- HIV treatment (ART) improves health and leads to near-normal life expectancy for many people
- However, not all people experience complete normalization of their immune system with ART
- A large study found that a low cell ratio was linked to about a 25% increased risk for some cancers in people with HIV
When used as prescribed, treatment for HIV (ART) can usually suppress levels of HIV in the blood. Continued use of ART can keep HIV suppressed, which results in improved measures of health. It also results in HIV not being transmitted to sexual partners. The power of ART is so profound that researchers project that many ART users will have near-normal life expectancy.
However, ART does not resolve all immunological issues that can accompany HIV. Research has found that HIV infection triggers excessive levels of inflammation and immune activation. ART significantly reduces but does not normalize these issues. Research with HIV-negative people suggests that persistent excess inflammation and/or immune activation can contribute to an increased risk for a range of conditions, including the following:
- cardiovascular disease
- type 2 diabetes
- kidney disease
- degenerative diseases that affect the brain
- excessive fat in the liver
- thinning of bones
It is therefore possible that excess inflammation and immune activation have the potential to contribute to similar issues in people with HIV.
Specific risk factors
As a population, people with HIV tend to have a higher risk of exposure to viruses that are associated with an increased risk for immunological problems or cancers, such as the following:
- EBV (Epstein-Barr virus), which is associated with certain lymphomas.
- Hepatitis B and C viruses, which can cause liver cancer.
- Human papillomavirus (HPV), which causes cancer of the anus, cervix, penis, back of the tongue, throat, vagina and vulva.
- Human herpes virus-8 (HHV-8), which causes Kaposi’s sarcoma (KS).
Reports from clinics suggest that there are high rates of smoking among some people with HIV. According to the U.S. National Cancer Institute, smoking is associated with an increased risk for cancers affecting the following parts of the body (in alphabetical order): bladder, bone marrow, cervix, colon and rectum, throat, kidney, liver, lung, mouth and pancreas.
Thanks to ART, many people with HIV are living longer, healthier lives. However, as the immune system ages, it gradually weakens. A study of 47,000 HIV-positive people in North America found that between 1995 and 2009, 10% of deaths were related to cancer. What’s more, the same study found that among people aged 55 and older, cancer was responsible for 13% of deaths. This connection between aging and cancer risk does not mean that all or even most people with HIV who are older will get cancer. However, it does mean that their risk for cancer is likely increased compared to younger people with HIV. Therefore, finding ways to predict cancer risk will become more important as people with HIV grow older.
About the CD4/CD8 ratio
The ratio of two types of cells of the immune system—CD4+ and CD8+ cells (CD4/CD8)—can provide doctors with a sense of the overall health of the immune system. In most people with a well-functioning immune system, the CD4/CD8 ratio is 1.0 or greater.
Studies have found that a low CD4/CD8 ratio is associated with untreated HIV infection, older age, increased inflammation and premature aging of the immune system.
Important Canadian research on early initiation of ART and the CD4/CD8 ratio is presented later in this bulletin.
In North America
A team of researchers in North America with an ongoing study called the NA-ACCORD collected and analysed health-related information from nearly 84,000 people with HIV who were initially cancer free and monitored them from 1998 to 2016. During this time, nearly 7% developed cancer.
The researchers found that participants who had a low CD4/CD8 ratio (in this case 0.3) had a 24% increased risk for some cancers developing between six and 24 months after they developed a low cell ratio. This finding was statistically significant; that is, not likely due to chance alone.
The average profile of participants when they entered the study was as follows:
- 87% male, 13% female
- age – 43 years
- major ethno-racial groups: White – 43%; Black – 37%; Hispanic – 11%
- CD4+ count – 413 cells/mm3
- CD4/CD8 ratio – 0.47
- proportion with less than 500 CD4+ cells/mm3 – 58% (note that 90% of participants initiated ART once in the study)
- proportion with an undetectable viral load – 58%
- history of AIDS-related illness – 14%
- chronic hepatitis C virus – 21%
- chronic hepatitis B virus – 7%
- history of tobacco use – 34%
- length of time in the study – 9 years
Overall, 17% of participants died. A total of 7% of participants died from complications arising from new cancers. The most common cancers in the study were as follows:
- prostate cancer – 817 people
- lung cancer – 755 people
- KS – 501 people
- non-Hodgkin’s lymphoma – 497 people
- liver cancer – 347 people
- colorectal cancer – 221 people
Cancer risk – six months
The researchers explored the impact of different CD4/CD8 ratios on the subsequent risk for cancer. They found that people who had a CD4/CD8 ratio of 0.3 (compared to people who had a ratio of 0.8) had a 24% increased risk of certain cancers regardless of the following factors:
- CD4+ cell count
- HIV viral load
- age at the time they entered the study
- history of AIDS
- smoking status
- BMI (body mass index)
- alcohol consumption
- whether they acquired HIV sexually or via sharing equipment for drug use
The researchers stated that this increased risk for cancer six months after a low CD4/CD8 ratio occurred was associated with the following cancers:
- non-Hodgkin’s lymphoma
- lung cancer
- anal cancer
- colorectal cancer
Cancer risk – a longer timeline
The researchers also assessed the relationship between a low CD4/CD8 ratio and subsequent risk of cancer 12, 18 and 24 months later. They found that having a low CD4/CD8 ratio increased the risk of cancer (the types previously mentioned). The results were similar whether or not people were on ART at the time the low CD4/CD8 count was assessed.
Bear in mind
The association between a low CD4/CD8 ratio and subsequent cancer risk suggests that immunological dysfunction contributes to the development and/or growth of cells from some tumours. In addition to factors listed previously, the researchers mentioned others that may play a role in causing persistent immunological dysfunction (and thereby contributing to ongoing cancer risk), including the following:
- chronic infection with a member of the herpes virus family—cytomegalovirus (CMV)
- having a large burden of HIV-infected cells in the body
- persistent immune activation and inflammation
Canadian research on the CD4/CD8 ratio
A separate 3,218-person study in Canada found that initiating ART earlier in the course of HIV (when CD4+ cell counts are higher) increases the chances of achieving a normal CD4/CD8 ratio. Among people who initiated ART when their CD4+ count was greater than 500 cells/mm3, 68% subsequently had a normalized CD4/CD8 ratio five years later. In contrast, only 16% of people who initiated ART when their CD4+ count was 200 cells/mm3 or lower subsequently had a normalized CD4/CD8 ratio five years later.
This Canadian research is yet another line of evidence supporting the earlier initiation of ART.
The NA-ACCORD study is a good step forward in trying to find ways to estimate cancer risk for people with HIV. As with all studies, the recent analysis from the NA-ACCORD is imperfect. The researchers noted that they had incomplete information on smoking from participants.
However, the research team calls for additional studies to find out how CD4/CD8 ratios can be best used in cancer screening and clinical care for people with HIV. Such studies will need to consider specific cancers, demographic information, medical history and immunological assessments. The latter assessments may become more important.
A small but detailed study by researchers at Yale University and the U.S. military suggests that blood samples from people with HIV who develop cancer showed signals of immunological exhaustion about 12 months prior to the diagnosis of cancer. In this study the researchers focused on a limited set of cancers (HPV-associated cancers, lung cancer and lymphoma). Although the study was small, it is part of a growing body of evidence linking immunological issues with an increased risk for cancer.
Recent research suggests that, in general, cancer is a growing problem worldwide. Everyone’s cancer risk is different and dependent on multiple issues, such as behaviour, socioeconomic status, genetics and other factors. Some risk factors can be modified, but others (such as one’s family history or genetics) cannot. Reducing those risks that can be modified can generally lead to better overall health.
The following lists contain tips for better health in general and, in particular, ideas about cancer prevention and screening that can be discussed with a healthcare professional. These lists are not comprehensive.
General health tips
- Get help for cutting down and ultimately quitting smoking.
- Get help for reducing alcohol intake.
- Consult with a harm reduction organization to learn about ways to reduce the risk of exposure to hepatitis C virus.
- Maintain a healthy weight.
- Engage in regular exercise.
- Eat a diet rich in colourful fruits and vegetables (including cruciferous vegetables).
Cancer prevention and screening
In general, screening for breast, colon and prostate cancer is routinely done in many high-income countries depending on age and other factors. Specific groups may consider one or more of the following additional interventions for discussion with a doctor or nurse:
- screening for HPV-related diseases and HPV vaccination
- screening for hepatitis B and C viruses, and, if necessary, treatment; a vaccine for HBV is available to prevent infection with this virus
- lung cancer screening for people with a history of smoking
—Sean R. Hosein
French researchers investigate second cancers in people with HIV who survived a first cancer – CATIE News
Second cancer risk after surviving Hodgkin's lymphoma in people with HIV – CATIE News
Can the CD4/CD8 ratio be used to predict the risk of anal cancer in HIV-positive people? – CATIE News
Changes in CD4+ cell count after cancer treatment linked to survival among HIV-positive people – CATIE News
Cancer – Government of Canada
Cancer – Government of Quebec
- Castilho JL, Bian A, Jenkins CA, et al. CD4/CD8 ratio and cancer risk among adults with HIV. Journal of the National Cancer Institute. 2022; in press.
- Patterson S, Cescon A, Samji H, et al. Life expectancy of HIV-positive individuals on combination antiretroviral therapy in Canada. BMC Infectious Diseases. 2015 Jul 17;15:274.
- Engels EA, Yanik EL, Wheeler W, et al. Cancer-attributable mortality among people with treated human immunodeficiency virus infection in North America. Clinical Infectious Diseases. 2017 Aug 15;65(4):636-643.
- Poizot-Martin I, Lions C, Allavena C, et al. Determinants of second primary cancer type in survivors of virus-related and non-virus-related cancer living with HIV in the French Dat’AIDS Cohort. Cancer Control. 2021;28:1-7.
- Poizot-Martin I, Lions C, Delpierre C, et al. Prevalence and spectrum of second primary malignancies among people living with HIV in the French Dat’AIDS cohort. Cancers. 2022; in press.
- Abrahão R, Brunson AM, Kahn JM, et al. Second primary malignancy risk after Hodgkin lymphoma treatment among HIV-uninfected and HIV-infected survivors. Leukemia and Lymphoma. 2022; in press.
- Verdu-Bou M, Tapia G, Hernandez-Rodriguez A, et al. Clinical and therapeutic implications of Epstein–Barr virus in HIV-related lymphomas. Cancers. 2021; 13(21):5534.
- Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Compton K, Dean FE, et al. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: A systematic analysis for the Global Burden of Disease Study 2019. JAMA Oncology. 2022; in press.
- Chavez-Dominguez R, Perez-Medina M, Aguilar-Cazares D, et al. Old and new players of inflammation and their relationship with cancer development. Frontiers in Oncology. 2021 Nov 22;11:722999.
- 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.
- Medzhitov R. The spectrum of inflammatory responses. Science. 2021 Nov 26;374(6571):1070-1075.
- Frasca D, Pallikkuth S, Pahwa S. Effects of aging on metabolic characteristics of human B cells. JAIDS. 2022 Feb 1;89(Suppl 1):S23-S28.
- Isaguliants M, Bayurova E, Avdoshina D, et al. Oncogenic effects of HIV-1 proteins, mechanisms behind. Cancers (Basel). 2021 Jan 15;13(2):305.
- 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.
- Royston L, Isnard S, Lin J, et al. Cytomegalovirus as an uninvited guest in the response to vaccines in people living with HIV. Viruses. 2021 Jun 29;13(7):1266.
- Isnard S, Ramendra R, Lin J, et al. Anti-cytomegalovirus immunoglobulin G is linked to CD4 T-cell count decay in human immunodeficiency virus (HIV) elite controllers. Clinical Infectious Diseases. 2021 Jul 1;73(1):144-147.
- Ramendra R, Isnard S, Lin J, et al. Cytomegalovirus seropositivity is associated with increased microbial translocation in people living with human immunodeficiency virus and uninfected controls. Clinical Infectious Diseases. 2020 Sep 12;71(6):1438-1446.
- Strindhall J, Löfgren S, Främsth C, et al. CD4/CD8 ratio <1 is associated with lymphocyte subsets, CMV and gender in 71-year-old individuals: 5-year follow-up of the Swedish HEXA Immune Longitudinal Study. Experimental Gerontology. 2017 Sep; 95:82-87.
- Nikolich-Žugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nature Immunology. 2018 Jan;19(1):10-19.
- Hadrup SR, Strindhall J, Køllgaard T, et al. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. Journal of Immunology. 2006 Feb 15;176(4):2645-53.
- Pangrazzi L, Weinberger B. T cells, aging and senescence. Experimental Gerontology. 2020 Feb 22; 134:110887.
- de Vries S, Schaapveld M, Janus CPM, et al. Long-term cause-specific mortality in Hodgkin lymphoma patients. Journal of the National Cancer Institute. 2021 Jun 1;113(6):760-769.
- Schaapveld M, Aleman BM, van Eggermond AM, et al. Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. New England Journal of Medicine. 2015 Dec 24;373(26):2499-511.
- Díaz-Álvarez J, Roiz P, Gorospe L, et al. Implementation of a lung cancer screening initiative in HIV-infected subjects. PLoS One. 2021 Dec 10;16(12):e0260069.
- 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 of Immunotherapy for Cancer. 2022 Apr;10(4):e004564.
- Molina-Montes E, Ubago-Guisado E, Petrova D, et al. The role of diet, alcohol, BMI, and physical activity in cancer mortality: Summary findings of the EPIC Study. Nutrients. 2021 Nov 28;13(12):4293.
- Connolly EL, Sim M, Travica N, et al. Glucosinolates from cruciferous vegetables and their potential role in chronic disease: Investigating the preclinical and clinical evidence. Frontiers in Pharmacology. 2021 Oct 26; 12:767975.
- Zhabokritsky A, Szadkowski L, Cooper C, et al. Increased CD4: CD8 ratio normalization with implementation of current ART management guidelines. Journal of Antimicrobial Chemotherapy. 2021 Feb 11;76(3):729-737.