HBV治疗的进展(55届美国肝病学会年会)(已翻译）

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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]

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Copyright ?2004 Medscape.

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特深沉

HBV治疗的进展(55届美国肝病学会年会) 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

范围包括：第55届美国肝病研究会年会

Developments in the Management of Hepatitis B Daniel Pratt, MD 乙肝控制的进展

Introduction

导言 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.

乙肝病毒是世界上主要的健康问题。估计有3.5亿~4亿人慢性感染。慢性乙肝患者肝硬

化，晚期肝病，和发展成肝癌的风险逐渐增大，包括无症状患者。

从80年代中期开始，干扰素被用来治疗HBV,并取得有限结果。长效干扰素的效果现在

被积极的评价。核苷和核苷类似物的发展和应用很大程度上改变了慢性HBV患者的治

疗。不幸的是，这些药品使用的增加，特别是单独治疗，产生了病毒耐药变异，与治疗

HIV的情况非常相似。研究人员希望确定这些变异，并考察联合治疗对病毒相应的改进，

减少病毒耐药。

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.

本报告回顾了一些主要的HBV相关临床研究，这些研究结果都在本次年会上公布。

Hepatitis B and the Risk of Developing HCC

乙肝和发展成肝癌的风险

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.

众所周知，HBeAg 阳性的HBV患者，有更大的风险发展成肝病和肝癌。这意味着，（虽

然并不明显），HBV病毒载量和和疾病进程、肝癌风险是相互关联的。陈和他的同事们

在他们10年的研究中关注此问题. 3464名HBV表面抗原阳性在1992~93年开始记录

他们的预后情况. 10年以后, 2354患者因没有足够的肝功基准，或没有足够得跟踪资料

而无法统计死亡率。1681名患者有足够的基准肝功纪录，并愿意重新接受身体检查，实

验室检查，肝B超检查。所有患者按起始时候的病毒载量不同分成3组：

低于检测标准 (< 1.6 x 103 copies/mL),

低浓度 (< 105 copies/mL but >/= 1.6 x 103 copies/mL),

高浓度 (>/= 105 copies/mL)

肝病表现分成正常，轻微，中等，严重（依据Dionysos 标准）。肝癌诊断标准是：B超

检查块状物大于2cm，甲胎蛋白水平> 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.

这些患者中，起始时候高病毒浓度组，相比其他组，统计中发现明显高的肝病死亡率和

肝癌发生。虽然还没有达到统计学上的显著，低病毒载量也发现，死亡率和肝病发展，

肝癌，同病毒载量低于检测标准组相比，风险更高。

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.

该研究潜在的重要暗示了慢性HBV患者的控制。有个关于免疫耐受阶段的患者（即患

者有高HBV DNA水平，转氨酶正常，肝活组织检查没有或很少坏死）是否要接受治疗

的争论。关于此争论，陈及同事的研究提供了更多的砝码，可能这些患者会从治疗中得

到更多好处；并提示需要设计新的试验，考察这个特殊的问题。这项研究的最后指出，

肝炎进程和肝癌发生，需要很多年时间评估，需要招募更多患者参加。另外，该研究需

要用不同的抗病毒药物来阻止病毒的耐药。希望类似陈及其同事这样的研究，能推动这

些方面的研究调查。

Prevention of Hepatitis B

预防乙肝

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.

使用被动或主动免疫来减少乙肝的垂直感染是在临床实践中广为接受的。出生时刻注射乙肝

免疫球蛋白(HBIg), 联合3针重组乙肝疫苗（出生6个月中），被证明有95%的效能阻止垂直

感染发生。然而，发生垂直感染的风险随母亲病毒载量的增加而增加。一些有高病毒载量的

母亲（HBV DNA >/= 1.2 x 109 copies/mL）， 风险高达28% 。情况表明，如果出生时刻，母

亲的病毒载量能够减少，垂直感染的风险可能被降低。这正是徐及其同事在中国及菲律宾考

察的结果。这项考察是结构适当，多中心，随机，双盲，安慰剂控制下的研究。

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.

慢性乙肝感染(HBsAg-positive)并有高病毒载量的母亲（血清HBV DNA > 1000 mEq/mL） 被

招募参加研究。114名母亲完成了研究；56名母亲接受了拉米夫丁，每天100mg, 开始于怀

孕32周，持续到分娩后4周。对照组59名母亲使用安慰剂。所有婴儿接受标准的预防措施

（出生24小时内注射免疫球蛋白，出生6个月内注射3针重组HBV疫苗）。

第一个终止点是婴儿在1年内出现乙肝表面抗原阳性；第2个终止点是婴儿1年内乙肝表面

抗体阳性，或HBV DNA阳性。

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.

不出意料，接受拉米夫定治疗的母亲大多（98%）都减少了病毒载量到< 1000 mEq/mL，对照

组（31）。这些病毒载量的减少转变为改善了婴儿的结果。这可能降低了婴儿在1年内乙肝表

面抗原阳性率(18% vs 39%; P = .014)，或viremic (20% vs 46%; P = .003)。婴儿还有更多机会

在1年内表面抗体阳性(84% vs 61%; P = .008)。接受治疗组和对照组母亲和婴儿没有发现其他

不利方面的差异。

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.

虽然该研究有部分患者退出，但并不影响强烈地提示出，对高病毒载量的母亲，在怀孕3个

月后使用拉米夫定治疗，是减少垂直感染风险的有效手段，超过了被动免疫和主动免疫达到

的效果。另外，该治疗对母亲和婴儿都是安全的。在我们等待进一步试验的时候，拉米夫定

可以考虑在怀孕3个月，慢性HBV感染，高病毒载量，传染婴儿风险高的母亲身上使用。

特深沉

New and Old Therapies for Hepatitis B

新/旧 乙肝治疗方法

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. ose

恩地卡为，一种 2’-脱氧肌苷酸碳环类似物， 是有效的，选择性的抑制HBV聚合酶。Rosmawati

及其同事报告了恩第卡为3期临床结果。（5mg恩地卡为/天，对照100mg拉米夫定/天）。HbeAg

阳性慢性HBV患者使用48周。研究人员特别关注那些初始转氨酶(ALT)水平低（<正常水平

2.6倍）的患者。这样关注的原因是，先前的2期临床试验提示，恩地卡为可以在低ALT基

准水平的患者身上与高ALT水平同样有效。对此感兴趣是因为ALT正常或接近正常的患者

使用干扰素或拉米夫定的效果不如高ALT的患者好。该研究者没有解释为什么门槛值设定为

ALT最高为正常值的2.6倍。

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.

ALT低于正常值2.6倍的患者，恩地卡为48周内产生了平均HBV DNA水平减少6.79个数

量级，对照拉米夫定减少4.85数量级(P < .0001)。在那些ALT水平大于2.6倍正常值的患者

里，恩地卡为48周内产生了HBV DNA平均7.18个数量级的降低，对照的拉米夫定是6.15

个数量级(P < .0001)。恩地卡为大多可以在48周内将HBV DNA 降低到< 400 copies/mL水平

（链式聚合酶反应测定）。没有提供关于HbeAg减少或血清转换的数据。

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.

在1/2期临床试验中，克拉夫定，一种L-核苷，在12周实验中显示有抗HBV能力。Lee及

其同事考察了克拉夫定的安全性和抗病毒活性。30mg/天，21名HbeAg阳性患者，超过24

周，韩国，7个地点。结果显示在表1种，表明克拉夫定有很好的抗HBV活性，24周比12

周显著变好。没有病毒突变报道。

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%

表1 病毒抑制和ALT正常化

结束点…………………………………….….….12周………………………24周

HBV DNA降低数量级………………………….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.

Marcellin及其同事报告了144周阿地福为的长期研究数据。10mg/天，84名 HbeAg阳性患者

使用，持续跟踪144周。这些患者享受到了逐渐增加的HbeAg血清转换率（48周12%，96

周29%，144周43%），HBV DNA被抑制（定义为< 1000 copies/Ml）（48周28%，96周45%，

144周56%），ALT变正常。

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.

其他重要发现包括144周后低的变异率（3.1%），在144周跟踪中，没有发现任何肾脏不良。

该研究显示阿地福为可以被安全的用于更长期的治疗，并带来更大效果。HbeAg患者最希望

得到的终点是e抗原血清转化。非干扰素治疗还在持续进行中。这项研究表明虽然48周血清

转换率只有12%，经过1年治疗可上升到15%. 可以相信所有治疗的患者最终都可达到血清

转换，假如没有发生耐药的话。这更加支持了使用多种药物疗法来阻止耐药发生，并等待血

清转换。

特深沉

Combination Therapies for Chronic Hepatitis B

慢性乙肝的联合治疗

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.

迄今为止，HBV的联合治疗还没有显示出病毒学上的效果。研究过的特别的治疗方法包括：

拉米夫定+LdT(太比夫定)，阿地福为+拉米夫定。然而，在本年会上发表的1项研究中，Lau

及其同事，评估了阿地福为+ emtricitabine的疗效。30名未经治疗过的HbeAg阳性患者，血

清ALT水平>1.3倍正常值，随机使用阿地福为（10mg/天）+ emtricitabine (200 mg /天)，或阿

地福为（10mg/天）+安慰剂，共48周。24周后，联合治疗组产生了中值3.14数量级的减少，

对照单独使用阿地福为2.16(P = .004)。48周结果为3.48vs2.22 (P = .036)

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.

两组中HbeAg血清转换没有差别。需要更多的研究来确定是否存在血清转换差别。这是联合

治疗首次在病毒学反应上显示出改善。重要的是要记住，联合治疗的好处不仅是病毒学反应

改善，而且减少了病毒的耐药性。

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.

有很多研究都联合使用长效干扰素和拉米夫定。Piratvisuth及其同事报告了他们的研究结果。

长效干扰素α-2a（180 mcg/周）+拉米夫定（100mg/天），179人；长效干扰素+安慰剂，177

人，单独拉米夫定，181人，均为HbeAg阴性慢性HBV。所有组都接受了48周的治疗，并

跟踪了24周。其结果见 [表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

[表2.] 长效干扰素α-2a+拉米夫定 vs 单独拉米夫定（ HbeAg阴性慢性HBV）

72周…………….…..长效干扰+安慰剂….…长效干扰+拉米……….拉米……..P值

ALT正常化…………..……….59%………………60%……………….44%…….004/.003

HBVDNA < 20000 co/Ml………43%…………….44%………………..29%……007/.003

HBsAg 减少………………….4.00%……………2.80%………………0%……..007

HbsAg血清转换………………..3%………………2%………………..0%………0.29

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.

接受长效干扰素α-2a的患者，无论有没有拉米夫定，统计结果都好于单独使用拉米夫定。研

究者还注意到使用长效干扰素α-2a，无论有没有拉米夫定，都有治疗相关的ALT上升，没

有明显关系,显示治疗中ALT显著上升（定义为超过正常值10倍）和持续ALT正常有关联。

这些ALT上升在大部分患者中没有关系到安全问题，没有患者表现出肝功不全，没有患者从

治疗中推出。这些数据显示，长效干扰素α-2a对HbeAg阴性的患者有效，附加的拉米夫定

好处微乎其微。没有提供耐药性数据来指示是否联合治疗防护了拉米耐药性。

特深沉

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.

同一科研组还考察了HbeAg患者的反应预期。他们发现低HBVDNA水平和高ALT基准水平

预示有治疗反应——准确标志着这样的HbeAg阳性患者有积极的治疗反应。他们还发现基因

型D的患者在长效干扰素和拉米联合治疗中的表现好于单独使用长效干扰素（该发现没有在

基因型B,C中看到）。然而，研究人员警告，基因D型样本数量小，还需要更多数据来确认。

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.

Lao及其同事比较了：

长效干扰素α-2a（180 mcg/周）+拉米夫定（100 mg/天）（271人）；

长效干扰素α-2a（180 mcg/周）+安慰剂 （271人）；

拉米夫定（100 mg/天）（272人）；

患者为HbeAg阳性。持续治疗48周，跟踪24周。结果见[表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

[表3.] 长效干扰素α-2a+拉米夫定 vs 拉米夫定 （HbeAg阳性患者）

结果……………………..…长效干扰+拉米……长效干扰+安慰剂……拉米………..P值

ALT正常化……………………39% ………………….41%…………… 28%…….. .006/.002

HBVDNA <100000cop/mL……34%……… ………….32%…………… 22%……. .003/.012

HbeAg血清转换………………. 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.

长效干扰素使用48周后，在HbeAg阳性患者中产生了卓越的结果，而且耐受良好。48周的

时间比标准干扰素α-2a，-2b的16周，24周要长。拉米夫定没有增加好处。没有提供耐药

数据。

小艾

真心感谢以上两位的工作。

特深沉

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.

Janssen及其同事研究了对比

长效干扰素α-2b(100 mcg/周持续32周，然后50mcg/周持续20周)+拉米100 mg/天，130人;

长效干扰素+安慰剂，136人；

患者为HbeAg阳性。患者随后后增加了26周治疗。7%使用干扰素的患者，无论有无拉米，

结束跟踪后发现HbsAg转阴。基因型A型的患者最容易HbsAg消失（14%）而基因型D的

患者只有2%。没有任何患者，包括基因型D的人，能从长效干扰+病毒唑联合治疗获益。没

有提供耐药数据。

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.

以上研究表明，长效干扰素看上去对HbsAg阳性和阴性的病人都有效，特别是对HBVDNA

水平低和ALT水平高的人。最佳治疗持续时间看来至少1年，特别是HbsAg阴性的患者。

拉米夫定似乎没有增加好处，除了也许在基因D型中——但此发现还需要确认。

特深沉

Drug Resistance in Hepatitis B

乙肝耐药性

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.

HBV对拉米夫定耐药发生率使用每年约有15~20%。有4种明确记录的，主要的变异模式获

得耐药：L180M + M240V（可见于60%患者中），V173L + L180M + M204V, M204I, 和L180M

+ M204I.所有这些模式都包括M240V 或M204I, 发生于YMDD区域的变异。全都获得对拉

米高水平的耐药。

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]

Delaney及其同事打算观察4种拉米耐药株针对不同抗病毒药物的交叉耐药性。研究人员通过

生产细胞线表达野生株或拉米耐药变种。抗HBV化合物测试包括：

L-核苷类（拉米夫定，emtricitabine,* telbivudine,* L-dC,* L-dA,* and clevudine*）；

无环核苷磷酸酯类(adefovir, tenofovir,* and alamifovir*),

恩地卡为，

DXG（鸟嘌呤核苷二氧戊烷）。

所有拉米耐药模式毒株都获得了对L-核苷类药物高度耐药性。无环核苷磷酸酯类全都可以继

续对所有变异模式有效。恩地卡为和DXG处在中间，对不同毒株有不同耐药水平。该研究

提示拉米耐药的出现，没有任何L-核苷药物能有效抑制病毒。无环核苷磷酸酯类会继续对拉

米耐药株有效果。恩地卡为是个有趣的话题。虽然拉米变异毒株在培养皿中都对恩地卡为耐

药，恩地卡为在3期临床试验中可以有效抑制拉米耐药毒株（针对HbeAg阳性患者）。

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.

与拉米相比，阿地福为耐药只在很小比例患者中发生（3年内3%~4%）。在阿地福为耐药的

患者里，检测到了2种逆转录酶变异模式——A181V 和 N236T。

Locarnini及其同事打算在培养皿试验中进一步描述该变异的效果。使用了变异点定向法，他

们在野生株和前C区变异株中产生了A181V 和 N236T变异HBV结构，并转导进HepG2细

胞，然后将之暴露在不同浓度的拉米夫定，阿地福为，特纳福为中，评估他们的耐药情况。研究人员发现，变异株所获得的阿地福为耐药只能微弱减少药物敏感度。

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.

不像使用拉米夫定看到的快速、完全猛涨，发生阿地福为耐药的患者，HBVDNA只有缓慢上

升，有一些被Dr. Locarnini在论文中精细地描述为“病毒学指标爬升”。“爬升”的原因是对

阿地福为药物敏感度的少量降低，而与拉米耐药的YMDD变异所发生的敏感度大幅降低相区

别。非常重要和让人舒心的要点是，阿地福为耐药相关的变异株，还保留对拉米夫定（大概

还包括所有L-核苷）及特纳福为的药物敏感。

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.

恩地卡为被证明在治疗“未经治疗的HBV”和拉米耐药的患者有效。恩地卡为的2期临床中，

2名患者发生病毒指标反弹。2个科研组通过研究这些患者，来更好理解变异的发生。发现了

两类恩地卡为耐药：M250V 和T184G + S202I。有趣的是，恩地卡为耐药只发生在已经存在

拉米耐药的患者中。在他发表的论文中，Dr. Tenney报告了很小比例的患者，以前没有接受

过任何治疗，在做恩地卡为实验前发现拉米耐药，甚至他们在过去从未接受过拉米治疗。

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.

我们怎么看待这些发现呢？除长效干扰素外，所有新HBV药物都发现了耐药。我们获得的

教训是非干扰素外的单一药物都有产生病毒耐药的风险，特别是需要长期治疗的患者。如果

使用一种单一药物，最好不是拉米夫定，因为很可能会快速产生耐药，而且拉米耐药株倾向

于产生恩地卡为耐药。