however, lamivudine-resistant mutations were detected in 27% of patients and in some this was accompanied by clinical deterioration.
Adefovir
Recently, the addition of adefovir with continued use of lamivudine in patients with lamivudine resistance was reported in 135 patients with chronic hepatitis B [67]. Ninety-five patients with compensated chronic hepatitis B were randomized to receive adefovir 10 mg/d or placebo for 52 weeks while continuing lamivudine. Forty patients with decompensated disease or post-transplantation received open-label adefovir along with lamivudine. HBV-DNA response (defined as decline in serum HBV DNA level to 105 copies/mL or greater than 2 log10 reduction baseline) was seen in 85% of patients on combination therapy, compared with only 11% on lamivudine plus placebo. In the patients with decompensated disease or post-transplantation receiving open-label combination therapy, HBV-DNA response was seen in 92%. In another study of 196 patients with recurrent hepatitis B post-liver transplantation, adefovir at a dose of 10 mg induced a 3 to 4 log reduction in HBV DNA at 48 weeks [57].
Recently, the effect of adefovir given alone or in combination with lamivudine in patients with lamivudine-resistant hepatitis B was reported. In this study, 59 HBeAg-positive patients were randomized to receive adefovir 10 mg/d, lamivudine 100 mg/d, or combination therapy (adefovir and lamivudine) [68]. Rapid reduction in HBV DNA was seen as early as 4 weeks in the adefovir and adefovir plus lamivudine groups, which continued in both groups through 48 weeks. These studies suggest that long-term use of combination therapy may not be needed, because a similar effect, at least on HBV-DNA suppression, can be achieved with adefovir alone in patients with lamivudine-resistant hepatitis B. Although these data are promising, longer follow-up is needed to establish the long-term efficacy of adefovir dipivoxil in patients with lamivudine-resistant HBV mutants.
Drug Resistance in Antiviral Therapy of Chronic Hepatitis B
Lamivudine-resistant HBV
One of the main concerns with continued use of lamivudine is the development of drug-resistant mutants, which involve the polymerase (P) gene of the HBV genome. Three mutations have been well defined: these include methionine to valine or isoleucine (rtM204V/I) substitutions involving the YMDD locus in domain C and leucine to methionine substitution (rtL180M) in domain B [69]. Patients who develop resistance usually have a virologic and biochemical breakthrough with reappearance of HBV DNA in serum using nonamplified assay after being undetectable and this is also followed by rise in serum liver enzymes [70]. Factors related to the development of resistance included non-Asian ethnicity, high pretreatment serum HBV-DNA level, male sex, and high body mass index [37]. High pretreatment ALT level and serum HBV greater than 103 copies/mL after 6 months of treatment have also been shown to predict the development of lamivudine resistance [71].
When patients develop lamivudine resistance, management options include continuing lamivudine especially if a patient has normal or low ALT levels, to discontinuing treatment and monitoring closely for hepatitis flares, or adding another antiviral agent such as adefovir. If a patient has cirrhosis or is immunosuppressed, however, stopping lamivudine can lead to clinical decompensation if a flare develops. In this circumstance, it may be best to consider adding another agent such as adefovir and stop lamivudine once ALT is normalized or stable and HBV-DNA level is suppressed.
Adefovir-resistant HBV
Although adefovir-resistant mutations in the DNA polymerase region have not been seen in earlier studies, emerging data suggest that with longer duration adefovir resistance is being reported. In a recent report of long-term adefovir, rates of adefovir-related resistant mutations (rtN236T and rtA181V) were noted to be 3.9 at 96 weeks and 5.9% at 144 weeks, respectively [52]. Further data in larger number of patients are needed before we know the full impact of adefovir-resistant mutations on the clinical course of chronic hepatitis B.
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