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CROI 2015: Smoking Outweighs HIV-Related Risk Factors for Non-AIDS Cancers


Smoking appears to contribute most to the burden of non-AIDS-defining cancers diagnosed in people living with HIV in the U.S., out of all the potential modifiable risk factors -- including hepatitis B or C, low CD4 cell count, an AIDS diagnosis, or having an unsuppressed viral load -- according to a study reported last week at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

The study, presented by Keri Althoff of Johns Hopkins Bloomberg School of Public Health, found that the population attributable fraction (PAF) -- or the proportion of non-AIDS cancer cases that could be avoided by people with HIV if they had the same level of smoking as the reference population -- was 37% for all non-AIDS cancers and 29% if lung cancer was excluded.

Cancer Among People with HIV

As noted by other presenters at the conference, the risk of AIDS-defining cancers is greatly elevated in people living with HIV, though these cancers have become less common since the introduction of antiretroviral therapy (ART). However, the risk of certain other types of cancer is also elevated, and may be increasing among people with HIV -- particularly as they live to older ages on effective HIV treatment.

A number of factors are thought to contribute to this increased burden of non-AIDS cancers, including a higher frequency of smoking, recreational drug or alcohol use, and higher rates of coinfection with other viruses associated with specific cancers such as hepatitis B virus (HBV) and hepatitis C virus (HCV), which cause liver cancer, and human papillomavirus (HPV), which causes anal, cervical, genital, and oral cancer. In addition, HIV infection itself, the chronic inflammation associated with HIV ongoing replication, or HIV-related immunosuppression may also play significant roles in the development of non-AIDS cancers.

For instance, another presentation at the meeting by Keith Sigel of the Icahn School of Medicine at Mount Sinai looked specifically at the association between HIV-related immune suppression and lung cancer over 2 years in a cohort of 26,065 veterans living with HIV from the Veterans Aging Cohort Study (VACS).

This study found that having an average CD4 cell count (over the 24-month period) below 200 cells/mm3 was associated with a 70% greater risk of lung cancer, and having a CD4 count between 200-500 cells/mm3 was associated with a 30% increased risk compared to HIV-positive people with CD4 cell counts above 500 cells/mm3. Similarly, having a CD4/CD8 cell ratio below 0.4 was associated with a 70% increase in lung cancer risk compared to higher ratios. Immune suppression, however, did not appear to be associated with a higher rate of lung cancer-associated mortality, although it was associated with greater overall or all-cause mortality.

Although Sigel maintained that it remains unproven, it is hoped that earlier and more effective ART would reduce the risk of lung cancer and possibly other non-AIDS cancers in people living with HIV. However, a better understanding of how much cancer is due to various risk factors may help identify interventions that could prevent even more cases.

Non-AIDS Cancer in NA-ACCORD

That was the objective of Althoff’s study, which looked at the incidence of non-AIDS-defining cancer among 16 participating cohorts from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) from January 1, 2000 through December 31, 2009. The study included almost 39,000 adults, almost 600 of whom received new non-AIDS cancer diagnoses. Lung cancer was the most common non-AIDS cancer diagnoses in this cohort.

Cancer type:

  • Anal cancer: 96 cases, 16%
  • Bladder cancer: 7 cases, 1%
  • Brain and nervous system cancer: 3 cases, 1%
  • Breast cancer: 42 cases, 7%
  • Colon and rectal cancer: 31 cases, 5%
  • Esophageal cancer: 8 cases, 1%
  • Hodgkin lymphoma: 54 cases, 9%
  • Kidney and renal pelvis cancer: 24 cases, 4%
  • Larynx cancer: 10 cases, 2%
  • Leukemia: 12 cases, 2%
  • Liver cancer: 42 cases, 7%
  • Lung cancer: 101 cases, 17%
  • Melanoma: 22 cases, 4%
  • Myeloma: 11 cases, 2%
  • Oral cavity and pharynx (mouth and throat): 26 cases, 4%
  • Ovarian cancer: 5 cases, 1%
  • Penis cancer: 5 cases, 1%
  • Pancreatic cancer: 10 cases, 2%
  • Prostate cancer: 60 cases, 10%
  • Soft tissue (including heart): 2 cases, 0%
  • Stomach cancer: 3 cases, 1%
  • Testicular cancer: 7 cases, 1%
  • Thyroid cancer: 6 cases, 1%
  • Vulvar cancer: 5 cases, 1%
  • Total: 592 cases, 100%

Again, the goal of the study was to determine how much non-AIDS cancer can be attributed to smoking as compared to other HIV-related risk factors. There are 2 key elements to consider when calculating PAF: 1) the prevalence of the risk factor -- and the prevalence of smoking was quite high among participants in NA-ACCORD, and 2) the risk related to that factor.

Overall, smoking had a much greater impact compared with the other risk factors that were considered. In fact, having a low CD4 cell count was a distant second in this analysis.

                                                            PAF                             PAF

                                                            all non-AIDS             excluding

                                                            cancer                       lung cancer


Ever smoking (vs never)                37%                                29%

HBV+ (vs HBV-)                              3%                                  4%

HCV+ (vs HCV-)                             0%                                  0%

CD4 <200 (vs CD4 >200)              8%                                  8%

HIV RNA >400 (vs <400)               4%                                  5%

AIDS diagnosis (vs none)              6%                                  5%  

In other words, 37% of non-AIDS cancer "could be avoided among individuals living with HIV if we were able to move them from the 'ever smoking' category to the 'never smoking' category," said Althoff, while using ART to preserve immune function, maintain viral suppression, and halt progression to AIDS could prevent up to 8% of non-AIDS cancer.

Althoff concluded that, in order to reduce the non-AIDS cancer burden in HIV-positive adults, effective interventions to reduce smoking are needed, along with a continued focus on HIV treatment.

"We really need to start targeting individuals at risk for HIV and intervene for smoking prevention programs for young adults," she said.

She noted that one limitation of the study was that there were no data available on alcohol use, the participants' body mass index, and HPV infection, so it is not possible to calculate the contribution of those risk factors to the burden of non-AIDS cancer.

In addition, the data in NA-ACCORD did not characterize the history of smoking -- whether participants were current smokers, the number of pack-years, and whether or when they had quit -- so the study cannot determine the number of cancers that might be avertable with smoking cessation. In addition, while other studies are now collecting more detailed smoking histories, Althoff stressed that very large cohorts may be needed to distinguish the effects of quitting smoking, particularly among people who were previously heavy smokers.

Even so, it is safe to say, as Eric Engels of the National Cancer Institute said at the end of CROI’s thematic discussion session on cancer, "We have to do better to get people living with HIV to stop smoking."


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KN Althoff, SJ Gange, C Achenbach, et al. Smoking Outweighs HIV-Related Risk Factors for Non-AIDS-Defining Cancers. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 726.

K Sigel, K Crothers, K Gordon, et al. CD4 Measures as Predictors of Lung Cancer Risk and Prognosis. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 728.