泰国艾滋病毒感染妇女宫颈癌筛查策略的评价

IF 20.1 1区 医学 Q1 ONCOLOGY
Patumrat Sripan, Myrtille Prouté, Nicole Ngo-Giang-Huong, Samreung Rangdaeng, Chaiwat Putiyanun, Guttiga Halue, Prattana Leenasirimakul, Suchart Thongpaen, Sudanee Buranabanjasatean, Sophie Le Coeur, Tristan Delory
{"title":"泰国艾滋病毒感染妇女宫颈癌筛查策略的评价","authors":"Patumrat Sripan,&nbsp;Myrtille Prouté,&nbsp;Nicole Ngo-Giang-Huong,&nbsp;Samreung Rangdaeng,&nbsp;Chaiwat Putiyanun,&nbsp;Guttiga Halue,&nbsp;Prattana Leenasirimakul,&nbsp;Suchart Thongpaen,&nbsp;Sudanee Buranabanjasatean,&nbsp;Sophie Le Coeur,&nbsp;Tristan Delory","doi":"10.1002/cac2.70000","DOIUrl":null,"url":null,"abstract":"<p>Women living with human immunodeficiency viruses (WLHIV) are six times more likely to develop cervical cancer than the general population; they represent less than 1% of the world's population, but account for more than 5% of cervical cancers [<span>1</span>]. WLHIV also have higher prevalence of human papilloma virus (HPV) infection with high-risk oncogenic genotypes (HR-HPV) than the general population [<span>2</span>]. In Asia, an estimated 35% (95% confidence interval [95% CI]: 30%-39%) of WLHIV carry HR-HPV infection [<span>3</span>]. Before 2021, Thailand's national cervical cancer screening program recommended cervical cytology. Since then, the Thai Ministry of Public Health, in line with the World Health Organization (WHO), has approved screening of all women aged 30-60 years (including those living with HIV) with standalone (primary) HPV test every 5 years [<span>4</span>].</p><p>In this context, to determine the optimal cervical cancer screening strategy for WLHIV, we used data from the PapilloV cohort (NCT01792973) in which WLHIV had yearly screening for cervical cancer using cytology, HPV-DNA testing with full genotype subtyping (PapilloCheck<sup>®</sup>, Greiner Bio-One, Germany), and histology if necessary. Women in the cohort were all receiving antiretroviral therapy (ART), their HIV infection was well-controlled and they were highly compliant with the screening study protocol: 90% with at least 2 visits and 81% with at least 3 visits.</p><p>We designed 17 screening strategies (Supplementary Figure S1), including cytology alone, primary HPV testing alone, reflex HPV testing (HPV test after abnormal cytology), reflex cytology (cytology after positive HPV testing), and co-testing (simultaneous cytology and HPV testing). For HPV testing, we considered four genotype combinations, among those prevalent in Asia and associated with cancer: “HR-HPV 16/18”, “HR-HPV 16/18/31/33/52”, “any HR-HPV”, and “any HR-HPV or potentially HR (pHR)-HPV” [<span>3, 5</span>–<span>7</span>]. Methods are detailed in Supplementary Materials and Methods.</p><p>Among 179 WLHIV who underwent a total of 251 check-up visits with three interpretable screening tests (cytology, HPV test, and biopsy) over the 3-year follow-up, we diagnosed 40 (15.9%, 95% CI: 11.9%-20.9%) cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and 24 (9.6%, 95% CI: 6.5%-13.8%) CIN3+ at biopsy. The population selection and its characteristics including HIV infection history, cytology, histology and HPV testing results are detailed in Supplementary Tables S1-S2 and Supplementary Figure S2.</p><p>We estimated the diagnostic performance of each screening strategy and its probability of not detecting high-grade cervical lesions. Depending on the strategy, 4 to 40 CIN2+ lesions could be detected with a sensitivity ranging from 16% to 100%, specificity from 3% to 93%, positive predictive value from 16% to 53%, and negative predictive value from 77% to 100% (Supplementary Table S3). The CIN2+ detection rate was greater than 75% for five strategies: (1) primary HPV test for any HR-HPV (78%); (2) primary HPV test for any HR-HPV or pHR-HPV (82%); (3) co-testing with HPV test for HPV16/18/31/33/52 (88%); (4) co-testing with HPV test for any HR-HPV (98%); and (5) co-testing with HPV test for any HR-HPV or pHR-HPV (100%) (Figure 1A).</p><p>The probability of missing CIN2+ lesions ranged from 8% to 15% for standalone strategies, from 10% to 23% for reflex strategies, and from 0% to 9% for co-testing strategies (Figure 1B). Reflex strategies led to the lowest number of colposcopies to detect one CIN2+ (2 to 3) compared with primary HPV testing (3 to 6) or co-testing strategies (4 to 6) (Supplementary Table S3). It also led to the lowest probability of excess diagnosis (Figure 1C, Supplementary Table S4). Results for CIN3+ lesions are provided in Supplementary Materials.</p><p>Policy makers have to strike the right balance between the need to detect high-grade lesions and the need to avoid over-diagnosis. Thus, we ranked strategies according to whether they favor the detection of high-grade lesions (co-testing and primary HPV testing) or limit over-diagnosis (reflex-based strategies) (Figure 1D), based on the comparison of the probabilities of excess diagnosis over missing CIN2+ lesions (Figure 1E).</p><p>As strategy's performance may vary according to the burden of HIV infection and cervical lesions, the proportion of women with undetected precancerous/cancerous lesions at the population level may be substantial. It is essential to identify needs-based regional strategies to translate the progress of the cervical cancer prevention strategies into implementation, uptake and further integration into population-based health programs. Therefore, we applied our results to different settings worldwide depending on the prevalence of HIV (from 0.1% to 20%) and CIN2+ lesions (from 0% to 20%) in WLHIV to project the number of women with undetected CIN2+ lesions at population-level [<span>1</span>]. We found that with any strategy other than co-testing, the fraction of women with CIN2+ lesions missed would increase at least 4-fold. At most, using HPV testing to screen for any HR-HPV or pHR-HPV, in settings where HIV and CIN2+ prevalence is 20%, the number of women with undetected CIN2+ lesions in the population would be between 2,462 and 2,651 per 100,000 women with standalone or reflex strategies, compared with 606 per 100,000 women with co-testing (Figure 1F).</p><p>In our analysis among WLHIV, the current screening strategy using primary HPV testing, as recommended by WHO [<span>8</span>], offers a good balance between benefits and harms of colposcopy/biopsy. However, its sensitivity was relatively low compared with co-testing, particularly when the number of HPV genotypes targeted was small, as with HPV 16/18 alone. Even when the range of HPV genotypes was extended to the most potent HR-HPV (HPV 16/18/31/33/52), the percentage of missed CIN2+ lesions remained lower with co-testing than with primary HPV testing (5% versus 8%). Therefore, using primary HPV testing in settings with a wide variety of HR-HPV genotypes, such as in Asia or sub-Saharan Africa, a large number of CIN2+ lesions may go undetected [<span>3</span>]. To improve the detection of high-grade lesions, an HPV-based screening program should ideally use a wide range of alpha-genus genotypes, encompassing those identified as involved in most cancers [<span>7</span>]. Markers for HPV integration such as E6/E7 oncoproteins are being tested as alternative primary test or triage strategies.</p><p>Screening guidelines and practices involve difficult trade-offs, involving considerations of costs, resources and access constraints, as well as potential harms and benefits for women's health. Referral for colposcopy/biopsy represents a bottleneck in the care cascade, as colposcopes are sometimes only available in tertiary hospitals, far from women's home. Over-diagnosis may lead to over-referral for colposcopy and over-treatment of healthy women. Our results suggest that reflex-based strategies could be a good alternative to co-testing and primary HPV testing, in line with the latest WHO recommendations (conditional) among WLHIV [<span>8</span>].</p><p>The robustness of cytology for high-grade lesion detection, regardless of immune status or ART duration, was highlighted in a previous study in Kenya in which all WLHIV underwent colposcopy/biopsy [<span>9</span>]. It is not possible to compare with our results because women with cytology and HR-HPV tests both negative were included, ART coverage was lower and overall prevalence of CIN2+ lesions was higher.</p><p>In conclusion, our results suggest that in regions where the HIV epidemic and the prevalence of CIN2+ are lowest, primary HPV testing may achieve the same results as complex population-based co-testing programs, in line with the latest WHO recommendations (strong) [<span>8</span>]. In resource-limited settings, when the burden of both HIV and cervical cancer is highest [<span>10</span>], co-testing may be the best screening strategy to limit the number of missed precancerous/cancerous lesions in WLHIV.</p><p>Sophie Le Coeur and Tristan Delory conceived and designed the project. Samreung Rangdaeng performed quality control of all cytological and histological samples. Nicole Ngo-Giang-Huong performed the HPV testing analyses. Myrtille Prouté and Patumrat Sripan analyzed the data. Chaiwat Putiyanun, Guttiga Halue, Prattana Leenasirimakul, Suchart Thongpaen, and Sudanee Buranabanjasatean collected patient samples. Patumrat Sripan, Myrtille Prouté, Sophie Le Coeur, and Tristan Delory drafted the manuscript. All authors reviewed and approved the final manuscript.</p><p>This study was supported by the Institut de Recherche pour le Développement (IRD), Marseille, France; the National Cancer Institute (INCA), France (grant number: 2011-169), and the Fondation de France (grant number: 14942). This research work was also partially funded by Chiang Mai University. Finally, the follow-up of the WLHIV was partially supported by the Global Funds to Fight AIDS, Tuberculosis and Malaria (GFATM) (grant number: PR-A_N_008 RCC). Patumrat Sripan received a grant from the Office of the International Relations and Partnerships at Ined for her one-month stays as visiting researcher in 2023 and 2024.</p><p>The PapilloV study was registered on clinicaltrials.gov (NCT01792973).</p><p>The study protocol was approved by the ethics committees of the Institute for the Development of Human Research Protections, Ministry of Public Health, Thailand (SKM 1420/2554); the Faculty of Associated Medical Sciences, Chiang Mai University, Thailand (019E/55); the Research Institute for Development (IRD), and the 24 local hospitals. All women provided written informed consents.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"525-528"},"PeriodicalIF":20.1000,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70000","citationCount":"0","resultStr":"{\"title\":\"Evaluation of cervical cancer screening strategies in women living with HIV in Thailand\",\"authors\":\"Patumrat Sripan,&nbsp;Myrtille Prouté,&nbsp;Nicole Ngo-Giang-Huong,&nbsp;Samreung Rangdaeng,&nbsp;Chaiwat Putiyanun,&nbsp;Guttiga Halue,&nbsp;Prattana Leenasirimakul,&nbsp;Suchart Thongpaen,&nbsp;Sudanee Buranabanjasatean,&nbsp;Sophie Le Coeur,&nbsp;Tristan Delory\",\"doi\":\"10.1002/cac2.70000\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Women living with human immunodeficiency viruses (WLHIV) are six times more likely to develop cervical cancer than the general population; they represent less than 1% of the world's population, but account for more than 5% of cervical cancers [<span>1</span>]. WLHIV also have higher prevalence of human papilloma virus (HPV) infection with high-risk oncogenic genotypes (HR-HPV) than the general population [<span>2</span>]. In Asia, an estimated 35% (95% confidence interval [95% CI]: 30%-39%) of WLHIV carry HR-HPV infection [<span>3</span>]. Before 2021, Thailand's national cervical cancer screening program recommended cervical cytology. Since then, the Thai Ministry of Public Health, in line with the World Health Organization (WHO), has approved screening of all women aged 30-60 years (including those living with HIV) with standalone (primary) HPV test every 5 years [<span>4</span>].</p><p>In this context, to determine the optimal cervical cancer screening strategy for WLHIV, we used data from the PapilloV cohort (NCT01792973) in which WLHIV had yearly screening for cervical cancer using cytology, HPV-DNA testing with full genotype subtyping (PapilloCheck<sup>®</sup>, Greiner Bio-One, Germany), and histology if necessary. Women in the cohort were all receiving antiretroviral therapy (ART), their HIV infection was well-controlled and they were highly compliant with the screening study protocol: 90% with at least 2 visits and 81% with at least 3 visits.</p><p>We designed 17 screening strategies (Supplementary Figure S1), including cytology alone, primary HPV testing alone, reflex HPV testing (HPV test after abnormal cytology), reflex cytology (cytology after positive HPV testing), and co-testing (simultaneous cytology and HPV testing). For HPV testing, we considered four genotype combinations, among those prevalent in Asia and associated with cancer: “HR-HPV 16/18”, “HR-HPV 16/18/31/33/52”, “any HR-HPV”, and “any HR-HPV or potentially HR (pHR)-HPV” [<span>3, 5</span>–<span>7</span>]. Methods are detailed in Supplementary Materials and Methods.</p><p>Among 179 WLHIV who underwent a total of 251 check-up visits with three interpretable screening tests (cytology, HPV test, and biopsy) over the 3-year follow-up, we diagnosed 40 (15.9%, 95% CI: 11.9%-20.9%) cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and 24 (9.6%, 95% CI: 6.5%-13.8%) CIN3+ at biopsy. The population selection and its characteristics including HIV infection history, cytology, histology and HPV testing results are detailed in Supplementary Tables S1-S2 and Supplementary Figure S2.</p><p>We estimated the diagnostic performance of each screening strategy and its probability of not detecting high-grade cervical lesions. Depending on the strategy, 4 to 40 CIN2+ lesions could be detected with a sensitivity ranging from 16% to 100%, specificity from 3% to 93%, positive predictive value from 16% to 53%, and negative predictive value from 77% to 100% (Supplementary Table S3). The CIN2+ detection rate was greater than 75% for five strategies: (1) primary HPV test for any HR-HPV (78%); (2) primary HPV test for any HR-HPV or pHR-HPV (82%); (3) co-testing with HPV test for HPV16/18/31/33/52 (88%); (4) co-testing with HPV test for any HR-HPV (98%); and (5) co-testing with HPV test for any HR-HPV or pHR-HPV (100%) (Figure 1A).</p><p>The probability of missing CIN2+ lesions ranged from 8% to 15% for standalone strategies, from 10% to 23% for reflex strategies, and from 0% to 9% for co-testing strategies (Figure 1B). Reflex strategies led to the lowest number of colposcopies to detect one CIN2+ (2 to 3) compared with primary HPV testing (3 to 6) or co-testing strategies (4 to 6) (Supplementary Table S3). It also led to the lowest probability of excess diagnosis (Figure 1C, Supplementary Table S4). Results for CIN3+ lesions are provided in Supplementary Materials.</p><p>Policy makers have to strike the right balance between the need to detect high-grade lesions and the need to avoid over-diagnosis. Thus, we ranked strategies according to whether they favor the detection of high-grade lesions (co-testing and primary HPV testing) or limit over-diagnosis (reflex-based strategies) (Figure 1D), based on the comparison of the probabilities of excess diagnosis over missing CIN2+ lesions (Figure 1E).</p><p>As strategy's performance may vary according to the burden of HIV infection and cervical lesions, the proportion of women with undetected precancerous/cancerous lesions at the population level may be substantial. It is essential to identify needs-based regional strategies to translate the progress of the cervical cancer prevention strategies into implementation, uptake and further integration into population-based health programs. Therefore, we applied our results to different settings worldwide depending on the prevalence of HIV (from 0.1% to 20%) and CIN2+ lesions (from 0% to 20%) in WLHIV to project the number of women with undetected CIN2+ lesions at population-level [<span>1</span>]. We found that with any strategy other than co-testing, the fraction of women with CIN2+ lesions missed would increase at least 4-fold. At most, using HPV testing to screen for any HR-HPV or pHR-HPV, in settings where HIV and CIN2+ prevalence is 20%, the number of women with undetected CIN2+ lesions in the population would be between 2,462 and 2,651 per 100,000 women with standalone or reflex strategies, compared with 606 per 100,000 women with co-testing (Figure 1F).</p><p>In our analysis among WLHIV, the current screening strategy using primary HPV testing, as recommended by WHO [<span>8</span>], offers a good balance between benefits and harms of colposcopy/biopsy. However, its sensitivity was relatively low compared with co-testing, particularly when the number of HPV genotypes targeted was small, as with HPV 16/18 alone. Even when the range of HPV genotypes was extended to the most potent HR-HPV (HPV 16/18/31/33/52), the percentage of missed CIN2+ lesions remained lower with co-testing than with primary HPV testing (5% versus 8%). Therefore, using primary HPV testing in settings with a wide variety of HR-HPV genotypes, such as in Asia or sub-Saharan Africa, a large number of CIN2+ lesions may go undetected [<span>3</span>]. To improve the detection of high-grade lesions, an HPV-based screening program should ideally use a wide range of alpha-genus genotypes, encompassing those identified as involved in most cancers [<span>7</span>]. Markers for HPV integration such as E6/E7 oncoproteins are being tested as alternative primary test or triage strategies.</p><p>Screening guidelines and practices involve difficult trade-offs, involving considerations of costs, resources and access constraints, as well as potential harms and benefits for women's health. Referral for colposcopy/biopsy represents a bottleneck in the care cascade, as colposcopes are sometimes only available in tertiary hospitals, far from women's home. Over-diagnosis may lead to over-referral for colposcopy and over-treatment of healthy women. Our results suggest that reflex-based strategies could be a good alternative to co-testing and primary HPV testing, in line with the latest WHO recommendations (conditional) among WLHIV [<span>8</span>].</p><p>The robustness of cytology for high-grade lesion detection, regardless of immune status or ART duration, was highlighted in a previous study in Kenya in which all WLHIV underwent colposcopy/biopsy [<span>9</span>]. It is not possible to compare with our results because women with cytology and HR-HPV tests both negative were included, ART coverage was lower and overall prevalence of CIN2+ lesions was higher.</p><p>In conclusion, our results suggest that in regions where the HIV epidemic and the prevalence of CIN2+ are lowest, primary HPV testing may achieve the same results as complex population-based co-testing programs, in line with the latest WHO recommendations (strong) [<span>8</span>]. In resource-limited settings, when the burden of both HIV and cervical cancer is highest [<span>10</span>], co-testing may be the best screening strategy to limit the number of missed precancerous/cancerous lesions in WLHIV.</p><p>Sophie Le Coeur and Tristan Delory conceived and designed the project. Samreung Rangdaeng performed quality control of all cytological and histological samples. Nicole Ngo-Giang-Huong performed the HPV testing analyses. Myrtille Prouté and Patumrat Sripan analyzed the data. Chaiwat Putiyanun, Guttiga Halue, Prattana Leenasirimakul, Suchart Thongpaen, and Sudanee Buranabanjasatean collected patient samples. Patumrat Sripan, Myrtille Prouté, Sophie Le Coeur, and Tristan Delory drafted the manuscript. All authors reviewed and approved the final manuscript.</p><p>This study was supported by the Institut de Recherche pour le Développement (IRD), Marseille, France; the National Cancer Institute (INCA), France (grant number: 2011-169), and the Fondation de France (grant number: 14942). This research work was also partially funded by Chiang Mai University. Finally, the follow-up of the WLHIV was partially supported by the Global Funds to Fight AIDS, Tuberculosis and Malaria (GFATM) (grant number: PR-A_N_008 RCC). Patumrat Sripan received a grant from the Office of the International Relations and Partnerships at Ined for her one-month stays as visiting researcher in 2023 and 2024.</p><p>The PapilloV study was registered on clinicaltrials.gov (NCT01792973).</p><p>The study protocol was approved by the ethics committees of the Institute for the Development of Human Research Protections, Ministry of Public Health, Thailand (SKM 1420/2554); the Faculty of Associated Medical Sciences, Chiang Mai University, Thailand (019E/55); the Research Institute for Development (IRD), and the 24 local hospitals. 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摘要

感染人类免疫缺陷病毒(WLHIV)的妇女患宫颈癌的可能性是一般人群的六倍;他们只占世界人口的不到1%,但却占宫颈癌患者总数的5%以上。WLHIV感染高危致癌基因型(HR-HPV)的人乳头瘤病毒(HPV)感染的流行率也高于普通人群bb0。在亚洲,估计有35%(95%可信区间[95% CI]: 30%-39%)的WLHIV携带HR-HPV感染。2021年之前,泰国国家宫颈癌筛查计划建议进行宫颈细胞学检查。从那时起,泰国公共卫生部按照世界卫生组织(世卫组织)的要求,批准每5年对所有30-60岁妇女(包括艾滋病毒感染者)进行一次单独(初级)HPV检测。在这种背景下,为了确定WLHIV的最佳宫颈癌筛查策略,我们使用了来自PapilloV队列(NCT01792973)的数据,其中WLHIV每年进行宫颈癌筛查,使用细胞学,HPV-DNA检测和全基因型亚型(PapilloCheck®,Greiner Bio-One,德国),必要时进行组织学检查。队列中的妇女都接受抗逆转录病毒治疗(ART),她们的艾滋病毒感染得到很好的控制,她们高度遵守筛查研究方案:90%的人至少两次就诊,81%的人至少三次就诊。我们设计了17种筛查策略(补充图S1),包括单独细胞学检查、单独原发HPV检测、反射性HPV检测(异常细胞学检查后的HPV检测)、反射性细胞学检查(HPV检测阳性后的细胞学检查)和联合检测(细胞学检查和HPV检测同时进行)。对于HPV检测,我们考虑了在亚洲流行并与癌症相关的四种基因型组合:“HR-HPV 16/18”,“HR-HPV 16/18/31/33/52”,“任何HR-HPV”和“任何HR-HPV或潜在HR (pHR)-HPV”[3,5 - 7]。方法详见补充资料和方法。在3年的随访中,179例WLHIV患者共接受了251次检查,其中包括三种可解释的筛查试验(细胞学、HPV检测和活检),我们在活检中诊断出40例(15.9%,95% CI: 11.9%-20.9%)宫颈上皮内瘤变2级或更高(CIN2+), 24例(9.6%,95% CI: 6.5%-13.8%) CIN3+。人群选择及其特征,包括HIV感染史、细胞学、组织学和HPV检测结果详见补充表S1-S2和补充图S2。我们估计了每种筛查策略的诊断性能及其未检测到高级别宫颈病变的概率。根据不同的策略,可以检测到4 ~ 40个CIN2+病变,灵敏度为16% ~ 100%,特异性为3% ~ 93%,阳性预测值为16% ~ 53%,阴性预测值为77% ~ 100%(补充表S3)。五种策略的CIN2+检出率均大于75%:(1)任何HR-HPV的原发性HPV检测(78%);(2)进行HR-HPV或pr -HPV的原发性HPV检测(82%);(3)与HPV检测联合检测HPV16/18/31/33/52 (88%);(4)与HPV联合检测任何HR-HPV (98%);(5)与HPV检测共同检测HR-HPV或pr -HPV(100%)(图1A)。单独检测策略遗漏CIN2+病变的概率为8% - 15%,反射检测策略为10% - 23%,联合检测策略为0% - 9%(图1B)。与原发性HPV检测(3至6)或联合检测策略(4至6)相比,反射策略导致阴道镜检查检测1个CIN2+(2至3)的次数最少(补充表S3)。这也导致了最低的超额诊断概率(图1C,补充表S4)。CIN3+病变结果见补充资料。决策者必须在检测高级别病变的需要和避免过度诊断的需要之间取得适当的平衡。因此,我们根据是否有利于检测高级别病变(联合检测和原发性HPV检测)或限制过度诊断(基于反射的策略)(图1D)对策略进行排名,基于对错过CIN2+病变的过度诊断概率的比较(图1E)。由于战略的执行情况可能因艾滋病毒感染和宫颈病变的负担而有所不同,因此在人口水平上患有未被发现的癌前病变/癌性病变的妇女比例可能很大。必须确定基于需求的区域战略,将宫颈癌预防战略的进展转化为实施、吸收和进一步纳入以人口为基础的保健方案。因此,我们将我们的结果应用于世界范围内不同的环境,根据WLHIV的HIV患病率(从0.1%到20%)和CIN2+病变(从0%到20%)来预测人群水平上未检测到CIN2+病变的妇女人数。 我们发现,除联合检测外,采用任何其他策略,漏检CIN2+病变的女性比例将增加至少4倍。在艾滋病毒和CIN2+患病率为20%的情况下,最多使用HPV检测筛查任何HR-HPV或pr -HPV,人群中未检测到CIN2+病变的女性人数在每10万名单独或反射策略的女性中为2,462至2,651人,而联合检测的女性为每10万名606人(图1F)。在我们对WLHIV的分析中,目前使用初级HPV检测的筛查策略,如世卫组织[8]推荐的,在阴道镜检查/活检的利弊之间提供了良好的平衡。然而,与联合检测相比,其敏感性相对较低,特别是当目标HPV基因型数量较少时,如单独使用HPV 16/18。即使将HPV基因型范围扩展到最有效的HR-HPV (HPV 16/18/31/33/52),联合检测的CIN2+病变漏诊率仍然低于原发性HPV检测(5%对8%)。因此,在具有多种HR-HPV基因型的环境中,例如在亚洲或撒哈拉以南非洲,使用原发性HPV检测,大量CIN2+病变可能未被检测到。为了提高对高级别病变的检测,以hpv为基础的筛查程序应该理想地使用广泛的α -属基因型,包括那些被确定与大多数癌症有关的基因型。HPV整合的标记物,如E6/E7癌蛋白,正在作为替代的初级检测或分诊策略进行检测。筛查准则和做法涉及艰难的权衡,涉及考虑成本、资源和获取限制,以及对妇女健康的潜在危害和益处。转诊阴道镜检查/活检是护理级联的瓶颈,因为阴道镜检查有时只能在三级医院提供,远离妇女的家。过度诊断可能导致过度转诊阴道镜检查和过度治疗健康妇女。我们的研究结果表明,基于反射的策略可能是联合检测和原发性HPV检测的一个很好的替代方案,符合世卫组织在WLHIV人群中的最新建议(有条件的)。无论免疫状态或抗逆转录病毒治疗持续时间如何,细胞学检测高度病变的稳健性在肯尼亚先前的一项研究中得到了强调,该研究中所有WLHIV患者都接受了阴道镜检查/活检。不可能与我们的结果进行比较,因为包括细胞学检查和HR-HPV检查均为阴性的妇女,ART覆盖率较低,CIN2+病变的总体患病率较高。总之,我们的研究结果表明,在艾滋病毒流行和CIN2+患病率最低的地区,初次HPV检测可能达到与复杂的基于人群的联合检测计划相同的结果,符合最新的世卫组织建议(强)bb0。在资源有限的情况下,当艾滋病毒和宫颈癌的负担最高时,联合检测可能是限制WLHIV中癌前病变/癌前病变漏诊数量的最佳筛查策略。Sophie Le Coeur和Tristan Delory构思和设计了这个项目。Samreung Rangdaeng对所有细胞学和组织学样品进行质量控制。Nicole ngo - jiang - huong进行了HPV检测分析。Myrtille proout<e:1>和Patumrat Sripan分析了这些数据。Chaiwat Putiyanun、Guttiga Halue、Prattana Leenasirimakul、Suchart Thongpaen和Sudanee Buranabanjasatean收集了患者样本。帕图姆拉特·斯里潘、默蒂尔·普鲁托尔、索菲·勒·科尔和特里斯坦·德洛里起草了手稿。所有作者都审阅并批准了最终稿件。这项研究得到了法国马赛的人体健康发展研究所的支持;法国国家癌症研究所(INCA)(资助号:2011-169)和法国基金会(资助号:14942)。这项研究工作也得到了清迈大学的部分资助。最后,全球抗击艾滋病、结核病和疟疾基金(GFATM)(赠款编号:PR-A_N_008 RCC)对全球艾滋病毒后续行动提供了部分支持。帕图姆拉特·斯里潘获得了国际关系和伙伴关系办公室的资助,她将在2023年和2024年作为访问研究员停留一个月。PapilloV研究已在clinicaltrials.gov注册(NCT01792973)。该研究方案已获得泰国公共卫生部人类研究保护发展研究所伦理委员会的批准(SKM 1420/2554);泰国清迈大学联合医学学院(019E/55);发展研究所(IRD)和24家当地医院。所有女性都提供了书面知情同意书。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Evaluation of cervical cancer screening strategies in women living with HIV in Thailand

Evaluation of cervical cancer screening strategies in women living with HIV in Thailand

Women living with human immunodeficiency viruses (WLHIV) are six times more likely to develop cervical cancer than the general population; they represent less than 1% of the world's population, but account for more than 5% of cervical cancers [1]. WLHIV also have higher prevalence of human papilloma virus (HPV) infection with high-risk oncogenic genotypes (HR-HPV) than the general population [2]. In Asia, an estimated 35% (95% confidence interval [95% CI]: 30%-39%) of WLHIV carry HR-HPV infection [3]. Before 2021, Thailand's national cervical cancer screening program recommended cervical cytology. Since then, the Thai Ministry of Public Health, in line with the World Health Organization (WHO), has approved screening of all women aged 30-60 years (including those living with HIV) with standalone (primary) HPV test every 5 years [4].

In this context, to determine the optimal cervical cancer screening strategy for WLHIV, we used data from the PapilloV cohort (NCT01792973) in which WLHIV had yearly screening for cervical cancer using cytology, HPV-DNA testing with full genotype subtyping (PapilloCheck®, Greiner Bio-One, Germany), and histology if necessary. Women in the cohort were all receiving antiretroviral therapy (ART), their HIV infection was well-controlled and they were highly compliant with the screening study protocol: 90% with at least 2 visits and 81% with at least 3 visits.

We designed 17 screening strategies (Supplementary Figure S1), including cytology alone, primary HPV testing alone, reflex HPV testing (HPV test after abnormal cytology), reflex cytology (cytology after positive HPV testing), and co-testing (simultaneous cytology and HPV testing). For HPV testing, we considered four genotype combinations, among those prevalent in Asia and associated with cancer: “HR-HPV 16/18”, “HR-HPV 16/18/31/33/52”, “any HR-HPV”, and “any HR-HPV or potentially HR (pHR)-HPV” [3, 57]. Methods are detailed in Supplementary Materials and Methods.

Among 179 WLHIV who underwent a total of 251 check-up visits with three interpretable screening tests (cytology, HPV test, and biopsy) over the 3-year follow-up, we diagnosed 40 (15.9%, 95% CI: 11.9%-20.9%) cervical intraepithelial neoplasia grade 2 or higher (CIN2+) and 24 (9.6%, 95% CI: 6.5%-13.8%) CIN3+ at biopsy. The population selection and its characteristics including HIV infection history, cytology, histology and HPV testing results are detailed in Supplementary Tables S1-S2 and Supplementary Figure S2.

We estimated the diagnostic performance of each screening strategy and its probability of not detecting high-grade cervical lesions. Depending on the strategy, 4 to 40 CIN2+ lesions could be detected with a sensitivity ranging from 16% to 100%, specificity from 3% to 93%, positive predictive value from 16% to 53%, and negative predictive value from 77% to 100% (Supplementary Table S3). The CIN2+ detection rate was greater than 75% for five strategies: (1) primary HPV test for any HR-HPV (78%); (2) primary HPV test for any HR-HPV or pHR-HPV (82%); (3) co-testing with HPV test for HPV16/18/31/33/52 (88%); (4) co-testing with HPV test for any HR-HPV (98%); and (5) co-testing with HPV test for any HR-HPV or pHR-HPV (100%) (Figure 1A).

The probability of missing CIN2+ lesions ranged from 8% to 15% for standalone strategies, from 10% to 23% for reflex strategies, and from 0% to 9% for co-testing strategies (Figure 1B). Reflex strategies led to the lowest number of colposcopies to detect one CIN2+ (2 to 3) compared with primary HPV testing (3 to 6) or co-testing strategies (4 to 6) (Supplementary Table S3). It also led to the lowest probability of excess diagnosis (Figure 1C, Supplementary Table S4). Results for CIN3+ lesions are provided in Supplementary Materials.

Policy makers have to strike the right balance between the need to detect high-grade lesions and the need to avoid over-diagnosis. Thus, we ranked strategies according to whether they favor the detection of high-grade lesions (co-testing and primary HPV testing) or limit over-diagnosis (reflex-based strategies) (Figure 1D), based on the comparison of the probabilities of excess diagnosis over missing CIN2+ lesions (Figure 1E).

As strategy's performance may vary according to the burden of HIV infection and cervical lesions, the proportion of women with undetected precancerous/cancerous lesions at the population level may be substantial. It is essential to identify needs-based regional strategies to translate the progress of the cervical cancer prevention strategies into implementation, uptake and further integration into population-based health programs. Therefore, we applied our results to different settings worldwide depending on the prevalence of HIV (from 0.1% to 20%) and CIN2+ lesions (from 0% to 20%) in WLHIV to project the number of women with undetected CIN2+ lesions at population-level [1]. We found that with any strategy other than co-testing, the fraction of women with CIN2+ lesions missed would increase at least 4-fold. At most, using HPV testing to screen for any HR-HPV or pHR-HPV, in settings where HIV and CIN2+ prevalence is 20%, the number of women with undetected CIN2+ lesions in the population would be between 2,462 and 2,651 per 100,000 women with standalone or reflex strategies, compared with 606 per 100,000 women with co-testing (Figure 1F).

In our analysis among WLHIV, the current screening strategy using primary HPV testing, as recommended by WHO [8], offers a good balance between benefits and harms of colposcopy/biopsy. However, its sensitivity was relatively low compared with co-testing, particularly when the number of HPV genotypes targeted was small, as with HPV 16/18 alone. Even when the range of HPV genotypes was extended to the most potent HR-HPV (HPV 16/18/31/33/52), the percentage of missed CIN2+ lesions remained lower with co-testing than with primary HPV testing (5% versus 8%). Therefore, using primary HPV testing in settings with a wide variety of HR-HPV genotypes, such as in Asia or sub-Saharan Africa, a large number of CIN2+ lesions may go undetected [3]. To improve the detection of high-grade lesions, an HPV-based screening program should ideally use a wide range of alpha-genus genotypes, encompassing those identified as involved in most cancers [7]. Markers for HPV integration such as E6/E7 oncoproteins are being tested as alternative primary test or triage strategies.

Screening guidelines and practices involve difficult trade-offs, involving considerations of costs, resources and access constraints, as well as potential harms and benefits for women's health. Referral for colposcopy/biopsy represents a bottleneck in the care cascade, as colposcopes are sometimes only available in tertiary hospitals, far from women's home. Over-diagnosis may lead to over-referral for colposcopy and over-treatment of healthy women. Our results suggest that reflex-based strategies could be a good alternative to co-testing and primary HPV testing, in line with the latest WHO recommendations (conditional) among WLHIV [8].

The robustness of cytology for high-grade lesion detection, regardless of immune status or ART duration, was highlighted in a previous study in Kenya in which all WLHIV underwent colposcopy/biopsy [9]. It is not possible to compare with our results because women with cytology and HR-HPV tests both negative were included, ART coverage was lower and overall prevalence of CIN2+ lesions was higher.

In conclusion, our results suggest that in regions where the HIV epidemic and the prevalence of CIN2+ are lowest, primary HPV testing may achieve the same results as complex population-based co-testing programs, in line with the latest WHO recommendations (strong) [8]. In resource-limited settings, when the burden of both HIV and cervical cancer is highest [10], co-testing may be the best screening strategy to limit the number of missed precancerous/cancerous lesions in WLHIV.

Sophie Le Coeur and Tristan Delory conceived and designed the project. Samreung Rangdaeng performed quality control of all cytological and histological samples. Nicole Ngo-Giang-Huong performed the HPV testing analyses. Myrtille Prouté and Patumrat Sripan analyzed the data. Chaiwat Putiyanun, Guttiga Halue, Prattana Leenasirimakul, Suchart Thongpaen, and Sudanee Buranabanjasatean collected patient samples. Patumrat Sripan, Myrtille Prouté, Sophie Le Coeur, and Tristan Delory drafted the manuscript. All authors reviewed and approved the final manuscript.

This study was supported by the Institut de Recherche pour le Développement (IRD), Marseille, France; the National Cancer Institute (INCA), France (grant number: 2011-169), and the Fondation de France (grant number: 14942). This research work was also partially funded by Chiang Mai University. Finally, the follow-up of the WLHIV was partially supported by the Global Funds to Fight AIDS, Tuberculosis and Malaria (GFATM) (grant number: PR-A_N_008 RCC). Patumrat Sripan received a grant from the Office of the International Relations and Partnerships at Ined for her one-month stays as visiting researcher in 2023 and 2024.

The PapilloV study was registered on clinicaltrials.gov (NCT01792973).

The study protocol was approved by the ethics committees of the Institute for the Development of Human Research Protections, Ministry of Public Health, Thailand (SKM 1420/2554); the Faculty of Associated Medical Sciences, Chiang Mai University, Thailand (019E/55); the Research Institute for Development (IRD), and the 24 local hospitals. All women provided written informed consents.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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