August 16th, 2025

Anal Cancer Screening in HIV: When Guidelines Get Ahead of the Evidence

Should every person with HIV over age 35 (if MSM or transgender woman) or 45 (everyone else) have an anal Pap smear, a digital anal rectal exam (DARE), and possibly a high-resolution anoscopy every 1–2 years? According to recent guidelines, yes. But here’s the problem: we don’t know if this screening effort actually prevents cancer.

First, some facts:

  1. Human papillomavirus (HPV) infection is necessary, but not sufficient, for the development of anal cancer.
  2. Both HPV prevalence and anal cancer incidence are higher in PWH than in those without HIV.
  3. The natural history of HPV leading to anal cancer is similar to cervical cancer.
  4. Cervical cancer screening programs have reduced incidence of that disease.
  5. In the ANCHOR trial, treatment of biopsy-confirmed, high-grade squamous intraepithelial lesions (HSIL) in PWH reduced the risk of anal cancer.

So far, so good.

The temptation, therefore, is to apply our cervical-cancer-prevention model directly to anal cancer, and that’s an approach many have advocated for years. But here’s the problem — there’s no proof this works. As Dr. Hayden Andrews wrote in a recent State-of-the-Art review in Clinical Infectious Diseases (Note: I am currently editor-in-chief of this journal):

To date, no trial has been conducted to determine if anal cancer screening among PWH decreases anal cancer incidence.

And if you think about it for a nanosecond, that’s not surprising! Demonstrating that cancer screening improves outcomes is notoriously hard. Just ask anyone who studies breast, prostate, lung, or colorectal screening — and those cancers are far more common than anal cancer, and have been far more widely studied.

This gets to the core of why I believe the International Anal Neoplasia Society guidelines — later reinforced by the Department of Health and Human Services HIV guidelines — are premature and overly aggressive. They’re posted in our clinic workroom, so I’m constantly reminded of just how broad they are. The recommendations show up in this Bluesky post of mine, along with my incredulous query:

Calling all HIV/ID providers: How many are able to do this screening for anal cancer according to IANS? Including the HRA and repeat screening every 1-2 years (!!) for normal results? Wow, that's a lot of screening tests in a lot of people! #IDSky #HIVsky onlinelibrary.wiley.com/doi/10.1002/…

Paul Sax (@paulsaxmd.bsky.social) 2025-08-15T17:39:22.614Z

Wow (again) — all MSM and transgender women older than 35? All men and women older than 45? Referral of all abnormal results to high-resolution anoscopy? Then repeat the process if normal results every 1-2 years? My goodness.

Some issues that make broad screening problematic:

  • Poor test performance: Anal cytology via Pap smears has low sensitivity for HSIL even in high-prevalence populations; it also has high interobserver variability and lots of unsatisfactory or ASCUS results. Read Dr. Amit Achhra’s paper describing their experience at Yale — disappointing, both in terms of accuracy of anal cytology and patient participation! Digital anal rectal exams (DARE) can pick up anal cancer, but lack sensitivity for HSIL, the key precancerous lesions.
  • Limited access to the best test:  High-resolution anoscopy (HRA) is superior to anal cytology, but many clinical sites have few or even no trained providers to do the exams. I know of one site that cares for thousands of patients and has zero access to HRA.
  • Patient burden:  Local anaesthesia, discomfort, repeat visits, cost, and anxiety aren’t trivial.
  • Unclear screening frequency:  The evidence for how often to screen is even weaker than whether we should screen at all.

Add to this the medicolegal bind these guidelines create — if you follow them, you may overwhelm your local system or excessively burden your patients; if you don’t, you risk looking negligent in hindsight. It’s the perfect recipe for a frustrated group of HIV providers, as we’re doomed to fail (and we obsessive ID types hate failing). I really do wonder what fraction of us are in “compliance” with these guidelines. I’d bet good money it’s very low!

As the late David Sackett, one of the founders of evidenced-based medicine, once wrote, “the fundamental promise we make when we actively solicit individuals and exhort them to accept preventive interventions must be that, on average, they will be the better for it… Without evidence from positive randomized trials … we cannot justify soliciting the well to accept any personal health intervention.”

That’s exactly the unease many of us feel with these guidelines (and thanks to Amit for pointing me to this great quote).

I shared my concerns with Dr. Grant Ellsworth, a member of the DHHS guidelines committee who heads the HPV section, and obviously knows a lot more about this field than I do. In addition to looking forward to a time when HPV testing is routinely incorporated to reduce over-screening, he made some additional valuable comments:

Amit Achhra’s paper really highlights how poor a screening tool cytology can be. They had high unsatisfactory rates and frankly outlying poor performance — even at a place like Yale. If Yale can’t pull it off, who can? My other hesitation with the current recommendations is that I’m not sure ANCHOR’s results can be reproduced in the real world. The study sites had an onerous and expensive training process, with ongoing audits to maintain quality. Sure, we can screen for anal HSIL, but will your clinic be able to find and treat it at the same level as ANCHOR?

That last question is key — if the idealized trial environment can’t be replicated in everyday practice, then the guidelines risk being aspirational rather than accomplishing their goal.

Here’s what I’d do until we have better evidence.

  • State up front that although we know that anal cancer is more common in people with HIV, we don’t know if screening helps reduce the risk over a strategy of not screening.
  • Start discussions at age 50 (or younger if other strong risk factors:  low nadir CD4, smoking).
  • Offer shared decision-making, not automatic screening. What does the patient want? We do this with the PSA, why not this test?
  • Skip the anal Pap entirely, and go directly to HRA for those who choose screening. If HRA isn’t available, focus on HPV testing.
  • Repeat no more often than every 3-5 years, or some other interval to be determined by baseline risk.

This approach acknowledges that the ANCHOR trial answered only one question — whether treating HSIL reduces cancer incidence. It emphatically did not address the important questions of how to screen, whom to screen, and how often to do it.

I’m afraid answers will only come from further clinical studies.

11 Responses to “Anal Cancer Screening in HIV: When Guidelines Get Ahead of the Evidence”

  1. R Laurits says:

    Shouldn’t Dr. Sackett’s quote have been applied to the COVID -19 vaccine mandates?

  2. David Lee says:

    Anal cancer screening is always compared to cervical cancer screening, but you cannot treat anal cancer/dysplasia with conization or hysterectomy like you do cervical cancer, thus I doubt the benefits will be as large with anal cancer screening as with cervical cancer screening.

    David Lee, MD
    Dallas, TX

  3. Victor Leung says:

    And another point to emphasize is increasing HPV-9 vaccine uptake. For this intervention, we have RCT results.

  4. Elizabeth Buechler says:

    Thank you for this summary.
    As a gynecologist with years of experience with HR-A and anal cancer screening (in both men and women), I find the 1-2 year recommendation too aggressive. I mimic the recommendations for following women at risk for cervical disease. No data on this approach either, of course.

  5. Adam Lake says:

    I’d love to see less anal cancer, but I don’t want to shift the burden of pathology from the 1 in 5,882 (10,000/17) human we save from cancer to the 5,881 in 5,882 humans who have the discomfort, pain, follow ups, treatments, and anxiety but no benefit. Plus all the health care folks who track, follow up, manage, perform, and result all 5,882 of these tests.

    I would be for an annual “well man” exam that includes a genital and perianal exam, especially for my HIV+MSM. I find plenty of verrucae and fistulas that wouldn’t have come up otherwise. I think we could triage the anal paps a lot harder than we do in the IANS guidelines, especially because we have no HRA locally. My folks with solid organ transplants or long periods with low CD4 counts and intermittent ART adherence are higher priority than the 45 year old MSW who was diagnosed with HIV in rehab with a CD4 of 800.

  6. Taylor Kelamis says:

    Thanks, Dr. Sax, for shining a light in a typically-overlooked and underrated aspect of health. The anus deserves the attention given all it does for us.

    Calling all primary care, internal medicine, infectious disease, gynecology, pathology, gastroenterology, colorectal surgery, GYN ONC, transplant medicine and community health practitioners—let’s work together to put into action the evidence-based guidelines born from the groundbreaking, multisite and multidisciplinary ANCHOR study while doing our part to add to the body of evidence. Take the excellent IANS’s HRA course and learn high resolution anoscopy as others have around the world.

    Let’s remember Dr. Georgios Papanikolaou and his wife, Andromache, who screened herself for years to offer evidence supporting his hypothesis that precancerous cells could be detected via a swab and help prevent cancer. Thanks to the intangible contributions of Dr. Ian Frazer and Dr. Jian Zhou, the HPV vaccine has prevented countless persistent HPV infections and related cancers. Unfortunately, the HPV vaccination uptake was recently reported as ‘stagnant’ and, in some communities, especially in the rural South, declining.

    Let’s do their hard work and dedication justice by talking about HPV, vaccination, and, if needed, screening. Reference the CDC’s and ASCCP’s adapted anal cancer screening guidelines.

    While people living with HIV, SOTR, men who have sex with men, long-term steroid users have higher rates of anal cancer precursors, post-menopausal women are disproportionately affected by anal cancer. The most common STI can lead to frank human suffering. One case is worth preventing. Remember Farrah. Listen to Marcia.

  7. Joel Palefsky, Naomi Jay, Julia Pugliese, Cristina Brickman, Stephen Goldstone says:

    We read with interest Dr. Sax’s comments on Health and Human Services (HHS) and International Anal Neoplasia Society (IANS) anal cancer screening guidelines (1,2). The ANCHOR study showed that identification and treatment of anal HSIL can lead to a substantial reduction in progression of HSIL to anal cancer (3). The monitoring arm of the ANCHOR study showed that the progression rate from untreated anal HSIL to cancer in people with HIV (PWH) is unacceptably high. Similar rates of progression in the cervix would never be tolerated and would mandate implementation of a prevention program. HPV vaccination is a cornerstone of anal cancer prevention for but unfortunately, most individuals living with HIV are past the age where vaccination will confer much benefit. This leaves treatment of anal HSIL as the best opportunity to reduce the incidence of anal cancer in PWH and other groups at high risk of anal cancer.

    Dr. Sax comments on the current state of anal cancer screening and states that there is no proof that it works. He quotes Dr. Hayden Andrews, “To date, no trial has been conducted to determine if anal cancer screening among PWH decreases anal cancer incidence”. That is technically true but since the ANCHOR study showed that treating anal HSIL works to reduce the incidence of anal cancer, the real question is whether screening to identify anal HSIL works and whether it can be done in a cost-effective manner that maximizes benefits and minimizes harm. Recently data were published showing that anal cancer screening using anal cytology and HPV triage for men who have sex with men (MSM) with HIV above the age of 35 years is in fact cost-effective (4). In addition to reducing progression to cancer, screening has also been shown to reduce mortality from anal cancer- in the Netherlands, men who were screened had reduced mortality from anal cancer compared with unscreened men, most likely due to earlier diagnosis of the cancers (5).

    He further quotes Dr. David Sackett, “Without evidence from positive randomized trials … we cannot justify soliciting the well to accept any personal health intervention.” Here we must face reality: a screening study with the outcome of reduced anal cancer incidence will never be done given the required size and time, the enormous expense, and ethical issues with following a group of people at very high risk of anal HSIL without treatment in light of ANCHOR findings.

    Dr. Sax cites the extensive efforts used in ANCHOR needed to ensure high quality of HRA performance and treatment as a concern for an anal cancer screening program, since it can’t be guaranteed that success achieved in the ideal trial environment can be replicated in clinical practice. Isn’t that always true? The need to monitor performance among HRA trainees is no different from the extensive efforts used to ensure that all cervical colposcopists are clinically competent. There is every reason to believe that anoscopists outside of the context of the ANCHOR trial can achieve clinical competence with sufficient training and mentoring, and this does not render the guidelines aspirational any more than cervical screening is aspirational. It just takes commitment.

    In the interest of encouraging efforts to identify HSIL in at-risk groups as soon as possible, a consensus panel of HHS, the HIV Medicine Association and the Infectious Diseases Society of America issued guidelines for PWH, and IANS for PWH and other high-risk groups (1,2). The ANCHOR-based recommendation to treat anal HSIL had the strongest strength of recommendation and quality of evidence rating “AI, Strong, recommendation, one or more randomized trials with clinical outcomes and/or validated laboratory endpoints”. However, there was widespread acknowledgement that there was a paucity of data to inform the screening guidelines, and the quality of the evidence for screening approaches to identify HSIL was graded as “BIII, moderate recommendation, expert opinion”. In the absence of optimal data, the HHS approach was to model the first set of guidelines after cervical cancer prevention guidelines for women with HIV. These guidelines, whether cervical or anal, have always been, and will remain, a work in progress. The guidelines will change as new data or technologies become available.

    So what are the best screening tests available right now? What results should prompt referral for high resolution anoscopy (HRA), the gold standard for diagnosis of anal HSIL? What should screening intervals be for those whose test results do not mandate HRA referral? Given the very high prevalence of anal HSIL in PWH and other at-risk populations, it would be ideal to perform HRA as a diagnostic measure on all such individuals. However, HRA is not feasible as a screening tool given the expense, specialized equipment, and most critically, the limited number of individuals trained in this procedure (6). Similar issues exist for cervical cancer screening programs, and tests such as cervical cytology and HPV detection are used as first steps to determine which women need referral for cervical colposcopy. A similar approach is needed to determine which patients need referral for HRA while minimizing the number of referrals for those who do not.

    The tests that are currently most commonly available as first steps for anal cancer screening are anal cytology and HPV detection. A major advantage of these tests is that they can be performed using a relatively simple procedure, i.e., insertion of an anal swab, with relatively little training. But that does not mean that no training is needed. The experience of the Yale group is unfortunate, but in our experience it is quite common that insufficiency rates are high for new groups embarking on performing anal cytology, even for excellent institutions such as Yale. This is almost always corrected with additional training. Most medical procedures require some training and quality assurance, and collection of anal cells using an anal swab is no exception. Even when adequate, similar to cervical cytology, anal cytology has low sensitivity and high specificity for detection of HSIL (7). Like cytology, HPV testing has limitations, notably high sensitivity and low specificity, and this is one of the reasons for recommending co-testing with HPV, the preferred approach in the HHS guidelines. It is also important to note that both the HHS and IANS guidelines suggest additional criteria beyond the results of cytology and HPV testing that can be used to triage patients for HRA when HRA capacity is limited.

    Both the HHS and IANS guidelines include a digital anorectal examination (DARE) as part of the screening procedure whether or not HRA is available. DARE is not intended to detect anal HSIL. The primary purpose of DARE is to detect a prevalent anal cancer, whereas anal cytology, HPV testing and HRA are primarily aimed at detecting HSIL for cancer prevention. If HRA is not available, it is not recommended to perform anal cytology or HPV testing, since the results of the testing cannot be acted on. Performing only a DARE on people at high risk of anal cancer is not ideal, but it is preferable to doing nothing. Naturally the procedure needs to be explained well to patients, and both provider and patient must be properly prepared. Guidance on how to perform a DARE for detection of anal cancer has been published by IANS (8). Data on the utility of DARE for detection of anal cancer are limited, but an analysis of DARE in the screening population for the ANCHOR study shows high sensitivity and specificity (9).

    So what do we do now? We owe it to our patients to do something. We strongly advocate to start the process of implementing the existing screening guidelines since these are based on the best information that we have today, imperfect as they are. This includes training more people to perform HRA, and ensuring that primary care and other providers are properly trained in the performance of anal cytology and DARE. It will be critical to perform the research needed to optimize the guidelines, including development and assessment of new tests such as methylation or extended HPV genotyping. New data will be coming- as just one example, efforts are now underway to analyze specimens collected at screening of more than 10,000 PWH and follow-up in the ANCHOR Study. The large number of specimens in the ANCHOR Biorepository will allow for analysis of performance of new tests. They will contribute to development of biomarkers for anal HSIL progression and regression, and hopefully new tests for detection of prevalent anal cancer. Other specimen collections and studies will undoubtedly provide additional data.

    Here’s a suggestion for a change that could be implemented in the next revision of the guidelines: The cost-effectiveness analysis referred to above showed that longer screening intervals were more cost-effective than the intervals currently in the guidelines. Adjustment of screening intervals could result in lower costs and reduced burden on patients and providers.

    In the meantime, it is our collective responsibility to move forward with prevention programs, be they primary (HPV vaccination) or secondary (screening for and treatment of HSIL and cancer) to ensure the best possible care for our patients at risk of anal cancer.

    References

    1. Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. National Institutes of Health, HIV Medicine Association and Infectious Diseases Society of America, August 2024. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/human?view=full, accessed August 22, 2025
    2. Stier EA, Clarke MA, Deshmukh AA, Wentzensen N, Liu Y, Poynten IM, Cavallari EN, Fink V, Barroso LF, Clifford GM, Cuming T, Goldstone SE, Hillman RJ, Rosa-Cunha I, La Rosa L, Palefsky JM, Plotzker R, Roberts JM, Jay N. International Anal Neoplasia Society’s consensus guidelines for anal cancer screening. Int J Cancer. 2024 May 15; 154(10):1694-1702.
    3. Palefsky JM, Lee JY, Jay N, Goldstone SE, Darragh TM, Dunlevy HA, Rosa-Cunha I, Arons A, Pugliese JC, Vena D, Sparano JA, Wilkin TJ, Bucher G, Stier EA, Tirado Gomez M, Flowers L, Barroso LF, Mitsuyasu RT, Lensing SY, Logan J, Aboulafia DM, Schouten JT, de la Ossa J, Levine R, Korman JD, Hagensee M, Atkinson TM, Einstein MH, Cracchiolo BM, Wiley D, Ellsworth GB, Brickman C, Berry-Lawhorn JM, ANCHOR Investigators Group. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med. 2022 06 16; 386(24):2273-2282.
    4. Deshmukh AA, Damgacioglu H, Sigel K, Palefsky JM, Clarke MA, Wentzensen N, Nyitray AG, Ortiz AP, Lin YY, Chiao EY, Stier E, Jay N, Gaisa M, Liu Y, Meissner EG, Lazenby G, Giuliano AR, Goldstone SE, Clifford GM, Sonawane K, Chhatwal J. Screening for Anal Cancer Among Men Who Have Sex With Men With HIV: Benefits, Harms, and Cost-Effectiveness Analyses. Ann Intern Med. 2025 Jul;178(7):975-986.
    5. van der Zee RP, Wit FWNM, Richel O, van der Valk M, Reiss P, de Vries HJC, Prins JM; ATHENA national observational HIV cohort. Effect of the introduction of screening for cancer precursor lesions on anal cancer incidence over time in people living with HIV: a nationwide cohort study. Lancet HIV. 2023 Feb;10(2):e97-e106.
    6. Rim SH, Saraiya M, Beer L, Tie Y, Yuan X, Weiser J. Access to High-Resolution Anoscopy Among Persons With HIV and Abnormal Anal Cytology Results. JAMA Netw Open. 2024 Mar 4;7(3):e240068.
    7. Clarke MA, Deshmukh AA, Suk R, Roberts J, Gilson R, Jay N, Stier EA, Wentzensen N. A systematic review and meta-analysis of cytology and HPV-related biomarkers for anal cancer screening among different risk groups. Int J Cancer. 2022 Dec 1;151(11):1889-1901. Erratum in: Int J Cancer. 2023 Sep 1;153(5):E2.
    8. Hillman RJ, Berry-Lawhorn JM, Ong JJ, Cuming T, Nathan M, Goldstone S, Richel O, Barrosso LF, Darragh TM, Law C, Bouchard C, Stier EA, Palefsky JM, Jay N. International Anal Neoplasia Society Guidelines for the Practice of Digital Anal Rectal Examination. J Low Genit Tract Dis. 2019 Apr; 23(2):138-146.
    9. Dunlevy HA, Berry-Lawhorn M, Jay N, Ellsworth G, Conageski C, Schouten J, Kwon D, Pugliese J, Goldstone SE, Palefsky JM. Utility of digital anorectal exam (DARE) for anal cancer screening. Proceedings of the 34th International Papillomavirus Conference, 12-15 November 2024; Edinburgh, Scotland.

  8. Richard C Turner says:

    As a long-standing practitioner of high resolution anoscopy, I am pleased to see that the topic of anal cancer screening remains a subject of robust discussion.

    In response to Dr Sax’s comprehensive piece and Dr Palefsky’s detailed reply, I would like respectfully raise some initial thoughts of my own.

    1. The ANCHOR study demonstrated that treating anal HSIL in a high-risk group significantly reduced the incidence of anal cancer.
    2. It did not provide evidence that screening per se reduced anal cancer incidence.
    3. However, a large-scale population-based screening trial is unfeasible and unaffordable.
    4. it is highly likely that other cancer screening programs have been implemented without the need for such rigour, for justifiable moral and ethical reasons.
    5. We cannot afford to discriminate against the at-risk population for anal cancer by delaying a screening program for want of “further evidence”.
    6. All anal cancer screening guidelines – notably IANS – acknowledge and provide strategies for situations where HRA capacity is limited or non-existent, as well as acknowledging the need for updates pending more evidence.
    7. The anal neoplasia community is actively seeking to address shortfalls in capacity/capability by:
    – training in DARE, cytological sampling, HRA, and HRA-guided treatments – with a focus not only on technical competence, but also the patient experience.
    – promoting certification in HRA
    – refinement of screening tests to narrow down the groups most at-risk for progression
    – ongoing prospective data collection to better define rates of progression, thus enabling rationalisation of screening intervals.
    8. So in this respect, we are doing the required “further clinical studies”, but awaiting their eventual results is no reason to deny those at risk of anal cancer the opportunity for secondary prevention.

  9. Tim Lahey says:

    Thank you, Paul, for brokering such an interesting and important discussion! I appreciate the many colleagues who have weighed in too.

    You make a strong case that while treatment of HSIL has been proven beneficial, screening for anal dysplasia is only supported by lore and a shallow pool of retrospective studies subject to the usual biases.

    When the evidence to inform our clinical practice is that weak, I agree as a ID clinician and ethicist that we should respect our patients enough to engage them in shared decision-making. That helps us navigate away from the extremes of ostriching vs advocating more strongly for a practice than the data support.

    While navigating such murky waters, we are well-served by vigorous debate like this, and by the exhibition of virtues like curiosity, epistemically humility, and expertise. For example, I appreciate your attitude of curiosity and openness to dialog despite having fair claim to the title of expert in HIV care. Similarly I commend Dr Palefsky and co. for their longstanding commitment to the field, for lending their thoughtful perspectives here, and, importantly, citing van der Zee et al as an important piece of retrospective evidence, albeit imperfect.

    Amid such discussions, we should avoid two major related pitfalls seen in previous debates about other screening tests: (1) We should avoid equating doing something, anything, with conferring benefit. Cancer screening can help by averting advanced cancer, or harm via medicalization eg unwarranted biopsies or treatments. If the evidence isn’t strong, we do not know whether the net effect in a given population is to help or harm. To torture the wording of Dr Palefsky et al, what we owe our patients, first and foremost, is not to harm them. (2) We should avoid equating doing medical procedures with the avoidance of discrimination, as some proponents of screening do. Much as there is real and unjust neglect of patients at highest risk of anal dysplasia, there is as rich and troubling a history of well-intended but unconsented experimentation on historically marginalized patients as there is of depriving such groups of proven care. Especially when such power dynamics are at play, respect for patient autonomy in the form of shared decision-making is a vital antidote to the perils of parentalism.

    Whatever the unknown current-day Truth about the balance of benefits and harms of anal dysplasia screening, I have every hope the future will see a tilt toward harm as HPV vaccination lowers overall risk and thus the magnitude of the potential benefits of screening. This likely shifting of the epidemiological sands further supports individualization of care and investments in high quality trials.

    While I appreciate the enormous logistical obstacles to conducting high quality randomized trials of anal dysplasia screening, and the likely injustices investigators seeking funding for that work face in the present era, we should take heart from the history of other screening tests whose use was ultimately supported (in most cases) by the assiduous conduct of exactly such trials.

    Tim Lahey, MD, MMSc, HEC-C

  10. Amit Achhra (Yale) says:

    Thanks, Paul, for citing our work! I am thrilled to see an exciting discussion on the topic. Also, would like to thank Dr Joel Palefsky for his exemplary work in this field, including the landmark ANCHOR study. I also read Dr Palefsky and Dr Turner’s counterpoints, though from what I see, they all, in fact, agree with severely limited evidence in most if not all aspects of this screening program. They nevertheless urge us to march with more screening, which is where discrepancy arises. Some points in response:

    1. Drs Sax and Palefsky both mention poor performance of initial screening test anal cytology, especially terrible sensitivity for HSIL. Yale was not alone in its experience- cytology is a hit and a miss even in the best of the settings. A very high prevalence of HPV in MSM population leaves this additional test also of limited utility. A good screening program requires a good screening test!
    2. Routine Digital rectal exam of asymptomatic people has been studied even less. HSIL (lesion studied in ANCHOR) can NOT be palpated (as Dr Palefsky also mentions). While feeling out early cancer sounds good in theory, one can easily see flurry of false+ves with this approach (e.g. hemorrhoids etc). The claim that DARE is “preferable to doing nothing” demands high-level evidence.

    3. Dr Palefsky- the lead author of ANCHOR, correctly states that ANCHOR was not designed as a screening trial, yet it gets cited as the basis for screening!! Perhaps the “A1” grading in the guidelines is misplaced!

    4. They cite an observational study (Zee et al) in support of mortality benefit from anal ca screening. As we all know, such studies are heavily susceptible to lead time and other biases. E.g this study starts to see mortality difference immediately after the start of screening program- an implausible effect.
    Ironically, these are the very studies David Sackett cautioned us about. EBM literature is full of examples where too much reliance on retrospective cohort studies has led us astray (see The arrogance of preventive medicine by David Sackett CMAJ 2002).

    5. Anal cancer screening is frequently compared to that of cervical cancer. It is worth pointing out to readers that these two are fundamentally different organs and cancers behave differently: e.g. Cervical cancers are prone to later stage diagnosis without screening, HSIL progression is much slower for anal Ca, HPV testing may have much more value in heterosexual women groups etc.

    6. Dr Sax and Dr Palefsky both suggest alternative strategies e.g. HRA only strategy, and/or reducing screening frequency- but who is right? Only a randomized study can tell.

    Overall, I felt a little disappointed when the leaders in the field state that a “we must face reality…a screening study.. will never be done”. But at the same time can we justify investing resources in millions of asymptomatic healthy people subject to getting millions of clinic and procedure visits, DAREs, PAPs and HRAs…without trying to learn full scale of harms, benefits and most efficient and least disruptive strategies? We cannot forget the basic principle of medicine that the bar for evidence for screening healthy people is higher, not lower, as opposed to treating sick people. Compare this to other cancer screening strategies: we have at least 8 RCTs for breast, 9 for colorectal, 3 for lung and so on.

    I share Dr Palefsky and Dr Turner’s passion for preventing our patients from this nasty cancer. I also agree with them that we owe it to our patients “to do something”. But, as Paul said, that “something” must be more studies and efforts to learn more. We cannot abandon basic principles of EBM and WHO screening criteria, blinded by our passion. As Ben Franklin said “Let passion guide you but let reason hold the reins”. I really look up to Dr Palefsky and the rest of the leadership in the field to create large networks where we can empirically study these questions, and serve our patients right.

  11. Luis Barroso, Elizabeth Stier, Michelle Khan, Richard Turner, Troy Brennan, Tamzin Cuming on behalf of IANS Board and Guideline writing group says:

    The 14th century philosopher Jean Buridan proposed a thought experiment regarding a hungry donkey equidistant between two identical piles of hay. Without a perfect set of criteria to make a choice, the animal took no action until it died of starvation. Philosophers refer to this paradox by the moniker of “Buridan’s ass”, and it illustrates the problem of awaiting perfect criteria before taking practical action.

    Dr. Sax’s objections strike us as falling into this vein of thinking. He brings up several valid points of contention and difficulties with anal dysplasia screening, but his conclusion is one with which we wholeheartedly disagree.

    There are important salient facts that are not in contention: 1) The incidence of anal cancer among PLWHIV is unacceptably high 2) Like cervical cancer, anal cancer is preceded by a pre-malignant state 3) Treatment of this pre-malignant state reduces the incidence of invasive disease [Palefsky et al].
    We have various tools to find and intervene on the pre-malignant state of anal dysplasia. We agree with Dr. Sax that these tools are far from perfect. Dr. Palefsky’s reply summarizes many issues with cytology and potential solutions on the horizon. But despite the compromised sensitivity of cytology, the lack of specificity of HPV testing, and heavy prevalence of disease that requires frequent triage to HRA, these are tools that we have available now. Their shortcomings are significant but far from insurmountable, several anal dysplasia screening clinics exist today that function proficiently using currently available tools such as cytology paired with HPV testing.
    Moreover, it is known that both patients and clinicians shy away from talking about the butt or examining the butt, and the refusal of any action without perfect trial data only serves to further stigmatize this area of the body and keeps patients and clinicians from addressing the excess anal cancer risk for PLWH.

    In a properly functioning medical system better evidence and tools are always forthcoming. If we insist on waiting for them then we end up doing nothing until the proverbial tomorrow that never comes. Cervical cancer screening suffers from many of the same shortcomings: cytology is imperfect, colposcopy is difficult and requires special training, and women must be followed for years. Nevertheless, through the dedicated action of pioneers we have decades of evidence that show that cervical cancer screening saves lives, and we have accomplished that end through more cost effective and less invasive means over time.
    Of note, cervical cancer screening has never been shown to save lives through a randomized controlled trial. Nor has smoking cessation, or HPV vaccination, or any variety of other recommendations that nevertheless can be firmly described as “evidence based”. We have no doubt that Dr. Sax (and anyone of credibility) would suggest that we pursue them, but they are not supported by perfect evidence. Nothing is.

    Where does that leave us now? We have tools, albeit imperfect, that can detect anal HSIL in high risk groups. We have treatments that have been proven by the highest evidential standard to decrease progression to invasive cancer without a long term significantly negative impact on patients’ quality of life [Atkinson]. High resolution anoscopy (HRA) is well tolerated, has no major risks (unlike GI endoscopy for example) and almost all HRA treatments are office-based. There is some reasonable uncertainty about the best application of these tools, and that uncertainty is reflected in the IANS Guidelines [Stier]. There are practical resource limitations that challenge the application of these tools on a sufficient scale, these limitations are acknowledged in IANS Guidelines with practical suggestions for proceeding under various resource limited settings.

    Finally, we agree with Dr. Sax’s suggestion of shared decision making but suggest that it not be performed in a vacuum of feigned equipoise. We can communicate uncertainties where they exist, note limitations, and use IANS Guidelines as all guidelines were designed: not as restrictions to force care that is neither feasible nor desired, but as guardrails to ensure that patients are offered the best possible care in accordance with their wishes, goals, available resources, and best available evidence. Unquestionably these Guidelines will evolve as better evidence emerges, Dr. Palefsky already notes several possible improvements in the future. For example, a recent analysis demonstrated that screening HIV+ MSM starting at age 35 with cytology is cost-effective [Deshmukh]. The analysis did find, however, that the screening would be more cost effective if less frequent—and suggested q4year screening as effective. This will be reflected in any update to guidelines in future iterations.

    The availability of better options in the future should not preclude us from offering our patients the best options that we have in the present.
    If our only standard is perfection then we can always justify a failure to act, but in every practical sense that matters to patients, such a failure would be asinine.

    Palefsky JM, Lee JY, Jay N, Goldstone SE, Darragh TM, Dunlevy HA, Rosa-Cunha I, Arons A, Pugliese JC, Vena D, Sparano JA, Wilkin TJ, Bucher G, Stier EA, Tirado Gomez M, Flowers L, Barroso LF, Mitsuyasu RT, Lensing SY, Logan J, Aboulafia DM, Schouten JT, de la Ossa J, Levine R, Korman JD, Hagensee M, Atkinson TM, Einstein MH, Cracchiolo BM, Wiley D, Ellsworth GB, Brickman C, Berry-Lawhorn JM; ANCHOR Investigators Group. Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. N Engl J Med. 2022 Jun 16;386(24):2273-2282. doi: 10.1056/NEJMoa2201048. PMID: 35704479; PMCID: PMC9717677.
    Atkinson TM, Mazumdar M, Van Hyfte G, Lee JY, Li Y, Lynch KA, Webb A, Holland SM, Lubetkin EI, Goldstone S, Einstein MH, Stier EA, Wiley DJ, Mitsuyasu R, Rosa-Cunha I, Aboulafia DM, Dhanireddy S, Schouten JT, Levine R, Gardner EM, Dunlevy H, Barroso LF, Bucher G, Korman J, Stearn B, Wilkin TJ, Ellsworth G, Pugliese JC, Cella D, Berry-Lawhorn JM, Palefsky JM. Health-Related Quality of Life for Persons Treated or Monitored for Anal High-Grade Squamous Intraepithelial Lesions (AMC-A01). JCO Oncol Pract. 2025 Mar 6:OP2400830. doi: 10.1200/OP-24-00830. Epub ahead of print. PMID: 40048673; PMCID: PMC12221156.
    Stier EA, Clarke MA, Deshmukh AA, Wentzensen N, Liu Y, Poynten IM, Cavallari EN, Fink V, Barroso LF, Clifford GM, Cuming T, Goldstone SE, Hillman RJ, Rosa-Cunha I, La Rosa L, Palefsky JM, Plotzker R, Roberts JM, Jay N. International Anal Neoplasia Society’s consensus guidelines for anal cancer screening. Int J Cancer. 2024 May 15;154(10):1694-1702. doi: 10.1002/ijc.34850. Epub 2024 Jan 31. PMID: 38297406.
    Deshmukh AA, Damgacioglu H, Sigel K, Palefsky JM, Clarke MA, Wentzensen N, Nyitray AG, Ortiz AP, Lin YY, Chiao EY, Stier E, Jay N, Gaisa M, Liu Y, Meissner EG, Lazenby G, Giuliano AR, Goldstone SE, Clifford GM, Sonawane K, Chhatwal J. Screening for Anal Cancer Among Men Who Have Sex With Men With HIV: Benefits, Harms, and Cost-Effectiveness Analyses. Ann Intern Med. 2025 Jul;178(7):975-986.

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.