HBVDNA作为评价慢性乙肝的主要研究终点时机尚不成熟

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HBVDNA作为评价慢性乙肝的主要研究终点（研究药物的有效标准）时机尚不成熟

　　在HEPATOLOGY最新一期上发表了一篇文章，作者Mommeja-Marin对26篇核苷类似物和干扰素的研究结果进行了分析，认为HBV-DNA病毒载量变化与组织学积分 等级、生化学反应间存在着有统计学意义的一致联系。因此可以作为乙肝治疗的主要研究终点，抗乙肝的主要治疗目的是要持续抑制病毒。知名肝病专家Alfredo Alberti发表了自己的观点：

　　慢性乙肝的最终治疗目标是预防肝硬化和合并症的发生，预防肝癌和乙肝相关死亡。但在临床试验中，使用上述标准不现实，因此需要“替代”的指标作为 研究终点。但提出恰当的指标并不容易，因为该指标需要反映出真实的疾病严重程度。在2000年NIH组织的乙肝工作会议和2002年乙肝EASL共识会议上对病毒学、 生化学、组织学和综合反应均做了定义，但未提出何为最合适的主要研究终点。

　　Mommeja-Marin等人的研究中将抗病毒治疗后的HBVDNA水平变化与肝组织学的改变作了回归分析，认为有很好的相关性，但得出这样的结果有以下漏洞：

　　1、作者采用的HBVDNA定量结果均是平均值或中位值，不能代表个体；
　　2、26项研究中的HBVDNA的检测方法不统一；
　　3、有些研究中采用的是联合干扰素和拉米夫定的研究结果，不能代表单个药物的结果；
　　4、乙肝病毒复制活性并不是肝脏损害的主要原因，并没有直接的相关；
　　5、HBVDNA下降至105/ml以下和HAI积分下降2分以上并未公认为是反映病毒学和组织学反应的理想标准；

　　Alberti总结HBVDNAPCR定量检测是临床上判断和比较抗病毒药物疗效的有用工具，但作为乙肝主要研究终点尚不成熟。在以后的临床试验中，应采用积极的 治疗手段作为对照组，应用综合的反应标准（病毒学和生化学反应）评价疗效，而且应当评价停药后的持续疗效。  

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此为附件：
Can Serum HBV-DNA Be Used as a Primary End Point to Assess Efficacy of New reatments for Chronic Hepatitis B?

See Article in HEPATOLOGY 2003;37:1309-1319

Therapy of chronic hepatitis B virus (HBV) infection is rapidly evolving.1 Three drugs have been approved for this disease, and include interferon (IFN) alfa, available since the early 1980s; lamivudine, a nucleoside analog introduced in the late 1990s; and the most recently approved adefovir, a nucleotide analog with efficacy similar to lamivudine but with a more favorable resistance .
治疗慢性传染性乙肝的研究被迅速开展，三种药物被批准用于治疗这个疾病，包括：20世纪80年代早期批准的ａ干扰素，20世纪90年代末批准的核柑类似物拉米夫定，以及近期被批准的阿德福韦，一种核柑类似物功效类同拉米夫定但是具有更良好的抗病毒能力。


A number of other compounds are currently investigated in phase II/III clinical trials. Most are nucleos(t)ide analogs and include emtricitabine, clevudine, entecavir, beta-1 L-nucleoside, and other molecules.
一些其他的药物正在研究，二三期临床，多数都是核柑类似物，包括：emtricitabine, clevudine, entecavir(恩替卡韦), beta-1 L-nucleoside, 以及其他核柑类药物。.

Other studies are assessing different ways of combining anti-HBV therapies (IFN and PEG-IFN plus lamivudine or adefovir, lamivudine plus adefovir, other nucleos(t)ide analogs combinations) with the hope of improving the limited efficacy of onotherapy.
其他一些学者正在采用不同的方式组合进行抗hbv治疗（干扰素和长效干扰素+拉米夫定或阿德福韦，拉米夫定+阿德福韦，其他核柑类似物结合使用）

Faced with this expanding armamentarium of potentially useful treatments, there is the need to identify parameters that accurately reflect their clinical efficacy.

面对这些庞大的潜在的有效治疗方法，需要鉴别参数为了精确的反映他们的临床效果。


The final goal of therapy in chronic hepatitis B is to prevent cirrhosis and its complication, hepatocellular carcinoma, and HBV-related death.
In clinical trials, it is unrealistic to assess for these 搕rue?end points due to the slow course of initially compensated chronic hepatitis B. Therefore, 搒urrogate?
end points need to be used. However, identi-fication of surrogates that adequately describe clinically significant events is not an easy task in chronic hepatitis B, due to the great virologic and clinical heterogeneity of the disease, its complex athogenesis, and the type of response obtainable with therapy in most patients, i.e., short-term
suppression rather than complete eradication of HBV.

The difficulties and uncertainties in proposing a well-
Abbreviations: HBV, hepatitis B virus; IFN, interferon; HAI, histologic activity
index; HBeAg, hepatitis B e antigen; ALT, alanine aminotransferase.
From the Department of Clinical and Experimental Medicine, University of
Padova and Venetian Institute of Molecular Medicine, Padova, Italy.
Address reprint requests to: Alfredo Alberti, M.D., Department of Clinical and
Experimental Medicine, University of Padova, Via Giustiniani 2, 35121 Padova,
Italy. E-mail: [email protected]; fax: (39) 049-8211826.
Copyright ?2003 by the American Association for the Study of Liver Diseases.
0270-9139/03/3801-0004$30.00/0
defined parameter/time point as gold standard of response
to antiviral therapy in chronic hepatitis B are reflected by
the conclusions of the 2000 HBV Workshop organized
by the National Institutes of Health4 and of the 2002
European Consensus Conference on Hepatitis B.5 These
documents describe a number of types (virologic, biochemical,
histologic, composite) and time points (early,
end-of-therapy, maintained during long-term therapy,
sustained after therapy) of response to be considered without
indicating a specific type/time point to be adopted as
a primary efficacy end point.
In recent registration trials of nucleos(t)ide analogs,
2,3,6,7 liver histology, defined as a decrease in histologic
activity index (HAI) by 2 or more points with no
worsening of fibrosis score, was adopted as the primary
efficacy end point. This approach, however, has a number
of limitations: (1) it requires an invasive procedure, to be
performed twice, with the potential for bias when the
percent of patients agreeing to a repeat biopsy is low; (2) it
uses a poorly standardized semiquantitative assessment of
a noncontinuous variable such as HAI; (3) it implies the
unproven assumption that an HAI reduction of 2 points
or more is clinically relevant and that improvement in
liver histology after a certain duration (usually 1 year) of
therapy can be maintained if treatment is stopped; (4) it
does not allow early prediction of response; and (5) it is
unsuitable in every day clinical practice.
Recently, highly sensitive polymerase chain reaction?
based methods that measure serum HBV-DNA levels
with a wide dynamic range have become available and can
now be used to precisely assess and compare the potency
of different anti-HBV treatments in suppressing HBV
replication.8-10 Since improvement of liver disease with
antiviral therapies is thought to depend on suppression of
HBV replication, can we consider serum HBV-DNA
measurement a surrogate of clinically significant events
and use it as a primary end point of efficacy in clinical
trials, as in the case of antiviral therapy for chronic hepatitis
C? The use of virologic end points is fully justified in
hepatitis C based on the high (
50%) rate of virus eradication
that can be obtained with therapy,11-12 the demonstration
that virus eradication can be accurately
predicted by HCV-RNA testing at well-defined time
points during therapy,13 the very high (
95%) rate of doi:10.1053/jhep.2003.50280
18
HEPATOLOGY, Vol. 38, No. 1, 2003
durability of sustained response, and the correlation between
sustained virologic response and improvement in
long-term clinical outcomes. Unfortunately, this is not
the case with hepatitis B. All types of anti-HBV treatments
evaluated so far have resulted in long-term virus
suppression with a finite course only in a small minority of
patients. Virus eradication is rarely if ever achieved as the
vast majority of patients remain hepatitis B surface antigen
positive. Most cases need prolonged therapy to suppress
liver disease activity and progression. Unfortunately,
an initial response can be lost with time if drug resistance
develops. If the virus cannot be completely eliminated,
the question is to which levels and for how long its replication
should be suppressed to ensure a significant benefit
on clinical outcomes.
To propose HBV-DNA measurement as a primary end
point of response to anti-HBV therapies, several criteria
need to be fulfilled: (1) serum HBV-DNA changes should
correlate with the end points for which surrogacy (i.e.,
improvement in clinical outcome) is proposed; (2) the
extent and timing of 揷linically significant?HBV-DNA
suppression should be precisely defined; and (3) HBVDNAchanges
should predict changes in 搕rue?end points
at the individual patient level, as assessed by the 損ercent
of effect explained.?Last but not least, HBV-DNA quantitative
assays should be standardized as in the case of
HCV-RNA assays. Unfortunately, most of these issues
have not been yet solved.
In the previous issue of HEPATOLOGY, Mommeja-
Marin et al.14 addressed the question on whether changes
in serum HBV-DNA during antiviral therapies reflect
changes in liver disease activity. The investigators have
considered median (or mean) HBV-DNA levels observed
in untreated patients and median (or mean) HBV-DNA
changes seen during antiviral treatment, as derived from
26 published studies, and have correlated them by regression
analysis with the corresponding median (or mean)
levels and changes in HAI scores. By doing this, statistically
significant correlations between HBV-DNA levels
and histologic activity in the absence of treatment and
between HBV-DNA changes and histologic improvement
during therapy could be shown. Can we conclude
from these data that measurement of serum HBV-DNA is
indeed a surrogate of disease activity and, more importantly,
of disease improvement during therapy? The results
of Mommeja-Marin et al. provide some positive
evidence but certainly not a definitive answer in favor of
this. A major reservation about this study must be in the
use of median (or mean) values instead of individual patient
data. Also, many different HBV-DNA assays were
used in the studies analyzed, these assays were not stan-
19 ALBERTI
dardized, values at critical time points were missing in
some studies, and quantitative values were not available in
many. Besides, the investigators combined IFN and nucleoside
trials, but the effects of these drugs on virus suppression
and histologic improvement may not be
comparable considering their different mechanisms of action.
More importantly, the finding of a correlation, although
statistically significant, does not prove true
surrogacy. The demonstration in Mommeja-Marin抯 article
that HBV-DNA levels correlate with histologic activity
in a linear fashion is an example of the potential bias
of the methodology adopted. It is well known thatHBVis
not directly cytopathic and that liver disease is largely
mediated by the host immune response.15 Some degree of
HBV replication is therefore necessary but not sufficient
per se to induce liver damage, and the existence of hepatitis
B e antigen (HBeAg) carriers with extremely high viremia
but minimal liver disease is well recognized.16 Even the
existence of a universal cutoff level of viremia below which
an active and progressive disease could be excluded is
unlikely considering the great variability and frequent
wide fluctuations of HBV-DNA seen in different patient
subgroups, i.e., HBeAg positive versus HBeAg negative,17
mild versus advanced disease, immunocompetent versus
immunocompromised. A cutoff level of 105 copies/mL
was proposed by the 2000 HBV NIH Workshop to discriminate
active and progressive from inactive or mild
forms of chronic HBV infection, but this value is not yet
validated and cannot be used on its own to establish liver
disease status and to decide treatment.
With regard to serum HBV-DNA measurement during
therapy, its implementation as the primary surrogate
end point of response should require not only proof that
HBV-DNA changes correlate with histologic improvement,
but also, and more importantly, proof that they
explain histologic improvement in a large proportion of
patients. Also, a 2 points or higher reduction in the HAI
score might not be the ideal target as its reflection on
disease activity and progression may vary depending on
the pretreatment grade and stage of disease. Furthermore,
suppression of HBV-DNA must be sustained during extended
therapy and more importantly after treatment is
withdrawn.
In future clinical trials, when active treatment rather
than placebo will be used as control, and more importantly,
in clinical practice, it might be more appropriate to
use composite (virologic and biochemical) end points to
assess response: in initially HBeAg-positive cases, in clinical
practice, therapy could be stopped 3 to 4months after
anti-HBe seroconversion with normal alanine aminotransferase
(ALT) levels, whereas in clinical trials the end
ALBERTI 20
point could be stable anti-HBe seroconversion with
HBV-DNA suppression and ALT normalization, and
this should be sustained for a certain period (6 months?)
after therapy withdrawal. In this respect it will be important
to define whether a given HBV-DNA change (log
reduction) or absolute level during therapy could predict
durable response. In the absence of anti-HBe seroconversion
and in initially HBeAg-negative cases, the extent and
durability of HBV-DNA suppression with normal ALT
levels in the absence of breakthrough or/and resistance
would be important, and the end point to be assessed
could be maintenance of such a profile at given time
points during prolonged therapy and after its withdrawal.
Also in these cases it will be important to determine if
early viral kinetics will predict the durability of a composite
response.
In conclusion, while serum HBV-DNA measurement
by polymerase chain reaction朾ased assays is already a
most useful tool to assess and compare the antiviral potency
of different anti-HBV compounds and strategies, to
monitor the virologic response in individual treated patients,
and to identify cases with a reduced response or
emergence of drug resistance, its implementation as the
primary surrogate end point of efficacy in the assessment
of new anti-HBV therapies appears premature.
ALFREDO ALBERTI, M.D.
Department of Clinical and Experimental Medicine
University of Padova
Venetian Institute of Molecular Medicine
Padova, Italy


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