* Pre- and Post-HAART eras defined as before or after 07/01/96.
** For comparison of HIV positive to HIV negative IRs within Pre- or Post-HAART eras.
*** For comparison of Pre- to Post-HAART IRs.
HIV Infection is Associated with an Increased Risk for Lung Cancer Mortality Independent of Smoking
Gregory D. Kirk1,2, Christian Merlo2, Peter O’Driscoll1, Shruti Mehta1, David Vlahov1,3, Jonathan Samet1
Departments of Epidemiology1 and Medicine2, Johns Hopkins University, Baltimore, MD; 3New York Academy of Medicine, NYC, NY
Dr. Gregory D. Kirk
615 N Wolfe St, E6533
Baltimore, MD 21205
- Study Population:
- The AIDS Linked to the Intra-Venous Experience (ALIVE) study is a natural
- history study following the incidence and progression of HIV infection among
- intravenous drug users (IDUs) in Baltimore, MD.
- 2946 IDUs were recruited at cohort inception in 1988, with further recruitment of
- 735 additional subjects in 1994-95, 1998 and 2000.
- At baseline, 25% of the cohort were HIV infected and 334 seroconverters
- identified during follow-up.
- All participants were required to be >17 years of age, free of AIDS, and able to
- provide informed consent.
- Annual retention rate of ~95% among those who returned for at least one visit
- and who remain alive.
- Data Collection:
- Participants underwent semiannual visits including structured interviews, an
- ACASI questionnaire, clinical evaluation, and collection of blood specimens.
- Elicited information includes lifestyle factors such as smoking and detailed
- information on illicit drug use, including type, route and intensity of use.
- Bacterial pneumonia diagnoses were based on medical record review with
- CXR infiltrates and at least 2 clinical findings (fever, purulent cough, leukocytosis); 40% had bacterial organisms confirmed by sputum or blood culture, PCP, viruses, or TB were excluded.
- Lung Cancer Mortality Ascertainment:
- Deaths were ascertained from family members or partners through regular
- follow-up procedures.
- Linkage on name, date of birth and SSN with the National Death Index (NDI).
- Standard NDI-plus nosology used in determining causes of death according to
- the reported immediate and underlying causes.
- Smoking Exposure:
- Tobacco smoking was evaluated as a time-dependent variable representing the
- cumulative average number of packs smoked per day during follow-up. This rolling average was updated after each 6-month follow-up interval by adding
- number of packs smoked in preceding 6-months to prior cumulative total divided
- by number of follow-up visits.
- Intervals with missing data on cigarette smoking (<1% of visits) were included as
- 0 packs smoked.
- Patterns of smoking were assessed as a categorical variable: never,
- intermittent, always.
- Statistical Analyses:
- Due to poor survival after diagnosis, lung cancer mortality serves as a good
- surrogate for lung cancer incidence.
- Lung cancer death rates in both the pre- and the post-HAART eras were
- evaluated using Poisson regression techniques.
- Cox proportional hazards regression models were used to examine the effect of
- HIV infection on lung cancer death while controlling for other covariates.
- Tobacco Use in the ALIVE Cohort:
- 84% of participants reported smoking at cohort entry
- 45% smoked at least 1 pack and 10% at least 2 packs
- 63% reported smoking at every follow-up visit while only 7% never
- reported smoking.
- No differences in smoking prevalence by gender or HIV status.
- ALIVE Lung Cancer Deaths:
- With 22,000 person-years, 27 of the participants died from lung
- cancer; 14 were HIV infected and 13 HIV uninfected (Table 1).
- HIV positive cases were slightly younger than HIV negative (51 vs.
- 55 yrs) but had similar gender, racial, smoking and drug use
- Most lung cancer deaths (19/27, 70%) occurred during the post-
- HAART era (after 7/1/1996). Incidence rates suggested an
- increase in the post-HAART compared to the pre-HAART era
- (Table 2).
- In both periods, the incidence of lung cancer death was higher
- among HIV infected (Table 2); this was more pronounced during
- the post-HAART era.
Background: HIV-infected persons have an elevated risk of lung cancer, due in part to a high prevalence of smoking. Prior studies are limited by the inability to directly control for smoking.
Methods: Since 1988, the ALIVE Study has prospectively followed a cohort of injection drug users (IDUs) in Baltimore, MD with semi-annual collection of clinical, laboratory and behavioral data. Clinical diagnoses are confirmed through medical record abstraction. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer death, while controlling for other covariates including smoking (average packs / day) and drug use variables.
Results: Among 3,681 ALIVE participants followed for 22,000 person-years, we identified 27 individuals that died from lung cancer; 14 were HIV+ and 13 HIV-. Although not statistically significant, lung cancer death rates were increased in the post-HAART (after 7/1/96) compared to pre-HAART era (RR 1.37, 95% CI: 0.58-3.64). HIV+ cases were slightly younger than HIV-‘s (51 vs. 55 yrs, p=0.06) but had similar gender, racial, smoking and drug use patterns. Smoking and age >50 were strongly associated with lung cancer mortality. After adjusting for age, gender and smoking, HIV+’s had a 3.24 increased hazard for lung cancer death compared to HIV-‘s (1.44-7.29). Further, recurrent pneumonia (2 or > hospitalizations) was associated with lung cancer death (RH 5.72; 2.16-15.2) and explained some of the HIV effect (RH reduced to 2.39; 1.00-5.70). Neither injection nor inhaled drug use were associated with lung cancer mortality. Among HIV+ lung cancer deaths, the median CD4 nadir was 208 cells/μl and HIV RNA maximum level was 133,000 copies/ml; only 5 of 14 had ever received HAART. Smoking and age >50 remained the primary risk factors in analysis of HIV+’s only; CD4 count, viral load and HAART use were not associated with lung cancer mortality.
Conclusions: With prolonged survival of HIV+ persons in the post-HAART era, lung cancer deaths are increasing. After controlling for the high prevalence of smoking, HIV infection remained a significant risk factor for dying from lung cancer. Increased lung cancer risk following recurrent pneumonia may explain some but not all of this association. Although limited by small numbers, lung cancer mortality among HIV+’s was not associated with advanced immune suppression nor with HAART use.
Table 2. Lung Cancer Mortality Rates in Pre-HAART Compared to Post-HAART Era
Table 4. HIV and Lung Cancer Death Controlling for Drug Use and Pneumonia
* Adjusting for age, gender and average packs/day smoked.
** This column presents adjusted HR estimated for HIV seropositivity adjusting for age, gender, smoking, plus variable of interest.
- Predictors of Lung Cancer Mortality:
- While controlling for age, gender, and smoking (Table 3),HIV
- positives had over a 3-fold increased risk forlung cancer death
- compared to HIV negatives.
- As expected, older age and smoking were strongly associated with
- lung cancer mortality.
- Illicit drug use by either injecting or inhaled route was not associated
- with increased lung cancer death (Table 4).
- Prior pneumonia diagnoses, especially recurrent episodes, were
- strongly associated with lung cancer death.
- Although still significant, the HIV association was partly due to
- increased pneumonia diagnoses. Other variables did not greatly
- modulate the HIV-lung cancer death association (Table 4).
- HIV Disease Markers, HAART, and Lung Cancer Mortality:
- Among the 14 HIV positive lung cancer deaths, the median CD4
- nadir was 208 cells/μl (IQR 55-408) and median HIV RNA
- maximum level was 133,000 copies/ml (IQR 23,000-737,000).
- 5 of 9 HIV positive lung cancer deaths in HAART era had ever
- taken HAART at some time in follow-up.
- In stratified analysis among the 1,192 HIV positives followed for
- 9,120 p-yrs within ALIVE:
- Older age and smoking remained the primary
- predictors of lung cancer mortality.
- No significant association with lung cancer death was
- observed for CD4 strata, HIV RNA level or recent
- HAART use.
Table 1. Demographic and Behavioral Characteristics of ALIVE Lung Cancer Deaths by HIV Status
Table 3. Predictors of Lung Cancer Mortality
- Lung cancer death rates appear to be increasing in post-HAART era.
- Even after extensive adjustment for smoking exposure, HIV infection was associated with an increase in lung cancer mortality.
- Some, but not all, of the HIV association with lung cancer death may be mediated through previous bacterial pneumonias.
- The degree of HIV-related immunosuppression was not strongly associated with lung cancer mortality.
- Mechanisms of increased susceptibility to tobacco carcinogens and of recurrent pulmonary infections among HIV infected persons merit further investigation.
- HIV-infected persons have elevated risk for lung cancer.
- HIV-infected persons also have higher prevalence of smoking.
- Prior studies of the association of HIV with lung cancer have been limited by: - Inability to directly adjust for smoking - Lack of an appropriate HIV negative comparison group
* Adjusting for age, gender and average packs/day smoked.
* Age at the time of death
** Chi-square exact for categorical variables, t-test for continuous
+ At last follow-up visit
++ At any visit in follow-up