- 现金
- 3700 元
- 精华
- 16
- 帖子
- 1790
- 注册时间
- 2002-12-9
- 最后登录
- 2021-4-14
|
1楼
发表于 2005-2-16 02:01
http://www.medscape.com/viewarticle/495209
January 26, 2005
Medscape coverage of: 55th Annual Meeting of the American Association for
the Study of Liver Diseases
Developments in the Management of Hepatitis B
Daniel Pratt, MD
Introduction
Hepatitis B virus (HBV) is a major healthcare problem around the world. It
is estimated that 350-400 million people are chronically infected.[1,2]
Patients with chronic hepatitis B are at increased risk for progression to
cirrhosis and end-stage liver disease and for the development of
hepatocellular carcinoma (HCC), including patients who are asymptomatic.
Interferon has been used to treat hepatitis B since the mid-1980s with
limited results. The efficacy of pegylated interferon is now being actively
investigated. The development and availability of nucleoside and nucleotide
analogues has greatly altered the management of patients with chronic
hepatitis B. Unfortunately, the increased use of these drugs, particularly
when used as monotherapy, has produced mutations that confer viral
resistance, much as what was seen in the management of HIV. Investigators
have sought to define these mutations and to examine the role of combination
therapy to improve virologic response and reduce viral resistance.
This report reviews some of the most clinically interesting HBV-related
research presented during this year's meeting of the American Association
for the Study of Liver Diseases.
Hepatitis B and the Risk of Developing HCC
It is known that patients with chronic hepatitis B who are hepatitis B e
antigen (HBeAg)-positive are at greatest risk for both the progression of
liver disease and the development of HCC.[3] What this implies, but what
hasn't been clearly shown, is that the HBV viral load also correlates with
disease progression and the risk of HCC. Chen and colleagues[4] looked at
this issue in their 10-year, prospective cohort study of 3464 patients found
to be hepatitis B surface antigen (HBsAg)-positive at screening between 1992
and 1993. Ten years later, 2354 of these patients had either sufficient
baseline serum samples or adequate follow-up information to allow them to be
included in a mortality analysis; 1681 patients had both sufficient baseline
serum samples and were willing to undergo rescreening with physical
examination, laboratory tests, and liver ultrasound. All of the patients
were placed in 1 of 3 viral load categories on the basis of their viral
loads at the time of entry: undetected (< 1.6 x 103 copies/mL), low titer (<
105 copies/mL but >/= 1.6 x 103 copies/mL), and high titer (>/= 105
copies/mL). Liver disease was characterized as normal, mild, moderate, or
severe on the basis of adapted Dionysos criteria. HCC was diagnosed by the
presence of a > 2-cm mass on ultrasound and an alpha-fetoprotein level > 400
ng/mL.
The patients in the high-titer virus group at entry were found to be at a
statistically significant greater risk for mortality from progressive liver
disease or HCC than patients with low or undetectable viral loads. Although
it did not reach statistical significance, low viral load also appeared to
be associated with an increased risk of mortality from progressive liver
disease or HCC when compared with patients with an undetectable viral load.
This study has potentially significant implications for the management of
patients with chronic hepatitis B. There is controversy regarding whether
patients in the immunotolerant stage of HBV infection (patients with high
levels of HBV DNA, normal aminotransferases, and little to no
necroinflammatory activity on liver biopsy) should be treated. This study by
Chen and colleagues[4] provides additional weight to the argument that
perhaps these patients would benefit from being treated and highlights the
need for a trial to be designed to look at this specific question. The end
points of such a study, the progression of liver disease and the development
of HCC, would take many years to assess and will require the enrollment of
large numbers of patients. In addition, the study would need to use multiple
anti-HBV agents to prevent the development of viral resistance. Hopefully,
studies, such as this one by Chen and colleagues,[4] will provide the
impetus for such future investigation.
Prevention of Hepatitis B
The use of passive and active immunity to reduce the risk of vertical
transmission of hepatitis B is well accepted in clinical practice.[5]
Hepatitis B immunoglobulin (HBIg), given at the time of birth in combination
with 3 doses of the recombinant hepatitis B vaccine given over the first 6
months of life, has proven to be as much as 95% effective in preventing
vertical transmission.[6] However, the risk of vertical transmission of
hepatitis B increases as the mother's viral load increases. In one series of
mothers with high viral loads (defined as HBV DNA >/= 1.2 x 109 copies/mL),
this risk was as high as 28%.[7] It stands to reason that if the mother's
viral load could be reduced at the time of birth, the risk of vertical
transmission could also be reduced. This is exactly what Xu and
colleagues[8] examined with a well-structured, multicenter, randomized,
double-blind, placebo-controlled study carried out at centers in China and
the Philippines.
Mothers chronically infected with hepatitis B (HBsAg-positive) and with high
HBV viral loads (defined as a serum HBV DNA > 1000 mEq/mL) were enrolled.
One hundred fourteen mothers completed the study; 56 mothers received
lamivudine, 100 mg a day, beginning at the 32nd week of gestation and
continuing until 4 weeks post partum. The control group of mothers (n = 59)
received placebo. All of the infants received standard prophylaxis (HBIg
within 24 hours of birth and vaccination with the recombinant HBV vaccine; 3
injections over the first 6 months of life). The primary end point of the
study was HBsAg positivity in the infants at 1 year. Secondary end points
were hepatitis B surface antibody (HBsAb) positivity and HBV DNA positivity
in the infants at 1 year.
Not surprisingly, the mothers treated with lamivudine were more likely (98%)
to have a reduction in their viral loads to < 1000 mEq/mL than the controls
(31%). This reduction in viral load translated into improved outcomes for
the infants of mothers receiving lamivudine. They had a lower likelihood of
being HBsAg-positive at 1 year of age (18% vs 39%; P = .014) or to be
viremic (20% vs 46%; P = .003). Infants also had a greater chance of being
HBsAb-positive at 1 year of age (84% vs 61%; P = .008). There was no
difference seen in adverse events between the treatment and control groups
in either the mothers or the infants.
Although this study had some issues with patient dropout, it nonetheless
strongly suggests that the use of lamivudine in the third trimester of
pregnancy in mothers with high HBV viral loads is effective in reducing the
risk of vertical transmission beyond what can be achieved with passive and
active immunization. In addition, this therapy is safe for both the mother
and the infant. While we await additional trials, lamivudine* should be
considered for use in the third trimester in those mothers infected with
chronic hepatitis B at greatest risk for passing the infection on to their
infants -- ie, those with high viral loads.
New and Old Therapies for Hepatitis B
Entecavir, a carbocyclic analogue of 2'-deoxyguanosine, is a potent and
selective inhibitor of HBV polymerase. Rosmawati and colleagues[9] reported
the results of a phase 3 trial comparing entecavir, .5 mg a day, with
lamivudine, 100 mg a day, for 48 weeks in patients with HBeAg-positive
chronic hepatitis B. The investigators chose to pay particular attention to
those patients with low-baseline alanine aminotransferase (ALT) levels,
defined as < 2.6 times the upper limit of normal. The reason for this focus
was a previously completed phase 2 trial that suggested that entecavir may
be as effective in patients with low-baseline ALT as in those with more
elevated ALT. This was of interest because patients with normal or
near-normal ALT levels at baseline respond less well to interferon or
lamivudine than do patients with elevated ALT. The investigators did not
explain why the threshold value of 2.6 times the upper limit of normal was
chosen for this particular analysis. The results showed that in those
patients with a baseline ALT < 2.6 times the upper limit of normal,
entecavir produced a mean log reduction in the HBV DNA of 6.79 at 48 weeks
compared with a 4.85 log reduction for lamivudine (P < .0001). In those
patients with a baseline ALT of >/= 2.6 times the upper limit of normal,
entecavir produced a mean log reduction in the HBV DNA of 7.18 at 48 weeks
compared with a 6.15 log reduction for lamivudine (P < .0001). Entecavir was
much more likely to suppress the HBV DNA to < 400 copies/mL by polymerase
chain reaction at week 48. No data were provided on HBeAg loss or
seroconversion.
In a phase 1/2 clinical trial, clevudine, an L-nucleoside, was shown to have
potent anti-HBV activity over a 12-week period. Lee and colleagues[10]
examined the safety and antiviral activity of clevudine, 30 mg a day, in 21
patients with HBeAg-positive chronic hepatitis B over 24 weeks at 7 sites in
South Korea. The results shown in Table 1 suggest that clevudine has
excellent anti-HBV activity with increased benefit at 24 weeks compared with
12 weeks. There was no viral breakthrough reported.
Table 1. Viral Suppression and Normalization of ALT
End Point Week 12 Week 24
Log reduction in HBV DNA 4.05 4.64
HBV DNA < 4700 copies/mL 59% 82%
HBV DNA < 400 copies/mL 24% 59%
Normalization of ALT 47% 76%
HBeAg loss 12% 24%
ALT = alanine aminotransferase; HBeAg = hepatitis B e antigen
Marcellin and colleagues[11] reported the 144-week data in a long-term study
of adefovir, 10 mg a day, in patients with HBeAg-positive chronic hepatitis
B. Eighty-four patients were followed through the 144 weeks. These patients
enjoyed increasing rates of HBeAg seroconversion (12% at 48 weeks, 29% at 96
weeks, and 43% at 144 weeks), HBV DNA suppression defined as < 1000
copies/mL (28% at 48 weeks, 45% at 96 weeks, and 56% at 144 weeks), and
normalization of ALT.
Other important findings included the low resistance rate at 144 weeks
(3.1%) and the absence of any renal dysfunction in patients followed through
the 144 weeks. This study shows that adefovir can be used safely for an
extended period of time with increasing efficacy. The most desired end point
of any treatment for HBeAg-positive chronic hepatitis B is e-antigen
seroconversion. Treatment with any noninterferon therapy should be continued
until this occurs. This study shows that although the rate of seroconversion
at 48 weeks is only 12%, the rate increases over time at a rate of 12% to
15% per year of therapy. It is conceivable that all of the treated patients
might eventually achieve seroconversion, assuming that resistance has not
developed. This is further support for the use of multidrug regimens to
prevent resistance while awaiting the development of seroconversion.
Combination Therapies for Chronic Hepatitis B
Up until this point, combination therapies for HBV have not been shown to
improve virologic response. Specific therapies that have been examined
include lamivudine + LdT (telbivudine) and adefovir + lamivudine. However,
in a study presented during this year's meeting, Lau and colleagues[12]
evaluated the efficacy of adefovir + emtricitabine. Thirty treatment-naive,
HBeAg-positive patients with serum ALT > 1.3 times the upper limit of normal
were randomized to either adefovir (10 mg a day) plus emtricitabine (200 mg
a day) or adefovir (10 mg a day) plus placebo for 48 weeks. Combination
therapy produced a median log10 reduction of 3.14 vs 2.16 for adefovir alone
(P = .004) at 24 weeks and 3.48 vs 2.22 (P = .036) at 48 weeks. There was no
difference in HBeAg seroconversion between the groups. Larger studies will
be required to determine whether there is a difference in seroconversion.
This was the first time that a combination therapy regimen showed improved
virologic response over monotherapy. It is important to keep in mind that
the primary benefit of combination therapy will likely not be an improved
virologic response, but rather a decreased rate of viral resistance.
There were a number of studies looking at the combination of pegylated
interferon* and lamivudine. Piratvisuth and colleagues[13] reported the
results from a study comparing pegylated interferon alfa-2a, 180 mcg/week,
plus lamivudine, 100 mg/day (n = 179), with pegylated interferon plus
placebo (n = 177), and lamivudine alone (n = 181) in HBeAg-negative chronic
hepatitis B. All groups received 48 weeks of treatment and were followed for
an additional 24 weeks. The results are shown in Table 2.
Table 2. Pegylated Interferon Alfa-2a ?Lamivudine vs Lamivudine Alone in
HBeAg-Negative Chronic Hepatitis B
Week 72 Peg IFN +
Placebo Peg IFN +
LAM LAM P Value (Peg IFN vs LAM/
Peg IFN + LAM vs LAM)
ALT normalization 59% 60% 44% .004/.003
HBV DNA < 20,000 copies/mL 43% 44% 29% .007/.003
HBsAg loss 4.00% 2.80% 0% .007
HBsAg seroconversion 3% 2% 0% .029
ALT = alanine aminotransferase; HBV = hepatitis B virus; HBeAg = hepatitis B
e antigen; Peg IFN = pegylated interferon; LAM = lamivudine; HBsAg =
hepatitis B surface antigen
Patients receiving pegylated interferon alfa-2a, with or without lamivudine,
had statistically better results for each of the measured end points than
those receiving lamivudine alone. The investigators also noted that the use
of pegylated interferon alfa-2a, with or without lamivudine, had on-therapy
ALT elevations and that there was a significant association between a marked
on-therapy elevation of the ALT (defined as an ALT level > 10 times the
upper limit of normal) and a sustained ALT normalization. These ALT
elevations were not associated with serious safety issues in the majority of
patients -- no patients experienced hepatic decompensation and no patient
was withdrawn from therapy. These data suggest that pegylated interferon
alfa-2a has efficacy in patients with HBeAg-negative chronic hepatitis B and
that the addition of lamivudine adds little benefit. No resistance data were
provided to indicate whether the combination therapy protected against the
development of lamivudine resistance.
The same study group examined predictors of response in these patients
(HBeAg-negative chronic hepatitis B).[14] They found that a low-baseline HBV
DNA and a high-baseline ALT level were predictive of response -- the exact
positive predictors described in patients with HBeAg-positive chronic
hepatitis. It was also found that patients with genotype D disease did
better with the combination of pegylated interferon alfa-2a and lamivudine
than with pegylated interferon alfa-2a alone -- a finding not seen with
genotypes B or C. However, the investigators cautioned that the small
numbers of subjects involved (with genotype D) make it necessary to confirm
these data.
Lau and colleagues[15] compared the efficacy of pegylated interferon alfa-2a
180 mcg/week plus lamivudine 100 mg/day (n = 271); pegylated interferon
alfa-2a (180 mcg/week) + placebo (n = 271); and lamivudine 100 mg/day (n =
272), in patients with HBeAg-positive chronic hepatitis B. The duration of
therapy was 48 weeks with a 24-week follow-up. The results are shown in
Table 3.
Table 3. Pegylated Interferon Alfa-2a ?Lamivudine vs Lamivudine in
HBeAg-Positive Chronic Hepatitis B
End Points Peg-IFN +
LAM Peg-IFN +
Placebo LAM P Value (Peg-IFN + LAM vs LAM/
Peg-IFN vs LAM)
ALT normalization 39% 41% 28% .006/.002
HBV DNA <
100,000 copies/mL 34% 32% 22% .003/.012
HBeAg seroconversion 27% 32% 19% .023/< .001
ALT = alanine aminotransferase; HBV = hepatitis B virus; HBeAg = hepatitis B
e antigen; Peg-IFN = pegylated interferon; LAM = lamivudine
The use of pegylated interferon for 48 weeks provided excellent results in
this group of HBeAg-positive chronic hepatitis B patients, and was well
tolerated. The 48-week duration is longer than the 16- to 24-week duration
typically used with standard interferon alfa-2a and -2b. Lamivudine added no
additional benefit. No resistance data were provided.
Janssen and colleagues[16] studied the combination of pegylated interferon
alfa-2b (100 mcg/week for 32 weeks, then 50 mcg/week for 20 weeks) in
combination with lamivudine 100 mg/day (n = 130) or placebo (n = 136) in
HBeAg-positive chronic hepatitis B. Patients were followed for an additional
26 weeks of treatment. Seven percent of patients treated with pegylated
interferon, with or without lamivudine, were HBsAg-negative at the end of
follow-up. Patients with genotype A disease were most likely to have HBsAg
loss (14%), whereas those who were genotype D were least likely to achieve
HBsAg loss (2%). None of the patients, including those with viral genotype
D, seemed to derive any benefit from the combination of pegylated interferon
and ribavirin. No resistance data were provided.
On the basis of these studies, pegylated interferon looks promising in both
HBeAg-positive and HBeAg-negative chronic hepatitis B, particularly for
those patients with low-baseline HBV DNA and high-baseline ALT levels. The
optimal duration of treatment appears to be at least 1 year, particularly in
the HBeAg-negative patients. Lamivudine appears to add no benefit, except
perhaps in the subset of patients with genotype D disease -- but this
finding will require confirmation.
Drug Resistance in Hepatitis B
HBV resistance to lamivudine occurs at a rate of 15% to 20% per year of use.
There are 4 well-described, major mutational patterns that confer
resistance: L180M + M240V (seen in about 60% of patients), V173L + L180M +
M204V, M204I, and L180M + M204I.[17] All of these patterns include either
M240V or M204I, the mutations that affect the YMDD site. All confer high
levels of resistance to lamivudine.
Delaney and colleagues[17] aimed to look at the cross-resistance profiles of
various anti-HBV agents against each of the 4 lamivudine-resistant
mutational patterns. The investigators did this by producing cell lines that
expressed wild-type or lamivudine-resistant HBV variants. The anti-HBV
compounds tested included the L-nucleosides (lamivudine, emtricitabine,*
telbivudine,* L-dC,* L-dA,* and clevudine*), the acyclic phosphonate
nucleotides (adefovir, tenofovir,* and alamifovir*), entecavir,* and DXG*
(dioxolane guanosine). All of the patterns of lamivudine resistance
conferred a high degree of resistance to all of the L-nucleosides. The
acyclic phosphonate nucleotides all maintained efficacy against all of the
mutational patterns. Entecavir and DXG fell in between, with varying levels
of resistance. This study suggests that in the presence of lamivudine
resistance, none of the L-nucleosides will be effective in suppressing
viremia. The acyclic phosphonate nucleotides will maintain their efficacy in
the presence of lamivudine resistance. Entecavir is an interesting story.
Although the lamivudine mutations all had resistance to entecavir in vitro,
entecavir effectively suppressed viremia in a phase 3 study of this drug in
lamivudine refractory, HBeAg-positive patients.[18]
Compared with lamivudine, adefovir resistance occurs in only a small
percentage of patients (about 3% to 4% at 3 years). Two mutations have been
identified in the reverse transcriptase of patients with adefovir
resistance -- A181V and N236T.[19] Locarnini and colleagues[20] aimed to
further characterize the effects of these mutations with an in vitro assay.
Using site-directed mutagenesis, they produced mutant HBV constructs with
the A181V and N236T mutations in both wild-type HBV and in precore mutant
HBV, transduced into HepG2 cells, and then exposed them to different
concentrations of lamivudine, adefovir, and tenofovir to assess their
resistance profiles. The investigators found that the mutations that
conferred resistance to adefovir caused only small decreases in drug
sensitivity. Unlike the rapid and complete breakthrough seen with
lamivudine, there is a slow rise in the HBV DNA in patients who develop
adefovir resistance, something described nicely by Dr. Locarnini during the
presentation of this study as "virologic creep." The reason for the "creep"
is explained by the small decreases in drug sensitivity to adefovir seen
with either of the described mutations, in contrast to the dramatic decrease
in sensitivity seen with the YMDD mutants in lamivudine-resistant patients.
It is important and reassuring to note that mutants associated with adefovir
resistance remain relatively sensitive to lamivudine (and presumably all
L-nucleosides) and tenofovir.
Entecavir has demonstrated efficacy in the treatment of "naive HBV" and in
lamivudine-refractory HBV. In a phase 2 trial of entecavir, 2 patients
developed virologic rebound. Two groups studied these patients to better
understand the mutations involved.[21,22] Two classes of entecavir
resistance were seen: M250V and T184G + S202I. Of interest, the entecavir
resistance only developed in patients with pre-existing lamivudine-resistant
mutations. During his presentation of his study results, Dr. Tenney[22]
reported that a small percentage of patients previously naive to all
therapies and on entecavir preselected for the lamivudine-resistant
mutations, even in the absence of prior treatment with lamivudine.
What are we to make of these findings? Resistance has been reported with
every new HBV therapy except pegylated interferon. The lesson to be learned
is that monotherapy with any of the noninterferon agents runs the risk of
producing viral resistance, particularly in those patients who will require
long-term therapy. If a single agent will be used, it should not be
lamivudine, given the high likelihood of resistance developing rapidly and
the possibility that lamivudine resistance may predispose to the development
of entecavir resistance.
Concluding Remarks
The management of hepatitis B will continue to be a challenge. The risk of
disease progression and HCC can be tied to the serum viral load, making it
easy to identify those patients at greatest risk. What should be done for
these patients remains a point of controversy. The availability of newer
agents (lamivudine) has made it possible to decrease the risk of perinatal
transmission of HBV in those women at greatest risk for passing on the
disease. Newer agents that are moving through the evaluation pipeline
(entecavir and clevudine) will be welcome additions to our growing anti-HBV
armamentarium. The long-term data on adefovir are quite promising: There is
increasing efficacy with low resistance and good safety data. Pegylated
interferon, both alfa-2a and alfa-2b, are proving to be more effective
therapies for hepatitis B than their nonpegylated predecessors, and there is
no risk of developing viral resistance. They appear most beneficial in
patients with a baseline elevated ALT and low HBV DNA. The duration of
treatment should be at least 1 year in both HBeAg-positive and
HBeAg-negative patients. Lamivudine has not been shown to provide any
additive benefit to pegylated interferon. Viral resistance is a growing
problem, and the specific mutations that have been reported have been fully
categorized. We now need to find a way to prevent resistance from
developing. The role of combination therapy, even at the onset of treatment,
needs to be further investigated.
*The US Food and Drug Administration has not approved this medication for
this use.
This program was supported by an independent educational grant from Gilead.
[此贴子已经被特深沉于2005-2-16 19:56:43编辑过] |
|