Longitudinal Study of Human Papillomavirus Persistence and Cervical Intraepithelial Neoplasia Grade 2/3: Critical Role of Duration of Infection

Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, Torre La Sabana, 7mo piso, Sabana Norte, San José 10203, Costa Rica.
Journal of the National Cancer Institute (Impact Factor: 12.58). 02/2010; 102(5):315-24. DOI: 10.1093/jnci/djq001
Source: PubMed


The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women's age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease.
At enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5-7 years (passively followed), whereas higher-risk participants (n = 2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction-based method. We determined, by four age groups (18-25, 26-33, 34-41, and > or =42 years), the proportion of prevalent infections (found at baseline) and newly detected infections (first found during follow-up) that persisted at successive 1-year time points and calculated absolute risks of CIN 2 and CIN grade 3 (CIN 3) or worse during follow-up. P values are two-sided.
Regardless of the woman's age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease. For newly detected infections, the rate of progression to CIN 2+ (or CIN 3+), after 3 years of follow-up, was not higher for women aged 34 years and older than for younger women. Moreover, rates of newly detected infections declined sharply with age (in the actively followed group, at ages 18-25, 26-33, 34-41, and > or =42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P < .001). Among prevalent infections, persistent infections among older women (> or =42 years) was higher than that among younger age groups or new infections at any age (P < .01 for comparison of eight groups). Most (66 of 85) CIN 2 or worse detected during follow-up was associated with prevalent infections. Only a small subset (25 of 1128) of prevalent infections persisted throughout follow-up without apparent CIN 2 or worse.
The rate of new infections declines with age, and new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low.

Download full-text


Available from: Robert D Burk, May 19, 2014
451 Reads
  • Source
    • "In our study, the average age at menopause was lower than that of general population (average age, 48.3 versus 52). In the general population, persistence of HPV infection is higher in women who are 42 or older when compared to younger women [28, 29] and the prevalence of high grade cervical dysplasia and cancer increases with age [29, 30]. Considering that there were only small numbers of high grade SILs in our study, we were not able to assess whether high grade cervical lesions are statistically more prevalent in older HIV-infected women. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: More HIV-infected women are reaching older age and menopause, but there is limited information on cervical squamous intraepithelial lesions (SILs) on these women. Methods: To assess the effect of HAART and menopause on SILs in HIV-infected women, we reviewed the results of Papanicolaou (Pap) tests obtained between 1991 and 2011 on 245 women. Progression to SILs was determined by comparing Pap test results. The association of HAART and transition to menopause on SILs was assessed using survival analysis. Results: Women receiving HAART had a 52% reduced risk in the progression to SILs compared to women receiving any other antiretroviral regimen or no regimen (CI: 0.33-0.70, P = 0.0001). A greater increase of CD4(+) cell counts was associated with a greater reduction on the risk of progression to SILs. Menopausal women had a 70% higher risk of progression to SILs than premenopausal women (CI: 1.11-2.62, P < 0.0001), adjusting for HIV medications, CD4(+) count, duration of HIV infection, moderation effect of menopause by age, prior IV drug use, and smoking. Conclusion: HAART had a positive long-term effect on the progression to SILs. However, being younger and menopausal increases the risk of progression.
    Infectious Diseases in Obstetrics and Gynecology 12/2013; 2013:784718. DOI:10.1155/2013/784718
  • Source
    • "In the subsequent age-classes, the prevalence declined and stabilized. These results are supported by substantial data that indicate that the first HPV infections often occur soon after the first sexual intercourse [50-53]. In our adolescent group (16–17 years old), the prevalence of low-risk HPV infections was higher than that of probable/possible risk and high-risk HPV genotypes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human Papillomavirus (HPV) is the most common sexually transmitted infection. In Italy, HPV vaccination is now offered free of charge to 12-year-old females. However, some regional health authorities have extended free vaccination to other age-groups, especially to girls under 18 years of age. We conducted a multicentre epidemiological study to ascertain the prevalence of different genotypes of HPV in young Italian women with normal cytology, with the aim of evaluating the possibility of extending vaccination to older females. The study was performed in 2010. Women aged 16-26 years with normal cytology were studied. Cervical samples were analyzed to identify the presence of HPV by PCR amplification of a segment of ORF L1 (450 bp). All positive HPV-DNA samples underwent viral genotype analysis by means of a restriction fragment length polymorphism assay. Positivity for at least one HPV genotype was found in 18.2% of the 566 women recruited: 48.1% in the 16-17 age-class, 15.4 in the 18-20 age-class, 21.9% in the 21-23 age-class, and 15.5% in the 24-26 age-class; 10.1% of women were infected by at least one high-risk HPV genotype. HPV-16 was the most prevalent genotype. Only 4 (0.7%), 4 (0.7%) and 3 (0.5%) women were infected by HPV-18, HPV-6 and HPV-11, respectively. Of the HPV-DNA-positive women, 64.1% presented only one viral genotype, while 24.3% had multiple infections. The HPV genotypes most often involved in multiple infections were high-risk. A high prevalence was noted in the first years of sexual activity (48.1% of HPV-DNA-positive women aged 16-17 years); HPV prevalence subsequently declined and stabilized.The estimate of cumulative proportions of young women free from any HPV infection at each age was evaluated; 93.3% and 97.1% of 26 year-old women proved free from HPV-16 and/or HPV-18 and from HPV-6 and/or HPV-11, respectively. Our findings confirm the crucial importance of conducting studies on women without cytological damage, in order to optimise and up-date preventive interventions against HPV infection, and suggest that vaccinating 26-year-old females at the time of their first pap-test is to be recommend, though this issue should be further explored.
    BMC Infectious Diseases 12/2013; 13(1):575. DOI:10.1186/1471-2334-13-575 · 2.61 Impact Factor
  • Source
    • "of screen-detected HPV infections represent persistent HPV infections. However, it should be noted that some HPV types will never cause neoplastic progression, even if they do persist (Schiffman et al, 2005; Rodriguez et al, 2010). HPV DNA testing has emerged as a highly sensitive screening test that can detect cervical precancerous lesions earlier than cytology (Naucler et al, 2007; Sargent et al, 2010; Rijkaart et al, 2012a). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Large-scale data on type-specific HPV prevalences and disease burden are needed to monitor the impact of HPV vaccination and to plan for HPV-based cervical screening. Methods: 33 043 women (aged 25–65) were screened for HPV by a Hybrid Capture 2 (HC2) in a population-based programme. HPV-positive women (n=2574) were triaged by cytology and HPV genotyped using PCR-Luminex. Type-specific prevalence of HPV infection and its correlation to findings in cytology triage and histology as well as Population Attributable Fractions for a referral to colposcopy and findings in histology were calculated. Results: Among HC2-positive women, 61.5% had normal, 23.1% had ASC-US and 15.5% had LSIL or more severe (LSIL+) results in cytology. Out of HC2-positive samples, 57% contained the 13 Group 1/2A HPV types, which were targeted by the HC2, 15% contained Group 2B types, 8.5% Group 3 types and 30% were found to be negative in HPV genotyping. The proportion of samples positive for HPV by the HC2, but negative in HPV genotyping increased with age and decreased with increasing cytological abnormality. The most frequent types were HPV 16 (0.9% of screened women and 12.1% of the HC2-positive women), HPV 31 (0.7% and 8.9%, respectively) and HPV 52 (0.5% and 6.3%, respectively). The prevalence of Group 1/2A HPV types increased with increasing CIN grade and attributed 78.3% (95% CI 53.4–89.9) of the CIN 3+ lesions, while HPV 16 attributed 55.8% (40.0–67.5) of them. Conclusion: The type-specific prevalence of HPV were slightly lower than the average in international meta-analyses. Genotyping for HPV 16 better identified women with CIN 3+ than cytology triage at the threshold of LSIL+. The high proportion of women that were HC2-positive but HPV-negative in genotyping suggests that HPV genotyping may be useful also for validation of results in HPV screening. The large-scale HPV genotyping data were found to be directly useful for planning further preventive efforts for cervical cancer.
    British Journal of Cancer 10/2013; 109(11). DOI:10.1038/bjc.2013.647 · 4.84 Impact Factor
Show more