Understanding oral health in HPV-related oropharyngeal cancer in people with HIV

Little is known about why people living with HIV have a much higher rate of oral human papilloma virus (HPV) infection and oropharyngeal cancer (OPC) than the general population. And it’s not only those with advanced untreated HIV infection, known as AIDS.

"Even when they do become undetectable, they still have challenges with managing HPV as well," says Winship researcher Lisa Flowers, MD, MPH, FACOG, director of colposcopy and anoscopy services at Grady Cancer Center and president of the American Society for Colposcopy and Cervical Pathology. "They do better, but there's still challenges with managing the virus."

Supported by a five-year, $3.9 million R01 grant (R01DE032243) from the National Institutes of Health, Flowers, co-principal investigator Canhua Xiao, PhD, RN, FAAN, Winship researcher and associate professor in the Nell Hodgson Woodruff School of Nursing at Emory University, and their research team plan to enroll 500 people in the study, "Oral microbiome and periodontal diseases in oral HPV infection among people living with HIV." The study will examine the associations among the oral microbiome, periodontal diseases and the immunological underpinnings of oral HPV infection in people with HIV.

The researchers want to develop a better understanding of what contributes to the persistence of HPV infection in those living with HIV and move toward developing a way to determine who is at risk—and how to prevent them from developing OPC.

"Where we haven't been able to do the greatest job, where we still need a lot of work," says Flowers, "is in being able to detect HPV in the oropharyngeal cavity and have a screening test that could actually detect cancer early on, where we can prevent it like we can prevent cervical and anal cancer."

Winship co-investigators include Deborah Watkins Bruner, RN, PhD, FAAN, senior vice president for research, Robert W. Woodruff Chair in Nursing and professor of radiation oncology; Timothy D. Read, PhD, professor in the Division of Infectious Diseases in the Department of Medicine and professor, Department of Human Genetics at Emory University School of Medicine; Minh Ly T. Nguyen, MD, associate professor in the Division of Infectious Diseases, Department of Medicine at Emory University School of Medicine and an investigator with the Center for AIDS Research at Emory University; Terry Hartman, PhD, MPH, RD, professor of epidemiology in the Department of Epidemiology at Rollins School of Public Health at Emory University; and Vijayakumar Velu, PhD, assistant professor, Division of Microbiology and Immunology, Emory National Primate Research Center. The research team also includes David A. Reznik, DDS, director, Oral Health Center, Grady Infectious Disease Program; Gypsamber D’Souza, PhD, MS, professor, epidemiology and international health, Bloomberg School of Public Health, Johns Hopkins University; and Elizabeth R. Unger, MD, PhD, chief, Chronic Viral Diseases Branch, Centers for Disease Control and Prevention.

HPV is the most common sexually transmitted infection in the United States. There is no cure for the virus. Approximately 26 million Americans are believed to have an oral HPV infection on any given day.

OPC is one of the most common head and neck squamous cell carcinomas in the world, and HPV causes approximately 70% of OPC in the United States. HPV16 is the viral strain associated with 90% of HPV-associated OPC. HPV16 also is associated with cervical, anal and penile cancers. More males than females will develop OPC, and white non-smoking males age 35 to 55 are most at risk, four to one over females.

Although there are some commercial tests in the dental community, the value of such testing is unclear as testing positive for oral HPV on a particular day doesn't prove the infection is persistent, which is the main concern as most people eventually eliminate and develop resistance to the virus. There are no visible oral signs of an HPV infection, and no drugs to kill it. There are also no established genital tests for men. Anal brush cytology tests are available for those who engage in anal sexual practices, and those tests can be early predictors of HPV-caused anal cancers.

The researchers hypothesize that people living with HIV are more prone to having HPV and developing OPC because of the status of their oral microbiome. "The whole oral cavity, like the gut, is full of germs," says Xiao. "With HIV infection, it's likely their oral microbiome status is different from healthy people."

Add a higher incidence of periodontal disease among people with HIV, and the picture becomes a bit clearer. "Thinking of people who have periodontal disease," says Flowers, "you can imagine the environment of inflammation and other susceptibility to infection that the mucosa, the oral cavity, can lead to an environment by which HPV can easily set itself in."

For this reason, the researchers hope to get an idea of the relationship between periodontal disease and how it changes the protective components of the oral microbiome so those components don’t prevent the persistence of the virus. Flowers says, "We're hoping that we'll get an idea which inflammatory markers are either contributors to the persistence of the virus or might be assisting in having a resolution of the infection."

Xiao adds, "Although many factors contribute to inflammation, I think that's one of the reasons for us to study how the oral microbiome is linked to inflammation and may be associated with those periodontal diseases and, subsequently, the HPV infection as well."

Flowers emphasizes that the widely available HPV vaccine is the best prevention of these cancers in that it prevents HPV infection, obviating persistence and the development of OPC. She says the researchers want to better understand which inflammatory markers are either contributors to the persistence of the virus or might be assisting in resolving the infection.

Contributing toward the development of a screening test that could detect OPC early on, like the available screens for cervical and anal cancer, is another of the study's aims.

"What we hope to do with this project," says Flowers, "is, by having a good understanding of what contributes to the persistence of HPV infection—which we know is needed for carcinogenesis—we might then be able to have an effect on decreased rates of cancer."

Flowers adds, “I think we're going to get a lot of information from this, and I think it's going to end up providing us a better way by which we can understand the dynamics and maybe find some important teaching points for our patients to take better oral cavity care. It could also lead to other agents that might fortify the microbiome and make it more protective—different things that might be able to intervene to impact HPV infection."

The work is supported by the National Institute of Dental & Craniofacial Research of the National Institutes of Health under award number R01DE032243.