Risk factors contributing to the persistent infection of high-risk Human papillomavirus (HPV)

Human papillomavirus (HPV) infection in the reproductive tract is one of the most prevalent sexually transmitted infections worldwide. Persistent infection with high-risk HPV (HR-HPV) types is a major contributor of cervical cancer and its precancerous lesions. The severity and progression of these lesions are closely linked to multiple HPV infections and viral load. Emerging research indicates that the persistence of HR-HPV infection is influenced not only by viral genetic mutations and trait variations but also by host immune response and genetic factors. Investigations into these risk factors are gaining momentum and hold promise for breakthroughs in the diagnosis and identification of prognostic markers for cervical cancer. This review provides a comprehensive overview of recent advancements in this field.

Human papillomavirus; Cervical cancer; Persistent infection

[1] Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. Journal of the National Cancer Institute. 2008; 100: 513–517.

[2] Trottier H, Franco EL. The epidemiology of genital human papillomavirus infection. Vaccine. 2006; 24: S1–S15.

[3] Bekkers RL, Massuger LF, Bulten J, Melchers WJ. Epidemiological and clinical aspects of human papillomavirus detection in the prevention of cervical cancer. Reviews in Medical Virology. 2004; 14: 95–105.

[4] Shi R, Devarakonda S, Liu L, Taylor H, Mills G. Factors associated with genital human papillomavirus infection among adult females in the United States, NHANES 2007-2010. BMC Research Notes. 2014; 7: 544.

[5] Zeeshan M, Khan AM, Sibgatullah M, Jayesh, Lanke RB, Ramanarayana B, et al. To determine the role of human papillomavirus in oral cancer—a prospective study. Journal of Pharmacy and Bioallied Sciences. 2025; 16: S3218–S3220.

[6] Tao H, Yu F, Yang L, Pei X, Mao S, Fan X. Comparing the performance of DeoxyriboNucleic Acid methylation analysis and cytology for detecting cervical (pre)cancer in women with high-risk human papillomavirus-positive status in a gynecologic outpatient population. BMC Cancer. 2024; 24: 1352.

[7] Burd EM. Human papillomavirus and cervical cancer. Clinical Microbiology Reviews. 2003; 16: 1–17.

[8] Damasus-Awatai G, Freeman-Wang T. Human papilloma virus and cervical screening. Current Opinion in Obstetrics and Gynecology. 2003; 15: 473–477.

[9] Lei J, Cuschieri K, Patel H, Lawrence A, Deats K; YouScreen trial team; Sasieni P, Lim AWW. Human papillomavirus genotype and cycle threshold value from self-samples and risk of high-grade cervical lesions: a post hoc analysis of a modified stepped-wedge implementation feasibility trial. PLOS Medicine. 2024; 21: e1004494.

[10] Dalstein V, Riethmuller D, Prétet JL, Le Bail Carval K, Sautière JL, Carbillet JP, et al. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. International Journal of Cancer. 2003; 106: 396–403.

[11] Den X, Yang Y, Pang X, Wen X, Dai Z. Prevalence and cognitive factors influencing high-risk HPV infection and cervical diseases in women aged 18–45 in Shijiazhuang city. Medicine. 2025; 104: e41436.

[12] Li F, Chen A, Shan Y, Yao Y, Lu P, Li N, et al. Factors associated with human papillomavirus persistence after loop electrosurgical excision procedure in patients with cervical squamous intraepithelial lesion. Journal of Obstetrics and Gynaecology Research. 2024; 50: 639–646.

[13] Hajia M, Sohrabi A. Possible synergistic interactions among multiple HPV genotypes in women suffering from genital neoplasia. Asian Pacific Journal of Cancer Prevention. 2018; 19: 785–789.

[14] Wang W, Zhang XH, Li M, Hao CH, Zhao ZM, Liang HP. Association between viral loads of different oncogenic human papillomavirus types and the degree of cervical lesions in the progression of cervical cancer. Clinica Chimica Acta. 2018; 483: 249–255.

[15] Schellekens MC, Dijkman A, Aziz MF, Siregar B, Cornain S, Kolkman-Uljee S, et al. Prevalence of single and multiple HPV types in cervical carcinomas in Jakarta, Indonesia. Gynecologic Oncology. 2004; 93: 49–53.

[16] Swan DC, Tucker RA, Tortolero-Luna G, Mitchell MF, Wideroff L, Unger ER, et al. Human papillomavirus (HPV) DNA copy number is dependent on grade of cervical disease and HPV type. Journal of Clinical Microbiology. 1999; 37: 1030–1034.

[17] Sun CA, Liu JF, Wu DM, Nieh S, Yu CP, Chu TY. Viral load of high-risk human papillomavirus in cervical squamous intraepithelial lesions. International Journal of Gynecology & Obstetrics. 2002; 76: 41–47.

[18] Josefsson AM, Magnusson PK, Ylitalo N, Sørensen P, Qwarforth-Tubbin P, Andersen PK, et al. Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study. The Lancet. 2000; 355: 2189–2193.

[19] Ylitalo N, Sørensen P, Josefsson AM, Magnusson PK, Andersen PK, Pontén J, et al. Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study. The Lancet. 2000; 355: 2194–2198.

[20] Sun CA, Lai HC, Chang CC, Neih S, Yu CP, Chu TY. The significance of human papillomavirus viral load in prediction of histologic severity and size of squamous intraepithelial lesions of uterine cervix. Gynecologic Oncology. 2001; 83: 95–99.

[21] Mittal S, Basu P, Muwonge R, Banerjee D, Ghosh I, Sengupta MM, et al. Risk of high-grade precancerous lesions and invasive cancers in high-risk HPV-positive women with normal cervix or CIN 1 at baseline—a population-based cohort study. International Journal of Cancer. 2017; 140: 1850–1859.

[22] Lorincz AT, Castle PE, Sherman ME, Scott DR, Glass AG, Wacholder S, et al. Viral load of human papillomavirus and risk of CIN3 or cervical cancer. The Lancet. 2002; 360: 228–229.

[23] Cuzick J, Terry G, Ho L, Hollingworth T, Anderson M. Type-specific human papillomavirus DNA in abnormal smears as a predictor of high-grade cervical intraepithelial neoplasia. British Journal of Cancer. 1994; 69: 167–171.

[24] Mansell ME, Ho L, Terry G, Singer A, Cuzick J. Semi-quantitative human papillomavirus DNA detection in the management of women with minor cytological abnormality. British Journal of Obstetrics and Gynaecology. 1994; 101: 807–809.

[25] Hildesheim A, Wang SS. Host and viral genetics and risk of cervical cancer: a review. Virus Research. 2002; 89: 229–240.

[26] Kim J, Kim BK, Jeon D, Lee CH, Roh JW, Kim JY, et al. Type-specific viral load and physical state of HPV type 16, 18, and 58 as diagnostic biomarkers for high-grade squamous intraepithelial lesions or cervical cancer. Cancer Research and Treatment. 2020; 52: 396–405.

[27] Berumen J, Ordoñez RM, Lazcano E, Salmeron J, Galvan SC, Estrada RA, et al. Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study. Journal of the National Cancer Institute. 2001; 93: 1325–1330.

[28] Veras VS, Cerqueira DM, Martins CR. L1 sequence of a new human papillomavirus type-58 variant associated with cervical intraepithelial neoplasia. Brazilian Journal of Medical and Biological Research. 2005; 38: 1–4.

[29] Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. The New England Journal of Medicine. 2003; 348: 518–527.

[30] El-Sherif AM, Seth R, Tighe PJ, Jenkins D. Quantitative analysis of IL-10 and IFN-γ mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer. The Journal of Pathology. 2001; 195: 179–185.

[31] Lee SJ, Cho YS, Cho MC, Shim JH, Lee KA, Ko KK, et al. Both E6 and E7 oncoproteins of human papillomavirus 16 inhibit IL-18-induced IFN-γ production in human peripheral blood mononuclear and NK cells. Journal of Immunology. 2001; 167: 497–504.

[32] Lee KA, Cho KJ, Kim SH, Shim JH, Lim JS, Cho DH, et al. IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response. Cancer Letters. 2005; 229: 261–270.

[33] Uchimura NS, Ribalta JC, Focchi J, Simões MJ, Uchimura TT, Silva ES. Evaluation of Langerhans’ cells in human papillomavirus-associated squamous intraepithelial lesions of the uterine cervix. Clinical and Experimental Obstetrics & Gynecology. 2004; 31: 260–262.

[34] Wu Y, Chen Y, Li L, Cao Y, Liu Z, Liu B, et al. Polymorphic amino acids at codons 9 and 37 of HLA-DQB1 alleles may confer susceptibility to cervical cancer among Chinese women. International Journal of Cancer. 2006; 118: 3006–3011.

[35] Sierra-Torres CH, Au WW, Arrastia CD, Cajas-Salazar N, Robazetti SC, Payne DA, et al. Polymorphisms for chemical metabolizing genes and risk for cervical neoplasia. Environmental and Molecular Mutagenesis. 2003; 41: 69–76.

[36] Chan TY. World Health Organization classification of tumours: pathology & genetics of tumours of the urinary system and male genital organs. Urology. 2005; 65: 214–215.

[37] Aden D, Zaheer S, Khan S. Navigating the landscape of HPV-associated cancers: from epidemiology to prevention. Pathology Research and Practice. 2024; 263: 155574.

[38] Esch M. Sexual health: a nursing approach to supporting the needs of young adult cancer survivors. Clinical Journal of Oncology Nursing. 2021; 25: 501–506.

[39] Naber KG, Bergman B, Bishop MC, Bjerklund-Johansen TE, Botto H, Lobel B, et al. EAU guidelines for the management of urinary and male genital tract infections. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). European Urology. 2001; 40: 576–588.

[40] Emilio S, Luigi V, Riccardo B, Carlo G. Lifestyle in urology: cancer. Urologia. 2019; 86: 105–114.

[41] Hansel DE. A 25-year perspective on advances in the pathologic assessment and diagnosis of urologic cancers. Urologic Oncology. 2021; 39: 582–594.

[42] Li N, Yang L, Zhang Y, Zhao P, Zheng T, Dai M. Human papillomavirus infection and bladder cancer risk: a meta-analysis. The Journal of Infectious Diseases. 2011; 204: 217–223.

[43] Crook J, Grimard L, Tsihlias J, Morash C, Panzarella T. Interstitial brachytherapy for penile cancer: an alternative to amputation. Journal of Urology. 2002; 167: 506–511.

[44] Li X, Gao C, Yang Y, Zhou F, Li M, Jin Q, et al. Systematic review with meta-analysis: the association between human papillomavirus infection and oesophageal cancer. Alimentary Pharmacology & Therapeutics. 2014; 39: 270–281.

[45] Won L, Li Y, Kim YJ. Association of GSTM1 and GSTT1 copy number variation with chromosomal aberrations in nuclear power plant workers exposed to occupational ionizing radiation. Toxics. 2025; 13: 73.

[46] Manjunath S, Smita S, Arul A, Devi V, Kumar N, Kiran A, et al. Kadukkai maathirai (Indian herbal drug) prevents hepatocellular cancer progression by enhancing GSTM1 expression and modulating β catenin transcription: in-silico and in-vivo study. F1000Research. 2024; 13: 639.

[47] Pierre CJ, Azeez TA, Rossetti ML, Gordon BS, La Favor JD. Long-term administration of resveratrol and MitoQ stimulates cavernosum antioxidant gene expression in a mouse castration model of erectile dysfunction. Life Sciences. 2022; 310: 121082.

[48] Sucato A, Serra N, Buttà M, Gregorio LD, Pistoia D, Capra G. Human papillomavirus infection in partners of women attending cervical cancer screening: a pilot study on prevalence, distribution, and potential use of vaccines. Vaccines. 2025; 13: 172.

[49] Shen S, Zhao S, Shan J, Ren Q. Metabolomic and microbiota profiles in cervicovaginal lavage fluid of women with high-risk human papillomavirus infection. Scientific Reports. 2025; 15: 796.

[50] Brahimi N, Croitoru D, Saidoune F, Zabihi H, Gilliet M, Piguet V. From viral infection to skin affliction: unveiling mechanisms of cutaneous manifestations in COVID-19 and Post-COVID conditions. Journal of Investigative Dermatology. 2025; 145: 257–265.

[51] Pan Z, Liu Y, Dai H, Xu S, Qin M, Wang K, et al. Identification of interferon-stimulated response elements (ISREs) in canines. BMC Veterinary Research. 2025; 21: 128.

[52] Watrowski R, Schuster E, Polterauer S, Van Gorp T, Hofstetter G, Fischer MB, et al. Genetic variants of interleukin-8 and interleukin-16 and their association with cervical cancer risk. Life. 2025; 15: 135.

[53] Sharma N, Changotra H, Kaur M. Molecular epidemiology of human papillomavirus variants in cervical cancer in India. Indian Journal of Medical Research. 2024; 160: 531–551.

[54] Krause KD, D'Avanzo PA, Karr AG, Rhem C, Halkitis PN. Vaccination uptake in LGBTQ adults in two US states: findings from the QVax study. Vaccine. 2024; 42: 126320.

[55] Varesano S, Ciccarese G, Paudice M, Mazzocco K, Gaggero G, Ferrero S, et al. Evaluating HPV viral load and multiple infections for enhanced cervical cancer risk-based assessment. Life. 2025; 15: 153.

[56] Lee M, Lee EJ, Kang J, Lee KH, Lee SJ, Hong SH, et al. Roles of cancer histology type and HPV genotype in HPV ctDNA detection at baseline in cervical cancer: implications for tumor burden assessment. Pathobiology. 2024; 27: 1–10.

[57] Omenai SA, Ajani MA. The interplay between programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) genotypes in cervical carcinomas: findings of a Nigerian Tertiary Hospital. Pan African Medical Journal. 2024; 48: 90.

[58] Luo Q, Zhang H, Zeng X, Han N, Ma Z, Luo H. HPV specificity and multiple infections and association with cervical cytology in Chongqing, China: a cross-sectional study. BMC Infectious Diseases. 2024; 24: 804.

[59] Khatra J, Sang JM., Wang C, Bacani N, Lachowsky NJ, Grennan T, et al. Longitudinal uptake of the human papillomavirus vaccine among gay, bisexual and other men who have sex with men in British Columbia, Canada 2012–2019. Sexually Transmitted Infections. 2022; 98: 302–306.

[60] Alahmadi RM, Awadalla M, Marraiki N, Alswayyed M, Alshehri HA, Alsahli A, et al. Profiling the tumor immune microenvironment of HPV-associated base of tongue squamous cell carcinoma. OncoTargets and Therapy. 2025; 18: 263–281.