Poppers and cancer risk in HIV negative and HIV positive gay men
Gareth Hardy, HIV i-Base
Previous research has shown that use of poppers may be associated with transient immunosuppression in animal models and may facilitate infection with cancer-causing viruses such as human herpes virus-8 (HHV-8), which causes Kaposi’s Sarcoma (KS).
A new report from the prospective observational Multicentre AIDS Cohort Study (MACS) suggests that heavy use of poppers might be associated with increased risk of individual virus-associated cancers. This link was observed in HIV negative men but not in men who were HIV positive. Heavy use was defined as daily or weekly for at least a year. The study was reported by Anupriya Dutta and colleagues from the Dana-Farber Cancer Institute in Boston, Massachusetts. 
Increasing numbers of HIV positive people live into older age, with increased risk of many cancers, especially those associated with viruses such as HHV-8, human papilloma virus (HPV), Epstein Barr Virus (EBV), and hepatitis B and C viruses (HBV and HCV).
Previous studies of cancer risk in HIV positive MSM have tended to examine cohorts of mixed sexual orientation, which means that risk factors specific to MSM may be overlooked, such as sexual transmission of cancer-associated viruses like HHV-8 or HPV. There is a higher frequency of cancers in HIV positive MSM that are caused by sexually transmitted viruses  and it is not known whether recreational drug use contributes to this by increasing rates of high risk sex  or for other reasons.
One concern is that unlike most recreational drugs, poppers are thought to cause transient immuno-suppression  and so they may facilitate sexual transmission of cancer-associated viruses. Dutta and colleagues investigated the association between popper use and cancer risk in HIV positive and negative MSM.
Participants from MACS attended semi-annual clinic visits at which behavioral, clinical and laboratory data were obtained. Out of a total 6972 participants, 3223 were eligible (1660 HIV negative and 1563 HIV positive). Popper use was self-reported and usage level was defined as:
- Heavy (daily or weekly use for at least 1 year).
- Light (monthly or less).
- Non-use, comprising the control group.
Data was also collected on cancer occurrence per 100,000 person years, viral load, CD4 count, CD4/CD8 ratio and ART use, which was stratified according to whether participants started ART early (1996 to 2000) or late (2001 to 2010). Poisson regression models were generated and adjusted for age, race, and ART calendar period and models restricted to HIV positive MSM were also adjusted for CD4 count and viral load.
Heavy popper users (20.3% HIV negative and 33% HIV positive) reported more sexual partners, more sexually transmitted infections (syphilis and genital warts) and more poly-drug use compared to non-popper use controls. There were no differences in CD4 count, CD4:CD8 ratio or viral load between heavy popper users and non-use controls.
Within the 3223 participants, there were 327 incidents of cancer among 296 participants. Single cancers occurred in 269 participants, two different cancers occurred in 24 participants and three cancers occurred in three participants.
The crude incidence of many cancers was higher in heavy popper users than controls, in both HIV positive and HIV negative MSM. These cancers included Non-Hodgkins Lymphoma (NHL), squamous cell carcinoma of the skin, prostate cancer and others. The incidence rate of anal cancer was higher among heavy popper users only in the HIV negative participants. Conversely, melanoma was higher among heavy poppers users only in the HIV positive participants. As expected there was a much higher incidence of cancers in HIV positive participants, independently of popper use.
Importantly, the significant association between heavy popper use and risk (incidence rate ratio/IRR) of NHL (IRR 1.98%; 95% CI: 1.1 to 3.57) or squamous cell carcinoma of the skin (IRR 1.54; 95%CI: 0.9 to 2.63), was only apparent in unadjusted models. In adjusted models, heavy popper use was not associated with risk of any cancers.
When the researchers looked at just HIV positive MSM in adjusted models, there was no association between heavy popper use and incidence of virus-associated cancers, including KS, anal cancer or squamous cell carcinoma of the skin.
An association between heavy popper use and cancer risk in HIV negative MSM alone was harder to determine as the incidence of cancers in this group was much lower. In order to gain sufficient numbers to power this assessment the researchers created a composite group of individual cancers, which consisted of KS, NHL, Hodgkin’s lymphoma and anal cancer. In HIV negative MSM, heavy popper use was significantly associated with risk of composite virus associated cancers among older men aged 50 to 70 years old in adjusted models (IRR 3.04; 95%CI: 1.01 to 9.12).
Furthermore, using a continuous variable of cumulative popper exposure in adjusted models, increasing cumulative exposure to poppers was significantly associated with increased risk of virus associated cancers among older HIV negative MSM (IRR 1.012 [1.003 – 1.022]) per day of use, per year over the first five years of study enrollment.
This research provides evidence that heavy use of poppers (daily or weekly for at least 1 year), is significantly associated with the risk of virus-related cancers in MSM who are HIV negative and this risk becomes greater over the age of 50.
The researchers speculate that the most likely reason why there was no apparent effect of popper use on cancer risk in HIV positive MSM is because the immunodeficiency induced by HIV is far more profound than any immunosuppressive effect of poppers.
- Dutta A et al. Long-term nitrite inhalant exposure and cancer risk in MSM. AIDS. 2017.
- Boehmer U et al. Cancer and men who have sex with men: A systematic review. Lancet Oncol. 2012. 13. E545-e553.
- Daskalopoulou M et al. Recreational drug use, polydrug use and sexual behaviour in HIV-diagnosed men who have sex with men in the UK: results from the cross-sectional ASTRA study. Lancet HIV. 2014. 1. e22-e31.
- Guo GL, et al. Acute exposure to the abused inhalant, isobutyl nitrite, reduced T cell responsiveness and spleen cellularity. Toxicol Lett. 2000. 116:151-158.