Acceptability of digital anal cancer screening examinations in HIV-positive homosexual men
Correspondence: Dr Tim R. H. Read, Melbourne Sexual Health Centre, 580 Swanston St, Carlton, Victoria 3053, Australia. Tel: +61438002565; fax: +61393416269; e-mail: firstname.lastname@example.org
Anal cancer is more common in HIV-positive homosexual men than in HIV-negative homosexual men and the general population. Earlier diagnosis leads to improved prognosis. We aimed to determine if regular anal inspection and digital examination of asymptomatic homosexual men attending for routine HIV care were acceptable and to record the rate of referral for diagnosis of potentially malignant anal lesions.
We offered anal examinations to consecutive homosexual men with HIV infection aged ≥ 35 years during their routine HIV clinic visits, aiming to complete three examinations over a 12-month period. Acceptability questionnaires were completed at baseline and after each examination and doctors recorded examination findings and all resulting interventions. Hospital referral outcomes were collected and interventions were costed using the Australian Medical Benefits Schedule.
Of 142 men who were offered enrolment in the study, 102 [72%; 95% confidence interval (CI) 64–79%] participated. Following the initial anal examinations, four men were referred to surgeons. Cancer was excluded in three men (3%; 95% CI 1–8%) and one was diagnosed with anal squamous cell carcinoma (SCC). Three men had anoscopy performed at the time and two were referred for colonoscopy. Ninety-eight per cent (95% CI 93–100%) of respondents said that they would probably have the examination next time. The intervention was estimated to cost approximately Australian $16 per examination.
Regular anal digital examinations are an acceptable and inexpensive addition to the routine care of homosexual men with HIV infection.
Anal squamous cell carcinoma (SCC) is caused by oncogenic types of human papillomavirus (HPV) and is an uncommon cancer in the general community, occurring at a rate of about 1/100 000 per year ; however, it is much more common among HIV-positive homosexual men. A meta-analysis estimated the rate of anal cancer in this group to be 78/100 000 per year since the introduction of effective antiretroviral therapy .
The prognosis of anal cancer is closely related to the size of tumours at diagnosis, and tumours are often diagnosed late, when they are quite large. The 5-year survival in the USA between 1988 and 2001 was 80% for those with tumours of ≤ 2 cm, 66% for those with tumours of 2–5 cm, and 45% for those with tumours of > 5 cm . A French case series of 69 patients with tumours < 1 cm in diameter had a 100% 5-year cancer-specific survival, and 89% of patients were disease-free at 5 years . In a series of HIV-infected men with anal cancer, men with tumours < 3 cm in diameter had a 5-year survival rate of 95% compared with 0% in those with tumours ≥ 3 cm . In a review of 128 cases of anal SCC from an Australian centre, 52% were externally visible at diagnosis, mean tumour diameter was 36 mm and 94% were ≥ 1 cm .
The high incidence of anal cancer in homosexual men, particularly those with HIV infection, has led several investigators to develop and recommend methods of screening for the precursor lesion, high-grade anal intraepithelial neoplasia (HGAIN), such as anal cytology, high-resolution anoscopy and biopsy [7-10]. However, screening for HGAIN is only available in a few HIV clinics in high-income countries and there are concerns about the tolerability of these procedures, the efficacy of treatment of HGAIN and the high prevalence of HGAIN [2, 11, 12].
Two sets of clinical guidelines recommend routine digital anal examinations to detect anal cancer at an earlier stage, when the prognosis is better [13, 14]. However, this recommendation is based on expert opinion rather than empirical evidence. As a first step in testing whether routine regular anal examinations could be recommended, we studied the acceptability of introducing anal examinations into the routine HIV care of a group of homosexual men. Because the ideal frequency of examinations is unknown, we aimed to perform three examinations over a 12-month period and examined whether the acceptability or the examination findings varied over the year.
We recruited homosexual men with HIV infection aged ≥ 35 years into a 1-year cohort study from consecutive eligible patients seen by a subset of participating clinicians, during their regular visits to the HIV clinic at Melbourne Sexual Health Centre (MSHC), Australia, from November 2010 to February 2011.
Participants and doctors were advised that three anal examinations should be conducted over a 12-month period, with at least 10 weeks between examinations. The examinations were carried out on the day of enrolment and then every 3–4 months, depending on the scheduling of their routine HIV clinic attendance. An examination involved external inspection of the anus followed by careful digital palpation of the anal canal for lumps, ridges or thickened areas. A prostate examination was usually performed but was not considered a mandatory part of the examination. Doctors were encouraged to further examine any palpable internal abnormality by anoscopy, without magnification. Doctors completed a case report form describing their findings and any resulting treatments or referrals. Hospital referral letters and replies were collected.
Questionnaires assessing the acceptability of examinations were completed by men in the clinic at recruitment and another questionnaire was e-mailed to participants 2 weeks after each examination. Responses to five-item Likert scales were, with one exception, collapsed to binary variables for reporting in Table 3 (see later).
As a measure of risk for anal cancer and to assess the applicability of these findings to other populations, we determined the prevalence of anal HPV infection. Towards the end of the study period, an anal swab from each participant was sent for HPV polymerase chain reaction (PCR) and typing by linear array (Roche Molecular Diagnostics, Pleasanton, CA). Untypable PCR-positive samples were typed by PapType (Genera Biosystems, Scoresby, Vic, Australia).
The cost of anal cancer screening using this methodology was estimated based on the rebate payable from the Australian Medicare Benefits Schedule (the health funding insurance scheme in Australia). This was done to estimate the cost to the public health system of introducing this type of screening. The rebate for a standard 15-min general practice consultation was divided by the estimated mean time spent on examinations to calculate the cost of clinic time spent on the intervention. The costs of surgical consultations, sigmoidoscopies, colonoscopies and biopsies resulting from referral of asymptomatic patients were included in calculating the cost of the intervention, even if some of these were not specifically required to diagnose anal cancer. The costs resulting from referral or treatment of symptomatic individuals were not included, as these referrals or treatments were likely to have occurred regardless of screening.
The primary outcome of interest was the rate of referral for definitive diagnosis of potentially malignant anal lesions. Confidence intervals (CIs) were calculated by binomial methods. Analyses were performed using stata version 11 (Stata Corporation, College Station, TX).
Participants provided written consent and the study was approved by the Alfred Health Human Ethics Committee.
Of 142 men who were offered enrolment in the study, 102 (72%; 95% CI 64–79%) participated. Of the 40 who declined participation, 29 gave a reason, including unwillingness to complete questionnaires (n = 7; 5%; 95% CI 2–10%), preference to have the examination another day (n = 8; 6%; 95% CI 2–11%), and not feeling comfortable with having an anal examination (n = 6; 4%; 95% CI 2–9%). No reason was provided by the remaining 11 men. One year after the last enrolled patient had completed follow-up, the medical records of 35 of the 40 who declined to participate were examined. The other five refusals could not be linked to a record so it was not possible to examine their records. Of 35 who declined, 17 (49%; 95% CI 31–66%) had subsequently had digital rectal examinations (DREs) at MSHC or another clinic, either for screening or because of symptoms.
The 102 men recruited to the cohort had a mean age of 48 years (range 35–86 years) and a median CD4 count of 542 cells/μL (range 174–1720 cells/μL), and 86 (84%) had HIV RNA < 50 HIV-1 RNA copies/ml. Not all men were tested for HPV because some had completed the study before HPV testing began. Of 72 patients (71%) tested for anal HPV, 24 (33%; 95% CI 22–44%) had HPV 16 detected, 53 (74%; 95% CI 63–84%) had at least one high-risk type detected and 65 (90%; 95% CI 83–97%) had at least one type of HPV detected (Table 1).
Table 1. Characteristics of the cohort of 102 HIV-infected homosexual men who had anal examinations
|Age (years) [median (range)] (n = 102)||48 (35–86)|| |
|CD4 count (cells/μL) [median (range)] (n = 102)||542 (174–1720)|| |
|Viral load < 50 copies/ml||86 (84)||76–91|
|HPV 16 (n = 72)||24 (33)||22–44|
|High-risk HPV†||53 (74)||63–84|
|Any HPV||65 (90)||83–97|
All 102 men had at least one examination, 96 men (94%; 95% CI 88–98%) had two examinations and 84 men (82%; 95% CI 74–89%) had three examinations, making a total of 282 examinations within the 12-month follow-up period. Reasons for not completing the three examinations included failure to return to the clinic during the study period (n = 7; 7%; 95% CI 3–14%), unwillingness to complete the study questionnaires (n = 3; 3%; 95% CI 1–8%), awaiting the outcome of surgical referral from the first examination (n = 3; 3%; 95% CI 1–8%) and other more important issues during consultations (n = 2; 2%; 95% CI 0–7%); in three men (3%; 95% CI 1–8%) the reason was not documented.
The 102 first examinations resulted in three men requiring anoscopy in the clinic and four referrals to the surgical clinic for diagnosis of potentially malignant lesions. One man had a confirmed SCC (1%; 95% CI 0–5%) and cancer was excluded in the other three (3%: 95% CI 1–8%). Surgeons identified polyps during sigmoidoscopy in two of these men and referred them for full colonoscopy and biopsy. In one man, no rectal polyp was seen at colonoscopy and in the other, biopsy of the rectal polyp revealed chronic inflammation. In the third man, the suspect lesions were clinically identified to be small anal canal warts.
Nine (9%; 95% CI 4–16%) other anal abnormalities were found after the first round of examinations, leading in one case to a surgical referral for symptomatic haemorrhoids (Table 2). Three further referrals because of symptoms occurred at the time of the second and third examinations, but these subsequent examinations did not result in any additional referrals to exclude cancer. First and subsequent examinations led to diagnoses of warts, haemorrhoids and herpes simplex, and no men were referred for prostatic abnormalities.
Table 2. Findings and referrals resulting from offering three examinations to 102 HIV-infected homosexual men over 12 months
|Referred for possible cancer; one was confirmed||4 (4, 1–10)||0 (0, 0–2)|
|Colonoscopy and biopsy attributable to screening*†||2 (2, 0–7)||0 (0, 0–2)|
|Referrals attributable to screening*||3 (3, 1–8)||0 (0, 0–2)|
|Referred for symptoms – no cancer concern||1 (1, 0–5)||3 (2, 0–5)|
|Herpes simplex||2 (2, 0–7)||1 (1, 0–3)|
|Warts||3 (3, 1–8)||7 (4, 2–8)|
|Haemorrhoids||3 (3, 1–8)||5 (3, 1–6)|
Follow-up questionnaires (Table 3) were returned after 234 of 282 (83%) examinations, comprising 97 of 102 (95%) initial examinations and 137 of 180 (76%) second or third examinations. Proportions of patients reporting significant pain, bleeding, being embarrassed by the examination or finding the experience unpleasant were all below 5% (Table 3). Less than 3% of patients were dissatisfied with the amount of time spent on their HIV care or said that they would not have the examination next time it was due. The only issue concerning a large proportion of men was that they might not be clean: 56% (95% CI 46–66%) expressed some degree of concern after the first examination.
Table 3. Acceptability of anal examinations: responses to questionnaires 2 weeks after each examination
|Pain during the examination|| || |
|Little or none||97 (100, 96–100)||137 (100, 97–100)|
|A fair bit/quite a lot||0 (0, 0–4)||0 (0, 0–3)|
|Bleeding after the examination|| || |
|None||94 (97, 91–99)||135 (99, 95–100)|
|Just a little/some blood||3 (3, 1–9)||2 (1, 1–5)|
|Embarrassed having anus touched|| || |
|Not at all/a little||92 (96, 90–99)||137 (100, 97–100)|
|A fair bit/quite a lot||4 (4, 1–10)||0 (0, 0–3)|
|Worried might not be clean|| || |
|Not at all||42 (44, 34–54)||52 (38, 30–47)|
|A little||37 (39, 29–49)||61 (45, 36–53)|
|A fair bit/quite a lot/very much||17 (18, 11–27)||24 (18, 12–25)|
|Examination was emotionally upsetting|| || |
|Not at all/a little||95 (99, 94–100)||137 (100, 97–100)|
|A fair bit||1 (1, 0–6)||0 (0, 0–3)|
|Satisfied with amount of time spent on their HIV care|| || |
|Very satisfied/satisfied||94 (98, 93–100)||137 (100, 97–100)|
|Dissatisfied||2 (2, 0–7)||0 (0, 0–3)|
|Overall experience|| || |
|Unpleasant||4 (4, 1–10)||3 (2, 0–6)|
|Neither good nor bad/acceptable||93 (96, 90–99)||134 (98, 94–100)|
|Will probably have examination next time it is due|| || |
|Yes||96 (100, 96–100)||131 (98, 94–100)|
|No||0 (0, 0–4)||4 (3, 1–7)|
Table 4 lists the components of the cost of the screening intervention and resulting referrals and investigations. Examinations took less than 5 min, but because a small number generated extra work in the form of referrals or anoscopies, we estimated an average of 5 min for the purpose of costing the intervention. The cost of a screen was estimated to be Australian $16.34 after including three surgical referrals and two colonoscopies.
Table 4. Average cost* in Australian dollars (AUD) of performing 282 examinations on 102 men, including referrals and procedures attributable to screening; this excludes the cost of the one case of cancer and of the symptomatic referrals
| || ||Cost of screening||$4608|| |
| || ||Cost per examination||$16.34|| |
To our knowledge, this is the first study of the acceptability and cost of anal cancer screening examinations of homosexual men with HIV infection attending for routine care. Most men who were approached agreed to participate in this study, and 94% of participants had more than one examination. Anal examinations had high rates of acceptability, and generated referrals for potentially malignant lesions in 3% (95% CI 1–8%) of first examinations and in no subsequent examinations. We estimated the cost of the intervention to be Australian $16 per examination. These findings suggest that regular anal examinations are likely to be an acceptable and inexpensive addition to the routine HIV care of homosexual men.
There are a number of points to consider when interpreting these results. First, the study was undertaken by sexual health physicians who were familiar with anal examinations. Other clinicians, less experienced in this examination, may have a higher rate of referral, although training may address this issue. Secondly, the study did not have the power to address the sensitivity of this procedure because anal cancer would be expected in only approximately one in every 1000 homosexual men with HIV infection each year. However, we believe that it is unlikely that cancers were missed by the first examination, as 96% of men had a second examination 3 to 6 months later and all of these were negative. Thirdly, the estimated cost of the intervention may not apply to other health funding systems which may operate differently and we did not measure the time spent on the examination. Finally, our study population came from a single clinic and it is possible that they may not be representative of all homosexual men with HIV infection. Nevertheless, the risks for anal cancer and intraepithelial neoplasia in our study population are probably similar to those of other populations because the prevalence of anal HPV type 16 (33%) was close to the 35% reported in a recent meta-analysis .
Some previous studies have examined the spectrum of anorectal disease in HIV-infected people and others have assessed either the acceptability of DREs for prostate cancer screening or the acceptability of anal cytology with high-resolution anoscopy (HRA) for anal cancer screening. In a cross-sectional study, all 384 HIV-positive out-patients (96% were male) who attended a Chilean hospital for HIV care during 1 month were examined. Of this group, 13% had anorectal pathology and 92% of these cases were anal warts . Three other studies of anorectal conditions in HIV-infected patients [16-18] were hospital-based, retrospective surgical case series. All reported a spectrum of diagnoses, with warts and ulcers being the most common, similar to the current study, and less frequently, haemorrhoids, cancers, abscesses, fissures and fistulae. Our study differs from these by being a prospective study of anorectal diagnoses, resulting referrals and the acceptability of routinely examining mostly asymptomatic homosexual men receiving HIV care.
Studies of acceptability of anal examinations generally report the proportion of men (sexuality not specified) who accept DRE for prostate cancer screening. Two studies of men screened for prostate cancer [19, 20] report uptake by 66%  and 88%  of men offered DRE and prostate-specific antigen blood testing. Of 472 respondents in the study by Kirby et al. , 97% reported no or little discomfort and 95% indicated that they would undergo screening again. These findings are very similar to our results of 72% accepting the examination and 96% saying that they would have it again.
The acceptability of anal cytology with HRA and biopsy has also been assessed in homosexual men, but these were generally referred patients who had accepted the screening process, and methods of measuring acceptability vary widely. These studies have been described in detail by Landstra  and variously report (1) no significant effect of screening on anxiety, depression or quality of life [22, 23], (2) high acceptability (86%) of self-collected cytology swabs  and (3) high acceptability (91%) of high-resolution anoscopy , although 93% of patients required intervention for pain. The only data comparing DRE, cytology and HRA come from an ongoing cohort study of HIV-positive and HIV-negative homosexual men having all three procedures. Interim data indicate that moderate to severe pain is reported by approximately 6% of men after digital anal examination, by approximately 25% after anal swabbing for cytology and by approximately 35% after high-resolution anoscopy .
Our study also suggests that regular anal examinations in homosexual men with HIV infection are a practical and inexpensive way to screen for early cancer, with an acceptably low rate of referrals for investigation of false-positive examinations. However, a significant amount of the cost of examining this cohort came from the colonoscopies.
Because the examination is screening for anal cancer, and not other colorectal cancers, it is debatable whether polyps seen during anal cancer screening require the same management as if they were seen in a person who was selected for screening because of their higher risk of colorectal cancer. An organized screening programme may need guidelines limiting investigations to those required for the diagnosis of anal lesions. We found that the second and third examinations detected no additional potentially malignant lesions. This suggests that the cost of the intervention may fall with subsequent examinations, after the investigation of abnormal findings from first examinations. In order to examine changes in the acceptability and findings over a series of examinations, we performed three examinations in 1 year; however, it is more likely that clinics would perform this once per year.
Our study did not investigate whether regular examinations result in earlier diagnosis of anal cancer, nor did it determine the required frequency of examinations. Anal SCC is typically a slow-growing cancer , and currently it is diagnosed late when at least half of tumours are externally visible and the mean tumour size is 36 mm  One might reasonably assume that regular examinations will diagnose it earlier; however, there are no data to support this assumption. A prospective study to address this question would require a very large sample size, of some thousands of individuals followed for at least 5 years, given that the incidence of anal cancer in this group approaches 1 per 1000 per year. The question for HIV clinical services is whether to devote considerable resources to measuring the effectiveness of screening, or to simply introduce a safe and inexpensive examination which seems likely to improve care while we wait for the refinement of screening for histological or molecular precursors. It is likely that the cohort study comparing DRE, cytology and HRA  will provide further useful data on this.
We acknowledge the contributions of Rabia Thompson and Clare Bellhouse to this study.
Conflicts of interest
TR is a site investigator on a Merck HPV vaccine study.