Low‐level persistence of human papillomavirus 16 DNA in a cohort of closely followed adolescent women

Abstract

Most human papillomavirus (HPV) infections in young women become undetectable by standard assays after a few months. It is possible that many HPV infections do not actually clear, but persist at very low levels for years, becoming detected again later in life. The purpose of this study is to describe HPV 16 clearance, reappearance, and low-level persistence in a cohort of adolescent women. Adolescent women (N = 66), not vaccinated against HPV, were recruited from 1998 to 2008 into a longitudinal study. Self-collected vaginal samples were obtained quarterly and tested for HPV by Linear Array HPV Genotyping Test (LA-HPV). To explore low-level persistence, a type-specific nested PCR for HPV 16 (TSN-PCR-16) was developed. Women with HPV 16 detected by LA-HPV had their negative swabs retested with TSN-PCR-16. Forty-two participants with HPV 16, followed for a mean of 6.3 years, were analyzed. Using LA-HPV, the median duration of HPV 16 detection was 428 days (SD 852.5 days). TSN-PCR-16 detected HPV 16 during periods of LA-HPV non-detection in samples from many women. Using a combination of LA-HPV and TSN-PCR-16 results, the median duration of HPV 16 detection was 1,022.5 days (SD 943.7 days). The durations of detection differed significantly between the two methods (P = 0.0042) with a mean difference of 434.5 days. In adolescent females, duration of HPV 16 detection was significantly longer when TSN-PCR-16 was combined with LA-HPV. Some apparently cleared HPV 16 could be shown to persist at low levels using nested PCR.

Human Papillomavirus Laboratory Testing: the Changing Paradigm

“…HPV infections are common, and it is estimated that approximately 75% to 80% of sexually active individuals will become infected in their lifetime (88,89). Most women become infected shortly after becoming sexually active, and the highest prevalence is seen in women under age 25.…”

“…Most women become infected shortly after becoming sexually active, and the highest prevalence is seen in women under age 25. Common risk factors for HPV infection in young women include earlier age of onset of sexual activity, two or more sexual partners in the previous year, and coinfection with Chlamydia trachomatis, herpes simplex virus, or bacterial vaginosis (89,90). Cross-sectional studies indicate a second peak of infection in women aged 35 to 54 years, which corresponds to the age of highest incidence of cervical cancer.…”

“…HPV infections in adolescents and young and middle-aged women are usually transient, at least when duration is measured by how long the virus can be detected in cervical cytology specimens using molecular tests. Up to half of adolescents and young to middle-aged women who develop an incident infection will clear the infection within 6 months, and 70 to 90% will clear within 12 to 30 months (89,94). Large-cohort studies with follow-up of up to 15 years have shown that once cleared, as measured by one or two negative HPV molecular tests, there is a very low risk of risk of subsequent carcinoma (76).…”

Characterizing the Temporal Dynamics of Human Papillomavirus DNA Detectability Using Short-Interval Sampling

“…Several recent studies using highly sensitive PCR-based tests to measure HPV DNA have reported that recurrent detection of an HPV type after a period of non-detection is common, ranging from around 8% to 19.4% (1–3). Weaver, et al, reported that samples testing HPV16 negative in between runs of HPV16 DNA positivity by standard consensus primer PCR (linear array, LA) were found to be HPV16 positive when more sensitive type-specific amplification assays were used, suggesting that recurrent detection is more likely to represent viral load fluctuations of a persistent infection or periods of latency and reactivation, rather than re-infection of a previously cleared viral type (4). …”

Significance of “Not Detected but Amplified” Results by Real-Time PCR Method for HPV DNA Detection

“…Alternatively, low level persistence may signify containment of HPV-infected cells by cellular immunity resulting in a small lesion that may be difficult to adequately sample by standard methods. Therefore, the clinical significance of low level persistent infection of HPV and the appropriate interpretation of low level HPV DNA existence become more important [21]. …”