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AIDS:
doi: 10.1097/QAD.0b013e3283633111
Clinical Science

Progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men

Tong, Winnie W.Y.a; Jin, Fengyib; McHugh, Leo C.c; Maher, Taraa; Sinclair, Bretta; Grulich, Andrew E.b; Hillman, Richard J.a,c,∗; Carr, Andrewa,∗

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Author Information

aCentre for Applied Medical Research, St Vincent's Hospital

bThe Kirby Institute for Infection and Immunity in Society, University of New South Wales

cWestern Sydney Sexual Health Centre, The University of Sydney & Westmead Hospital, Sydney, Australia.

Richard J. Hillman and Andrew Carr contributed equally to this article.

Correspondence to Dr Winnie Tong, Clinical Research Program, St Vincent's Centre for Applied Medical Research, Level 4, Xavier Building, St Vincent's Hospital, 390 Victoria Street, Sydney, NSW 2010, Australia. E-mail: wtong@stvincents.com.au

Received 27 February, 2013

Revised 12 May, 2013

Accepted 13 May, 2013

Data presented in part at the 14th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV, Washington DC, 19–21 July 2012 and the 13th International Union on Sexually Transmitted Infections World Congress, Melbourne, 15–17 October 2012.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ( http://www.AIDSonline.com).

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Abstract

Objective:

To quantify incidence of, and risk factors for, progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions (ASILs).

Design:

Retrospective review of patients at St Vincent's Hospital Anal Cancer Screening Clinic during a period when high-grade ASILs were not routinely treated (2004–2011).

Methods:

All patients who had an anal Papanicolaou smear or high-resolution anoscopy were included, except for patients with previous anal cancer. High-grade anal intraepithelial neoplasia (HGAIN) was defined as a composite of histologically confirmed grade 2 or 3 anal intraepithelial neoplasia (AIN2/3) and/or high-grade squamous intraepithelial lesion on anal cytology. Analyses were repeated restricting to histologically confirmed AIN3.

Results:

There were 574 patients: median age 45 years (interquartile range, IQR 36–51), 99.3% male and 73.0% HIV-infected [median HIV duration was 13.8 years (IQR 6.4–19.8), median CD4+ T-lymphocyte count was 500 cells/μl (IQR 357–662), 83.5% had undetectable plasma HIV viral load]. Median follow-up was 1.1 years (IQR 0.26–2.76). Progression rate to HGAIN was 7.4/100 person-years (95% confidence interval, CI 4.73–11.63). No risk factor for progression to HGAIN was identified; progression to AIN3 was more likely with increasing age (Ptrend = 0.004) and in those who were HIV-infected [hazard ratio 2.8 (95% CI 1.18–6.68) versus HIV-uninfected; P = 0.019], particularly in those whose nadir CD4+ T-lymphocyte count was less than 200 cells/μl (Ptrend = 0.003). In 101 patients with HGAIN, 24 (23.8%) patients had spontaneous regression [rate 23.5/100 person-years (95% CI 15.73–35.02)], mostly to AIN1. Regression was less likely in older patients (Ptrend = 0.048). Two patients with HGAIN developed anal cancer.

Conclusion:

High-grade ASILs frequently spontaneously regress. Longer-term, prospective studies are required to determine whether these regressions are sustained.

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Introduction

In the era of combination antiretroviral therapy (cART), anal cancer has become the most common non-AIDS-defining cancer in HIV-infected adults in some developed countries [1]. HIV-infected MSM are at highest risk of anal cancer, with incidence rates approximately 15 times higher than HIV-uninfected MSM [2]. As with cervical cancer, anal squamous cell carcinoma (SCC) is caused by persistent infection with high-risk type human papillomavirus (HPV).

Anal SCC is preceded by a precancerous phase of intraepithelial neoplasia termed high-grade squamous intraepithelial lesion (HSIL) [3], which is further subclassified into grade 2 or 3 anal intraepithelial neoplasia (AIN2, AIN3). Similar to grade 3 cervical intraepithelial neoplasia (CIN3), AIN3 has the higher risk of progression to anal cancer. The few natural history studies of anal HPV infection and anal squamous intraepithelial lesions (ASILs) report only progression rates to high-grade ASIL [4,5]. There are no published estimates of regression rates of high-grade ASILs, although an estimated 40% of CIN2 and 33% of CIN3 spontaneously regress [6].

CD4+ T-lymphocytic-predominant infiltrations are associated with regressing human genital warts [7]. HPV type 16 (HPV16)-positive cervical cancers are associated with impaired CD4+ T-lymphocyte responses to HPV16 proteins [8]. Therefore, it is biologically plausible that CD4+ T-lymphocyte immunodeficiency caused by HIV infection may impair host defences against HPV infection, leading to higher rates of progression to and persistence of intraepithelial neoplasia and lower rates of regression from intraepithelial neoplasia.

Anal cancer screening is not recommended within widely accepted national guidelines for the management of people with HIV [9,10]. Despite this, some centers with appropriate expertise offer high-risk populations screening for ASILs with anal Papanicolaou smears and/or high-resolution anoscopy (HRA) with biopsy of abnormal lesions [11]. An anal cancer screening clinic was established at St Vincent's Hospital in Sydney, Australia with one anoscopist (R.J.H.). High-grade ASILs diagnosed at this clinic were not routinely treated because there is no high-quality evidence to indicate current treatments prevent anal cancer [12,13]. The practice at St Vincent's Hospital is to discuss risk of progression with individual patients and, taking into account patient preferences, to co-manage those who prefer intervention with a colorectal surgeon.

We studied our cohort of men with untreated high-grade ASILs with the aim of describing, quantifying, and examining risk factors for progression to and regression of high-grade ASILs. Our hypotheses were that high-grade ASILs can regress spontaneously, and the likelihood of progression to or regression of high-grade ASILs is related to HIV status and degree of CD4+ T-lymphocyte immunodeficiency.

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Methods

Study population

All 574 patients who had an anal Papanicolaou smear or HRA performed at the St Vincent's Hospital anal cancer screening clinic from its inception in February 2004 to 21 January 2011 were included, except for seven patients with previous anal cancer. The majority of men attending this clinic were MSM (>95%). Almost half (N = 76) of our HIV-uninfected patients were participants in a clinical trial of the prophylactic quadrivalent HPV vaccine in preventing ASILs [14], and inclusion criteria for this trial included being aged 16–26 years with less than five lifetime sexual partners. St Vincent's Hospital Human Research Ethics Committee approval for the present analyses was granted on 6 December 2010 (File Number 10/210).

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Study design

This was a retrospective clinical audit of a cohort of patients with at least one visit for anal Papanicolaou smear or HRA. Patients were referred from within the St Vincent's Hospital HIV service and from local general practitioners specializing in HIV care. Each patient's enrolment date (hereafter referred to as baseline) was set as the date of their first anal Papanicolaou smear or HRA, whichever was first. Papanicolaou smear and HRA results within 90 days of each other were considered to be from the same visit. HRAs were performed as previously described [15], including staining of the intra-anal mucosa with acetic acid and Lugol's iodine to identify areas of abnormality suspicious for ASILs. Biopsies were taken with Tischler's forceps of these abnormal areas, particularly areas with vascular patterns or lesion features (such as surface contours, punctation, and ulceration) and staining characteristics suggestive of high-grade ASILs. Liquid-based anal cytology and histology were reported by St Vincent's Hospital's diagnostic laboratory (SydPath) using standard laboratory protocols developed for cervical reporting.

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Data collection

Medical records for all patients who attended the clinic were reviewed to confirm the dates of anal Papanicolaou smears and HRAs, Papanicolaou smear and HRA findings, previous anal surgery, HIV status, and date of HIV diagnosis. Any purported results that could not be verified against the medical record were considered missing. All anal cytology and intra-anal histology diagnoses (from HRA biopsies and anal surgery) were reviewed by one physician (WT) against the electronic medical record for accuracy and consistency with current terminology (the 2001 Bethesda System for cytology [16] and the Lower Anogenital Squamous Terminology Standardization Project for histology [3]). CD4+ T-lymphocyte counts, HIV viral loads, and date of HIV diagnosis were extracted from clinical and laboratory databases. Data were entered into a spreadsheet by an independent person. One hundred (17%) patient records were audited to confirm accurate data entry.

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Endpoint definitions

The most abnormal result was used if histology results were available from more than one biopsy collected at any one HRA.

A composite endpoint of histologically confirmed AIN2/3 and/or HSIL on anal cytology was defined as high-grade anal intraepithelial neoplasia (HGAIN) [17].

Progression to HGAIN was defined as:

HGAIN with prior lower-grade histology.

If no prior histology was available, then by prior:

  1. anal cytology negative for intraepithelial lesion or malignancy; or
  2. visually normal HRA.

Regression of HGAIN was defined as:

HGAIN with subsequent lower-grade histology.

If no subsequent histology was available, then by subsequent:

  1. anal cytology negative for intraepithelial lesion or malignancy; or
  2. visually normal HRA.

Analyses were also performed using an alternative endpoint based on histologically confirmed AIN3.

Progression to AIN3 was defined as:

Histologically confirmed AIN3 with prior lower-grade histology.

If no prior histology was available, then by prior:

  1. anal cytology negative for intraepithelial lesion or malignancy; or
  2. visually normal HRA.

Regression of AIN3 was defined as:

Histologically confirmed AIN3 with subsequent lower-grade histology.

If no subsequent histology was available, then by subsequent:

  1. anal cytology negative for intraepithelial lesion or malignancy; or
  2. visually normal HRA.

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Statistical analysis

Logistic regression was used for cross-sectional analyses and Cox regression for longitudinal analyses. For analyses of progression, person-years were measured from baseline until an endpoint was reached (or if no endpoint was reached, until the last visit for each patient). For analyses of regression, person-years were measured from the diagnosis of HGAIN or AIN3 until a subsequent lower-grade diagnosis as defined above (or if HGAIN or AIN3 persisted until the last visit for each patient). P values of 0.05 or less were considered significant. Analyses were performed using Stata 12.1 (StataCorp, College Station, Texas, USA). We used four measures of CD4+ T-lymphocyte immunodeficiency: current absolute count, nadir absolute count, time-weighted area under the curve (TWAUC, an estimate of cumulative degree of CD4+ T-lymphocyte immunodeficiency) [18], and percentage of time (of available results) spent under thresholds of 200, 350, and 500 cells/μl. One patient was HIV-uninfected at enrolment but seroconverted 4 months later and was considered HIV-infected for the purposes of analysis.

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Results

Patients

Baseline characteristics of the 574 included patients (99.3% men, 73.0% HIV-infected) are shown in Table 1. The HIV-uninfected patients had a median age of 26 years [interquartile range (IQR) 22–42]. Baseline cytology results were available on 155 (100%) HIV-uninfected patients and of these 2.6% had a diagnosis of HSIL. Baseline histology results were available on 77 (49.7%) HIV-uninfected patients, an already selected population with abnormal Papanicolaou smears, and of these 40.3% had a diagnosis of AIN2/3. The HIV-infected patients had a median age of 47 years (IQR 42–53). Baseline cytology results were available on 417 (99.5%) HIV-infected patients and of these 6.2% had a diagnosis of HSIL. Baseline histology results were available on 183 (43.7%) HIV-infected patients and of these 48.1% had a diagnosis of AIN2/3. Considering only the HIV-infected patients, the median duration of HIV infection was 13.8 years (IQR 6.4–19.8) with a median absolute CD4+ T-lymphocyte count of 500 cells/μl (IQR 357–662); 83.5% had undetectable HIV viral load.

Table 1
Table 1
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Frequency of testing and follow-up

The mean number of clinic visits was 2.7 [standard deviation (SD) 2.60, range 1–19]. At least one anal Papanicolaou smear was performed on 573 patients (1381 smears, mean 2.4 smears per patient, SD 2.59). The mean interval between anal Papanicolaou smears was 7.4 months (SD 7.85).

At least one HRA was performed on 323 patients (534 HRAs, mean 1.7 HRAs per patient, SD 1.36). The mean duration between HRAs for those with at least two HRAs (N = 211) was 11.6 months (SD 8.57). Four hundred and fifty-five (85.0%) HRAs were visually abnormal, of which 432 (94.9%) proceeded to biopsy. Reasons for not performing intra-anal biopsies on visually abnormal HRAs included scarring, radiation proctitis, anticoagulation, hemorrhoids, and having peri-anal biopsies performed. When intra-anal biopsies were taken, a mean 1.9 biopsies (SD 0.99, range 1–6) were taken per HRA. Of 1009 histology results, 82% were from HRA-directed biopsies and the remainder were from anal surgery specimens.

Three hundred and twenty-two (56%) patients (211 HIV-infected, 111 HIV-uninfected) were seen on more than one occasion and were included in the longitudinal analysis. For these patients, the median duration of follow-up was 1.1 years (IQR 0.26–2.76) and the mean time between visits was 0.5 years (SD 0.61). There were 16 637 CD4+ T-lymphocyte counts on 411 HIV-infected patients, and 15 182 HIV viral loads on 405 HIV-infected patients.

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Progression

Of 152 patients included in the analysis of progression to HGAIN, 19 (12.5%) developed incident HGAIN over 256.1 person-years of follow-up, an incidence of 7.4 per 100 person-years [95% confidence interval (CI) 4.73–11.63; Table 2 and Supplemental Digital Content 1, http://links.lww.com/QAD/A367]. The 19 patients who progressed were followed for 37.1 person-years versus 219.0 person-years for the 132 who did not progress (mean 2.0 and 1.7 person-years follow-up, respectively). Having an abnormal baseline diagnosis (i.e. AIN1 on histology) was not significantly associated with increased risk of progression to HGAIN (Ptrend = 0.120).

Table 2
Table 2
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Of 199 patients included in the analysis of progression to AIN3, 25 (12.6%) developed incident AIN3 over 308.4 person-years of follow-up, an incidence of 8.1 per 100 person-years (95% CI 5.48–12.00; Table 3). The 25 patients who progressed were followed for 45.3 versus 263.1 person-years for the 174 who did not progress (mean 1.8 and 1.5 person-years of follow-up, respectively). Having an abnormal baseline diagnosis (i.e. AIN1 or AIN2 on histology) was significantly associated with increased risk of progression to AIN3 (hazard ratio 3.9, Ptrend <0.001).

Table 3
Table 3
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No risk factor was identified for progression to HGAIN. Increasing age, being HIV-infected, and having a nadir CD4+ T-lymphocyte count less than 200 cells/μl (Fig. 1) were significantly associated with increased risk of progression to AIN3. Restricting analyses to the HIV-infected group, increasing age was not significantly associated with increased risk of progression to AIN3 (Ptrend = 0.163). Current CD4+ T-lymphocyte count, TWAUC CD4+ T-lymphocyte count, and percentage of time spent with CD4+ T-lymphocyte counts less than 200, 350, and 500 cells/μl (data not shown) were not significantly associated with differences in risk of progression to HGAIN or AIN3.

Fig. 1
Fig. 1
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Regression

Of 101 patients included in the analysis of regression of HGAIN, 31 regressed. Of these, six regressed after surgical excision and one after topical imiquimod treatment at an overseas clinic. Therefore, 24 (23.8%) patients experienced spontaneous regression from HGAIN over 102.2 person-years of follow-up, an incidence of 23.5 per 100 person-years (95% CI 15.73–35.02). Seventeen (71%) patients regressed to AIN1 and seven (29%) regressed to negative biopsies. The 24 patients who spontaneously regressed were followed for 33.6 person-years versus 68.6 person-years for the 70 who did not spontaneously regress (mean 1.4 and 1.0 person-years follow-up, respectively).

Of 55 patients included in the analysis of regression of AIN3, 35 regressed. Of these, eight regressed after surgical excision and one after imiquimod treatment. Therefore, 26 (47%) patients experienced spontaneous regression from AIN3 over 37.8 person-years of follow-up, an incidence of 68.9 per 100 person-years (95% CI 46.88–101.14). Eleven (42%) regressed to AIN2, 11 (42%) regressed to AIN1, and four (15%) regressed to negative biopsies. The 26 patients who spontaneously regressed were followed for 24.0 versus 13.8 person-years for the 21 who did not spontaneously regress (mean 0.9 and 0.7 person-years follow-up, respectively).

Increasing age was significantly associated with decreased risk of spontaneous regression of HGAIN (Ptrend = 0.048). Restricting analyses to the HIV-infected group, increasing age was not significantly associated with decreased risk of spontaneous regression of HGAIN (Ptrend = 0.151). HIV-infected patients had similar spontaneous regression rates of HGAIN (hazard ratio 0.6, P = 0.254) and of AIN3 (hazard ratio 0.5, P = 0.149) compared to HIV-uninfected patients. Current and nadir CD4+ T-lymphocyte count, TWAUC CD4+ T-lymphocyte count, and percentage of time spent with CD4+ T-lymphocyte counts less than 200, 350, and 500 cells/μl (data not shown) were not significantly associated with differences in risk of spontaneous regression of HGAIN or AIN3.

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Cancer

There were six patients with histologically confirmed anal SCC in this cohort, of which two were baseline diagnoses. Therefore, four incident anal cancers occurred, of which two had documented HGAIN before cancer diagnosis (Table 4). With two cases over 161.5 person-years of follow-up, the incidence of anal cancer in patients with HGAIN was 1.2 per 100 person-years (95% CI 0.31–4.95).

Table 4
Table 4
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Discussion

This is the first study to quantify spontaneous regression of high-grade ASILs in a cohort of HIV-infected and HIV-uninfected MSM untreated for their anal HPV-associated disease. We found that 23.5% per year (95% CI 15.73–35.02) of men with HGAIN (AIN2/3 on histology and/or HSIL on cytology) spontaneously regressed, mostly to AIN1. In contrast, the rate of progression from HGAIN to anal cancer was 1.2% per year (95% CI 0.31–4.95).

According to a recent systematic review, the incidence of high-grade ASILs is 8.5–15.4% per year in HIV-infected MSM and 3.3–6.0% in HIV-uninfected MSM [2]. These rates are comparable to the rates found in our study: HIV-infected men had an incidence of progression to HGAIN of 6.6% per year and to AIN3 of 13.1% per year; HIV-uninfected men had an incidence of progression to HGAIN of 7.9% per year and to AIN3 of 4.5% per year.

Spontaneous regression of high-grade ASILs has not been previously described, in part because many centers that diagnose high-grade ASILs immediately treat them. We found 37.1% per year of HGAIN spontaneously regressed in HIV-uninfected men and this is broadly comparable to the estimates of CIN2/3 regression (overall 33–40%, annual rate not reported) in HIV-uninfected women [6]. In HIV-infected men, we found 19.2% per year of HGAIN and 55.4% per year of AIN3 spontaneously regressed. Spontaneous regression rates of AIN3 are higher than of HGAIN in our analyses because a large proportion (42%) of AIN3 regressed only to AIN2.

HIV-infected men were more likely to progress to AIN3 (hazard ratio 2.81) and tended to be less likely to spontaneously regress from AIN3 (hazard ratio 0.52) than HIV-uninfected men. This trend was not seen in the analysis of progression to and spontaneous regression of HGAIN, probably because of a lack of power but also because a higher proportion of HIV-infected men already met the definition of HGAIN at baseline compared to HIV-uninfected men. If this finding is replicated in future larger prospective studies, it provides a possible explanation for the increased risk of anal cancer in HIV-infected adults: increased risk of progression to AIN3 combined with a decreased risk of spontaneous regression from AIN3 results in AIN3 persistence which, over time, increases the risk of progression to cancer.

The rate of progression from HGAIN to anal cancer was 1.2% per year (95% CI 0.31–4.95), which is similar to high-grade cervical squamous intraepithelial lesions [19] but much higher than the theoretical rate of one in 377 per year in HIV-infected MSM calculated in the meta-analysis by Machalek et al.[2]. Both incident anal SCCs occurred in HIV-infected patients with nadir CD4+ T-lymphocyte counts less than 200 cells/μl. Our data support current guidelines that recommend any abnormality on anal cytology warrants further investigation with HRA [9,20], as two of four incident anal cancers had only low-grade cytology a short time before the diagnosis of cancer.

The only measure of CD4+ T-lymphocyte immunodeficiency that was associated with increased risk of progression to AIN3 and tended toward decreased risk of spontaneous regression of AIN3 was being HIV-infected with a nadir CD4+ T-lymphocyte count less than 200 cells/μl. Other measures of CD4+ T-lymphocyte immunodeficiency were not associated with changes in risk of progression to or regression of HGAIN or AIN3. The association of low nadir CD4+ T-lymphocyte count and increased risk of incident high-grade ASILs has previously been described [5], and it is also a known risk factor for anal cancer in HIV-infected adults [21,22]. It may be that the repertoire of lymphocytes required to successfully patrol the anal mucosa and effect clearance of HPV infection and intraepithelial neoplasia is irreversibly damaged only if there is severe CD4+ T-lymphocyte immunodeficiency from HIV infection, which never recovers despite reconstitution of systemic CD4+ T-lymphocyte counts with cART. The central role of low nadir CD4+ T-lymphocyte counts in the natural history of ASILs in HIV-infected adults may provide an explanation as to why rising anal cancer incidence rates have plateaued [23], as the CD4+ T-lymphocyte count threshold for starting cART has increased (from 200 cells/μl in the early cART era to currently ≥350 cells/μl [24]).

Using undetectable HIV viral load as a surrogate marker for effective cART, we did not find any association between being on effective cART and changes in risk of progression to or regression of HGAIN or AIN3. This is consistent with the prospective study by Piketty et al. [25] that found cART initiation did not appear to have any effect on the natural history of ASILs in HIV-infected MSM. However, 83.5% of our cohort had undetectable HIV viral load at baseline, with only 16 patients (4.0%) who were initially detectable becoming undetectable during follow-up. Therefore, our cohort is not powered to assess the effect of cART initiation on ASILs.

Definitions of progression and regression of ASILs are problematic due to the multifocal nature of the disease and the limitations of anal cytology and HRA. Compared to cervical cytology, anal cytology is significantly less sensitive and specific for detecting high-grade disease at every cut-off (area under receiver operating characteristic curve 0.70 for anal cytology compared to 0.86 for cervical cytology) [26]. HRA itself is an imperfect reference standard [27], because the highly involuted surface of the anal epithelium means that high-grade lesions can be missed [28] on visual inspection or at biopsy. It is generally accepted that a finding of HSIL on anal cytology has high specificity (93%) and good positive predictive value (89%) for high-grade ASILs, particularly in high prevalence populations such as HIV-positive MSM [11] and may signify high-grade ASILs that were missed at HRA. Given there is no consensus definition of progression and regression of ASILs in the literature, we adopted a composite definition of high-grade ASILs that included histologically confirmed AIN2/3 and/or HSIL on anal cytology (which we labeled HGAIN). This is in keeping with the current recommended two-tiered nomenclature [3] and similar to the classification used by Wentzensen et al.[17].

Our study has limitations. First, it was retrospective with selection bias particularly toward those patients who were more likely to return for follow-up (e.g. symptomatic patients who may have more severe disease). Also, our HIV-uninfected patient group was significantly younger and not directly comparable to the HIV-infected group. While we found that increasing age was strongly associated with increased risk of progression to AIN3 and decreased risk of spontaneous regression of HGAIN, younger age is confounded by being HIV-uninfected in our cohort. Approximately, 25% of our HIV-uninfected group would have received the active prophylactic quadrivalent HPV vaccine; therefore, our estimates of HGAIN and AIN3 incidence in the HIV-uninfected group may be underestimates. Our study was underpowered, particularly for the analyses of regression and we could not assess independent predictors of our endpoints. We do not have data on HPV DNA, size of high-grade lesions, smoking history, details of cART regimens, and relevant behaviors. As is the case in many longitudinal studies of ASILs, many visits had an anal Papanicolaou smear that was not accompanied by HRA and biopsies. There is likely to be variability in the reporting of anal cytology and histology results due to more than one reporting pathologist [29,30]. The technical skill of the anoscopist in diagnosing high-grade ASILs may have improved over the study period, although this effect would not be expected to affect our analyses of progression and regression of disease within individual patients as all HRAs were performed by the one anoscopist. Finally, this type of analysis does not take into account the likely dynamic nature of ASILs. Our overall follow-up duration was short and we do not know whether the spontaneous regressions we describe are complete or sustained. The only way to address these limitations is with a detailed, prospective natural history study of ASILs with several years of follow-up. An example of this is the Study of the Prevention of Anal Cancer, which is currently being conducted at St Vincent's Hospital [31].

Strengths of our study include our robust endpoint definitions, despite the lack of agreement in the literature and the inherent limitations of anal cytology and HRA. The similarity of our progression to high-grade ASIL rates with those in the literature increases our confidence that our definitions are appropriate, and that our estimation of spontaneous regression rates of high-grade ASIL is meaningful. We repeated our analyses using histologically confirmed AIN3 as the most robust indication of precancer, and have presented both sets of results for comparison. We had very comprehensive CD4+ T-lymphocyte count and HIV viral load data on our HIV-infected patients.

The implications for clinical care from our data will vary according to local practice. For those who currently adopt a ‘watchful waiting’ approach in the management of high-grade ASILs, our data provide reassurance that high-grade ASILs diagnosed at any one time point are much more likely to spontaneously regress than progress to cancer. For those who currently treat high-grade ASILs, it may be that the risk of treatment in some patients would outweigh the benefits.

In summary, this is the first study to quantify spontaneous regression of high-grade ASILs. Spontaneous regression occurs far more commonly than progression to cancer, suggesting that not all patients with high-grade ASILs warrant treatment. Future studies in this field should report regression as well as progression rates. Prospective studies to delineate risk factors and biomarkers that predict those at highest risk of progression to cancer are needed so that intervention can be targeted, and avoided in those for whom it is unlikely to be of value.

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Acknowledgements

W.T. had primary responsibility for study design, data collection, and analysis and article preparation. R.J.H. assessed the patients. F.J. analyzed the data with input from L.M. T.M. and B.S. collected clinical data. A.C. and R.J.H. conceived the study. A.C., R.J.H., and A.E.G. supervised and provided support for study design, data collection, and data analysis. All authors contributed to article writing.

The authors would like to thank Graham Jones, Leon McNally, Alexander Carrera, and Philip Cunningham at SydPath Pathology for assistance with data extraction and Karl Hesse, Sharon Mitchell, and Yen Peng Lim at St Vincent's Hospital for assistance with data collection and entry, and Leon Botes for permission to include data from some patients.

They thank the St Vincent's Clinic Foundation for an Annual Grant in 2011 that supported this work.

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Conflicts of interest

W.T., F.J., L.Mc., T.M., and B.S. declare no conflicts of interest.

A.G. has received honoraria and research funding from CSL Biotherapies, honoraria and travel funding from Merck, and sits on the Australian advisory board for the Gardasil HPV vaccine.

R.H. has received travel assistance from Merck & CSL, and served on the International Scientific Advisory Board for Merck for Gardasil in males.

A.C. has received research funding from Baxter, Gilead Sciences, MSD, and Pfizer; consultancy fees from Gilead Sciences, MSD, and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences, MSD, and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD, and ViiV Healthcare.

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Keywords

anal canal; CD4+ lymphocyte count; HIV; human papillomavirus; intraepithelial neoplasia; precancerous conditions; spontaneous neoplasm regression

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