EXPERT VIEWPOINT
What Should Clinicians Do to Reduce HBV Drug Resistance?
Stephen Locarnini, MD, PhD, FRC (Path)
Associate Professor
Head, Research & Molecular Development
Victorian Infectious Diseases Reference Laboratory (VIDRL)
North Melbourne, Victoria, Australia
Treatment of chronic hepatitis B has advanced significantly during the past
15 years as a result of the development of safe and efficacious orally
available antiviral nucleoside and nucleotide analogues. The first of these,
lamivudine, a synthetic deoxycytidine analogue with an unnatural
L-conformation, gained approval from the United States Food and Drug
Administration (FDA) for treatment of chronic hepatitis B in 1999, and
related L-nucleosides, including emtricitabine, telbivudine, and clevudine,
have since progressed to late-stage clinical trials. Adefovir dipivoxil, a
prodrug for the acyclic dAMP analogue adefovir, gained FDA approval in 2002,
and clinical trials of structurally similar tenofovir disoproxil fumarate,
which is currently used to treat HIV infection, are underway.[1] The most
potent anti-HBV drug discovered to date is the deoxyguanosine analogue
entecavir, which has recently been recommended by the FDA Antiviral Drugs
Advisory Committee for approval for first-line use against HBV.[2,3] Despite
the development of these new drugs, treatment of chronic hepatitis B remains
a clinical challenge, and the primary goal of current treatment remains
relatively modest: to arrest disease progress and delay or prevent the onset
of its potentially fatal sequelae.[1,4]
After uptake and intracellular activation, nucleoside and nucleotide
analogues act as specific inhibitors of the viral polymerase and cause
immediate termination of HBV DNA synthesis, which results in rapid and
dramatic decreases in viral load. This impressive early response occurs in
the majority of cases, but long-term response rates are poor, with
frequencies of HBeAg seroconversion after 1 year of the order of 20% or
less. Post-treatment relapse is common, even in individuals who undergo
HBeAg seroconversion, and HBsAg seroconversion occurs rarely. Thus, overall
long-term responses to nucleoside and nucleotide analogues are only slightly
better than responses to interferon-alpha, the only drug previously approved
for treatment of chronic hepatitis B in most countries. Interferon may still
be the treatment of choice in some cases, despite disadvantages of limited
efficacy, high cost, and frequent occurrence of dose-limiting adverse side
effects.[1,4,5] Preliminary evidence from clinical trials indicates that use
of pegylation can improve both pharmacologic properties and efficacy of
interferons (see below).
Continuing long-term treatment with nucleoside and nucleotide analogues
increases the risk of drug resistance, which occurs in vivo as a result of
selection for viral mutants that encode altered polymerases.[5,6] Resistance
develops at cumulative frequency of about 20% per year of treatment with
lamivudine. Adefovir resistance occurs less frequently (about 2% annually)
and, although data are preliminary, entecavir resistance may occur even less
frequently. Drug-resistant HBV mutants have been found to replicate
inefficiently in vitro and were initially considered less fit, but the
emergence of drug-resistant HBV is often associated with hepatic flares and
decreased clinical benefit in patients with compensated disease, and with
more serious clinical consequences in patients with advanced liver disease;
moreover, drug-resistant HBV remains potentially infectious.
As more antiviral drugs become available, resistance is becoming an
increasing concern.[5] Clinicians can help to prevent the spread of drug
resistance in 3 main ways:
avoiding unnecessary drug use,
careful choice of drugs and drug combinations, and
continuous surveillance for drug resistance.
Avoiding Unnecessary Drug Use: Prevention Is Better Than Cure
The most obvious way to reduce drug resistance is to avoid unnecessary drug
use. Because of the unusual replication strategy used by HBV, viral
populations are genetically heterogeneous, implying that even
treatment-naive patients may harbor drug-resistant mutants that constitute
only a minor component of the population in the absence of selection
pressure from antiviral drugs.[5] A majority of patients may not require
antiviral therapy. Several concerned organisations, (including AASLD, EASL,
APASL, and the NIH) publish regularly updated guidelines to assist
clinicians with recognition, diagnosis, prevention, and management of
chronic hepatitis B: these are unanimous in recommending that therapy should
be considered only for patients with more active or advanced liver disease
and others most likely to respond.[4] Treatment algorithms have been
developed to assist in identification of suitable candidates for treatment
and to determine when to initiate treatment.[5,7]
Careful Choice of Drugs Can Minimize the Incidence of Resistance
Expansion of drug-resistant mutant populations is absolutely dependent on
replication, so antiviral therapy, once initiated, should aim to suppress
viral replication as potently and as rapidly as possible.[1,4,5] Currently,
interferon, lamivudine, or adefovir dipivoxil can all be considered as
first-line therapy for individuals with noncirrhotic liver disease, and
entecavir will soon become an additional option. Mutations that confer
resistance to lamivudine confer cross-resistance to other L-nucleosides and
reduce sensitivity to entecavir but not to adefovir or tenofovir.
Conversely, mutants that are resistant to adefovir and tenofovir remain
sensitive to L-nucleosides and entecavir. Multiple mutations are required
for high-level resistance to entecavir.[8] The lower risk of resistance to
adefovir dipivoxil and entecavir supports their use in liver transplant
patients and those with cirrhosis or decompensated liver disease, since
development of drug resistance is more likely to precipitate clinical
deterioration in these groups.[5]
In the future, combination chemotherapy will almost certainly be used
increasingly to treat chronic hepatitis B. Provided that appropriate drug
combinations are used, this approach gives well-recognized benefits,
including reduction of the risk of drug resistance. This is because, while
the preexistence or rapid evolution of viral mutants with the potential to
resist individual drugs is almost guaranteed by high HBV loads and rapid
turnover in vivo, the preexistence or evolution of multidrug-resistant
mutants is much less likely. Ideally, drugs used in combination should have
different mechanisms of action and act additively or synergistically.[9] Use
of interferon in combination with nucleoside or nucleotide analogue(s)
therefore seems logical. Although early clinical trials of such combinations
were disappointing, recent results from trials with pegylated interferon and
lamivudine are more promising.[10-12] While combinations of L-nucleosides
are unlikely to provide any benefit, the lack of cross-resistance between
lamivudine and adefovir dipivoxil, as well as some clinical data, supports
their use in combination.[13,14] Preliminary data also supports the use of
entecavir in combination with some other nucleoside/nucleotide analogues,
but definitive recommendations will require support from ongoing clinical
and cost-benefit studies.
Be Prepared: Surveillance for Drug Resistance
Progress during treatment should be monitored carefully so that drug
resistance, if it occurs, is detected early, before disease progression
resumes as a consequence of viral breakthrough. Serum HBV DNA titer is the
best available indicator of HBV replication. Reductions in serum HBV DNA
always precede biochemical and histologic responses; conversely, rebounds in
serum HBV DNA precede reversals of biochemical and histologic responses. A
standardized ranking system is needed to facilitate comparisons of the
effects of alternative treatment regimes, since ways in which treatment
efficacy is currently measured vary widely. The following definitions have
recently been proposed.[5] An antiviral effect is defined as a minimum
reduction in serum HBV DNA ?1 log10 IU/mL from the pretreatment baseline
within the first 3 months. Failure to achieve this decrease constitutes
primary treatment failure. A confirmed increase in serum HBV DNA of ?1 log10
IU/mL from the nadir following initially effective treatment constitutes
secondary treatment failure.
Assays for serum HBV DNA and ALT should be performed 3 and 6 months after
starting therapy to check for efficacy and compliance, the latter being the
most common cause of primary treatment failure. Further assays at 6-month
intervals during the first 2 years of treatment are recommended for patients
with mild liver disease. Three-month assessments are recommended after 2
years, when the probability of developing resistance increases. Consequences
of resistance manifest more rapidly and are more life threatening to
individuals with advanced disease, for whom 3-month assessments are
recommended.[5]
Managing Drug-Resistant HBV Infection
To date, only lamivudine resistance has been extensively studied. There are
arguments both for and against continuing lamivudine treatment of
individuals with compensated liver disease and without evidence of
cirrhosis.[5] Switching to adefovir dipivoxil with or without continued
lamivudine are alternative options. Although switching to entecavir (at a
daily dose of 1 mg rather than 0.5 mg recommended for treatment-naive
patients) after lamivudine failure has been shown to be effective in
clinical trials, this strategy may encourage development of resistance to
entecavir.[8] Patients with severe disease should be given add-on
combination therapy immediately on confirming the presence of drug-resistant
virus, since stopping therapy or switching drugs are both regarded as too
risky for this group.[5] The relative clinical benefits and
cost-effectiveness of these and other alternatives are still being assessed.
Intensive research aimed at characterizing the behavior of different
clinically important HBV mutants is underway in many laboratories worldwide.
The results, in particular those delineating patterns of resistance and
cross-resistance, will be crucial for the design of optimal therapeutic
strategies and maximizing the benefit from new antivirals. Ideally,
treatment for HBV infection should begin at diagnosis, but this is not yet
feasible because of limitations of existing drugs. Ongoing clinical trials
and concurrent improvements in diagnostic technology guarantee that
treatment options and opinions on patient management will continue to
evolve, emphasising the importance of staying up-to-date with this exciting,
rapidly-developing field.
References
1. Perrillo RP. New data on hepatitis B treatment. Published online at:
http://clinicaloptions.com/hepatitis.
2. Bristol's Baraclude (entecavir) recommended for first-line Hep B
treatment
http://www.fdaadvisorycommittee.com/FDC/AdvisoryCommittee/Committees/Antiviral+Drugs/031105_entecavir/031105_EntecavirR.htm
3. Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B.
Expert Rev Anti Infect Ther. 2004;2:853-871.
4. Lok ASF. HBV treatment guidelines: questions and controversies. Published
online at: http://clinicaloptions.com/hepatitis.
5. Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral
resistance in patients with chronic hepatitis B. Antivir Ther.
2004;9:679-693.
6. Tacke F, Manns MP, Trautwein C. Influence of mutations in the hepatitis B
virus genome on virus replication and drug resistance: implications for
novel antiviral strategies. Curr Med Chem. 2004;11:2667-2677.
7. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the
management of chronic hepatitis B virus infection in the United States. Clin
Gastroenterol Hepatol. 2004;2:87-106.
8. Tenney DJ, Levine SM, Rose RE, et al. Clinical emergence of
entecavir-resistant hepatitis B virus requires additional substitutions in
virus already resistant to lamivudine. Antimicrob Agents Chemother.
2004;48:3498-3507.
9. Shaw T, Locarnini S. Combination chemotherapy for hepatitis B virus: the
path forward? Drugs. 2000;60:517-531.
10. Chan HL, Leung NW, Hui AY, et al. A randomized, controlled trial of
combination therapy for chronic hepatitis B: comparing pegylated
interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med.
2005;142:240-250.
11. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon
alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic
hepatitis B: a randomised trial. Lancet. 2005;365:123-129.
12. Jang MK, Chung YH, Choi MH, et al. Combination of alpha-interferon with
lamivudine reduces viral breakthrough during long-term therapy. J
Gastroenterol Hepatol. 2004;19:1363-1368.
13. Westland CE, Yang H, Delaney WE 4th, et al. Activity of adefovir
dipivoxil against all patterns of lamivudine-resistant hepatitis B viruses
in patients. J Viral Hepat. 2005;12:67-73.
14. Maynard M, Parvaz P, Durantel S, Chevallier M, Chevallier P, Lot M,
Trepo C, Zoulim F. Sustained HBs seroconversion during lamivudine and
adefovir dipivoxil combination therapy for lamivudine failure. J Hepatol.
2005;42:279-281.
http://clinicaloptions.com/hep/ev/2005-4.asp | 
发表于 2005-4-12 09:26
