Persistence and clearance of human papillomavirus infection: a prospective cohort study

doi:10.1016/j.ajog.2008.06.033

American Journal of Obstetrics and Gynecology

Volume 199, Issue 6, December 2008, Pages 617.e1-617.e7

https://doi.org/10.1016/j.ajog.2008.06.033 Get rights and content

Objective

The objective of the study was to identify epidemiological correlates for persistence and clearance of human papillomavirus (HPV) infection.

Study Design

Cervical smears collected in a prospective cohort study to perform Papanicoloau cytology and HPV deoxyribonucleic acid (DNA) detection at baseline and during the follow-up. Outcomes analyzed were: (1) persistence of HPV DNA; (2) conversion; and (3) clearance of HPV.

Results

Among 501 women the incidence of HPV was 12.3%. Thirty-four women were persistently infected with HPV, which was associated with age below 21 years at first intercourse and 4 or more sexual partners during their lifetime. In a median of 19 months, 80.7% of women had clearance of HPV, which was associated with black race, coinfection with Chlamydia trachomatis at baseline, and a history of previous Papanicoloau smear.

Conclusion

Strategies for sexual orientation may modify the rates of HPV persistence. The association of HPV clearance with a history of previous Papanicolaou smear screening highlights the importance of improving cervical screening programs. Further studies on the association of gynecological infections with HPV clearance are needed.

Section snippets

Study design and population

A cohort study was started on February 2003 to explore potential risk factors for persistence and clearance of cervical HPV infection. Persistence of HPV was defined as the presence of the same oncogenic type of HPV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) at baseline and at follow-up. Lifestyle, behavioral, and reproductive factors were investigated.

The study population was defined as asymptomatic women attending a primary care clinic in the city of Porto Alegre in

Characteristics of the cohort

Until February 2006, 1500 asymptomatic women who attended a primary care clinic in Porto Alegre in southern Brazil were consecutively enrolled in a cohort study that originated the present study sample. All participants signed a consent form before entering the study. A total of 69 women who did not reach the eligibility criteria were excluded from the cohort. From the remaining 1431 participants, the overall prevalence of HPV DNA was 24.6% (352/1431) at entrance.

The present study sample

Comment

We found HPV16 as the most frequent HPV subtype causing infection in cervical smears. Our results are in accordance with the literature, in which a worldwide report showed that HPV16 was 2 times more common than other subtypes in all regions of the world, with the exception on sub-Saharan Africa, where HPV35 is equally common, but 4-5 times less prevalent than HPV16 in other regions.²¹ In Brazil, HPV16 is also the predominant subtype recovered from invasive cervical cancer.22, 23, 24, 25, 26

Acknowledgment

The authors wish to thank Professor Álvaro Vigo for the statistical support given for this work.

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Human papilloma virus (HPV) infections are associated with almost all cervical cancers and to a lower extend also with anogenital or oropharyngeal cancers. HPV proteins expressed in HPV-associated tumors are attractive antigens for cancer vaccination strategies as self-tolerance, which is associated with most endogenous tumor-associated antigens, does not need to be overcome. In this study, we generated a live attenuated cancer vaccine based on the chimeric vesicular stomatitis virus VSV-GP, which has previously proven to be a potent vaccine vector and oncolytic virus. Genes at an earlier position in the genome more to the 3′ end are expressed stronger compared to genes located further downstream. By inserting an HPV16-derived antigen cassette consisting of E2, E6 and E7 into VSV-GP either at first (HPVp1) or fifth (HPVp5) position in VSV-GP’s genome we aimed to analyze the effect of vaccine antigen position and consequently expression level on viral fitness, immunogenicity, and anti-tumoral efficacy in a syngeneic mouse tumor model. HPVp1 expressed higher amounts of HPV antigens compared to HPVp5 in vitro but had a slightly delayed replication kinetic which overall translated into increased HPV-specific T cell responses upon vaccination of mice. Immunization with both vectors protected mice in prophylactic and in therapeutic TC-1 tumor models with HPVp1 being more effective in the prophylactic setting. Taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine and first position of the vaccine antigen in a VSV-derived vector seems to be superior to fifth position.
Immunoinformatics-based characterization of immunogenic CD8 T-cell epitopes for a broad-spectrum cell-mediated immunity against high-risk human papillomavirus infection
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Human papillomavirus (HPV) represents the most prevalent sexually transmitted infectious agent worldwide. Vaccination has been an approach successfully used as a prophylactic measure against this infectious agent in patients without previous contact with the genotypes present in the vaccine. In this work, we use a computational approach to predict CD8 T cell epitopes from HPV proteins to promote cell-mediated immunity. We evaluated immunogenicity, conservation, toxicity, stability and population coverage of epitopes. Finally, a molecular docking analysis was performed to confirm the stability of the complexes formed. We identified 17 epitopes with affinity for several HLA alleles, covering 5 binding supermotifs (A2, A3, A24, B62 and B57). The analyses showed that these epitopes have a high population coverage and are highly conserved among several HPV genotypes. Seven of them (NWKNFFSTTW_E1594-603, KVSAFQYRVFRV_L163-74, LQFIFQLCK_L1372-380, RVFRVQLPDPNK_L170-81, FNKPYWLHR_L1307-315, FITCVDTTR_L1330-338 and HLRREQIFAR_L1248-257) were 100% conserved. Finally, molecular docking confirmed the stability of the complexes by means of a large network of hydrogen bonds formed and the calculated low bonding energy. The epitopes identified in this study are potential candidates as components of therapeutic vaccines and we suggest that these epitopes can be used in future studies aiming to activate antigen-specific CD8 T cells.
Diversity of human papillomavirus typing among women population living in rural and remote areas of Brazilian territory
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Citation Excerpt :
The general positivity for high-risk HPV reported in this current study was 10.6%: 11.5% observed in the casuistic of cases collected at the Prevention Department of HCB and 10% detected in women examined at mobile units, respectively. Data documented by other Brazilian studies showed positive rates ranging from 9.7% to 10.5% [13–17]. Recently, Torres and colleagues reported HPV-DNA frequency of 19.1% in women of remote areas of the Amazon, a region reputed as the site with the highest indexes of HPV prevalence in the Brazilian territory [18].
Genotyping HPV from samples tested positive to careHPV™ assay in rural and remote areas of Brazilian territory.
A total of 5079 women were enrolled in an opportunistic screening from the Barretos Cancer Hospital, through mobile units or ambulatory unit. All careHPV™ hr-HPV positive samples were tested by a Luminex-based protocol in order to evaluate the HPV infecting types.
Positive hr-HPV results were obtained in 10.6% (536/5068) of women. Among these cases, HPV-56 and HPV-51 were the most common types detected in 32.3% and 31.4%, respectively. HPV-53 (20.5%), HPV-18 (18.5%), HPV-58 (17.6%), HPV-52 (16.0%) and HPV-16.6%) were the other most frequent types detected. These frequencies represent prevalences of 2.35%, 2.12%, 2.02%, 1.84% and 1.80% respectively, within the population studied. Regarding low-risk HPVs, HPV-6 was detected in 12.9% of the samples. The less frequent types (<3%) were: HPV-70, HPV-11 and HPV-26.
The most frequent types detected were: HPV-56, HPV-51, HPV-53, HPV-18, HPV-58, HPV-52 and HPV-16 according to decreasing rates.
Therapeutic vaccines for high-risk HPV-associated diseases
2018, Papillomavirus Research
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Maturation of virions occurs after terminal differentiation of epithelial cells, and their release coincides with natural shedding of senescent cells at the end of the epithelial cell life cycle [9]. Most infections are cleared by the immune system [17,18]; however, some benign cervical lesions progress to cancer. Continuous infection results in low-grade CIN 1 lesions.
Cancer is the second leading cause of death worldwide, and it is estimated that Human papillomavirus (HPV) related cancers account for 5% of all human cancers. Current HPV vaccines are extremely effective at preventing infection and neoplastic disease; however, they are prophylactic and do not clear established infections. Therapeutic vaccines which trigger cell-mediated immune responses for the treatment of established infections and malignancies are therefore required. The E6 and E7 early genes are ideal targets for vaccine therapy due to their role in disruption of the cell cycle and their constitutive expression in premalignant and malignant tissues. Several strategies have been investigated for the development of therapeutic vaccines, including live-vector, nucleic acid, peptide, protein-based and cell-based vaccines as well as combinatorial approaches, with several vaccine candidates progressing to clinical trials. With the current understanding of the HPV life cycle, molecular mechanisms of infection, carcinogenesis, tumour biology, the tumour microenvironment and immune response mechanisms, an approved HPV therapeutic vaccine seems to be a goal not far from being achieved. In this article, the status of therapeutic HPV vaccines in clinical trials are reviewed, and the potential for plant-based vaccine production platforms described.
Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota
2017, Mucosal Immunology
Cervical human papillomavirus (HPV) infection may increase HIV risk. Since other genital infections enhance HIV susceptibility by inducing inflammation, we assessed the impact of HPV infection and clearance on genital immunology and the cervico-vaginal microbiome. Genital samples were collected from 65 women for HPV testing, immune studies and microbiota assessment; repeat HPV testing was performed after 6 months. All participants were HIV-uninfected and free of bacterial STIs. Cytobrush-derived T cell and dendritic cell subsets were assessed by multiparameter flow cytometry. Undiluted cervico-vaginal secretions were used to determine cytokine levels by multiplex ELISA, and to assess bacterial community composition and structure by 16S rRNA gene sequence analysis. Neither HPV infection nor clearance were associated with broad differences in cervical T cell subsets or cytokines, although HPV clearance was associated with increased Langerhans cells and HPV infection with elevated IP-10 and MIG. Individuals with HPV more frequently had a high diversity cervico-vaginal microbiome (community state type IV) and were less likely to have an L. gasseri predominant microbiome. In summary, HPV infection and/or subsequent clearance was not associated with inflammation or altered cervical T cell subsets, but associations with increased Langerhans cells and the composition of the vaginal microbiome warrant further exploration.
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For ages 25 to 33 years, we eliminated four strategies that did not fall on either efficiency frontier, while one strategy was efficient with respect to both efficiency metrics. Compared with current practice in Norway, two strategies detected more precancers at lower monetary costs, but some required more colposcopies. Similar results were found for women aged 34 to 69 years.
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View all citing articles on Scopus

: Cite this article as: Rosa MI, Fachel JMG, Rosa DD, et al. Persistence and clearance of human papillomavirus infection: a prospective cohort study. Am J Obstet Gynecol 2008;199:617.e1-617.e7.

: This study was supported by the National Council of Scientific and Technological Development (CNPq), Brazil. M.C.B. is the recipient of a research award from the CNPq.

View full text

ResearchGeneral gynecologyPersistence and clearance of human papillomavirus infection: a prospective cohort study

Objective

Study Design

Results

Conclusion

Section snippets

Study design and population

Characteristics of the cohort

Comment

Acknowledgment

Lancet Oncol

Lancet

Lancet

Virus Res

Res Microbiol

Lancet

J Infect

Lancet

Eur J Obstet Gynecol Reprod Biol

Eur J Cancer

Adv Cancer Res

Human papillomavirus is a necessary cause of invasive cervical cancer worldwide

J Pathol

Cancer facts and figures 2007

Estimativa 2006—incidência de câncer no Brasil

Natural history of cervicovaginal papillomavirus infection in young women

N Engl J Med

Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer

J Infect Dis

HPV co-factors related to the development of cervical cancer: results from a population-based study in Costa Rica

Br J Cancer

Chapter 4: Genital tract infections, cervical inflammation, and antioxidant nutrients—assessing their roles as human papillomavirus cofactors

J Natl Cancer Inst Monogr

The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii

Cancer Epidemiol Biomarkers Prev

Multifactorial etiology of cervical cancer: a hypothesis

Med Gen Med

Role of different etiological factors in progression of cervical intraepithelial neoplasia

Diagn Cytopathol

Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia

JAMA

Determinants of genital human papillomavirus infection in low-risk women in Portland, Oregon

Sex Transm Dis

Use of PGMY primers in L1 consensus PCR improves detection of human papillomavirus DNA in genital samples

J Clin Microbiol

PCR assessment of Chlamydia trachomatis infection of semen specimens processed for artificial insemination

J Clin Microbiol

Interpreting multinomial logistic regression

Stata Tech Bull

Research
General gynecology
Persistence and clearance of human papillomavirus infection: a prospective cohort study