ARTICLE
Anal HPV prevalence in a cohort of individuals infected with HIV-1

INTRODUCTION

Human Papillomavirus (HPV) is the main causative agent for the development of neoplastic lesions in uterine cervix. In anal tissue, the progression of HPV-positive high-grade lesions to an invasive cancer can require years. This progression can occur more rapidly in young HIV-infected individuals. However, there is a paucity of information on the consequences of HIV/HPV coinfections with regard to neoplastic lesions. Prospective studies can better clarify on the factors that may contribute to the severity and progression of disease surrounding HIV/HPV coinfection. Few studies have reported on the major risk factors associated with HIV/HPV coinfections such as unprotected sex and a high number of sexual partners^1,2. The aim of this study was to evaluate the HPV prevalence and to cross-analyze clinical, sociodemographic, and behavioral data from HIV-infected subjects diagnosed with anal intraepithelial lesions.

OBJECTIVE

To analyze the HPV prevalence, clinical, epidemiological, and behavioral data in a cohort of HIV-seropositive individuals from the National Institute of Infectious Diseases, FIOCRUZ, RJ.

METHODS

RESULTS

Study population

Age of the patients included in this study ranged from 33.5 to 48.1 years. Average age of the HIV-infected individuals was 42 (±0.9) years and that for the non HIV-infected individuals was 33.6 (±2.5) years. Among the biopsies from HIV-positive patients, 21 presented with normal squamous epithelium, 39 with low-grade neoplasia (AIN I), and 39 samples with high-grade neoplasia (AIN II/III). In the HIV-positive group, the average age of individuals with normal squamous epithelium was 38.5 (±1.8) years; that for low-grade AIN was 41.5 (±1.4) years; and for high-grade AIN, the average was 44.4 (±1.6) years.

In all of the samples collected, high-risk HPV was detected in 78.5% of biopsies while non-high-risk HPV was seen in 44.6% (Table 1). Based on HIV status, more than 80% of the samples from positive individuals showed high-risk HPV compared to 40% for negative patients. Of the individual HPV high-risk genotypes, HPV 16 showed the greatest prevalence with a total of 18 different types identified (Table 1). HIV-1-positive individuals with high-grade AIN had a higher prevalence of high-risk HPV types in the anal secretion specimens compared to individuals without lesions (normal) and low-grade AIN; however there was no statistically significant difference (p>0.05).

Table 1:

HPV genotypes found on the anal secretion by Papillocheck according the Histopathology diagnostic (2010-2013).

HPV: human papillomavirus; HIV: human immunodeficiency virus; AIN: anal intraepitherlial neoplasia; hr: high risk.

For non-high-risk HPV, detection was more frequently observed in AIN I or AIN II/III tissue samples than normal tissue (Table 1). When examining for infections by multiple HPV genotypes (Table 2), it is clear that a large number of samples were positive for two or more HPV genotypes. Surprisingly, we found poor agreement between the two methods analyzed (Papillocheck and PCR), except for the diagnosis of HPV 11, which showed moderate agreement (k=0.57; p=0.000) and a high specificity for genotypes 31, 43, and 53 (Table 3). A graphical representation of the HPV genotype data is shown in Figure 1.

Table 2:

Multiple HPV types in anal secretions by Papillocheck according the Histopathology diagnostic (2010-2013).

Fisher's exact test, p<0,005; HPV: human papillomavirus; HIV: human immunodeficiency virus; AIN: anal intraepitherlial neoplasia.

Table 3:

Sensitivity and specificity of HPV genotypes found in the biopsies of anal secretion (Papillocheck) (2010-2013).

HPV: human papillomavirus.

Figure 1:

HPV prevalence found in the anal secretion.

DISCUSSION

HPV is the main etiologic agent related to cervical cancer and its association with the development of anal intraepithelial neoplasia is more frequently observed with HIV-1 infections. Over 90% of anal carcinoma in HIV-infected individuals is associated with a persistent HPV infection by at least one HPV genotype with multiple infections being common^4,5.

Some studies have reported age as an important factor in HPV infection⁶. In this study, the average age among HIV-infected individuals was 42 years and 33.6 years for those individuals not infected with HIV, such that this group only provided tissue samples that were diagnosed as being without lesions by histopathology. However, in this study, the average age of participants who were HIV positive and diagnosed with anal lesions showed a slight increase in relation to the lesion severity. The mean age of the subjects with normal samples, AIN I and II/III were 38.5; 41.5, and 44.4 years, respectively, with a statistically significant difference. Our results agree with data reported in our previous study⁷.

In that study conducted in Brazil, it was found that, in cervical cancer cases, women with HIV/HPV coinfection had an average age of 51.1 years. Another study of HIV-infected women in a Brazilian cohort also analyzed samples of AIN and the association with HPV. In this study, women diagnosed with AIN had an average age of 42 years⁸. In a recent study with the same cohort patients, Nicol and colleagues found that HIV-positive women with <30 years of age had a higher prevalence of HPV 6, 11, 16, and 18 with a tendency for HPV seroprevalence of the genotypes 6, 16 in HIV-negative women above 30 years⁸.

Some other known risk factors for the development of HPV-associated lesions have been preestablished, such as an early initiation of sexual activity, multiple sexual partners, history of sexually transmitted diseases, teenage pregnancy, and smoking⁶. When analyzing the number of sexual partners of individuals included in the study, we found that the average number of sexual partners for women was 1 over the last 6 months, and that for men was 14.1 in the last 12 months. Even if the analysis time has been different for men and women, the largest number of sexual partners among men compared to women is remarkable; mainly in the number of male sexual partners reported by men. Given that this corroborates the literature, in which studies have shown that men who have sex with men (MSM) are up to 37 times more likely to progress to anal cancer and are considered risk group⁹.

Among patients who reported smoking, approximately 38% had pathological diagnosis of high-grade AIN, and all were infected with HIV. As for the report of receptive anal sex, most patients were infected with HIV and were diagnosed with either low- or high-grade AIN. This feature is consistent with previous studies on AIN where men and women are considered to display risk factors for the development of AIN and anal cancer through their receptive anal sex history, high number of sexual partners, and smoking. For women, these same risk factors apply to cervical cancer⁴.

Data from this study showed a high prevalence (94.4%) of patients with CD4⁺ nadir <50 cells/mm³ who were diagnosed with high-grade AIN. However, the results disagree with one particular study that found that 14.8% of individuals with a high-grade AIN had CD4 nadir below 50 cells/mm³ in a cohort in Brazil of HIV-infected women¹⁰. In another study, where multivariate analysis was performed, it was observed that a low CD4⁺ count (≤200 cells/mm³) does not show a strong predictor of high-risk HPV infection².

Currently, the increased life span of HIV-infected individuals may be explained due to the impact of treatment with cART. In this study, 81.8% of HIV-1-infected patients were under cART treatment and 42.9% had detectable viral load. No correlation was found between peripheral levels of CD4⁺ and the use of HAART. In our previous study with cervical samples, this type of correlation was also not observed¹¹.

HIV/HPV coinfections lead to important biological changes that entail the development of progression of AIN to anal cancer. While most studies that address the immune response against HPV/HIV are directed to cervical cancer, it has been shown that the infection by only HPV displayed no activation of the immune response mediated by Th1 lymphocytes, whereas in the coinfection a profile shift to Th2 occurs¹².

Among the HPV genotypes detected in anal secretion of HIV-infected individuals, HPV 51 showed statistical differences in the samples without lesion. Studies show that infection with high-risk HPV is common in anal samples of HIV-infected individuals, and usually HPV 51 appears moderately associated with anal lesions. In this study, a weak association was found between the HPV types detected in the anal secretion and biopsies, which indicates that HPV detected in secretion is not necessarily of the same type of those underlying the intraepithelial lesion¹³.

Of the population analyzed, more than 45% of HIV-negative and 57% of HIV-positive subjects had already been exposed to the four HPV types covered by the current quadrivalent HPV vaccine, suggesting that HPV vaccination should be considered as a prophylactic approach to reduce the risk of anal intraepithelial lesion development on this population. Further studies should be done in a larger population of individuals. The present study has as limitation the nonavailability of some analyzed variables for all patients. However, the data suggest some important clinical approaches.

CONCLUSION

This study showed that there was a strong association in HIV-1-infected individuals between the development of anal intraepithelial lesions to stage AIN II/III with the increasing age and peripheral blood CD4⁺ nadir <50 cells/mm³. In addition, most HIV-infected individuals analyzed have already been exposed to the four HPV types targeted by the current quadrivalent vaccine (MSD-HPV types 6, 11, 16, and 18) suggesting that vaccination against HPV could be regarded as a prophylactic measure to reduce the risk of anal intraepithelial lesions in HIV-infected individuals.