One of the fundamental lessons we learn as medical providers is that the effectiveness and safety of drugs often vary between patients. Accordingly, patient selection may be key for making the best treatment decision. The stakes are even higher when drugs with predictable adverse effects are considered. All of these issues assume center stage when determining the type of antiviral therapy to treat hepatitis B.
Tolerability of antiviral therapy
Interferon accounts for no more than 10 percent of prescriptions for antiviral therapy in Europe and North America.1 The major reason for this is the inherently safer profile for nucleoside analogues and the need for less complex monitoring. It should be noted, however, that interferon-treated hepatitis B patients have better quality of life and improved tolerability than similarly treated patients with hepatitis C.2
Unfortunately, better patient acceptance with nucleoside analogues does not necessarily ensure better compliance, because as many as 30 percent of patients are not compliant with maintenance nucleoside analogue therapy.
Interferon is always contraindicated in patients with any level of liver decompensation due to flares of hepatitis and risk for serious infection. Practical experience indicates that interferon is less well tolerated in patients over the age of 60 and in those with significant co-morbid illnesses.
Differences in virologic response
Loss of hepatitis B surface antigen (HBsAg) is an important event, leading to improved outcomes and reduced rates of long-term complications.3 It is the closest one that comes to a clinical cure in hepatitis B.
Studies with standard or pegylated interferon have shown that 24 to 48 weeks of treatment accelerates the time to HBsAg loss. This occurs in a small number (3 percent to 5 percent) of hepatitis B cases initially, but prolonged follow-up demonstrates further gains in HBsAg clearance as long as durable hepatitis B virus (HBV) DNA suppression is maintained after treatment.4,5 By contrast, loss of HBsAg rarely occurs with nucleoside analogues, even with several years of therapy. Recent experience with tenofovir challenges this concept, but unlike the situation with interferon, HBsAg clearance has thus far been confined to non-Asians with hepatitis B virus e antigen (HBeAg)-positive hepatitis B. The reasons for the different kinetics of HBsAg clearance with the two classes of drug are not well understood, but the immunomodulatory effect of interferon is likely to play an important role.
The low rate of initial HBsAg clearance with both interferon and nucleoside analogue therapy has led to the use of “intermediate” efficacy endpoints such as sustained lowering of HBV DNA and HBeAg seroconversion. While “comparable” efficacy rates have been claimed, clinical extension trials of nucleoside analogues demonstrate that several years of treatment generally elapse before the rate of HBeAg seroconversion is equivalent (~30 percent) to that observed with interferon.
Patient selection
The efficacy of interferon, however, is very modest in HBeAg-positive cases with low alanine transaminase (ALT) (less than two times ULN) and high HBV DNA levels (greater than 200 million mIU/mL). In such cases, nucleoside analogue therapy is advisable. In my experience, it is also reasonable to use nucleoside analogue therapy as first-line treatment when baseline ALT is greater than or equal to five times ULN because this predicts a greater than 50 percent rate of HBeAg loss with one year of treatment.
Viral genotype is an especially important feature in determining the likelihood of response to interferon in HBeAg-positive hepatitis. Genotype A and B patients respond best and are more likely to lose not only HBeAg, but HBsAg. A treatment algorithm has recently been published by Janssen et al. that is based on the relationship between baseline patient features, viral genotype and the rate of HBeAg loss in a large number of pegylated interferon-treated cases.6 The accompanying table indicates what I have found to be the most important factors in my day-to-day experience.
Unfortunately, there are no clear-cut predictors of response in HBeAg-negative hepatitis B, a condition where relapse is frequent with 48 weeks of interferon or several years of nucleoside analogue therapy. The relationship between durable HBV DNA suppression off therapy and viral genotype is less well understood, but some studies have demonstrated that genotype D patients are especially difficult to treat. Ironically, HBsAg clearance has been demonstrated to occur in genotype D patients treated with pegylated interferon.6
Combination antiviral therapy
We do not know if pegylated interferon combined with newer nucleoside analogues such as entecavir or tenofovir results in a higher rate of durable viral suppression, HBeAg clearance or HBsAg clearance. Preliminary studies have suggested enhanced efficacy compared to previous studies using lamivudine. This may be due to the lower rates of resistance associated with newer agents. Ongoing treatment trials in HBeAg-positive and -negative hepatitis B, including one sponsored by the NIH (Hepatitis B Research Network, http://www.hepbnet.org/), will address this more definitively. Should significantly higher rates of response be found with combination therapy, it will be important to determine the baseline characteristics that predict a higher rate of response compared to either drug alone. Thus, patient selection is likely to remain key in the future as well, as better therapies are demonstrated. For me, hepatitis B is a condition where the old adage of “one size fits all” is likely to never apply.
References
1.Perrillo R. Benefits and risks of interferon therapy for hepatitis B. Hepatology 2009; 49:S103-11.
2.Marcellin P, Lau GK, Zeuzem S, et al. Comparing the safety, tolerability, and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alfa-2a. Liver Int 2008; 28:477-85.
3.Fattovich G, Giustina G, Sanchez-Tapias J, et al. Delayed clearance of serum HbsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol 1998; 93:896-900.
4.Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology 2008; 135:459-67.
5.Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2. Gastroenterology 2009; 136:2169-79.
6.Buster EH, Hansen BE, Lau GK, et al. Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon alfa. Gastroenterology 2009; 137:2002-9.
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