Smoking is the biggest risk factor for non-AIDS-defining cancers in people living with HIV

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Smoking appears to contribute most to the burden of non-AIDS-defining cancers diagnosed in people living with HIV in the US, 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 Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA.

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 living with HIV

As noted by other presenters at the conference, the risk of AIDS-defining cancers is greatly elevated in people living with HIV, although 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 co-infection with other viruses associated with specific cancers such as hepatitis B virus (HBV) and hepatitis C virus (HCV), which can cause liver cancer, and human papillomavirus (HPV), which can cause anal, cervical, genital and oral cancer. In addition, HIV infection itself – whether the chronic inflammation associated with HIV’s ongoing replication, or HIV-related immunosuppression – may also play a significant role in the development of non-AIDS-related cancers.


AIDS defining condition

Any HIV-related illness included in the list of diagnostic criteria for AIDS, which in the presence of HIV infection result in an AIDS diagnosis. They include opportunistic infections and cancers that are life-threatening in a person with HIV.

human papilloma virus (HPV)

Some strains of this virus cause warts, including genital and anal warts. Other strains are responsible for cervical cancer, anal cancer and some cancers of the penis, vagina, vulva, urethra, tongue and tonsils.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.


The general term for the body’s response to injury, including injury by an infection. The acute phase (with fever, swollen glands, sore throat, headaches, etc.) is a sign that the immune system has been triggered by a signal announcing the infection. But chronic (or persisting) inflammation, even at low grade, is problematic, as it is associated in the long term to many conditions such as heart disease or cancer. The best treatment of HIV-inflammation is antiretroviral therapy.

For instance, a presentation 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 two years in a cohort of 26,065 US 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 and 500 cells/mm3 was associated with a 30% increased risk compared to people living with HIV who had 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-defining 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-related 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 1 January 2000 to 31 December 2009. The study included almost 39,000 adults, almost 600 of whom received new non-AIDS-defining cancer diagnoses. Lung cancer was the most common non-AIDS-defining cancer diagnoses in this cohort.

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 two key elements to consider when calculating PAF: the prevalence of the risk factor – and the prevalence of smoking was quite high among participants in NA-ACCORD – and 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.

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 adults living with HIV, 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 programmes 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 characterise 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 averted by 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."


Althoff KN et al. Smoking outweighs HIV-related risk factors for non-AIDS-defining cancers. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 726, 2015.

View a webcast of this presentation.

Sigel K et al. CD4 measures as predictors of lung cancer risk and prognosis. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 728, 2015.

View a webcast of this presentation.