篩查和早期治療可將 HIV 感染者的肛門癌風險降低 57%
資料來源：Liz Highleyman / 2022 年 2 月 17 日 /aidsmap /財團法人台灣紅絲帶基金會編譯
圖片來源：CROI 2022 的 Joel Palefsky 教授。
–
根據在反轉錄病毒和機會性感染會議 (CROI 2022) 上公佈的 ANCHOR 研究結果，篩查癌前肛門細胞變化並及早治療可降低 HIV 感染者進展為肛門癌的風險。
「這是第一次證明篩查和治療可以降低患肛門癌的風險」，加州大學舊金山分校的 ANCHOR 首席研究員 Joel Palefsky 教授說。 「我認為數據支持將 [篩查和治療] 納入 35 歲以上 HIV 感染者的照護標準」。
Palefsky 說，肛門癌在整個人群中並不常見，但自 1970 年代以來，男性和女性的發病率一直在上升。與子宮頸癌一樣，肛門癌是由人乳頭瘤病毒 (HPV) 引起的，人乳頭瘤病毒是最常見的性傳播感染之一。該病毒會引發異常的細胞變化，進而發展為癌前發育不良（稱為高級別鱗狀上皮內病變， high-grade squamous intraepithelial lesions, HSIL）和浸潤性癌症。
愛滋病毒感染者的肛門癌發病率要高得多，對他們來說，它是第四大常見癌症。先前的研究顯示，愛滋病毒感染者攜帶更多類型的 HPV，自然清除病毒的可能性較小，並且會更快地發展為 HSIL 或癌症。即使是接受有效抗反轉錄病毒治療且 CD4 計數高的人也可能患上肛門發育不良和癌症。男男性行為者特別容易患肛門癌；其他面臨風險的群體包括老年人、患有子宮頸癌的婦女以及因其他原因而導致免疫力下降的人。
自 1950 年代以來，廣泛的篩查和早期治療顯著降低了宮頸癌的患病率和死亡率，但這些介入措施並不是針對有肛門癌風險的 HIV 陽性人群的照護標準。 Palefsky 說，原因是缺乏證據顯示它們會起作用。許多高危人群有多個癌前病變，臨床醫生可能會漏診或治療不充分，治療後經常出現新病變，導致 Palefsky 稱之為「肛門打地鼠」。
–
研究設計
ANCHOR（或肛門癌 HSIL 結果研究）試驗旨在解決這個問題。該研究旨在確定治療肛門 HSIL 是否可以降低 HIV 感染者肛門癌的發生率，以及這樣做是否安全。它還著眼於生活品質，並正在創建一個數據和樣本庫，以幫助進一步研究導致疾病進展的因素。
該研究在美國 15 個城市招募了 35 歲及以上的愛滋病毒感染者。在研究開始時，他們使用肛門巴氏塗片（細胞學）和一種稱為高分辨率肛門鏡 (high-resolution anoscopy) 檢查的技術對他們進行 HSIL 篩查，其中使用放大鏡檢查肛管。如果懷疑 HSIL，則收集活檢樣本進行分析。
被發現患有 HSIL 的參與者被隨機分配接受立即治療或主動監測。監測組中的人員每六個月返回一次進行重複篩查，如果被認為風險更高，則更頻繁地進行篩查。在任何時候發現患有肛門癌的人都會被轉診以進行進一步的評估和治療。
最常見的治療方法是電灼（hyfrecation）或紅外線凝固，這兩種方法使用電或熱去除異常病變。其他治療包括局部咪喹莫特 (imiquimod) 或 5-氟尿嘧啶 (5-fluorouracil) 乳膏，或在最晚期病例中進行手術。
2014 年 9 月至 2021 年 8 月期間，共有 10,723 名愛滋病毒感染者接受了篩查。超過一半（53% 的男性、46% 的女性和 63% 的跨性別者）在研究開始時被發現患有 HSIL，17 人被診斷出患有預先存在的肛門癌。 Palefsky 指出，HSIL 的患病率與男性的預期水平差不多，但高於女性的預期，女性以前大多沒有接受過篩查。
在該組中，4,446 名 HSIL 患者被隨機分配到即時治療組（2,227 人）或主動監測組（,2219 人）。隨機參與者的中位年齡為 51 歲，他們感染 HIV 的中位時間為 17 年。絕大多數（80%）是男性——主要是同性戀或雙性戀——16%是女性，大約3%是變性人。大約三分之一是白人，42% 是黑人，16% 是拉丁裔。超過 80% 的患者接受抗反轉錄病毒治療，病毒載量檢測不到，CD4 計數中位數約為 600。
該試驗於 2021 年 10 月提前停止，此前一項中期分析顯示篩查和早期治療具有明顯的益處：去除 HSIL 可顯著降低進展為肛門癌的風險。數據安全和監測委員會建議監測部門的每個人都應接受治療，並將繼續跟踪參與者。
立即治療組中的 9 人和主動監測組中的 21 人被診斷出患有浸潤性肛門癌，這顯示治療組的風險降低了 57%。即刻治療組的肛門癌發生率為每 100,000 人年追蹤 173 例，而監測組為 402 例。在兩個研究組中被診斷出患有肛門癌的人中，大多數都處於早期階段。
在研究過程中，86% 的參與者接受了一種治療，10% 接受了兩種治療，約 2% 接受了三種或四種治療。治療通常是安全的並且耐受性良好。即刻治療組中的 7 人和監測組中的 1 人經歷了與活檢或治療程序相關的嚴重不良事件。
–
對愛滋病毒感染者的影響
Palefsky 在 CROI 媒體簡報會上告訴記者，這些發現支持將常規篩查和早期 HSIL 治療納入 HIV 感染者照護標準的一部分。結果還應鼓勵衛生系統和保險公司承擔這些程序的費用。
雖然 ANCHOR 研究僅限於 HIV 感染者，但結果可能適用於其他肛門癌風險增加的群體，包括與男性發生性關係的 HIV 陰性男性、有子宮頸癌或其他 HPV 相關癌症病史的女性，以及因 HIV 以外的原因而導致免疫抑制的人。
然而，缺乏接受過高分辨率肛門鏡檢查訓練的臨床醫生仍然是一個障礙。更重要的是，需要生物標誌物來幫助預測誰最有可能發生 HSIL 進展，或者相反，誰最有可能在沒有治療的情況下出現復原。 Palefsky 說，肛門 HSIL 的治療還有「改進的空間」。
直腸指檢 (digital rectal exam) 可以檢測肛門異常生長，帕列夫斯基建議將此作為愛滋病毒感染者的第一步。當高分辨率肛門鏡檢查的可用性有限時，他說應該優先考慮有肛門 HSIL 或癌症症狀的人，包括疼痛、出血和新腫塊。下一個優先事項應該是老年人和那些低量或最低點（有史以來最低）CD4 計數的人。
儘管肛門癌目前很少見，但在許多國家的 HIV 感染者中，HPV 的流行率很高。 「隨著愛滋病毒人口老齡化，肛門癌將增加」，帕列夫斯基說。「這是培訓員工並讓他們為不可避免的增長做好準備的好時機」。
雖然這些結果是好消息，但預防肛門癌甚至比早期發現和治療更好。儘管吸煙（HPV 相關癌症的一個已知風險因素）在 ANCHOR 中沒有達到統計顯著性的閾值，但 Palefsky 指出，進展為肛門癌的人中有 60% 以上是吸煙者，而整個研究人群中這一比例約為 30%。
接種疫苗可以首先預防 HPV 感染。 Gardasil 9 疫苗可預防九種導致癌症或生殖器疣的高危 HPV 類型。該疫苗被推薦用於美國 11 歲或 12 歲的女孩和男孩，以及英國 12 歲或 13 歲的女孩和男孩，並在一般人群中於 25 歲或 26 歲之前進行補種接種。 HIV 專家協會和指引建議 45 歲以下的 HIV 感染者若在年輕時錯過疫苗接種，應與他們的醫生討論。
參考文獻：
Palefsky J et al. 治療肛門高級別鱗狀上皮內病變，預防肛門癌。反轉錄病毒和伺機性感染會議，摘要 106LB，2022。
Screening and early treatment reduce anal cancer risk by 57% in people living with HIV
Liz Highleyman / 17 February 2022 / aidsmap
Professor Joel Palefsky at CROI 2022.
Screening for precancerous anal cell changes and treating them early lowers the risk of progression to anal cancer in people living with HIV, according to results from the ANCHOR study presented this week at the Conference on Retroviruses and Opportunistic Infections (CROI 2022).
“This is the first demonstration that screening and treatment reduces the risk of anal cancer,” said ANCHOR lead investigator Professor Joel Palefsky of the University of California at San Francisco. “I think the data support inclusion [of screening and treatment] in the standard of care for people with HIV over 35.”
Anal cancer is uncommon in the population at large, but rates have been rising for both men and women since the 1970s, Palefsky said. Like cervical cancer, anal cancer is caused by human papillomavirus (HPV), one of the most common sexually transmitted infections. The virus triggers abnormal cell changes that can progress to precancerous dysplasia (known as high-grade squamous intraepithelial lesions, or HSIL) and invasive cancer.
The incidence of anal cancer is much higher among people living with HIV, for whom it is the fourth most common cancer. Previous research has shown that people living with HIV have more types of HPV, are less likely to naturally clear the virus and experience more rapid progression to HSIL or cancer. Even people on effective antiretroviral therapy with a high CD4 count can develop anal dysplasia and cancer. Men who have sex with men are especially prone to anal cancer; other groups at risk include older individuals, women with cervical cancer and people with compromised immunity for other reasons.
Widespread screening and early treatment have dramatically lowered the prevalence and mortality of cervical cancer since the 1950s, but these interventions are not the standard of care for HIV-positive people at risk for anal cancer. The reason, Palefsky said, has been lack of evidence that they would work. Many at-risk people have multiple precancerous lesions, clinicians may miss or inadequately treat lesions, and new lesions often arise after treatment, leading to what Palefsky termed “anal whack-a-mole”.
Study design
The ANCHOR – or Anal Cancer HSIL Outcomes Research – trial was designed to address this question. The study aimed to determine whether treating anal HSIL can reduce the incidence of anal cancer in people living with HIV and whether doing so is safe. It also looked at quality of life, and is creating a data and specimen bank to aid further research into factors that contribute to disease progression.
The study enrolled people with HIV aged 35 and older in 15 US cities. At study entry, they were screened for HSIL using anal Pap smears (cytology) and a technique called high-resolution anoscopy, in which a magnifying scope is used to examine the anal canal. If HSIL was suspected, a biopsy sample was collected for analysis.
Participants found to have HSIL were randomly assigned to receive immediate treatment or active monitoring. Those in the monitoring arm returned for repeat screening every six months or more often if deemed to be at higher risk. People found to have anal cancer at any point were referred for further evaluation and treatment.
The most common treatments were electrocautery (hyfrecation) or infrared coagulation, two methods that use electricity or heat to remove abnormal lesions. Other treatments included topical imiquimod or 5-fluorouracil creams, or surgery in the most advanced cases.
Study results
A total of 10,723 people with HIV were screened between September 2014 and August 2021. More than half (53% of men, 46% of women and 63% of transgender people) were found to have HSIL at study entry, and 17 were diagnosed with pre-existing anal cancer. HSIL prevalence was about what was expected for men, but it was higher than expected for women, a group that mostly had not been screened before, Palefsky noted.
Out of this group, 4446 people with HSIL were randomly assigned to the immediate treatment arm (2227 people) or the active monitoring arm (2219 people). The median age of the randomised participants was 51 and they had been living with HIV for a median of 17 years. A large majority (80%) were men – mostly gay or bisexual – 16% were women and about 3% were transgender. About a third were White, 42% were Black and 16% were Latino. More than 80% were on antiretroviral therapy with an undetectable viral load and the median CD4 count was approximately 600.
The trial was halted ahead of schedule in October 2021 after an interim analysis showed that screening and early treatment confers a clear benefit: removing HSIL significantly reduced the risk of progression to anal cancer. A data safety and monitoring board recommended that everyone in the monitoring arm should be offered treatment, and participants will continue to be followed.
Nine people in the immediate treatment arm and 21 people in the active monitoring arm were diagnosed with invasive anal cancer, reflecting a 57% risk reduction in the treatment group. The incidence of anal cancer was 173 cases per 100,000 person-years of follow-up in the immediate treatment group compared with 402 cases in the monitoring group. Among those diagnosed with anal cancer in both study arms, most were at an early stage.
Over the course of the study, 86% of participants received one type of treatment, 10% received two types and about 2% received three or four types. Treatment was generally safe and well tolerated. Seven people in the immediate treatment group and one in the monitoring group experienced serious adverse events related to biopsy or treatment procedures.
Implications for people with HIV
These findings support the inclusion of routine screening and early HSIL treatment as part of the standard of care for people living with HIV, Palefsky told reporters at a CROI media briefing. The results should also encourage health systems and insurers to cover the cost of these procedures.
Although the ANCHOR study was limited to people with HIV, the results will likely be applicable to other groups at increased risk for anal cancer, including HIV-negative men who have sex with men, women with a history of cervical or other HPV-related cancers, and people with immunosuppression for reasons other than HIV.
However, the lack of clinicians trained to perform high-resolution anoscopy remains a barrier. What’s more, there is a need for biomarkers to help predict who is at greatest risk for HSIL progression or, conversely, who is most likely to experience regression without treatment. And there is “room for improvement” in the treatment of anal HSIL, Palefsky said.
A digital rectal exam can detect abnormal anal growths, and Palefsky recommended this as a first step for people living with HIV. When the availability of high-resolution anoscopy is limited, he said that first priority should go to people who have symptoms of anal HSIL or cancer, including pain, bleeding and new lumps. The next priority should be older individuals and those with a low current or nadir (lowest-ever) CD4 count.
The prevalence of HPV is high among people with HIV in many countries, even if anal cancer is currently rare. “Anal cancer will increase as the HIV population ages,” Palefsky said. “This is a great time to train the workforce and get them ready for when that inevitable increase happens.”
While these results are good news, prevention of anal cancer would be even better than early detection and treatment. Although smoking – a known risk factor for HPV-related cancers – did not reach the threshold for statistical significance in ANCHOR, Palefsky noted that just over 60% of people who progressed to anal cancer were smokers compared with about 30% of the study population as a whole.
Vaccination can prevent HPV infection in the first place. The Gardasil 9 vaccine protects against nine high-risk HPV types that cause cancer or genital warts. The vaccine is recommended for girls and boys at age 11 or 12 in the US and at age 12 or 13 in the UK, with catch-up vaccination through age 25 or 26 in the general population. HIV specialist societies and guidelines recommend that people living with HIV under the age of 45 who missed vaccination when they were younger discuss it with their doctor.
References
Palefsky J et al. Treatment of anal high-grade squamous intraepithelial lesions to prevent anal cancer. Conference on Retroviruses and Opportunistic Infections, abstract 106LB, 2022.