2006-8月-核苷类抗病毒药物综述-低科技等翻译

medline

2006-8月-核苷类抗病毒药物综述-低科技等翻译
--------------------------------------------------

2006年12月15日收到低科技短消息后补充， 将标题改为已翻译。

低科技的翻译在第10楼

我发的贴是来自Hepatology期刊的原文，目的是给病友参考。
我没有翻译，这一点非常不好。多谢ardejiang，草样年华谁精彩,
以及特别是低科技的翻译。

草样年华谁精彩说我是抄的:
我说明一下：你给的连结是抄我的， 他没有给出出处。
我是看到文献之后觉得不错贴出来的。我是 2006-8-31 5:38:32 发的首贴。
他是2006-9-3 0:11:32 转贴的。不过他是博克，可能是自己用的。也没什么。

我不图名，不图利，只是看到好文章希望能和大家分享一下。
如果大家能帮忙翻译我更愿意将看到的英文资料共享。

--------------------------------------------------

这是 Dr. Lok 写的评Tenofovir（临床试验中）的文章。
对其他核苷类抗病毒药物有较好的评点。
Dr. Lok 在各大药物公司研究资金，并且是顾问，所以本文可以看成广告。

文章比较有参考价值，但没排版，没时间翻译，先贴过来占个位。有空了再弄

 Hepatology. 2006 Aug;44(2):309-13

Potential conflict of interest: Dr. Lok receives research support and
serves on the advisory board of Roche, GlaxoSmithKline, Bristol Myers
Squibb, Idenix and Gilead.


Tenofovir disoproxil fumarate: Role in hepatitis B treatment
Stephen N. Wong, Anna S.F. Lok *§
Division of Gastroenterology, University of Michigan Medical School,


Article Text

The introduction of lamivudine ushered in a new era in the treatment
of chronic hepatitis B when safe, effective, and well-tolerated oral
medications were made available. Since then, two new nucleosid(t)e
analogs (NAs), adefovir and entecavir, have been approved for the
treatment of hepatitis B. In addition, two NAs approved for the
treatment of human immunodeficiency virus (HIV) infection,
emtricitabine and tenofovir disoproxil fumarate, also have activity
against hepatitis B virus (HBV). However, only a small percentage of
patients with chronic hepatitis B have sustained viral suppression
after a defined course of NA therapy. Thus, long-term treatment is
required in most patients to maintain viral suppression.

Problems associated with long-term NA therapy include drug resistance,
side effects, cost, and compliance. Emergence of antiviral-resistant
HBV mutants can have major consequences including negation of initial
response, hepatitis flares and occasionally hepatic decompensation and
death, and potential cross-resistance with other NA.[1][2] Several
recent studies showed that rapid viral suppression decreases the risk
of antiviral resistance.[3-5] Therefore, the ideal NA for hepatitis B
should have potent antiviral activity against wild-type HBV and HBV
mutants resistant to currently approved therapies, high genetic
barrier to resistance, and excellent safety profile.


The availability of adefovir brought a lot of excitement because
initial studies showed that it was effective in suppressing wild-type
and lamivudine-resistant HBV and extensive sequence analysis did not
reveal any resistant mutations after 1 year of therapy.[6] However, it
was quickly evident that response to adefovir was inconsistent, with
as many as 50% of patients failing to achieve adequate viral
suppression, defined as <3.5 log10 copies/mL decrease in serum HBV DNA
compared to baseline after 1 year of treatment[7] or serum HBV DNA >4
log10 copies/mL after 6 months of treatment,[8] despite the absence of
adefovir-resistant mutations. The high proportion of patients with
poor initial response may be due to an inadequate dose of adefovir, as
the phase III clinical trial in HBeAg-positive patients clearly
demonstrated that the approved dose of 10 mg was less potent than the
30 mg dose.[9] Furthermore, resistant mutations to adefovir were
identified[10] and the rate of genotypic resistance was found to
increase with the duration of treatment.[11] In one study of 125
NA-naïve patients with HBeAg-negative chronic hepatitis B, the rate of
genotypic resistance to adefovir increased from none after year 1 to
29% after year 5.[12] Several recent studies reported rates of
adefovir resistance of 18% to 25% after 1-2 years of
treatment.[8][13][14] The higher rates of adefovir resistance in these
latter studies may be related to the inclusion of patients with prior
lamivudine resistance switched to adefovir monotherapy and the use of
more sensitive techniques to detect resistant mutations.

Entecavir is more potent than lamivudine in suppressing wild-type HBV.
Resistant mutants have not been detected after 2 years of treatment in
NA-naïve patients.[15-17] Although entecavir was approved for the
treatment of lamivudine-resistant HBV, in vitro studies showed that
its activity against lamivudine-resistant HBV is 6- to 10-fold lower
compared to wild-type HBV.[1][18] Thus, despite the use of a higher
dose (1 mg vs. 0.5 mg) of entecavir in the phase III trial on
lamivudine-refractory patients, 60% of patients still had HBV DNA
detectable by PCR after 96 weeks of treatment.[19] Entecavir-resistant
mutations were detected in 4.4% patients at the start of entecavir,
increasing to 12% at the end of year 2.[17] Furthermore, while
entecavir-resistant mutations alone decrease susceptibility to
entecavir by only 6- to 9-fold, the combined presence of lamivudine-
and entecavir-resistant mutations decrease susceptibility to entecavir
by more than 1,000-fold.[18] In addition, we recently demonstrated
that lamivudine-resistant HBV mutations were detected in all 20 clones
from a patient who developed entecavir resistance, up to 45 months
after lamivudine was stopped and treatment switched to entecavir
monotherapy.[20] Thus, while entecavir is a potent treatment for
NA-naïve patients, it is not an optimal treatment for patients with
lamivudine resistance.

Tenofovir Disoproxil Fumarate
Abstract        Adefovir        Entecavir       Tenofovir Disoproxil Fumarate   References

Tenofovir disoproxil fumarate, an acyclic nucleotide analog closely
related to adefovir has been approved for the treatment of HIV
infection. In vitro studies showed that it has activity against HBV
with equimolar potency as adefovir.[1]

Antiviral Activity Against HBV.

Clinical studies confirmed the efficacy of tenofovir in suppressing
HBV replication. Most of the studies were based on retrospective
analysis of small subsets of patients with HIV-HBV coinfection who
received tenofovir primarily for HIV infection.[21-25] Activity of
tenofovir was also observed in small case series of patients with HBV
monoinfection.[26-28] The vast majority of patients in these reports
had lamivudine-resistant HBV. Tenofovir resulted in a 4-6 log
reduction in serum HBV DNA level, and 30% to 100% of patients had HBV
DNA undetectable by PCR assay after more than 24 weeks treatment.
(Table 1) The in vivo antiviral activity of tenofovir appears to be
similar among patients with and without HIV coinfection.

Table 1. Summary of Studies With HBV DNA > 5 log10 Copies/mL at Start
of Tenofovir and With > 24 Weeks of Therapy
Study   n       HIV Co-Infection        HBeAg- Positive Prior
Non-Responder/Resistance to:    TDF Treatment Duration in Weeksa        HBV DNA
at TDF Start (Log10 Copies/mL)a HBV DNA Suppression (Log10
copies/mL)a     (-) HBV DNA by PCR at End of ff-up      HBeAg Seroconversion
LAM     LAM&ADV
van Bömmel[26]  20      0       19 (95) -       20 (100)        48 (16-96)      6.5 (4-9.3)     3.8
(1.4-6.7)       19 (95) 0/19
Schildgen[27]   3       0       2 (67)  -       3 (100) 75 (75-125)     7.7 (7.7-8.7)   6.2
(5.7-6.7)       3 (100) 0/2
Kuo[28] 9       0       9 (100)         9 (100) 48 (24-64)      8 (6.4-9)       4.5 (3.2-6.3)   7
(77.8)  2/9 (22.2)
van Bömmel[29]  35      21 (60) 31 (88.6)       35 (100)        -       (72-130)        9.4     5.5     35
(100)   11/31 (35)
Benhamou[25]    65      65 (100)        54 (83.1)       42 (64.6)       -       48 (32-68)b 40
(28-68)c        8.2 (7.3-8.3)b 4.8 (2.7-6.4)c   4.6 (3.3-5.6)b 2.5
(0.4-4.1)c      16 (29.6)b 6 (55.5)c    2/54 (3.7)
Lacombe[21]     28      28 (100)        24 (85.7)       18 (64.3)       -       74 (21-115)     7.5     4.6     21
(75)    4/24 (16.7)
Nunez[22]       12      12 (100)        9 (75)  7 (58.3)        -       34 (24-48)      6.6
(4.7-8.2)       3.8(0.7-5.7)    7 (58.3)        1/9 (11.1)
Dore[23]        15      15 (100)        14 (93.3)       6 (40)  -       48      8.6     4.5     NA      2/14 (14.3)
Stephan[24]     31      31 (100)        19 (61.3)       15 (48.4)       -       48      NA      5.4 (3.6-7)     22
(71)    1/19 (5.3)
 a Median (range).
 b Results presented separately for HBeAg-positive
  and
 c HBeAg-negative
  patients.
  Abbreviations: LAM, lamivudine; ADV, adefovir; TDF, tenofovir; PCR,
polymerase chain reaction-based assay (lower limit of detection = 2-3
log10 copies/mL).

Several clinical studies suggest that tenofovir results in more marked
suppression of HBV replication than does adefovir, possibly related to
the use of a higher dose: 300 mg vs. 10 mg. In a non-randomized study
of 53 patients with lamivudine-resistant HBV, serum HBV DNA decreased
by 5.5 vs. 2.8 log10 copies/mL after 48 weeks of tenofovir and
adefovir treatment, respectively.[29] In another study, 52 patients
with HIV-HBV coinfection - most of whom had prior lamivudine treatment
- were randomized to receive tenofovir vs. adefovir; the mean
time-weighted average change in serum HBV DNA from baseline to week 48
(DAVG48) for the two groups were -4.44 vs. -3.21 log10 copies/mL,
respectively.[30]

The higher potency of tenofovir 300 mg is highlighted by two reports
where viral rebound was documented when 4 patients who had suppression
of serum HBV DNA while receiving tenofovir for lamivudine-resistant
HBV were switched to adefovir 10 mg.[31][32]

In this issue of HEPATOLOGY, van Bommel et al.[26] report on their
experience in 20 patients with chronic HBV infection who were switched
to tenofovir monotherapy after a poor virological response (serum HBV
DNA <4 log10 copies/mL) to 4-28 months of adefovir monotherapy. All
patients had virologic breakthrough to lamivudine prior to switching
to adefovir monotherapy. No adefovir-resistant mutations were
identified at the start of tenofovir therapy. Serum HBV DNA decreased
by a median of 3.8 log10 copies/ml after 3-24 months (median 12) of
tenofovir treatment, and 19 (95%) patients had serum HBV DNA levels
undetectable by PCR assay. The only patient with persistently
detectable HBV DNA had dose reduction due to renal insufficiency.

Thus, accumulating evidence indicate that tenofovir 300 mg is more
potent than adefovir 10 mg in suppressing HBV replication. Data from
the ongoing phase III trials will confirm if this difference applies
to nucleoside-naïve HBV monoinfected patients, and whether it persists
beyond 1 year.

Tenofovir-resistance.

To date, there has only been one report of tenofovir-resistant
mutation, possibly related to the limited clinical experience thus far
and to the fact that most patients had concomitant administration of a
second antiviral (lamivudine or emtricitabine). It is possible that,
as with adefovir,[4][8] switching patients with lamivudine-resistant
HBV to tenofovir monotherapy may be associated with a higher
likelihood of tenofovir resistance. One study found rtA194T (alanine
to threonine substitution at codon 194) in conjunction with
lamivudine-resistant mutations in 2 of 43 (5%) HIV-HBV coinfected
patients who had persistently detectable HBV DNA levels despite 24
weeks of combination therapy of tenofovir and lamivudine.[33] The
A194T mutation was detected 48-77 weeks after initiation of tenofovir.
One patient had a hepatitis flare at the time A194T was first
detected. However, the hepatitis flare coincided with an increase in
CD4 cell count, and serum HBV DNA level remained suppressed. Serum HBV
DNA increased from 2.6 to 4.1 log10 copies/mL over the next 14 months
but aminotransferase levels remained normal. The other patient had
progressive decrease in serum HBV DNA and normal ALT levels after the
detection of A194T mutation. Transfection experiments showed that the
rtA194T mutation alone resulted in a 7.6-fold decrease in
susceptibility to tenofovir but in association with
lamivudine-resistant mutations led to a > 10-fold decrease in
susceptibility. The significance of the A194T mutation needs to be
confirmed as the 2 cases reported above do not represent the typical
clinical pattern seen in patients who develop antiviral-resistant
mutations, and surveillance for other tenofovir-resistant mutations
should be continued.

Adverse Events.

Long-term use of tenofovir is clouded by concerns regarding
nephrotoxicity. Several case reports have been published on the
occurrence of renal insufficiency and tubular dysfunction in patients
treated with tenofovir. In most instances, the renal problems resolved
after tenofovir was discontinued.[34-36] It is important to note that
all cases of tenofovir-related nephrotoxicity occurred in patients
with HIV infection who were receiving multiple medications, some of
which may be nephrotoxic or compete for renal tubular secretion of
tenofovir.[37][38] In addition, renal dysfunction and hypophosphatemia
are not uncommon in HIV patients.[39] One study showed that 31% of HIV
patients had hypophosphatemia at baseline, and this proportion did not
increase with tenofovir treatment.[35] Registration trials of
tenofovir for HIV infection and a large retrospective cohort analysis
showed that a decrease in creatinine clearance occurred in a small
proportion of patients (<1 to 4%) after 12-36 months of tenofovir
treatment.[40-42] In addition, most of the changes were mild and did
not result in the discontinuation of tenofovir.

Early studies on animals given much higher doses of tenofovir showed
adverse effects of tenofovir on the skeletal system. To date, the
effects appear to be non-progressive in humans and manifested only as
a mild decrease in bone mineral density.[41]

Role in HBV Treatment.

Among the antivirals currently undergoing phase 2 or phase 3 studies,
tenofovir appears to be the most promising. Accumulating evidence
suggest that tenofovir is more potent in suppressing HBV replication
than adefovir. Tenofovir appears to be equally effective against
wild-type and lamivudine-resistant HBV. With the widespread use of
lamivudine worldwide, and the development of compounds that select for
cross-resistant mutants (emtricitabine, telbivudine and clevudine), a
safe and effective rescue therapy that has potent and long-lasting
antiviral activity against lamivudine-resistant HBV is urgently
needed. Whether tenofovir will replace adefovir in the treatment of
hepatitis B will depend on the confirmation of superior antiviral
activity and comparable safety in the phase 3 trials of tenofovir in
hepatitis B patients. The role of tenofovir in the rapidly expanding
armamentarium of hepatitis B treatments will depend on the
demonstration of long-term safety (renal and skeletal), efficacy
against wild-type HBV and HBV mutants that involve substitution of
methionine within the tyrosine-methionine-aspartate-aspartate (YMDD)
motif (mutants resistant to lamivudine, emtricitabine, telbivudine, or
clevudine), and a very low rate of tenofovir resistance in NA-naïve as
well as NA-experienced patients.

[此贴子已经被作者于2006-12-16 13:54:14编辑过]

ardejiang

大意是新药 Tenofovir(替诺夫韦)相对其他核苷类药拉米夫定,还有恩第卡维,阿德副为脂,是最为有前景的抗病毒药物. 在抑制病毒复制方面有更大的潜力,且对野生株以及拉米变异株同时有效.替诺夫韦是否会取代阿德副为脂需等待三期临床在安全性(对肾和骨骼)和抗病毒活性(野生和YMDD变异)的研究.

duqingwu

谢谢2楼

ardejiang

不客气,我有一问题想请您帮忙.

可否知道在北京或上海哪家医院和哪位医生治疗胃癌较为在行.

谢谢

blazejiang

有时间我也来翻一翻

草样年华谁精彩

斑竹你也好意思直接把别人发的粘在这里

本文在此已有  http://www.xydiagnostics.com/6kbbs/show.asp?id=6874&bd=23&totable=1&bn=2

你说的和人家原话一样

草样年华谁精彩

偶正在努力翻译，一个下午翻译了1/7吧，先贴在这里一部分，可能因为专有名词的原因，翻译有不太正确的地方，请专家们见谅啊。

Tenofovir disoproxil fumarate（药名）: 在乙肝治疗中的作用

引进拉米夫定这一安全、有效、有较好耐受性的口服药剂，开创了慢性乙型肝炎治疗的新时代，此后，两种新核苷类药物：恩替卡维,阿德福维被认可用于治疗乙型肝炎。另外，两种用于治疗人类免疫缺陷病毒（HIV）感染的核苷类药物：恩曲他滨（emtricitabine）和泰诺福维（tenofovir disoproxil fumarate）同样对于治疗乙型肝炎有效。然而只有一小部分的慢性乙肝患者在接受核苷类疗法整个疗程之后能够持续抑制病毒，因此大多数患者需要依靠长期的治疗来保持对病毒的抑制。
伴随长期核苷类疗法而产生的问题包括：耐药性、副作用、费用以及依赖性。antiviral-resistant（抗滤过性病原体的）病毒突变体的出现会有以下主要的后果，包括：negation of initial response初始反应，  hepatitis flares肝炎加重，偶尔性的肝能损伤甚至死亡，以及使用其他核苷类似物时潜在的抗力转移。

几个最近的研究表明，快速的病毒抑制降低了抗病毒耐药性（antiviral resistance）的风险。因此，治疗乙型肝炎的理想化的核苷类似物，在治疗对于最近被许可的疗法有抵抗性的野生类hbv、病毒变异和高基因性的阻碍，有强有力的抗病毒效果。

……

阿德福维的出现给人们带来了极大的激动，早先的研究表明阿德福维对于抑制野生类以及耐拉米夫定病毒是有效的，大量的后果分析在1年的治疗后没有反映出任何的耐药性变异。[6]然而，很快研究发现对阿德福维的反应是不持续的，有多达50%的患者不能达到足够的病毒抑制水平，虽然不存在抗阿德福维的变异，治疗1年后明显表现为<3.5 log10 copies/mL，血清中HBVDNA转阴，[7]或是在6个月的治疗后血清中HBV DNA >4 log10 copies/mL。
最初反应不好的大部分患者可能是由于服用阿德福维剂量不够。对HbeAg阳性患者的临床试验第III阶段很明显的说明，一般采取的剂量10mg不如30mg有效。

另外，在治疗过程中，对阿德福维的耐药性变异得到了验证，基因型耐药的比率也随治疗而上升。

在一项对125位NA-naïve HbeAg阴性的慢性乙型肝炎患者的研究中，对阿德福维基因型耐药的比率从1年后的零上升到了5年后的29%。最近的几项研究得到的结果是，在1-2年的治疗之后，对阿德福维的耐药性为18%-25%。后面这些研究中对阿德福维耐药性的高比率可能与患者中包括之前采用拉米夫定产生耐药性，后又转到阿德福维单一疗法的人有关，还与使用更加敏感的方法来观测耐药性变异有关。

在抑制野生类病毒方面，恩替卡维比拉米夫定更加有效。在对NA-naïve患者两年的治疗后，没有检测出耐药性变异。

低科技

感兴趣，试着翻一下。望指正，望完善。

低科技

肝脏病学，2006年8月，44（2），309－23

可能的利益冲突：Dr. Lok 接受研究资助，并且在Roche，GlaxoSmithKline, Bristol Myers Squibb, Idenix 和 Gilead 的顾问团任职。

 

泰诺福韦酯：在乙肝治疗中的脚色

Stephen N. Wong, Anna S. F. Lok*

密西根大学医学院肠胃病学系

 

原文

拉米夫定的采用开创了慢性乙肝治疗的新纪元，有了安全、有效和具有良好耐受的口服药。 此后，此后有两种核苷类似物，阿德福韦和恩替卡韦，被批准用于乙肝治疗。另外，两种获准用于治疗人类免疫缺陷病毒（HIV）感染的核苷类似物，恩曲他滨和泰诺福韦酯，同样具有抗乙肝病毒活性。然而，经过一个核苷类似物疗法的规定的疗程后，只有很小部分的慢性乙肝患者获得持续的病毒抑制。因此，对大多数患者来说，为了维持病毒抑制，需要长期的治疗。

与长期核苷类似物疗法相关的问题包括：抗药、副作用、费用和顺从性。抗病毒耐药HBV突变株的出现可能具有严重的后果，这包括初始应答的否定、肝炎爆发和偶然性的肝失代偿和死亡，可能的与其他核苷类似物的交叉耐药性。[1][2]最近的几个研究表明迅速的病毒抑制能减小抗病毒耐药的风险。[3-5]因而，理想的治疗乙肝的核苷类似物，对野生型的HBV和对当前批准的治疗耐药的HBV变异株，应该具有有效的的抗病度活性、耐药的高基因屏障和极好的安全性。

阿德福韦的有效性很使人激动，因为初步的研究表明它在抑制野生型和拉米夫定抗药的HBV方面是有效的，并且大范围的序列分析没有发现一年的治疗后有任何的抗药突变。[6]然而，很明显，多达50％的患者对阿德福韦的应答缺乏一致性。尽管没有抗阿德福韦的变异株，这些患者也未能获得令人满意的的病毒抑制。这些患者，治疗一年以后，血清HBV DNA相对于基线下降<3.5log10 copies/ml [7],；或者治疗6个月后血清HBV DNA >4log10 copies/mL.[8]. 高比率的初始响应差的患者，可能是阿德福韦剂量不足造成的，因为在HbeAg阳性患者中进行的第三期临床试验清楚表明，被认可的10mg剂量不如30mg剂量有效。[9]此外，抗阿德福韦变异株已经确定, [10]并且发现基因型耐药的比率随治疗时间增长。[11]在一项对125位初次使用核苷类似物的HbeAg阴性的慢性乙肝患者的研究中，基因型耐药的发生，从一年内的0到第5年的29% 。[12]几个最近的研究报道，治疗1到2年后，阿德福韦的耐药比率是18%到25% 。[8][13][14]在这些近来研究中的高比率的阿德福韦耐药，可能与包含有拉米夫定耐药后转到单独阿德福韦治疗的患者有关，也可能与使用了更灵敏的检测耐药变异株的技术有关。

恩替卡韦抑制野生型HBV比拉米夫定有效。在初次使用核苷类似物的患者中，经过2年治疗后，没有检测到耐药变异株。[15-17]尽管恩替卡韦被批准用于拉米夫定耐药HBV，体外研究说明它抗拉米夫定耐药株HBV的活力是野生型HBV的1/6到1/10。[1][8]因而，在第三期临床试验中，对用拉米夫定难治的患者尽管使用了更高剂量（1mg相对0.5mg）的恩替卡韦，96周治疗后，仍有60%的患者被用PCP法检测出HBV DNA。[19]在4.4％的患者在开始恩替卡韦时检测到恩替卡韦耐药变异株，第2年年底，上升到12% 。此外，虽然恩替卡韦耐药株单独降低恩替卡韦的敏感性到1/6到1/9，合并出现的耐拉米夫定和恩替卡韦变异株把对恩替卡韦的敏感性下降到低于1/1000。[18]再者，我们最近证实耐拉米夫定变异株在一个恩替卡韦耐药患者的所有20个克隆中都被检测到。这个患者停拉米夫定长达45个月后后，换成恩替卡韦单独治疗，结果产生了恩替卡韦耐药。因而，虽然恩替卡韦是核苷类似物初治患者的有效疗法，但不是拉米夫定耐药患者的最佳疗法。