Figures
Abstract
Objectives
Anal cancer, usually driven by an oncogenic Human Papillomavirus, remains a leading cause of morbidity in men who have sex with men (MSM) living with HIV, despite combined antiretroviral therapy. Various recommendations advocate to perform regular examination and proctologist-performed samples to anticipate this risk and treat locally before cancer occurrence, an efficient strategy which has the drawback of requiring the proctologist’s availability. This study evaluates the acceptability, feasibility, and efficiency of self-performed samples to screen for HPV-infection and HPV-related anal dysplasia among MSM living with HIV followed in Hôtel-Dieu Hospital.
Methods
Between February 2015 and June 2015, MSM living with HIV and referred to the day-care hospital were offered to perform an anal self-sampling for cytologic and virologic evaluation. A self-sampling kit was provided, and a tutorial video was shown. A subset of participants had a proctology appointment after they did the self-sampling, and thus had a clinical examination and an anal swab sampling performed by the proctologist, using the same sampling material.
Results
Anal self-sampling was offered to 103 patients, and 100 accepted. Sixty-three samples were interpretable, of which 36 (57%) were normal and 27 (43%) showed abnormal results. Virologic analysis was performed for 60 (95%) interpretable samples: 50/60 (83%) of them were positive for HPV. Among HPV-carrier patients, 42/50 (84%) were infected with at least one HR-HPV. Twenty patients had a proctologist consultation. All clinician-performed samples were interpretable and 14 (70%) self-samples were interpretable.
Conclusions
This study highlights the acceptable accuracy of self-sampling screening method among MSM living with HIV and try out its acceptability and feasibility as a secondary prevention device. Although it cannot replace a proctologist consultation for high risk patients, self-sampling should be studied further as one of the ways of screening for anal cancer among low-risk outpatients.
Citation: Heid-Picard B, Cochand-Priollet B, Rozenberg F, Giang-Phang D, Viard J-P, La Torre V, et al. (2021) Ambulatory anal self-sampling in MSM living with HIV, an acceptable and reliable screening method. PLoS ONE 16(2): e0246338. https://doi.org/10.1371/journal.pone.0246338
Editor: Michael Scheurer, Baylor College of Medicine, UNITED STATES
Received: August 10, 2020; Accepted: January 18, 2021; Published: February 9, 2021
Copyright: © 2021 Heid-Picard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Combined antiretroviral therapy (cART) has dramatically reduced HIV/AIDS-related mortality and morbidity [1]. Anal cancer, however, remains a leading cause of morbidity in men who have sex with men (MSM) living with HIV [2].
In most cases, anal cancer is a squamous cell carcinoma, driven by an oncogenic, or High Risk Human Papillomavirus (HR-HPV), most commonly HPV type 16 and type 18 [3]. Similarly to cervical infection, HPV can cause benign condyloma or may induce intraepithelial anal lesion, the latter displaying a higher prevalence among MSM than among heterosexuals and enhanced by HIV co-infection [4]. Among the general population, HPV is often cleared in 6 months to 2 years. However, among immunocompromised patients, including PLWHIV, annual incidence of high grade squamous intraepithelial lesions is increased, reaching up to 8 to 15% [4].
Despite the use of cART, MSM living with HIV are especially at risk of anal cancer [5], with an incidence of 131 per 100 000 person-years, 30–100 times higher than in the general population, where prevalence ranges from 0.8 to 1.0 per 100 000 persons-year. Among PLWHIV, this association is observed even after immune recovery has been obtained [6], and is not necessarily associated with profound immune deficiency [7].
French guidelines recommend an annual day-care hospitalization to screen for non-communicable, non-AIDS comorbidities in PLWHIV [8]. Currently, there is no consensus about anal dysplasia screening. As this severe complication can easily be prevented by regular anal examination and preventive treatment, French guidelines recommend annual screening for PLWHIV with digital rectal examination and anoscopy, with or without systematic cytology among MSM, patients with condyloma history or women with cervical HPV-related lesions. Systematic screening for viral HPV DNA is not recommended, because the prevalence among MSM living with HIV is around 80% [9].
Yet, the regular examination of an intimate part can raise acceptability issues among PLWHIV [10] and requires an important availability of proctologists’ consultations. These problems can impair the achievement of a systematic screening program and increase its cost. Cytologic anal self-sampling could be an alternative to physician-performed sampling. It has already been studied against different controls and seemed to be acceptable [11–13], performing [14–16] and cost-effective [17].
The purpose of our study was to reassess the acceptability, feasibility, and efficiency of anal self-sampling to screen for HPV-infection and HPV-related anal dysplasia among MSM living with HIV.
Methods
OVHID is an outpatient cohort of PLWHIV followed in our clinical center. The inclusion in the cohort occurred on the day of admission in the day-care hospital for comprehensive screening of non-communicable, non-AIDS comorbidities according to French guidelines. The OVHID study protocol was approved by the Ethics Committee « Ile de France II » (N° ID RCB: 2010-A00417-32) and by the French general data protection regulation (CNIL). All participants signed written informed consent. MSM living with HIV and referred to the day-care hospital between February 2015 and June 2015 were offered to perform an anal self-sampling. If they were willing to perform such a self-sampling, a short educational video on how to perform the sampling was shown. Patients were advised to introduce the swab for 2 centimeters, to spin it and then to rub the brush against the wall of the preserving vial.
The sampling material was a sterile Dacron swab with a brush dedicated to this kind of anal sampling (Rovers society, Netherlands). The transport medium was a preserving PreserCyt® vial with ThinPrep® liquid, Hologic [18]. The tutorial video used the same material.
All samples were analyzed in the Pathology department of the Cochin Hospital, Paris. Cytologic analyzes were performed using ThinPrep® slides as well as the Papanicolaou staining. The results were reported according to the Bethesda System 2014 used for HPV-linked cervical cancer [19]. All samples with cytologic abnormalities were also tested in the virology department, using the residual ThinPrep liquid, to seek for HPV and its types, using Linear Array genotyping (Roche Laboratory) with MY09-MY11 primers. Samples were classified as satisfactory or unsatisfactory for evaluation following the criteria described in the Bethesda blue book 2014 [19]. To consider a sample adequate it was required to have enough well-preserved nucleated squamous cells; slides with a high number of predominantly anucleate squames or with cells obscured by fecal material or bacteria were considered as inadequate. HPV were classified as HR-HPV (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82), Low- Risk HPV (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP108) or Undetermined (62, 71, 83, 84, 85, 89) [20].
A subset of participants who had a planned proctology appointment as part of their day-care hospital, because of past anal dysplasia or systematic consultation scheduled every 3 years, did the self-sampling first and then had a clinical examination with high-resolution anoscopy and an anal swab sampling performed by the proctologist, using the same sampling material as described above.
Results
Anal self-sampling was offered to 103 patients, and 100/103 accepted (97.1%). Their median age was 56 years (min 26, max 75). Median CD4+ count was 704/mm3, median CD4+ nadir was 251/mm3 (1/mm3 to 912/mm3). Ninety-four percent of patients had an undetectable plasma viral load and the maximal viral was 550 copies/mL. A history of previous sexually transmitted infections, besides HIV and HPV, was found in 48% of patients, and 19% had a past episode of condyloma.
Out of 100 samples, 63 were interpretable, of which 36 (57%) were normal and 27 (43%) showed abnormal results. Among the samples unsatisfactory for evaluation, 19 (51%) evidenced intestinal glandular cells, 17 (46%) were acellular and 1 (3%) was agglutinated (Table 1). Among the abnormal results, 15 (55%) atypical squamous cells of undetermined significance (ASC-US), 11 (41%) low-grade squamous intra-epithelial lesions (LSIL), and 1 (4%) high-grade squamous intra-epithelial lesions (HSIL) were found (Table 1).
Virologic analysis was performed for 60 (95%) interpretable samples: 50 (86%) of them were positive for HPV, 8 (13%) were negative, 2 (3%) failed to provide a result (Table 1). Among HPV-carrier patients, 47 (94%) showed a coinfection with several HPV serotypes, 42 (84%) were infected with at least one HR-HPV, 4 (8%) with a low risk HPV, and 4 (8%) with an HPV of undetermined risk without another HPV. Among all samples tested, 22 (38%) were positive for HPV 16, 5 (9%) were positive for HPV 18 (one showing a co-infection with HPV16). Besides, 15 (26%) evidenced HPV 52, 9 (16%) HPV 51, 7 (12%) HPV 31, 7 (12%) HPV 53, 6 (10%) HPV 56, 6 (10%) HPV 66, 5 (9%) HPV 33, 5 (9%) HPV 58, 4 (7%) HPV 26, 4 (7%) HPV 59, 4 (7%) HPV 45, 1 (2%) HPV 39, 3 (5%) HPV 35, 3 (5%) HPV 73, 2 (3%) HPV 68, and 1 (2%) HPV 82 (Table 2). A detailed overview of the correspondence between cytologic and virologic results is provided in Table 2.
No significant differences were found between patients with cytological lesions and patients with normal self-sample except the CD4+ count, respectively at 690 /mm3 (227–1476) and 865/mm3 (164–1760) (Student’s Test p<0.05).
Twenty patients had an examination with a proctologist consultation planned for their day hospitalization, and thus had both self-sample and clinician-performed samples on the same day (3 of them had a biopsy instead of a sample, because of macroscopic lesions). All clinician-performed samples were interpretable. Fourteen (70%) self-samples were interpretable and 6 (30%) were not (Table 2). Among the patients with uninterpretable self-sample, all clinician-performed sample were normal. Self-samples evidenced 5 ASC-US (1 ASC-US, 1 LSIL with condyloma and 3 normal samples in the corresponding clinician-performed samples), 4 LSIL (3 LSIL and 1 normal sample in the clinician-performed samples), 1 HSIL (LSIL in the clinician-performed sample) and 4 normal samples (2 normal samples and 2 ASC-US in clinician-performed samples) (Table 2).
The 3 biopsies evidenced 1 low-grade dysplasia (self-sample showed LSIL), 1 low-grade dysplasia with condyloma (self-sample showed ASC-US) and 1 normal biopsy (self-sample showed ASC-US).
Only 1 patient had an HSIL according to the clinician-performed sample. Self-sample concluded to LSIL without being able to exclude HSIL and advised to perform a biopsy. The virologic sample evidenced HPV 16, HPV 26, HPV 58, HPV 70 and HPV 82.
Discussion
According to the studies we reviewed, the prevalence of histologically-proven squamous intra epithelial neoplasia in MSM living with HIV is around 20% [21] which is quite similar to cervical cancer before the development of screening programs for women [22].French guidelines recommend annual screening for MSM living with HIV, with digital rectal examination and anoscopy, with or without systematic cytology [8]. Yet, outpatients with uncomplicated, well controlled HIV infection are numerous and merely followed with consultations and annual day hospitalization. Their screening would require an important number of examinations by proctologists, who are not available at every care center. Patient-performed self-samples could be a cost-efficient method for screening this population of outpatients [26]. Self-sampling for screening of cervical cancer in women has already proven its feasibility [23, 24] and cost efficiency [25], and virologic tests keep being developed at lower costs [26]. Among MSM, anal self-sampling has already been studied against different controls and seemed to be acceptable [11–13], performing [14–16] and cost-effective [17].
Hereby, in a cohort of 100 patients, followed according to French guidelines with consultations and day hospitalization, we found a strong acceptability (97%), like in previous studies concerning PLWHIV [11, 13, 14], and a satisfactory accuracy (63%) of anal self-sampling. Among patients with interpretable samples, 86% were positive for HPV, of whose 84% were infected with a high-risk HPV. These numbers are close to those found in similar studies [13, 14, 27], and the variations of accuracy between cohorts could be attributed to different technical conditions and definitions of interpretability. On the counterpart, only 63% of the self-samples have been considered as “satisfactory for evaluation” which is a close percentage than in other studies [14, 27]. Our criteria to consider a sample “satisfactory for evaluation” were strict as previously explained. The criteria of adequacy and non-adequacy are well described and applied for the cervical cytology but there is a paucity of references concerning the anal cytology. In the study with the best results in terms of adequacy for anal self-sampling i.e. around 80% of adequacy [16], the criteria for adequacy were not described; it was only specified that “the number of nucleated squamous cells was sufficient or not” without any further comments. One of the points of our study was to compare the effectiveness of clinician-collected versus self-collected samples. 20% of patients had a consultation with a proctologist and a clinician-collected sample. The proportion of interpretable samples (100%) was greater than for self-samples (63%). There are some discrepancies between self- and clinician performed samples. We could expect the clinician-performed ones to be more accurate to find higher grade lesions, being sampled with direct vision and with our proctologists’ experience. We evidenced higher grade lesions with self-sampling for 5 (25%) patients, with clinical performed for 3(15%) patients, and concordant results for 6 (30%) patients. In this small number of patients, a higher performance to detect higher grade lesions wasn’t evidenced. The number of patients with a proctologist-performed sample was limited, which reduces the strength of the comparison, but we think that self-sampling, although less efficient, could be an acceptable first-line method for screening. Uninterpretable or anormal self-sampling should then lead to perform a proctologist consultation with anoscopy.
This study reports a prospective systematic screening cohort of 100 ambulatory patients, with cytologic and virologic results of self-samples for most of the patients. Despite being single-centered, it provides a viewing of the prevalence of AINs among MSM living with HIV. It corroborates the previously obtained data studies, concerning an important topic for MSM living with HIV which lacks cost-efficient screening methods. Furthermore, it provides an overview of HPV carriage among MSM living with HPV. This preliminary study does not aim to establish anal self-sampling as substitute for proctologist consultation. However, it does highlight the acceptable accuracy of this screening method among MSM living with HIV and try out anew its acceptability and feasibility as a secondary prevention device. Besides, considering the cost of screening and treating HPV infection, investigations for the efficiency of the HPV vaccine among MSM living with HIV. Just as it was recently investigated among women living with HIV [28], it should be assessed in MSM, especially in young MSM, in parallel to the assessment of effective screening methods to prevent from anal cancer in those already harboring HR-HPV. This work provides an interesting overview of HPV-carriage epidemiology among MSM living with in HIV and followed in Paris. We found an important carriage of HR-HPV, mainly HPV-16, HPV-52, HPV-51, HPV-31, HPV-56 and HPV-66. Some of these strains are currently not include in the marketed vaccines (Gardasil®, Gardasil9® and Cervarix®), but a cross-protection after HPV-vaccination has already been suggested [29]. Further studies are needed to evaluate the benefit of adapting the vaccine-strains to the different group of individuals, mainly based on their sexual activity habits [30].
To conclude, considering the high prevalence of HR-HPV among MSM living with HIV and the satisfactory accuracy of this low-priced ambulatory test, self-sampling strategy should be studied further as one of the ways of screening for anal cancer, among others. Further prospective studies are needed to evaluate its use among PLWHIV and to distinguish the respective usefulness of cytologic and virologic samples. Caution should be taken for high-risk patients, for instance those with history of condyloma, before skipping the visit with the proctologist. Higher performance of a clinician-performed sample and absence of direct visual control during a self-sample should be kept in mind. Yet, acceptability and proctologist availability being the main barriers to the consultation, positive anal sampling could help to convince the patient to attend proctologist’s consultation and should help to target the higher risk MSM living with HIV.
References
- 1. Trickey A, May MT, Vehreschild J-J, Obel N, Gill MJ, Crane HM, et al. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV. 2017 Aug 1;4(8):e349–56. pmid:28501495
- 2. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. The Lancet. 2014 Jul 19;384(9939):241–8. pmid:25042234
- 3. Burd EM. Human Papillomavirus Laboratory Testing: the Changing Paradigm. Clin Microbiol Rev. 2016 Apr;29(2):291–319. pmid:26912568
- 4. Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis Off Publ Infect Dis Soc Am. 2006 Jul 15;43(2):223–33. pmid:16779751
- 5. Heard I, Poizot-Martin I, Potard V, Etienney I, Crenn-Hebert C, Moore C, et al. Prevalence of and Risk Factors for Anal Oncogenic Human Papillomavirus Infection Among HIV-Infected Women in France in the Combination Antiretroviral Therapy Era. J Infect Dis. 2016 May 1;213(9):1455–61. pmid:26690345
- 6. Guiguet M, Boué F, Cadranel J, Lang J-M, Rosenthal E, Costagliola D, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. 2009 Dec;10(12):1152–9. pmid:19818686
- 7. Goedert JJ, Coté TR, Virgo P, Scoppa SM, Kingma DW, Gail MH, et al. Spectrum of AIDS-associated malignant disorders. Lancet Lond Engl. 1998 Jun 20;351(9119):1833–9. pmid:9652666
- 8.
Bressy J. Prise en charge du VIH—Recommandations du groupe d’experts [Internet]. Conseil national du sida et des hépatites virales. 2018 [cited 2018 Dec 29]. Available from: https://cns.sante.fr/actualites/prise-en-charge-du-vih-recommandations-du-groupe-dexperts/
- 9. Vajdic CM, van Leeuwen MT, Jin F, Prestage G, Medley G, Hillman RJ, et al. Anal human papillomavirus genotype diversity and co-infection in a community-based sample of homosexual men. Sex Transm Infect. 2009 Sep;85(5):330–5. pmid:19342375
- 10. Read TRH, Vodstrcil L, Grulich AE, Farmer C, Bradshaw CS, Chen MY, et al. Acceptability of digital anal cancer screening examinations in HIV-positive homosexual men. HIV Med. 2013 Sep;14(8):491–6. pmid:23590621
- 11. Rosenberger JG, Dodge B, Van Der Pol B, Reece M, Herbenick D, Fortenberry JD. Reactions to self-sampling for ano-rectal sexually transmitted infections among men who have sex with men: a qualitative study. Arch Sex Behav. 2011 Apr;40(2):281–8. pmid:19847636
- 12. Ortiz AP, Alejandro N, Pérez CM, Otero Y, Soto-Salgado M, Palefsky JM, et al. Acceptability of cervical and anal HPV self-sampling in a sample of Hispanic women in Puerto Rico. P R Health Sci J. 2012 Dec;31(4):205–12. pmid:23844468
- 13. Tamalet C, Ravaux I, Dhiver C, Menard A, Colson P, Stein A. Feasibility and Acceptability of Anal Self-Sampling for Human Papillomavirus Screening in HIV-Infected Patients. Intervirology. 2016;59(2):118–22. pmid:27923228
- 14. Cranston RD, Darragh TM, Holly EA, Jay N, Berry JM, Da Costa M, et al. Self-collected versus clinician-collected anal cytology specimens to diagnose anal intraepithelial neoplasia in HIV-positive men. J Acquir Immune Defic Syndr 1999. 2004 Aug 1;36(4):915–20. pmid:15220697
- 15. Lampinen TM, Miller ML, Chan K, Anema A, van Niekerk D, Schilder AJ, et al. Randomized clinical evaluation of self-screening for anal cancer precursors in men who have sex with men. CytoJournal. 2006 Mar 20;3:4. pmid:16549010
- 16. Chin-Hong PV, Berry JM, Cheng S-C, Catania JA, Da Costa M, Darragh TM, et al. Comparison of patient- and clinician-collected anal cytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia in men who have sex with men. Ann Intern Med. 2008 Sep 2;149(5):300–6. pmid:18765699
- 17. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Palefsky JM. Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus–negative homosexual and bisexual men. Am J Med. 2000 Jun 1;108(8):634–41. pmid:10856411
- 18. Darragh TM, Jay N, Tupkelewicz BA, Hogeboom CJ, Holly EA, Palefsky JM. Comparison of conventional cytologic smears and ThinPrep preparations from the anal canal. Acta Cytol. 1997 Aug;41(4):1167–70. pmid:9250316
- 19.
Nayar R, Wilbur D, editors. The Bethesda System for Reporting Cervical Cytology: Definitions, Criteria, and Explanatory Notes [Internet]. 3rd ed. Springer International Publishing; 2015 [cited 2019 Jun 6]. Available from: https://www.springer.com/fr/book/9783319110738
- 20. Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic Classification of Human Papillomavirus Types Associated with Cervical Cancer. N Engl J Med. 2003 Feb 6;348(6):518–27. pmid:12571259
- 21. Machalek DA, Poynten M, Jin F, Fairley CK, Farnsworth A, Garland SM, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and meta-analysis. Lancet Oncol. 2012 May;13(5):487–500. pmid:22445259
- 22. Gustafsson L, Pontén J, Bergström R, Adami HO. International incidence rates of invasive cervical cancer before cytological screening. Int J Cancer. 1997 Apr 10;71(2):159–65. pmid:9139836
- 23. Wright TC, Denny L, Kuhn L, Pollack A, Lorincz A. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA. 2000 Jan 5;283(1):81–6. pmid:10632284
- 24. Arbyn M, Verdoodt F, Snijders PJF, Verhoef VMJ, Suonio E, Dillner L, et al. Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. Lancet Oncol. 2014 Feb;15(2):172–83. pmid:24433684
- 25. Polman NJ, Snijders PJF, Kenter GG, Berkhof J, Meijer CJLM. HPV-based cervical screening: Rationale, expectations and future perspectives of the new Dutch screening programme. Prev Med. 2018 Dec 27; pmid:30594536
- 26. Qiao Y-L, Sellors JW, Eder PS, Bao Y-P, Lim JM, Zhao F-H, et al. A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China. Lancet Oncol. 2008 Oct;9(10):929–36. pmid:18805733
- 27. Lampinen TM, Chan K, Anema A, Kornegay J, Hogg RS, Coutlee F. Self-screening for rectal sexually transmitted infections: human papillomavirus. Clin Infect Dis Off Publ Infect Dis Soc Am. 2006 Jan 15;42(2):308–9. pmid:16355352
- 28. McClymont E, Lee M, Raboud J, Coutlée F, Walmsley S, Lipsky N, et al. The Efficacy of the Quadrivalent Human Papillomavirus Vaccine in Girls and Women Living With Human Immunodeficiency Virus. Clin Infect Dis Off Publ Infect Dis Soc Am. 2019 Feb 15;68(5):788–94. pmid:29985988
- 29. Covert C, Ding L, Brown D, Franco EL, Bernstein DI, Kahn JA. Evidence for cross-protection but not type-replacement over the 11 years after human papillomavirus vaccine introduction. Hum Vaccines Immunother. 2019 Feb 20;15(7–8):1962–9.
- 30. Baussano I, Lazzarato F, Ronco G, Franceschi S. Impacts of human papillomavirus vaccination for different populations: A modeling study. Int J Cancer. 2018 Sep 1;143(5):1086–92. pmid:29603224