The value and limitations of long-term nucleoside antiviral therapy in chronic hepatitis B
Journal of Hepatology (February 2005)
Jules L. Dienstag*
Gastrointestinal Unit (Medical Services), Massachusetts General Hospital and Department of Medicine, Harvard Medical School, 55 Fruit Street, Boston 02114 MA, USA
"...The take-home message from these studies should be that short-term treatment is inadequate to achieve durable responses in HBeAg-negative chronic hepatitis B and that regimens will have to be designed that are tolerable for extended use, that achieve profound, unrelenting suppression of HBV replication, and that are not prone to the emergence of resistance. With the availability of a series of progressively more potent antiviral agents, we now have the ingredients for adequate antiviral control in the relatively treatment-refractory population of patients with HBeAg-negative chronic hepatitis B..."
Clinical trials of lamivudine, the first oral nucleoside analogue approved for the treatment of chronic hepatitis B, began in the early 1990s, and a substantial cohort of patients has emerged in whom treatment was continued for half a decade or longer. Patients in the early clinical experience with lamivudine, many of whom had already failed to respond to interferon, had no other options for treatment, and the early experience with lamivudine did not disappoint. Treatment with this new agent was very well tolerated, indistinguishable in side effects from treatment with placebo, and a year of treatment was associated with histologic, virologic, serologic, and biochemical improvement [1--6]. Moreover, unlike interferon, lamivudine was found to be effective in patients with high-level HBV DNA, in patients with decompensated cirrhosis, and in patients who had undergone liver transplantation for end-stage liver disease associated with chronic hepatitis B [7--15]. Recently, lamivudine treatment was shown to slow clinical progression, even suggested to prevent the emergence of hepatocellular carcinoma, in patients with advanced fibrosis (60% of whom were cirrhotic) 16. In short, during its 'reign' as the only oral antiviral approved for treatment of chronic hepatitis B, lamivudine improved the clinical and virological status of patients with chronic hepatitis B and saved many lives.
When antiviral therapy with interferon and lamivudine was being developed, the initial therapeutic focus fell upon patients with highly replicative, wild-type, HBeAg-reactive chronic hepatitis B. In this population treated with lamivudine, histologic necroinflammatory activity improved in more than half, progression of fibrosis was retarded, and regression of cirrhosis was documented in three quarters of a small cohort of patients treated cumulatively for 3 years [1,3--5,17,18]. Over the course of the last two decades, however, the increasing prevalence and global importance of HBeAg-negative chronic hepatitis B has been recognized 19. Patients with HBeAg-negative chronic hepatitis B now represent the majority of newly discovered cases of chronic hepatitis B in Europe and a growing proportion of those in North American and Asia. These patients, who have precore or core-promoter HBV mutations that interfere with gene transcription and protein translation of HBeAg, have levels of HBV DNA an order of magnitude lower than those observed in patients with HBeAg-reactive chronic hepatitis B. Yet, this subpopulation can have histologically severe and progressive chronic hepatitis.
Among the distinctions between patients with HBeAg-reactive and HBeAg-negative chronic hepatitis B, HBeAg-reactive patients have an opportunity to undergo HBeAg seroconversion during antiviral therapy, a serologic milestone that may be durable and that may allow discontinuation of therapy [20--22]. In HBeAg-negative chronic hepatitis B, HBeAg seroconversion is not an option or a treatment objective; although more than two thirds of HBeAg-negative patients treated for a year with lamivudine experience substantive reductions in HBV DNA, ALT, and histologic activity, discontinuation of therapy after a year leads almost invariably to virologic and biochemical relapse 6. Thus, for almost all patients with HBeAg-negative chronic hepatitis B, a year of nucleoside analogue therapy is insufficient, and long-term treatment is necessary to maintain clinical benefit.
Of course, no discussion of the benefits of lamivudine monotherapy is complete or balanced without consideration of its downside, the emergence of drug resistance. During an initial year of lamivudine therapy, YMDD mutations in HBV DNA polymerase emerge in a quarter of patients, and after 5 years of monotherapy, resistance can be demonstrated in as many as 70% [23--25]. The initial clinical experience with YMDD-mutant HBV during lamivudine therapy raised only limited concern. Despite increases in HBV DNA and ALT associated with YMDD mutations, during the first year of treatment, most patients with these lamivudine-related mutations maintained levels of HBV DNA and ALT, and even histologic activity scores, well below their baseline levels prior to therapy 23. Limited concern over the emergence of YMDD mutations was fueled by the demonstration that YMDD-mutant HBV was less replicatively competent in vitro [26--28], the maintenance of clinical benefit during the first year of therapy, the continued—albeit reduced—frequency of HBeAg seroconversion after YMDD mutation, and the return to pretreatment HBV DNA and ALT when lamivudine therapy was discontinued after YMDD mutation [23,29]. Furthermore, historically, lamivudine-associated YMDD-mutant HBV was encountered at a time when no other therapy was available that could be used to address such antiviral resistance. Weighed against the pathogenicity of wild-type HBV DNA, YMDD-mutant HBV was considered a 'lesser evil.'
As more experience has accumulated, however, complacency over the presence of YMDD mutations has diminished. Whether the result of additional compensatory mutations [24,30] or the potential for even low-pathogenicity mutants to inflict substantial injury given enough time, clinical experience has shown that the benefit of lamivudine therapy is eroded by the emergence of YMDD-mutant HBV [17,23,25,31,32]. Although compensated patients tolerate YMDD mutations well, severe reactivations of chronic hepatitis B, and even isolated reports of fatal reactivations, have been reported, especially in patients with pre-treatment cirrhosis and in liver-allograft recipients [12,13,33--35]. Among patients undergoing maintenance therapy for chronic B with advanced liver disease, the dramatic impact of lamivudine on limiting decompensation was reduced in the half of the lamivudine-treated group in whom YMDD mutations appeared. After a median of 32 months, clinical decompensation endpoints occurred in 18% of placebo recipients versus only 5% of lamivudine recipients without YMDD mutations; however, decompensation endpoints occurred in 11% of lamivudine recipients with YMDD mutations 16. Similarly, among patients with HBeAg-reactive chronic hepatitis B treated with lamivudine for a cumulative duration of three years, the proportion with improved necroinflammatory activity (>=2 point reduction in necroinflammatory component of histologic activity index) declined as a function of the duration or YMDD-mutant hepatitis B—from 77% in those without YMDD mutations, to 56% for those with YMDD mutations for <1 year, to 50% for those with YMDD mutations for 1--2 years, and to 36% for those with YMDD mutations for >2 years 17. On the other side of the coin, a pleasantly surprising outcome was the comparable frequency of reversal of cirrhosis in all groups, independent of the presence or duration of YMDD-mutant hepatitis B 17.
In a report in this issue of the Journal, Rizzetto and colleagues 36 amplify on the impact of long-term lamivudine monotherapy by describing the outcome in HBeAg-negative chronic hepatitis B. The design of the trial described is similar to that of the study cited above in HBeAg-reactive patients 17. Patients enrolled in the trial were derived primarily from prior trials in which they had been treated for half a year to a year 6, and the current report includes data on an additional 2 years of therapy, for a cumulative mean duration of just under 3 years. This study in HBeAg-negative patients differed from the comparable study in HBeAg-reactive patients in that baseline HBV DNA was a log10 lower, median histologic activity index was two points lower, and median age was 13 years older in the HBeAg-negative cohort. These differences are typical. Patients with HBeAg-negative chronic hepatitis B tend to be older, consistent with the acquisition of precore/core-promoter mutations later in the natural history of chronic hepatitis B, they have lower levels of HBV DNA, and the lower histologic activity may reflect the intermittent, often fluctuating pattern of biochemical activity in this patient group 19. As in the study of HBeAg-reactive patients, in this study of HBeAg-negative patients, after approximately three cumulative years of lamivudine monotherapy, virologic, biochemical, and histologic benefit was maintained for those without YMDD mutations but was degraded for those with YMDD mutations. Histologic improvement in necroinflammatory score (>=2 points) occurred in 64% of those without YMDD mutations but in only 15% with YMDD mutations; conversely, necroinflammatory activity worsened in only 5% without YMDD mutations but in 31% of those with YMDD mutations. As was the case for HBeAg-reactive patients, in this study of HBeAg-negative patients, progression to cirrhosis was unlikely, even among those with YMDD mutations, and cirrhosis reversed in three of six patients evaluated before and at three years of therapy, all three despite the presence of YMDD mutations. Similarly, bridging fibrosis improved over the course of three years of therapy in more than 40% of patients with bridging fibrosis at baseline (a quarter of whom had YMDD mutations). As was the case in the study among HBeAg-reactive patients, in this study of HBeAg-negative patients, fibrosis stage progressed from milder fibrosis to bridging fibrosis in a subset of study subjects confined to those with YMDD mutations.
Like the study in HBeAg-reactive patients, this study of long-term lamivudine therapy in HBeAg-negative patients reinforces the potential for reversibility of fibrosis and even cirrhosis when HBV replication is suppressed consistently over an extended time. On the negative side of the ledger, although reassuring in demonstrating absence of histologic deterioration in almost 70% of patients with YMDD mutations, this study confirms the observations in previous clinical trials that lamivudine-associated YMDD-mutant chronic hepatitis B is not benign but, when present for a sufficiently long time, can lead to histologic progression. In most patients with HBeAg-reactive chronic hepatitis B and in almost all patients with HBeAg-negative chronic hepatitis B, virologic and biochemical relapses follow a finite period of treatment; therefore, long-term antiviral therapy will be necessary, but the emergence of YMDD-mutant HBV limits the effectiveness of long-term lamivudine monotherapy. The authors of the current study concluded that additional therapies, e.g., the addition of adefovir dipivoxil [37,38], should be considered for patients with YMDD mutations.
When this study of HBeAg-negative chronic hepatitis B was initiated, lamivudine was the only available oral treatment for chronic hepatitis B. In a sense, the treating community encountered YMDD mutants during an isolated time in history when no salvage-treatment options were available for addressing this expression of antiviral drug resistance. In that setting, the conclusion reached was that continuing therapy in the face of resistance was better than stopping therapy 23. All our rationalizations for continuing lamivudine after the emergence of YMDD mutations are now moot. Currently, the appearance of YMDD-mutant hepatitis B during lamivudine therapy is considered an indication for adding the other approved oral agent, adefovir, and we no longer tolerate YMDD-mutant hepatitis B for any length of time, much less so for one to 2 years, as described in the extended-treatment trials by Rizzetto et al. 36 and Dienstag et al. 17 or the maintenance trial in patients with advanced liver disease by Liaw et al. 16 What we have gleaned from these studies is the proof of concept that long-term or maintenance therapy unencumbered by resistance provides substantial histologic and clinical benefit. Therefore, treatment regimens that can be administered safely and that are not limited by drug resistance should be favored; ideally, YMDD mutations should no longer be encountered.
Perhaps we can take solace from the fact that we have 'gotten away with' lamivudine monotherapy for as long as we did, that, at least for HBeAg-reactive hepatitis B, we were actually able with a finite course of therapy to effect sustained seroconversions and the accompanying transition from chronic hepatitis to inactive carriage [20,21]. We have also been reassured by the observation during monotherapy of chronic hepatitis B with either lamivudine or adefovir monotherapy that sequential addition of a second antiviral after the appearance of resistance has been effective in almost all cases [37--40]. As Richman 41 has pointed out, however, lessons learned from antiviral therapy of HIV infection are likely to apply as well to chronic hepatitis B. The selective pressure on rapidly replicating HBV during antiviral therapy fosters the emergence of pre-existing viral genetic variants, and the best way to interdict this process is to prevent it entirely, to avoid the emergence of irreversible mutations, which become archived and can resurface in the future. Although resistance to adefovir occurs much more slowly and at a much lower frequency than during lamivudine therapy [40,42,43], ultimately, after several years of adefovir monotherapy, the incidence of resistance will become unacceptable. From a virologic perspective, the Darwinian principles of antiviral drug resistance teach us that combination therapy from the outset with potent inhibitors of HBV replication that are sufficient to overcome the calculated mutation rate and frequency of pre-existent mutations will be required to realize the benefits of antiviral therapy without encountering resistance [41,44].
In the two-year interim analysis of the five-year lamivudine monotherapy trial described by Rizzetto et al. 36, no data are provided on criteria, if any, for stopping therapy. In fact, almost all patients with HBeAg-negative chronic hepatitis B treated for limited periods, up to a year, with either interferon, lamivudine, or adefovir relapse when therapy is stopped. For example, in an analysis of 216 patients with HBeAg-negative chronic hepatitis B treated with standard interferon for 5--12 months, the end-treatment response (undetectable HBV DNA in a hybridization assay with a sensitivity of 106 virions/ml and normal ALT) was 54%, but the response was sustained in only 24% a year after therapy and in only 18% a median of 7 years after therapy 45. In the initial clinical trials of lamivudine and adefovir for HBeAg-negative chronic hepatitis B, no study subjects were described who had sustained responses after a year of therapy [6,46]. Recently, Marcellin et al. 47 reported that a proportion of subjects with HBeAg-negative chronic hepatitis B treated for 48 weeks with pegylated interferon alfa-2a had 'sustained' biochemical and virologic responses measured 24 weeks after therapy. In this study, pegylated interferon monotherapy was compared to lamivudine monotherapy and to the combination of both drugs. Although combination therapy was associated with an additional reduction in HBV DNA at the end of therapy, the data presented suggested that the addition of lamivudine to pegylated interferon did not enhance the sustained response rate and that pegylated interferon was superior to lamivudine. Measured at week 72 for the pegylated interferon monotherapy arm, sustained biochemical responses occurred in 59%; sustained virologic responses were reported for maintenance of HBV DNA levels to <20,000 copies/ml—43%—and for the more stringent and contemporary standard of <400 copies/ml—19%. Based on these results, we might be led to conclude that 48 weeks of pegylated interferon monotherapy was the optimum regimen for patients with HBeAg-negative chronic hepatitis B. Lamivudine, however, is usually not stopped at the end of therapy, and at the end of the 48-week treatment period, lamivudine was actually superior to pegylated interferon in achieving undetectable HBV DNA below 400 copies/ml. Moreover, 24 weeks is not a very reliable milestone in measuring sustained responses in HBeAg-negative chronic hepatitis B; as in the study of standard interferon cited above 45, maintenance of undetectable HBV DNA and of normal ALT activity decline progressively the longer patients are followed after treatment. In the standard interferon study 45, the end-treatment virologic response (<106 virions/ml) was 54%, while in the pegylated interferon study, the end-treatment response (<105 virions/ml) was 44%; inevitably, additional follow-up will demonstrate a progressive reduction in sustained response. In addition, a recently published report has demonstrated that lamivudine monotherapy extended for two years can result in a sustained virologic response of 50% (despite the emergence of YMDD-mutant HBV in 25% of study patients) 48. The take-home message from these studies should be that short-term treatment is inadequate to achieve durable responses in HBeAg-negative chronic hepatitis B and that regimens will have to be designed that are tolerable for extended use, that achieve profound, unrelenting suppression of HBV replication, and that are not prone to the emergence of resistance. With the availability of a series of progressively more potent antiviral agents, we now have the ingredients for adequate antiviral control in the relatively treatment-refractory population of patients with HBeAg-negative chronic hepatitis B. The challenge for clinical investigators will be to design trials that exploit creatively the lessons learned and the available resources to address the demanding problem of treating this population.
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