HPV疫苗的预防效果主要位于宫颈外

美国科罗拉多州韦尔市——在由美国科罗拉多儿童医院举办的儿童感染性疾病会议上，科罗拉多大学丹佛分校的儿科/内科教授Myron J. Levin博士报告称，目前人们普遍将人乳头瘤病毒(HPV)疫苗视为预防宫颈癌的一种手段，但事实上该疫苗所能预防的所有癌症中有55%左右都发生于宫颈以外的其他部位。

就2种已上市HPV疫苗产品而言，与其HPV类型相关的宫颈外恶性肿瘤包括男性和女性肛门指肠癌和口咽癌，以及男性阴茎癌。事实上，在与HPV相关的所有癌症中大约1/3都见于男性而非女性，这也是去年美国疾病预防控制中心(CDC)免疫实践顾问委员会建议11~12岁男孩常规接种HPV疫苗的原因之一，之前已经规定相同年龄的女孩需常规接种。而且，男性接种也将间接保护女性不患上宫颈癌。

鉴于HPV疫苗显著的临床效果、良好的成本效益比以及迄今为止相当理想的安全记录，美国停滞不前的HPV接种率令人担忧。来自CDC 2010年全美接种调查青少年部分的数据显示，仅23%的13岁女孩接种了3剂HPV系列疫苗。“人口健康2020”计划的目标是80%的13~15岁青少年完成3剂接种。

尽管CDC的推荐意见是在11~12岁时常规接种，但Levin博士感觉许多医生都将接种时间推迟到了15~17岁。Levin博士说：“我认为这种做法是错误的，我们可能错过了一个很好的时机。相当大一部分女孩在15岁之前就有过性行为，如果等到15岁之后才接种可能会降低她们受保护的几率。”

HPV是全球最常见的性传播感染病原体之一，总人口中的大约3/4会被感染，并且3/4的感染都发生于15~24岁。此外，超过50%的感染者都是在发生性行为后2年内被感染，而研究表明20%以上的男性和女性在15岁之前就已经有过阴道性行为。

除了与HPV相关的疫苗可预防癌症的问题之外，还存在生殖器疣或尖锐湿疣的问题。在性活跃人群中，生殖器疣的发生率大约为每年1%。据全美疾病与治疗索引的数据显示，2010年共有376,000次初诊是因为生殖器疣。治疗成本约为每例患者300~1,000美元，复发很常见。多达90%的生殖器疣病例都是因HPV 6型和11型所致，2种已上市HPV疫苗产品中的一种所能预防的4种HPV类型中就包括6型和11型。生殖器疣的潜伏期只有几个月，而HPV相关恶性肿瘤的潜伏期则长达数年甚至数十年之久。

Levin博士重点提到了澳大利亚开展的一项具有里程碑意义的研究，该研究从人口层面反映了广泛采用四价HPV疫苗所能产生的深远影响。澳大利亚是最早资助12~26岁所有女性接种HPV疫苗的国家，该接种计划始于2007年7月。全国性的监测计划表明，在该接种计划启动后头2年内，在符合免费接种条件的女性中生殖器疣新确诊病例减少了59%(Lancet Infect. Dis. 2011;11:39-44)。

Levin博士还指出，有趣的是，在没有被纳入接种计划的12~26岁澳大利亚异性恋男性中，生殖器疣的发生率也下降了39%。这便是群体免疫效力的证据。而男性同性恋者的生殖器疣发生率则维持不变。

在后续发表的更新报告(数据截止2011年中)中，澳大利亚的研究者描述称在启动了针对女性的全国性HPV接种计划之后4年，在21岁以下女性和异性恋男性中生殖器疣病例“大幅减少，几乎消失”(Sex. Transm. Infect. 2011;87:544-7)。

Levin博士指出，值得关注的一项研究进展是，患者其实可能无需接种3剂HPV疫苗才能获得保护。这一观点是由美国国立癌症研究所的研究者提出来的，他们在哥斯达黎加大规模临床随机试验中发现，没有按期返回接种第3剂疫苗的女性与完成了3剂接种的女性相比，在中位随访4.2年后二价HPV 16/18疫苗(制造商：葛兰素史克)的预防效果是相似的。考虑到3剂接种方案成本较高，难以完成，2剂接种策略对于资源不足的国家很有吸引力(J. Natl. Cancer Inst. 2011;103:1444-51)。

Levin博士解释道：“我们目前还不清楚，从女性或男性的终身健康来看，2剂接种的效果是否和3剂接种一样好，但可能已经足够好了。我们最想保护的是那些处于性活跃高峰期以及最可能拥有多名性伴侣的人群，而当他们安定下来后所面临的风险就会很小，到那时疫苗的保护作用大小就不那么重要了。”

Levin博士声明担任了默克和葛兰素史克公司的顾问，持有默克Zostavax带状疱疹疫苗的知识产权。

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By: BRUCE JANCIN, Ob.Gyn. News Digital Network

VAIL, COLO. – The human papillomavirus vaccine is still widely perceived as a tool aimed at preventing cervical cancer, yet in fact roughly 55% of all the cancers it should protect against occur at other sites, according to Dr. Myron J. Levin.

The extracervical malignancies associated with HPV types covered by the two commercially available vaccines include anorectal and oropharyngeal cancers in both women and men, as well as penile cancer.

Indeed, one-third of all HPV-related cancers occur in men, not in women, which is one reason that last year the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices recommended routine HPV vaccination for 11- to 12-year-old boys, as is already the case for girls of the same age. Also, protecting boys will secondarily increase protection against cervical cancer in girls.

In light of the vaccine’s impressive clinical benefits, favorable cost-benefit estimates, and excellent safety record to date, the lagging U.S. HPV vaccination rates are disturbing, Dr. Levin said at a conference on pediatric infectious diseases sponsored by Children’s Hospital Colorado. Data from the CDC’s 2010 National Immunization Survey – Teen indicate only 23% of 13-year-old girls had received the three-dose series. The Healthy People 2020 goal is for 80% of 13- to 15-year-olds to have received three doses.

Even though the recommendation is for routine immunization at age 11-12, it’s Dr. Levin’s impression that many physicians are putting it off until their patients are 15-17 years old.

"I think we’re making a mistake. I think we’re missing a big opportunity. A significant number of girls become sexually active before age 15, and waiting until they’re that age to immunize them may compromise their chance of protection. All those favorable cost-benefit analyses don’t count if you don’t get the vaccine," said Dr. Levin, professor of pediatrics and medicine at the University of Colorado at Denver.

HPV is the most common sexually transmitted infection worldwide. Three-quarters of the general population become infected, and three-quarters of those infections occur at 15-24 years of age. Moreover, more than 50% of those who become infected do so within 2 years after becoming sexually active – and studies show that more than 20% of males and females have already had vaginal sex by age 15.

Beyond the whole issue of vaccine-preventable HPV-associated cancers, there is the matter of genital warts, or condylomata acuminata. The incidence of genital warts is about 1% per year among sexually active people. In 2010 there were 376,000 initial physician office visits for genital warts, according to data from the National Disease and Therapeutic Index. The cost of treatment is $300-$1,000 per case, and recurrences are common. Up to 90% of cases of genital warts are caused by HPV types 6 and 11, two of the four types targeted by one of the two commercially available vaccines. The incubation period for genital warts is just a few months, compared with years or decades for HPV-related malignancies.

Dr. Levin highlighted landmark research from Australia demonstrating the profound impact widespread adoption of the quadrivalent HPV vaccine can have at the population level. Australia was the first country to fund a vaccination program for all females aged 12-26 years, starting in July 2007. A national surveillance program demonstrated a 59% reduction in new diagnoses of genital warts among women eligible for the free vaccine during the first 2 years after the program started (Lancet Infect. Dis. 2011;11:39-44).

Interestingly, there was also a 39% drop in new cases among heterosexual Australian males aged 12-26, even though they weren’t included in the vaccine program. This is evidence of herd immunity, Dr. Levin said. In contrast, rates remained unchanged among men who have sex with men.

In a subsequent report with updated data through mid-2011, Australian investigators described "the dramatic decline and near disappearance" of genital warts in women and heterosexual men under age 21 years 4 years after the start of the national HPV vaccination program targeting females (Sex. Transm. Infect. 2011;87:544-7).

One development worth keeping an eye on is the possibility that patients may not really need three doses of HPV vaccine to be protected, Dr. Levin said. This prospect was raised by investigators at the National Cancer Institute, who observed in a large Costa Rican randomized clinical trial that the efficacy of GlaxoSmithKline’s bivalent HPV 16/18 vaccine was comparable after a median 4.2 years of follow-up in women who didn’t come back for their third dose and in those who received all three. Since the three-dose regimen is expensive and difficult to complete, a two-dose strategy could be particularly important in resource-poor countries (J. Natl. Cancer Inst. 2011;103:1444-51).

"We don’t know that two doses would be as good as three for the duration of a woman’s life or a man’s life, but it may be good enough. You really want to protect people when they’re most sexually active and most likely to have multiple partners. Then when they settle down, they’re less likely to be at risk, and it doesn’t matter as much if they’re not as protected," Dr. Levin explained.

He reported that he serves as a consultant to Merck and GlaxoSmithKline and holds intellectual property rights involving Merck’s Zostavax shingles vaccine.