Screening for Anal Cancer in the Population Living With Human Immunodeficiency Virus: A Step Closer? - EDITORIAL
-Routine Screening of Anal Cytology in Persons With Human Immunodeficiency Virus and the Impact on Invasive Anal Cancer: A Prospective Cohort Study-
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CID Sept 2019
Human immunodeficiency virus (HIV) infection is the major risk factor for a 50-fold incidence increase of invasive anal squamous cell carcinoma (IASCC), especially among men having sex with men (MSM) . IASCC is itself largely caused by an infection with 1 of the same oncogenic mucosal human papillomavirus (HPV) genotypes causing various other oro-genital cancers: in particular, cervical cancer . Given the mounting evidence that HPV vaccination is preventing cervical cancers, and possibly other HPV-related cancers, as well as precursor lesions and infections, we should eventually see a major reduction in the incidence of IASCC among the vaccinated population, and probably beyond by herd immunity [3, 4]. However, this will take a few decades and a wide implementation of HPV vaccination recommendations. Clearly, an alternate preventative approach to IASCC continues to be highly desirable, particularly in the population living with HIV.
Considerations about the epidemiology and pathogenesis of HPV anogenital infections and initial cost-effectiveness analyses led to the outline of a screening strategy inspired from the established and successful use of cervical cytology (Pap smear) to prevent cervical cancer . Even if the precise screening algorithms remain to be optimized , the concept was put into practice by many HIV clinics throughout the United States and elsewhere, but is typically not yet part of national guideline recommendations. Almost 20 years later, the critical question of whether this approach has reduced the incidence of IASCC in the population living with HIV still has no appropriate answer. After it was introduced for mass screening of cervical cancer in 1952, the cervical Pap smear was not submitted to prospective, randomized studies . Instead, it took the accumulation, until the early 2000s, of many observational studies of increasing quality and scope to fortunately lift all doubts about its effectiveness . The prompt and proper collection of evidence is imperative. This is why the work by B. Revollo and colleagues  in the present issue of the journal is an important, if initial, attempt at demonstrating the usefulness of anal screening for the prevention of IASCC in HIV subjects.
These authors retrospectively analyzed a cohort of individuals living with HIV, followed between 2005 and 2016 at their reference HIV Unit of the Hospital Germans Trias I Pujol in Barcelona, Spain. Subjects living with HIV, including MSM, men having sex with women (MSW), and women, were followed prospectively at this single institution. They were all offered participation in a cytology-based anal cancer screening program that allowed the periodic triaging of patients to high resolution anoscopy, biopsy, and treatment by infrared coagulation or surgery of high-grade anal intraepithelial neoplasia, which is the precursor lesion of IASCC. Patients suitable for analysis who accepted screening (n = 1691) were compared to those who declined or dropped out of the screening program after less than 6 months (n = 1420). The endpoint was the incidence of IASCC. The authors observed 2 IASCCs in the screening group (incidence rate of 21.9 per 100 000 person-years), with both in MSM; in comparison, there were 8 IASCCs in the no-screening group (incidence rate of 107.0 per 100 000 person-years), with 4 among MSM, 2 among MSW, and 2 among women. The hazard ratio after a propensity score adjustment was 0.17 (95% confidence interval 0.03-086). This suggests that cytologic screening offers a benefit for the prevention of anal cancer.
It is significant that neither of the 2 cases of IASCC in the screening group were identified directly by the screening strategy itself, but instead by the presence of symptoms or a mass, presumably detected by digital anorectal examination, which is an established practice. Nevertheless, both patients had hemorrhoids, which may have complicated the screening. Also, in the nonscreened group, the mortality rate was high (5 out of 8 patients). This would be a striking observation if this was the consequence of the anal cancer, but that information was not provided.
Several notes of caution are in order regarding these results and their impact. This was an observational study and the patients self-assigned to 1 of the 2 groups, choosing whether to be screened or remain unscreened. For reasons that are not obvious, the IASCC incidence in the unscreened group was particularly high, at about twice the rate that has been previously observed in persons living with HIV in North America . When baseline variables known to potentially affect the incidence of IASCC—such as risk group (MSM and MSW), baseline CD4+ cell count, CD4+ cell count nadir, CD4+ cell count nadir less than 200, and HIV viral load—were compared, the differences between the 2 groups were highly statistically significant. The noncomparability of groups at baseline is always a concern in observational studies, when randomization is not present to provide a relative protection against the effect of confounding variables. To correct for this problem and make the 2 groups more comparable, the authors used propensity scores, which is a standard approach. Propensity scores can be used in a large variety of ways that can be regrouped in 3 general strategies . They can be used to (1) stratify the 2 groups into more comparable subgroups; (2) match each member of a group to a comparable member of the other group; or (3) create a covariate whose values, the propensity scores, are used in a final regression analysis, which was the approach used here. The advantage is that there can be many confounding variables that need to be adjusted, which could affect the statistical power and reliability of the analysis. When entered as predictive factors in a logistic regression model, they produce a single variable: the propensity scoring. Guidelines have been proposed for the usually defective but important reporting of propensity score analyses .
There are indeed limitations to these techniques. For example, the validity of logistic regression is sensitive to extremely high correlations among the predictive factors. Baseline CD4+ cell count, CD4+ cell count nadir, CD4+ cell count nadir less than 200, and even HIV viral load are undoubtedly correlated variables, but the authors did not comment on this issue. Another concern is the dissimilar and multimodal distributions of the propensity scores in the 2 study groups (Supplementary Figure 1). Further analyses could have determined whether this problem was more apparent than real. A key step in the analysis is to verify that propensity scoring was successful in properly adjusting for the confounding variables. It is agreed that the absolute standardized differences for each of the confounding (quantitative) variables should fall below 10% after adjustment. Supplementary Figure 2 indicates that this was not the case for 2 of the 6 confounding variables. Finally, propensity scoring in an observational study does not fix any hidden confounding variables. For all these reasons, the present study should be interpreted with great prudence. Nevertheless, it is an important and informative effort that should serve as an encouragement for the publication of positive or negative (no doubt a more difficult proposition) experiences, similar in scope and design, but likely to have different strengths and weaknesses,. The authors mentioned the great expectations regarding the ongoing, randomized ANCHOR (Topical or Ablative Treatment in Preventing Anal Cancer in Patients with HIV and Anal High-Grade Squamous Intraepithelial Lesions) study (ClinicalTrials.gov identifier NTC02135419). However, its aim is not to assess the screening phase per se, but the intervention it should trigger. Although randomized studies are generally the most desirable, as they minimize the risk of confounding, in their absence the results of observational studies are essential. They also tend to reflect real-world practices better.
Screening approaches to prevent cancers are usually fastidious to develop and validate and, as exemplified by the recent controversies regarding screenings for breast and prostate cancers, the cost-benefit balance can end up being strongly contested long after the strategies seem accepted . We can thus better understand the many challenges to instituting a screening strategy for anal cancer in people living with HIV that parallels the strategy established for cervical cancer. Similarities have been noted, but there are discrepancies between the cervix and the anus. The latter does not have a transformation zone that may account for a lower incidence of HPV infections, but a higher incidence of cancer in the unscreened cervix, compared to the anus . As noted by Revollo et al , screening is particularly intensive and costly for IASCC, even if patients of both sexes living with HIV represent a small fraction of the general population. Hence, looking carefully at the cost-benefit balance will be important before a strategy can be endorsed by a national public health agency. The costs will be financial and diverse, including making sure that there are adequate numbers of trained practitioners, both to screen and intervene, and developing protocols that are standardized and optimized. The costs will also be psychological, like convincing those disinclined to be screened (almost half of the subjects in the Spanish study), whatever the reason, as well as handling the impact of false-positive results. Finally, there might be physical costs. Not all the subjects treated as a result of finding high-grade anal intraepithelial neoplasia would eventually develop IASCC if left untreated. Presently, this overtreatment cannot be avoided. Fortunately, the present screening strategies for IASCC and their associated interventions do not seem to cause lasting sequellae. Nevertheless, it is useful to remember that it took 50 years to start appreciating the adverse obstetric effects of treating the cervical cancer precursors that were discovered through screening .
In conclusion, the Spanish study takes us a little step closer to an appropriate, validated, and cost-effective screening approach for anal cancer prevention in those living with HIV, but the remaining ground to cover to enter public health policy could still be extensive and disputed. Ultimately, there is a very solid hope that HPV vaccination will alleviate the past challenges of prevention.
The cumulative incidence of IASCC was 0.1% (95% CI, .03-.4%) for the screening group and 0.6% (95% CI, .3-1.1%) for the nonscreening group (chi-square test, P = .051). Curves of time to anal cancer diagnosis are shown in Figure 4. The incidence rate of IASCC was lower in the screening group (21.9; 95% CI, 2.7-70.3 per 100 000 person/years) versus the nonscreening group (107.0; 95% CI, 46.2-202.0) (log-rank test, P = .027). The Cox regression model showed a statistically significant protective effect of being enrolled in the screening program (HR, 0.20; 95% CI, .04-.97). In other words, not being enrolled in the screening program was a risk factor for IASCC development (HR, 4.84; 95% CI, 1.03-22.82). The only risk factor associated with IASCC in multivariate analysis was "time from known HIV infection" (the longer the time, the greater the risk; HR, 1.14; 95% CI, 1.02-1.26). Sexual behavior, CD4+ nadir cell count, baseline CD4+ count, or HIV-1 plasma RNA were not identified as risk factors.
In the screening group, the cumulative incidence of IASCC in MSM was 0.2% (2 out of 1095; 95% CI, .1-.7%), with no cases among MSW (0%; 0 out of 257; 95% CI, .0-1.5%) or women (0%; 0 out of 339; 95% CI, 0.0-1.1). The incidence rates were 34 (95% CI, 4-108), 0 (95% CI, 0-186), and 0 (95% CI, 0-137) per 100 000 person-years, respectively. In the nonscreening group, the cumulative incidence of IASCC was 0.8% in MSM (4 out of 501; 95% CI, .3-2.0%), 0.3% in MSW (2 out of 631; 95% CI, .1-1.2%), and 0.7% in women (2 out of 288; 95% CI, .2-2.5%). The corresponding incidence rates were 159 (95% CI, 43-379), 58 (95% CI, 7-186), and 132 (95% CI, 6-422) per 100 000 person-years, respectively.
In the screening group, 2 subjects with IASCC have survived. In the nonscreening group, 5 out of 8 subjects with IASCC have died.
In fact, immunological status plays a pivotal role in the natural history of HPV infection leading to anal SIL and anal cancer in persons with HIV [27-29]. We identified no subjects with IASCC among those with a CD4+ nadir count greater than 150 cells among 14 595 person-years. These findings reinforce the concept that all persons with HIV-1 (MSM, MSW, and women) are a group at risk of IASCC in comparison to the general population and their inclusion in anal screening programs must be seriously evaluated.
Routine Screening of Anal Cytology in Persons With Human Immunodeficiency Virus and the Impact on Invasive Anal Cancer: A Prospective Cohort Study
CID Sept 2019 - Boris Revollo,1,2,3,a Sebastián Videla,3,4,a Josep M. Llibre,1,3 Roger Paredes,1,3,5,6 Marta Pinol,7 Francesc Garcia-Cuyas,7 Arelly Ornelas,3 Jordi Puig,3 David Parés,7 Javier Corral,7 Bonaventura Clotet,1,3,5,6 and Guillem Sirera1,3
1Infectious Diseases Department, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain; 2Department of Medicine, Autonomous University of Barcelona, Catalonia, Spain; 3Fight AIDS Foundation, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain; 4Clinical Research Support Unit, Clinical Pharmacology Department, Bellvitge University Hospital/Bellvitge Biomedical Research Institute (IDIBELL)/University of Barcelona, L'Hospitalet de Llobregat, Barcelona; 5IrsiCaixa AIDS Research Institute, Badalona, Catalonia, Spain; 6Universitat de Vic-UCC, Vic, Catalonia, Spain; 7Department of Surgery, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain.
The efficacy of screening programs to prevent anal cancer in persons with human immunodeficiency virus 1 (HIV-1) is unclear.
To examine the impact of a screening program to detect anal cancer precursors on the incidence of cases of invasive anal squamous-cell carcinoma (IASCC) in persons with HIV-1,
we performed a single-center, retrospective analysis of a prospective cohort of outpatients with HIV-1 attending a reference HIV unit from January 2005 onward.
All participants were invited to participate in a continued structured screening program for anal cancer prevention. We estimated the incidence of IASCC and performed a comparative analysis between subjects enrolled in the screening program (screening group) and those who declined to participate (nonscreening group). To reduce any selection bias, a propensity score analysis was applied.
We included 3111 persons with HIV-1 (1596 men-who-have-sex-with-men [MSM], 888 men-who-have-sex-with-women [MSW], 627 women; mean age, 41 years), with a median follow-up of 4.7 years (14 595 patient-years of follow-up); 1691 (54%) participated in the screening program.
Ten patients were diagnosed with IASCC: 2 (MSM) in the screening group and 8 (4 MSM, 2 MSW, and 2 women) in the nonscreening group.
The incidence rates of IASCC were 21.9 (95% confidence interval [CI], 2.7-70.3) and 107.0 (95% CI, 46.2-202.0) per 100 000 person-years, respectively.
After a propensity score adjustment, the difference was significant in favor of the screening group (hazard ratio, 0.17; 95% CI, .03-.86).
The number of cases of IASCC was significantly lower in persons with HIV engaged in an anal cytology screening program. These results should be validated in a randomized clinical trial.
In a prospective cohort including 14 595 patient-years of follow-up, PLHA enrolled in a structured anal screening program had a significantly lower rate of IASCC in a multiple logistic regression analysis adjusted for propensity score. To the best of our knowledge this is the first cohort analysis that demonstrates an impact on the incidence of IASCC of such a screening strategy. On the other hand, although among persons with HIV-1 the greater risk of IASCC (6 out of 10 IASCC cases) was in MSM, MSW and women must also be taken into account given that these 2 groups present a higher risk of IASCC in comparison to the general population .
In the absence of fully powered randomized clinical trials that conclusively establish a cause-effect relationship between enrollment in a screening program and reduced incidence of IASCC, data from prospective cohorts with multivariable-adjusted analyses offer the highest level of evidence available. These cohort data are currently lacking, and thus universal anal screening programs in PLHA were only based on expert consensus recommendations because of the similarities between cervical and anal cancer with HPV infection [24, 25]. The present analysis was only intended to gather data that would allow us to make a reasonably well-informed decision about whether or not to discontinue the screening program. The ANCHOR study is an ongoing National Cancer Institute-sponsored randomized trial aimed at determining whether anal screening prevents the development of IASCC, as compared with monitoring alone. Its results, expected by 2022, will put into context this issue.
There is no real consensus on the optimal design for a screening program to prevent anal cancer, with a variety of approaches currently in use. The approach taken in the present study is based on cytological detection of HPV-related abnormalities at each check-up, followed by histological confirmation of HSIL, and then treatment. Other more aggressive screening programs are based on histology as a first step and at each subsequent check-up (that is, both HRA and biopsy performed at each check-up). At present, diagnosis is dependent on histology, which generally hinges on HRA with biopsy . Cytological results have been shown to have limited sensitivity in detecting histologically proven high-grade AIN  and the prevalence of high-grade AIN is strikingly lower when based on a cytological diagnosis than when based on histology . Therefore, our findings may reflect an underdiagnosis of high-grade AIN. Nonetheless, despite this possible drawback, those patients who were enrolled in our screening program experienced a lower incidence of IASCC.
Among PLHA who did not engage in our screening program, the incidence rates for MSM (159 cases per 100 000 person-years) were similar to those previously reported by others (131 per 100 000 person-years), suggesting that this group really constitutes a correct control arm. With respect to MSW, the incidence rate (58 per 100 000 person-years) was comparable to that seen in other similar cohorts . However, the incidence rate in women (132 per 100 000 person-years) was greater than what has been previously reported (30 per 100 000 person-years, respectively) . This discrepancy may be at least partly explained by some of the baseline characteristics of this nonscreening cohort, with more than 50% having a CD4 nadir of less than 200 cells/μL compared with 36% in the screening group. In fact, immunological status plays a pivotal role in the natural history of HPV infection leading to anal SIL and anal cancer in persons with HIV [27-29]. We identified no subjects with IASCC among those with a CD4+ nadir count greater than 150 cells among 14 595 person-years. These findings reinforce the concept that all persons with HIV-1 (MSM, MSW, and women) are a group at risk of IASCC in comparison to the general population and their inclusion in anal screening programs must be seriously evaluated.
We noted that 2 PLHA involved in the screening program nonetheless developed an IASCC. In both cases, the carcinoma was characterized by a fast, aggressive evolution. The 2 patients shared various characteristics, including hemorrhoids at exploration, CD4 nadir of less than 200 cells/µL, normal anal basal cytology, and persistent infection by multiple high-risk HPV including genotype 16; and both received regular follow-up examinations in the proctology unit. It is noteworthy that one of them had cytology results showing LSIL but a normal HRA 4 years previously and the other had cytology results showing ASCUS but a normal HRA 6 years previously. In both cases, the IASCC was diagnosed after surgical treatment for hemorrhoids, which probably hindered an earlier IASCC diagnosis. From a clinical practice standpoint, when faced with a patient with abnormal anal cytology and hemorrhoids, the approach tends to be more conservative to avoid biopsy-induced bleeding. Hence, based on our experience, our recommendation for PLHA with hemorrhoids is to perform a careful HRA to try to identify possible lesions and, if a lesion is observed, it should be treated with trichloroacetic acid or major ambulatory surgery, with a particularly close subsequent follow-up.
Our study is subject to several limitations. The sample size of our cohort was relatively small and subjects were not randomly assigned to the screening strategy. Subjects who decided to refuse the screening program had baseline characteristics that entailed a higher risk of IASCC development, including lower baseline CD4+ counts, lower CD4+ nadir cell counts, and a higher percentage of HIV-1 RNA greater than 50 copies/mL. The confounding introduced by these baseline characteristics could suggest a more health-oriented behavior in patients who voluntarily entered the program. However, the main risk factor identified in association with IASCC is the time from known HIV-1 infection (which was similar between groups) and a Cox regression to compare HRs between groups adjusted for propensity score would appropriately correct the impact of these baseline variables into the model. It must be noted that propensity score adjustment cannot balance for unknown or known unmeasured confounding variables.
Likewise, due to the limited number of IASCC events, we cannot definitely exclude that other factors introduced into the analysis (sexual behavior, CD4+ nadir or baseline CD4+ count, or HIV-1 plasma RNA) would potentially be associated with IASCC development as well.
The population analyzed (all from a single geographical area) makes it risky to extrapolate our results beyond the population and conditions studied. Nevertheless, the incidence rates found among MSM and women not included in the screening program are within the reported ranges in other areas . Similarly, the small number of cases of IASCC reported here and the limited follow-up period (just over a decade) might also be insufficient to estimate accurately the incidence of this cancer.
Despite all these limitations, the model was able to identify a significant protective benefit of the anal screening strategy. High-resolution anoscopy is currently the gold-standard procedure for detection of lesions in the anal canal, but it is subject to interobserver bias (despite thorough training).
In conclusion, in a prospective cohort analysis the number of cases of IASCC was significantly lower in PLHA (MSM, MSW, and women) who were enrolled in a preventative screening program compared with a similar group who were not. These results support the continued implementation of such programs, while results from randomized clinical trials and analyses involving larger cohorts are eagerly awaited to further clarify the efficacy of this strategy.
Cancer remains an important cause of morbidity and mortality in people living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (PLHA) . Coinfection with oncogenic viruses (eg, human papillomavirus [HPV]) increases the risk of some types of cancers, such as invasive anal squamous-cell carcinoma (IASCC) [2-4]. This is especially true in men with HIV-1 who have sex with men (MSM), who have an estimated incidence rate of 131 (95% confidence interval [CI], 109-157) per 100 000 person-years , while the incidence rates of anal cancer in men with HIV-1 who have sex with women (MSW) and in women with HIV-1 are 46 (95% CI, 25-77) and 30 (95% CI, 17-50) per 100 000 person-years, respectively . These incidence rates of IASCC in PLHA are much higher than those seen in the general population (<2 new cases per 100 000 person-years) [6-15].
Although there are substantial differences between the natural histories of anal and cervical HPV infection , including slower anal HPV clearance in men and persisting rates of anal HPV infection and dysplasia with age, it is believed that, as with cervical cancer, IASCC could potentially be prevented through screening programs. For anal cancer, screening by means of anal cytology with follow-up high-resolution anoscopy (HRA) when needed should facilitate the detection and subsequent treatment of high-grade squamous intraepithelial lesions (HSILs). However, there is as yet no full consensus on the best strategy for detecting HSILs in such screening programs. A US National Cancer Institute-sponsored multicenter randomized trial (Anal Cancer HSIL Outcomes Research [ANCHOR] Study) is expected to shed light on whether these screening programs prevent the development of IASCC . However, definitive results are not expected until 2022. Although the approach is not uncontroversial, it has also been suggested that screening programs for anal cancer prevention should be implemented in HIV-negative women with previous cervical HPV-related disease , immune-suppressed transplant recipients, and all PLHA [19, 20].
In 2005, our HIV unit implemented a continued screening program for anal cancer prevention, based on cytological detection of HPV-related abnormalities at yearly check-ups, followed by histological confirmation of the presumed cancer-precursor lesion and treatment of HSILs . Our hypothesis was that such a screening program would reduce the incidence of IASCC in PLHA. After 12 years of operation, it was decided to gather data that might tentatively confirm or refute the initial hypothesis. We therefore examined the incidence of IASCC among those that had passed through a structured screening program and compared it with those who had not. The results of this exploratory analysis would endorse whether it was worth continuing the program or not.