四價HPV疫苗對於24至45歲婦女可能有效


  June 16, 2009 — 根據6月2日The Lancet期刊線上第一版報導,一項進行中的多中心、平行、隨機、安慰劑控制雙盲試驗的結果,四價人類乳突病毒(HPV)疫苗對於24至45歲、未感染相關HPV類型的婦女有效。
  
  哥倫比亞波哥大國家癌症研究中心的Nubia Munoz醫師等人寫道,雖然HPV感染的高峰期在發生初次性行為之後的5到10年間,所有婦女都有HPV感染風險。我們檢測四價HPV(6、11、16、18型)之L1類病毒顆粒疫苗用於24至45歲婦女的安全性、免疫性與效果。
  
  【四價HPV疫苗的效果】
  這項研究從社區型與學校型健康中心與一級健康照護開業機構招募24至45歲、沒有生殖器疣或子宮頸疾病病史的婦女。使用電腦亂數指派參與者在第1天、第2和6個月時,接受四價HPV疫苗(n = 1,911人)或安慰劑(n = 1,908人)。研究期間,1,910名婦女接受最後一劑的疫苗,1,907人接受最後一劑的安慰劑。
  
  所有的參與者、研究單位的研究人員、研究監督者、實驗室員工對於接受的治療都不知情。除了以計畫性族群進行初步效果分析,還進行治療意向分析。在計畫性族群中,所有參與者在第1天與第7個月時,疫苗相關HPV類型的檢測都是陰性。這些婦女全都在一年內接受全部的三劑疫苗,在第7個月時完成最後一次追蹤訪視。
  
  主要效果結果是測量6個月或更久的6、11、16、18型HPV感染和子宮頸與外陰部疾病(第一共同主要終點),以及單由16和18型HPV引起的(第二共同主要終點)。
  
  計畫性族群組的第一共同主要終點效果為90.5% (95%信心區間[CI])為73.7 - 97.5; 疫苗組為4/1,615個案例、安慰劑組為41/1,607個案例)。至於第二共同主要終點,效果為83.1% (95% CI,50.6 - 95.8;兩組分別是4/1,601個案例、23/1,579個案例)。
  
  治療意向組中,因為開始時出現感染和疾病,第一共同主要終點效果為30.9% (95% CI,11.1% - 46.5%;兩組分別是108/1,886個案例、154/1,883個案例)。至於第二共同主要終點,效果為22.6% (95% CI,–2.9% -41.9%;兩組分別是90/1,886個案例、115/1,883個案例)。沒有嚴重疫苗相關副作用報告。
  
  研究作者寫道,四價HPV疫苗對於未感染相關類型HPV的24至45歲婦女有效。混合組的效果較低(約30%)代表著,24至45歲婦女注射疫苗的公共衛生效果會比青少年注射疫苗的效果略低。這在後續的成本效益分析中必須提及。
  
  研究限制包括,固定事件設計,平均追蹤時間只有2年,臨床試驗之外,25至45歲婦女可藉由疫苗預防的疾病數量未知。此外,開始時的血清學檢測可能低估了之前的第6、11、16或18型HPV的曝露,特定的排除規範可能造成納入試驗婦女得到HPV的風險低於一般族群。
  
  國家癌症研究中心(NCI)癌症流行病學組、感染與免疫流行病學小組主任Allan Hildesheim博士向Medscape Ob/Gyn & Women's Health表示,此研究指出類病毒顆粒(VLP)為基礎的HPV疫苗對於25至45歲婦女有效,以前是指小於26歲者。不過,因為:1)新的HPV感染隨著年齡降低,2) HPV感染的程度與後來發生癌症及癌前病症的關係未知,因此還不清楚是否需要針對25歲以上的婦女進行疫苗施打計畫。
  
  【對於某些婦女來說,HPV疫苗是必要的嗎?】
  未參與本研究的Hildesheim醫師在接受Medscape Ob/Gyn & Women's Health邀請發表獨立評論時表示,目前的研究無法回答這個重要問題,因為它未評估25至45歲婦女施打疫苗是否會降低臨床相關狀況,如子宮頸癌前病灶或長期的(大於1到2年) HPV持續性,而無法導致改變/更積極的篩檢與處置。要回答這個問題,重點在於需要評估因為疫苗而預防的臨床相關狀況的數量(也就是絕對的疫苗影響)。發表的報告聚焦在疫苗效果的百分比,即使疫苗的絕對利益(臨床相關狀況的絕對減少值)低,此一百分比也可能很高。
  
  Hildesheim醫師建議,後續研究應直接評估成人施打HPV疫苗對臨床相關狀況絕對比率的影響。
  
  Hildesheim醫師結論表示,第一步是找到顯示可以將近100%有效預防HPV感染的疫苗,但是在建議25至45歲婦女施打相關疫苗之前,我們的重點在於要瞭解如此施打疫苗是否會顯著降低這些人的臨床相關疾病。
  
  Merck(美國)支持本研究且雇用其中9名作者。其他研究作者有些人宣告與Merck、Sanofi-Pasteur MSD、GlaxoSmithKline、Geneprobe、Roche和Abbott Diagnostics藥廠有各種的財務關係。Hildesheim醫師是NCI資助於哥斯大黎加進行的社區基礎HPV-16/18疫苗試驗的主要研究者。
  
  Lancet. 線上發表於2009年6月2日。
  

Quadrivalent HPV Vaccine May Be Effective in Women 24 to 45 Years Old

By Laurie Barclay, MD
Medscape Medical News

June 16, 2009 — The quadrivalent human papillomavirus (HPV) vaccine may be effective in women aged 24 to 45 years who are not infected with the relevant HPV types at enrollment, according to the results of an ongoing multicenter, parallel, randomized, placebo-controlled, double-blind trial reported in the June 2 Online First issue of The Lancet.

"Although the peak incidence of...HPV infection occurs in most populations within 5–10 years of first sexual experience, all women remain at risk for acquisition of HPV infections," write Nubia Munoz, MD, from the National Institute of Cancer in Bogota, Colombia, and colleagues. "We tested the safety, immunogenicity, and efficacy of the quadrivalent HPV (types 6, 11, 16, 18) L1 virus-like-particle vaccine in women aged 24–45 years."

Efficacy of the Quadrivalent HPV Vaccine

Women aged 24 to 45 years who had no history of genital warts or cervical disease were enrolled from community and academic health centers and from primary health-care practices. Computer-generated randomization was used to assign participants to receive quadrivalent HPV vaccine (n = 1911) or placebo (n = 1908) at day 1 and months 2 and 6. During the study, 1910 women received at least 1 dose of vaccine and 1907 received at least 1 dose of placebo.

All participants, study site investigators and staff, study monitors, and central laboratory staff were masked to treatment assignment. Although the per-protocol population was used for primary efficacy analyses, intent-to-treat analyses were also performed. In the per-protocol population, all participants tested negative for the relevant vaccine HPV type on day 1 and also up to month 7. These women also had all 3 vaccine doses within 1 year and had at least 1 follow-up visit after month 7.

The main efficacy outcome measures were 6 months' or more duration of infection and cervical and external genital disease caused by HPV 6, 11, 16, and 18 (first coprimary endpoint) and caused by HPV 16 and 18 alone (second coprimary endpoint).

Efficacy against the first coprimary endpoint in the per-protocol population was 90.5% (95% confidence interval [CI], 73.7 - 97.5; 4/1615 cases in the vaccine group vs 41/1607 in the placebo group). Against the second coprimary endpoint, efficacy was 83.1% (95% CI, 50.6 - 95.8; 4/1601 cases vs 23/1579 cases).

Because infection and disease were present at baseline, efficacy against the first coprimary endpoint was 30.9% (95% CI, 11.1% - 46.5%; 108/1886 cases vs 154/1883 cases) in the intent-to-treat population, and against the second coprimary endpoint, efficacy was 22.6% (95% CI, –2.9% to 41.9%, 90/1886 cases vs 115/1883 cases). No serious vaccine-related adverse events were reported.

"The quadrivalent HPV vaccine is efficacious in women aged 24–45 years not infected with the relevant HPV types at enrolment," the study authors write. "Lower effectiveness (about 30%) detected in the mixed population suggests that the public health effect of vaccinating women aged 25–45 years will be smaller than that recorded after vaccinating susceptible adolescents. This notion will be assessed in future cost–benefit analyses."

Limitations of this study include fixed-event design, mean follow-up time of only 2 years, and unknown amount of disease that would be prevented by vaccinating women between the ages of 25 years and 45 years outside of a clinical trial. In addition, the baseline serology test may have underestimated previous exposure to HPV 6, 11, 16, or 18, and specific exclusion criteria might suggest that women enrolled in this study were at somewhat lower risk of acquiring HPV vs those in the general population.

"The study demonstrates that virus-like particle (VLP)-based HPV vaccines are effective in women ages 25-45, as was previously shown for women <26 years of age," Allan Hildesheim, PhD, chief, Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), told Medscape Ob/Gyn &?Women's Health. "However, given that 1) new HPV infections decline with age and 2) the degree to which HPV infections acquired later in life are associated with the development of cancer and pre-cancer is unknown, it is not clear whether vaccination programs that target women older than 25 are warranted."

Are HPV Vaccinations Necessary for Certain Women?

"The present study cannot address this important question because it did not evaluate whether vaccination of adult women 25-45 years results in reductions in clinically relevant conditions such as cervical pre-cancer lesions that require treatment or long-term (>1 - 2 years) HPV persistence that lead to altered/more aggressive screening and management,” said Dr. Hildesheim, who was not involved with the study but was asked by Medscape Ob/Gyn & Women's Health to give independent commentary. "When addressing this latter question, it will be critical that the number of clinically relevant conditions prevented through vaccination (ie, absolute vaccine impact) be evaluated. The present paper focuses on the evaluation of percent vaccine efficacy, which can be high even if the absolute benefit of vaccination (as measured by the absolute reduction in clinically relevant conditions) is low."

Dr. Hildesheim recommended further research to directly assess the impact of adult HPV vaccination on absolute rates of clinically relevant conditions.

"Showing that a vaccine is nearly 100% effective at preventing HPV infection is an important first step, but before recommendations can be made regarding vaccination of adult women ages 25-45, it is important that we understand whether such vaccination would result in significant reductions in the amount of clinically relevant disease among vaccinated individuals," Dr. Hildesheim concluded.

Merck (USA) supported this study and employs 9 of the authors. Some of the other study authors have disclosed various financial relationships with Merck, Sanofi-Pasteur MSD, GlaxoSmithKline, Geneprobe, Roche, and Abbott Diagnostics. Dr. Hildesheim is the Principal Investigator on the NCI-funded community-based HPV-16/18 vaccine trial in Costa Rica.

Lancet. Published online June 2, 2009.

    
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