Poppers linked to increased risk of some cancers in older MSM without HIV

Association only detected in men aged 50-70

Keith Alcorn
Published: 04 April 2017

Daily or weekly use of poppers over a number of years is associated with a substantial increase in the risk of cancers caused by viruses in men who have sex with men (MSM) without HIV, but only in the 50-70 age group, a study published in the journal AIDS shows. Heavy use of poppers was not associated with an increased risk of these cancers in men with HIV.

Researchers do not rule out the possibility that use of poppers makes it easier to acquire the viruses that lead to some cancers, rather than encouraging these cancers to develop by suppressing the immune system. However, they note that their analysis shows no increase in cancer risk among men with a larger number of sexual partners or men with a higher frequency of sexually transmitted infections, both of which might lead to greater exposure to viral infections such as human papillomavirus (HPV).

Poppers, or nitrite inhalants, are used frequently by men who have sex with men during sex as a stimulant and to make anal intercourse easier. Animal models have shown poppers to cause transient immunosuppression, but numerous epidemiological studies have disproved claims that poppers were linked to immunosuppression in gay men with HIV or to the development of Kaposi’s sarcoma, the most common AIDS-defining cancer.

Nevertheless, concerns persist about possible cancer risks associated with frequent use of poppers, either because of immunosuppression or because they facilitate behaviours that increase the risk of acquiring cancer-causing viruses such as HPV.

The findings come from a large cohort study of men who have sex with men in the United States.

The cohort consisted of 3223 men (1563 with HIV and 1660 without) who were enrolled in the Multicenter AIDS Cohort Study (MACS) in the United States and who had at least one study visit between 1996 and 2010. Men were encouraged to attend study visits approximately once a year after enrolment. Participants had a median age of 43 at their first study visit and were followed for a median of 11 years after enrolment. Seventy-two percent were Caucasian, 18.8% African-American and 8.5% of other ethnicity.

MACS collects a broad range of health and behavioural data including information on recreational drug use, and on immunological markers in men without HIV infection. This analysis investigated the relationship between the use of nitrite inhalants (poppers) and cancer.

The investigators classified participants as heavy, light or non-users of poppers. Heavy use was classified as daily or weekly use reported for at least one year of study enrolment. Light use was classified as monthly use or less frequent use. Heavy use was compared to a control group combining light users and non-users.

Twenty percent of men without HIV and 33% of men with HIV were classified as heavy users of poppers. The study found no significant differences in immunological markers (CD4 count or CD4:CD8 cell ratio) between heavy users of poppers and the control group, in either men with HIV or men without HIV.

Three hundred and twenty-seven cancers were diagnosed in 296 participants. The incidence of non-Hodgkin lymphoma, squamous cell carcinoma of the skin, prostate cancer and other cancers was higher in heavy users of poppers, but after adjustment for age, race, calendar year and HIV status, this difference ceased to be significant.

Next, the researchers looked at the risk of virus-associated cancers in men with and without HIV. Virus-associated cancers include non-Hodgkin lymphoma, Hodgkin lymphoma (caused by EBV), Kaposi’s sarcoma (HHV-8) and anal and oropharyngeal cancer (HPV). Virus-associated cancers are more common in men who have sex with men living with HIV than in the rest of the population, tend to have a worse prognosis in people with HIV and remain an important cause of death in people with HIV.

In this study, cancers caused by hepatitis B or hepatitis C – most commonly liver cancer – were not included in the category of virus-associated cancers owing to the low prevalence of both viruses in the cohort.

Heavy use of poppers was not associated with an increased risk of any virus-associated cancer in men living with HIV after adjusting for age, race, CD4 cell count, viral load and period of antiretroviral treatment.

Increased risk in 50-70 year olds

An increased risk of virus-associated cancers was detected in heavy users of poppers without HIV, but only in men aged 50-70. Men in this age group were three times more likely to be diagnosed with a virus-associated cancer after adjusting for demographic factors, number of sexual partners and CD4 cell count. Among this age group, virus-associated cancers also made up a higher proportion of the total burden of cancers among heavy users of poppers compared to the control group.

The greater the use of poppers over the first five years after enrolment, the higher the risk of virus-associated cancers in men without HIV aged 50-70 (incidence rate ratio 1.011 per day per year of heavy use averaged over five years, 95% CI 1.002-1.020, p = .014), implying a substantially increased risk in very heavy users of poppers.

The incidence rate ratio (IRR) is the ratio of events in the exposed population – the heavy users of poppers – compared to the unexposed population.

The study’s lead author, Dr Dana Gabuzda, Professor of Neurology at the Dana Farber Cancer Institute, Boston, told aidsmap: “The IRR of 1.011 corresponds to an estimated 1% of excess risk per day of exposure per year averaged over five years, and an estimated 20% of excess risk per 20 days of exposure per year averaged over five years. These estimates suggest that excess risk of these cancers is more substantial at higher exposure. For example, 20% excess risk per 20 days of exposure per year averaged over five years, corresponding to 100 days of exposure over a 5-year period, is a substantial estimated increase in excess risk, while 1% excess risk per day of exposure per year averaged over five years, corresponding to only five days of exposure over a 5-year period, is negligible.”

To put these risks in context, Cancer Research UK reports that the lifetime risk of developing the more common virus-associated cancers for a man in the United Kingdom is:

  • Anal cancer, 1 in 795
  • Non-Hodgkin lymphoma, 1 in 48
  • Hodgkin lymphoma, 1 in 370

A doubling in risk – from 1 in 48 to 1 in 24, for example – would correspond to approximately twice-weekly use of poppers for five years. However, because the risk is only elevated in 50-70 year olds and the study was conducted in a US cohort, this change is an illustration rather than a firm estimate.

Models which took into account cumulative exposure adjusted for CD4 cell count and number of sexual partners, genital warts, syphilis, smoking or polydrug use produced very similar estimates of the increase in risk. The investigators note that the number of sexual partners or sexually transmitted infections were not associated with an increased risk of virus-associated cancers, leading them to remark that “it remains unclear whether the excess risk of virus-associated cancer associated with popper use is related to more sexually transmitted infections, transient immunosuppression, or other mechanisms.”

They say that the lack of association in men with HIV is probably due to the much greater impact of HIV-related immunodeficiency on cancer risk.

Reference

Dutta A et al. Long-term nitrite inhalant exposure and cancer risk in men who have sex with men: a prospective cohort study. AIDS, advance online publication, 18 March 2017.

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