This prospective study examined the influence of hrHPV genotypes on the regression rate. Further, potential interactions of hrHPV genotypes and clinical factors like age, interval between biopsy and cone excision, single or multiple hrHPV infections, number of sexual partners, age at first sexual intercourse, sexual activity span, parity, consistent condom use and smoking were evaluated.
The main finding was that consistent condom use significantly increased the regression rate in HPV16-, but not in hrHPV16+ lesions. Further, the number of sexual partners was higher and current smoking was more prevalent in hrHPV16+ than in hrHPV16- patients, with both differences reaching statistical significance both in univariate (Table
2) and multivariate analyses.
In the study population as a whole only consistent condom use was significantly associated with higher regression rates. However, the regression rate overall was not significantly different between hrHPV16+ and hrHPV16- patients.
HPV16 has been described as the genotype with the highest carcinogenic potential, the highest risk for progression to CIN3 and cervical cancer and the highest attribution to cervical cancer worldwide
[29, 34–36]. HPV16 infections also tend to last longer than infections caused by other hrHPV types
. However, the current study did not find a significantly lower regression rate in hrHPV16+ versus hrHPV16- patients, which is in line with previously published data
[18, 20, 37]. There was a relatively small (5%) difference in regression rate between the two hrHPV-genotype groups investigated in the current study. Based on a retrospective sample size calculation a study of 906 patients per group would be needed to detect this difference with a power of 80%.
A higher number of sexual partners in hrHPV16+ women has also been stated in other studies
[19, 38]. This could be explained by the fact that increased sexual contact with new partners increases the risk of being infected with HPV16 compared to other hrHPV genotypes, as HPV16 is the most frequent genotype
. A significant association between lower age at sexual debut and lower regression rate was found in hrHPV16- patients only.
Smoking is counted as a risk factor for CIN development
[6, 17, 39], but data on the effect of smoking in relation to HPV genotype are sparse. Previous studies have shown that cotinine and nicotine metabolites, which potentially have mutagenous effects on the cervical epithelium, accumulate in the cervical mucus of active cigarette smokers
[40, 41]. As current smoking was more prevalent among hrHPV16+ patients, smoking could potentiate the mutagenic effects of hrHPV16 resulting in an increased risk of developing CIN. Another potential explanation for the higher prevalence of smokers among hrHPV16+ patients is the association of smoking as a lifestyle combined with a higher-risk sexual behavior
. Both more sexual partners and smokers among hrHPV16+ patients could indicate that these risk factors are related to lifestyle.
Data indicate that condom use can have a positive effect on CIN regression
[33, 37]. Condom use reduces the repeated exposure of the cervical mucosa to HPV and the directly immunosuppressive effect of semen on the cervical epithelium. These factors strengthen the local immune system against the HPV infection and may promote CIN regression
[43, 44]. Another interesting hypothesis is that the latex of the condoms stimulates a general immune response, which might be beneficial in the clearance of HPV.
In hrHPV16- patients consistent condom use increased the regression rate significantly compared to none condom users. Additionally, age >15 years at first sexual intercourse was associated with a significantly higher likelihood of regression. None of the examined clinical factors had any significant effect on the regression rate in hrHPV16+ patients. This underlines the heterogeneity among hrHPV genotypes and that hrHPV16+ CIN lesions may behave differently compared to other hrHPV genotypes. HrHPV16+ lesions seem to be less susceptible to cofactors related to sexual behavior and consistent condom use.
Heterogeneity of high-grade CIN related to HPV16 has previously been described in a study by Wentzensen et al., which showed that hrHPV16+ lesions were associated with lower mean age, worse colposcopic appearance and a higher number of lifetime sexual partners compared to hrHPV16- lesions
As consistent condom use does not seem to affect regression rate of hrHPV16+ CIN lesions in contrast to hrHPV16- lesions, the behaviour and character of HPV16 and the subsequent immune reaction could be different compared to non-HPV16 high-risk genotypes. Recent studies have shown interesting results comparing epithelial and immune biomarkers in HPV16+ lesions versus HPV16- CIN2-3 lesions in relation to regression or not
[13, 20, 45].
A better understanding of the different behaviour of HPV genotypes could contribute to a more individualized follow-up and treatment of CIN2-3 patients than today’s standard treatment with cone excision of all CIN2-3 lesions.
Consistent use of condoms by the male partners of the women as contraception was rather infrequent. However, the current results showing that consistent condom use by sexual intercourse increases the chances for regression significantly with an odds ratio of 19 in hrHPV16- lesions, could motivate a substantial proportion of women and their partners to use condoms for a limited time period.
The strength of the current study is the prospective design and the histological definition of CIN regression. The study population was relatively homogenous due to the inclusion criterion of age between 25 and 40 and the standardized interval between biopsy and cone excision. Additionally, both CIN2/CIN3 and consistent condom use was equally distributed across the two HPV groups. All 145 patients had hrHPV positive DNA in the punch biopsies by LA. This strengthens the diagnosis of the current biopsies, and ensures the genotype of the actual HPV infection. Stavanger University Hospital is the only hospital in the region, making this a population-based cohort study with low selection bias.
The observational period of the study, however, was relatively short in relation to the natural history of CIN. On the other hand, a longer observational period of high-grade CIN regression with the risk of progression could not have been justified at the start of the study. With current data new trials with a longer interval between punch biopsy and cone excision are acceptable in women under 40 years of age with a first time onset CIN2-3 lesion. Further, the sample size is rather moderate, which limits the separate interpretation of clinical factors in each group.