Effective antiretroviral therapy, anal high-risk human papillomavirus, anal intraepithelial neoplasia and anal cancer: a systematic review and meta-analysis

Abstract

Background: We reviewed the association of antiretroviral therapy (ART) and HIV-related factors on anal HPV infection, anal intraepithelial neoplasia (AIN), and anal cancer among people living with HIV (PLHIV). Methods: We searched Medline and Embase for studies from 1 January 1996 to 18 April 2019 that reported the association of ART, HIV-RNA plasma viral load (PVL) and nadir or current CD4+ cell count with prevalence of anal HR-HPV, or prevalence, incidence, progression or regression of anal histological/cytological abnormalities, or anal cancer incidence. We performed random-effects meta-analyses; heterogeneity was examined using I2 statistic. Findings: 113 studies were included comprising 376,159 PLHIV (20%, 44% and 5% women, men-who-have-sex-with-men; men-who-have-sex-with-women, respectively; 31% of studies did not stratify findings by gender and/or sexual orientation). PLHIV taking ART had lower HR-HPV prevalence compared to ART-naive (crude Odds Ratio[cOR]=0.65, 95%CI:0.54-0.79; I2=12%) and prolonged ART use was associated with a reduction in HR-HPV prevalence (per year: aOR=0.90, 95%CI:0.85-0.95, I2=0%). PLHIV with undetectable PVL had lower HSIL/AIN2+ prevalence compared to those without (cOR=0.84, 95%CI:0.72-0.99, I2=0%), particularly if sustained for >1 year (cOR=0.60, 95%CI:0.44-0.81, I2=2%). In 9 studies that included 141,877 PLHIV, there was some evidence that ART was associated with an increase in anal cancer incidence (adjusted Hazard Ratio[HR]=1.40, 95%CI:0.98-2.00, I2=0%) but ART users with sustained undetectable HIV had lower risk of anal cancer compared to those without (aHR=0.56, 95%CI:0.44-0.70, I2=0%). Per 100 cells/µl increase in nadir CD4+ count was associated with a decrease in anal cancer incidence (cHR=0.60, 95%CI:0.46-0.78, I2=22%). Interpretation: Effective ART use, evidenced by sustained undetectable HIV, and early initiation at higher nadir CD4+ reduce anal HR-HPV and anal cancer risk. Funding Statement: This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 79658. Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: This review is registered on the PROSPERO database at the Centre of Reviews and Dissemination, University of York; registration number CRD42018007271.