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• W2895747229 abstract "Non-AIDS defining cancers have become more important than the classical AIDS-defining cancers Kaposi's sarcoma and non-Hodgkin lymphoma in the last one or two decades [1,2]. An important non-AIDS defining cancer is anal cancer. Its incidence is much more common in people living with HIV [3–5], and has risen strongly since effective combination antiretroviral therapy (ART) became available. Some studies indicate its incidence is still rising, while others suggest the incidence rate is plateauing [6,7]. The mortality of anal cancer is high, and quality of life after treatment can be severely affected. Prevention of anal cancer seems straightforward: vaccination against human papillomavirus (HPV), the causative virus in the overwhelming majority of anal cancers [8]. Unfortunately, people with HIV may not benefit from vaccination: a recent article reported on the results of a randomized controlled trial (RCT) of HIV-positive people randomized to the 4-valent vaccine or placebo [9]. The study was stopped early due to futility; vaccine efficacy was 0% [95% confidence interval (95% CI) −44 to 31] against histologically proven high-grade squamous intraepithelial lesions (HSILs), the precursor of anal cancer. Clearly, HPV vaccination should be given earlier, that is prior to HIV infection, or at an earlier age, or prior to or soon after sexual debut. This means that other means of prevention of anal cancer are needed for the foreseeable future. One promising approach has been screening of the anal mucosa for precursor stages of anal cancer, and treating these if present. This is done in analogy of cervical cancer prevention. Unfortunately, not all aspects of cervical disease, natural course, screening and treatment of precursors can be directly translated to anal pathology. The progression rate of HSIL to anal cancer is much lower than that of CIN2/3 to cervical cancer [4,10,11]. Probably, most HSILs never progress to anal cancer, or even regress spontaneously. Anal cytology is not very sensitive and not very specific [12–14]. Finally, and perhaps most importantly, the benefit of treating precursor stages of anal cancer is of unknown benefit. The only completed randomized clinical trial thus far noted success percentages of between 17 and 39% for different treatment modalities [15]. In nearly half of those with a complete treatment response, the lesion had reappeared 48 weeks posttreatment. So, there are many unanswered questions. We need better insights into the natural history of anal dysplasia, more effective treatments of HSIL and better ways of screening. Two large cohort studies are examining the natural history of anal HSIL: the SPANC in Australia [16], which started in 2010 and recently completed its 3-year follow-up, and the APACHES study in France, which started in 2014 [17]. Importantly, both studies test and screen (with HPV testing, cytology, histology and other markers), but do not treat HSIL; if anal cancer is diagnosed, the patient is treated. A large RCT studying the impact of HSIL treatment started in 2014 in the USA, the ANCHOR trial (anchorstudy.org). One of the key challenges in the field is screening. The current standard to screen for HSIL is high-resolution anoscopy (HRA). This is a cumbersome, expensive and unpleasant diagnostic procedure, which is difficult to learn. There are no clear predictors for HSIL, so currently there is no way to preselect HIV-positive people for HRA [18]. Also, performing an HRA is technically difficult. There is a learning curve [19,20], and there is variation between clinicians and clinics. Next, there is also variation between pathologists in diagnosing HSIL. An important step has been the publication of the International Guidelines for Practice Standards in the Detection of Anal Cancer Precursors [21] by the International Anal Neoplasia Society. These guidelines have set minimum standards for HRA. In this issue of AIDS, the French APACHES study group report baseline findings of a large multicentre study, with some important lessons for the field [22]. This study examined determinants of HSIL among HIV-positive MSM in France. The authors examined demographic, clinical, HIV-related, cytological and molecular variables. The strongest determinants were anal detection of DNA of high-risk HPV, notably of HPV-16, and HSIL cytology. Another important finding was the variation between clinics of the observed prevalence of HSIL. This large variation may be perceived as a weakness in many studies, as it may indicate undesirable heterogeneity in establishing the diagnosis between centres, but the authors turn this into a strength, by explicitly examining and discussing this between-clinic variation. This study contributes to the knowledge concerning HSIL and its determinants or predictors. The methods used to reach a histological diagnosis are robust, with a panel of pathologists examining all biopsies. Because of its size (n = 513), it was powered to detect important risk factors for anal HSIL, but, as with other studies before them, they found no behavioural, HIV-related or other demographic variables that were independently associated with HSIL. The only significant risk factor was smoking, a replication of a finding in several (though not all) earlier studies [23,24]. Another important finding is that cytology had a rather limited sensitivity in detecting histological HSIL and a low specificity. This confirms data from earlier studies and once again underlines the difference between cervical and anal HPV-induced disease. Finally, the authors note that two out of the six centres participating in the study had a very low detection rate of HSIL: 0 and 2.9% vs. 13.7% in the other four centres. This could not be attributed to variation in assessing the histological of biopsies (as these were done centralised by a panel of pathologists). HRA is a difficult procedure wherein much depends on the skills of the individual anoscopist; the IANS Guidelines recommend that in each patient undergoing a first HRA, at least one biopsy should be performed [21]. In two of the centres of APACHES, the biopsy rate was less than 20% (compared with over 50% in each of the other four centres). This large between-clinic variation is of course undesirable in a clinical study, but probably reflects actual variation in current clinical practice. So, the APACHES investigators may have work to do in training of the anoscopists in the various centres. But beyond APACHES, it may mean that many HRAs conducted in clinical practice are underdiagnosing HSILs. In conclusion, the APACHES report shows in a large multicentre study that cytology is far from ideal, that there are no demographic or HIV variables that may identify patients with anal HSIL and that HRA is a difficult technique that is not easily standardized. The finding that anal HPV-16 at the time of the HRA is the strongest risk factor for anal HSIL confirms its key role in anal pathogenesis, but may not be enough for screening purposes. More studies are needed to chart the natural history of anal HSIL and to identify biomarkers that may predict which patient has HSIL [25], or better still, will develop anal cancer. Acknowledgements Conflicts of interest The institution of M. F. SvdL received study funding from Sanofi Pasteur MSD and Janssen Infectious Diseases and Vaccines; he was a co-investigator in a Merck-funded investigator-initiated study; he was an investigator on a Sanofi Pasteur MSD sponsored trial; he served on a vaccine advisory board of GSK; his institution received in-kind contribution for an HPV study from Stichting Pathologie Onderzoek en Ontwikkeling (SPOO)." @default.
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• W2895747229 date "2018-10-23" @default.
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• W2895747229 title "Secondary anal cancer prevention in the HIV-infected" @default.
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