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High Rates of Anal squamous intraepithelial lesions and condyloma in HIV-infected heterosexual men, homosexual men and women: prevalence and associated factors in Paris, France
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AIDS:Volume 21(11)11 July 2007p 1457-1465
Abramowitz, Laurenta; Benabderrahmane, Dalilaa; Ravaud, Philippeb; Walker, Francinec; Rioux, Christophed; Jestin, Christinee; Bouvet, Elisabethd; Soule, Jean-Claudea; Leport, Catherinee; Duval, Xavierb,e,f
From the aAP-HP, Department of Gastroenterology and Proctology, Bichat Hospital, Paris, France
bAP-HP, Department of Biostatistics, Bichat University Hospital, Paris, France
cAP-HP, Department of Anatomopathology, Bichat Hospital, Paris, France
dAP-HP, Department of Infectious and Tropical Diseases A, Bichat Hospital, Denis Diderot University, Paris, France
eAP-HP, Department of Infectious and Tropical Diseases B, Bichat Hospital, Denis Diderot University, Paris, France
fInserm, Clinical Investigation Center 007; Inserm U738, Bichat, Paris, France.
"....The systematic screening for anal macroscopic HPV-related lesions conducted in this study on this large HIV-infected population during the HAART era revealed a high prevalence of anal condyloma (10%) and histological dysplasia (13%), of which half were exclusively endoanal. These findings concern not only the homosexual male population but also the heterosexual male population and the female population......Histologically confirmed anal HPV-related lesions or high-risk HPV anal infection are thus frequent in this large population of HIV-infected patients, including patients previously not considered to be at risk of anal cancer. Given their frequency and their potential relationship to anal neoplasia, systematic screening should be considered."
Abstract
Objective: To assess the prevalence of and factors associated with squamous intraepithelial lesions and condyloma [human papillomavirus (HPV)-related lesions) in HIV-infected patients.
Design: A cross-sectional study in a tertiary-care university hospital conducted in 516 consecutive outpatients.
Intervention: A systematic examination for macroscopic HPV-related lesions through anoscopy with histological confirmation, evaluation of dysplasia and HPV typing. Sexual behaviours were assessed using a semi-directive questionnaire.
Results:
Of 473 patients examined, (200 homosexual men, 123 heterosexual men, 150 women), 108 (23%) had histologically confirmed anal HPV-related lesions (36, 15 and 11% of the respective populations), including 51 (47%) with only endoanal localization.
Among these 108 patients, histological dysplasia of grades I or II and grade III were noted in 59 and two patients, respectively, invasive endoanal cancer in one; three patients also had high-risk oncogenicity HPV without dysplasia.
Independent identified associated factors of HPV-related condyloma were the number of incidents of sexual intercourse per month [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.06], CD4 cell count below 200 _ 106 cells/l (OR 3.22; 95% CI 1.37-7.60), history of anal HPV lesion (OR 4.57; 95% CI 2.13-9.81), and receptive anal intercourse (OR 2.30; 95% CI 1.11-4.77). The two latter factors remained associated with histological dysplasia (OR 2.82; 95% CI 1.38-5.76 for history of anal condyloma, and OR 4.29; 95% CI 2.18-8.44 for receptive anal intercourse).
Conclusion: The high rate of condyloma and histological dysplasia seen argues for a systematic screening for these lesions in HIV-infected individuals.
Introduction
The incidence of epidermoid anal cancer is reported to have increased in recent decades and may be even higher among HIV-positive men who have sex with men (MSM) [1-4]. There is strong evidence that anal squamous intraepithelial lesions (SIL), the putative precursor lesion, and anal cancer are both linked to some human papillomavirus (HPV) infections [4,5]. The detection of anal HPV through molecular techniques is frequent in both HIV-infected MSM and women [4,6], and to a lesser extent in HIV-negative individuals. In two recent reports, anal HPV was also detected in HIV-infected heterosexual men in the absence of anal intercourse [7,8]. Similarly, the detection of anal SIL through anal cytology samples is more frequent in HIV-positive than in HIV-negative MSM [9], and the risk of progression from low-grade SIL to high-grade SIL is higher in HIV-infected than in HIV-negative MSM [10].
Since the second half of the 1990s, HAART has dramatically decreased HIV morbidity and mortality. The effect of HAART on the incidence of anal cancer, precursor lesions and HPV prevalence can be complex, and results reported in the literature are conflicting [11-13]. On the one hand, the induced immune recovery could reduce the prevalence of HPV infection, anal SIL and their evolution to dysplasia; on the other hand, the increase in sexual activity and lengthened survival associated with HAART may paradoxically lead to an opposite effect [9,10,14].
Anal intraepithelial HPV infection may lead to different types of macroscopic lesions, depending on HPV types, with non-oncogenic HPV types leading to benign lesions usually named condyloma and oncongenic HPV types, such as types 16 and 18, leading to intraepithelial dysplasia. As HPV-induced anal dysplasia has been associated with an increased risk of anal cancer, it seemed important to us in the era of HAART to determine the prevalence of these different types of macroscopic HPV-related anal lesions [1,15].
We report here the results of a systematic screening for macroscopic anal HPV-related lesions with a systematic search for intraepithelial dysplasia or cancer in a large population of HIV-infected individuals. Our objective was to determine the prevalence of these lesions (condyloma and intraepithelial dysplasia) in the HAART era in consecutive MSM, women and heterosexual men, and to identify their risks factors.
Methods
Patients and study design
Beginning in May 2003 and during a 12-month period, screening for anal macroscopic HPV-related lesions was systematically proposed by the primary care physician during a routine follow-up visit to a sample of HIV-infected outpatients in the infectious diseases units of Bichat Claude Bernard University Hospital in Paris, France. The sample was composed of all consecutive patients consulting any of the medical doctors present during three randomly determined half-days per week. The three selected half-days were modified three times during the study period to allow for the screening of a representative sample of patients.
Data collected
We collected the following data for each patient (whether they accepted screening or not): sex, age, geographical origin, risk factors for HIV infection, mean interval since the detection of HIV-positive serostatus, worst Centers for Disease Control and Prevention stage of disease, CD4 cell nadir, CD4 cell count and HIV-RNA level at the time of the consultation, as well as current antiretroviral therapy. In patients who refused the screening, the reason for the refusal was noted (lack of time, anal HPV-related lesion already monitored by a proctologist, unwillingness). In patients who accepted the screening, a standardized questionnaire was filled out after anal examination by the proctologist. This questionnaire asked for information regarding previous sexually transmitted diseases, history of genital and anal condyloma including the date and type of the last treatment, and sexual activities and practices (anal sexual intercourse, frequency of acts of sexual intercourse per month, number of sexual partners per year, condom use). Men were considered to be homosexual or bisexual men if the reported HIV transmission risk factor was homosexuality or if they declared having receptive anal intercourse (hereafter referred to as homosexual men).
Anal examination
Anal examination was performed immediately after the HIV consultation in the infectious diseases unit by the same experienced proctologist (internal medicine physician with gastroenterology subspecialty training in proctology). The examination consisted of an ocular inspection (with and without aceto-white test, which is considered to increase the visibility of HPV intraepithelial lesions) of the anal margin (anal area visible before anoscopy examination) and an anal canal examination through anoscopy. Acetic acid was applied to the total area of the anal margin and canal. An HPV intraepithelial lesion was suspected in the case of either an aceto-white area or a slightly elevated mucosa resembling tumours white to pink in color or of exophytic elevated lesions easily distinguishable from normal mucosa. A biopsy was systematically performed to confirm the diagnosis of HPV-related lesion. In the case of lesions found during the screening, patients were asked if they had any related discomfort. In men, the external genital organs were also examined.
Histological analysis
HPV intraepithelial lesions were diagnosed by two independent observers using 4-_m thick, paraffin-embedded sections of formalin-fixed tissue and stained with haematoxylin eosin stain. Diagnosis was based on hyperpapillomatosis associated with hyperacanthosis and the presence of koilocytes. Low-grade SIL, also called 'anal intraepithelial neoplasia of grade I-II' (AIN 1 and 2) or low-grade dysplasia, was defined as thickening of the squamous epithelium and slight (lower third) to moderate (lower half) architectural disruption, with atypical cells but no atypical mitosis. High-grade SIL also called 'anal intraepithelial neoplasia of grade III' (AIN 3) or high-grade dysplasia, was defined as the loss of normal stratification of the cells, severe architectural disruption, and the presence of atypical cytoplasm and nuclear features throughout the epithelium, particularly with atypical mitosis. Invasive squamous carcinoma was defined as tumour with extensive infiltration of the lamina propria by clusters of tumour cells having deeply invaded the anal wall [1,16]. Macroscopic HPV-related lesions without dysplasia are hereafter referred to as 'condyloma'.
In-situ molecular techniques for detection of human papillomavirus
In-situ hybridization (ISH) was used for HPV screening and typing. For ISH, biotinylated and fluorescein isothiocyanate-labeled commercial genomic DNA probes were purchased from Argene (Varhiles, France) and Dakopatts (Glostrup, Denmark). ISH was performed according to our previously published protocol using probes specific to the various types of HPV: 6, 11, 16, 18, 31 and 33 (1). When previous specific ISH were negative, ISH was performed using low (HPV 6/11) and high-risk (16/18/31/33/35/39/45/51/52/56/58/59/68) probes (Dakopatts). It was amplified with the biotinyl-tyramide complex and the diaminobenzidine chromogen (Genpoint kit; Dakopatts). HPV detected by the high-risk probe or the specific 16, 18, 31 or 33 probes was considered as being an HPV type at high risk of oncogenicity.
Statistical analysis
Patients were classified into three levels: patients with no HPV-related lesions, patients with anal condyloma, and patients with histological anal dysplasia. We thus used a polytomous logistic regression model to assess the association between categories of patients and characteristics of patients. Characteristics that were related to categories of patients in bivariate analysis were kept in the multivariate analysis with stepwise selection of the covariables. In bivariate analysis, qualitative variables were compared using chi-squared or Fisher's exact test, when appropriate, and quantitative variables were compared by analysis of variance. In multivariate analysis, the 'patients with no lesions' category was the reference group. A significance level of 0.10 was required to include a variable in the model and a significance level of 0.05 was required for a variable to remain in the model. Odds ratios with a 95% confidence interval (CI) were estimated. All statistical analyses were performed using SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina, USA).
Ethics
All patients received written information before examination, and the local ethics committee approved the study.
Results
Anal examination was proposed to 516 HIV-infected patients, 473 of whom accepted (92%). Of the 43 patients who refused anal examination, 35 were men (11 homosexual and 24 heterosexual) and eight were women. The reasons for refusal included: known anal HPV intraepithelial lesion already monitored by a proctologist (seven patients); lack of time (13 patients); and unwillingness (23 patients). There was no difference in epidemiological data, CD4 cell count or nadir, plasmatic HIV-RNA value, Centers for Disease Control and Prevention (CDC) stage or percentage of HAART-receiving patients between the 473 patients who accepted and the 43 who refused the screening. The only difference observed was for injection drug addiction patients. Among the 43 patients who refused the screening, 10 (23%) were intravenous drug addicts, whereas there were 37 intravenous drug addicts (8%) among the 473 individuals who accepted (P = 0.003).
The characteristics of the 473 patients who accepted the screening are described in Table 1. The median age was 40 years [interquartile range (IQR) 35-46]; 28% patients were at CDC stage C, the median CD4 cell count was 454 _ 106 cells/l (IQR 296-618), and 60% of the patients had HIV-RNA below the limit of quantification (50 copies/ml). Twenty-four per cent of the 473 patients reported having unprotected sexual intercourse and 18% of the women reported receptive anal intercourse.
Among the 473 patients, 108 (23%) had macroscopic HPV-related lesions and 47% of them (51/108) had only anal canal lesions (38/200 homosexual men, 8/123 heterosexual men and 5/150 women). The proportion of HPV-related lesions was 36.5% (73/200) among homosexual men, 14.6% (18/123) among heterosexual men, and 11.3% (17/150) among women. In the 108 patients with HPV-related lesions, 47 had condyloma and 61 had histological dysplasia (13% of the 473 patients) with low-grade dysplasia (AIN 1-2) in 59 patients and high-grade dysplasia (AIN 3) in two patients. Localization of dysplasia between the anal margin and the anal canal is described in Fig. 1. The repartition of dysplasia among the three populations was as follows: 42/200 homosexual men (21%), nine out of 123 heterosexual men (7.3%) and 10/150 women (6.7%). High-risk oncogenicity HPV types were identified in 90% of the 61 patients with dysplasia; three patients also had high-risk oncogenicity HPV without dysplasia. One invasive anal carcinoma was detected in one patient.
Seventy patients (15%) had a previous history of anal condyloma, the last treatment for which had been performed on average 8 years ago. Seventy-seven per cent of patients with anal HPV-related lesions had no discomfort. Among the 473 screened patients, screening for anal HPV intraepithelial lesions had previously been proposed to only 10 (2.1%), of those nine were homosexual men and one was a woman. No patients had previously undergone anal cytology sampling.
Table 2 shows patient characteristics associated with anal condyloma or anal histological dysplasia among homosexual or bisexual men, heterosexual men and women. Table 3 shows bivariate analysis of associated factors for anal condyloma and for anal histological dysplasia. Multivariate analysis for independent risk factors associated with anal condyloma and anal histological dysplasia, compared with patients with no anal lesions is displayed in Table 4. The number of incidents of sexual intercourse per month [odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.06], CD4 cell count below 200 _ 106 cells/l (OR 3.22; 95% CI 1.37-7.60), history of anal HPV-related lesion (OR 4.57; 95% CI 2.13-9.81), and receptive anal intercourse (OR 2.30; 95% CI 1.11-4.77), were independently associated with anal condyloma, whereas only history of anal HPV-related lesion (OR 2.82; 95% CI 1.38-5.76) and receptive anal intercourse (OR 4.29; 95% CI 2.18-8.44) were associated with anal histological dysplasia.
Discussion
The systematic screening for anal macroscopic HPV-related lesions conducted in this study on this large HIV-infected population during the HAART era revealed a high prevalence of anal condyloma (10%) and histological dysplasia (13%), of which half were exclusively endoanal. These findings concern not only the homosexual male population but also the heterosexual male population and the female population.
The comparison of the characteristics of this screened population with those of the population who refused the screening in this study shows that they were comparable except for the proportion of intravenous drug addiction, which was a more frequent HIV transmission risk factor in the population of patients who refused the screening. The reason for the refusal in this population was essentially unwillingness. As the selected sample was randomly chosen, we assume that the studied population is representative of the whole population of HIV-infected outpatients seen in our hospital. One limitation of our study could be the referral bias of a large tertiary-care centre. As the study was conducted at a single centre, we cannot exclude the possibility that geographical variation in the characteristics of the HIV-infected patients may have influenced the results. The characteristics of the HIV-infected patients seen at our hospital are, however, comparable to those of patients seen in French hospitals based on the comparison of their characteristics using the DMI-2 software, in the French Hospital database on HIV.
The relationship between anal condyloma considered a benign lesion and anal histological dysplasia is very close as both diseases are linked to HPV infection and probably share transmission risk behaviours. A recent cohort study showed an incidence of anal intraepithelial neoplasia and anal cancer of 0.1 per 1000 patients a year in the HIV-infected population with anal condyloma [15]. Similarly, Frisch et al. [3] in analysing risk factors for anal cancer in women, reported an odds ratio of 9.8 in women with a history of anal condyloma. Looking specifically at associated factors for each disease may help understand the relationship between these two types of anal HPV infection.
There is no similar study in the literature performed before or during the HAART era with which our study could be compared as regards the prevalence of histologically confirmed anal HPV infection. Our results could, however, be analysed in light of the prevalence of anal HPV shedding in homosexual HIV-infected men, which has been extensively studied. The presence of condyloma and anal histological dysplasia detected in the heterosexual male population without any history of anal intercourse, which has never previously been studied, is not surprising because, on the one hand, anal HPV shedding has been detected in heterosexual men in a study by Piketty et al. [7], and on the other hand, husbands of women with cervical cancer have been found to be at an increased risk of anal cancer [17]. In the study by Piketty et al. [7], the heterosexual male population with no history of anal intercourse was restricted to male injection drug users, and therefore did not include all categories of heterosexual individuals. Interestingly, the increase in the rate of HPV-related lesions in HIV-infected homosexual patients compared with heterosexual patients found in the present study (36.5 versus 74.6%) is consistent with the twofold higher rate of HPV detection reported in homosexual men compared with heterosexual individuals in a previous study (85 versus 46%) [7].
The prevalence of anal HPV-related lesions (11.3%) in our population of women is much higher than that reported in a previous study (1.6%) [18]. The difference could be attributed to different reasons. First, it could be related to the anal region examined. Conley et al. [18] looked only for anal margin localization without looking for anal canal localization. Our prevalence, however, remained higher when we did not take into account the 3% (five out of 150 women) with intra-anal HPV-related lesions. Another reason may be the experience of the screening doctor. In our study, the examinations were performed by a senior proctologist, whereas they were performed by gynaecologists in the study by Conley et al. [18]. The prevalence we found in our study could not be overestimated because HPV-related lesions diagnosis in each case was based on the histological result.
Multivariate analysis of risk factors associated with on the one hand condyloma and on the other hand anal histological dysplasia reveals both common but also distinct characteristics. Neither virological (HIV-RNA) characteristics, CDC stage, geographical origins, length of known HIV-positive serology, nor the use of HAART were associated with the presence of anal condyloma or anal histological dysplasia. On the contrary, a CD4 cell count below 200 _ 106 cells/l at the time of screening was independently associated with the presence of condyloma, whereas it was not for histological dysplasia. In the literature, there are conflicting data concerning the identification of CD4 cell count, CD4 cell nadir or the current use of HAART as risk factors for HPV shedding or cytological dysplasia in homosexual men, heterosexual male injection drug users [7,8,19], and in women [4,13,18,20]. Given our results, and given that other authors have studied only anal HPV shedding rather than HPV-related histological lesions, we can hypothesize that immunity does not play the same role in controlling anal HPV shedding, benign anal HPV lesions (condyloma, related to non-oncogenic HPV) development, or anal dysplasia (related to oncogenic HPV) development.
A history of anal condyloma was a strong predictor of the detection of both HPV-related lesions (anal condyloma and histological dysplasia). Of note is the fact that the time interval between the last treatment of previous anal condyloma lesions and the screening was rather long (average 8 years), and that the treatment dates back to the pre-HAART period in most patients. As the large majority of our patients were receiving HAART and were in virological success, we hypothesize that their immunological status improved between these two periods, but this improvement was not sufficient to prevent the recurrence of HPV-related lesions. The results are similar to those of recent studies in which no effect of HAART on HPV-related lesions was observed [13,21].
Sexual practices were also independently associated with anal HPV-related lesions, such as the number of incidents of sexual intercourse, which has previously been reported to be associated with abnormal anal cytological findings in homosexual men [7]. In our population, however, the independent association between anal HPV-related lesions and the number of incidents of sexual intercourse was significant for condyloma, whereas it was only a trend for histological dysplasia. Receptive anal intercourse was a risk factor both for condyloma and histological dysplasia, which underlines the need to identify these sexual practices in women and bisexual men. As noted by others, however, the absence of anal intercourse cannot be used to rule out with certainty the presence of anal lesions or to exclude such patients systematically from a detection process [4,7,8].
Histologically confirmed anal HPV-related lesions or high-risk HPV anal infection are thus frequent in this large population of HIV-infected patients, including patients previously not considered to be at risk of anal cancer. Given their frequency and their potential relationship to anal neoplasia, systematic screening should be considered. Whether this detection should concern the entire HIV-infected population or only those patients at highest risk of HPV-related lesions has yet to be determined. The screening guidelines could differ between homosexual men, heterosexual men and women. These guidelines should also be implemented according to a criterion of cost effectiveness. A pragmatic approach could be proposed: in homosexual men, the presence of HPV-related lesions with histological signs of dysplasia in more than one fifth of patients suggests that this detection should include all homosexual HIV-infected men regardless of their CD4 cell count or the use of antiretroviral drugs, and especially in the case of frequent sexual activity and of a history (even long past) of anal HPV lesions. In heterosexual men and in women, detection should probably focus on patients with a history of HPV-related diseases and previously mentioned at-risk behaviours. This screening should also be accompanied by prevention information to help reduce the rate of at-risk behaviours for HPV exposure.
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