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作者：Janis C. Kelly  
出處：WebMD醫學新聞

　　February 17, 2010 — 人類乳突病毒(HPV)自然史的研究發現，讓研究者作出結論認為，年長(≧42歲)婦女使用HPV疫苗的潛在利益「低」。
　　
　　哥斯大黎加聖荷西INCIENSA基金會、Proyecto Epidemiol?gico Guanacaste的Ana Cecilia Rodriguez醫師所領導的研究團隊發現，新發生的HPV感染率隨著年紀降低，而且年長婦女的新感染一般不會變成等級2或3的子宮頸上皮內腫瘤(cervical intraepithelial neoplasia，CIN)。
　　
　　研究者發現，年長婦女在開始時的感染比年輕婦女更可能會持續(P< .01、共比較8個組別)，再者，追蹤時發現的等級2或者惡化的CIN，多數(85例中的66例)是與開始時已經出現的感染有關。
　　
　　登載於2月15日美國國家癌症研究院期刊(Journal of the National Cancer Institute)的這篇為期7年的哥斯大黎加婦女研究，是迄今探討年紀、HPV持續性與子宮頸癌前趨(驅)物的最大型研究。
　　
　　接受Medscape Oncology邀請發表獨立評論的Silvia Franceschi醫師表示，這是一篇偉大的報告，擁有在一定年齡範圍內婦女的最長追蹤期間的研究資料。
　　
　　法國里昂國際癌症研究局流行病學與生物小組協調者Franceschi醫師指出，看起來，25歲以上婦女接種疫苗可以獲得的幫助有限。
　　
　　她指出，危險的或持續的感染可能已經存在，而這無法以目前的HPV疫苗消滅，藥廠的主張是，疫苗應給予年長的婦女，因為HPV感染在某個年紀之後比較危險已經被證明並非事實。
　　
　　【這個HPV研究有超過9000名婦女，追蹤期間7年】
　　研究者在哥斯大黎加篩檢了超過9000名年紀18- 97歲的婦女，納入時有CIN 2或惡化者給予治療，但是不加以追蹤，至於其他的研究對象，CIN 2或惡化之風險低者，在5-7年時追蹤(被動式追蹤)，高風險者以及一開始沒有性生活的低風險婦女，則每年或每半年追蹤(主動)追蹤達7年。
　　
　　如前所述，研究期間診斷有CIN 2或惡化的婦女，多數是在研究開始時的檢查即已經感染有致癌的HPV菌株(普遍的感染)。
　　
　　在研究期間，無論婦女的年紀，多數新發現的HPV獲得緩解且不會造成CIN 2或惡化。在追蹤的前3年間，總累積CIN 2+相關新發現感染範圍為2.1% -6.2%。
　　
　　年紀相關的免疫力變化是關注焦點之一，資料顯示，在3年後，34歲以上婦女惡化成CIN 3的風險並沒有比年輕婦女高，17名34歲以上婦女中，沒有人的新診斷感染惡化成CIN3+，41名34歲以下婦女中，5人(12.2%)惡化成CIN3+。
　　
　　再者，新診斷HPV感染比率隨著年紀迅速降低，主動追蹤組中，從18-25歲的35.9%降低到42歲以上者的13.5%。
　　
　　在初次檢查時出現的感染中，42歲以上者比年輕婦女更常見有持續感染。
　　
　　研究者結論表示，子宮頸癌風險顯然與之前的致癌性HPV感染有關，而不是HPV 6 或HPV 11等引起的生殖器疣，也與年紀無關，研究者表示，現有的HPV疫苗可以預防之類型的新感染，在任何年紀當下的癌症風險小，且多數在2-3年內緩解。
　　
　　研究者寫道，女孩在初次發生性行為前接種疫苗者，可降低新感染致癌性HPV的機率，且將持續到25-30年才可能發生侵犯性子宮頸癌，不過，他們提醒醫師，多數的HPV感染是良性的，焦點在於HPV的持續性，避免對可能自我緩解的HPV感染的過度反應，這對於國內將HPV檢測導入子宮頸癌篩檢計畫而言相當重要。
　　
　　【30歲時，多數婦女已經感染HPV】
　　Rodriguez醫師向Medscape Oncology表示，現有的HPV疫苗是預防性的，它們只可以預防感染；它們無法治療已經存在的感染症。在平均15-17歲發生初次性行為的一群人中，30歲之後接種疫苗是沒有成本效益的。
　　
　　她指出，30歲時，多數婦女已經感染某些類型的HPV，包括了疫苗中的那些類型，婦女不會得到許多新感染；因此，疫苗可以提供的效益相當少。
　　
　　Rodriguez醫師表示，我們對於在42歲以上者發現之普遍感染的明確持續模式感到驚訝，對於所有其他盛行的感染和所有偶發的感染而言，無論婦女的年紀，持續的機會是相當類似的。18-25歲婦女中，開始時以聚合酶鏈鎖反應(PCR)偵測出的致癌性HPV感染持續6年以上者有5.1%，26-33歲的婦女中有14.4%、34-41歲的婦女中有12.2%、42歲以上婦女中則有18.2%。這是作者結論中的關鍵要素，認為是原本的感染期間確定了後續的風險，而非婦女的年紀。
　　
　　這延伸出一個問題：年長時施打疫苗是否可能可以預防年輕時已經清除的HPV類型的再度感染，Rodriguez醫師表示，至今，有些證據認為，再度出現之前已經清除的感染是相當罕見的，那些再度出現者並沒有高風險的CIN 2+，但是這需要進一步確認。
　　
　　【HPV篩檢間隔可能是2.5年或更久】
　　本研究對於HPV篩檢提供一些指引，Rodriguez醫師向Medscape Oncology表示，HPV篩檢資料必須根據篩檢頻率整合，而非婦女年紀。
　　
　　Franceschi醫師表示，任何年紀在篩檢計畫中發現單一種HPV陽性並不需要緊張，一種HPV陽性必須在約12個月後重複、且有持續感染才需要深入檢查，如果經組織學證實，則加以治療，PCR分析不應被用於篩檢計畫，因為它們會偵測到過多的無傷害感染。
　　
　　理想的HPV篩檢間隔還未被確立，但是，Rodriguez 醫師表示，對之前研究進行的分析建議，HPV篩檢需至少間隔2.5年，而且可以更久。
　　
　　作者們指出，結論認為任何年紀之新診斷的HPV感染一般不會進展成CIN 2或惡化，最重要的研究限制是，這在7年以上時應有所保留。
　　
　　Rodriguez 醫師表示，研究者計畫在初次篩檢之後20年左右時，再度訪視這一世代。
　　
　　Rodriguez醫師與Franceschi醫師皆宣告沒有相關財務關係。


Study Does Not Support HPV Vaccine in Older Women

By Janis C. Kelly
Medscape Medical News

February 17, 2010 — Findings from a natural-history study of human papillomavirus (HPV) have led the investigators to conclude that the "potential benefit" of HPV vaccination in older women (?42 years) is "low."

The research team, led by Ana Cecilia Rodriguez, MD, from the Proyecto Epidemiologico Guanacaste, Fundacion INCIENSA, in San Jose, Costa Rica, found that the rate of new HPV infections declines with age and that new infections usually do not progress to grade?2 or 3 cervical intraepithelial neoplasia (CIN) in older women.

The investigators found that infections at baseline were more likely to persist in older than in younger women (P?< .01 for a comparison of 8 groups). Furthermore, most of the grade?2 or worse CIN disease that was detected during follow-up (66 of 85 cases) was associated with infections already present at baseline.

The 7-year study of Costa Rican women — the largest ever to examine age, HPV persistence, and cervical cancer precursors — was published online February?15 in the Journal of the National Cancer Institute.

This is a great paper.

"This is a great paper, the longest follow-up study to date available on women in a broad age range," said Silvia Franceschi, MD, who was approached by Medscape Oncology for independent comment.

Dr. Franceschi, who is coordinator of the epidemiology and biology cluster at the International Agency for Research on Cancer in Lyon, France, noted that there seems to be very little to gain by vaccinating women older than 25 years or so.

"The 'dangerous' or persistent infections may be already there and will not be eliminated by the current HPV vaccines," she added. "The pharmaceutical industry's claim that vaccine should be given to older women because HPV infections are more dangerous after a certain age has been proven not to be true."

More Than 9000 Women, 7-Year Follow-Up in HPV Study

The researchers screened more than 9000 women, 18 to 97 years, in Costa Rica. Those with CIN?2 disease or worse at enrollment were treated and not followed any further. Among the remaining participants, those at low risk for CIN?2 or worse were rescreened at 5 to 7 years (passively followed), whereas higher-risk participants and subsets of low-risk women and initially sexually nonactive women were rescreened annually or semiannually (actively followed) for up to 7 years.

As noted above, most women diagnosed with CIN?2 or worse during the study period were already infected with a carcinogenic HPV strain (prevalent infection) at the time of initial testing.

Regardless of the woman's age, most newly detected HPV resolved and did not lead to CIN?2 or worse during the study period. Total cumulative CIN?2+ associated with newly appearing infections ranged from 2.1% to 6.2% over the first 3 years of follow-up.

Age-related changes in immunity have also been a concern, and the data showed that women older than 34 years were not at greater risk than younger women for progression to CIN3+ after 3 years. Newly detected infections led to a CIN3+ diagnosis in 0 of 17 women 34 years or older and in 5 of 41 (12.2%) women younger than 34 years.

Furthermore, rates of newly detected HPV infections declined sharply with age, from 35.9% in women 18 to 25 years to 13.5% in women 42 years and older in the actively followed group.

Among infections present at first examination, persistent infections were more common among women 42 years or older than among younger women.

The researchers conclude that cervical cancer risk is determined by the previous overt duration of carcinogenic HPV infections, not by genital warts caused by HPV?6 or HPV?11, and not by age. New infections, which are the only type that can be prevented by currently available HPV vaccination, carry little near-term cancer risk at any age, and most of them resolve within 2 to 3 years, say the investigators.

Vaccinating girls before they become sexually active reduces the chance that a new carcinogenic HPV infection will persist for the 25 to 30 years required to cause invasive cervical cancer, write the researchers. However, they remind clinicians that most HPV infections are benign. "[A] focus on HPV persistence, and avoidance of overreaction to HPV infections that are likely to resolve spontaneously, is essential for a rational introduction of HPV testing into cervical cancer screening programs."

By Age 30, Most Women Already Have HPV

"The HPV vaccines that are available now are prophylactic," Dr. Rodriguez told Medscape Oncology. "They can only prevent getting infected; they do not treat infections that are already present. In a given population with an average age at first sexual intercourse of around 15 to 17 years, to vaccinate women after the age of 30 is not cost-efficient."

"By age 30, most women would have been infected with the HPV types covered by the vaccines, and women are not getting that many new infections; therefore, the residual benefit provided by the vaccine is very small," she added.

We were surprised by the distinct persistence pattern observed for the group of prevalent infections among women 42+ years of age.

"We were surprised by the distinct persistence pattern observed for the group of prevalent infections among women 42+ years of age. For all other prevalent infections and for all incident infections, regardless of the woman's age, the chance of persistence was very similar," Dr. Rodriguez said. Persistence for 6 or more years of carcinogenic HPV infections detected by polymerase chain reaction (PCR) at baseline was 5.1% in women 18 to 25 years of age, 14.4% in women 26 to 33 years of age, 12.2% in women 34 to 41 years of age, and 18.2% in women 42 years or older. This was the key element that supported the authors' conclusion that previous infection duration, not a woman's age, determines subsequent risk.

This raises the question of whether there might be possible residual benefit of vaccination at older ages to prevent reacquisition of HPV types that were apparently cleared when the woman was younger. "Thus far, there is some evidence that reappearance of previously cleared infections is a very rare event and that those that reappear do not carry high risk for CIN?2+, but this requires confirmation," Dr. Rodriguez said.

HPV Screening Interval Should Probably Be 2.5 Years or Longer

This study offers some guidance on HPV screening. Dr. Rodriguez told Medscape Oncology that HPV screening data must be interpreted according to the frequency of screening, rather than the woman's age.

A single HPV-positive finding in a screening program must be not cause for alarm at any age.

"A single HPV-positive finding in a screening program must be not cause for alarm at any age," Dr. Franceschi said. "An HPV-positive test should just be repeated after approximately 12 months, and only persistent infections should be investigated in depth. If histologically proven, they are treated. PCR assays should not be used in screening programs, because they detect too many harmless infections."

The ideal HPV screening interval has yet to be determined, but Dr. Rodriguez said that previous analyses from the study suggested that HPV screens should at least 2.5 years apart, and could be longer.

The most important study limitation, note the authors, is that the conclusion that newly detected HPV infections typically do not progress to CIN?2 or worse at any age might not hold beyond the 7 years of follow-up. Dr. Rodriguez said that the researchers plan to revisit the cohort approximately 20 years after the initial screening visit.

Dr. Rodriguez and Dr. Franceschi have disclosed no relevant financial relationships.

J Natl Cancer Inst. 2010;102:305-324.