Over the last 10–15 years of the combination antiretroviral therapy (ART) era in developed countries, cancers have become an increasingly important contributor to morbidity and mortality in people infected with HIV . In fact, cancer was the leading cause of death in HIV-infected patients in France in 2010, accounting for one-third of all deaths; the proportion of deaths due to non-AIDS-defining malignancies (NADMs), excluding hepatocellular cancers, doubled from 2000 to 2010 . One theory for the increased risk of cancers in HIV-infected patients, particularly NADMs, is persistent immune activation and chronic inflammation. HMG CoA reductase inhibitors (known collectively as statins) have been noted to have several anti-inflammatory properties separate from their actions on cholesterol, and observational studies have shown benefits in myriad noncardiovascular diseases.
Data from two earlier studies in HIV-infected patients indicated that statin use was associated with a reduction in all-cause mortality  and reduced risk of non-Hodgkin lymphoma . In this issue of AIDS, Galli et al. have examined the risk of cancers [both NADMs and AIDS-defining malignancies (ADMs)] in HIV-infected patients taking antiretrovirals in a large cohort in Italy. They found that statin users had significant reductions in the incidence in all cancers, as well as NADMs and ADMs analyzed separately, and the effect remained robust after multivariable analysis. These findings strengthen the conclusions that can be drawn from the earlier studies suggesting a beneficial effect from statins on overall mortality in HIV-infected patients. The biological hypothesis that statins reduce inflammation and subsequent cancer risk in HIV-infected populations is certainly plausible, but does this study provide enough evidence for a causal relationship between statin use and cancer reduction?
The conclusions of the study would have been significantly strengthened if a ‘dose–effect’ relationship had been demonstrated, using additional information about total exposure using dose, duration, and adherence to statins. The authors considered patients ‘statin users’ if they had received a statin for at least 30 days. However, it may be that the protective effect of statins should be measured by total exposure by estimating the dose and duration of exposure cumulatively as in ‘area under the curve’, similar to the quantification of ‘cumulative viremia’ . As up to half of patients starting statins will discontinue them at least temporarily , the assumption that all patients initially prescribed a statin were still taking one for a prolonged period may not be valid. We also do not know the duration of statin use prior to cancer diagnosis, and it is not known how long (e.g. months, years, etc.) it would take for daily statin use to reverse the impact of chronic inflammation such that the subsequent cancer risk is reduced. Moreover, there is a great deal of heterogeneity of statin drugs and dosing included, and some statins may be more or less potent anti-inflammatory agents.
The authors observed that this study may have underestimated the protective effect of statins, but it is also possible that the ‘statin users’ had another factor(s) that reduced their risk for cancer development (residual confounding). Statin use has been associated with a ‘healthy user’ or ‘healthy adherer’ effect, whereby patients initiating and adhering to chronic therapies like statins are more likely to engage in other health-promoting behaviors; bias may result in epidemiologic studies that do not or cannot account for this possibility [8,9]. One such critical factor to consider is the HIV status and situation of the patients taking statins – it is possible (likely even) that statin users were more frequent visitors to clinic and therefore more likely to have controlled and suppressed viremia and higher CD4+ cell counts over time. These factors would have decreased the statin users’ risk for both ADMs (viremia and CD4+) and NADMs (CD4+). Moreover, interactions between antiretrovirals and the two preferred statins (rosuvastatin and pravastatin) may have dictated the choice of antiretroviral used by patients, with potential effects on the control of HIV infection. Both viral load and CD4+ cell count were significant in the multivariable model, but it is difficult to know whether the ‘time-updated’ methodology fully accounted for the cumulative time with unsuppressed viral load or low CD4+ cell count. Differences between the user and nonuser groups would grow more divergent with time, possibly leading to larger differences in cancer risk over time.
Although a very stimulating study, conclusions should be tempered somewhat by these limitations. In particular, caution should continue to be exercised when prescribing statins, with respect to the risk of adverse effects (e.g. rhabdomyolysis) and the numerous interactions between them and antiretrovirals.
When evaluating a hypothesis of causation from observational epidemiologic studies, it is always useful to consider the Bradford Hill conditions for causality when attempting to make the leap from association to causation. With a strong grounding of biological plausibility, this study adds to the limited literature on the effects of statins on cancer incidence in the HIV-infected population. The association is strengthened by the consistency, specificity, and coherence of the relationship. Future observational studies that can demonstrate a clear biological gradient with dosing and duration of usage and exclude confounders could certainly help to make more informed decisions, including concerns on costs and benefits. Large prospective cohorts with solid data on statin drug, dose, and duration can be utilized to corroborate the results of this excellent study.
Meanwhile, the recent work in other areas (chronic obstructive pulmonary disease and acute respiratory distress syndrome) translating encouraging observational data of statin benefits to clinical trials has not succeeded [10–12]. It would be difficult, but not impossible, to design a large-scale randomized trial to evaluate the effect of statin use for primary prevention of cancer in HIV-infected patients, especially one involving patients with no classic indication for statins. In conclusion, this is an intriguing study advancing the hypothesis that statin use, through reduction of chronic inflammation, may lead to reduction in cancer incidence in HIV-infected patients taking ART. More research is definitely needed in this field before any recommendations can be made.
Conflicts of interest
There are no conflicts of interest.
1. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study
. J Acquir Immune Defic Syndr
2. Morlat P, Roussillon C, Henard S, Salmon D, Bonnet F, Cacoub P, et al. Causes of death among HIV-infected patients in France in 2010 (national survey): trends since 2000
3. Moore RD, Bartlett JG, Gallant JE. Association between use of HMG CoA reductase inhibitors and mortality in HIV-infected patients
. PLoS One
4. Chao C, Xu L, Abrams DI, Towner WJ, Horberg MA, Leyden WA, et al. HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons
5. Galli L, Spagnuolo V, Poli A, Salpietro S, Gianotti N, Cossarini F, et al. Use of statins and risk of AIDS-defining and non-AIDS defining malignancies among HIV-1 infected patients on antiretroviral therapy
6. Zoufaly A, Stellbrink HJ, Heiden MA, Kollan C, Hoffmann C, van Lunzen J, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma
. J Infect Dis
7. Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, et al. Discontinuation of statins in routine care settings: a cohort study
. Ann Intern Med
8. Brookhart MA, Patrick AR, Dormuth C, Avorn J, Shrank W, Cadarette SM, et al. Adherence to lipid-lowering therapy and the use of preventive health services: an investigation of the healthy user effect
. Am J Epidemiol
9. Patrick AR, Shrank WH, Glynn RJ, Solomon DH, Dormuth CR, Avorn J, et al. The association between statin use and outcomes potentially attributable to an unhealthy lifestyle in older adults
. Value Health
10. Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD
. N Engl J Med
11. The National Heart Lung and Blood Institute ACTN. Rosuvastatin for sepsis-associated acute respiratory distress syndrome
. N Engl J Med
12. Drazen JM, Gelijns AC. Statin strikeout
. N Engl J Med