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Yale University study finds head and neck cancer linked to poor survival in people with HIV

Studies have found that people with HIV are at heightened risk for head and neck cancer. These cancers consist of tumours that can occur on the lips, mouth, throat and voice box; less commonly, the sinuses can be involved. Risk factors for head and neck cancers can include excessive sunlight (affecting the lips), use of alcohol and tobacco, and co-infection with viruses such as human papillomavirus (HPV) and Epstein-Barr Virus (EBV).

Chemicals in tobacco smoke and other substances, as well as HPV or EBV infection, can cause some cells lining the parts of the body previously mentioned to develop abnormally. Over time, some of these cells return to a normal development pathway. However, some cells may continue to develop abnormally, ultimately going on to become pre-cancer and cancer.

Ideally, cells of the immune system are supposed to patrol tissues and be on the lookout for pre-cancerous and cancerous cells. Upon finding these cells, patrolling cells of the immune system usually destroy them.

Despite the use of HIV treatment (ART), some degree of immunological dysfunction persists and pre-cancers and cancers may form.

The vaccine Gardasil-9 greatly reduces the risk of HPV-related cancers. However, this vaccine needs to be given when people are relatively young and have had no or few sexual partners. Many older people with HIV never had the opportunity to get the HPV vaccine when they were younger.

A vaccine to reduce the risk of EBV-related complications is under development.

At Yale University

A team of researchers at Yale New Haven Hospital conducted a study of head and neck cancers by reviewing data collected between 2002 and 2018 from people with and without HIV.

They found that after a diagnosis of head and/or neck cancer (hereafter simply called cancer), people with HIV had reduced survival (three years) vs. people without HIV with the same cancer (eight years). Sociodemographic and other factors could not explain the reduction in survival. Instead, statistical analysis pointed to something related to HIV.

It may be that the immune systems of people with HIV in this study were not functioning at an optimal level. It is also possible that there were unmeasured factors that the Yale University scientists missed when analysing the data.

The Yale researchers called for larger studies to confirm their findings. They also stated that people with HIV who have cancer should be offered more opportunities to participate in clinical trials exploring the use of drugs that help harness the anti-cancer activity of the immune system.

Study details

The Yale researchers accessed databases that collected information from people with cancer who sought care at the university’s clinic. Researchers matched data from each person with HIV with data from at least three other people without HIV of the same gender, age, cancer, stage of cancer and location of cancer at the time of cancer diagnosis.

There were 2,894 people without HIV and 48 people with HIV in the study.

Small samples of tumours were analyzed for the presence of proteins from HPV.

The average profile of the HIV-positive participants at the time their cancer was diagnosed was as follows:

  • 55 years
  • 36 males, 12 females
  • major ethno-racial groups – Black – 44%; White – 42%; Hispanic – 7%
  • current or former tobacco use – 89%
  • current or former alcohol use – 75%
  • currently using ART – 88%
  • viral load – 20 copies/mL; six people had a viral load greater than 200 copies/mL
  • CD4+ count – 341 cells/mm3
  • lowest-ever CD4+ count – 270 cells/mm3
  • CD4/CD8 ratio – 0.5
  • length of time since HIV diagnosis – 16 years
  • co-infected with hepatitis C virus (HCV) – 66%

Results

There were important similarities between people with and without HIV. For instance, the researchers found the following:

  • the locations of tumours were similar (usually the mouth and/or throat)
  • the time between cancer diagnosis and initiation of anti-cancer treatment was similar
  • the type of anti-cancer therapy prescribed was similar

After diagnosis, the overall survival of participants was distributed as follows:

  • people with HIV – 34 months
  • people without HIV – 94 months

When researchers focused only on people with a minimal number and size of tumours, they found improved survival among people with HIV (74 months), but it was still less than people without HIV (114 months).

Regardless of which timepoint after diagnosis researchers examined (two, eight and 10 years), HIV-positive people always had reduced survival compared to HIV-negative people.

Spurred by these findings, the study team performed statistical analyses hoping to uncover some factor(s) that might account for reduced survival among people with HIV. They were able to rule out the following factors measured at the time cancer was diagnosed:

  • current CD4+ count
  • current viral load
  • age
  • stage of cancer
  • socio-economic factors
  • tobacco use
  • type of health insurance

A problem with the immune system

Cells of the immune system have an important role in dealing with abnormal cells, particularly tumours. One important group of cells is called CD8+ cells. This is a group of T-cells that can kill virus-infected cells and tumours. The researchers analysed samples of tumours taken from participants. They found that there were fewer CD8+ cells in the samples taken from people with HIV compared to samples taken from people without HIV.

In general, the researchers reported that people with HIV developed cancer at a significantly younger age (55 years) than people without HIV (62 years). This is striking because, in general, as people age, their immune systems become gradually weaker, increasing their risk for cancer.

This finding of the low number of CD8+ T-cells in tumours combined with the younger age at which people with HIV were diagnosed with cancer caused the researchers to argue that a major issue was the presence of HIV. This virus was having an effect on the immune system of people diagnosed with cancer.

HIV infection causes chronic immune activation and inflammation. This is greatly reduced with the use of ART and achievement and maintenance of a suppressed viral load. However, the levels of immune activation and inflammation still remain elevated compared to people without HIV. Some scientists think that prolonged exposure to excess immune activation and inflammation can slowly degrade the immune system. This does not mean that all or even most people with HIV will get cancer. However, research suggests that ongoing immune activation and inflammation have the potential to increase the risk for cancer and contribute to an increased likelihood for the following issues:

  • cardiovascular disease
  • type 2 diabetes
  • chronic kidney disease
  • non-alcoholic fatty liver disease
  • conditions where the immune system attacks the body (such as arthritis)
  • neurodegenerative disorders

Bear in mind

The research from Yale University is a good first step at exploring the impact of HIV on the survival of people with cancer. Other studies have found that people with HIV are at heightened risk for cancer in the current era. This does not mean that most people with HIV will get cancer, but it does mean that their overall risk for cancer is increased.

The Yale study was relatively small and it is possible that some underlying drivers of poorer survival among people with HIV were not captured.

The Yale researchers need to cooperate with other cancer scientists to build a larger data set (with many more participants) to confirm their findings. Such a study will be expensive and will take years to accomplish, and the researchers will have to compete for scarce research funds.  

Resources

Canadian Cancer Society

Cancer – Government of Canada

Cancer – Government of Quebec

Second cancer risk after surviving Hodgkin’s lymphoma in people with HIV – CATIE News

French researchers investigate second cancers in people with HIV who survived a first cancer – CATIE News

Ontario study looks at trends in cancer in people with HIV – CATIE News

—Sean R. Hosein

REFERENCES:

  1. Salahuddin S, Cohen O, Wu et al. HIV is associated with poor overall survival among head and neck cancer patients. Clinical Infectious Diseases. 2023; in press.
  2. Lopez Angel CJ, Pham EA, et al. Signatures of immune dysfunction in HIV and HCV infection share features with chronic inflammation in aging and persist after viral reduction or elimination. Proceedings of the National Academy of Sciences U S A. 2021 Apr 6;118(14): e2022928118. 
  3. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019 Dec;25(12):1822-1832. 
  4. Martin GE, Sen DR, Pace M, et al. Epigenetic features of HIV-induced T-cell exhaustion persist despite early antiretroviral therapy. Frontiers in Immunology. 2021 Jun 4; 12:647688. 
  5. Chaudhary O, Trotta D, Wang K, et al. Patients with HIV-associated cancers have evidence of increased T cell dysfunction and exhaustion prior to cancer diagnosis. Journal for ImmunoTherapy of Cancer. 2022 Apr;10(4):e004564.