美国主流的HSK药物治疗方案----颠覆的是谁?


前几期的关于单疱病毒性角膜炎(HSK)的课件,相信大家对该病都已经熟悉。今天着重推出美国主流的HSK的治疗方案:从口服抗病毒药物治疗取代局部用药,从药物使用周期的变化,从局部用药处方的更改。。。。。这些方方面面的治疗变化,无不冲击着我们临床常用的治疗方案!!!

仔细阅读,肯定收获巨大。

Herpes Simplex Keratitis

MedicalTherapy药物治疗


The treatment of choice for manifestations associatedwith live virus is antiviral medications, whereas immunological reactions mustbe managed with corticosteroids . Each case of HSV keratitis is uniqueand must be managed in accordance with the evolving clinical course, withparticular attention to two factors: the presence of live virus, and thepresence of active immune-mediated disease. A guiding principle is that priorto the onset of immune-mediated disease, control and elimination of epithelialmanifestations is the highest priority. However, once immune-mediated diseasehas been established, management of stromal or endothelial manifestations, withtheir potential for irreversible visual impairment, has higher priority thancontrol of epithelial disease.

有活病毒的角膜炎,需要抗病毒治疗,而免疫性炎症则需要应用激素。每一例HSK角膜炎都是独一无二的,治疗需要与其病程特点相一致。

有两点需要特别注意:是否有活病毒,是否有活动性免疫介导反应。

一个基本原则是,在免疫介导启动之前,控制并治愈上皮病变是首要任务。然而,一旦免疫介导反应启动,基质或内皮病变可能带来不可逆视力损害,因此控制免疫反应的重要性,应该优于对上皮病变的控制。

Recommended Management推荐治疗

Epithelial上皮

Acyclovir 400 mg PO 5times daily x 21 days OR

阿昔洛韦,400mg,每天5次,PO,21天;或

Valacyclovir 500 mgPO 3 times daily x 21 days

伐昔洛韦,500mg,每天3次,PO,21天。

Consider debridement

上皮病灶刮除

Try to avoid topicalanti-viral therapy

尽量避免局部抗病毒治疗

Long-term oralanti-viral prophylaxis x 1 year if recurrent

如果系复发,长期口服抗病毒药物,以预防,时间为期一年。

Stromal基质

Appropriate steroidtherapy followed by slow taper

适宜的激素治疗,然后缓慢减量

Consider antiviralcoverage commensurate with steroid therapy

激素治疗时,予以相应的抗病毒

Long-term oralantiviral prophylaxis (1 year to indefinite)

长期口服抗病毒预防复发,一年或更长时间。


Endothelial内皮

Appropriate steroidtherapy followed by slow taper

适宜的激素治疗,然后缓慢减量

Consider antiviralcoverage commensurate with steroid therapy

激素治疗时,予以相应的抗病毒治疗

Long-term oralantiviral prophylaxis (1 year to indefinite)

长期口服抗病毒预防复发,一年或更长时间

Anterior chamber前房

Appropriate steroidtherapy followed by slow taper

适宜的激素治疗,然后缓慢减量

Strongly considerfull dose oral antiviral therapy

强烈建议足量抗病毒治疗

Long-term oralantiviral prophylaxis (1 year to indefinite)

长期抗病毒预防复发,一年或更长时间

Although HSV epithelial keratitis is self-limited inmost cases, the rationale for aggressive antiviral therapy is to preventcorneal nerve damage and potential future immunologic disease. Prior to theadvent of antiviral therapy, simple epithelial debridement was the treatment ofchoice. Later, topical antiviral therapy supplanted debridement. However,corneal toxicity related to the topical antivirals available in the UnitedStates led to a preference on the part of many specialists to rely exclusivelyon equally effective systemic therapy. Our preference is to use acyclovir 400mg PO five times daily or valacyclovir 1000 mg PO three times daily. We limituse of topical antiviral therapy to oral therapeutic failures. Although mostpractitioners prefer a short course of therapy, we treat our patients for atotal of 14 to 21 days to ensure complete eradication of replicating organisms.After successful treatment, therapy can be discontinued without tapering,unless long-term prophylaxis is used (see below; antiviral prophylaxis).

大多数HSV上皮角膜炎虽然可自愈,仍然需要积极的抗病毒治疗,这是因为避免角膜神经受损,以及蔓延至免疫性病变。

抗病毒药物问世之前,简单的上皮病灶刮除是唯一的治疗方法。后来,局部抗病毒治疗取代病灶刮除。

但是,美国市售的局部抗病毒药物带来的角膜毒性,让很多专家只选择效果相当的全身治疗方法。我们习惯用阿昔洛韦,400mg,每天5次口服,或者伐昔洛韦,1000mg,每天3次口服。对于口服治疗无效的病例,我们才予以局部抗病毒治疗。

虽然很多医生选择短期疗法,我们还是予以14~21天的疗程,确保复制的病毒被彻底清除。治疗奏效后,无需减量即可停药,除非需予以长期预防(见下,预防性抗病毒治疗)。

The treatment of choice for ISK, NSK, disciform(endothelial) keratitis, and keratouveitis is topical corticosteroids.Topical prednisolone acetate 1.0% or its equivalent should be administered in afrequency commensurate with that required to control the degree of inflammationthat is present. Our experience is that the optimal initial frequency is hourlyfor NSK, every two hours for ISK, and every three hours for disciformkeratitis. If concomitant epithelial disease is present, full systemicantiviral dosing is also required since steroid therapy exacerbates this condition.If epithelial disease is not present, systemic antiviral therapy is notmandatory, but is typically used by the majority of practitioners (see below;antiviral prophylaxis)

对于ISK、NSK、盘状角膜内皮炎和角膜葡萄膜炎,治疗以局部激素为主。局部予以1%醋酸强的松龙眼药水,或效力相似的激素眼药水,频度以能控制住炎症为宜。

我们的经验是,NSK病例以每小时一次开始,ISK每两小时一次,盘状角膜内皮炎每三小时一次。如果同时伴有上皮病变,则需要足量的全身抗病毒治疗,因为激素可能会加重上皮病变。如果未伴有上皮病变,全身抗病毒虽非必须,但是大多数医生都会选用(见下,预防性抗病毒)。

Whereas the decision to introduce antiviral and/orcorticosteroid therapy is relatively straightforward, tapering and/ordiscontinuation of these medications is quite complex and is the most commonsource of therapeutic setbacks in the management of the immune manifestationsof herpetic eye disease. Anti-inflammatory therapy should be maintained at theinitial dose until complete control of active inflammation has been achieved,after which the regimen should never be tapered by more than 50% at any onetime. Following each dosage reduction, it is important to ensure that the samedegree of control of inflammation is maintained; if not, it is mandatory toreturn to the prior regimen.

做出是否予以抗病毒和/或激素治疗的决定,相对简单,而减量和/或停用这些药物则要复杂的多,免疫性HSK治疗不当的最主要原因即在于此。

抗炎治疗应该维持到活动性炎症得到完全控制,此后的激素减量,每次不应超过50%。每次减量之后,必需确保前序治疗下的炎症反应得到同样控制而没有加重;如果炎症加重,激素治疗必须重回前序剂量水平。

The most common mistake in the management of HSVkeratitis is premature termination of topical steroid therapy. In such cases,there is almost invariably a reappearance of corneal inflammation that ismislabeled as "recurrent" disease, when, in fact, it is actually a"pseudo-recurrence" that is merely a continuation of the sameimmunological reaction that has now become clinically apparent due totherapeutic withdrawal. In the present case, we chose to discontinue topicalsteroids a bit more prematurely than our standard protocol (see below) becausethis was an initial episode of ISK and it was very mild. Nonetheless,reappearance of anterior stromal inflammation in exactly the same location andpattern confirmed that our apparent clinical cure had simply been suppressionof the active process to subclinical levels.


HSK角膜炎治疗最常见的错误是过早停用激素。这种情况下,角膜炎症几乎毫无例外地会重又抬头,而且常被误诊为“复发”,实际上,这是“假复发”,真正原因在于原来的炎症一直在继续,只是因为停药而重又表现出来。

我们刚才汇报的病例,因为其ISK系初发,也很轻,就较我们的治疗规范更早一点停用,尽管如此,前部基质同一部位、同一形状的炎症重新表现出来,证明所谓的临床治愈,仅仅是将活动性炎症控制到亚临床水平而已。

In our clinics, the taper for stromal keratitis andkeratouveitis is only one-third complete when it has been reduced toprednisolone acetate 1.0% once daily. After that, it is two-thirds completewhen it has been reduced to prednisolone acetate 0.125% daily and it is notcomplete until it has been reduced to prednisolone 0.125% once weekly. Forendothelial keratitis, the taper is one-half complete when it when the regimenhas been reduced to prednisolone acetate 1.0% to once daily and not completeuntil it has been reduced to prednisolone acetate 0.125% every other day.

在我们中心,将1.0%强的松龙眼药水减量到每天一次,仅是基质性角膜炎和角膜葡萄膜炎治疗三步骤中的第一步。

第二步是要减量到0.125%强的松龙每天一次。

最后一步是减量到0.125%强的松龙眼药水每周一次。

对于角膜内皮炎,分两步,第一步是减量到1%强的松龙每天一次,第二步是减量到0.125%强的松龙眼药水隔天一次。

Our preferred steroid use and taper regimens are basedupon whether or not the patient is a steroid-responder. If there are no IOPissues our protocol involves the following three treatments, in sequence:

我们对激素的选择和减量,主要取决于患者是否激素易敏人群(激素应用后眼压升高)。如果没有眼压升高之虞,我们的治疗方案分为以下三个步骤:

Prednisolone acetate 1.0%: initiate at full dose andgradually decrease to daily dose

1.0%醋酸强的松龙:开始时予以足量,逐渐减量至每天一次

Prednisolone acetate 0.125%: begin at four times dailyand gradually decrease to daily dose

0.125%醋酸强的松龙:开始每天4次,逐渐减量至每天一次

Prednisolone acetate 0.125%: every other day, thentwice weekly, then once weekly

0.125%醋酸强的松龙:隔天一次,然后是每周两次,最后是每周一次

In eyes of patients who have glaucoma or are steroidresponders, we prefer the following regimen, in sequence (with appropriate IOPmanagement):

如果患者系青光眼,或是激素易敏人群,我们的方案如下(按序进行,同时辅以合宜的眼压处理):

Rimexolone 1.0% (Vexol): initiateat full dose and gradually decrease to daily dose

1.0%Rimexolone:以足量开始,逐渐减量至每天一次

Loteprednol etabonate 0.5% (Lotemax): once daily

0.5%依碳酸氯替泼诺:每天一次

Loteprednol etabonate 0.2% (Alrex) or fluoromethalone0.25% (FML Forte): once daily

0.2%依碳酸氯替泼诺,或0.25%艾氟龙:每天一次

Fluoromethalone 0.10% (FML); daily, then every otherday, then twice weekly, then once weekly

0.10%艾氟龙:每天一次随后减量至隔天一次,再每周两次,最后每周一次

Antiviral prophylaxis预防性抗病毒

The introduction oforal antiviral prophylaxis constituted a major advance in the management ofchronic herpetic eye disease. The Herpetic Eye Disease Study (HEDS) from theNational Eye Institute found that the use of oral acyclovir 400 mg PO BID (orequivalent) was effective in (1) significantly reducing the incidence ofrecurrent epithelial keratitis and stromal keratitis; (2) possibly effective inreducing the incidence of recurrent endothelial keratitis and anteriorkeratouveitis; and (3) ineffective in preventing epithelial disease fromprogressing to stromal keratitis, endothelial keratitis, or keratouveitis.

口服抗病毒药物仍然是慢性疱疹性眼病治疗主要选项。

国立眼科研究所的HEDS(Herpetic Eye Disease Study)发现,每天两次口服阿昔洛韦400mg,或等效药物,能够明显有效减少角膜上皮炎和角膜基质炎的复发;对减少角膜内皮炎和角膜-前葡萄膜炎的复发也可能有效;而不能阻止上皮病变进展为基质炎、内皮炎或角膜葡萄膜炎。

Based uponthe HEDS findings and our own anecdotal experience, we currently utilize thefollowing guidelines for prophylactic therapy with either acyclovir 400 mg POBID or valacyclovir 500 mg PO daily for herpetic eye disease:

根据HEDS的研究成果,和我们自己的临床经验,我们现在予以每天口服阿昔洛韦400mg,或伐昔洛惟500mg,预防疱疹性眼病的方案如下:

HSV epithelial keratitis HSV角膜上皮炎

1. Initial episode: no prophylactic therapy

初次发作:无需预防性治疗

2. One or more recurrent episodes : oral therapy x 1 year

一次或多次复发:口服治疗,一年


HSV stromal keratitis HSV角膜基质炎

1. Initial episode (uncomplicated) :oral therapy x 1 year

初次发作(非复杂病例):口服治疗,一年

2. Initial episode (complicated) :oral therapy x 2 years

初次发作(复杂病例):口服治疗,两年

3. Chronic disease : oral therapy (2 years to indefinite)

慢性病例:口服治疗,两年以上至终生


HSV endothelial keratitis HSV角膜内皮炎

1. Initial episode : oral therapy x 1 year

初次发作:口服治疗,一年

2. Multiple episodes : oral therapy (2 years to indefinite)

多次发作:口服治疗,两年以上至终生


HSV keratouveitis HSV角膜葡萄膜炎

1. Initial episode : oral therapy x 1 year

初次发作:口服治疗,一年

2. Multiple episodes : oral therapy (2 years to indefinite)

多次发作:口服治疗,两年以上至终生


Post-phototherapeutickeratectomy :oral therapy (1 year)激光角膜治疗切削术后:口服治疗,一年


Post-keratoplasty(any type) = oral therapy (2 years to indefinite)

角膜移植术(无论哪种术式)后:口服治疗,两年以上至终生


There are no uniformly accepted guidelines governingthe use of antiviral prophylaxis in conjunction with topical corticosteroid usein situations where live viral manifestations are not present. Due to the veryhigh benefit-to-risk ratio associated with oral antiviral therapy, it is ourpreference to use these medications in every instance in which topicalcorticosteroids are utilized. For topical regimens of five or more drops ofprednisolone acetate 1.0% or equivalent a day, we use full antiviral dosing ofacyclovir 400 mg PO five times a day; for regimens of three or four daily dropswe do one-to-one frequency matching of the topical and oral medication; and,for regimens of two or fewer drops, we utilized the standard prophylactic doseof 400 mg PO BID.

没有活病毒感染时,如何局部应用激素联合预防性抗病毒治疗,目前尚无统一标准。

毋庸置疑,口服抗病毒治疗的收益-风险比很高,我们因此在局部应用激素时,都会联合口服抗病毒治疗。

1.0%醋酸强的松龙眼药水每天5次或更多时,予以足量的抗病毒口服,即每天5次口服阿昔洛韦400mg;激素眼药水每天3次~4次时,我们予以同等频次的口服抗病毒药物;激素眼药水减至每天两次或更少时,预防性抗病毒的剂量改为每天两次阿昔洛韦400mg。