North American study finds low CD4/CD8 ratio can help predict cancer risk in people with HIV

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CATIE News 06022022
  • 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

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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.

Aging

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.

Study details

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

Results

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
  • KS
  • 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.

Future research

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.

Reducing risks

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

Resources

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

Canadian Cancer Society

Cancer – Government of Canada

Cancer – Government of Quebec

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