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Combination therapy for chronic hepatitis B: A one-two knockout punch, or a swing and a miss?
  Gastroenterology March 2006
Sooyun Chun, MD, Stephen D. Zucker, MD
Article Outline
Janssen HLA, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, Simon C, So TMK, Gerken G, de Man RA, Niesters HGM, Zondervan P, Hansen B, Schalm SW (Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands; University of Istanbul, Istanbul, Turkey; University Hospital, Homburg am Saar, Germany; Ege University Hospital, Izmir, Turkey; Medical University, Kraclow, Poland; Princess Margaret Hospital, Hong Kong, China; University Hospital, Essen, Germany). Pegylated IFN alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123-129.
To me, boxing is like a ballet, except there's no music, no choreography and the dancers hit each other.-Jack Handey
Hepatitis B represents an enormous clinical burden, with an estimated 2 billion people infected and 350 million chronic carriers worldwide (N Engl J Med 1997;337:1733-1745). Approximately 15%-25% of those chronically infected with the hepatitis B virus (HBV) will develop complications of liver dysfunction and/or hepatocellular carcinoma (N Engl J Med 2002;346:1682-1683). Since the introduction of the hepatitis B vaccine, great strides have been achieved with regard to disease prevention (N Engl J Med 2004;351:2832-2838). However, in those individuals who have become carriers of the virus, attempts at eradication have been largely ineffective, with overall rates of hepatitis B surface antigen (HBsAg) clearance below 15% (Clin Gastroenterol Hepatol 2004;2:839-848). For this reason, the primary aims of treatment have been to halt disease progression and prevent the development of hepatocellular carcinoma. Because direct assessment of these goals requires protracted follow-up, surrogate end-points for evaluating treatment efficacy have generally included sustained suppression of viral DNA, seroconversion from hepatitis B early antigen (HBeAg) to early antibody (HBeAb), normalization of serum ALT, and reduced hepatic necroinflammatory activity by histological analysis (BMJ 2004;329:1080-1086).
Introduced in the 1980s, interferon (IFN)-a was the first drug found to be useful in the treatment of chronic hepatitis B. A host cytokine produced in response to viral invasion, IFN has both immunomodulatory and antiviral effects (J Viral Hepatitis 2004;11:97-107). In HBeAg-positive patients, IFN monotherapy (5 mU daily or 10 mU thrice weekly) administered subcutaneously for 16-26 weeks induces seroconversion to HBeAb in 20%-40%, and loss of HBsAg in approximately 8% of patients (J Hepatol 1994;21:646-655, Ann Intern Med 1993;119:312-323). However, these beneficial results come at the cost of numerous side-effects, such as an influenza-like illness, myelosuppression, thyroid dysfunction, autoantibody induction, emotional lability, and depression. More recently, pegylated IFN-a, at a dose of 180 g per week, has been shown to induce seroconversion in 27% of patients and is associated with fewer adverse events and a greater reduction in HBV DNA than standard IFN (N Engl J Med 2005;352:2682-2695). The first oral agent to be licensed for the treatment of chronic hepatitis B was lamivudine. As with all nucleoside analogues, it targets the viral polymerase, causing termination of DNA strand synthesis (Aliment Pharmacol Ther 2004;20:1211-1230). Seroconversion from HBeAg to HBeAb occurs in 15%-30% of patients following a 50-100-week course of oral lamivudine (100 mg once daily) (N Engl J Med 1998;339:61-68, N Engl J Med 1999;341:1256-1263, Gastroenterology 2000;119:172-180); however, the response is less durable than with IFN, with relapse rates ranging from 20% to 50% (Hepatology 2000;32:803-806). While lamivudine has an exceedingly benign side-effect profile, rates of viral resistance due to the emergence of mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif within the HBV polymerase gene approach 70% within 4 years of commencing treatment (Hepatology 2001;34:785-791, Hepatology 2000;32:1145-1153, J Viral Hepatitis 2005;12:398-404). In light of the low likelihood of a sustained virologic response to monotherapy and the growing proportion of individuals with chronic hepatitis B who are resistant to or intolerant of available therapeutic agents, attention has begun to focus on the use of drug combinations. Two large multicenter trials have examined the use of standard IFN-a and lamivudine in combination, one in treatment-naive (Gut 2000;46:562-568) and one in IFN nonresponders (J Hepatol 2003;38:818-826). While both failed to demonstrate superiority to monotherapy, these studies have been criticized for their relatively short duration (16 weeks) and the staggered introduction of IFN, 8 weeks after starting lamivudine (Antiviral Res 2001;52:139-146, Lancet Infect Dis 2001;1:232-241). Hence, the aim of the present multicenter study was to determine whether the addition of lamivudine to a prolonged course of pegylated IFN was superior to IFN alone. A total of 307 patients with chronic hepatitis B were randomized to receive pegylated IFN-a-2b (100 g once weekly) in combination with lamivudine (100 mg once daily) or placebo, and 266 subjects who were HBeAg-positive entered the treatment phase of the trial. At the end of the 52-week treatment period, rates of HBeAg clearance were significantly higher (P = .01) for subjects administered combination therapy (44%) versus monotherapy (29%). However, this difference was not sustained after 26 weeks of follow-up (35% vs 36%, respectively). Similarly, viral DNA and serum aminotransferase levels, which were significantly lower in the combination cohort at the completion of therapy (52 weeks), were no different at the end of the follow-up period (78 weeks). Factors predictive of a favorable response included HBV genotype A (versus genotypes C or D), low viral load, high serum ALT, and absence of previous IFN therapy.
There are several theoretical advantages to the use of combination therapy for the treatment of viral diseases, the most notable being that agents acting through different mechanisms can provide more effective viral suppression and reduce the risk of viral mutations. It is anticipated that this synergy will lead to more effective eradication, a shorter duration of therapy, and dose reductions resulting in fewer drug side-effects. In the case of hepatitis B, it has been proposed that the simultaneous administration of a nucleoside analogue (eg, lamivudine) would enhance the efficacy of an immunomodulatory agent (eg, IFN) by lowering the viral burden and preventing the infection of healthy hepatocytes (Lancet Infect Dis 2001;1:232-241). The present study by Janssen et al directly addresses this question in a carefully crafted and well-executed manner, clearly demonstrating that the combination of lamivudine and pegylated IFN offers no advantage over pegylated IFN alone. Notably, the rate of HBeAg loss at 78 weeks in the present study (35%) is almost identical to that observed by Lau et al (28%) using 48 weeks of pegylated IFN-a-2a plus lamivudine (N Engl J Med 2005;352:2682-2695) and by Chan et al (36%) in their examination of the efficacy of a 32-week course of peginterferon-a-2a combined with 52 weeks of lamivudine (Hepatology 2005;41:1357-1364).
The population studied by Janssen et al was comprised of HBV-infected individuals who were positive for the early antigen. Although this cohort of patients is easier to study because of the well-defined end-point of seroconversion, they represent a minority of chronic carriers, most of whom are HBeAg negative (Hepatology 2001;34:617-624). Since HBeAg seroconversion cannot be used as a marker of treatment efficacy in these patients, it is necessary to assess response using alternative means. If one examines the end-point of sustained suppression of HBV (eg, < 400 copies mL), combination therapy with IFN and lamivudine appears to achieve this goal in a lower percentage of patients who are HBeAg positive (7%-14%) as compared with those who are HBeAg negative (20%-25%) (N Engl J Med 2005;352:2682-2695, N Engl J Med 2004;351:1206-1217, J Viral Hepatitis 2005;12:262-268). While these statistics are not particularly encouraging with regard to viral clearance, they do suggest that HBeAg negative patients exhibit a marginally better therapeutic response.
It is notable that combination therapy does seem to achieve the desired effect of reducing rates of viral resistance. In the present study, only 7 of the 123 subjects (6%) receiving combination therapy who entered the trial without a pre-existing YMDD mutant developed such a mutation by the end of the 48-week treatment period. This is substantially lower than the 15%-32% rates of viral resistance at 1 year observed in patients receiving lamivudine monotherapy (Gastroenterology 2000;119:172-180, N Engl J Med 1999;341:1256-1263, N Engl J Med 1999;339:61-68, Hepatology 1999;29:889-896). Similarly, Lau et al (N Engl J Med 2005;352:2682-2695) found that 27% of those chronic carriers receiving a 48-week course of lamivudine monotherapy had detectable YMDD mutations versus 4% of those on both peginterferon-a-2a plus lamivudine (P < .001). Unfortunately, this lower likelihood of developing a YMDD mutant does not appear to translate into higher rates of viral clearance with combination therapy, despite the fact that anecdotal reports suggest that IFN is less effective when the YMDD mutation is present (J Gastroenterol Hepatol 2002;17:S333-S337).
Whether the lack of synergy between IFN and lamivudine against HBV is specific to this drug combination or reflects a more fundamental flaw in the rationale of combining an immunomodulatory agent and a nucleoside analogue has yet to be explored. A definitive conclusion awaits the results of studies combining pegylated IFN with other effective nucleoside and nucleotide agents, such as adefovir dipivoxil, entecavir, emtricitabine, and telbivudine. On the other hand, investigators have begun to explore the combined use of nucleoside analogues. In a study comparing the efficacy of telbivudine, lamivudine, or the combination in patients with chronic HBV, rates of HBeAg loss at the end of 52 weeks of therapy were no different in subjects receiving combination therapy (17%) versus telbivudine (33%) or lamivudine (22%) alone (Gastroenterology 2005;129:528-536). Similarly, in a cohort of HBeAg-positive patients with lamivudine-resistant HBV, at the end of treatment the combination of lamivudine and adefovir induced loss of HBeAg in 17% of patients as compared with 16% in the adefovir monotherapy arm. Moreover, the relapse rate was quite high (67%) (Gastroenterology 2004;126:91-101). While certainly not definitive, these data suggest that combination nucleoside therapy is unlikely to be a panacea, perhaps because the agents compete with each other for binding to the HBV DNA polymerase or for the phosphorylation required for drug activation (Semin Liver Dis 2005;25:S20-S28). In summary, it would seem that the use of combinations of currently available antiviral agents will not constitute a quantum leap in our ability to eradicate HBV from chronic carriers. Although the virus appears to have won this round, the hope remains that new drugs targeting alternative sites of viral replication will ultimately allow us to deliver a knockout blow.
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