Long-term Persistence of Oral HPV Over 7 Years of Follow-up

Abstract

Background: Human papillomavirus-related oropharyngeal cancer (HPV-OPC) incidence is increasing, but the natural history of the precursor-oral HPV-has not been well described.

Methods: This observational cohort study of people living with HIV and at-risk HIV uninfected people evaluated participants semiannually using 30-second oral rinse and gargle specimens over 7 years. Initially, 447 participants were followed for 4 years as part of the Persistent Oral Papillomavirus Study, and a subset of 128 who showed persistent infections at the last Persistent Oral Papillomavirus Study visit had an additional visit, as part of the Men and Women Understanding Throat HPV Study, on average 2.5 years later. Extracted DNA from oral rinse and gargle specimens was amplified using polymerase chain reaction and type specification of 13 oncogenic HPV types. Risk factors for oncogenic oral HPV clearance were evaluated using Cox models.

Results: The majority of oncogenic oral HPV infections cleared quickly, with a median time to clearance of 1.4 years (interquartile range = 0.5-3.9 years). After 7 years of follow-up, 97% of incident and 71% of prevalent infections had cleared. Lower HPV-16 viral load was statistically significantly associated with clearance (per 10-fold decrease in copy number: adjusted hazard ratio [aHR] = 2.51, 95% confidence interval [CI] = 1.20 to 5.26; P = .01). Adjusted analyses showed that oncogenic oral HPV clearance was lower among prevalent than incident-detected infections (aHR = 0.44, 95% CI = 0.35 to 0.55), among men than women (aHR = 0.74, 95% CI = 0.60 to 0.91), for older participants (aHR per 10 years increasing age = 0.81, 95% CI = 0.74 to 0.89), and among people living with HIV (aHR = 0.76, 95% CI = 0.60 to 0.95). One participant who had oral HPV-16 consistently detected at 10 study visits over 4.5 years was subsequently diagnosed with HPV-OPC.

Conclusions: This prospective study of oncogenic oral HPV infection is the longest and largest quantification of oral HPV-16 infections to date.

Figure 1.

A total of 447 Multicenter AIDS Cohort Study and Women’s Interagency HIV Study cohort study participants with 676 oncogenic oral human papillomavirus (HPV) infection. The Persistent Oral Papillomavirus Study (POPS) was from 2009 to 2015 and Men and Women Understanding Throat HPV (MOUTH) study visit included data collected from 2017 to 2018. The blue dots represent study visits that occurred at 6-month intervals during the POPS study. There was a lapse between POPS and MOUTH symbolized by the absence of dots. During the MOUTH study there was a one-time visit, which ranged between October 2017 and September 2018.

Figure 2.

Time to clearance of any oncogenic human papillomavirus among 676 infections in the 447 Multicenter AIDS Cohort Study/Women’s Interagency HIV Study participants enrolled in the Persistent Oral Papillomavirus Study and/or Men and Women Understanding Throat HPV study overall. Color band indicates the 95% confidence interval.

Figure 3.

Time to clearance of any oncogenic human papillomavirus (HPV) among 676 infections in the 447 Multicenter AIDS Cohort Study/Women’s Interagency HIV Study participants enrolled in the Persistent Oral Papillomavirus Study and/or Men and Women Understanding Throat HPV study by risk factor. By infection characteristics (prevalent vs incident: panel A); HPV-16 vs non-16 oncogenic HPV type (panel B); demographic characteristics (men vs women: panel C); and age (panel D). CI = confidence interval.

Figure 4.

Oral HPV-16 viral load across study visits, among participants with persistent and cleared infections. Each row is a distinct subject in the study who had oral HPV-16 DNA detected. Semi-quantitative signal intensity depicted by color as follows: strong (dark red), medium (red), weak (pink), and negative (white with -). Gray represents visits with no oral rinse sample collection. The asterisk (*) denotes the subject diagnosed with HPV-OPC. The figure is restricted to participants with at least 4 oral rinse samples tested. Participants joined the study at variable times. Oral rinse results are shown by calendar visit, labeled “V1” for the first biannual visit. Gray represents visits where oral rinse sample was not collected or tested (this includes visits before substudy enrollment for those who entered later, as well as some missed visits, and visits after study completion). Men and Women Understanding Throat HPV baseline study visit labeled “M.” HPV = human papillomavirus.