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Low CD4/CD8 Ratio and Bacterial Pneumonia Predict Lung Cancer With HIV

March 16, 2017

Bacterial pneumonia and measures of poor immune function (notably, a low CD4/CD8 ratio) predicted incident lung cancer in HIV-positive members of the Veterans Aging Cohort Study (VACS). In initial multivariate models, low CD4 count and high HIV RNA also predicted lung cancer.

Lung cancer ranks as the leading non-AIDS cancer in people with HIV and the leading cause of cancer death in HIV populations. HIV infection is independently associated with lung cancer risk. Mixed results emerged from previous studies of whether severity of CD4-cell-related immune suppression affects lung cancer risk, but these studies were often limited by a retrospective approach or small numbers of lung cancer cases. The prospective VACS study addressed these issues.

The analysis involved HIV-positive VACS members with at least three years of follow-up between January 1998 and December 2012. To identify new lung cancer cases during follow-up, the researchers linked VACS data to a veterans cancer registry. They used VACS records to collect longitudinal lab data and to identify episodes of bacterial pneumonia. Lab data were time-updated and lagged at least 12 months to minimize the chance that a lung cancer diagnosis affected lab values. The analysis excluded veterans who had lung cancer when they entered the observation period. To identify independent predictors of incident lung cancer, the VACS team used Cox proportional hazards regression models adjusted for demographic variables, smoking, alcohol and drug use disorders, chronic obstructive pulmonary disease (COPD), occupational lung disease and hepatitis C status.

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The study group included 21,666 veterans with a median of 3 CD4-cell measurements per year. Most cohort members (98%) were men. During a median 7.4 years of follow-up, 277 cases of lung cancer developed (1.3%). Compared with veterans who remained free of lung cancer, those diagnosed with lung cancer were older (median 50 versus 45 years, P < .0001), more likely to be non-Hispanic white (46% versus 41%, P = .02), more likely to smoke currently (73% versus 54%, P < .0001), more likely to have a baseline CD4/CD8 ratio below 0.4 (52% versus 46%, P = .01), more likely to have a COPD history (13% versus 4%, P < .0001), more likely to have an occupational lung disease history (1% versus less than 1%, P = .01) and more likely to die during follow-up (79% versus 25%, P < .0001).

Using 12-month lagged data, multivariate regression analysis determined that a CD4 count of 100 to 199 cells/mm3 or 200 to 500 cells/mm3 (versus above 500 cells/mm3) was associated with incident lung cancer (respectively, hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.6 to 3.4; or HR 1.2, 95% CI 1.2 to 2.1; P = .001). In a similar analysis a CD4/CD8 ratio below 0.4 or 0.4 to 1.0 (versus above 1.0) independently predicted lung cancer (respectively, HR 2.6, 95% CI 1.6 to 4.1; or HR 1.9, 95% CI 1.2 to 3.0; P = .001). A 12-month-lagged analysis also determined that a viral load at or above 500 copies/mL (versus below) independently raised lung cancer risk (HR 1.4, 95% CI 1.1 to 1.9, P = .025). Two or more episodes of bacterial pneumonia (versus none) were linked to incident lung cancer (HR 1.8, 95% CI 1.0 to 2.5, P = .0004), and one episode (versus none) yielded almost the same risk (HR 1.7, 95% CI 1.2 to 2.4, P = .0004).

In a model adjusted for significant time-updated variables (CD4 count, CD4/CD8 ratio, HIV RNA, bacterial pneumonia), two variables remained independent predictors of incident lung cancer: 12-month lagged CD4/CD8 ratio and cumulative bacterial pneumonia episodes (for CD4/CD8 ratio below 0.4, HR 2.6, 95% CI 1.4 to 4.9; for CD4/CD8 ratio 0.4 to 1.0, HR 2.4, 95% CI 1.4 to 4.3; P = .003; for one bacterial pneumonia episode, HR 1.3, 95% CI 1.1 to 2.3, P = .004).

The researchers propose that abnormal immune activation (indicated by low CD4/CD8 ratio) and prior bacterial pneumonia "could have a role in the development of lung cancer in people with HIV and could explain some of the increased risk of lung cancer in this population." They suggest that these risk factors -- along with traditional factors including age, smoking and COPD -- "could be used to target high-risk groups with lung-cancer prevention measures, such as CT-based screening." The authors caution that their study group consisted almost entirely of male veterans, so their findings may not apply to other groups with HIV.

Mark Mascolini writes about HIV infection.


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