Large study finds advanced stage cancer more common in HIV-positive people

CATIE News

Want to receive publications straight to your inbox?

CATIE
  • U.S. study finds people with HIV more likely to be diagnosed with advanced cancer
  • Researchers suggest HIV is likely also responsible for reduced chances of survival
  • The findings reveal the importance of regular cancer screening for people with HIV

HIV infection increases the risk of the following cancers:

Receive CATIE News in your inbox:

  • non-Hodgkin’s lymphoma – caused by Epstein-Barr virus
  • Kaposi’s sarcoma (KS) – caused by human herpes virus-8
  • invasive cervical cancer – caused by strains of human papilloma virus (HPV)

All of the viruses mentioned above that incite the development of abnormal cells that in some cases ultimately transform into pre-cancer and cancer are spread in similar ways as HIV.

The widespread availability and use of HIV treatment (ART) in Canada and other high-income countries has meant that new cases of AIDS-related infections and cancers are very rare in ART users. Nevertheless, the general risk for a wide range of cancers increases as people age.

Scientists at the U.S. National Cancer Institute (NCI) in Bethesda, Maryland, and from several U.S. universities have collaborated on a project to better understand how HIV infection could have an impact on a broad range of cancers. The team analysed health-related information captured in a cancer database. Their analysis focused on information from more than 14,000 HIV-positive people and six million HIV-negative people, all of whom were diagnosed with cancer.

The scientists found that HIV-positive people were generally more likely to be diagnosed with an advanced stage of cancer (more and bigger tumours) compared to HIV-negative people. Furthermore, HIV-positive people also had reduced chances of survival compared to HIV-negative people with the same cancer diagnosis. The scientists were largely able to rule out healthcare-related factors as a cause of these unfortunate outcomes. Instead, they suggested that HIV was likely responsible for the worse prognosis.

Study details

Scientists accessed the NCI database (NCDB) for information on people diagnosed with cancers between 2004 and 2014. They focused on data from the following people:

  • 14,453 HIV-positive people
  • 6,368,126 HIV-negative people

The scientists sought information on the following 14 sites affected by cancer:

  • anus
  • bladder
  • breast (in women)
  • cervix
  • colorectum
  • kidney
  • liver
  • lung
  • mouth
  • pancreas
  • prostate
  • skin
  • stomach
  • thyroid

Results

In general, the scientists found that HIV-positive people were more likely to be male (64% men, 36% women), younger and have a lower income than HIV-negative people.

Common cancer diagnoses were distributed as follows:

HIV-positive people

  • lung cancer – 29%
  • colorectal cancer – 14%
  • prostate cancer – 11%

HIV-negative people

  • breast cancer – 23%
  • prostate cancer – 18%
  • lung cancer – 18%

The scientists stated that HIV-positive people were “significantly more likely to be diagnosed with advanced stage cancers [affecting the following sites]”:

  • breast
  • liver
  • mouth
  • prostate
  • skin
  • thyroid

They also stated that “HIV was associated with elevated [risk of death] after a cancer diagnosis for 13 of 14 cancer sites evaluated, including an almost doubling and tripling of mortality for female breast and thyroid cancers, respectively. The persistence of these associations after adjustment for factors related to the receipt of healthcare provides support for a biological link between HIV-related immunosuppression and cancer progression.”

An exception to the trends above occurred in relation to anal cancer. According to the scientists, HIV-positive people “were substantially more likely to be diagnosed with less advanced anal cancers compared with their HIV-negative counterparts. This potentially represents an example of increased healthcare being directed towards the [HIV-positive] population, a distinct possibility given the ongoing targeting of anal cancer screening procedures to HIV-infected men who have sex with men.”

Missing data

The scientists relied on information in a cancer care database. Unfortunately, they did not have information on the HIV history of participants, including at least the following:

  • length of time living with HIV
  • lowest-ever CD4+ cell count
  • CD4+ count and viral load shortly before or at the time of diagnosis
  • classes of HIV treatments used

Such information could have provided a degree of additional insight into the health of HIV-positive people prior to the diagnosis of cancer.

The limits of ART

When used as prescribed and directed, ART is highly effective at suppressing the amount of HIV in the blood. Once viral suppression is achieved, the immune system begins to effect repairs. The benefits of ART are so profound that doctors and scientists increasingly expect many ART users to have near-normal life expectancy.

However, ART does not cure HIV infection and can only partially restore the immune system. CD4+ cell counts usually increase significantly in ART users, and this prevents AIDS. But many other teams of scientists have discovered that subtle injury to the immune system remains despite many years of good adherence to ART. The cause of this subtle injury to the immune system is uncertain. Perhaps one or more of the following issues cause such immunological injury:

  • the presence of residual HIV in the lymph nodes, spleen and other parts of the immune system
  • low levels of some germs—such as bacteria or fungi or proteins associated with these germs—enter the circulation via the gut and persist in the body. The concentration of these germs and/or their proteins are not sufficient to cause obvious infection but are enough to cause chronic activation of the immune system, gradually degrading it.
  • co-infection with a common member of the herpes virus family called CMV (cytomegalovirus)

It is important to note that the subtle injury to the immune system mentioned here is insufficient to cause AIDS to (re)appear, but it may be just enough to gradually weaken the immune system’s ability to detect and destroy some tumours. This does not mean that all or even a majority of ART users will ultimately get cancer. However, the study does suggest that the risk for unfavourable outcomes with cancer is increased among HIV-positive people.

Another group at heightened risk for cancer is people who have transplanted organs. Such people require regular use of transplant drugs to partially suppress their immune systems so that the transplanted organs survive.

All of this information taken together suggests the possibility that HIV itself may play a role in the issues that the cancer scientists found in the present study.

For the future

The present study underscores the need for HIV-positive people to get cancer screening as part of their overall health maintenance. If diagnostic tests uncover cancer, swift referral to care and treatment should be the standard. Although not mentioned by the research team, by flagging immune suppression as an issue, the study provides a rationale for considering studies testing immune therapy for cancer. In the past decade, several drugs that work by removing blocks (or check points) from the immune system of cancer patients have been tested in HIV-negative people with cancer, sometimes with prolonged remission. This class of drugs is called checkpoint inhibitors. Examples of two first-generation checkpoint inhibitors are:

  • Keytruda (pembrolizumab)
  • Opdivo (nivolumab)

Checkpoint inhibitors carry their own risks; they have unusual and sometimes intense immunologically driven side effects and they do not benefit every HIV-negative person who has taken them. Furthermore, they are very expensive. However, this does not mean that they should not be considered for large clinical trials in HIV-positive people.

Reducing cancer risk

Up until 1996, HIV infection was considered to be ultimately fatal. However, given the good news about ART, part of the burden of having a near-normal life expectancy is that more emphasis may be needed to help HIV-positive people reduce their cancer risk by doing the following:

  • speaking to a doctor about getting vaccinations against hepatitis B and HPV
  • getting help from a doctor or pharmacist to support the process of quitting smoking
  • reducing their intake of alcohol
  • if engaged in injecting or inhaling street drugs: seeking help from harm reduction organizations to minimize the risk of infection from cancer-causing viruses
  • getting screening and treatment for hepatitis C virus
  • getting advice about good dietary habits
  • learning stress management techniques
  • getting help for ways to manage anxiety, depression and other mental health issues
  • engaging in regular doctor-approved physical activity

—Sean R. Hosein

REFERENCES

  1. Coghill AE, Han X, Suneja G, et al. Advanced stage at diagnosis and elevated mortality among US patients with cancer infected with HIV in the National Cancer Data Base. Cancer. 2019 Aug 15;125(16):2868-2876.
  2. D’Arcy ME, Coghill AE, Lynch CF, et al. Survival after a cancer diagnosis among solid organ transplant recipients in the United States. Cancer. 2019 Mar 15;125(6):933-942.
  3. Uldrick TS, Gonçalves PH, Abdul-Hay M, et al. Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study. JAMA Oncology. 2019; in press.
  4. Fromentin R, DaFonseca S, Costiniuk CT, et al. PD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals. Nature Communications. 2019 Feb 18;10(1):814.
  5. Thompson CG, Rosen EP, Prince HMA, et al. Heterogeneous antiretroviral drug distribution and HIV/SHIV detection in the gut of three species. Science Translational Medicine. 2019 Jul 3;11(499).
  6. Costiniuk CT, Salahuddin S, Farnos O, et al. HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy. AIDS. 2018 Oct 23;32(16):2279-2289.
  7. Bernal E, Martinez M, Torres A, et al. T cell senescence predicts subclinical atherosclerosis in HIV-infected patients similarly to traditional cardiovascular risk factors. Antiviral Research. 2019 Feb;162:163-170.
  8. Duffau P, Ozanne A, Bonnet F, et al. Multimorbidity, age-related comorbidities and mortality: association of activation, senescence and inflammation markers in HIV adults. AIDS. 2018 Jul 31;32(12):1651-1660.
  9. Molina PE, Simon L, Amedee AM, et al. Impact of alcohol on HIV disease pathogenesis, comorbidities and aging: Integrating preclinical and clinical findings. Alcohol and Alcoholism. 2018 Jul 1;53(4):439-447.
  10. Heath JJ, Fudge NJ, Gallant ME, et al. Proximity of cytomegalovirus-specific CD8+ T cells to replicative senescence in human Immunodeficiency virus-infected individuals. Frontiers in Immunology. 2018 Feb 15;9:201.
  11. Ballegaard V, Brændstrup P, Pedersen KK, et al. Cytomegalovirus-specific T-cells are associated with immune senescence, but not with systemic inflammation, in people living with HIV. Scientific Reports. 2018 Feb 28;8(1):3778.
  12. Pallikkuth S, De Armas LR, Pahwa R, et al. Impact of aging and HIV infection on serologic response to seasonal influenza vaccination. AIDS. 2018 Jun 1;32(9):1085-1094.
  13. Desai SN, Landay AL. HIV and aging: role of the microbiome. Current Opinion in HIV/AIDS. 2018 Jan;13(1):22-27.
  14. Tanaskovic S, Price P, French MA, et al. Impaired upregulation of the costimulatory molecules, CD27 and CD28, on CD4+ T cells from HIV patients receiving ART is associated with poor proliferative responses. AIDS Research and Human Retroviruses. 2017 Feb;33(2):101-109.
  15. Cobos Jiménez V, Wit FW, et al. T-cell activation independently associates with immune senescence in HIV-infected recipients of long-term antiretroviral treatment. Journal of Infectious Diseases. 2016 Jul 15;214(2):216-25.
  16. Eberhard JM, Ahmad F, Hong HS, et al. Partial recovery of senescence and differentiation disturbances in CD8+ T cell effector-memory cells in HIV-1 infection after initiation of anti-retroviral treatment. Clinical and Experimental Immunology. 2016 Nov;186(2):227-238.
  17. Shive CL, Clagett B, McCausland MR, et al. Inflammation perturbs the IL-7 axis, promoting senescence and exhaustion that broadly characterize immune failure in treated HIV infection. Journal of Acquired Immune Deficiency Syndrome. 2016 Apr 15;71(5):483-92.
  18. Appay V, Sauce D. Assessing immune aging in HIV-infected patients. Virulence. 2017 Jul 4;8(5):529-538.
  19. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Medicine. 2006 Dec;12(12):1365-71
  20. Ramendra R, Isnard S, Mehraj V, et al. Circulating LPS and (1→3)-β-D-Glucan: A folie à deux contributing to HIV-associated immune activation. Frontiers in Immunology. 2019 Mar 18;10:465.
  21. Mehraj V, Ramendra R, Isnard S, et al. Circulating (1→3)-β-D-Glucan is associated with immune activation during HIV infection. Clinical Infectious Diseases. 2019; in press.
  22. Hoenigl M. Fungal Translocation: A driving force behind the occurrence of non-AIDS events? Clinical Infectious Diseases. 2019; in press.
  23. Dagenais-Lussier X, Aounallah M, Mehraj V, et al. Kynurenine reduces memory CD4 T-cell survival by interfering with Interleukin-2 signaling early during HIV-1 Infection. Journal of Virology. 2016 Aug 12;90(17):7967-79.
  24. Chen J, Xun J, Yang J, et al. Plasma Indoleamine 2,3-dioxygenase activity is associated with the size of the human immunodeficiency virus reservoir in patients receiving antiretroviral therapy. Clinical Infectious Diseases. 2019; in press.
  25. Swainson LA, Ahn H, Pajanirassa P, et al. Kynurenine 3-Monooxygenase inhibition during acute simian immunodeficiency virus infection lowers PD-1 expression and improves post-combination antiretroviral therapy CD4+ T cell counts and body weight. Journal of Immunology. 2019 Aug 15;203(4):899-910.
  26. Márquez-Coello M, Montes de Oca Arjona M, Martín-Aspas A, et al. Antiretroviral therapy partially improves the abnormalities of dendritic cells and lymphoid and myeloid regulatory populations in recently infected HIV patients. Scientific Reports. 2019 Aug 12;9(1):11654.
  27. Yero A, Farnos O, Rabezanahary H, et al. Differential dynamics of regulatory T-cell (Treg) and Th17 cell balance in mesenteric lymph nodes and blood following early anti-retroviral initiation during acute SIV infection. Journal of Virology. 2019; in press.
  28. Wang Z, Gurule EE, Brennan TP, et al. Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proceedings of the National Academy of Sciences USA. 2018 Mar 13;115(11):E2575-E2584.
  29. Abreu CM, Veenhuis RT, Avalos CR, et al. Infectious virus persists in CD4+ T cells and macrophages in antiretroviral therapy-suppressed simian immunodeficiency virus-infected macaques. Journal of Virology. 2019; in press.
  30. Nolan DJ, Rose R, Rodriguez PH, et al. The spleen is an HIV-1 sanctuary during combined antiretroviral therapy. AIDS Research and Human Retroviruses. 2018 Jan;34(1):123-125.