| Abstract|| |
Hepatitis B is the leading cause of viral hepatitis in the developing world; at least 350 million people are infected with chronic hepatitis B worldwide. Although there are now 6 drugs approved by FDA for treatment of hepatitis B, treatment with nucleoside analogues are complicated by the need for long term therapy and the emergence of resistant strains. On the other hand, Interferon based treatment, though time bound, requires injections and is associated with significant side effects. Hence, optimal treatment of hepatitis B continues to remain the subject of many clinical trials. Management of nucleoside resistant mutants has become a major challenge in clinical practice today. Analogous to its use in HIV, the rationale behind the use of combination therapy is to improve the efficacy and decrease the risk of developing drug resistant strains. In treating HIV infection, combination therapy with agents acting through different mechanisms increases the genetic barrier for developing resistance. What is the current status of "combination therapy"? Is "combination therapy" the way forward? Other contentious issues in the field of Hepatitis B management include the relevance of Anti-HBc screening for blood donors, and the number of doses needed for Hepatitis B vaccine: two doses or three doses? Besides, should patients with normal ALT be treated? And is the presence of IgM anti-HBc diagnostic of acute hepatitis B? This review will discuss these different controversies that arise during care of patients with Hepatitis B.
|How to cite this article:|
Choudhuri G, Piramanayagam P. Controversies in the management of hepatitis B. Hep B Annual 2006;3:165-79
| Introduction|| |
Hepatitis B is the leading cause of viral hepatitis in the developing world, including India and southeast Asia. At least 350 million people are infected with chronic hepatitis B worldwide. There are 6 drugs approved by FDA for treatment of hepatitis B. Treatment options available can be classified into immunomodulatory agents and nucleoside analogues. Treatment with nucleoside analogues are complicated by the need for long term therapy and emergence of resistant strains. Interferon based treatment, though time bound, requires injections and is associated with significant side effects. Therefore optimal treatment of hepatitis B is the subject of many clinical trials. This review will discuss some important controversies that arise during care of patients with Hepatitis B
1. Is the presence of IgM anti-HBc diagnostic of acute hepatitis B?
IgM anti-HBc has been used for diagnosis of acute hepatitis B infection. The assay used nowadays, is very sensitive for detecting IgM antibody against HBc antigen. Its specificity to diagnose acute hepatitis B has recently been questioned. On comparison of the index values of IgM anti-HBc between 20 patients with acute type B hepatitis and 22 chronic hepatitis B patients with acute flares using commercial kits [an index value of greater than 1.2 is used to diagnose acute hepatitis B], all 20 patients with acute hepatitis B were IgM anti-HBc positive, as were 11 (50%) of 22 chronic hepatitis B patients with acute flare. Although sensitive, the specificity of IgM anti-HBc for diagnosis of acute hepatitis B was estimated to be 65% (20/31). Eleven (35%) of the 31 patients with an index value of IgM anti-HBc greater than 1.2 indeed were chronic HBV hepatitis with acute flare. Hence, a positive IgM anti-HBc has to be interpreted with caution especially if overt signs of chronic liver disease are absent, as it could be an acute flare of chronic hepatitis B. The interpretation of IgM anti-HBc assay results in acute and chronic hepatitis B has been shown in [Table - 1].
2. Should patients with normal ALT be treated?
Elevated ALT is considered to be reflective of liver cell necrosis and has traditionally been used as a prerequisite for initiation of therapy. This stems from the era of interferon based treatment where raised ALT indicated active host immune response to the HBV infection and correlated with better chances of treatment response. Subsequently increased ALT was shown to be a positive predictor for attaining better seroconversion while being treated with interferon, pegylated interferon or lamivudine.
The present concept of not treating HBV infection with normal ALT values has its own caveats. Recent studies have shown that 12-24% of patients with normal ALT values and elevated HBV DNA levels have significant histological disease (fibrosis stage>2). Age >45 years was found to be a significant independent predictor of disease progression in normal ALT patients with chronic HBV infection.,,, In this subset of patients, it has been recommended that one should first do a liver biopsy and then offer treatment if significant necro-inflammation and fibrosis are present. Therefore, the practice of using ALT values alone as cutoff for initiation of therapy has been questioned.
To add fuel to fire, the time honored cutoff levels for normal ALT values have themselves been challenged. A large population based survey of ALT values in USA found the presently accepted cutoff values of 40 U/L to be too high and suggested >30U/L for males and >19 U/L for females as indicative of significant hepatic necro-inflammation. ALT activity may also vary with BMI and abnormal lipids. So, what is presently being passed of as normal ALT value may actually be abnormal?
There has also been a conceptual change in the pathogenesis of HBV infection. In the past, it was thought that liver cell injury was due only or mainly to active host immune response to HBV infected hepatocytes. Recent reports have indicated that HBV itself can cause liver damage and have demonstrated a significant correlation of HBV DNA viral load with risk of development of cirrhosis and HCC. The adjusted risk rate of development of cirrhosis increased from 2.5 [95% CI:1.6-3.8] when HBV DNA level was 4 log copies/ml to 6.5 (95% CI:4.1-10.2) when HBV DNA level was >6 log copies/ml. The risk of progression to cirrhosis is well correlated with increasing HBV DNA levels and is independent of "e Ag" status and ALT level. Risk of developing HCC seems directly related to HBV viral load., Thus, the load of HBV viral infection, independent of ALT level, may emerge as an indicator for treatment, especially as better drugs to suppress the viral replication become available.
3. Nucleoside analogues: Boon or bane?
Therapy with nucleoside analogues require good viral suppression maintained over long duration. Prolonged therapy with oral drugs is complicated by the emergence of viral resistance to these agents. The yearly rate of development of resistance to various nucleoside analogues is shown in [Table - 2].
[Figure - 1] illustrates the location of the various HBV polymerase resistance mutations associated with different nucleoside analogues
Management of nucleoside resistant mutants has become a major challenge in clinical practice today. We briefly review below the incidence, mechanism and management of nucleoside resistant HBV strains. The treatment options for various nucleoside analogue resistance has been summarized in [Table - 3].
Lamivudine was the first oral nucleoside analogue to be used in routine management of chronic hepatitis B. The development of resistance to lamivudine involves mutations in YMDD motif of HBV DNA polymersase gene. Two main mutations, both in the polymerase gene, have been identified with development of resistance: M204 V/I (formerly M552V/I) in the YMDD motif of the catalytic "C'" domain of HBV polymerase and L180M (formerly L528M) upstream of YMDD motif in "B" domain of HBV DNA polymerase [Figure - 1]. Up to 1/4th of patients have been reported to develop lamivudine resistant strains at 1 year of therapy, while 3/4th of the patients developed lamivudine resistance in 4 years. With such a high incidence of resistant strains, lamivudine alone is no longer considered as the first line therapy for chronic HBV treatment. Management of lamivudine resistant mutants has become a major challenge in clinical practice.
Adefovir was introduced into the market with the promise of low possibility of development of resistant strains. Resistant strains developed in <5% of patients in the first two years; however, up to 1/3rd of patients on adefovir develop resistance in 5 years. The primary mutation associated with adefovir resistance is N236T located in the domain D of the HBV polymerase gene.
Entercavir is one of the newer nucleoside analogues to be used in the management of HBV infection. The main benefit of Entecavir is the high threshold for developing resistant strains. Unlike its predecessors that require a single mutation, Entecavir requires mutations at three different sites of the HBV polymerase gene for development of virological resistance. Also, development of Entecavir resistance requires preexisting lamivudine resistance mutation plus additional mutations in HBV polymersase: T184, I 169 in domain B, S202 in domain C or M250 in domain E [Figure - 1]. In vitro studies showed that the mutations at positions 169, 184, 202 or 250, on their own, alter the susceptibility of the virus to Entecavir very little, but decreases it by 500-fold when two or more Entecavir-resistant mutations are present along with the lamivudine-resistant mutations. Follow up results of first two years of therapy have shown 3% resistance in treatment naοve patients and 9% resistance in lamivudine resistant HBV infection. Although follow up data with Entecavir is available for only 2 years, emergence of viral resistance seems to be the least with this drug. Longer follow up is however clearly needed with Entecavir.
Telbivudine is another newly marketed nucleoside analogue for use in HBV infection. Telbivudine achieves HBV-DNA viral suppression below detectable levels in up to 60% of patients over 48 weeks. The main concern with telbivudine is the high incidence of resistant strains. Telbivudine resistance occurs due to mutation in YMDD motif of HBV DNA polymerase [M204I]. Although the frequency of developing resistance is less than with lamivudine, it is substantial and increases exponentially after the first year of treatment. In a phase III study, the rate of development of resistance was 2-4% in the first year and 8-21% in the second year of therapy.
What is the current status of newer nucleoside analogues?
Several nucleoside analogues have been approved for the treatment of HBV infection of which Entecavir and Telbivudine have been approved recently by FDA. Tenofovir, Clevudine, Emtricitabine are under phase 3 clinical trials. The following section describes the salient results of entecavir, Telbivudine and Tenofovir. The relative efficacy of the newer antiviral drugs has been summarized in [Table - 4].
Entecavir inhibits HBV replication at three different steps: the priming of HBV DNA polymerase, the reverse transcription of the negative strand HBV DNA from the pregenomic RNA and the synthesis of the positive strand HBV DNA. Entecavir achieves viral suppression below detectable limits in 70-80% of patients at 48 weeks of therapy. Entecavir 0.5 mg once daily has been shown to have better histological, virological and biochemical responses than what are achieved with Lamivudine after 48 weeks of therapy, in both HBeAg positive and HBeAg negative patients [Figure - 2].,
Among HBeAg-positive patients who underwent HBeAg seroconversion during the first year and who stopped treatment at week 48, approximately 70% of patients remained HBeAg negative. Data on the durability of response among HBeAg negative patients is lacking. Role of Entecavir in decompensated cirrhosis is currently being evaluated by clinical trials. In Lamivudine refractory HBV, Entecavir in doses of 1mg once daily resulted in better histologic and biochemical improvement than Lamivudine alone. Entecavir is currently approved therapy for treatment naοve HBV infection and Lamivudine resistant HBV infection
Clinical trials have shown that Telbivudine is more potent than Lamivudine in suppressing HBV replication. However, Telbivudine is associated with a high rate of development of resistance and Telbivudine resistant mutations have cross-resistance to Lamivudine. The approved dose of Telbivudine is 600 mg daily. Doses should be adjusted for patients with estimated creatinine clearance <50 ml/min.
Tenofovir is structurally similar to Adefovir. One prospective randomized study of 52 patients with HIV and HBV coinfection found that Tenofovir produced a greater reduction in serum HBV DNA levels than Adefovir [Figure - 3]. Similar results have been obtained in HIV-negative patients with Lamivudine-resistant HBV. There have also been case reports of viral rebound when patients with virologic response were switched from Tenofovir to Adefovir and further viral reduction when patients with inadequate viral suppression were switched from Adefovir to Tenofovir. Tenofovir has been used in HBV/HIV co-infection and in Adefovir resisitant HBV infection. Tenofovir is yet to get FDA approval as therapy in HBV infection.
4. Is "combination therapy" the way forward?
Analogous to its use in HIV, the rationale behind the use of combination therapy is to improve the efficacy and decrease the risk of developing drug resistant strains. In treating HIV infection, combination therapy with agents acting through different mechanisms increases the genetic barrier for developing resistance. Various combinations of drugs have been tried in the treatment of HBV infection.
- Interferon and nucleoside analogue
- Combination of nucleos(t)ide analogues.
In the following section, we shall review the results of treatment with various modes of combination therapy used in clinical trials.
1. Interferon (IFN) and nucleoside analogue
Five randomized controlled trials have been reported with this combination; one used standard IFN while four used Peg IFN. In all the trials, combination therapy produced greater viral suppression and off-treatment sustained response compared with lamivudine alone, but, showed no significant benefit over interferon alone. Lamivudine resistance rates of 4% and 1% for the combination arms were however significantly lower than the 27% and 18% observed with Lamivudine monotherapy in patients with HBeAg-positive and -negative disease, respectively.,,,
2. Combination of nucleoside analogues
Lamivudine and Adefovir
Sung et al., showed that in treatment naοve patients, the rate of development of lamivudine resistance in patients treated with a combination of Lamivudine and Adefovir dipivoxil was only 2%, compared with 20% in patients treated with lamivudine alone. The antiviral efficacy of the combination was however comparable with Lamivudine monotherapy.
When resistance occurred with Lamivudine treatment, combination therapy was not found to be better in achieving viral suppression compared to Adefovir alone. However, resistance to Adefovir did not develop in patients continued on lamivudine compared to those who stopped Lamivudine and were switched to Adefovir.,, It therefore appears reasonable to add Adefovir to patients who develop resistance while on Lamivudine monotherapy to reduce the chances of development of Adefovir resistance.
Lamivudine and Telbivudine
One trial conducted in nucleoside naοve HBeAg-positive patients demonstrated that the combination of Lamivudine and Telbivudine was inferior vis-à-vis all parameters of response compared to Telbivudine alone.
Though none of the combination therapies has been proven to be superior to monotherapy in inducing sustained viral response, they have shown reduced rate of development of resistance to Lamivudine. More long term studies on combination therapy with different agents with varied resistant mutations profile are required. The burden of nucleoside resistance is likely to increase in the coming years in developing countries like India where Lamivudine monotherapy is often offered because of its easy affordability. In the setting of prohibitive costs of some newer nucleoside analogues and Pegylated interferon, there is need for an oral nucleoside combination therapy which is both affordable and efficacious.
5. Anti HBc screening for blood donors: Pros and cons
The incidence of transfusion associated-HBV (TAHBV) is estimated to be 1.5% in post-surgical recipients and 50% or more in multiple-transfusion recipients in India. Screening of potential blood donors for HBV infection in India is done by testing for HBsAg. There exists a subset of donors who had been infected with HBV in the past and who have lost HBsAg but are positive for anti HBc. These patients may be potential sources for HBV transmission as some of them have low level HBV viremia.
Not transfusing blood with high-titer anti-HBc which reportedly correlates with the presence of HBV DNA helped reduce TAHBV in Japan . While anti-HBc screening can eliminate residual risk of HBV transmission by transfusion in low-endemic areas, it would not be practical in most parts of the world where the prevalence of anti-HBc is >10% as too many otherwise healthy donors will be ineligible. Chaudhuri et al., reported that 10% of blood donors in a north Indian teaching hospital were positive for IgM anti-HBc, of which anti-HBc was the only marker of HBV infection in 4%.
Do we need to screen the contacts of HBsAg negative, anti-HBc positive patients? In Brazil, a cross-sectional study was performed to compare prevalence of HBV infection between contacts of HBsAg-positive blood donors (group I) and contacts of HBsAg-negative, anti-HBc-positive donors (group II). Contacts were submitted to a questionnaire and blood tests for HBV markers. In group I (n = 143), 53 (37.1%) were anti-HBc-positive and 11 (7.7%) were HBsAg-positive. In group II (n = 111), the figures were 9% and 0.9%, respectively. The authors concluded that contacts of HBsAg-negative, anti-HBc-positive individuals presented a much lower risk of having already been exposed to HBV and there was no need to screen them for HBV in low to moderate prevalence populations.
6. Hepatitis B vaccine: Two doses or three doses?
Heron et al., in a randomized controlled trial assessed the immunogenicity and safety of a two-dose hepatitis B immunisation regimen (n=126 patients; thiomersal-free Engerix-B 20 µg HBsAg doses 6 months apart) compared to the standard three-dose vaccination regimen (n=256 patients; preservative-free Engerix-B 10 µg HBsAg doses: 0, 1, 6 month dose schedule) in healthy adolescents aged 11-15 years. The seroprotection (anti-HBs >/=10 mIU/ml) rate in the two-dose (20 µg) group (96.7% seroprotected) was similar to the three-dose (10 µg) group (98.2% seroprotected). Both regimens were shown to be safe and well tolerated. Until further large randomized controlled studies are available, the current recommendation is to give 3 doses of vaccine. Including the preS1 and preS2 antigens with the surface (S) antigen might boost immunogenicity further; the protective antibodies (anti-HBs) were found to rise faster (100% vs 45% at 1 month after 2nd dose) and achieve higher levels in this group (56045 vs 2216 IU/mL) compared with those receiving the conventional vaccine. A 2 dose vaccine is expected to improve compliance and perhaps prove beneficial for immuno-compromised patients as well as those with chronic renal failure, in whom the currently used vaccine has a high rate of failure.
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Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3]
[Table - 1], [Table - 2], [Table - 3], [Table - 4]