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Treatment options for chronic hepatitis B not responding to interferon
See Lamivudine article
Journal of Hepatology
Volume 38, Issue 6, June 2003, Pages 853-855
Stephanos J. Hadziyannis. Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Avenue, Athens, Greece
1. The natural course of chronic hepatitis B and the need for treatment
Chronic hepatitis B (CHB) defined by the presence of hepatitis B surface antigen (HBsAg) in serum, high levels of circulating hepatitis B virus (HBV) DNA and chronic necroinflammation of the liver is separated into two forms based on the hepatitis B e antigen (HBeAg) and antibody (anti-HBe) status. The HBeAg-positive CHB considered as the typical, prototype form of the disease, occurs in earlier phases of chronic HBV infection than HBeAg-negative CHB, it prevails in European and North American patients infected with HBV genotype A and is characterized by persistently high serum aminotransferases (ALT) and hepatitis B viraemia levels. In perinatally acquired HBV infection, which is common in geographical areas of high HBV prevalence like Asia, it appears to follow a period of immune tolerance of HBV during which HBV DNA levels are high while ALT levels keep normal or nearly normal and liver necroinflammtion is minimal or absent. When HBeAg-positive CHB develops serum ALT levels increase and liver damage progresses to severe necroinflammation with advancing fibrosis. If HBeAg-positive CHB is left untreated it may subside spontaneously terminating into loss of HBeAg, seroconversion to anti-HBe, suppression of HBV replication to non-detectability by molecular hybridization techniques or to <103-104 copies/ml by polymerase chain reaction, return of ALT to normal and resolution of liver disease activity. However, the probability of spontaneous resolution of HBeAg-positive CHB is limited to approximately 10-12% per year (ranging in the various studies from 2 to 24%. Thus, a large number of untreated patients with HBeAg-positive CHB are left with severe liver necroinflammation which persists for several years and results in an increased likelihood of progression of liver damage to advanced stages of fibrosis, cirrhosis and even development of hepatocellular carcinoma (HCC), the most dire consequence in the natural history of CHB.
In a recent study, the relative risk of HCC among men positive both for HBsAg and HBeAg was 60.2 compared to 9.2 in those with only HBsAg. The need, therefore, for early and effective therapeutic intervention in HBeAg-positive CHB is obvious, but unfortunately it has remained an unresolved issue of clinical hepatology for more than 20 years now.
In the HBeAg-negative form of CHB, which prevails in the Mediterranean Area and Asia and is mostly due to precore HBV mutants, serum HBV DNA levels are lower than in HBeAg-positive CHB, generally between 104 and 108 copies/ml. Both HBV DNA and serum ALT levels are often fluctuating. However, spontaneous remissions are extremely rare and prognosis is poor with frequent progression to cirrhosis and HCC. Therefore, similar to HBeAg-positive CHB, the need for effective therapeutic intervention is again obvious.
2. Efficacy of currently available therapies in chronic hepatitis B.
Treatment of CHB is aiming to suppress HBV replication and to induce remission in liver disease before cirrhosis and HCC develop. Biochemical, virologic and histological responses achieved under any treatment should be durable after discontinuation of therapy (sustained responses or SR).
Currently there are three approved treatments for CHB aiming at SR: interferon alfa (IFNa), lamivudine and recently adefovir dipivoxil. The efficacy of these therapies differs greatly between HBeAg-positive and HBeAg-negative CHB. In general, the goal of SR appears to be achievable in HBeAg-positive CHB, albeit at low frequencies, by finite courses of treatment with any of the three existing drugs whereas in HBeAg-negative CHB only IFNa may be able to induce SR but only in a small percentage of patients.
In HBeAg-positive CHB therapy with IFNa, lamivudine, and adefovir dipivoxil of defined duration, ranging from 12 to 24 weeks for IFNa and for 24-52 weeks for the nucleos(t)ide analogs, appears to achieve loss of HBeAg, seroconversion to anti-HBe, normalizaion of ALT and loss of HBV DNA by molecular hybridization techniques at roughly comparable frequencies of 20-30%, two to three times higher compared to untreated controls. Responses to IFNa seem to be durable, probably more than responses to lamivudine, being subsequently followed by loss of HBsAg in approx 8%. The efficacy of IFNa treatment in HBeAg-positive CHB seems to increase with longer duration of therapy and probably with the administration of pegylated IFNa2a. Extension of lamivudine treatment in HBeAg-positive CHB from 1 to 3 and more years has also been reported to increase the HBeAg seroconversion rate.
IFNa treatment of HBeAg-negative CHB for 12 and more months has also been effective in inducing SR in 15-20% of treated and retreated patients followed, in some of them, by clearance of HBsAg as well. On the other hand, SR to lamivudine treatment in HBeAg-negative CHB, whatever its duration, have hitherto been reported only in rare instances while no information regarding SR after stopping adefovir dipivoxil treatment in HBeAg-negative CHB is available yet. Thus, several investigators are currently treating patients with HBeAg-negative CHB indefinitely with nucleos(t)ide analogs to achieve long-lasting virologic, biochemical and histological responses.
2. Treatment options for chronic hepatitis B refractory to IFNa
For patients with CHB not responding to a first course of IFNa there are three possible options aiming at SR: (a) re-treatment with IFNa, preferably pegylated IFNa and for longer periods of time; (b) treatment course with lamivudine or adefovir dipivoxil; and (c) some short of combination therapy. However, for the time being, few if any evidence-based recommendations can be made for the management of IFNa non-responders.
Since SR to IFNa may be achieved several months after therapy has been discontinued, patients should not be considered as IFNa non-responders prior to at least 6 months of post-treatment follow-up. A second treatment regimen may then be initiated with the aim to reduce the duration of active liver disease. But what type of treatment can be effective in these patients? There are few available data and these should be considered separately for HBeAg-positive and HBeAg-negative patients.
In HBeAg-positive patients with CHB who did not respond to a first course of IFNa, re-treatment for 6 months with 9 MU of IFNa thrice weekly has been associated with a 33% SR rate compared to 10% in untreated controls. In an earlier study of a small group of patients who failed a first course of IFNa only 11% responded to a 16-week regimen with a daily dose of 1.5-5 MU of IFNa.
Data on IFN re-treatment of patients with HBeAg-negative CHB are very limited. A recent study reported a SR of 31% after a second course of IFNa among 51 patients with HBeAg-negative CHB who had relapsed or had no response to previous IFNa treatment.
HBeAg-positive patients who had previously failed IFNa monotherapy have been included in trials of lamivudine and adefovir dipivoxil monotherapy. Of 17 IFNa failures treated with lamivudine, five achieved sustained HBV DNA clearance and three HBeAg seroconversion to anti-HBe. In the recently published adefovir studies response rates under therapy did not differ between treatment-naive and previously IFNa-treated patients both in the HBeAg-positive and HBeAg-negative groups.
Finally Mutimer et al. have used combination of IFNa with lamivudine for 16 weeks in 20 patients who had previously failed IFN monotherapy. Its efficacy was disappointing, however, only one patient out of four achieving HBeAg seroconversion during treatment with maintaining this response after stopping treatment. However, in a recent pilot study of sequential treatment with lamivudine and IFNa monotherapies in CHB patients not responding to IFNa alone, sustained serum HBV DNA clearance 6 months after the end of sequential treatment was achieved in eight out of 14 patients, HBeAg to anti-HBe seroconversion in five out of 11 and HBsAg seroconversion to anti-HBs in three out of 14 patients.
In this issue of the Journal, Schiff et al. report the results of a multi-center trial on the efficacy of lamivudine monotherapy versus combination of lamivudine with IFNa or no treatment in 238 HBeAg-positive CHB patients who were non-responders to a previous course of IFNa. Lamivudine given for 52-68 weeks was found to be as effective in IFNa non-responders as in previously reported treatment-naive patients and significantly superior than the combination of lamivudine for 24 weeks and IFNa for 16 weeks, both in terms of histologic response and HBeAg loss (52 and 33% versus 32 and 21%, respectively). In the placebo group the rates of histologic improvement and of spontaneous HBeAg loss were 25 and 13%, respectively. However, seroconversion to anti-HBe was not statistically better in the lamivudine (18%) than in the combination (13%) and the placebo group (12%).
The results of this study bring again into the therapeutic scenery the existing controversy over the efficacy of various schemes and dosages of combination therapies of interferon and lamivudine or other antiviral agents for patients with CHB.
Schiff et al., constrained by regulatory considerations, could not include a pegylated-IFNa regimen, and had to restrict the duration of IFNa only to the approved period of 16 weeks. They have also considered that IFNa non-responders were unlikely to respond to re-treatment with standard IFNa because the promising results of two recent studies on IFNa re-treatment were not available at the time this trial was designed. Thus, 8 weeks of lamivudine treatment followed by a 16-week period of combination of lamivudine with IFNa were compared to a full year and more of lamivudine monotherapy. The authors recognize these problems and in a thoughtful discussion they stress the need for other approaches to combination therapies of IFNa with nucleoside analogs in treatment-naive patients and IFNa non-responders with CHB. In this context the results of two large multi-center trials with combination therapy for 1 year with pegylated IFNa and lamivudine versus lamivudine and pegylated IFNa monotherapy also for 1 year both in HBeAg-positive and -negative patients are anxiously awaited.
Regardless of existing conjectures, it is becoming increasingly obvious that the strategy of combining IFNa with nucleoside analogs whatever the order and duration of application of the two drugs, may improve the efficacy of finite courses of treatment but is not expected to revolutionize the management of CHB neither in treatment-naive nor in IFNa resistant patients. Therefore many investigators are turning from the IFNa based therapeutic approaches to long-term suppression of HBV replication by safe nucleoside analogs with little or no viral resistance. The recent availability of adefovir with an excellent safety and resistance profile makes this approach realistic and attractive.
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