乳头瘤病毒

译者：孙欣主治医师

北京佑安医院

北京市性病艾滋病诊疗中心

Sun_xin@163.com

北京佑安医院

北京市性病艾滋病诊疗中心

Human papillomaviruses (HPV) belong to the Papillomaviridae family. They are made of a small, naked, icosahedral capsid (55 nm in diameter) that encloses a circular, double-stranded DNA genome whose organization is common to all papillomaviruses. The genome includes a non-coding region (upstream regulatory region), a region that codes for non-structural genes, mostly expressed early in the viral cycle (E1, E2, E4, E5, E6, and E7), and a region that encodes the only two capsid proteins, which are expressed late (L1 and L2). The sequence of L1 gene is what defines the distinct HPV genotypes, whose numbers do not cease to increase. There are 92 fully characterized HPV genotypes as of February 2002, but an additional 130 or so have been partially characterized. They all infect the squamous stratified epithelia of the body, but each genotype exhibit a predilection for different anatomic regions. This has led to the recognition of three major groups of HPVs. The first group, the cutaneous HPVs are those that cause infections and diseases, mostly warts, of the hands, feet, and face. The two most important and common genotypes are HPV1 and HPV2. The second group, causes a rare disease called epidermodysplasia verruciformis (EV) in subjects with a genetic predisposition. The singular feature of this condition is the transformation by the second decade of life of the scaly lesions of EV into squamous cell carcinomas in the sun-exposed areas of the patient’s body. Only a subset of the EV-associated HPVs have this high-risk oncogenic potential. One also finds this distinction between low- and high-risk HPVs with the viruses that form the third and most important group for the physician, the genital (or mucosal) group. These HPVs cause benign lesions, warts or condylomas, but also incipient and invasive cancers of the genitalia (cervix, anus, vagina, vulva, penis) and upper aero-digestive tract. HPV6 and to a lesser frequency HPV11 are the most common agents of anogenital warts, whereas HPV16 and to a lesser degree HPV18 are the most common causes of the malignant anogenital lesions.

人类乳头瘤病毒（HPV）属于乳头瘤病毒科，象其他乳头瘤病毒一样，HPV由微小、没有被膜的二十面体外壳（直径55 nm）组成，其内包裹着环形双链DNA基因。基因组包括非编码区（上游调节区）、编码病毒早期表达蛋白（E1, E2, E4, E5, E6, 和E7）的非结构基因以及编码两个晚期表达的衣壳蛋白（L1和L2）的第三部分。HPV基因型分类是由L1基因的序列来决定。因此,被定名的HPV基因型数目不断的在增加。截止2002年2月，有92个基因型的序列已经完全清楚，大约130个基因型还没有完全清楚。HPV感染人体的复层鳞状上皮，但是每一种基因型有不同的易感部位。根据易感部位的不同，HPV可以分成三大类：第一类HPV可以导致皮肤感染，大多数表现为手、足、面部的疣病，这类病毒以HPV1和HPV2最常见和最为重要。第二类HPV可以在一些遗传易感性的患者中，导致一种罕见的疾病“疣状表皮发育不良” (EV)。该病的一个特点是暴露部位的EV皮损经过二十年后可以转变为鳞状细胞癌，只有一组EV-相关的HPV具有高的潜在致癌性。第三类也是最重要的一类HPV感染是生殖道感染，这类病毒同样也有低危与高危之分。这种HPV病毒可以引起疣病或尖锐湿疣等良性病变，也可以引起生殖器（宫颈、肛门、阴道、外阴、阴茎）和上呼吸消化道的侵袭性肿瘤。HPV6和相对较少的 HPV11最常引起生殖器疣，而HPV16和HPV18最常引起生殖道恶性病变。

HPV infections are extremely common but the vast majority of them are asymptomatic and remain that way. Cutaneous HPVs cause cutaneous warts, a common disease, especially in the school-age population, with a prevalence ranging from about 1 to 20 percent. Three main types of cutaneous warts are recognized: common, plantar, and flat warts, each representing approximately 70%, 25%, and 5% of the lesions. The mode of transmission seems to be through direct contact or fomites, the latter being responsible for plantar warts transmission in communal baths or swimming pools.

HPV感染非常的普遍，但是大多数为无症状感染并持续这种状态。皮肤的HPV感染导致皮肤疣，皮肤疣是一种常见病，尤其在学龄期人群中，发病率为1%到20%。皮肤疣通常分为三类:寻常疣、跖疣和扁平疣，分别占70%、25%和5%。只要通过直接接触和污染物的间接接触传播，其中后者对于跖疣在洗浴或者游泳池中的传播起重要作用。

Genital infections are mostly acquired through sexual contact. Early initiation of sexual intercourse and multiplicity of sexual partners are the major risk factors. Hence, the peak incidence of genital warts is found in subjects in their early 20's. Incidence rates vary from less than 1% to 13%, with an overall prevalence estimated to be around 1%. In women, HPV infections of the cervix occupy an important place given that they are responsible for the majority of Papanicolaou (Pap) smear abnormalities. The incidence of HPV cervical infections peaks in the third decade with an incidence of about 20%, but that can exceed 50% in some sub-populations. HPV infections result in rates of abnormal Pap smear that range between 1 and 5%. Recurrent respiratory papillomatosis is a disease caused by genital HPVs types 6 or 11. Its bimodal distribution is believed to reflect two different mechanisms of transmission: mostly a peripartum transmission from an infected birth canal for the juvenile form of the disease, which has an incidence of 4.3 per 100,000, and oral sexual contact for the adult form whose incidence is 1.8 per 100,000.

性接触是生殖器疣的最主要的传播途径，第一次性交的年龄和多性伴是主要的危险因素。因此，生殖器疣的高峰发病年龄是二十几岁，发病率从不到1%到13%不等，总的发病率估计1%左右。妇女的宫颈HPV感染非常重要，是导致巴氏涂片异常的最主要的原因。三十多岁是宫颈HPV感染的高峰期，发病率可以达到20%，在某些人群中可以超过50%。HPV感染会有1%到5%人发生巴氏涂片异常。呼吸道复发性HPV感染是由生殖器HPV6型和11型引起。由于传播方式的不同而呈现双峰分布：幼儿的感染主要是围产期通过受感染的产道传染，发病率为十万分之四点三，而成人的感染主要是因为口腔的性接触引起，这部分人的发病率为十万分之一点八。

Plantar warts (verrucae plantaris, myrmecias) are deep-seated, often painful, lesions measuring typically from 2 to 10 mm, made of a sharp margin surrounding a slightly elevated, flat-topped, irregular bundle of cornified fibers. Because flat warts have a predilection for the weight-bearing areas of the foot, they have to be differentiated from corns or calluses. This is accomplished by paring the surface of the lesion with a scalpel, which in the case of a wart reveals bleeding or thrombosed, punctuate capillaries.

跖疣是深在的，一般会有疼痛，2~10mm大小，边界清楚，中央略隆起、表面扁平、有不规则角化纤维。因为跖疣容易发生在足的负重部位，因此需要与胼胝和鸡眼鉴别。用手术刀削皮损的表皮，跖疣的皮损就会流血或者毛细血管血栓形成，这可以鉴别以上疾病。

Common warts (verrucae vulgaris) are round, well delineated hyperkeratotic papules, 1 to 10 mm in diameter, with a surface that ranges from coarse to cauliflower-like and on which the normal pattern of skin ridges is disrupted. They are typically distributed over the dorsal aspect of the hand, and on the lateral aspects of the fingers, including near the nail beds. On the feet, common warts appear as mosaic warts, at hyperkeratotic, clustered and confluent, painless papules. Plane warts (verrucae plana, juvenile warts) are very at, small, asymmetric, supple, easily missed papules. They are pink to skin-colored, with a dull surface reflection caused by the disruption of the skin ridges. They are found on the face, neck, and the dorsum of the hands. The diagnosis of cutaneous warts is usually easy and is made by history and inspection. Magnifying optics (e.g., a loupe or a magnifying glass) are helpful to reveal the discontinuity of the skin ridges at the edge of the lesion and appreciate the papillomatous surface contour. Paring of the lesion may be necessary to distinguish a plantar wart from a corn or callus.

寻常疣是圆形的、过度角化的丘疹，直径1~10mm大小，表面从粗糙到菜花样，皮肤的纹理中断。通常皮损发生在手背，手指的侧缘以及甲床周围。在足部，寻常疣表现为马赛克样疣体：过度角化的、成簇的、融合的无痛性丘疹。扁平疣又称为青年疣，为小、无症状的柔软的扁平丘疹，易被忽略。粉色到皮肤颜色，由于皮嵴崩解，皮损表面晦暗。扁平疣可以发生在面部、颈部和手背。通过病史和临床表现皮肤疣容易诊断。光学放大（例如放大镜）对发现皮损边缘皮嵴中断以及乳头瘤样的表面鉴定有帮助。皮损削剥有助于疣与胼胝和鸡眼的鉴别。

Genital warts (condylomata acuminata, venereal warts, anogenital warts) are fleshy papules that range from slightly pedunculated dome-shaped lesions with a more or less pronounced mulberry-like appearance, to taller, jagged cockscomb-like structures. In most patients they are asymptomatic or the cause of minimal discomfort. Nevertheless, they have a psychosexual impact in a majority of patients.

生殖器疣（尖锐湿疣、性病疣、肛门疣）表现为小的桑葚样圆顶实性丘疹，大的皮损可以呈锯齿状鸡冠样外观。大多数患者没有症状或者有轻微的不适，但大多数患者会有性心理的影响。

Genital warts can be located on the keratinized skin or on the external mucosal surfaces. In circumcised men, genital warts are mostly located on the penile shaft, while the preputial cavity is the site of predilection in circumcised men. On occasion warts can be located in the fossa navicularis, but more proximal involvement of the urethra is extremely rare. In women, warts are more widely spread over the genitalia, involving in particular the posterior introitus, and the labia minora and majora. Perianal anal involvement is not uncommon in women, less so in men. It does not necessarily reflect anal intercourse. However, if the patient reports anal intercourse or anal symptoms, an anoscopic examination is recommended to rule out internal disease.

生殖器疣可以发生在角化的皮肤或者暴露的粘膜表面。在包皮环切术后的男性，生殖器疣最常发生在阴茎体，而包皮内板是这部分男性的好发部位。有时疣体会发生在舟状窝，但是发生在尿道的十分少见。对于女性，疣体可以发生在生殖器的各个部位，尤其是后联合、小阴唇和大阴唇。肛周和肛门损害女性较为常见，而男性较少，并且不一定和肛交有关。然而，如果病人提供有肛交的经历或者有肛门的症状，需要做肛镜检查以排除内在的疾患。

The diagnosis of genital warts is usually made clinically with the naked eye. The male patient is typically examined in a standing position, and the female patient in the lithotomy position. Because condylomata acuminata may be small and may need to be differentiated from the lesions of several other diseases, the use of magnifying optics (e.g., loupe, magnifying glass, colposcope) can be helpful. The soaking for 3 to 5 minutes in 3% to 5% acetic acid of the genitalia prior to examination is likely to turn the lesions white (acetowhitening) -particularly on the mucosal surfaces-, which make them easier to detect when they are small. Flat aceto-white macules or patches may be recognized. Although they may reflect sub-clinical HPV disease, acetowhitening lacks specificity, and treatment of these sub-clinical lesions is not recommended.

生殖器疣主要通过临床肉眼诊断，检查时男性采用站立位，女性采用截石位。因为尖锐湿疣可能非常小，需要与其他几种疾病鉴别，使用放大镜（小型放大镜或阴道镜）对诊断会有帮助。检查之前于生殖器涂3%~5%的醋酸，3到5分钟后皮损会变白（醋白反应），在粘膜表面这种反应尤其明显，当疣体较小时，就更容易发现皮损，可疑皮损会变为扁平的白色斑块或者斑点。由于醋白试验特异性差，虽然能发现亚临床感染，但是并不推荐对这些亚临床皮损进行治疗。

Anogenital HPV infection may lead to the development of incipient cancers, also called intraepithelial neoplasias or dysplasias. On the external anogenital areas, these lesions may appear as pigmented papules or erythematous plaques or macules. They may assume the appearance of a giant papilloma or a verrucous mass. Ulceration or bleeding may occur. Ultimately, one has to be concerned that these lesions may represent invasive squamous carcinomas. In the anal canal, the vagina, and on the cervix the same array of benign lesions (condylomas), intraepithelial neoplasias, and carcinomas may occur as a result of HPV infection. They are the province of the specialist.

肛门生殖器疣有可能发展成早期癌，或者叫做上皮内瘤样病变或者不典型增生。在肛门外生殖器，皮损可以表现为色素性丘疹、红斑或者斑点，也可以表现为巨大乳头瘤或者巨大疣，可能发生溃疡和出血。最后，我们需要注意的是这些皮损有可能发展为侵袭性鳞状细胞癌。HPV感染肛管、阴道或者宫颈，同样会引起良性损害（尖锐湿疣）、上皮内瘤样病变和癌等一系列疾病，需要就诊于专科医生。

Two other areas where HPV lesions may manifest are the oral cavity and the larynx. Genital HPV types cause squamous papillomas and condylomata acuminata, and cutaneous HPV types cause verrucae vulgaris. These entities are more aptly distinguished by histology, than by clinical features, and therefore may all fall under the convenient label of oral warts. An altered cry in infants or voice hoarseness in speaking older individuals are the main symptoms that lead to the diagnosis of recurrent respiratory papillomatosis.

HPV感染生殖器可以导致鳞状细胞乳头瘤和尖锐湿疣， HPV感染皮肤可以引起寻常疣，除此之外HPV还可以感染口腔和喉部。这两个部位的感染的诊断主要依靠病理而不是临床表现，两者可以统称为口腔疣。复发性呼吸道乳头瘤病毒感染在婴儿主要表现为哭声的改变，大些的孩子表现为声音嘶哑。

The diagnosis of cutaneous warts is clinical and rarely requires the need of a biopsy for histologic confirmation. The same applies for the anogenital HPV lesions, except for cervical lesions. For anogenital lesions, biopsy should be considered if there is a doubt on the diagnosis, in particular if an intraepithelial neoplasia or carcinoma is of concern. This can be the case if indicative clinical features are present, or if the lesions are large, form plaques, bleed, are present in atypical locations, or if a lesion is resistant to treatment. Although when to collect a biopsy is a matter of judgment, the threshold is lowered when dealing with an immunosuppressed or immunodeficient patient.

皮肤疣的诊断主要通过临床，很少需要病理学的证实。除了宫颈损害之外，其他肛门生殖器HPV感染得诊断也主要通过临床。当肛门生殖器损害的诊断有疑问，尤其考虑有上皮内瘤样病变或者癌变的可能的时候应该考虑做病理检查。如果出现指示性的临床表现或者损害体积大、形成斑块、出血、出现在不典型的位置以及治疗很不敏感的病例需要做病理检查。虽然做活体组织检查的时机需要评判，但是当病人是免疫抑制或者免疫缺陷的病人应该相对放宽活检的标准。

Cervical lesions are typically detected by cytology (Pap smear). The Bethesda system, initially proposed in 1988 and most recently revised in 2001 (http://www.bethesda2001.cancer. gov), is a widely used interpretation scheme (1). It assesses the adequacy of the specimen, classifies its finding, and offers guidelines for management and follow-up. Squamous cell abnormalities, which are pertinent to HPV infection, are classified into four categories: (1) atypical squamous cell of (a) undetermined significance (ASC-US), or (b) cannot exclude high-grade squamous intraepithelial lesion (ASC-H) (( a) and ( b) used to be grouped under a single category of ASCUS); (2) low-grade squamous intraepithelial lesion (LSIL), a diagnosis that regroups the previous cytologic and histologic diagnoses of koilocytotic or condylomatous atypia, mild dysplasia, and cervical intraepithelial neoplasia (CIN) 1; (3) high-grade squamous intraepithelial lesion (HSIL), encompassing the previous categories of moderate and severe dysplasias, CIN 2 and CIN 3/carcinoma in-situ (CIS); and (4) squamous cell carcinoma (SCC). Management guidelines are available (2).

宫颈损害一般是通过细胞学检查发现的（巴氏涂片）。Bethesda系统是应用最广泛的解释方案(1)，该方案最早1988年提出，最近一次修订是2001年（http://www.bethesda2001.cancer. gov）。这种方案包括对标本的满意度进行评估、对结果进行分类并且提供治疗和随访指南。与HPV感染相关的鳞状细胞异常分为四级：（1）非典型鳞状细胞包括：（ａ）不明确意义(ASC-US)（ｂ）不除外鳞状上皮高度病变(ASC-H)（（ａ）和（ｂ）通常被统称为ASCUS）；（2）低度鳞状上皮内病变(LSIL)包括以前组织细胞学诊断为凹空细胞或者湿疣不典型增生、轻度异生、宫颈上皮内瘤样病变（CIN）1级等；（3）高度鳞状上皮内病变(HSIL),包括之前的中度和重度异生、CIN 2 and CIN 3/原位癌(CIS)；（4）鳞状细胞癌（SCC）。不同级别有相应的处置指南(2)。

The role of colposcopy, which is the examination of the cervix with special magnifying optics- the colposcope- and after application of acetic acid and/or Lugol solutions, is to establish whether a biopsy is necessary and where. Criteria and scoring schemes have been developed that allow a presumptive diagnostic based on the colposcopic appearance. Cervicography, the interpretation of photographs of the cervix taken with a special colposcopic camera, has been developed as a patented independent screening tool for cervical cancer. The principles and methods of colposcopy have been applied to the examination of the anal canal in the human immunodeficiency virus-infected population. This promising approach, named high resolution anoscopy, has not yet been routinely validated and integrated in the management of these patients.

阴道镜检查是用来检查宫颈病变的，外用乙酸或者复方碘溶液之后，应用一种特殊的放大镜－阴道镜－观察宫颈病变，可以确定是否需要活检以及活检的部位。我们已经有了基于阴道镜图像的诊断标准和评分方案。子宫颈影像，采用一种特殊的阴道镜摄像机拍摄宫颈的图片，已经发展为一种独立的宫颈癌的筛查方法。阴道镜的原理和方法已经应用到HIV感染者的肛管的检查，这种有前景的方法叫做高分辨率肛镜，但是这种方法还没有得到系统的认证，还不是常规的处置方法。

The diagnosis of HPV infection, as opposed to HPV disease, is based in clinical practice on the demonstration of HPV DNA in cells or tissues. The Hybrid Capture II assay (Digene Diagnostics Inc.) is presently the only commercially available assay. It is based on a liquid-phase hybridization reaction in which the sample DNA is reacted with RNA probes contained in two pools. The probes in pool A correspond to genital low-risk HPVs, while those of poll B represent high-risk genital HPVs. The assay is slightly less sensitive overall than investigational assays based on the polymerase chain reaction (PCR), but its performance characteristics are superior for those conditions (e.g., LSIL) that are relevant for screening. HPV DNA testing has now been integrated in the cervical cancer screening guidelines (2).

只有确实证实细胞或者组织中有HPV DNA，才能诊断HPV感染（不是HPV疾病）。Hybrid Capture II assay 杂交捕获II实验(Digene Diagnostics Inc.)是目前唯一商业化的实验方法。该方法的工作原理是标本的DNA与RNA探针在两个反应池发生液相杂交反应，其中A池中的探针与低危生殖道HPV相关，B池中的探针与高危生殖道HPV相关。这种方法的敏感性略低于PCR，但是与临床的相关度要更好，而这正是筛查所需要的。现在HPV DNA检测已经写进了宫颈癌筛查的指南(2)。

Most HPV infections are latent and do not cause any cellular alterations, however during an active infection, HPV stimulate the growth of the squamous stratified epithelium. This process is directly responsible for the characteristics histologic features of benign HPV lesions, namely the proliferation of the stratum spinosum (acanthosis), stratum granulosum (parakeratosis), and stratum corneum (hyperkeratosis). In addition, there is an increase of the normal undulation of the basement membrane (rete ridges) and of the epithelium above that accounts for the papillomatosis. Finally, the presence of koilocytes (large cells with a shriveled nucleus surrounded by a halo) in the upper stratum spinosum is an almost patho gnomonic signature of HPV benign disease. The viral cycle starts with the infection of the basal cells, however most of the viral replication occurs in the stratum spinosum, and the viral cycle is tied to the differentiation of the epithelium. Viral particles form in the upper layers of the epithelium and are released in the desquamating cornified shells.

如果为活动性感染，HPV可以引起复层鳞状上皮的生长，但大多数的HPV感染为潜伏感染，不会引起任何细胞学改变。良性HPV损害的组织学表现为棘层、颗粒层以及角质层的增生（过度角化）。HPV感染会导致基底膜的波动，基底膜上方的上皮细胞发生乳头瘤样增生，最后在棘层的上部还会出现挖空细胞（细胞体积变大，核皱缩，核周被晕包绕），这几乎是良性HPV感染的特征性病理表现。病毒周期开始于基底层细胞的感染，然而大多数的病毒复制发生在棘层。病毒周期与上皮的分化紧密相关，病毒颗粒形成于表皮的上部，并且释放到角化的鳞屑中。

HPV DNA infection is a necessary but not sufficient condition for the development of cervical cancer. Two viral proteins are important to the oncogenic process: E6 and E7. With high-risk HPVs these two proteins associate and neutralize the function of two important tumor suppressor cellular proteins, p53 (E6) and the retinoblastoma protein (RB) (E7). The abnormal proliferation of the basal cell layer and the presence of mitoses, normal and abnormal, much above the basal membrane defines the process of intraepithelial neoplasia. Based on how many thirds of the thickness of the epithelium are involved, the intraepithelial neoplasia is graded from 1 to 3. Rupture of the basement membrane defines invasive squamous cell carcinoma.

HPV DNA感染对宫颈癌来说是必要条件而不是充分条件。E6和E7两个病毒蛋白在肿瘤的形成中的作用十分重要。感染高危型HPV 后，这两种蛋白会分别使两个重要的肿瘤抑制蛋白P53(E6)和视网膜母细胞瘤蛋白质RB(E7)功能丧失。我们用基底细胞的异常增生、正常或者异常的核分裂像以及是否超过基底膜来定义上皮内瘤样病变的进程。将表皮分为三份，根据受累的厚度不同，上皮内瘤样病变分为1到3级。突破基底膜称为侵袭性鳞癌。

There are no routine tests available for the screening and testing of anti-HPV drugs. Depending on the targeted gene or protein, in vitro assays can be designed to screen for potential drugs (3). Organotypic skin culture systems have been used to produce artficial skin (or mucosa) infected with HPV (4-7). However, these systems are complex and have not been used to any large extent for the evaluation of potential drugs (8).

没有常规的方法筛查和检测抗HPV药物。体外实验可以利用靶基因或者靶蛋白来筛选可能有效的药物(3)。利用皮肤组织培养的方法可以制作出感染HPV的人造皮肤（或者粘膜）(4-7)，但是这种方法非常的复杂，还没有在大规模的药物评价中使用(8)。

The cottontail rabbit (Shope) papillomavirus (CRPV) is a virus that can also infect the domestic rabbit in whom it induces within 1-6 weeks skin papillomas (9). They may either regress, persist, or progress to carcinomas. This model has been used for the evaluation of drugs against papillomaviruses (5-fluorouracil, CTC-96 [doxovir], and various nucleoside analogues, including ribavirin, and cidofovir) (10-15), as well as surgical treatments (photodynamic therapy) (16, 17) and vaccines (18-21).

白尾棕色兔乳头状瘤病毒（CRPV）也可以感染家兔，在1-6周内引起皮肤乳头瘤病(9)，乳头瘤可以消退、持续或者发展为癌。这个模型已经用来抗乳头瘤病毒的药物（5-氟尿嘧啶、CTC-96 [doxovir]、西多福韦和利巴韦林等核苷类似物）(10-15)、手术治疗(16, 17)以及疫苗的评价(18-21)。

One has to use HPV-infected human xenografts (usually foreskin fragments) implanted in immunodeficient mice (e.g., athymic [nude] and severe combined immunodeficiency [SCID] mice) for the study in vivo of drugs against HPV (limited to types 6, 11, 16, and 40 at present) (22). These models have been used for the evaluation of 9-(2-phosphonylmethoxy) ethylgua nine (PMEG) an antisense oligonucleotide, and various microbicides (11, 23-25). A similar murine model has been used to study antivirals against CRPV (26).

把感染HPV的人体组织（一般是包皮的碎片）植入到免疫缺陷的小鼠（例如没有胸腺[裸鼠]或者重症联合免疫缺陷[SCID]小鼠）体内，可用于抗HPV（目前仅限于6、11、16和40型）(22)药物的体内研究。一种反义寡核苷酸9-(2-phosphonylmethoxy) ethylgua nine (PMEG)和多个杀菌剂的评价就是通过这个模型(11, 23-25)。一个近似小鼠的模型已经用作抗CRPV的药物研究(26)。

There are presently no true antimicrobial therapy available for HPV infections. Consequently, the current therapeutic strategies to deal with HPVs are different from those available for other viral infections, because they are not directed at infections but at associated diseases, and the relief of their symptoms. Given that HPVs cause both benign and malignant tumors many of the therapeutic options are destructive or excisional, and are usually more accessible to a surgeon than to the primary care practitioner. Therefore, the emphasis of this chapter is on the diseases and therapies relevant to the primary care provider, the surgical techniques being presented to facilitate the choice of a referral. The medical armamentarium is very eclectic, often unbounded by the absence of comparative data.

目前没有真正能抗HPV的药物。目前抗HPV的治疗策略与其他病毒感染不同，抗病毒治疗不是针对HPV感染，而是针对HPV相关的疾病和缓解患者的症状。因为HPV可以引起良性和恶性的肿瘤，许多都需要切除或有创性治疗，因此主要是由外科医生完成其治疗而不是初级保健医生。我们这个章节的重点是与初级保健医生有关的治疗，外科手术治疗在这里作为补充。医学上的处理是多元的，且常常缺乏对照研究。

Acids: Salicylic acid, on the account of its keratolytic properties, has been a very common agent used alone or in combination with lactic acid for the treatment of cutaneous warts (Table 1). It is found in many over-the-counter medications. It is well tolerated, but when mixed with collodion, hypersensitivity reaction to collophony, a component of collodion, may occur. Table 1 lists some of its formulations and the expected complete response rates.

酸：水杨酸有角质溶解的特性，因此常来单独或者与乙酸联合治疗皮肤疣(Table 1)。它是非处方药，并且耐受性好，但是当与火棉胶混合使用时，有可能发生松香过敏，松香是火棉胶中的一种成份。Table 1列出了它的一些配方和预期的治愈率。

Bichloracetic acid (BCA) and more commonly trichloracetic acid (TCA) enjoy a great popularity with gynecologists (Table 2). They are cauterizing and keratolytic agents that are employed for the treatment of warts on the mucosal (moist) surfaces, which in addition to the non-hairy vulva also include the anal canal (27). Only one of 14 treated condylomata was found to retain HPV DNA after treatment (28). The treatment is painful and may cause discomfort, ulcerations, and scabbing more readily than cryotherapy (29, 30). Therefore, these compounds can be applied on relatively small areas while avoiding the healthy surrounding tissues. Given the favor these compounds enjoy, there is surprising little published about them (Table 2). TCA has been found equivalent in efficacy to cryotherapy (29, 30), and podophyllin plus TCA was not superior to podophyllin alone at three month follow-up (31). These acids are regarded safe to use during pregnancy, although this impression is based on collective experience more than experiment. One study of 32 pregnant women with condylomata acuminata treated with TCA and laser therapy, had wart clearance in 31 patients (97%), with 2 cases of recurrence (32).

妇科医生喜欢用二氯乙酸（BCA）尤其是三氯乙酸(TCA) (Table 2)。它们都是腐蚀剂和角质溶解剂，可以用来治疗生长在潮湿粘膜表面的疣体，还可以用在没有毛发的外阴和肛管(27)。十四个患有尖锐湿疣的患者，经过治疗后，仅有一个人再次检测到HPV DNA。这些治疗会引起疼痛不适，溃疡，比冷冻疗法更容易结痂(29, 30)。因此，相对小的面积的时候可以应用这类药物，并且要避免接触到周围的正常组织。虽然是常用的治疗药物，但是这方面的文章却很少(Table 2)。TCA疗效与冷冻疗法相当(29, 30)，经过三个月的随访，发现TCA与鬼臼树脂联合应用并不比单独应用鬼臼树脂疗效好。这些酸性物质用于孕妇被认为是安全的，虽然这只是基于大家的经验而不是试验研究。在某研究中，32例患有尖锐湿疣的孕妇，经过TCA和激光的治疗，有31例疣体脱落（97%），其中2例复发(32)。

The above two classes of acids have been used in combination for the treatment of plantar warts. Monochloracetic acid in combination with 60% salicylic acid resulted in a greater rate of wart clearance than placebo, 83% versus 54% (33) .

以上两类酸曾联合用来治疗跖疣。一氯乙酸和60%水杨酸联合治疗跖疣，疣体的清除率高于安慰剂，分别为83%和54%(33)。

Fixatives: Plantar warts have been successfully treated with tissue fixatives such as formaldehyde (40%) and glutaraldehyde (10%) solutions (Table 1) (34, 35). These compounds are potentially sensitizing. Formaldehyde has been associated with the development of painful plantar fissures, and glutaraldehyde causes a brown discoloration of the skin (Table 1).

组织固定剂：组织固定剂例如甲醛（40%）和戊二醛（10%）溶液可以成功的治疗跖疣(Table 1) (34, 35).这类物质有可能会引起过敏。甲醛会导致足底皲裂，引起疼痛，戊二醛会导致皮肤棕色变(Table 1)。

Bleomycin: Bleomycin is a mixture of glycopeptides isolated from Streptomyces verticillus that creates breaks in single and double stranded DNA. This cytotoxic agent, which is used in oncology, has been evaluated for the intralesional treatment of cutaneous warts, particularly those located around the nails (Table 1) (36-45). It has been used on occasion for the treatment of genital warts, giant condylomas, and oral warts (46-48). Efficacy results, which are based on case series, are summarized in Table1. Bleomycin sometimes causes severe local pain that can be reduced by the addition of lidocaine to the bleomycin (49). The drug is devoid of systemic adverse reactions at the recommended doses (< 5 mg per patient). Because of the pain and tediousness, the intralesional route of administration limits the number of lesions that can be treated at each session. This has prompted the search for alternate modes of delivery, which have included so far the use of a bifurcated needle, a tatooing machine, and a medicated topical dressing (37, 50-52). Bleomycin use is contraindicated in children, during pregnancy, and in the presence of peripheral vascular disease.

博来霉素：博来霉素是轮丝链霉菌中分离的糖多肽的混合物，可以导致单链和双链DNA的断裂。这类通常用于肿瘤的细胞毒性物质，我们已对皮肤疣皮损内治疗做了评价，尤其是发生在甲周围的疣体(Table 1) (36-45)。有时也用来治疗生殖器疣、巨大尖锐湿疣以及口腔疣(46-48)。队列研究的疗效见表1.博来霉素有时会引起剧烈的疼痛，加入利多卡因后，可以缓解疼痛(49)。该药在推荐剂量（每人小于5mg）下应用，不会引起系统性不良反应。由于引起疼痛和繁琐，皮损内给药限制了每次治疗的皮损数目。这促进了我们去寻找新的给药途径，目前的方法有使用分体针（一种纹身器材）和局部封包(37, 50-52)。博来霉素禁用于儿童，孕妇和患有周围血管疾患的患者。

Cantharidine: Cantharidin is a compound extracted from the blister beetle, Cantharis vesicatoria (Spanish fly). Topical application causes acantholysis, a painful, non-scarring blistering of the skin. Several reports have described its usage for the treatment of cutaneous warts (Table 1) (53-55). Because of its vesicant properties, cantharidin should not be applied on healthy skin and the mucous membranes, particularly the conjunctiva. Ingestion of cantharidin causes severe toxicities (56).

斑蝥素：斑蝥素是一种斑蝥的（西班牙绿芫青）的提取物。局部应用会引起棘层松解、疼痛、不留瘢痕的皮肤水疱。有些报道用它治疗皮肤疣(Table 1) (53-55)。因为有发疱的特性，斑蝥素不能用在正常的皮肤和粘膜，尤其是不能用于结膜。食入斑蝥素后会产生严重的毒性(56)。

Silver Nitrate: Silver nitrate sticks are one of the oldest therapies of cutaneous warts still in use. Silver nitrate is known as a cautery. Its efficacy for the treatment of common warts was demonstrated in a single blind trial in which the patients were randomized to receive three applications at three day intervals of either silver nitrate or ink (placebo) (57). Complete wart clearance was noted in 15/35 (43%) in the silver nitrate group and in 4/35 (11%) in the placebo group (p = 0.006).

硝酸银：硝酸银棒是最古老的治疗皮肤疣的方法，至今仍在应用。它是一种腐蚀剂。它治疗寻常疣的效果在一个单盲的实验中得到证实，患者随机接受每三天一次的硝酸银或者墨水（安慰剂）治疗(57)，硝酸银和安慰剂疣体的完全清除的情况分别为15/35(43%)和4/35(11%)( p = 0.006)。

Imiquimod: Imiquimod, (1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine), is with resiquimod an imidazoquinolineamine derivative with biological response modifying activity (58). Imiquimod induces the production of IFN-a and of other cytokines, including interleukins 1,5,6,8,10,12, tumor necrosis factor a, macrophage chemotactic protein (MCP-1) and other chemokines (59). Wart clearance after treatment with imiquimod is associated with an increased expression of the IFN-a , -b , -g, and TNF-a genes (60).

咪喹莫特：咪喹莫特(1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine) 由瑞喹莫德（一种咪唑喹啉胺）衍生而来，衍生之后发生生物活性改变(58)。咪喹莫特可以诱导产生IFN-a 及白细胞介素1、5、6、8、10、12、肿瘤坏死因子因子-a、巨噬细胞趋化因子(MCP-1) 和其他细胞因子(59)。应用咪喹莫特之后疣体的清除与IFN-a、-b、-g,和TNF-a 基因高表达有关(60)。

Imiquimod has been approved by the Food and Drug Administration (FDA) as a 5% cream (Aldara) for the topical self-treatment of condylomata acuminata (Table 2). This represents a significant recent addition to the medical armamentarium. Several randomized controlled trials have defined the therapeutic profile of the preparation (61). In one of the first studies, 108 patients with genital warts were randomized to the 5% cream or vehicle only (62). They applied the preparation 3 times a week, every other day for up to 8 weeks. 37% of the imiquimod-treated patients had complete wart clearance at the end of treatment compared to none in the vehicle group (p < 0.001). Remarkably, only 3 of 16 patients (19%) had recurrences after 10 weeks of follow-up. A second study examined imiquimod treatment with a 5%, 1%, and a vehicle cream for up to 16 weeks (63). Wart clearance rates at 16-week in these three groups were 54/109 (50%), 21/102 (21%), and 11/100 (11%), respectively; the 5% cream preparation being significantly superior to either of the two others (p < 0.001). In the three groups, complete response rates were higher among women than men. Recurrence rates were also low, 13%, 0%, and 10%, respectively. The study was replicated, but the frequency of treatment was increased from thrice weekly to daily (64). At the end of the treatment phase, wart clearance rates in the 5%, 1%, and vehicle groups were 49/94 (52%), 13/90 (14%) and 3/95 (4%), respectively (p < 0.0001). As in the previous trial, women responded better than men, 27/42 (64% ) versus 22/52 (42%).

5%咪喹莫特霜（艾达乐）已经被美国食品药品监督管理局（FDA）批准用于尖锐湿疣患者自我局部治疗(Table 2)。这代表了当前医疗手段的重要进展。几个随机对照实验给出了这种药物的治疗情况(61)。在一个最早的研究中，108名尖锐湿疣患者随机应用5%咪喹莫特霜或者仅用乳膏基质(62)。每周三次或者隔天一次应用8周后，咪喹莫特治疗组37%的患者疣体全部消除，而对照组则没有一个人的疣体消除（p < 0.001）。值得注意的是，10周后随访，16个人中只有3人复发。第二个实验中，检测了咪喹莫特5%、1%和乳膏基质应用16周后的效果(63)，三个治疗组疣体清除率分别为54/109 (50%)、 21/102 (21%) 和11/100 (11%),5%乳膏的效果显著优于其他两种方法(p < 0.001)。在三组中女性的完全应答率高于男性。复发率也低，三组分别为13%,、0%,和10%。另一个研究中重复了上述研究，但是用药频率从每周三次增加到每天一次(64)。治疗结束后，5%、1%和乳膏基质组的疣体清除率分别为49/94 (52%)、13/90 (14%) 和3/95 (4%) (p < 0.0001)。

A fourth trial, limited to men, examined different schedules of self-treatment with 5% imiquimod cream: thrice weekly, once daily, twice daily, and thrice a day (65). There was no overall statistically significant difference in the wart clearance rate among the four groups (range 14% to 35%), and no suggestion of a dose-response effect. However, this and the previous trials demonstrated that the local side-effects were related to the dose, and were most severe when the drug was applied more than once a day. In another open label study, 90 women were randomized to the same treatment groups except for the thrice a day application (66). There were no differences in wart clearance rates among groups. They ranged from 62% to 73%, but the incidence of the side effects was directly related to the frequency of administration. Imiquimod 5% cream applied thrice weekly every other day was as effective as daily application for the treatment of foreskin-associated warts in uncircumcised men, with complete clearance rates of 21/34 (62%) and 17/30 (57%), respectively (67). These observations have been replicated in another study (68).

第四个临床实验中所有受试者均为男性，比较了每周三次、每天一次、每天两次和每天三次等不同用药频率的疗效(65)。在四组中疣体清除率没有显著的不同(从14%到35%)，并没有显示剂量依赖反应。然而在这个实验和之前的实验表明局部副作用与剂量有关，当每天应用一次以上时，副作用最严重。在另外一项开放式研究中，90名女性随机进行了同样的研究，但是没有每天三次的治疗组(66)。疣体清除率为62%到73%之间，不同治疗组间的没有显著性差异，但是副反应的发生率与应用咪喹莫特的频率有直接关系。未割包皮的男性治疗包皮疣体时，5%咪喹莫特每周三次与每日一次效果相同，疣体的清除率分别为21/34 (62%)和17/30 (57%) (67)。另一项研究中也对此进行了相同的观察(68)。

The results of large international, open-label trial of imiquimod self-administered thrice weekly for up to 16 weeks summarize the therapeutic expectations with the compound (69). Initial complete response rate was 451/943 (48%) within a 6-month follow-up period. Patients who failed or who had recurrences were offered a second course of treatment that resulted in wart clearance in an additional 52 patients (5.5%). Females were 1.3 times more likely to have a complete clearance than males. The recurrence rates were 9% and 23% at 3 and 6 months of follow-up, respectively.

大的国际性、公开实验的结果总结了该化合物的治疗前景(69)，自用咪喹莫特每周三次并且持续16周。6个月内随访期间，初次治疗完全应答率为451/943 (48%)。治疗失败或者复发的患者重复一个疗程的治疗后，又有52名患者疣体清除（5.5%）。女性完全清除的概率是男性的1.3倍。三个月和六个月后，复发率分别为9%和23%。

A 2% imiquimod cream has been under evaluation for the European market. Two randomized, placebo-controlled trials in men and women have shown excellent results (70, 71).

Limited anecdotal evidence suggests that imiquimod may be useful in the treatment of common, plantar, and flat warts (72-75). Imiquimod may also have a place in the treatment of Bowen's disease (76-78).

2%咪喹莫特乳膏的效果正在欧洲进行评估，男性和女性两个随机的安慰剂对照实验显示出了极好的结果(70, 71)。

有些没有对照的研究中，咪喹莫特还可以用来治疗寻常疣、跖疣和扁平疣(72-75)，在Bowen病的治疗中，咪喹莫特也占有一席之地(76-78)。

Local erythema, usually mild or moderate is reported by about two-thirds of patients. About a third of patients report erosions. Other adverse effects include edema, scabbing, induration, ulceration, and vesicles. About a third of the patient will report pain or itching at least once, burning and tenderness being less frequent. These adverse events rarely lead to drug discontinuation. There are no data on the use of imiquimod in pregnant women or nursing mothers.

三分之二的患者会出现轻度到中度的限局性红斑，大约三分之一的患者出现糜烂。还会出现水肿、结痂、硬结、溃疡、小疱等其他不良反应。大约三分之一的患者至少出现过一次疼痛或者瘙痒，烧灼感和压痛较少发生。这些副反应很少导致停药。目前还没有咪喹莫特用于孕妇或者哺乳妇女的资料。

Podophyllin and Podofilox: Podophyllin was for a long time the mainstay of genital wart therapy. This is a resin that is extracted from the rhizome of the American mandrake (May apple, Podophyllum peltatum) or, outside North America, the more potent but dwindling Himalayan P. emodi (hexandrum). Used originally as a cathartic, it is now prepared in a benzoin tincture, podophyllum (USP) 25% for the treatment of warts (Table 2). It consists of two major groups of chemicals: avonoids and lignans. The latter are responsible for the anti-wart activity, in particular the chemical podophyllotoxin. Podophyllin contains about 10% of podophyllotoxin, whose generic name has become podofilox in the United States (79). Podofilox is synthesized and purified from Podophyllum and Juniperus plant species.

鬼臼树脂和普达非洛：鬼臼树脂很长时间以来是治疗尖锐湿疣的骨干药。它是从美国曼德拉草（鬼臼属植物，盾叶鬼臼）根状茎提取出来的一种树脂，而生长在喜马拉雅的这种植物效力更强，较矮小。现在被制作为鬼臼树脂安息香酊，其中浓度为25%用来治疗疣体（Table 2）。它主要由黄酮醇和木脂素等两类物质组成，其中后者具有抗病毒活性，尤其是在鬼臼毒素中。鬼臼树脂为10%的鬼臼毒素，在美国它的通用名为普达非洛(79)。普达非洛是鬼臼属和刺柏属植物的合成纯化物。

Podophyllin and podofilox, like colchicine bind to tubulin and block tubule polymerization (80). The most obvious consequence is the disruption of the mitotic spindle, which causes mitotic arrest of the cell. Because HPV-infected tissues divide more actively than the surrounding healthy epithelium, they are primarily affected by podophyllin. Podofilox may also damage HPV DNA itself (28).

鬼臼树脂和普达非洛能像秋水仙碱一样，结合微管蛋白并且阻止微管聚合(80)，这将导致纺锤体的破坏，从而抑制细胞的有丝分裂。因为HPV感染的组织的分裂活动比周围的正常表皮更加活跃，因此鬼臼树脂主要对病变起作用。普达非洛还可能直接损伤HPV DNA(28)。

The variable content in podofilox of podophyllin affects its potency and toxicity (81). Therefore the introduction of purified podofilox as a commercial product (Table 2) made available a product that was less toxic and more active on a weight basis (82). An important consequence was that podofilox became the first drug for genital warts that could be self-administered by the patient (83, 84).

鬼臼树脂的成份会影响药物的效果和毒性(81)。提纯的普达非洛，作为一种商品化产品(Table 2)，毒性更低并且在相同剂量下疗效更强(82)。因此它成为尖锐湿疣患者第一个可以自用的药物(83, 84)。

Podophyllin has been compared to various therapies but not to placebo for the treatment of genital warts. There has been either no difference between podophyllin and podofilox (85-89), or the latter has been superior to the former in yielding a complete response (90, 91). Podophyllin was inferior to either cryotherapy or electrosurgery (92), and to cold-blade excisional surgery (93, 94) in clearing warts.

Podophyllin has been used for the treatment of extra-genital warts, such as plantar warts (95) and oral warts (96), but this represents an uncommon use (Table 1).

鬼臼树脂已经和多种治疗生殖器疣的方法进行过比较，但是没有与安慰剂的比较。有些研究中，鬼臼树脂和普达非洛没有显著性差异(85-89)，而在另一些研究中，在反应的完全性方面，后者要好于前者(90, 91)。鬼臼树脂疗效略逊于冷冻和电外科治疗 (92)，并且在清除疣体方面比挖除效果差(93, 94)。

鬼臼树脂还可以用于生殖器以外的疣体的治疗，例如扁平疣(95)和口腔疣(96)，但是应用的比较少(Table 1)。

Podofilox 0.5% solution, which is now commercially available (Table 2), has been superior to placebo vehicle (97-99). Formulation of podofilox in a viscous vehicle was desirable because the solution tends to run-off on the healthy skin. A 0.5% cream formulation has been evaluated in Scandinavia, and was found to be superior to the placebo vehicle (100-103), or interferon cream (102, 103). It was as effective as the solution formulation in inducing wart clearance (104-106). A podofilox 0.5% gel formulation that was also approved for the treatment of perianal warts has been introduced on the American market. In a randomized, double blind, placebo-controlled study, 81 of 181 (45%) patients treated with the podofilox gel formulation had complete wart clearance after 8 weeks, compared to only 5 of 93 (4%) vehicle recipients (107). The sex of the patient or the location, perianal or external genital, of the warts did not affect the treatment response. A shortcoming of podofilox, and of podophyllin as well, is the high rate of relapse or recurrence (Table 2). Prophylactic application of podofilox has been found to prevent recurrences during the prophylaxis period, but this is not likely to be a convenient solution for most patients (108).

普达非洛的0.5%溶液已经上市，效果优于安慰剂。因为该溶液易于流到正常皮肤(Table 2)，所以普达非洛的粘着基质的制剂效果会更满意(97-99)。在斯堪的纳维亚，已经对0.5%的乳膏做了评估，疗效优于安慰剂(100-103)和干扰素乳膏(102, 103)。在诱导疣体清除方面，它与溶液制剂的效果相当(104-106)。普达非洛0.5%的凝胶已经在美国上市，被批准用于肛周疣体的治疗。在一个随机、双盲、安慰剂对照的研究中，181名患者在应用普达非洛凝胶8周后81名患者疣体完全消除（45%），而在93名应用基质安慰剂的患者中仅有5例疣体清楚（4%）(107)。患者的性别和疣体的部位（肛周或者外阴）均对疗效没有影响。普达非洛以及鬼臼树脂的缺点是高复发率(Table 2)。预防性的应用普达非洛可以阻止疣体的复发，但是对大多数患者来说，这种溶液使用起来可能并不方便(108)。

Podophyllin and podofilox may cause local and systemic side-effects (81, 109, 110). Itching, pain, inflammation, erosions or ulcerations, bleeding, burns are found in decreasing order of frequency, with rates ranging from 17% to 1% (87, 90-94, 111-113). Occasionally this may lead to scarring or fecal incontinence (90, 94). Also, contact dermatitis to the benzoin vehicle or guaiacum wood contaminants can occur at the site of application. Because of the risk of severe inflammation and tissue necrosis, painting the healthy skin and leaving the medication more than 24 hours should be avoided.

普达非洛以及鬼臼树脂可能会引起局部和全身性副作用(81, 109, 110)。在应用17%到1%的浓度时，瘙痒、疼痛、炎症、糜烂、溃疡、出血、烧灼等的发生率递减(87, 90-94, 111-113)。偶尔还会引起瘢痕形成或者大便失禁(90, 94)。在应用药物的部位，还有可能发生安息香基质或者愈创木杂质接触性皮炎。因为有可能导致严重的炎症和组织坏死，所以应该避免用于正常皮肤，而且药物作用时间不应该超过24小时。

Podophyllin should not be applied more than once a week (114). One should be aware that the histology of the treated skin may exhibit the presence of large keratinocytes (podophyllin cells) and abnormal mitoses in the lower third of the epidermis; features that may be confused with intraepithelial neoplasia (115, 116). Systemic side-effects, particularly with podophyllin, may develop after topical therapy because the drug is readily absorbed by the skin. Typically, nausea and vomiting precede neurological signs of sensory and motor neuropathy, seizure, and coma. Death may occur (82, 114). Hematologic (neutropenia, leucocytyosis, pancytopenia), pulmonary (tachypnea, respiratory failure), and renal (hematuria, renal insufficiency) may also develop systemic side-effects (114). Podophyllin use is contraindicated during pregnancy because the compound is mutagenic and abortifacient (117, 118).

鬼臼树脂最多每周就能应用一次。应用该药物后皮损处可以出现体积增大角质蛋白细胞（鬼臼树脂细胞）和在表皮下三分之一会出现异常有丝分裂的组织学改变，后者容易与上皮内瘤样病变混淆(115, 116)。在局部应用后，药物会很快被皮肤吸收，可以引起全身性的副作用，尤其是鬼臼树脂。一般情况下，早期会引起恶心、呕吐，之后还有可能出现感觉和运动神经系统的体征、癫痫发作以及昏迷。还有可能引起死亡(82, 114)。全身性的副作用还有血液系统（嗜中性白血球减少症、白细胞减少症和全血细胞减少），肺脏（呼吸急促、呼吸衰竭），肾脏（血尿、肾功能不全）(114)。孕妇禁用鬼臼树脂，因为它是诱突变剂，还会导致流产(117, 118)。

5-Fluorouracil: 5-Fluorouracil (5-FU) is a structural analog of thymidine, a pyrimidine, that blocks the methylation of deoxyuridylic acid into thymidylic acid thus interfering with the synthesis of DNA and, to a lesser extent, RNA. Dividing cells are particularly susceptible to its action, and it has been used topically in dermatology for the treatment of varied condition, including genital warts (Tables 1 and 2).

5-氟尿嘧啶：5-氟尿嘧啶是一种嘧啶类化合物，与胸苷的结构类似，可以阻止脱氧尿苷酸的甲基化变成成胸苷酸的过程，从而抑制DNA的合成，对RNA也有轻微的抑制作用。它对分裂期细胞的抑制作用最强，皮肤科已经应用5-氟尿嘧啶局部外用治疗包括生殖器疣在内的多种疾病(Tables 1 和2)。

A great variety of regimens, most with a 5% cream, have been reported in the literature for the treatment and prophylaxis of genital warts (119-132). The results are difficult to evaluate given the diverse dosings, from twice a day to weekly and from a few days to 10 weeks, and the paucity of comparative studies. In a randomized study, 5-FU 5% cream applied at bedtime for two weeks was not different than podophyllin applied weekly for 4 weeks in the rate of genital warts resolution in males, 6 of 18 (33%) versus 10 of 19 (53%) patients, respectively (p = 0.33) (123). No statistically significant difference was noted in female patients with past genital warts in the prophylactic activity of 5-FU compared to no intervention (126). Intrameatal warts in the male appear to be one of the few first-line treatment indications of 5-FU. Daily administration for 3 to 14 days has produced lesion resolution rates of up to 95% (121, 122, 133). 5-FU can also be used for the treatment of mosaic warts (134).

文献报道了治疗和预防生殖器疣的多种治疗方案，其中以使用5%的乳膏研究最多(119- 132)。用药次数从每天两次到每周一次，治疗周期也从几天到10周不等，由于剂量的不同很难对结果进行评价，缺少对比研究。在一项关于男性患者随机研究中，5%的5-FU乳膏每晚应用，疗程为4周，生殖器疣体的清除率与鬼臼树脂没有明显区别，分别为18人中有6人（33%）和19人中有19人（53%）的疣体清除(p = 0.33) (123)。既往患过尖锐湿疣的女性预防性应用5-FU与不做任何干预没有显著的不同(126)。5-FU是男性腔道内疣体治疗的一线推荐用药，是仅有的一线推荐治疗方法。每天应用该药，3到14天后，皮损的清除率可以达到95%以上(121, 122, 133)。5-FU还可以用于治疗马赛克样疣(134)。

Adverse reactions to topical application of 5-FU vary greatly in their frequency and nature, according to the regimens used. Pain, itching, burning, erosions, hyperpigmentation are the more common local side-effects, encountered in up to half of the patients. Fair-skinned individuals might be particularly susceptible (135). Not as frequent but more serious events may include contact and allergic dermatitis, and, with vaginal therapeutic use, chronic vaginal ulcerations (136-138). The development of vaginal adenosis and vaginal clear cell carcinomas have been linked to 5-FU intravaginal use. 5-FU has also caused hematologic complications (leukopenia, thrombocytopenia, toxic granulations, and eosinophilia) (139). The administration of 5-FU during pregnancy has not been associated with adverse effects on the baby, but safety cannot be considered to be established (140-142).

局部应用5-FU的副作用与用药的频率和体质关系密切。疼痛、瘙痒、灼烧、糜烂、色素沉着是最为常见的副作用，高达半数的患者可能出现。浅肤色的患者会尤其明显(135)。少见但更加严重的副作用有接触性过敏反应，当应用于阴道时，还有可能出现慢性女阴溃疡(136-138)。阴道腺体病和阴道透明细胞癌与阴道内应用5-FU有关。5-FU还有可能引起血液系统的并发症（白细胞减少、血小板减少、中毒颗粒和嗜酸性细胞增多症）(139)。孕期应用5-FU不会对婴儿有副作用，但是用药的安全性还不确定(140-142)。

Interferons: Interferons (IFN) are cytokines with immunomodulatory, antitumor, and antiviral properties (143). Three major classes are recognized: a, b, and g (Table 2) . IFN-a and -b share the same cellular receptor, while IFN-( uses a different one. Mucosal high-risk HPVs oncogenes (especially E7) downregulate the expression of IFN-responsive genes, including the tumor suppressor protein interferon regulatory factor-1, and a net effect is the reversal of the antiproliferative and antitumoral functions of IFN (144-148). The results of in vitro experiments suggest that these effects may vary from individual to individual, thus accounting for heterogeneity in treatment response (149). IFNs are manufactured as full, truncated, consensus, or hybrid gene products in human lymphoid cell cultures (e.g., IFN-b, IFN-a-2a) or by recombinant technology (e.g., IFN-a-2a, -2b, -2c). Further molecular alterations, such as pegylation, has been used to alter the pharmacologic pro le of IFN-a-2a and -2b and lengthen their half lives (150).

干扰素：干扰素（IFN）是一种细胞因子，具有免疫调节、抗肿瘤、抗病毒作用 (143)。主要包括a,b 和 g 三类(Table 2)，其中a 和b的细胞受体相同，而IFN-g 使用另一个受体。粘膜的高危HPV基因（尤其是E7），可以下调肿瘤抑制蛋白干扰素调节因子-1，净效应就是逆转IFN的抗增殖和抗肿瘤作用(144-148)。体外研究表明，这种效应的个体差异很大，所以每个人的治疗反应也有很大不同(149)。IFN可以通过人淋巴样细胞培养获得全长的、部分的、均一或者混合的基因产物(例如, IFN-b, IFN-a-2a)，也可以通过基因重组技术获得(例如, IFN-a-2a, -2b, -2c)。进一步的修饰，例如聚乙二醇化，用以改进IFN-a-2a和-2b药理学缺陷，延长它们的半衰期(150)。

Topical IFN preparations are not available in the United States. By and large they have proven ineffective for the treatment of genital warts (151-154), despite some investigators reporting favorable results with a natural IFN-a ceam or gel (102, 103, 155). It is unclear if the efficacy differences among trials can be accounted by the vehicle used (103, 153). An IFN-b gel may be useful for the prevention of recurrences after excisional or ablative therapy (156).

美国没有局部外用的IFN。虽然有些研究表明，应用天然IFN-a乳膏或者凝胶会对疾病有帮助(102, 103, 155)，但总体上，这已经证明IFN治疗生殖器疣体无效(151-154)。还不清楚这些实验的不同结果能否因实验所用的溶剂不同来解释(103, 153)。手术或者腐蚀治疗后,可用IFN-b凝胶来预防其复发(156)。

Intralesional administration of IFN has been widely assessed for the treatment of condylomata acuminata, especially in randomized, controlled trials. It has shown superiority to placebo, but the net effect has been modest, imperfectly sustained, and limited usually to the injected lesions (113, 114, 143, 157-169). Pain on injection is the main adverse effect. This and the fastidious mode of delivery limit the number of lesions that can be treated at each session. Intralesional IFN has been ineffective for the treatment of plantar warts (170).

局部注射IFN治疗尖锐湿疣被广泛的评价，尤其是随机对照实验。研究表明这种治疗比安慰剂效果好，但是作用较弱，不能持续，作用仅局限于注射部位(113, 114, 143, 157-169)。注射的主要副作用是疼痛。还有给药方式的复杂也限制了只能用于皮损数目少的病人。局部注射IFN治疗跖疣无效(170)。

Parenteral (intramuscular or subcutaneous) IFNs for the treatment of genital warts have not been found to be superior to placebo or to add anything in combined treatments in most randomized studies (162-165, 171-183). Parenteral IFN has probably a biologic effect on benign genital disease, but one that is usually too weak. This impression is based on the results of a couple of placebo-controlled, randomized clinical trials in which a statistically significant treatment effect was found, with relative risks of 4.5 (184) and 1.8 (185). It also takes into consideration the results observed with parental IFN in the treatment of recurrent respiratory papillomatosis (186, 187).

大多数随机研究表明，静脉注射（肌肉注射或者皮下注射）IFN治疗生殖器疣的效果并不比安慰剂好，对综合治疗没有任何的帮助(162-165, 171-183)。静脉注射IFN有可能会对良性生殖器疾病有效，但是通常是十分微弱的。这个结论是基于一个双安慰剂对照随机的临床研究，该研究发现了显著的治疗效果，相对危险度分别为4.5(184)和1.8(185)。静脉注射IFN治疗复发性呼吸道乳头瘤病毒的效果也值得考虑(186, 187)。

The adverse reactions associated with IFNs are well known. They are in part dose-related and usually reversible after drug cessation. The most common symptoms resemble those of influenza except for the respiratory component and include fever, chills, malaise, headache, myalgias, and fatigue. They appear within 2 to 8 hours of the drug administration and wane within 24 to 48 hours. In the clinical trials of IFN for the treatment of genital warts, these clinical symptoms have been almost the only ones encountered. They can be curbed by the intake of acetaminophen or nonsteroidal anti-inflammatory agents at the time of IFN administration. The intensity of these symptoms progressively wanes during treatment. More serious adverse reactions include lethargy, confusion, anxiety, depression, suicide, insomnia, weight loss, anorexia, nausea, vomiting, alopecia, cutaneous necrosis, and peripheral neuropathies. Biological abnormalities, mostly asymptomatic, may include neutropenia, thrombocytopenia, high serum transaminases, and occasionally anemia and hypertriglyceridemia. Patients may develop binding, and possibly neutralizing, antibodies to IFN. Pregnancy is a contraindication to the use of IFN. Although there are differences in efficacy and the intensity of the side-effects among IFNs, they are small and usually of no clinical significance (160, 168, 172, 173, 188).

IFN相关的副作用为大家所熟知，有部分的剂量相关性并且停药之后可以逆转。最常见的症状是发热、寒战、不适感、头痛、肌痛和疲乏等，与流行性感冒相似，但是没有呼吸道症状。应用药物2到8小时后出现症状，24到48小时内逐渐减弱。IFN治疗生殖器疣的临床研究中，这些症状几乎是唯一出现的不良反应。应用IFN的同时口服对乙酰氨基酚或者非甾体类抗炎药可以缓解这些症状。更严重的副作用包括昏睡、意识模糊、焦虑、抑郁、自杀倾向、精神失常、体重下降、食欲减退、恶心、呕吐、脱发、皮肤坏死和其他的周边神经病变。嗜中性白细胞减少症、血小板减少症、血清转氨酶升高以及很少发生的贫血和高甘油三酯血症等生物学异常，通常没有症状。患者还会产生可结合的IFN抗体，很可能这些抗体具有中和作用。虽然IFN的疗效和副作用的强度存在争议，但是疗效很小，没有临床意义(160, 168, 172, 173, 188)。

Curettage and Cold-Blade Excision: Surgical curettage has been used to treat cutaneous warts, especially plantar, and occasionally genital warts (189-191). This old technique has not been rigorously evaluated (192). Its main shortcoming is the possible formation of scars, which may be painful. Curettage has to be done under local anesthesia by local injection. The EMLA cream (lidocaine and prilocaine) has been unsatisfactory for the topical anesthesia of plantar warts (193).

刮除和剪除：外科刮除术用来治疗皮肤疣，尤其是跖疣，有时也会用来治疗生殖器疣(189-191)。这种古老的方法没有严格的评价(192)。它的最主要的缺点是有可能形成瘢痕，并且会有疼痛。刮除术必须在局部麻醉下才能进行，跖疣患者应用恩纳乳膏（利丙双卡因）表面麻醉的效果不理想(193)。

Genital warts can be excised with scissors, especially if they are few in number. Thomson and Grace described a widely used technique (194). This is an effective treatment, and although scarring may occur in up to 10% of patients, it is usually minimal in extent (Table 2) (93, 195, 196). In comparative trials, excision has proven superior to podophyllin, notably because of the much smaller recurrence rates, thus giving at 9-12 months net wart clearance rates of 13/18 (72%) and 20/30 (67%) in two different studies (93, 94).

生殖器疣可以用剪刀剪除，尤其是当疣体较少时。汤姆松和格拉斯描述了这种被广泛应用的方法(194)。这是一种有效的治疗方法，虽然有接近10%的人会导致瘢痕形成，但是瘢痕一般范围很小(Table 2) (93, 195, 196)。在对照研究表明，剪除效果优于鬼臼树脂，复发率更低。两个不同的研究中，随访9-12周后疣体的清除率分别为72%（13/18）和67%（20/30）(93, 94)。

Cryotherapy: Cryotherapy is the treatment by cold. Cold is delivered by either spraying the lesion with liquid nitrogen (boiling point, BP = -196°C), or applying a cryoprobe, a cryogenic pencil, or a cotton swab cooled with liquid nitrogen, nitrous oxide (BP = -89.5°C), or carbon dioxide (BP = -78.5°C). Spraying is not necessarily superior to contact freezing at the same temperature. However, because HPV DNA can be recovered on fomites and because cryogenic pencils have been associated with wart transmission, liquid nitrogen spraying is the preferred method of cryotherapy delivery unless disposable contact equipment is used (197-199). Cotton swabs are preferable to freeze lesions that are close to fragile structure such as the eye. Freezing techniques vary, but they aim at the abrupt cooling of the lesion and a surrounding halo of normal skin, thus causing them to turn white (200-202). The duration of freezing varies with the lesion size, but typically ranges from 20 to 30 seconds. Some practitioners recommend after thawing the application of a second freezing, which might be advantageous for the treatment of plantar warts, and perhaps hand warts (203). Very often several sessions, one to two weeks apart are necessary to achieve a complete clearance. Cryotherapy leads to tissue necrosis but not in the destruction of HPV DNA (28, 204, 205).

冷冻疗法：冷冻疗法是通过低温进行治疗。低温可以通过液氮（沸点BP =-196°C）喷布皮损或者应用冷冻器、制冷笔或者用棉签蘸取液氮、氧化亚氮-89.5°C)、二氧化碳(BP = -78.5°C)来获得。在相同温度下，喷布法并不一定优于接触法冷冻。然而因为HPV DNA可以在污染物中复活，制冷笔有可能造成病毒的传染。因此除非采用一次性的接触设备，喷布法是首选的冷冻疗法(197-199)。容易受伤的部位（例如眼睛）周围的的皮损最好采用棉签法来冷冻。尽管冷冻的方法很多，但是原理都是使病损及周围的正常皮肤的温度突然降低，导致皮肤变白(200-202)。冷冻的时间随着皮损大小变化，但一般是20至30秒。有些医生主张在病损完全融冻后再次冷冻，这可能对跖疣和掌疣的治疗有帮助(203)。如果想皮损完全清除，一到两周后需要几次重复治疗。冷冻治疗会导致组织坏死，但是不能破坏HPV DNA(28, 204, 205)。

An intense pain is associated with the application of the cryogenic. Because of its brevity, most patients tolerate it. Should local anesthesia be used, the EMLA cream is a convenient and effective solution, as long as the patient can apply it about 1 hour before the procedure (206-208). After thawing, up to half the patients will experience mild to moderate discomfort, itching, burning, or pain (177, 209). Excessive freezing may cause blistering and edema. This should be avoided. Long-term, skin discoloration was noted 6 months after cryotherapy in a quarter of patients treated for genital warts (177). This is likely to disappear with time. Joint damage and neuropathies have resulted from cryotherapy (210, 211). Pregnancy is not a contraindication.

冷冻治疗会引起严重的疼痛。但是一般都非常短暂，大多数病人都能耐受。也可以应用局部麻醉，恩纳乳膏是非常有效和方便的，只需要在冷冻治疗前1小时应用(206-208)。冷冻的皮损融冻后，一半的患者发生轻度至中度的不适、瘙痒、烧灼或者疼痛(177, 209)。过度的治疗会导致发疱和水肿，应该尽量避免发生。冷冻治疗六周后，治疗生殖器疣得患者中有四分之一出现长期的色素减退(177)，这种情况会慢慢消失。冷冻疗法还有可能导致关节损害和神经疾病(210, 211)。怀孕并不是冷冻疗法的禁忌症。

Cryotherapy is one of the most often used treatment modalities for genital warts (Table 2). Its efficacy has been established mostly in open studies without a control group (111, 212-217), and in a few instances in comparison to established therapies (30, 92, 218, 219). Complete response rates typically range from 65% to 85%, but recurrences occur in 20 to 40% of patients. Therefore, the net clearance rate is about 60%. This rate allows to gauge the relative efficacy of cryotherapy (Table 2). This comparative ranking has been confirmed by several randomized comparative trials. Hence cryotherapy is superior to podophyllin (92, 219) and podofilox, but equivalent to TCA (29, 30), and probably electrosurgery (92). Cryotherapy appears to be well-suited to the treatment of intrameatal warts (220).

冷冻疗法是治疗生殖器疣最常用的方法(Table 2)。它的疗效大多数是通过没有对照组的开放式研究证实的(111, 212-217)，也有少数研究把冷冻疗法与其他治疗方法做了比较(30, 92, 218, 219)。总体的应答率为65%至85%，但是会有20%至40%的患者复发，因此总的清除率大概为60%。这个清除率用来衡量冷冻疗法的效果(Table 2)，一些随机对照研究已经确认了相应的评分标准。因此冷冻疗法的效果优于鬼臼树脂和普达非洛(92, 219)，与TCA疗效相当(29, 30)，与电外科治疗的疗效也大概近似(92)。冷冻疗法也十分适合用于腔道内的疣体(220)。

Cryotherapy is also used for the treatment of cutaneous warts, and is favored by patients for the treatment of hand warts (Table 1) (221). Long-term clearance rates of about 50% can be expected (222). The technique is the same as with genital warts (197, 222, 223). Plantar warts tend to be more resistant to cryotherapy than hands warts (224, 225).

冷冻疗法也可以治疗皮肤疣体，有些手部疣体的患者乐于接受冷冻疗法(Table 1) (221)。方法与生殖器疣的治疗相同(197, 222, 223)。治疗跖疣的效果要比手部疣体差(224, 225)。

Electrosurgery: Electrosurgery includes various techniques that ablate tissue with electric current (226). These techniques are not necessarily interchangeable. They vary according to the amperage, voltage, and wave-form of the current, whether one or two electrodes are used, and whether they touch the treated tissue. Hence the names of electrocautery, electrodiathermy, electrodessication, electrofulguration, electrocoagulation, and electrosection in a nomenclature that is not always consistent among authors. Although commonly used by dermatologists and surgeons, the methods of electrosurgery have not been compared to one another, and only rarely with other techniques for the treatment of genital warts or cutaneous warts.

电外科手术：电外科手术包括多种技术，都是利用电流切除病损组织。这些技术並不是不能相互取代的，这会随着以下因素发生变化：电流、电压、电流的波形、电极的数量和是否与组织接触。因此电烙法、电透热疗法、电子干燥、电灼疗法、电凝法、电切除术等术语的表述并不一致。虽然皮肤科和外科都经常用到电外科治疗，但是他们之间并没有做过比较，只有很少的研究将它与其他治疗生殖器疣或者皮肤疣的方法进行了比较。

For the treatment of genital warts, electrocoagulation has yielded a clearance rate of 58/100 (227), while in another study comparing podophyllin, cryotherapy, and electrodessication, the net clearance rates at 3 month, assuming that subjects lost to follow-up were failures, were 9/63 (14%), 36/83 (43%), and 33/68 (49%), respectively (92). These differences were statistically significant among treatment groups ( p < 10^-4), but not when electrosurgery was compared to cryotherapy. Another study comparing electrocautery to cryotherapy was unable to demonstrate a statistically significant difference, with genital wart clearance rates of 10/11 (91%) and 10/16 (63%), respectively (218). Electrodiathermy was superior to either intramuscular or subcutaneous IFN (228). Intralesional IFN-a may reduce the number of recurrence after electrocautery (163, 229).

应用电凝治疗生殖器疣，可以达到58%的疣体清除率(227)，然而在另一个与鬼臼树脂、冷冻疗法和电外科治疗的比较研究中，假定失访的病例是治疗失败的，三组经过治疗三个月后的净清除率分别为9/63(14%)、36/83（43%）和33/68（49%）(92)。治疗组之间有显著性差异，但是电外科手术与冷冻疗法之间没有差异。另一个研究对比电外科手术与冷冻疗法，两者之间没有显著性差异，生殖器疣的清除率分别为0/11 (91%) 和10/16 (63%)(218)。电外科手术效果优于肌肉或者皮下注射IFN (228)。电灼手术后局部注射IFN-a，能降低复发率(163, 229)。

Electrofulguration is suitable for the treatment of facial warts (230). However, electrosurgery is usually not recommended for the treatment of plantar warts because the painful scarring that may ensue (230).

Regardless of the site and method used, scarring, with the possibility of sphincter strictures, is the main risk of electrosurgery. The technique should be left to the hands of the expert. The procedure itself is painful and requires local anesthesia, which can be provided by the application of the EMLA cream (193, 231, 232).

Electrosurgery, like laser surgery, emits a plume of smoke that contains HPV DNA (233, 234). This is a potential infectious risk for the operator and the assistants that can be handled by smoke evacuation systems.

电灼疗法可以用来治疗面部的疣体，但是跖疣不推荐电外科手术治疗，因为有可能形成疼痛性瘢痕。

不管用什么方法或者什么部位，瘢痕形成和可能发生的括约肌狭窄是电外科手术的主要风险。电外科手术需要专业由专业人员来操作。操作本身会引起疼痛，需要局部麻醉，使用恩纳乳膏可以达到局部麻醉的效果(193, 231, 232)。

与激光手术一样，电外科手术会产生含有HPV DNA的烟雾，这使得手术者有被传染的风险，助手使用排风系统可以解决这个问题。

Laser Surgery: Lasers emit a narrow monochromatic light that is in phase and whose waves travel in separate parallel planes, thus without loss of energy in transparent media. A great variety of medical lasers exist, and among them the pulse dye, Er:YAG, and Nd:YAG lasers, which are pulsed-wave instruments, and the argon, and KTP lasers, which are continuous-wave lasers, have been used for the treatment of warts (235-237). However, it is the CO₂ laser, a continuous wave instrument that has been the most extensively used for the treatment of anogenital disease. It has a wavelength (10,600 nm) that is absorbed by water and is converted into heat. This allows the vaporization of the treated tissues. The laser can be used for cutting when using a narrow, intense beam (238). By using a broader spot the lesion itself can be destroyed. A lower intensity beam ("brushing technique") will cause tissue coagulation and hemostasis.

激光手术：激光发射窄谱单色光，光波在同一时相沿单独的平行面传播，因此在传播介质中没有能量的损失。有很多种医用激光，其中Er:YAG和Nd:YAG脉冲激光用来治疗疣体，该激光由脉冲装置、氩气、和KTP连续波激光组成。而二氧化碳激光，一种连续波装置，最常用于治疗肛门生殖器疣。它的波长为(10,600 nm)，可以被水吸收并且转变成热能，这可以使接受治疗的病变组织气化。集中的强束激光可以用来切割组织，如果用大的光束，病变组织可以被破坏，低能量的光束会引起病变组织凝固并且有止血作用。

Laser surgery destroys the treated tissue but not the HPV DNA (239). Indeed, as with electrosurgery, HPV DNA can be found in the plume of smoke produced by the vaporizing laser. This HPV DNA can also be detected in the operator's upper airways and on the walls of the surgical suite (233, 234, 240, 241). This appears to represent a real infectious risk because a higher incidence of hand and nasopharyngeal warts has been reported in laser surgeons (242). Consequently, a smoke evacuation system should be part of the equipment, and the operator should wear gloves, gown, mask, and goggles. This infectious risk probably varies with the type of laser used, for example, the erbium: YAG laser does not seem to release HPV DNA (243).

激光手术可以破坏病变组织而不是HPV DNA(239)。事实上激光手术与电外科手术一样，蒸发的激光所产生的烟雾中可以检测到HPV DNA，在激光术者的上呼吸道以及手术设施的表面也可以检测到HPV DNA(233, 234, 240, 241)。这确实有感染的危险，有报道证实，激光术者手和鼻咽部疣的发病率升高(242)。因此，排风装置是必备装置，而且手术者需要戴手套、穿隔离衣、佩戴面罩和护目镜。这种感染风险的高低与激光的类型相关，例如，YAG激光就很少释放HPV DNA(243)。

Anogenital warts are amenable to laser surgery (Table 2) (135, 235, 236, 244-246). However, it is very difficult to ascertain the true merit of this modality because most of the literature is made of case-series, and techniques and operator’s experience vary (247). One randomized controlled trial has compared laser surgery to a treatment consisting of either cold-blade surgery, electrosurgery, or both (196). Fourteen of 21 (67%) patients remained free of lesions at up to 6 months follow-up in the laser treated group, compared to 13/22 (59%) in the other group. The other available randomized controlled trials have only compared laser surgery to laser surgery plus something else given to reduce the recurrence risk. Table 2 summarizes the clearance rates observed in the laser surgery alone arm of these trials.

激光手术治疗肛门生殖器疣确实有效(Table 2) (135, 235, 236, 244-246)。以前的文献大部分为一组病例，而且技术和术者的经验不断变化，所以很难明确这种方法的优点(247)。一个随机对照实验对激光手术、剪除手术、电外科手术或者两者联合做了比较(196)。经过激光治疗6个月后，21人中有14人没有复发，清除率为67%，而其他组的清除率为59%（13/22）。另一项随机对照试验对单纯激光治疗和激光联合其他用来减少复发的方法做了比较。Table 2概述了这个实验中单纯应用激光组的疣体清除率。

Laser surgery has been also used to eradicate cutaneous warts, particularly plantar warts, common warts, including the periungual and subungual variants (Table 1). No comparative, randomized studies are available to permit a reliable assessment of an efficacy that is otherwise reported to be good. As with genital warts, the CO₂ laser has been the favored instrument (236, 248-254). However, a greater diversity of lasers are used, including the pulse dye laser (255-262), the KTP laser (263), the Nd:YAG laser (264), and the Er:YAG laser (265, 266). The Er:YAG laser induces little thermal damage, yet the hyperthermia may be sufficient to eliminate plantar warts and the HPV particles present within (205).

激光治疗还可以治疗皮肤疣，尤其是跖疣、寻常疣（包括甲周的和甲下疣）(Table 1)。各种报道显示治疗效果好，但是没有对比的随机研究对其疗效做确切的评估。二氧化碳激光最常用来治疗生殖器疣(236, 248-254)，然而有各种各样的激光可以治疗皮肤疣，包括脉冲染料激光(255-262)、KTP激光(263)、Nd:YAG激光(264)、Er:YAG激光(265, 266)等等。Er:YAG激光的热损伤很小，而高热可以充分清除跖疣和内部的HPV颗粒(205)。

Laser surgery requires anesthesia usually delivered locally by injection or by the application of EMLA cream (267-269). Nevertheless, general anesthesia may be needed, especially if the lesions are extensive. This of course adds to the cost, usually high, of the procedure. The side effects of laser surgery, which occur in up to a quarter of patients, include postoperative pain, bleeding, discharge, swelling, dysuria, meatal stenosis and scarring (135, 196, 270-273). Laser surgery can be used during pregnancy.

激光治疗通常需要局部麻醉，可以注射局部麻醉或者外用恩纳乳膏(267-269)。然而有时候也需要全身麻醉，尤其是当皮损广泛的时候。激光手术通常都比较贵，麻醉过程也会导致费用增加。四分之一的患者会出项手术后疼痛、出血、渗出、肿胀、排尿困难、尿道口狭窄和瘢痕形成等副作用(135, 196, 270-273)。怀孕期间也可以应用激光治疗。

This chapter is limited to the treatment of cutaneous and external anogenital warts. Other HPV-associated lesions such as warts, papillomas, intraepithelial and invasive neoplasias affecting the internal teguments (upper airways, mouth, cervix, vagina, anal canal) are the province of different specialists, as is the treatment of external pre-invasive and invasive neoplasias.

由于篇幅所限，皮肤和肛门生殖器以外的疣不能详述。其他HPV相关的损害例如疣、乳头瘤、上皮内瘤及侵袭性肿瘤可以感染体内上皮（上呼吸道、口腔、宫颈、阴道、肛管），这些需要专科医生的治疗，体表的癌前期和侵袭性肿瘤也同样需要专科医生来处理。

In addition to possible symptoms, cosmetic considerations are important in deciding to treat warts. It is therefore important to select and apply treatments that not only are unlikely to cause permanent symptoms, but also will not leave scars or other unsightly results. It is important to remember that cutaneous and external anogenital warts are very rarely life-threatening, progress almost never to malignancy in the presence of an intact immune system, and are likely to spontaneously resolve over time. For example, in children the rates of spontaneous resolution of cutaneous warts are 50% and 90% at 1 and 5 years, respectively (274). A meta-analysis of the placebo arm of several clinical trials suggest a 30% clearance rate at 10 weeks (275). Adults are expected to have lower rates of spontaneous clearance. For genital warts, the rate of spontaneous resolution may be as high as 10-20% after 3-4 months of follow-up (172, 173). It is unfortunately impossible to predict which patients will have a spontaneous regression.

在选择治疗方案的时候，除了可能的症状之外，还要考虑到美容。因此我们所应用的方案不仅要没有长期的症状还要不遗留瘢痕或者其他不美观的东西，这一点十分重要。而且我们要知道皮肤疣和表面的肛门生殖器疣体很少会威胁生命，在免疫力健全的情况下几乎不会恶变，经过一段时间还有可能自动消退。例如，儿童皮肤疣经过1年和5年后，疣体自动消退的几率分别为50%和90%(274)。对一些临床实验的结果进行meta分析后证实，10周疣体的自动清除率为10%(275)。成人的自动清除率较低。尖锐湿疣经过3-4月后的自动清除率为10%-20%(172, 173)。不幸的是我们并不能预测什么人可以自动清除。

Failure to respond to previous treatment defines a recalcitrant or refractory wart. Most patients with recalcitrant warts, especially anogenital, are not necessarily more likely to fail the next treatment than a patient treated for the first time (113, 161, 276). It does not seem that size or number of anogenital warts is a reliable predictor of failure (113, 159, 277). Long disease duration seems a better predictor of refractoriness of anogenital warts (157, 159, 172, 277). Immunosuppression or immunodeficiency is a major hindrance to wart clearance.

对之前的治疗没有反应，定义为难治性或者顽固性疣。难治性疣的患者，尤其是肛门生殖器疣的患者，进行下一个治疗时，并没有比第一次接受治疗的患者更容易治疗失败(113, 161, 276)。通过疣体的大小和数量也不能预测出是否更容易治疗失败(113, 159, 277)，而长病程是肛门生殖器疣治疗抵抗的较好的预测指标(157, 159, 172, 277)。免疫抑制或者免疫缺陷是疣体清除的主要障碍。

Cutaneous Warts: Most cutaneous warts remain untreated because they cause little or no inconvenience and resolve spontaneously. When treatment is requested and/or is appropriate, the practitioner is confronted with many treatment options for which, unfortunately, the current literature and its dearth of comparative trials fail to provide good objective decision criteria (Table 1). Consequently, availability, familiarity, safety, and cost of the treatment modalities are the major elements in making a decision. Several guidelines try to offer further guidance (52, 275, 278, 279). As a general principle, plantar warts, especially mosaic warts, are more difficult to eradicate than hand warts. Flat warts clear best (Table 3).

皮肤疣：因为皮肤疣很少或者没有不适症状并且会自动消除，所以大多数皮肤疣不需要治疗。如果确实需要治疗或者病人要求治疗，医生可以有很多种选择。但是不幸的是当前的文献缺少对照性研究，不能提供一个客观的选择标准(Table 1)。因而可行性、熟练程度、安全性以及花费是做选择治疗方法时需要考虑的要素(52, 275, 278, 279)。一般来说，跖疣，尤其是马赛克样疣比手部疣更难清除，而扁平疣是最容易清除的(Table 3)。

Home treatment should be privileged, and among them salicylic acid preparations, which are 4 times more effective than placebo (275). As a second line of home treatments, one may prescribe glutaraldehyde or formaldehyde. Before applying these paints, it is recommended to eliminate the excess of keratin by abrasion with a pumice stone, sand paper, or an emery board. This is particularly important for the treatment of plantar warts. Softening of the warts by soaking the area in hot water may help. Occlusive bandages improves the clearance of plantar warts. For the products in a collodion base, the collodion film needs to be removed before the next treatment. Silver nitrate sticks may also be tried by the patient.

家庭治疗是有必要的，这些药物中，配制的水杨酸制剂效果是安慰剂的4倍(275)。甲醛和戊二酸可以作为家庭治疗的二线药物。在应用药水之前，最好是用海浮石、砂纸或者金刚砂板将过度角化的皮肤磨掉。这点对跖疣的治疗尤其重要。将疣体在热水中浸泡以软化疣体对治疗也有帮助。局部封包可以提高跖疣的清除率。使用火棉胶产品时，下一次治疗之前需要将前一次的火棉胶薄膜去除。硝酸银棒也可以用来治疗皮肤疣。

Cryotherapy is among the favored of office-based therapies. In addition to abrasive tools, the practitioner may pare the wart with a scalpel to remove the excess of keratin prior to treatment. Complete curettage of the lesion may be done, although the risk of scarring should be considered. If cryogenics are not available, several drugs may be used, such as podophyllin, but preferably podofilox (81), or cantharidin. Bleomycin is another option, particularly for warts around the nails. Electrosurgery or laser surgery is more expeditious modalities, but they are also more expensive and cumbersome to implement because of the equipment required and the need to administer local or general anesthesia. Flart warts respond well, but plantar warts are a relative contraindication to electrosurgery. Lasers offer many choices that can be tailored to the specific location. In particular they can be useful for the removal of peri-and subungual warts.

Other treatments, including 5-FU, retinoids, cidofovir, allergic sensitization, and heat therapy are fourth line options.

冷冻疗法是诊室最常采用的治疗方法。除了削磨工具之外，治疗前操作者使用手术刀将过度角质刮除。虽然有瘢痕形成的危险，但刮除术也可选择。如果没有冷冻疗法，有几个药物可以选择，例如鬼臼树脂，但是最好是普达非洛(81)，或者斑蝥素。博来霉素是另一种选择，尤其是生长在甲周围的疣体。电外科手术或者激光手术是快速的方法，但是他们花费更多，操作更繁琐，因为需要专门的设备，而且需要局部或者全身麻醉。扁平疣的反应良好，而跖疣是电外科治疗的相对禁忌症。一些特殊部位对激光治疗都能耐受，特别是用来去除甲周和甲下的疣体。

其他治疗还有5-FU、维A酸、西多福韦、致敏疗法和热疗，这些都是四线治疗。

Anogenital Warts: Patients with condylomata acuminata often seek treatment. One of the reasons, particularly among women, is the significant psychosexual impact of the disease (280-284).

It is not clear how treatment affects potential HPV transmission to a sexual partner or, during pregnancy, to the baby, but it is likely that it diminishes it. Because the risk of progression to malignancy of condyloma acuminata in the normal host is extremely low, it is unknown how this risk is affected by treatment.

肛门生殖器疣：患者患有尖锐湿疣后通常都会寻求治疗，其中的一个原因就是这种疾病对性心理有明显的影响，尤其是女性患者(280-284)。

治疗可以减少性伙伴之间的传染以及减少怀孕期间对婴儿的传染，但是其中的机制还不清楚。因为普通患者的尖锐湿疣恶变的几率十分低，还不清楚治疗会对恶变的风险有影响。

There is no evidence that treating the male diseased partner of a woman with genital warts is indicated to prevent relapses, reinfection, or the risk of CIN development (285, 286). However, in the reverse situation, that of the female partner of a male patient with warts, we do not know the impact of partner treatment and evaluation. At present the Centers for Disease Control and Prevention (CDC) does not recommend partner evaluation and treatment (287). Yet, in practice the partner might be evaluated because of (a) the concern for other sexually transmitted diseases for which partner treatment is desirable; (b) the psychosexual burden on the patient of not knowing if one's partner is "clean"; and (c) the opportunity the encounter with the partner offers for couple counseling.

对女性尖锐湿疣患者的男性患病性伴进行治疗，并不会减少女性的复发、再感染或者发展为CIN的危险(285, 286)。然而在相反的情况下，我们并不清楚对男性患者的患病女性伴的治疗是否会影响男性的治疗和评价。目前美国疾病控制及预防中心（CDC）并不推荐性伴的评价和治疗(287)。但是实际中一般会对性伴进行评估，因为（a）性伴的一些其他性病需要对其进行评估（b）不知道他的性伴是否“干净”是患者的性心理负担（c）有些患者的性伴也会要求夫妻同时治疗。

Anogenital warts in infants and children present the particular problem of possible sexual abuse (288, 289). Evaluation guidelines are available, and referral to an experienced pediatrician is recommended (290). The concern of sexual abuse should also be present when evaluating an adolescent with anogenital warts, but in addition, the presence of risky sexual practices (e.g., anal intercourse, multiplicity of partners, lack of barrier protection) and behavior (alcohol and drug use) should receive particular attention.

婴儿和儿童感染肛门生殖器疣提出了一个特殊问题----有可能发生性虐待(288, 289)。一个有经验的儿科医生给我们提供了评价标准(290)。青少年患有肛门生殖器疣的时候我们也需要考虑性虐待的问题，另外我们还要特别注意他们是否有高危的性活动（例如肛交、多性伴和无保护性交）和行为（酗酒和吸毒）。

Treatment options for anogenital warts are varied, but none is totally satisfactory (Tables 2 and 3). The patient should also be informed of the risk of treatment failure and lesion recurrence. Location of lesions may affect outcome. Lesions in moist areas appear to resolve better than ones on dry areas, but not necessarily because of treatment received (63, 172). Furthermore, warts located within the occluded foreskin have a favorable outcome (277).

肛门生殖器疣的治疗多种多样，但是没有一个完全满意的。患者应该被告知有治疗失败和复发的危险。病变的部位可能会影响治疗效果。不管采用什么治疗方法，潮湿部位的病变比干燥部位的病变更容易消退(63, 172)。此外包皮里面的疣体会有满意的结果(277)。

Several detailed consensus treatment guidelines that also offer a review of the literature according to evidence-based criteria can be consulted for additional information (114, 286, 287, 291). Although costs of the different therapies vary considerably and should be considered in recommending a particular treatment, none of the available cost-benefit analyses provide consistent results (292-295).

其他信息我们可以查阅一些详细的治疗指南，指南还提供了一些相关文献的综述，这些文献都是有证据可查的(114, 286, 287, 291)。虽然不同治疗方法的花费相差很大，我们制定具体的治疗方案的时候应该考虑治疗费用，但是还没有一致的花费-益处分析(292-295)。

Self-treatment offers privacy and convenience, and is rated highly by patients (296). Therefore, imiquimod and podofilox are the two first-line options (Table 3). The main disadvantages of these treatments is the length of treatment duration for imiquimod, and a relatively high relapse rate for podofilox. Patients may want immediate removal of lesions, in which case of ce-based methods are required. Usually, experience and availability guide the choice of the treatment modality. Excision with a cold-blade is particularly suitable for few and relatively small lesions. Otherwise, electrosurgery, infrared coagulation ablation or laser surgery are alternate choices. Laser surgery is well-suited for the removal of large and extensive lesions. Often, however, these two methods are used as a second-line of approach because of cost and availability. The patient may accept an office-based treatment that usually requires several visits. In that regard application of BCA or TCA and cryotherapy are two widely used options. The requirement for several visits may be appreciated by some patients as it offers greater exibility and effectiveness for education and counseling.

自我治疗法具有私密性和便利性，有些患者是适用的。咪喹莫特和普达非洛是目前两种一线药。主要的缺点是使用咪喹莫特治疗周期长而使用普达非洛复发率高。患者可能希望马上就清除病变组织，这种情况下就需要医生选择治疗方法。通常经验和条件会决定治疗的方式。如果病损较少而且体积较小，可以采用剪除的方法，其他情况下就需要选择电外科手术、红外热凝术或者激光手术。激光手术尤其适合大的广泛性损害。但是由于花费高或者没有条件，这两种方法是次选方法。有些患者愿意接受诊室治疗，这一般需要数次就诊。在这种情况下，BCA或者TCA和冷冻疗法是最广泛采用的方法。有些患者能够接受数次就诊，这种方式更为灵活，还可以提供有效的健康教育和咨询。

Podophyllin is an obsolescent drug and it should be avoided unless in settings where costs and ease of access to drugs are major considerations. For warts that are recalcitrant, one may try repeating the same therapy after a pause (perhaps with a more intense regimen as with imiquimod) or, preferably, using an alternate standard modality. Among the more ultimate options, one may choose among allergic sensitization, IFN -notably intralesional IFN for the large single lesion-, cidofovir either topically or intralesionally, 5-FU, photodynamic surgery. One may also use as adjunct therapy I3C/DIM dietary supplements. 5-FU, along with cryotherapy has a place in the treatment of meatal warts (121, 122, 133, 220).

鬼臼树脂是一种过时的药物，除非较多的考虑花费和是否可以得到药物时才会使用。治疗抵抗的疣体我们在一段间歇之后可以用相同的方法重复治疗（采用咪喹莫特治疗的时候可能需要增加用药的频率），而采用新的治疗方法会更好。除了基本治疗选择之外，患者还可以选择致敏法、大的单独的疣体可以选择病损部位注射IFN、西多福韦局部外用或者病损部位注射、5-FU、光动力疗法。患者也可以服用营养保健品I3C/DIM辅助治疗。腔道内的疣体可以用5-FU和冷冻疗法来治疗(121, 122, 133, 220)。

Pregnancy restricts the treatment options to cryotherapy, BCA/TCA, electrosurgery, cold-blade excision, and laser surgery. Although the possibility of transmitting the HPV infection to the baby is cause for concern, the risk is low enough that cesarean section is not advocated (297, 298). Obstruction of the birth canal by the warts is a treatment indication.

怀孕会限制治疗的选择，只能采用冷冻疗法、BCA/TCA、电外科手术、剪除和激光手术。虽然需要考虑婴儿传染HPV的可能性，但是可能性很低，不推荐剖宫产术(297, 298)，除非疣体阻塞产道。

The treatment of HPV diseases and anogenital warts specifically, in the immunodeficient host is a challenge because lower clearance rates should be expected. Therefore the management goal may be limited to controlling the extent of the disease and screening for possible malignancies.

免疫缺陷患者的HPV疾病和肛门生殖器疣的治疗是一个挑战，因为可以预期到清除率是很低的。所以治疗的目的仅限于控制疾病的范围和筛查可能发生的恶变。

Patient follow-up after treatment is useful to assess response to therapy. Typically, a 3 month visit will detect most recurrences. However, often when the disease recurs, the patient will initiate the encounter. More sustained follow-up, perhaps yearly, is probably wise in patients who are immunocompromised or whose lesions presented a particular therapeutic challenge.

患者治疗后的随访可以为治疗的评估提供帮助。通常情况下，3个月后随访可以发现大多数的复发。通常当疾病复发时，患者将会前来就诊。当患者免疫耐受或皮损特别难治的时候，需要随访更长时间，大概每年一次是明智之举。

Counseling is an important component of the therapeutic encounter with adults and adolescents (299). Educational materials and addresses of support groups for the patient can be found on the web sites of the Centers for Diseases Control and Prevention (CDC) (http://www.cdc.gov/nchstp/dstd/dstdp.html) and of American Social Health Association (ASHA) (http://www.ashastd.org). Both organizations also operate hotlines: CDC's is 1-800-227-8922 (Monday through Friday from 8: 00 a. m. to 11: 00 p. m., ET) and ASHA's is (919) 361-4848 (Monday through Friday from 2: 00 p. m. to 7: 00 p. m., ET).

咨询辅导是成人和青少年治疗的重要组成部分(299)。教材和患者支持小组的地址可以在美国国家疾病控制与预防中心（CDC） (http://www.cdc.gov/nchstp/dstd/dstdp.html) 的网站以及美国社会卫生协会(ASHA)的网站(http://www.ashastd.org)上找到。这两个组织还都有热线：CDC的热线是 1-800-227-8922 (周一到周五从早晨8:00 到晚上11: 00) ，ASHA的热线是 (919) 361-4848 (周一到周五下午从2: 00到7: 00) 。

Immunodeficiency presents a challenge for the treatment of cutaneous and anogenital warts, as well as other HPV-associated diseases. Cutaneous warts and anogenital warts are more common in these patients. The incidence of cutaneous warts increases by about ten-fold in patients with lymphomas, and by 4-12-fold in HIV-seropositive patients (300-302). Three years after renal allograft transplantation, between 25% and 42% of patients have cutaneous warts; a number that rises to 92% after 5 years or more (303). The risk of developing anogenital warts is similarly increased in that population (304). In HIV patients, the odds of having anogenital warts are 3 to 8 times higher than in HIV-seronegative controls (305, 306). In an immunocompromised host, these lesions tend to be resistant to therapy. For example, the odds of anogenital wart relapse after treatment were found to be 22-fold higher in HIV patients (307).

免疫缺陷给治疗皮肤和肛门生殖器疣以及其他HPV相关疾病提出了很大的挑战。皮肤和肛门生殖器疣在这些患者中十分常见。淋巴瘤患者皮肤疣的发生率升高10倍，HIV-阳性的患者升高4-12倍(300-302)。肾脏移植手术后三年皮肤疣的发生率是25%到42%，而五年的发生率升高到92%以上(303)。在这些人群中，发生肛门生殖器疣的危险也有相似的升高(304)。HIV阳性病人发生肛门生殖器疣的几率是HIV阴性对照组的3到8倍(305, 306)。在免疫耐受的病人，这些损害容易发生治疗抵抗。例如，HIV患者肛门生殖器疣的复发率会升高22倍(307)。

The response of cutaneous warts to specific treatment in HIV patients has been little studied. Anecdotes suggest that imiquimod is effective for the treatment of labial and at warts (308, 309).

Several treatment modalities have been evaluated in HIV patients, mostly in individual cases or small case series. Podophyllin or podofilox seems largely ineffective (310-312). Cold-blade excision in combination to electrosurgery may offer some benefit in the treatment of anal condylomas (310, 313). Although intralesional IFN-a alone has proven to be ineffective (314), it appears useful when used with electrosurgery for the treatment of intra-anal warts (229). A randomized, controlled study has examined the efficacy of imiquimod 5% cream in HIV seropositive patients with a CD4 count equal or greater than 100 cell/mm³ (315). Complete clearance rates of the anogenital warts were 7/65 (11%) and 2/25 (6%) in the imiquimod and placebo groups (p = 0.49), respectively. Nevertheless, the rate of partial (50% or more) responses was significantly higher with imiquimod than with placebo, 50% versus 14% (p = 0.01). This suggests that imiquimod could be used to control the disease. Imiquimod has also been advocated as adjunctive therapy, but this has not been rigorously evaluated (316).

HIV患者皮肤疣的特殊治疗研究很少，没有对照的研究表明咪喹莫特治疗唇疣有效 (308, 309)。

个体和小规模的的治疗已经对HIV患者的一些治疗做了评估。鬼臼树脂和普达非洛很大程度上似乎无效(310-312)。剪除联合电外科手术对肛门尖锐湿疣的治疗有帮助(310, 313)。虽然病损处注射IFN-a 单独应用没有效果(314)，但是当与电外科联合治疗肛管内疣体还是有用的(229)。一个随机对照研究显示：5%咪喹莫特乳膏治疗CD4高于或者等于100个/mm³的HIV阳性患者 (315)，肛门生殖器疣体的完全清除率咪喹莫特组为7/65（11%），而安慰剂组为2/25（6%）（p = 0.49）。然而部分有效率（50% 或者以上）咪喹莫特组显著高于安慰剂组，分别为50%和14%(p = 0.01)。这表明咪喹莫特可以控制疾病。有人还提倡用咪喹莫特作为辅助治疗，但是缺乏严格的评价(316)。

Topical cidofovir 1% gel has been shown in a case-series and a small placebo-controlled study to be effective in the clearance of anogenital warts (317, 318, 319). Another randomized study compared surgery alone, topical 1% cidofovir gel daily 5 days a week for up to 6 weeks alone, and surgery followed by topical cidofovir (319). At the end of treatment, the clearance rates were 17/29 (93%), 20/26 (76%), and 19/19 (100%), respectively. At 6 month follow-up, the relapse rates in 49 patients who were followed were 74% , 35% , and 27% ( p = 0.02), respectively.

一个病例队列研究和一个小的安慰剂对照研究已经表明：局部外用1%西多福韦凝胶可以使得肛门生殖器疣消退(317, 318, 319)。另外一个随机研究比较了单独应用外科治疗、局部应用1%西多福韦凝胶（每周5天，每天1次共6周）和外科手术之后外用西多福韦的疗效(319)。治疗结束后疣体清除率分别为17/29 (93%), 20/26(76%), 和19/19(100%),6个月之后随访的49名患者中复发率分别为74%，35%，和27% ( p = 0.02)。

Antiretroviral treatment, particularly the highly active antiretroviral treatment (HAART), does have an impact on HPV disease, but it is at present a confusing one. It appears that HAART is associated with an increased incidence of condylomata acuminata (320). HAART has also been associated with an increased incidence of oral warts (321). A decrease in HIV viral load, although not antiretroviral therapy itself, was also linked to an increased incidence of oral warts in a case-control studies (322). In contrast, HAART was not noted to affect the incidence of anal intraepithelial lesions, while discordant results, increases and decreases in incidence, were reported for CIN (323-330). Anecdotally, antiretroviral treatment has contributed to the clearance of common warts in one patient (331).

抗病毒治疗特别是高效抗病毒治疗(HAART)，对HPV疾病有影响，但是目前令人困惑，似乎HAART与尖锐湿疣的发病率高有关(320)。HAART与口腔疣发病率升高也有关系(321)。在一个病例对照研究中显示，HIV病毒裁量的降低，而不是抗病毒治疗与口腔疣的发病率升高相关(322)。还没有HAART对肛门上皮内瘤样病变有影响的报道，但是HAART对CIN的发生率影响的结果并不一致(323-330)。有人报道在一个患者中观察到抗病毒治疗会促进寻常疣的消退，但是没有对照。

Drug Therapy, Immunotherapy, Allergic Sensitization: 1-nitro, 2, 4-dinitrochlorobenzene (DNCB) is a potent allergic sensitizer that has been used in dermatology to treat various benign skin conditions, including recalcitrant cutaneous and genital warts (332). The subject is first sensitized by the application of DNCB on the volar aspect of the arm (333). A week later the warts are painted with DNCB. The resultant inflammatory reaction is thought to trigger the wart clearance that, in uncontrolled small studies and case reports, has been reported to be about 80% -100% for cutaneous warts (334-337). The occurrence of severe allergic reactions with DNCB has led to a disaffection for this agent (338). It is now largely replaced by safer sensitizing compounds such as 2, 3-diphenylcyclopropenone, squaric acid dibutyl ester, and 10% masoprocol cream (Actinex) (332). Another seemingly successful approach has been the intralesional injection in cutaneous warts of either mumps or candida commercial antigens in subjects with a positive intra-dermal reaction to one of these antigens (339). Warts cleared completely in 29/39 (74%) of the patients.

药物治疗、免疫治疗、致敏疗法：2,4-二硝基-1-氯苯（DNCB）是一种强的致敏剂，已经被用来治疗各种皮肤良性疾病包括难治性皮肤疣和生殖器疣(332)。受试者首先在手掌应用DNCB致敏(333)，一周后于疣体的部位外用DNCB，之后发生的炎症反应被认为会促进疣体的清除。一个没有对照的小规模研究和一些病例报道中，皮肤疣的清除率大概为80%-100% (334-337)。不能令人满意的是DNCB有可能导致严重过敏反应(338)。现在已经被安全的致敏剂例如二苯基环丙烯酮、方酸二丁酯和10%马索罗酚(Actinex)等所代替(332)。另一种看似成功的做法是：皮内实验阳性的受试者皮损内注射腮腺炎或者念珠菌的商品化抗原，(339)，疣体完全清除率为29/39 (74%)。

Recombinant Therapeutic Vaccines: Therapeutic vaccines are in development. One that merit attention is the HPV16 HspE7 vaccine (StressGen Biotechnologies) that is developed for the treatment of anal HSIL. The HPV16 E7 protein is covalently linked to the p65 heat-shock protein (Hsp) from Mycobacterium bovis BCG strain that serves as adjuvant. A retrospective review of patients with anal HSIL treated with the vaccine indicated that of 14 patients who also had anogenital warts, 2 had a complete resolution, and 10 had a partial resolution (340).

重组治疗性疫苗：治疗性疫苗正在研制中。一个值得关注的是人乳头瘤病毒16型HspE7疫苗（stressgen生物技术），用于治疗肛门HSIL。HPV16 E7蛋白与从牛型分枝杆菌卡介苗株提取的p65热休克蛋白（ HSP ）共价键连接。一个应用这种疫苗治疗生殖器HSIL的回顾性调查研究表明：14名有肛门生殖器疣的患者，2名患者疣体完全消退，10名患者的疣体部分消退(340)。

Cidofovir: Cidofovir, or (S)-1-( 3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC) is an acyclic nucleotide analog that is available for the intravenous treatment of cytomegalovirus retinitis. Cidofovir is converted by the cell into cidofovir diphosphate, which is incorporated into the growing CMV DNA and blocks the CMV DNA polymerase. HPVs do not possess a DNA polymerase, yet cidofovir was found to have an antiproliferative activity in in vitro and in vivo models of HPV infection (341, 342) (14, 343). The mechanism of action is not well understood but appears to involve the formation of the triphophorylated form of cidofovir and the induction of apoptosis (341, 342).

西多福韦：西多福韦或者(S)-1-[3-羟基-2-(膦酰基甲氧基)丙基]胞嘧啶(HPMPC)是一种膦酸无环核苷，可以用来治疗巨细胞病毒视网膜炎。西多福韦在细胞内转变为二磷酸盐，嵌入生长期的巨细胞病毒DNA并且阻断病毒DNA聚合酶。HPV没有DNA聚合酶，但是我们却发现它对体内和体外的HPV感染模型均有抗增殖活性(341, 342) (14, 343)。其中的作用机制我们还没有能完全搞懂，但是好像与西多福韦的三磷酸盐的形成及诱导凋亡有关(341, 342)。

Intralesional injection of the compound has been found effective in a small number of patients with condyloma acuminatum or upper digestive HPV tumors (344, 345). However, it is for the treatment of recurrent respiratory papillomatosis that intralesional cidofovir has attracted the greatest enthusiasm after a case-series of 17 patients with severe disease, often an untractable problem, reported a complete clearance of 82% (346). Other favorable anecdotal evidence was subsequently added about intralesional and/or parenteral cidofovir as an adjunct therapy of laryngeal and lung papillomas (347-349).

病损内注射这种化合物对少数患尖锐湿疣和上呼吸道HPV肿瘤的患者有效(344, 345)。一个病例队列研究中报道，17名严重的难以处理的患者，病损内注射后疣体的完全清除率为82%(346)，这之后唤起了病损内注射西多福韦治疗复发性呼吸道乳头瘤的热情。之后又有了其他有利的证据证实病损内注射或者静脉注射西多福韦可以作为喉头和肺部乳头瘤病的辅助治疗，但是没有做对照研究(347-349)。

Although a commercial preparation is not available, cidofovir can be compounded and several authors have reported favorably on the use of topical formulations for the treatment of various HPV diseases, including condylomata acuminata, VIN, CIN 3, recalcitrant oral papillomatosis, common and plantar warts (350-356).

虽然西多福韦外用制剂还没有商品化，但是我们可以自行配制，有些作者报道局部应用西多福韦可以治疗尖锐湿疣、VIN、CIN3、难治性口腔乳头瘤、寻常疣和跖疣等许多种HPV疾病(350-356)。

A decisive demonstration of the efficacy of cidofovir was given in a double-blind trial that enrolled men and women with condylomata acuminata (357). Patients were randomized 2:1 to receive cidofovir 1% gel or the vehicle gel. The treatment was applied daily for 5 consecutive days every other week, up to 6 cycles. Patients with complete clearance were given an additional cycle and were evaluated 1 and 6 months later. At the end of 12 weeks of treatment, 9/19 (47%) patients in the cidofovir group compared to none of 11 in the vehicle groups had a complete wart clearance (p = 0.006). Only one of the 9 patients in the cidofovir group had a recurrence. There were no differences in the incidence rates of adverse reactions between the two groups. Pain, pruritus, or rash was noted in 68% of the cidofovir recipients and 64% of the vehicle recipients. Erosions or ulcerations were observed in 32% and 45% of the two groups, respectively. It should be noted that cidofovir is a potential carcinogen and its long-term safety in humans is not well-known.

有一项评价西多福韦疗效的重要研究，对男女尖锐湿疣患者进行了双盲试验(357)。患者按照2：1的比例随机应用1%西多福韦凝胶或者凝胶基质。每天一次，隔周连续用药5天，共6个治疗周期。疣体完全清除的患者加用一个治疗周期，之后1月和6月随访。12周的治疗后，西多福韦组的疣体清除率为47%（9/19）而对照组11名患者中没有人疣体完全清除（p = 0.006），9名患者中只有1名复发。副作用的发生率两组之间没有差别。疼痛、瘙痒或红斑的出现西多福韦组的发生率为68%而对照组为64%。糜烂或者溃疡的发生率两组分别为32%和45%。需要引起注意的是西多福韦有潜在的致癌性，人类长期应用的安全性还不清楚。

Retinoids: Retinoids, which include tretinoin, isotretinoin, etretinate, are synthetic compounds derived from the vitamin A analog retinol (358). They have been evaluated for the prevention and treatment of anogenital HPV diseases because they stimulate the desquamation and curb the proliferation of keratinocytes, including those infected by HPV (359). In addition, low levels of vitamin A and beta-carotene have been linked to the development of CIN (360, 361). Although topical 0.372% tretinoin cream might cause the regression of CIN 2 (but not of CIN 3) lesions, retinoids have been ineffective the treatment of condylomata acuminata (362, 363).

维A酸类：维A酸类包括维A酸、异维A酸和阿维A酯，是一种合成的维生素A类似物(358)。因为它们可以促进角化脱落并且抑制包括感染HPV的角质形成细胞增生(359)，所以我们对它们治疗和预防肛门生殖器疣的效果进行了评估。而且低水平的维生素A和β-胡萝卜素与CIN的发生有关(360, 361)。虽然局部应用0.372%的维A酸可以使CIN2（不是CIN3）损害消退，但是维A酸治疗尖锐湿疣无效(362, 363)。

Daily application of a 0.05% tretinoin cream has been effective for the treatment of at warts in children, with a complete response rate of 85% in 25 tretinoin treated children compared to 32% in 25 controls (364). Oral retinoids have also been found to be beneficial for the treatment of plantar and common warts in case reports (365, 366). In a case series of 20 children with extensive cutaneous warts, daily treatment with 1 mg/kg of etretinate for up to 3 months led to a complete response, free of relapse, in 16 subjects (367).

每天应用0.05%的维A酸乳膏治疗儿童疣有效，25个应用维A酸的患者中疣体完全清除率为85%而对照组中为32%(364)。也有病例报道表明，口服维A酸对跖疣和寻常疣的治疗同样有益处(365, 366)。20名泛发性皮肤疣的儿童，每天服用阿维A酯1 mg/kg，3个月后有16名患者的疣体完全消退，并且没有复发(367)。

Cimetidine: Cimetidine, an H2 -blocker, has known a fad as a treatment of cutaneous warts. However, two randomized, double-blind, placebo-controlled trials have failed to confirm any activity (368, 369).

西咪替丁：西咪替丁，一种H2-受体阻滞剂，曾经是治疗皮肤疣的常用方法。然而两个随机、双盲研究证实它没有效果(368, 369)。

Homeopathy: Homeopathy is one of the leading modalities of "alternative" medicine and is used for the treatment of cutaneous warts (370). However, three randomized, double-blind trials have failed to demonstrate a difference with placebo, or even detect a trend (371-373).

顺势疗法：顺势疗法是替代疗法中种主要治疗方法之一，被用来治疗皮肤疣(370)。然而，三个随机双盲试验并未发现它与安慰剂组疗效有何差异，甚至连这种趋势都没有(371-373)。

Heat: Heat is another agent used to treat warts. An infrared coagulation causes circumscribed necrosis of the skin (374). This technique has been used for the removal of tatoos, as well as the treatment of skin and cervical lesions (375-377). In an open study, 61 of 74 (82%) women treated for condylomata acuminata remained free of lesions at 6 month follow-up (376). Eleven of 21 patients (52%) with hand or plantar warts had wart clearance after treatment with the infrared coagulator (377). Local anesthesia is necessary, but the technique is otherwise well-tolerated. An intriguing application of heat has been the successful treatment of cutaneous warts by raising the local temperature of the lesion to 40-50°C in a water bath or by using a radiofrequency current (378-380).

热疗：热疗是另一种治疗疣体的方法。红外线热凝法可以导致皮肤的局限性坏死(374)。这种技术被用来治疗纹身和皮肤或者宫颈的损害(375-377)。在一个开放式研究中，74个女性尖锐湿疣患者经过治疗后6个月随访时有61个(82%)患者没有复发(376)。经过红外线凝固器治疗21名掌跖疣的患者中有11名（52%）疣体消退(377)。这种方法需要局部麻醉，但是在其他方面耐受性良好。热疗的一个有意思的应用是用热水或者射频电流将病损的温度升高到40-50°C可以成功的治疗皮肤疣(378-380)。

Heat delivered by ultrasound has been used to treat genital and cutaneous, particularly plantar warts (381-385). It is difficult to assess the efficacy of this approach given the absence of proper controls. A different approach is the use of high-energy ultrasound to ablate tissues. This requires general anesthesia. In one study of women with recalcitrant vulvar condylomata acuminata, 14 of 18 (78%) of the women treated had no recurrence (386).

超声波热源治疗皮肤疣尤其是跖疣有效(381-385)。但是由于没有适当的对照，它的效果很难评价。另一种方法是用高能量超声来融化掉病损，这需要全身麻醉。一项关于女性难治性外阴尖锐湿疣的研究中，18名患者中有14名（78%）治疗后没有复发(386)。

Photodynamic Therapy: Photodynamic therapy (PDT) relies on laser light to activate the cytotoxicity of a compound either applied topically to the lesion (5-aminolevulinic acid, 5-ALA) or parenterally (such as meso-tetra (m-hydroxyphenyl) porphyrin -m- THPP - or 5 - ALA) (387, 388). The technique has been used for various internal HPV diseases, but only on a limited basis for the treatment of recalcitrant hand and foot warts (389, 390). Nevertheless, a randomized placebo-controlled trial has demonstrated with PDT results superior to placebo when clearance of individual warts was compared (390). It is unclear how these results translate for the patient.

光动力学治疗：光动力学治疗(PDT)是指局部（δ-氨基-γ-酮戊酸，5-ALA)或者全身应用（meso-四(间羟基苯基)二氢卟啉）(387, 388)，然后通过激光照射，激发这些物质的细胞毒性。这项技术已经被用作多种内部HPV疾病，但是用来治疗难治性掌、跖疣的资料还有限(389, 390)。然而一个随机安慰剂对照实验已经证实：PDT组疣体的清除率高于安慰剂对照组(390)。还不清楚如何向病人解释这些结果。

Suggestion and Hypnosis: The idea that cutaneous warts respond to suggestion has been has been perpetuated by several authors (391-396). However, only few randomized, controlled studies have been conducted, and they have failed to provide convincing evidence of a suggestion effect (395, 397). Some have argued that hypnosis is superior to suggestion for the treatment of cutaneous warts, but the studies available show inconsistent results and defective methods (392-395, 397-399).

暗示和催眠：有些学者认为暗示法治疗皮肤疣有效(391-396)。然而只有几个随机对照实验对此进行了研究，并没有令人信服的证据证明暗示的效果(395, 397)。有些人争论催眠法优于暗示法，但是目前的数据还没有一致的结果，催眠治疗还是一个有缺陷的方法(392-395, 397-399)。

Combination therapy is not part of the standard approaches to the treatment of cutaneous or anogenital warts. It is impossible in the absence of comparison groups to judge the relative benefits of combination therapy for plantar warts including for example cryotherapy plus salicylic acid, or salicylic acid, podophyllin, and cantharidin (400, 401).

联合治疗并不是治疗皮肤或者肛门生殖器疣的常规方法。如果没有对照组，将很难判断跖疣联合治疗的益处。例如冷冻疗法加水杨酸、鬼臼树脂或者斑蝥素(400, 401)。

Imiquimod has been used in combination with podofilox for the treatment of anogenital warts in children or with other treatment modalities in HIV patients (316, 402). Several randomized controlled studies have been conducted evaluating combinations including either IFN, laser surgery, or both (113, 162-165, 174-183, 196, 403). In these studies, IFN was added to surgical ablative methods to prevent recurrence. The results of this extensive effort only showed that intralesional IFN-alpha plus podophyllotoxin was superior to podophyllotoxin alone, and that when combined with laser surgery +/- TCA, IF-alpha was better than either laser surgery +/- TCA and 5-FU or laser surgery +/- TCA alone (113, 181).

咪喹莫特可以联合普达非洛治疗儿童或者HIV患者(316, 402)的肛门生殖器疣。有些随机对照实验对IFN、激光手术和两者联合治疗分别进行了评价(113, 162-165, 174-183, 196, 403)。在这些研究中，IFN联合外科方法可以减少复发率。这么多的研究只是证实了病损注射IFN-α联合鬼臼毒素的效果优于单独应用鬼臼毒素，当联合应用激光+/- TCA时,IFN-α优于激光+/-TCA和5-FU，也优于激光+/- TCA (113, 181)。

Contraception, Smoking, and Shaving: The discontinuation of oral contraception may help eradicate condylomata acuminata. (406). Smokers should also be encouraged to stop because smoking may increase the risk of anogenital wart development (407). Shaving of the pubic hair should be discouraged as it disseminates the virus and probably favors the development of lesions by creating a wound epithelium.

避孕药、吸烟和剃须：停用口服避孕药可能会对尖锐湿疣的清除有帮助(406)。应该鼓励吸烟者戒烟，因为吸烟会促进肛门生殖器疣的生长(407)。禁止剔除阴毛，这会导致病毒的播散，如果损伤表皮还有可能促进皮损发展。

Indole-3-Carbinol and Diindolylmethane: Indole-3-carbinol (I3C) is a molecule that is derived from the autolysis of glucobrassicin in cruciferous vegetables (broccoli, cabbage, cauliflower, etc.) (408). I3C and its main active metabolite, diindolylmethane (DIM) , the dimer condensate of I3C, increase the 2 hydroxylation of estradiol. This results in the formation of 2-hydroxyestrone, a non-estrogenic, antiproliferative, anti-angiogenic, and apoptotic compound instead of 16 alpha-hydroxyestrone. 16 alpha-hydroxyestrone and estradiol stimulate the growth of papillomas in tissues that are estrogen sensitive, such as the cervix and the larynx (408, 409). The inhibitory effect of I3C/DIM on the growth of HPV-11-infected papillomas has been demonstrated in the nude mouse xenograft model (410). On the basis of several uncontrolled evaluations, I3C (Theranaturals Inc., PO. Box 344, Orem UT 84059-0344, tel. 801-224-8893) has become a popular dietary supplement used as an adjunctive therapy for the treatment of recurrent respiratory papillomatosis (408). A recent randomized, placebo-controlled study of oral I3C for the treatment of biopsy-proven CIN 2 or 3 has brought more credible evidence of its efficacy (411). Patients were administered 400, 200, or 0 mg a day of I3C for 12 weeks, and at the end of treatment a biopsy was done showing regression in 4 of 9 patients in the high dose group, 4 of 8 patients in the low dose group, and in none of the 10 patients in the placebo groups. It is likely that these results will encourage the study of this compound in the adjunctive treatment of condylomata acuminata. DIM is available as Phytosorb-DIM (Bio-Response Nutrients L.L.C., P.O. Box 288, Boulder, CO 80306, tel. 303-447-3841) and the manufacturer recommends a 5-8 mg/kg daily oral dose. The safety profile appears to be excellent. I3C/DIM induce phase I and II enzymes (specifically CYP1A1 and CYP1A2), which has resulted in the inactivation of certain drugs, including phenytoin (412). Otherwise, because of their anti-estrogenic activity, these compounds have a theoretical risk of osteoporosis and infertility that has not been yet seen (408).

吲哚-3-甲醇和二吲哚基甲烷：吲哚-3-甲醇(I3C)是从十字花科蔬菜（青花菜，洋白菜，花椰菜等）中含有的葡萄糖芸苔素水解物中提取的一种物质(408)。I3C和它的主要代谢活性成份二吲哚基甲烷(DIM)，I3C的二聚体冷凝液，可以使雌二醇二羟基化，生成2-羟基雌酮，它不是雌激素，抗增殖、抗血管生成和导致凋亡，可以取代16α-羟基雌酮。16α-羟基雌酮和雌二醇会促进雌激素敏感的乳头瘤病变的生长，例如宫颈或者喉头的病变(408, 409)。裸鼠的异体移植模型中证实I3C/DIM会抑制HPV-11相关的乳头瘤生长(410)。基于几个没有对照的评价，I3C（ theranaturals公司，信箱344 ，Orem UT 84059-0344 ，电话： 801-224-8893 ）已经成为治疗复发性呼吸道乳头瘤病的一个常用的食物辅助疗法(408)。在最近进行的一个关于I3C治疗CIN2或者CIN3的随机安慰剂对照研究中(411)， I3C的效果有了更确信的证据。患者分别服用400、200或者0mg的I3C，12周后进行病理活检，发现高剂量组9例患者中4例病变消退，低剂量组8例患者中4例病变消退而安慰剂组10例患者中没有病变消退。这些结果很有可能将促进这种物质成为尖锐湿疣的一种辅助治疗的方法。商业化的DIM叫做Phytosorb-DIM（Bio-Response Nutrients L.L.C.，信箱288, Boulder, CO 80306，电话303-447-3841)，厂家推荐每天口服5-8 mg/kg，它的安全性极好。I3C/DIM诱导第一阶段和第二阶段的酶（特别是CYP1A1和CYP1A2活性），这导致包括苯妥英在内的某些药物的失活(412)。然而，因为他们的抗雌激素活性，这些物质理论上有发生骨质疏松症和不孕症的风险，但是至今尚未看到(408)。

The endpoints for monitoring the treatment of anogenital warts, cutaneous warts, and HPV-associated diseases in general (with the exception of invasive cancers) are purely clinical: the eradication of lesions. The eradication of HPV DNA is not presently a treatment goal.

肛门生殖器疣、皮肤疣和HPV相关的一般疾病（侵袭性癌除外）的治疗终点仅是损害的临床消退，清除HPV DNA并不是目前的治疗目的。

Since June 2006, the first prophylactic vaccine against human papillomaviruses (HPV) has been available for the prevention of diseases related to HPV types 6, 11, 16, and 18. HPV-6 and -11 account for over 90% of genital warts, and types 16 and 18 for over 70% of cervical cancers (7a, 19a). This quadrivalent vaccine, Gardasil (Merck), has received indications in the United States for the prevention in women of cervical cancer, adenocarcinoma in situ, cervical intraepithelial neoplasia grades 1, 2, and 3, vaginal intraepithelial neoplasia (VAIN) grades 2 and 3, vulvar intraepithelial neoplasia (VIN) grades 2 and 3, and genital warts. The vaccine is now approved in at least 85 countries. An bivalent vaccine, Cervarix (GlaxoSmithKline), directed at HPV-16 and -18, has been first approved early 2007 in Australia. Since then licenses have been granted in the Philippines, Kenya, the United Arab Emirates, and in the European Union.

2006年6月以来，第一个针对人乳头瘤病毒得预防性疫苗已经问世，可以预防HPV6、11、16、18型相关的疾病。90%以上的生殖器疣是由HPV6和11型引起的，而70%以上的宫颈癌由16和18型引起(7a, 19a)。美国已经批准了Gardasil (Merck)这种四价疫苗用于预防女性宫颈癌、原位腺癌、宫颈上皮内瘤样病变1、2、3级、阴道上皮内瘤样病变(VAIN)2、3级、外阴上皮内瘤样病变(VIN) 2、3级以及生殖器疣的预防。这种疫苗目前已经推广到85个国家。Cervarix (葛兰素史克)是一个针对HPV16和18型的二价疫苗，2007年已经开始在澳大利亚应用。之后在菲律宾、肯尼亚、阿拉伯联合酋长国和欧盟都获准应用。

Both vaccines are based on the expression of the gene coding for the major capsid protein (L1) of HPV in either a yeast (Gardasil) or baculovirus (Cervarix) system, which leads to the self-assembly of the proteins into a virus-like particle (VLP) that has the same size, appearance, and immunologic properties as of the native capsid, but is not infectious because it is devoid of HPV DNA.

以上两种疫苗都建立在HPV主要衣壳蛋白（L1）的基因编码区的表达，或者通过酵母(Gardasil) 或者通过杆状病毒(Cervarix)系统来实现。该系统可以自动将蛋白质装配成与天然病毒衣壳大小、外观、和免疫学性质一样的病毒样颗粒（VLP），但是因为没有HPV DNA，所以没有传染性。

Early work had shown that these HPV VLP induce a strong immune response that neutralizes the homologous papillomavirus infection (23a, 24a). This concept of using papillomavirus VLPs as a vaccine was validated in animal papillomavirus infection models (5a). These experiments established that protection is conferred by the development of neutralizing antibodies. This was followed by phase I studies in man demonstrating the immunogenicity and tolerance of an HPV L1 VLP vaccine (9a, 13a).

早期工作已表明，这些人乳头瘤病毒VLP诱发强烈的免疫反应,可以中和同源性乳头状瘤病毒感染(23a, 24a)。用乳头瘤病毒的VLPs作为疫苗的想法已经在动物乳头瘤病毒感染模型中得到验证(5a)。这些实验确定这种保护是由产生的中和抗体提供的。之后在人体中进行了HPV L1 VLP疫苗的一期临床研究，证实了该疫苗的免疫原性和耐受性(9a, 13a)。

The ability of the vaccine to prevent HPV infection was demonstrated in a randomized trial in which 1533 evaluable females aged 16-23 years received either an HPV-16 L1 VLP intramuscular immunization in an aluminum hydroxide adjuvant or the adjuvant alone at day 0, month 2, and month 6. After a median follow up of 17.4 months, 41 subjects in the control group had developed a persistent HPV-16 infection versus none in the vaccine group (17a.

一个随机试验证实了该疫苗预防HPV感染的能力。1533名16-23岁的女性，分别于0、2、6月肌肉接种HPV-16 L1 VLP疫苗（以氢氧化铝作为佐剂），或者仅有接种佐剂作为对照。经过平均17.4月的随访，对照组中有41例发生了HPV16感染，而在接种疫苗组没有一例感染(17a)。

The current indications of Gardasil are supported by a series of Phase III studies (1a, 10a, 15a, 16a). They have been summarized elsewhere (2a, 4a). Gardasil was shown to be 99% effective in preventing CIN 2 or 3, and AIS caused by HPV-16 or -18 in pooled studies totaling 17,000 females ages 16-26 years, comparing the vaccine versus the adjuvant alone (1a). This endpoint, with up to 3 years of follow-up, was assessed in the per-protocol susceptible population of women who were negative at entry by serology and cervical viral DNA testing for the HPV types included in the vaccine. By the same criteria, the vaccine was found to be 100% effective preventing any CIN grades and AIS caused by any of the vaccine types, VAIN and VIN, as well as external genital warts.

目前Gardasil的适应症为一系列的III期临床研究所支持(1a, 10a, 15a, 16a)。很多地方已经做了总结(2a, 4a)。在总共17000的16-26岁女性的研究中表明，与单纯接种佐剂相比，接种Gardasil疫苗以后99%可以防止HPV16或者18型引起的CIN2、3和AIS(1a)。该项研究经过了3年的随访，入组时女性易感染群的HPV 阴性，最终采用血液学或者宫颈HPV DNA检测，包括疫苗的HPV 基因型。采用同样的标准，该疫苗可以100%的预防疫苗HPV型引起的任何级别的CIN和AIS、VAIN 和VIN以及生殖器疣。

Even by including subjects who had not received all three immunizations, or might have had an abnormal Pap smear, and by counting cases after the first immunization the efficacy of the vaccine still ranged from 82 to 98% for the the different end-points enumerated above. This as long as the subjects were HPV seronegative and DNA negative at entry. Including these subjects in the analysis impacted on the vaccine efficacy, which ranged from 44% for CIN2/3 and AIS, to 76% for genital warts. These efficacy figures are likely to increase with time failures accrued faster in the control arm than in the vaccine arm of the studies. It is clear that the greatest impact of the vaccine is when it is administered prior to the onset of sexual activity, that is prior to the likely acquisition of any genital HPV infection. It has been feared that the vaccine impact might be minimal when administered to a less selective population especially when looking at all cervical lesions irrespective of HPV types (25a). However, early results show that at 3-year follow-up, the vaccine leads to a reduction by half of all high-grade squamous intraepithelial lesions (the cytologic equivalent of CIN2/3), including those caused by non-vaccine HPV types, irrespective of serostatus or HPV infection at baseline (20a).

完成第一次免疫后计数病例，即使包括那些没有能接受完三次免疫的受试者、之前已经有巴氏涂片异常的受试者，该疫苗的效果依然能达到82%到98%，但入组时HPV血清学反应阴性、DNA阴性。受试者中44%CIN2/3和AIS、76%患有生殖器疣，包含这些病例的分析会影响疫苗的有效性，有效数据可能会随时间的推移而增加，而失败率在对照组中增加更快。很显然，疫苗的最大作用是如果在性生活之前接种，接种者会首先获得保护作用。曾有担心当疫苗用于更广的人群，尤其不管宫颈损害是哪种HPV引起的时候，疫苗的效果会减弱(25a)。然而一项研究的早期结果显示：不管接种前是否有存在HPV感染，经过3年的随访，疫苗可以减少半数重度鳞状上皮内瘤样病变(相当于细胞学 CIN2/3)的发生，这包括了那些非疫苗HPV 型别引起的病变，也不管病人基线的血清学和基线的HPV感染状况(20a)。

Very comparable efficacy results have been observed with Cervarix in the Phase II studies so far reported (11a, 12a). Cervarix also offered cross-protection against infections caused by HPV-31, which is related to HPV-16, and HPV-45, which is related to HPV-18 (12a). Gardasil also exhibit some cross-protection against infections caused by types not included in the vaccine (6a).

Neutralizing titers are induced by Gardasil in young girls aged 9-15 years, titers that are actually higher than in older females (3a, 21a, 22a). These results are the basis for the vaccine approval in females from age 9 to 26 years (18a).

目前已经有Cervarix II临床研究的报道，获得了非常好的效果(11a, 12a)。Cervarix可以对HPV31(与HPV16有关)和HPV45(与HPV18有关)有交叉保护作用(12a)。Gardasil也会对其它非疫苗型别的HPV感染呈现出交叉保护作用(6a)。

Gardasil在9-15岁的年轻女孩中诱导产生的抗体滴度高于年纪大的女性(3a, 21a, 22a)，基于这个结果，疫苗接种范围为9至26岁女性 (18a)。

The American Committee on Immunization Practices (ACIP) has issued guidelines for the administration of Gardasil (18a). The vaccine is given in a volume of 0.5 ml, by an intra-muscular injection in the deltoid area at day 0, month 2, and month 6. The contraindications are hypersensitivity to the active substances or excipients of the vaccine (the vaccine is made in Saccharomyces cerevisiae). Subjects who develop an hypersensitivity reaction should not receive another dose. Pregnancy is a contra-indication (pregnancy category B) and, if initiated, the immunization series should be completed after delivery. Breast feeding is not a contra-indicated. The vaccine can be administered with other childhood immunizations, although data showing safety and maintenance of efficacy are only available for the concomitant administration of the hepatitis B vaccine. An abnormal cervical cytology or the presence of cervical HPV DNA are not contra-indications to the vaccine, as it may still protect against diseases caused by at least some of the HPV types in the vaccine.

美国免疫接种顾问委员会(ACIP) 已经颁步了关于Gardasil的指南(18a)。在第0、2、和6个月，于三角肌接种0.5 ml疫苗。接种的禁忌症是对疫苗的活性成份或者赋形剂过敏，（啤酒酵母生产）。发生过敏反应的受试者将停止以后的接种。这疫苗不应用于孕妇（孕期B类药），如果已经开始接种，则在分娩之后再完成免疫接种。然而，哺乳并不是接种的禁忌症。该疫苗可以与青少年的其他免疫同时接种，虽然这方面安全性和效果持续性的资料仅仅来自于与乙肝疫苗同时接种。宫颈细胞学异常或者检测到宫颈HPV DNA并不是接种的禁忌症，因为仍然可以预防疫苗所包含型别的HPV相关疾病。

The use of hormonal contraceptive does not affect the vaccine efficacy, but the effectiveness of the vaccine in immunosuppressed or immunodeficient subjects is not established; yet, being an inert, non-infectious vaccine, it is not contra-indicated in that population. One should emphasize that the vaccine has no therapeutic effect on existing lesions, and that it does not substitute for the routine cervical cytology screening (14a, 18a).

使用激素类避孕药不会影响疫苗的效果，但是在免疫抑制或者免疫缺陷的病人中效果还不确定，因为该疫苗是灭活的、没有感染性的，所以在这部分人群中应用并不是禁忌症。需要强调的是疫苗对已经存在的损害没有治疗作用，也不能代替常规的宫颈细胞学筛查(14a, 18a)。

The ACIP recommends vaccinating 11-12 year-old girls (but the vaccine may be given from 9 to 26 years). They also recommend a catch-up vaccination for 13-18 year-old girls (18a). The cost of the vaccine to the provider is $120 per shot. Poor children are the beneficiaries of the Vaccine for Children Fund that makes the vaccine available free of charge.

ACIP推荐的接种人群是11-12岁的女孩（9至26岁都可以得到接种），他们还推荐在13-18岁的女孩儿中需要加强免疫(18a)。接种一次的费用是120美元。生活贫困的孩子可以从儿童基金会那里得到免费的疫苗。

There are unresolved issues regarding the vaccine. The durability of the protective antibody response is not known yet, but appears to be at least 5 years with both Gardasil and Cervarix (12a, 26a). Long term follow-up studies that aThere are unresolved issues regarding the vaccine. The durability of the protective antibody response is not known yet, but appears to be at least 5 years with both Gardasil and Cervarix (12a, 26a). Long term follow-up studies that are in place should answer this question. The issue of replacement of the vaccine HPV types by non-vaccine HPV types has been raised. Such phenomenon has not been seen yet (12a), and epidemiologic modeling actually suggests a possible indirect reduction of the non-vaccine HPV types (8a). The efficacy of the vaccine in women older than 26 years and in men is being examined and results should be available in 2008. It will be important to determine the role the HPV VLP vaccine may have in preventing recurrent respiratory papillomatosis and head and neck cancers. Although the vaccine has no therapeutic effect on existing lesions, its impact on disease recurrence and natural history also needs to be evaluated.

关于疫苗还有些问题，疫苗产生的保护性抗体反应能持续多久还不是清楚，但是接种Gardasil and Cervarix后保护性抗体持续最少要5年。长期的随访研究可以回答这个问题。还有一个问题：接种疫苗后，非疫苗亚型是否会补充疫苗基因型，目前还没有发现这种现象。流行病学提示没有接种的HPV亚型有可能会间接地减少。疫苗对于26岁以上女性和男性的作用正在观察中， 2008年会有数据提供。明确HPV VLP疫苗在预防复发性呼吸道乳头瘤病和头颈部肿瘤中的作用，这非常重要。虽然这种疫苗对已经出现的疾病损害没有治疗作用，但是对疾病的复发和自然病程的影响还需要进一步评估。

HPV transmission can be prevented by the proper sterilization of surgical instruments, the disposal of reusable instruments and materials that may be contaminated. Contaminated surfaces can be sterilized with household bleach (5.25% sodium hypochlorite) diluted 1:10 in water. During electrosurgery or laser surgery, a smoke evacuation system should be available and the operator should wear gloves, gown, mask, and goggles.

通过再使用器具和物品的消毒处理，HPV 感染可以预防。污染物品表面可用家用漂白剂（5.25%次氯酸钠）1:10稀释后使用。电灼和激光手术时，应有烟雾排出系统，术者应穿戴手套、隔离衣、口罩和护目镜。

Little is known of the effectiveness of barrier methods in preventing HPV transmission. However, wart dressing while swimming has been effective in preventing the incidence of plantar warts (413). It is unclear at present whether condoms protect against HPV transmission, but there is some evidence that they may offer a degree of protection against cervical cancer, CIN, and anogenital warts (414). Condom use should be encouraged for patients with multiple sex partners or who engage in anal intercourse. They are also advocated during the treatment period and during the following three months (291). Although circumcision reduces the risk of HPV transmission, it is not possible at the moment to offer firm recommendations about its use (415).

Cesarian section is not advocated for the delivery of babies from a mother with condylomata acuminata (297, 298).

使用屏障手段在预防HPV 传播过程中是否有效？人们所知甚少。尽管如此，游泳时包扎好疣体已经证明在预防跖疣方面非常有效(413).迄今为止，人们仍不知道安全套是否能够预防HPV 感染，但有证据表明，安全套在预防宫颈癌、CIN、肛门生殖器疣方面可提供某种程度的保护作用。在多性伴和有肛交的患者中，应鼓励使用安全套。在治疗期间和随后的三个月随访中，也应提倡使用安全套(291)。尽管包皮环切降低了HPV的传播，但目前强烈推荐包皮环切术的应用(415)不太可能。

The presence of anogenital warts is associated with an increased risk of cervical and anal cancer (416, 417). It is therefore important to make sure that women are appropriately screened for cervical cancer with Pap smears, using any of the guidelines currently available (418, 419). According to the guidelines of the American Cancer Society modified by the recommendations of the Centers for Disease Control and Prevention, (a) one should obtain the first Pap smear when the patient becomes sexually active or reaches her 18th birthday. This should be followed by at least two other annual Pap smears; (b) the Pap smear should be obtained every 6 months the year that follows the diagnosis of HIV infection and annually thereafter; (c) in the absence of HIV infection or other sexually transmitted diseases (including anogenital warts) in the previous year, the frequency of Pap smears is left to the discretion of the physician, but probably could be decreased to every 3-5 years, providing a good follow-up is possible. Otherwise Pap smear should be obtained annually (287, 420). At this time, no routine screening strategy has been validated for anal cancer, including in HIV seropositive patients.

肛门生殖器疣增加了宫颈和肛管发生癌症的危险(416, 417)。因而，用目前提供的指南(418, 419)保证妇女筛查宫颈癌非常重要。按照美国癌症协会根据CDC建议修订的指南，(a)女性18周岁或有性生活后，应当开始宫颈抹片，之后至少连续两年的每年一次刮片；(b)宫颈抹片在HIV 感染确立后每6个月一次，其后每年一次。(c)HIV 阴性人群或无其他性传播疾病人群（包括肛门生殖器疣）中，宫颈抹片应该3-5年一次，否则应每年一次(287, 420).到目前为止，还没有关于肛管癌的筛查策略，包括HIV 阳性人群。

Recommendations for treatment of Human Papillomavirus (HPV) among HIV exposed and infected infants [Download PDF]

HIV感染者和儿童感染者治疗人类乳头瘤病毒（HPV）的建议[Download PDF]

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