Human papillomavirus types from infection to cancer in the anus, according to sex and HIV status: a systematic review and meta-analysis

Abstract

Background: Data on carcinogenicity of human papillomavirus (HPV) types in the anus are needed to inform anal cancer prevention through vaccination and screening. This is particularly the case for people infected with HIV, who are at an increased risk of anal cancer.

Methods: We did a systematic review of studies published from January, 1986, to July, 2017, in MEDLINE, Embase, and the Cochrane Library on anal HPV infection, without any language restrictions. Eligible studies reported type-specific HPV prevalence by strata of cytopathological or histopathological anal diagnosis, sex, and HIV status. Data requests were made to authors when necessary. We did a meta-analysis of type-specific HPV prevalence across the full spectrum of anal diagnoses, from normal cytology to anal cancer. We assessed the main outcome of type-specific HPV prevalence ratios [PR], calculated across strata of anal diagnoses, gender, or HIV status, by use of generalised linear models.

Findings: 95 studies were identified from the search, published between 1992-2017, from which 18 646 individuals fulfilled the criteria for inclusion in the analyses: 8534 people with normal cytology, 5730 with low-grade lesions, 2024 with high-grade lesions, and 2358 with anal cancer. HPV prevalence varied in normal cytology from 42% in HIV-negative women to 76% in HIV-positive men and, for each diagnosis, was higher in individuals who were HIV positive than those who were HIV negative. HPV16 positivity increased with diagnosis severity, being the only HPV type accounting for more HPV infection in anal cancer than normal cytology, both in individuals who were HIV negative (PR 5·0, 95% CI 3·8-6·6, p<0·0001) and those who were HIV positive (2·3, 1·9-2·7, p<0·0001). HPV16 positivity increased even between high-grade lesions and anal cancer, whereas other high-risk HPV types accounted for high proportions of low-grade or high-grade lesions but their prevalence decreased in anal cancer. However, HPV16 was less frequent in HIV-positive than HIV-negative anal cancer, both in men (PR 0·8, 95% CI 0·7-0·9, p<0·0001) and women (0·8, 0·6-1·0, p=0·063), and in HIV-positive versus HIV-negative high-grade lesions in women (0·6, 0·5-0·9, p=0·0077). Type-specific attribution of the non-HPV16 fraction of HIV-positive anal cancer is hindered by a high prevalence of multiple HPV infections.

Interpretation: HPV16 is by far the most carcinogenic HPV type in the anus, with enrichment of HPV16 even from high-grade lesions to anal cancer, both in individuals who are HIV negative and those who are HIV positive. Nevertheless, the fraction of anal cancer attributable to HPV16 is smaller in the HIV-positive population.

Funding: International Agency for Research on Cancer.

Figure 1

Study selection

Figure 2

Overall HPV prevalence by sex, anal diagnosis and HIV status HPV=human papillomavirus. *Low-grade diagnosis is defined as atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion, or anal intraepithelial neoplasia grade 1. †High-grade diagnosis is defined as high-grade squamous intraepithelial lesion, atypical squamous cells but cannot exclude high-grade squamous intraepithelial lesion, or anal intraepithelial neoplasia grade 2 or 3. ‡Anal cancers of unknown HIV status are assumed to be HIV negative (see appendix p 15 for sensitivity analysis including known HIV-negative anal cancers only).

Figure 3

Prevalence of HPV16, HPV18, and HPV31/33/45/52/58 and prevalence ratios by anal diagnosis and HIV status, in HPV-positive men and women HPV=human papillomavirus. PR=prevalence ratio. *Low-grade diagnosis is defined as atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesion, or anal intraepithelial neoplasia grade 1. †High-grade diagnosis is defined as high-grade squamous intraepithelial lesion, atypical squamous cells but cannot exclude high-grade squamous intraepithelial lesion, or anal intraepithelial neoplasia grade 2 or 3. ‡Anal cancers of unknown HIV status are assumed to be HIV negative (see appendix p 16 for sensitivity analysis including known HIV-negative anal cancers only). §PR comparisons are HIV positive versus HIV negative.

Figure 4

Cancer/normal prevalence ratios in HPV-positive samples by HPV type and HIV status HPV=human papillomavirus. PR=prevalence ratio. *Anal cancers of unknown HIV status are assumed to be HIV negative (see appendix p 17 for sensitivity analysis including known HIV-negative anal cancers only). †Adjusted by sex and region.

Figure 5

Prevalence of high-risk HPV types by type of sample in HIV-positive men with HPV-positive high-grade anal lesions High-grade diagnosis is defined as high-grade squamous intraepithelial lesion, atypical squamous cells but cannot exclude high-grade squamous intraepithelial lesion, or anal intraepithelial neoplasia grade 2 or 3. HPV=human papillomavirus. PR=prevalence ratio.