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Safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade cervical intraepithelial neoplasia associated with human papillomavirus: a systematic review protocol.

ABSTRACT: INTRODUCTION:Eighty per cent of the sexually active population will get human papillomavirus (HPV) infection, which is the most prevalent sexually transmitted disease worldwide. Persistence of high-grade HPV infection may evolve to a cervical intraepithelial neoplasia (CIN), and these lesions may be precursors of cervical cancer. However, this progression can be prevented by the administration of therapeutic vaccines which use the main oncoproteins responsible for cancer development in an attempt to trigger a more specific and effective immunological response against this disorder. We aim to evaluate the safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade CIN 2/3 associated with HPV. METHODS AND ANALYSIS:A systematic review of clinical trials will be undertaken. Medline, Excerpta Medica Database, Cochrane Central Register of Controlled Trials, Web of Science, Latin American and Caribbean Health Sciences Literature, Scientific Electronic Library Online and Scopus will be searched, with no restriction regarding publication date. Primary outcomes will include measures related to safety, efficacy and the immunogenicity of the therapeutic vaccines used in these patients. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methodological appraisal of the studies will be assessed by the Cochrane Risk-of-Bias Tool for randomised controlled trials, and the quality evidence of the risk of bias in single studies will be evaluated by Grading of Recommendations Assessment, Development and Evaluation. A narrative synthesis will be done for all included studies. Outcomes will be analysed according to the subgroups of HPV type, CIN grade, route of vaccine administration and vaccine type. Also, if sufficient data are available, a meta-analysis will be conducted. The effect sizes will be generated using Hedges' g score for both fixed and random effect models. I2 statistics will be used to assess heterogeneity and identify their potential sources. ETHICS AND DISSEMINATION:Ethical approval is not required as primary data will not be collected. Findings will be disseminated widely via peer-reviewed publication and in different media, for example, conferences, congresses or symposia. PROSPERO REGISTRATION NUMBER:CRD42017077428.

SUBMITTER: Goncalves CA

PROVIDER: S-EPMC6661674 | biostudies-other | 2019 Jul

REPOSITORIES: biostudies-other

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Safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade cervical intraepithelial neoplasia associated with human papillomavirus: a systematic review protocol.

Gonçalves Caroline Amélia CA Lopes-Júnior Luís Carlos LC Nampo Fernando Kenji FK Zilly Adriana A Mayer Paulo César Morales PCM Pereira-da-Silva Gabriela G

BMJ open 20190717 7

<h4>Introduction</h4>Eighty per cent of the sexually active population will get human papillomavirus (HPV) infection, which is the most prevalent sexually transmitted disease worldwide. Persistence of high-grade HPV infection may evolve to a cervical intraepithelial neoplasia (CIN), and these lesions may be precursors of cervical cancer. However, this progression can be prevented by the administration of therapeutic vaccines which use the main oncoproteins responsible for cancer development in a ...[more]

PMID: 31320349

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Project description:BACKGROUND: The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected. METHODS: Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (? 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58. RESULTS: Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2). CONCLUSIONS: Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.

Project description:Cervical intraepithelial neoplasia (CIN) is the premalignant condition of cervical cancer. Whereas not all high grade CIN lesions progress to cervical cancer, the natural history and risk of progression of individual lesions remain unpredictable. Therefore, high-grade CIN is currently treated by surgical excision: large loop excision of the transformation zone (LLETZ). This procedure has potential complications, such as acute haemorrhage, prolonged bleeding, infection and preterm birth in subsequent pregnancies. These complications could be prevented by development of a non-invasive treatment modality, such as topical imiquimod treatment. The primary study objective is to investigate the efficacy of topical imiquimod 5% cream for the treatment of high-grade CIN and to develop a biomarker profile to predict clinical response to imiquimod treatment. Secondary study objectives are to assess treatment side-effects, disease recurrence and quality of life during and after different treatment modalities.The study design is a randomized controlled trial. One hundred forty women with a histological diagnosis of high-grade CIN (CIN 2-3) will be randomized into two arms: imiquimod treatment during 16 weeks (experimental arm) or immediate LLETZ (standard care arm). Treatment efficacy will be evaluated by colposcopy with diagnostic biopsies at 20 weeks for the experimental arm. Successful imiquimod treatment is defined as regression to CIN 1 or less, successful LLETZ treatment is defined as PAP 1 after 6 months. Disease recurrence will be evaluated by cytology at 6, 12 and 24 months after treatment. Side-effects will be evaluated using a standardized report form. Quality of life will be evaluated using validated questionnaires at baseline, 20 weeks and 1 year after treatment. Biomarkers, reflecting both host and viral factors in the pathophysiology of CIN, will be tested at baseline with the aim of developing a predictive biomarker profile for the clinical response to imiquimod treatment.Treatment of high-grade CIN lesions with imiquimod in a selected patient population may diminish complications as a result of surgical intervention. More knowledge on treatment efficacy, side effects and long-term recurrence rates after treatment is necessary.EU Clinical Trials Register EU-CTR2013-001260-34 . Registered 18 March 2013. Medical Ethical Committee approval number: NL44336.068.13 (Medical Ethical Committee Maastricht University Hospital, University of Maastricht). Affiliation: Maastricht University Hospital. Registration number ClinicalTrials.gov: NCT02329171.

Dataset Information

Safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade cervical intraepithelial neoplasia associated with human papillomavirus: a systematic review protocol.

Publications

Safety, efficacy and immunogenicity of therapeutic vaccines in the treatment of patients with high-grade cervical intraepithelial neoplasia associated with human papillomavirus: a systematic review protocol.

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