Beyond Viral Suppression: Persistent HPV-Associated Cancer Risk in People With HIV

In the past 2 decades, a central tenet of human immunodeficiency virus (HIV)-associated oncology has been that viral suppression, and the immune restoration that follows, reduces the excess cancer risk driven by HIV for certain malignancies. This has been the case for cancers caused by oncogenic viruses, which were historically termed “acquired immunodeficiency syndrome-defining cancers” and include Kaposi sarcoma and subtypes of non-Hodgkin lymphomas, whose incidence has fallen significantly in the antiretroviral therapy (ART) era [1]. Cancers caused by human papillomavirus (HPV), however, have been persistent in the modern ART era [2, 3]. Cervical cancer incidence has changed little relative to the general population [4], and the risk of cancers of the anus, penis, and vulva remains elevated and, in some settings, continues to increase [5–7]. This observed difference between incidence of virus-associated cancers that recede with immune reconstitution and those that do not raises a fundamental question: can HPV-related oncogenesis be reversed with ART, or are control of HIV and prevention of HPV-associated malignancies distinct objectives? In the accompanying study, Mendu and colleagues address this question in Botswana, a country with high burden of both HIV and HPV-associated cancer [8, 9]. The investigators use 2 large population-based cohorts; first is a prospective cancer cohort and, second, is a random community sample from the Ya Tsie HIV prevention trial. Botswana has a mature public ART program with near universal coverage, which permits evaluation across a range of treatment durations. Applying a case-cohort design, the investigators emulate a target trial to estimate how anogenital cancer risk changes with increasing duration of ART. The study included 4 major HPV-associated anogenital malignancies, impacting both women and men, and differing in their incidence and availability of preventative measures. In the setting of widespread ART coverage and viral suppression (98% below 1000 copies/mL among 80% with an available measurement), the relative risk of cervical, anal, vulvar, and penile cancer did not decline with longer treatment. Rather, among people with HIV (PWH) receiving ART for a decade or more, the marginal relative risk of anogenital cancer was 7-fold higher than that of people without HIV, with even higher estimates for penile and vulvar cancers. Importantly, duration of ART and duration of HIV infection were nearly identical in this population. Additionally, those with longer ART duration had a history of advanced HIV disease, reflecting CD4+ T cell–based criteria used to initiate treatment in the earlier years of the HIV epidemic. The findings highlight that control of HIV replication and prevention of HPV-associated anogenital cancers are not interchangeable outcomes. Few studies have evaluated long-term cancer outcomes in treated HIV populations with comparable methodological rigor. The findings should not be interpreted as evidence that ART lacks anticancer benefit or promotes carcinogenesis. In fact, recent observational studies and long-term follow-up from randomized trials suggest that earlier ART initiation reduces subsequent malignancy risk [10–12], although neither the ATHENA nor START studies focused on HPV-associated anogenital cancers alone. One explanation is that the biologic window during which ART most influences cancer risk occurs early in HIV infection, before persistent immune dysfunction and HPV-mediated carcinogenesis are fully established. The study by Mendu and colleagues was not designed to test that hypothesis because it compared duration of ART rather than timing of ART initiation relative to HIV acquisition. In the study population, duration of ART functions as a marker of cumulative HIV infection, rather than as an independent exposure. Furthermore, the long latency of HPV-mediated carcinogenesis is central to the interpretation of the study findings. HPV-associated cancer development spans years to decades. HPV infection can precede ART initiation or occur during periods of uncontrolled infection [13]. In spite of immune reconstitution, there may be incomplete restoration of antitumor surveillance or reversal of oncogenic processes already under way. Persistent immune activation, immune senescence, inflammaging, and altered tissue microenvironments have all emerged as plausible mechanisms linking treated HIV infection to ongoing cancer risk [14–17]. The a priori definition of advanced HIV disease used in the study, which included a World Health Organization stage 3 or 4 illness and nadir CD4+ T-cell count <250 cells/µL, were developed to predict opportunistic infections and guide ART initiation, not to stratify cancer risk. If persistent cancer risk reflects multiple biologic pathways, prevention must also be multifaceted. HPV vaccination, smoking cessation, and prompt ART initiation remain essential, but they address only part of the process of HPV-associated cancer development. Screening and treatment of precancerous lesions provide an independent opportunity to interrupt progression to invasive cancer. The ANCHOR trial demonstrated that treatment of anal high-grade squamous intraepithelial lesions reduces progression to anal cancer in PWH, establishing proof that secondary prevention can reduce cancer incidence in PWH [18]. Whether similar strategies can be successfully implemented in global low-resource settings remains uncertain. In the present study, the more modest increase in cervical cancer risk compared to anal, vulvar, and penile cancers may reflect Botswana's longstanding national cervical screening program [19], again highlighting the impact of secondary prevention. Reducing the burden of HPV-associated cancers will require multidisciplinary integration of prevention, screening, timely diagnosis, cancer treatment, and survivorship care. The study findings highlight future opportunities for cancer biology and implementation science to shape prevention efforts. Biomarkers beyond CD4+ T-cell count and viral load are needed to better characterize persistent immune dysfunction, improve cancer risk stratification, and identify new drug targets. On the implementation side, effective prevention strategies, such as anal cancer screening, need to be scaled to reach the populations most likely to benefit. ART has transformed outcomes for PWH; extending that success to cancer prevention will require a deeper understanding of why cancer risk persists despite viral suppression. Viral suppression remains the foundation of HIV care, but it should not be regarded as the final measure of long-term success. As PWH age, the challenge shifts from controlling infection to preventing its chronic sequelae, among the most consequential of which are HPV-associated malignancies. The work of Mendu and colleagues reminds us that successful HIV treatment and successful cancer prevention are related but distinct goals. Achieving both will require continued advances in our understanding of determinants of persistent cancer risk and integration of that knowledge into prevention strategies, clinical guidelines, and comprehensive HIV care. Financial support. G. S. receives funding from the National Institutes of Health/National Cancer Institute/NCI and ARPA-H that are unrelated to this manuscript.