Elsevier

Oral Oncology

Volume 50, Issue 12, December 2014, Pages 1169-1176
Oral Oncology

Incidence and risk factors of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma in HIV-infected individuals

https://doi.org/10.1016/j.oraloncology.2014.09.011Get rights and content

Summary

Objectives

To examine the risk and trends of HPV-related and HPV-unrelated Head and Neck Squamous Cell Carcinoma (HNSCC) in HIV-infected individuals and assess whether immunosuppression (measured through CD4 cell count) and other risk factors impact HNSCC risk.

Materials and methods

Incident HNSCCs at HPV-related and HPV-unrelated anatomic sites were detected in HIV-infected participants from pooled data from 17 prospective studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) between 1996 and 2009. HNSCC cases were validated using chart review or cancer registry matching. Risk factors for incident HPV-related and HPV-unrelated HNSCC were explored using mixed effects Poisson regression in a full prospective analysis, and the effect of CD4 prior to cancer diagnosis was examined in a nested case control analysis.

Results

66 HPV-related and 182 HPV-unrelated incident HNSCCs were detected among 82,375 HIV-infected participants. Standardized incidence ratios (SIRs) for both HPV-related (SIR = 3.2, 95%CI = 2.5–3.4) and HPV-unrelated (SIR = 3.0, 95%CI = 2.5–4.1) HNSCC were significantly elevated in HIV-infected individuals compared with the US general population. Between 1996 and 2009, the age-standardized HPV-related HNSCC incidence increased non-significantly from 6.8 to 11.4 per 100,000 person-years (p-trend = 0.31) while the age-standardized incidence of HPV-unrelated HNSCC decreased non-significantly from 41.9 to 29.3 per 100,000 person-years (p-trend = 0.16). Lower CD4 cell count prior to cancer diagnosis was significantly associated with increased HPV-related and HPV-unrelated HNSCC risk.

Conclusion

The standardized incidence of HPV-related and HPV-unrelated HNSCC are both elevated in HIV-infected individuals. Immunosuppression may have a role in the development of both HPV-related and HPV-unrelated HNSCC.

Introduction

Human papillomavirus (HPV) infection, tobacco, and alcohol use are three major causes of Head and Neck Squamous Cell Carcinoma (HNSCC) [1], [2]. In the general population of North America, the incidence of many types of HNSCCs, such as oral cavity cancer, have been decreasing over the past several decades due to decreases in tobacco use [3], [4]. In contrast, incidence of HNSCCs related primarily to oral HPV infection (i.e. oropharyngeal cancers), have been increasing over the same time period [3], [4], [5].

Less is known about HNSCC in the HIV-infected population of North America, as few studies have been large enough to explore this heterogeneous malignancy. Large cohort and HIV/AIDS-Cancer registry match studies have suggested that HIV-infected individuals have a 1.5–4-fold higher risk for HNSCC compared with the general population [6], [7], [8]. However, many of these studies have combined HPV-related oropharyngeal cancers with other HPV-unrelated HNSCCs together in one “oral cavity and pharynx cancer” category, so it is unclear whether this increased HNSCC risk may be explained by higher levels of tobacco and alcohol use, higher exposure to HPV, faster progression of carcinogenesis due to immunosuppression (lower CD4 cell count), or a combination of these factors [9], [10].

The incidence of several cancers caused by infectious agents, such as Kaposi’s sarcoma, has decreased dramatically in HIV-infected individuals after the introduction of effective antiretroviral therapy (ART, also known as HAART or cART) around 1996. In contrast, there is evidence that the incidence of some HPV-related cancers such as anal cancer [11], [12], [13], [14], and perhaps oropharyngeal cancer [11], may have increased in HIV-infected individuals over the past two decades.

The role of HIV and immunological factors such as reduced CD4 cell count in the development of HNSCC is unclear as some preliminary studies have suggested an association with increased HNSCC risk [15], [16], [17], but another did not [18]. Using data from the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design) [19], a collaboration of longitudinal studies of HIV-infected individuals, we explored the risk and trends of HPV-related and HPV-unrelated HNSCC, and assessed the degree to which immunosuppression plays a role in increasing HNSCC risk.

Section snippets

Study population and design

The NA-ACCORD is a large collaboration of longitudinal cohort studies involving HIV-infected individuals in North America and is a part of the International Epidemiologic Databases to Evaluate AIDS (IeDEA) initiative [19]. HNSCCs were identified and validated from HIV-infected individuals from three interval cohorts and fourteen clinically based cohort studies between 1996 and 2009. Each cohort submitted demographic, treatment, clinical, and laboratory data to the NA-ACCORD data management

Participant characteristics

This study included 82,375 HIV-infected participants from 17 cohort studies in the NA-ACCORD. These participants contributed 463,784 person-years between 1996 and 2009, with a median follow-up time of 4.9 (IQR = 2.0–8.9) years. Only a subset of participants were on ART at entry into the study (20%); however most of the study participants had been exposed to ART by the end of follow-up (78%). There were 248 incident HNSCCs ascertained during follow-up. These HNSCC cases were more likely to be

Discussion

In this large prospective study, we determined that the standardized incidence of HPV-related and HPV-unrelated HNSCC were both threefold higher in HIV-infected individuals than the US general population. This study also supports a modest role for immunosuppression (low CD4 cell count) prior to cancer diagnosis. This supports evidence from other studies [7], [31], that immunosuppression from HIV may impact the head and neck carcinogenesis process.

The three fold higher incidence of HNSCC in this

Conflict of interest statement

Michael Silverberg has ongoing grants from Pfizer and Merck, Gypsyamber D’Souza received previous received funding from Merck, John Gill is a board member of BMS Abbvie, Janssen, and Gilead Viiv, and Marina Klein has consulted with Glaxo Smith Klein and VIIV and has a current grant with Merck. For the remaining authors no conflicts of interest were declared.

Funding support

National Institute of Allergy & Infectious Diseases, with supplemental funding from the National Cancer Institute. This work was supported by grants: U01-AI069918, U01-AA013566, U24-AA020794, U01-AA020790, U01-AI31834, U01-AI34989, U01-AI34993, U01-AI34994, U01-AI35004, U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, U01-AI35043, U01-AI37613, U01-AI37984, U01-AI38855, U01-AI38858, U01-AI42590, U01-AI68634, U01-AI68636, U01-AI69432, U01-AI69434, U01-HD32632, U10-EY08057, U10-EY08052, U10-

Acknowledgements

NA-ACCORD participating cohorts and representatives (∗indicates contributed data to this study): ∗AIDS Link to the IntraVenous Experience (ALIVE; G. Kirk), Adult AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT; C. Benson, R. Bosch, A. Collier, ∗HIV Research Network (HIVRN; K. Gebo); ∗Johns Hopkins HIV Clinical Cohort (JHHCC; R. M.), ∗HAART Observational Medical Evaluation and Research (HOMER; R. Hogg), ∗HIV Outpatient Study (HOPS; J.T.B.), ∗Johns Hopkins HIV Clinical

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