Risk factors for human papillomavirus infection, cervical intraepithelial neoplasia and cervical cancer: an umbrella review and follow-up Mendelian randomisation studies

Abstract

Background Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear. Methods In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995). Results We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89–2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27–1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40–1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation. Conclusions Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

Association between serum P16ink4A concentration and CIN and cervical cancer among women attending a cervical cancer clinic in western Uganda: A case control study

“…Other genetic and life style factors can increase chances of HPV infection ( Haukioja, 2014 ). HIV has been categorically proven to be a risk factor for HPV persistence ( Bowden, 2023 ) which in turn increases expression of P16ink4A. This further explains the observation of raised P16ink4A serum concentrations in control groups, who were mostly HIV positive, compared to controls.…”

Recent advances in treating female genital human papillomavirus related neoplasms with topical imiquimod

“…These emerging scenarios prompt new studies focusing not only on the relationship between imiquimod and HPV but also on its interactions within the vaginal microbiome, aiming to discern which patients should receive imiquimod treatment as an alternative to conization surgery. Other factors such as HIV infection and the use of immunosuppressive drugs that may affect the immune response against HPV could also impact the response to imiquimod and should be considered 98 . Interestingly, a recent pilot study showed good efficacy by combining imiquimod with topical 5‐fluorouracil for CIN 2‐3, 75 but we need further results for the efficacy of this drug combination.…”

Coinfections with additional oncoviruses in HPV+ individuals: Status, function and potential clinical implications

“…HPV infection is a well‐established cause of cervical oropharyngeal, anal, penile, vaginal, and vulvar cancers, and of other associated diseases, including cutaneous and anogenital warts 3 . Certain other risk factors such as smoking, may influence which women exposed to HPV are more likely to develop cervical cancer 4 . In addition, some coinfected pathogens, such as human immunodeficiency virus (HIV) and chlamydia, have been reported to increase the risk of women exposed to HPV for developing cervical cancer 5,6 …”

“…3 Certain other risk factors such as smoking, may influence which women exposed to HPV are more likely to develop cervical cancer. 4 In addition, some coinfected pathogens, such as human immunodeficiency virus (HIV) and chlamydia, have been reported to increase the risk of women exposed to HPV for developing cervical cancer. 5,6 An oncovirus or oncogenic virus is a virus that can cause cancer.…”