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

• HIV treatment can greatly strengthen the immune system but some weakness may persist
• A French study found that 9% of people with HIV who survived an initial cancer subsequently developed a new cancer
• Programs need to be designed and tested to help HIV-positive people reduce their cancer risk

Cases of some cancers were prominent in the first 15 years of the HIV pandemic. In that era, common cancers associated with HIV included the following:

• Kaposi’s sarcoma – caused by human herpes virus 8 (HHV8)
• non-Hodgkin’s lymphoma – caused by Epstein-Barr virus (EBV)
• invasive cervical cancer – caused by human papillomavirus (HPV)

These three cancers are lumped together as AIDS-defining cancers because historically their presence in HIV-positive people suggested profound immune deficiency.

In 1996, in Canada and other high-income countries, potent HIV treatment (ART) became available. ART was able to suppress levels of HIV in the blood. This suppression allowed the immune system to repair itself sufficiently so that the risk of AIDS-related infections and cancers became very rare.

Researchers predict that, based on data collected since 1996, many ART users are likely to have a near-normal life expectancy. However, ART cannot resolve all issues, and it is plausible that over time a minority of people will become at increased risk for cancer for at least the following reasons:

Cancer-causing viruses

Some people with HIV are co-infected with other viruses known to cause cancer. Such viruses include hepatitis B and C, which infect the liver and increase the risk for liver cancer; strains of HPV that can cause cancer of the anus, cervix, mouth, lips, throat, penis and vulva; and Epstein-Barr virus, a member of the herpes virus family that increases the risk for some forms of lymphoma.

Tobacco smoke

Surveys have found that a relatively high proportion of people with HIV smoke tobacco. Smoking tobacco is responsible for many cancers. According to the U.S. National Cancer Institute, tobacco smoking causes the following: “cancer of the lung, larynx (voice box), mouth, esophagus, throat, bladder, kidney, liver, stomach, pancreas, colon and rectum, and cervix, as well as acute myeloid leukemia.”

Alcohol

The National Cancer Institute has stated that the greater the amount of alcohol consumed, the greater the risk for cancers affecting the following parts of the body: “mouth, throat, esophagus, larynx (voice box), liver, and breast.”

Excess inflammation

HIV infection is associated with higher-than-normal levels of inflammation and immune activation. ART reduces but does not normalize these issues. It is at least plausible that chronic inflammation and excess immune activation may modestly weaken or age the immune system. Excess inflammation could also increase the risk for the formation of abnormal cell development, leading to pre-cancer and cancer.

Cytomegalovirus (CMV)

CMV co-infection is relatively common among people with HIV. Some researchers in Canada suggest that CMV can accelerate the aging of the immune system and also contribute to excess inflammation and immune activation.

Dat’AIDS

Researchers in France have been collecting health-related information from people with HIV for a database called Dat’AIDS. The database began enrolling participants as early as 1983 and periodically in subsequent years. Dat’AIDS has amassed information on almost 45,000 people. From time to time, researchers analyze the information in the database and produce useful reports.

A recent analysis from Dat’AIDS focused on people who survived an initial occurrence of cancer. Researchers found that 9% of participants who survived their first cancer went on to develop a second, different (new) form of cancer, which is referred to as a “second primary cancer”. Many of the people who developed a second new cancer had a very low CD4+ count in the past (less than 200 cells/mm³) and had long-standing HIV infection, diagnosed prior to 1996.

The French researchers stated that “second primary cancers are now a major concern in HIV-positive cancer survivors, justifying the development of monitoring strategies after a first cancer.”

Study details

Researchers reviewed health-related information collected from 17 major clinics in France. Participation recruitment began in 1983 and the data were analyzed to the end of 2015.

The researchers divided cancers into the following three groups:

• AIDS-defining cancers – Kaposi’s sarcoma, non-Hodgkin’s lymphoma and invasive cervical cancer
• virus-related non-AIDS-defining cancers – including those caused by hepatitis B and C viruses, HPV, EBV (this can cause Hodgkin’s lymphoma) and Merkel cell polyomavirus (this can cause Merkel cell cancer)
• all other cancers

A brief profile of participants at the time they entered the cancer analysis was as follows:

• 83% men, 17% women
• age at first cancer – 46 years
• first cancer occurred in 1996 or earlier – 22%
• first cancer occurred after 1996 – 78%
• 77% had a CD4+ count below the 200-cell/mm mark at some point in the past prior to initiating ART, indicating profound immune deficiency
• 60% were diagnosed with HIV prior to 1996
• 16% were co-infected with HCV
• 9% were co-infected with HBV
• 32% were past smokers and 37% were current smokers

On average, participants were monitored for nine years.

Results

Out of the 44,642 people in Dat’AIDS, 444 (9%) developed one cancer and then later a second cancer that was different from the first one.

At the end of the study period, the distribution of participants who developed cancer was as follows:

• alive – 55%
• deceased – 35%
• lost contact with their clinic – 10%

First cancer

The average age at the time of first primary cancer (that is, the cancer was new and not a recurrence or spread of another cancer) was 46 years.

The distribution of first primary cancers was as follows:

• AIDS-defining cancers – 269 people
• virus-related non-AIDS-defining cancers – 51 people
• all other cancers – 124 people

Second cancer

The average age at the time of second primary cancer was 51 years. On average, people developed a second cancer four years after the first one was diagnosed; this did not differ by gender.

The distribution of second primary cancers was as follows:

• AIDS-defining cancers – 130 people
• virus-related non-AIDS-defining cancers – 85 people
• all other cancers – 229 people

Comparing the first and second cancers, one can see that AIDS-related cancers comprised a majority of first cancer, while “all other cancers” were more common in cases of second cancer.

Types of second cancer

The most common second cancers were distributed as follows, in descending order:

Men

• non-Hodgkin’s lymphoma
• skin cancer
• Kaposi’s sarcoma
• cancers of the digestive tract
• lung cancer
• anal cancer

Women

• breast cancer
• skin cancer
• non-Hodgkin’s lymphoma
• Kaposi’s sarcoma
• lung cancer
• liver cancer

The researchers noted that among HIV-negative women in France, breast cancer is the most common second cancer. Also, proportionally, more women than men injected street drugs in Dat’AIDS, so that is likely how they became exposed to HCV. Therefore, it should not be surprising that liver cancer, a consequence of HCV infection, was more common among women.

Bear in mind

Based on information in Dat’AIDS, the following is clear:

• 63% of participants were diagnosed with HIV prior to 1996 when ART became available
• 77% of participants had a CD4+ cell count below the 200-cell/mm³ mark at some point

Taken together, these two points suggest that some participants spent a period of time with profound immune deficiency and would have had uncontrolled production of HIV. It is possible that during this time their immune systems were too weak to recognize and eliminate persistent co-infections of cancer-causing viruses. What’s more, it is likely that during this period of profound immune deficiency, cancer-causing viruses could have transformed some infected cells into an abnormal state. In addition, emerging research suggests that some of HIV’s proteins can help transform abnormal cells into pre-cancer and cancer.

The present report from the Dat’AIDS study is important and shows that second new cancers are affecting almost 10% of people with HIV who survived their first 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, socio-economic status, genetics and other factors. Some risk factors can be modified, but others (such as one’s family history or genetics) cannot. Focusing on risks that can be modified and reducing such risks can generally lead to better overall health and, likely, reduced chances of developing cancer.

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
• people with a history of smoking can find out about the availability of lung cancer screening

—Sean R. Hosein

Resources

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

REFERENCES:

1. 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.
2. 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.
3. 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.
4. Gottlieb GJ, Ragaz A, Vogel JV, et al. A preliminary communication on extensively disseminated Kaposi’s sarcoma in young homosexual men. American Journal of Dermatopathology. 1981 Summer;3(2):111-4.  
5. Centers for Disease Control (CDC). Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men—New York City and California. MMWR Morbidity and Mortality Weekly Report. 1981 Jul 3;30(25):305-8.
6. Thomsen HK, Jacobsen M, Malchow-Møller A. Kaposi sarcoma among homosexual men in Europe. Lancet. 1981 Sep 26;2(8248):688.
7. Medzhitov R. The spectrum of inflammatory responses. Science. 2021 Nov 26;374(6571):1070-1075.
8. 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. 
9. 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. 
10. 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. 
11. Isaguliants M, Bayurova E, Avdoshina D, et al. Oncogenic effects of HIV-1 proteins, mechanisms behind. Cancers (Basel). 2021 Jan 15;13(2):305.
12. 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.  
13. 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. 
14. 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.
15. 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.
16. 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. 
17. 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.
18. 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. 
19. 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.
20. 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.
21. Kaiser AE, Baniasadi M, Giansiracusa D, et al. Sulforaphane: A broccoli bioactive phytocompound with cancer preventive potential. Cancers (Basel). 2021 Sep 25;13(19):4796.
22. Mercié P, Arsandaux J, Katlama C, et al. Efficacy and safety of varenicline for smoking cessation in people living with HIV in France (ANRS 144 Inter-ACTIV): a randomised controlled phase 3 clinical trial. Lancet HIV. 2018 Mar;5(3):e126-e135.