Introduction
The advent of effective antiretroviral therapy (ART) has increased the lifespan of many people living with HIV. As a result, cancers driven by high-risk human papillomavirus (HPV) infection have emerged as an increasingly important cause of mortality in this population. The complex interplay between HIV and HPV necessitates a deep understanding of the HPV-related cancer burden in people living with HIV and the integration of effective prevention strategies into their care. Implementing preventive measures, such as HPV vaccination and comprehensive screening programmes, is crucial and will require addressing existing health inequities and developing tailored interventions for people living with HIV. The development of enhanced secondary prevention tools and innovative treatment modalities is essential to mitigate the burden of HPV-associated cancers and improve the overall health outcomes for this vulnerable population.
Disease Burden
HPV infections cause an estimated 690,000 cancer cases globally each year. The highest excess in cancer incidence and mortality in people living with HIV over the general population is observed for HPV-related cancers. Anal cancer risk is around 40 times higher among people living with HIV than among the general population. Among people living with HIV, men—especially men who have sex with men (MSM)—have higher risk than women of developing anal cancer. Vulvovaginal cancer risk is eight times and penile cancer risk is about four times higher in people with HIV than the general population. Women living with HIV have a six-fold increased risk of cervical cancer than the general population, with substantial variation worldwide. The International Agency for Research on Cancer (IARC) has estimated that the global burden of HPV-related cancer diagnosed among people living with HIV falls predominantly in sub-Saharan Africa, and is dominated by cervical cancer.
Primary Prevention
HPV vaccination is a major advance in cervical cancer prevention that has the potential to greatly reduce HPV-related malignancies. There is evidence that vaccination in adolescence before exposure to HPV can also offer protection against other HPV-related cancers, making it a cornerstone of long-term HPV-related cancer control. Studies suggest that HPV vaccines are safe and elicit a robust initial immune response in people living with HIV, although the titers are lower than in the general population. Vaccinating this population even after sexual debut is nonetheless considered desirable, as it is expected that HPV vaccines should protect people living with HIV from new HPV infections. The updated WHO recommendations from December 2022 include a single-dose option for immunocompetent children and adolescents aged 9–20 years.
Reducing new HIV infections through condom use, pre-exposure prophylaxis, and other prevention measures directly lowers the number of people living with HIV at high risk for developing HPV-related cancers. In addition, HPV-related cancer risk among people living with HIV can also be partly reduced by ART, particularly when initiated early. Therefore, the high age-standardized cervical cancer incidence, largely observed in unscreened women with HIV in sub-Saharan Africa, is predicted to decline with wider and earlier access to ART. However, because ART also increases life expectancy, even if age-standardized incidence rates decrease, absolute numbers of women living with HIV diagnosed with cervical cancer in sub-Saharan Africa might increase further in the absence of effective HPV vaccination and cervical cancer screening measures.
Secondary Prevention
HPV DNA testing-based primary screening is the emerging standard of care for cervical cancer screening, replacing cytology and visual inspection with acetic acid (VIA). An advantage of HPV DNA testing-based screening is that it permits the use of self-collected cervicovaginal specimens or urine for HPV DNA testing. Guidelines recommend HPV DNA testing-based screening every 3–5 years for women living with HIV aged 25–49 years or twice the frequency of screening for the general population of women. The negative predictive value of HPV DNA testing for cervical precancer and cancer is excellent because of its sensitivity. Appropriate triage of women positive for HPV and living with HIV, for example through partial genotyping, is at least as relevant as in the general HPV-positive population.
For anal cancer screening, high-resolution anoscopy (HRA) is recommended for the diagnosis and treatment of high-grade anal squamous intraepithelial lesions (HSIL) in people living with HIV. Anal cytology has been the most widely used primary screening test among people living with HIV and, along with HPV testing including HPV-16 genotyping, is considered to show acceptable performance. Genotyping for HPV-16 improves risk discrimination and screening efficiency. Self-collected anal specimens, combined with a test that discriminates true anal precancer from benign HPV infection, would maximize the efficiency of anal cancer screening in people living with HIV.
HPV-Related Cancer Prevention Challenges and Opportunities
Stigma and discrimination related to HIV, HPV, and anal sex remain significant barriers to accessing prevention and care services. The integration of HPV prevention strategies within existing HIV care frameworks is considered a crucial opportunity to enhance the reach and effectiveness of interventions. Self-sampling for HPV testing is proposed as a method to overcome the stigma associated with HPV screening and to improve participation, especially among men who have sex with men (MSM). There is also an emphasis on the need for innovative biomarkers and therapeutic HPV vaccines to address the limitations of current prevention and treatment strategies.
Conclusion
The article concludes by stressing the need for targeted research and tailored interventions to address the unique challenges faced by people living with HIV in managing HPV-related cancers. It calls for equitable access to prevention and treatment services and highlights the importance of policy development to address the specific needs of people living with HIV, particularly in low-resource settings.
Citation: Uusküla, A., Tisler, A., DeHovitz, J., Murenzi, G., Castle, P.E. and Clifford, G. (2025). Prevention and control of HPV-related cancers in people living with HIV. The Lancet HIV, 12(4). doi:https://doi.org/10.1016/s2352-3018(25)00011-6.
