High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease

Abstract

Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of 2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR 5 19.2, 95% CI 5 4.4-83.2) and single non-16 carcinogenic infections (OR 5 9.2, 95% CI 5 2.1-39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR 5 27.2, 95% 5 3.5-213.5) had a strong association between high viral load and incident CIN2; non-16 carcinogenic high viral load was not associated with incident CIN2 (OR 5 0.7, 95% CI 5 0.2-1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident CIN2 (OR 5 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent CIN2; however HPV16 was uniquely associated with incident CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident CIN2. ' 2007 Wiley-Liss, Inc.Key words: human papillomavirus; viral load; genotype; screening Human papillomaviruses (HPV) are the causal agent of invasive cervical cancer.1 Current screening guideline in the US incorporate HPV DNA testing of cervical samples to clarify equivocal Pap tests and as an adjunct to cytology in primary screening among women over age 30 years. A negative HPV test greatly reduces the risk of a cancer precursor. This allows women with equivocal cytology to return to the general screening pool and women 30-years and older with normal cytology and no high-risk HPV to extend their screening interval to 3 years. Although HPV testing is clinically useful, many women with self-limited carcinogenic HPV infections test positive and are subjected to unnecessary procedures. Therefore, identifying markers that indicate which HPV infections will persist and result in progression to cancer precursors is an important research objective.High concentration of HPV DNA in cervical specimens (HPV viral load) [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] has been evaluated as a marker for the presence of prevalent cervical cancer precursors (defined in the United States for treatment purposes as CIN2 or worse, CIN2) or incident CIN2. Following a typical infectio...

Is Human Papillomavirus Viral Load a Clinically Useful Predictive Marker? A Longitudinal Study

“…Therefore, it is impossible to predict from a single measurement, made at an indeterminate point during the natural history of that infection, what the viral load kinetics of that infection will be: An initially low viral load may be followed by a high viral load, and vice versa. This may explain, in part, the discrepant results reported by longitudinal studies, which relate the acquisition or the progression of cervical neoplasia to a single measurement of viral load made in a baseline sample (1)(2)(3)(4). Although our repeated observations allowed us to define the maximum HPV viral load attained during an episode of cervical HPV infection, even this single measurement was insufficient to distinguish those women who acquired an incident cervical cytologic abnormality from those who did not.…”

“…When viral load is measured using real-time quantitative PCR (qPCR) and normalized for specimen cellularity, longitudinal studies fail to reveal a consistent association between the viral load of cervical HPV infections and the risk of acquiring an epithelial abnormality of the cervix (1)(2)(3)(4). Program trials have concluded that a measurement of viral load provides little or no additional useful clinical information beyond that provided by cytologic examination or testing for the presence of high-risk HPV (1)(2)(3)(4)(5). However, in almost all of these studies, viral load is measured at a single point in time.…”

Viral Load of High-Risk Human Papillomaviruses as Reliable Clinical Predictor for the Presence of Cervical Lesions

“…HPV viral load has been proposed as a candidate, which potentially can discriminate significant from insignificant HPV infections. Viral load can be measured by a variety of methods, including the semiquantitative HC2 (7) and visual assessment of reverse line blot or dot blot signals (8), or truly quantitative singleplex or multiplex quantitative real-time PCR (qRT-PCR) (9,10). The majority of cross-sectional studies reported an association of increasing viral load with advancing disease severity, which was strongest for HPV16, but less strong or even absent for other Hr-HPV types (8)(9)(10)(11).…”

Human Papillomavirus in Cervical Cancer Screening: Important Role as Biomarker

“…This approach precludes cutoff values for high-grade CIN on the basis of high viral loads, as such limiting the clinical applicability of viral load analysis (35). A recent publication concludes that high viral load is associated with prevalent cervical cancer precursors for most HR-HPV genotypes, but only HPV16 load predicts the development of incident disease (66). HPV Integration.…”