Both HIV-positive and HIV-negative people who use statins to manage cardiovascular disease risk also have a lower risk of cancer, according to research presented at the 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018) in Boston. Statin users were about 40% less likely to develop cancer overall, with an even larger risk reduction seen for certain cancers caused by viruses, Dr Roger Bedimo of the Veterans Affairs North Texas Health Care Centre in Dallas reported.
Statins are commonly used to lower blood lipid levels and reduce the risk of cardiovascular disease. But in addition to inhibiting cholesterol synthesis, this class of medications has other effects including reducing inflammation and influencing T-cell proliferation and activity in a way that may enhance immune responses against tumours, Bedimo noted as background.
Some previous research has shown that statin use is associated with reduced risk of cancer in the general population, but study results have been inconsistent. Beneficial effects might be greater for people with HIV, hepatitis C and other long-term infections that can cause chronic immune activation and inflammation. But to date, the link between statin use and cancer in HIV-positive people has only been explored in small and short studies.
Bedimo and colleagues at Yale University, the Icahn School of Medicine at Mt Sinai, James J Peters VA Medical Centre in the Bronx, University of Washington in Seattle, VA Greater Los Angeles Health Care System and the VA Connecticut Healthcare System, analysed associations between statin exposure and cancer risk in the Veterans Aging Cohort Study (VACS), a large observational study of US military veterans, using cancer registry and pharmacy data. The VACS includes all HIV-positive people receiving care through the VA system, matched 2-to-1 with HIV-negative people with similar characteristics.
The researchers identified statin users in the cohort between 2000 and 2012. They adjusted for known and potential confounding factors including age, smoking history, chronic conditions such as diabetes, hypertension, hepatitis C and heavy alcohol use, and lab values such as LDL cholesterol levels and liver fibrosis markers.
After propensity score matching, the analysis cohort included 12,014 statin users and an equal number of non-users. In both groups combined, 5105 were HIV positive and 19,067 were HIV negative. Being a veterans cohort, the population consisted of mostly men.
The study looked at the risk of all cancers, Aids-related cancers (Kaposi’s sarcoma, non-Hodgkin lymphoma) and non-Aids cancers, and several specific cancer types. It also analysed virus-related cancers including anal and oral cancer (caused by human papillomavirus or HPV), liver cancer (caused by hepatitis B or C) and Hodgkin and non-Hodgkin lymphoma (associated with Epstein-Barr virus).
Cancer was newly diagnosed in 449 HIV-positive people (9.0%) and 1,350 HIV-negative people (7.1%) during a follow-up period of four to five years. Of note, just 64 cases were Aids-defining cancers.
Overall, statin use was associated with a 39% lower risk of all cancers combined. In general, the protective effect of statins was stronger among people with HIV compared with HIV-negative people (49% vs 35% overall reduction, respectively). However, the interaction between statin use and HIV status did not reach statistical significance for specific cancer types or categories.
The risk of non-Aids cancers fell by 37% – similar to the overall reduction – but Aids-defining cancers were 69% less likely among statin users. Interestingly, HIV-negative as well as HIV-positive people saw a decrease in Aids-defining cancers. Non-virus-related cancers and virus-related cancers as a group fell to a similar extent (by 37% and 36%, respectively).
Specific cancer types were quite variable, however. The risk of anal cancer and liver cancer both decreased by 38%, with a much larger drop among HIV-positive compared with HIV-negative people. Hodgkin lymphoma fell by 57%, oral cancer fell by 65% and non-Hodgkin lymphoma decreased by 71%. Lung cancer – which is considered non-virus-related but some research has linked to HPV – fell by 51% among people who took statins. Prostate cancer fell by just 17%.
Looking at all-cause mortality, the risk of death was 45% lower among statin users compared with non-users, Bedimo reported.
Based on these findings, the researchers concluded, “Statin exposure is associated with lower risk of cancer independent of HIV status. This protective effect appears to be stronger for virus-related cancers.”
It is important to note that seemingly large changes in relative or comparative risk can mask quite small absolute numbers of cases, particularly for less common cancers, which limits confidence in the results. But the fact that the risk of many cancer types consistently fell among statin users – with no increase observed for any type – and that risk reductions were usually larger for HIV-positive people, suggest that this is a real effect that warrants further study.
A large study known as REPRIEVE (Randomised Trial to Prevent Vascular Events in HIV) is evaluating whether daily statins can reduce the risk of heart disease among people with HIV, and it will also look at cancer and other non-Aids conditions. The study is currently enrolling participants at more than 100 sites in North and South America, Africa and India.
Beyond inhibition of cholesterol biosynthesis, statins appear to have pleiotropic effects, including modulation of cell growth, apoptosis, and inflammation. Statins may also reduce cancer risk, particularly among HIV-infected (HIV+) subjects who experience chronic inflammation and immune activation. Small observational studies have suggested an association between statin use and lower cancer risk in HIV+ but small sample sizes limited cancer type-specific analyses. Comparison of the association of statin exposure with cancer in HIV+ and HIV-uninfected comparators (HIV-) is also lacking. We used the Veterans Aging Cohort Study (VACS), a large observational cohort with cancer registry linkage and detailed pharmacy data to address these questions
We followed statin users identified between 2000-2012, beginning 180 days after an index date defined as first statin prescription for users and a random visit date in the same year for non-users. To account for known and potential confounders we fit a propensity score (PS) model for statin use including age, calendar year, smoking, chronic diseases (e.g., diabetes, hypertension, HCV co-infection, alcohol use disorder), and laboratory values (e.g., LDL, albumin). We matched each statin user to up to four non-users by PS. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) associated with statin use for all cancers, individual cancers, infection-related cancers (anal, colorectal, head and neck, liver, lymphoma, and stomach) and notinfection-related cancers.
The PS-matched sample included 48,214 participants, of whom 23,512 (48.8%) were incident statin users. Incident cancers were diagnosed in 940 (9.7%) of 9,649 HIV+ and 3,079 (8.0%) in 38,565 uninfected. Overall, statin use was associated with ~20% reduced risk of any cancer [HR 0.82 (95% CI 0.77 – 0.88)] and ~40% lower risk for infection-related cancers [HR 0.62 (95% CI 0.55 – 0.70)]. In general, the association was stronger in HIV+, but the interaction did not reach statistical significance except for non-Hodgkin lymphoma
Statin exposure is associated with lower risk of cancer independent of HIV status. This protective effect appears to be stronger for infection-related cancers.
Roger Bedimo, Fatma Shebl, Keith M Sigel, Sheldon T Brown, Kristina Crothers, Matthew B Goetz, Amy C Justice, Janet Tate