Association of antiretroviral therapy with anal high-risk human papillomavirus, anal intraepithelial neoplasia, and anal cancer in people living with HIV: a systematic review and meta-analysis

Summary

Background

The effect of antiretroviral therapy (ART) on the natural history of anal high-risk HPV and anal lesion progression is not well established. We reviewed the association of ART and other HIV-related factors on anal HPV infection, anal intraepithelial neoplasia (AIN), and anal cancer among people living with HIV.

Methods

For this systematic review and meta-analysis, we searched MEDLINE and EMBASE for studies published between Jan 1, 1996, and Oct 30, 2019, that reported the association of HIV-related exposures (ART or highly active ART [HAART], HIV-RNA plasma viral load [PVL], and nadir or current CD4 cell count) with outcomes of anal high-risk HPV prevalence, incidence, and persistence; prevalence, incidence, progression, or regression of anal histological and cytological abnormalities; and anal cancer incidence. Effect estimates were extracted whenever available; otherwise, they were calculated from raw data. We assessed the risk of bias of included studies using the Newcastle-Ottawa scale, and random-effects meta-analyses were done to examine heterogeneity using the I² statistic. This study is registered on the PROSPERO database, CRD42018007271.

Findings

We identified 6777 studies, of which 5377 were excluded before full-text review. 122 studies providing estimates for 130 distinct populations matched the inclusion criteria. The populations comprised 417 006 people living with HIV (women, men who have sex with men, and men who have sex with women). 41 (32%) population estimates were not stratified by sex or sexual orientation. People living with HIV receiving ART had 35% lower high-risk HPV prevalence than ART-naive people (crude odds ratio [OR] 0·65, 95% CI 0·54–0·79; I² 12·1%, p=0·31) in 18 studies, and prolonged ART use was associated with a 10% reduction per year in high-risk HPV prevalence in two studies (adjusted OR 0·90, 0·85–0·95; I² 0%, p=0·88). People living with HIV with undetectable PVL had lower HSIL-AIN2+ prevalence than those with detectable PVL (crude OR 0·84, 0·72–0·98; I² 0%, p=0·80) in 16 studies, particularly if sustained for more than 1 year (crude OR 0·62, 0·47–0·81; I² 0%, p=0·51). ART was not associated with anal cancer incidence when adjusted for years living with HIV in three studies (adjusted hazard ratio [HR] 1·11, 95% CI 0·68–1·80; I² 0%, p=0·57), but ART users with sustained undetectable HIV PVL had 44% lower risk of anal cancer than those without (adjusted HR 0·56, 0·44–0·70; I² 0%, p=0·94) and for each increase in nadir CD4 cell counts of 100 cells per μL, there was a 40% decrease in anal cancer incidence (crude HR 0·60, 0·46–0·78; I² 21·7%, p=0·26).

Interpretation

Effective ART use and early initiation at high nadir CD4 counts might reduce anal high-risk HPV infection and anal cancer risk. Although most studies were cross-sectional in design and few adjusted for potential confounders, this analysis provides comprehensive estimates of the effect of ART and HIV-related factors on the natural history of anal HPV-related disease in people living with HIV.

Funding

EU Marie Skłodowska-Curie Actions programme.

Introduction

People living with HIV are at increased risk of high-risk human papillomavirus (HPV) infection and persistence,¹ anal high-grade squamous intraepithelial lesions (HSIL) or high-grade anal intraepithelial neoplasia (AIN) 2, and incidence of anal cancer.2, 3 Anal cancer is the fourth most common cancer in men who have sex with men (MSM) living with HIV,⁴ and evidence suggests increased incidence of anal cancer in women living with HIV and men who have sex with women (MSW) living with HIV compared with their HIV-negative counterparts.3, 5, 6, 7

As antiretroviral therapy (ART) is scaled-up, increased survival times in people living with HIV might be associated with an increase in the incidence of anal and other cancers. A 2015 meta-analysis of observational studies evaluating the incidence of malignancies before and after the introduction of highly active antiretroviral therapy (HAART) reported that the risk of anal cancer was four times higher in the post-HAART period than in the pre-HAART period.⁸ Given the limitations in anal cancer screening,9, 10 high rates of recurrence following management of anal lesions,¹¹ and low access to HPV vaccination in people living with HIV,¹² evidence of the effect of ART on the prevalence and incidence of anal high-risk HPV infection, anal lesions, and anal cancer is needed.

Research in context

Evidence before this study

We searched MEDLINE and EMBASE for all available publications in English from Jan 1, 1996, to Oct 30, 2019, using search terms for HPV, squamous intraepithelial lesions (SIL), anal intraepithelial lesions (AIN), anal cancer, antiretroviral therapy (ART and highly active ART [HAART]), and HIV. Studies were eligible if they reported the effect of ART on the prevalence, incidence, and persistence of high-risk HPV infections identified in the anal canal, the prevalence and incidence of anal pre-cancerous lesions, and the incidence of anal cancer. We were able to evaluate the association of ART, HIV plasma viral load, and markers of immune response such as CD4 cell counts (the lowest recorded [nadir] and the current, or CD4 counts measured at the same time as the outcome) with the different outcomes explored. However, most studies were cross-sectional in design, restricting our understanding of the effect of ART duration; few studies had rigorous histological verification for outcomes of low-grade and high-grade anal lesions; few studies adjusted for potential confounders including the history or frequency of receptive anal intercourse; and finally, few studies were done in population groups other than men who have sex with men in high-income settings.

Added value of this study

To our knowledge, this is the first meta-analysis investigating the association of ART use, HIV plasma viral load, and CD4 cell count with the outcomes of anal high-risk HPV infection, cytology-confirmed and histology-confirmed anal lesions, and anal cancer incidence in people living with HIV. Our findings suggest that current rather than historical immunosuppression could be effective in clearing high-risk HPV infection, whereas measures of past immunosuppression could be more predictive of anal cancer risk. A potential differential effect of HPV genotypes could not be explored.

Implications of all the available evidence

This study has practical implications for the management of people living with HIV and control of anal cancer worldwide. Given the high prevalence of anal lesions in high-risk populations such as people living with HIV and the challenges in diagnosis and effective management of anal lesions, our study highlights the need to emphasise early diagnosis of HIV infection and rapidly initiate and maintain effective ART in populations at increased risk of anal cancer.

In a previous meta-analysis,¹³ we reported that despite wide variability in the degree of immune deficiency of included participants, effective ART (evidenced by early initiation; sustained adherence consistent with undetectable HIV RNA plasma viral load [PVL] and sustained high CD4 cell count) was associated with reductions in the prevalence of cervical high-risk HPV infection, incidence or progression of cervical intraepithelial neoplasia (CIN), and incidence of invasive cervical cancer.

The aims of this study were to systematically review and summarise the literature on the association of ART and HIV-related factors, including HIV PVL and nadir and current CD4 cell count, with anal high-risk HPV prevalence; prevalence, incidence, progression, and regression of atypical squamous cells of undetermined significance or anal intraepithelial neoplasia, grade 1 or greater (ASCUS-AIN1+), or high-grade squamous intraepithelial lesions or anal intraepithelial neoplasia, grade 2 or greater (HSIL-AIN2+); and anal cancer incidence.