HIV contributes to lung cancer risk, independent of smoking

HIV-positive individuals have a significantly increased risk of dying of lung cancer, and this increased risk of death is independent of smoking, according to US research published in the July 1^st edition of Clinical Infectious Diseases. The investigators point to evidence that pre-existing lung diseases, including non-infectious ones, such as asthma, may be a possible explanation of their finding.

Although it is not considered an AIDS-defining condition, lung cancer is the third most common malignancy (after the AIDS-defining cancers, non-Hodgkin’s lymphoma and Kaposi’s sarcoma) seen in people with HIV in the USA. Several epidemiological studies have shown an increased risk of lung cancer amongst HIV-positive individuals. Thanks to potent antiretroviral therapy the number of deaths caused by HIV has declined sharply in recent years, but it is thought that this reduction in HIV-related deaths could mean that there is an increase in the amount of illness and death caused by lung cancer in HIV-positive patients.

It is currently uncertain whether the increased risk of lung cancer observed in HIV-positive patients is simply due to the higher prevalence of smoking in this population. Studies looking at the link between lung cancer and smoking have not adequately addressed this question as they have been limited by the lack of an HIV-negative control group, lack of data from the era after the introduction of effective anti-HIV treatment, and often by small sample size.

Investigators from the ALIVE study (AIDS Link to the Intravenous Experience) therefore examined the association between HIV infection and lung cancer death, taking into account smoking. Individuals were tested for HIV at baseline and at six monthly follow-up appointments. At these appointments they were also asked to provide information about their use of illicit drugs and smoking. In the period after July 1996, when effective HIV therapy first became available, HIV-positive individuals were asked to provide details of their anti-HIV treatment regimens.

Information on admissions to hospital for lung disease was obtained from medical records, and details of lung cancer deaths were obtained from family members, partners and the National Death Index. The investigators then performed a number of statistical analyses to see if there was an independent association between HIV infection and lung cancer after controlling for a number of factors, most notably smoking.

Results

The study population included almost 2100 injecting drug users recruited in Baltimore since 1988. Approximately a quarter of these individuals were HIV-positive at baseline and a further 334 individuals seroconverted during follow-up. Individuals had a median age of 35 years, 75% were male and 92% were African American.

At baseline, 84% of individuals reported smoking, and of these 45% said they smoked at least 20 cigarettes a day, with 10% indicating they reported 40 or more cigarettes daily. However, there was no difference in either the prevalence of smoking between HIV-positive (92%), and HIV-negative (94%) individuals, or in the intensity of smoking.

A total of 27 lung cancer deaths were recorded; of these 14 were in individuals who were HIV-positive. All lung cancer deaths in HIV-positive patients occurred a minimum of four years after HIV seroconversion.

HIV-positive individuals dying of lung cancer tended to be younger than HIV-negative patients (51 versus 55 years), but the difference was not statistically significant. The investigators also noted that there were no significant differences in the sex, race, smoking status, drug use patterns, or in pre-existing lung disease diagnoses between HIV-positive and HIV-negative patients dying of lung cancer.

The investigators calculated that in the entire period of their analysis, HIV-positive individuals had a 50% increased risk of death from lung cancer. They stress that such a risk is not considered significant.

In further analysis, the investigators looked at the factors predicting lung cancer death in the entire study population. They found that the risk increased by 80% with each additional pack of cigarettes smoked. Furthermore, after adjusting for factors including smoking status, the investigators found that a statistically significant 3.4 fold increased risk of lung cancer death for HIV-positive patients.

Illicit drug use, either injected or inhaled, did not increase lung cancer risk. However, previous lung disease, including the non-infectious disease asthma, did seem to increase the risk of fatal lung cancer. Individuals experiencing two or more episodes of noninfectious lung disease had a statistically significant 24-fold increase in risk fatal lung cancer compared to those with no recorded episodes of lung disease.

HIV disease markers, such as CD4 cell count and viral load, were then examined to see if these could predict which HIV-positive patients in the study had a greater risk of lung cancer death. The median lowest ever CD4 cell count of the 14 HIV-infected individuals dying of lung malignancy was 260 cells/mm³, and the median highest ever viral load was 55,000 copies/ml. Only five patients had received a diagnosis of AIDS before dying of lung cancer, of ten patients dying of the malignancy in the period after 1996, four received potent antiretroviral therapy at some time.

When the investigators restricted their analysis to HIV-infected patients, smoking remained the primary predictor of lung cancer, with the risk increasing by 70% each additional 20 cigarettes smoked. The only other significant factor was hospitalisation with non-infectious lung disease. Lung cancer mortality was unrelated to either lower CD4 cell count or higher viral load.

“We present strong evidence that HIV infection contributes to lung cancer, independent of smoking”, comment the investigators, “after adjusting for individual smoking exposure, we identified a statistically significant ~ 3.5-fold elevation for lung cancer risk associated with smoking.”

Possible explanations offered for this increased risk of lung cancer for HIV-positive patients are: a cancer-causing role for HIV itself; immune damage caused by HIV; lung damage from concurrent and recurrent lung disease leaving HIV-positive individuals more vulnerable to lung cancer; and, HIV increasing an individual’s susceptibility to the cancer-causing effects of tobacco.

The investigators found their findings consistent with the third of these explanations as “we found trends of increased lung cancer risk with all categories of pre-existing lung disease, particularly non-infectious diseases, such as asthma.”

They conclude, “our data support the hypothesis that HIV infection increases lung cancer risk and provide evidence that this effect is independent of smoking effect.”