Eric A. Engels

HIV Infection Is Associated with an Increased Risk for Lung Cancer, Independent of Smoking

BACKGROUND Human immunodeficiency virus (HIV)-infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question. METHODS The Acquired Immunodeficiency Syndrome (AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. 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 risk, controlling for smoking status, drug use, and clinical variables. RESULTS Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 (96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre-highly active antiretroviral therapy period (mortality rate ratio, 4.7; 95% confidence interval, 1.7-16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk (hazard ratio, 3.6; 95% confidence interval, 1.6-7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. CONCLUSIONS HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status.

Elevated Incidence of Lung Cancer Among HIV-Infected Individuals

PURPOSE People with HIV infection in the United States frequently smoke tobacco. We sought to characterize lung cancer incidence among HIV-infected individuals, examine whether cancer risk was related to HIV-induced immunosuppression, and assess whether the high prevalence of smoking explained elevated risk. METHODS We conducted a retrospective cohort study at an HIV specialty clinic in Baltimore, MD (1989-2003). Incident lung cancers were identified using hospital records. We used negative binomial regression to compare incidence across subgroups defined by demographics, use of highly active antiretroviral therapy (HAART), and HIV markers. Standardized incidence ratios (SIRs) compared incidence with an urban reference population (Detroit, MI). We adjusted SIRs for the effect of smoking, using smoking prevalences estimated from part of the cohort and the general population. 95% CIs and P values were two sided. RESULTS Thirty-three lung cancers were observed among 5,238 HIV-infected patients (incidence: 170 per 100,000 person-years). Incidence increased with age (P < .0001), but did not differ by sex, race, or CD4 count. Incidence tended to increase with calendar year (P = .09) and HAART use (P = .10), and was inversely related to HIV viral load (P = .03), but these associations were attenuated with age adjustment. The SIR was 4.7 (95% CI, 3.2 to 6.5) versus the general population. Twenty-eight lung cancer patients (85%) and 69% of the cohort were smokers. After smoking adjustment, risk remained elevated (SIR, 2.5; 95% CI, 1.6 to 3.5). CONCLUSION Lung cancer risk was substantially elevated in HIV-infected individuals. Incidence was unrelated to HIV-induced immunosuppression. Notably, incidence remained high after adjustment for smoking, suggesting the involvement of additional factors.

Incidence and outcomes of malignancy in the HAART era in an urban cohort of HIV-infected individuals.

Objective:To investigate trends, patient characteristics, and survival associated with AIDS-defining cancer (ADC) and non-AIDS defining cancer (NADC) in the HAART era. Design:Retrospective analysis of all incident malignancies occurring in 1996–2005 among 2566 patients in an urban HIV clinic. Methods:Clinical profiles of NADC were compared with ADC and the general cohort. Incidence was examined by Poisson analysis. Standardized incidence ratios (SIR) compared cancer risk with that in the general population. Survival was analyzed by Kaplan–Meier and Cox proportional hazards models. Results:Between 1996 and 2005, 138 ADC and 115 NADC were diagnosed. ADC rates decreased from 12.5 to 3.5 cases/1000 person-years (P < 0.001 for trend) while NADC rates increased from 3.9 to 7.1 cases/1000 person-years (P = 0.13 for trend). Incidence of the most common NADC was higher than expected, including cancers of the lung [n = 29; SIR, 5.5; 95% confidence interval (CI), 3.7–8.0], liver (n = 13, SIR, 16.5; 95% CI, 8.8–28.2), anus (n = 10; SIR, 39.0; 95% CI, 18.7–71.7), head and neck (n = 14; SIR, 5.1; 95% CI, 2.8–8.6), and Hodgkins lymphoma (n = 8; SIR, 9.8; 95% CI, 4.2–19.2). Survival after cancer diagnosis did not differ between ADC and NADC. Advanced age was associated with NADC (P < 0.01 for trend) and increased mortality in ADC (age ≥ 50 years adjusted hazard ratio, 2.21; 95% CI, 1.00–4.89). Conclusions:Rates of ADC decreased while NADC increased within this cohort. Several NADC occurred at rates significantly higher than expected. Screening and suspicion for NADC should increase in care for HIV-infected patients.

Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care.

Objective: Lung cancer is more common in HIV-infected patients than in the general population. We examined how effectively lung cancer was being diagnosed in our HIV-infected patients. Methods: Retrospective study assessing clinical diagnosis of lung cancer in HIV-infected patients at Johns Hopkins Hospital between 1986 and 2004. Results: Ninety-two patients were identified. Compared to HIV-indeterminate patients (n = 4973), HIV-infected individuals were younger with more advanced cancer. CD4 counts and HIV-1 RNA levels indicated preserved immune function. Mortality was higher in HIV-infected patients, with 92% dying of lung cancer (hazard ratio, 1.57; 95% confidence interval, 1.25-1.96), compared to HIV-uninfected patients. Advanced stage and black race were associated with worse survival. After adjustment for these factors, HIV infection was not associated with increased mortality (hazard ratio, 1.04; 95% confidence interval, 0.83-1.32). Of 32 patients followed in our HIV clinic, 60% of chest radiographs had no evidence of neoplasm within 1 year of diagnosis compared to only 1 (4%) of 28 chest computed tomography scans. Nonspecific infiltrates were observed in 9 patients in the same area that cancer was subsequently diagnosed. Conclusions: HIV-infected lung cancer patients have shortened survival mainly due to advanced stage. Low clinical suspicion and overreliance on chest radiographs hindered earlier detection. Aggressive follow-up of nonspecific pulmonary infiltrates in these patients is warranted.

Immunologic and virologic predictors of AIDS-related non-Hodgkin lymphoma in the highly active antiretroviral therapy era.

HIV-infected persons treated with highly active antiretroviral therapy (HAART) continue to have elevated risk for non-Hodgkin lymphoma (NHL). We conducted a retrospective cohort study of NHL among patients at an urban HIV clinic (N = 3025). Proportional hazards models identified immunologic and virologic predictors of NHL. Sixty-five NHLs arose during 1989 to 2006. NHL incidence declined over time. Nonetheless, 51 NHLs (78%) occurred within the HAART era (1996-2006). NHL risk increased with declining CD4 count (P trend < 0.0001) and increasing HIV viral load (P trend = 0.005). In a multivariable model, NHL risk was independently associated with both current CD4 count (hazard ratios 7.7 and 3.8, respectively, for CD4 counts 0-99 and 100-249 vs. 250+ cells/mm3; P trend < 0.0001) and prior time spent with a viral load above 5.00 log10 copies/mL (hazard ratios of 3.4, 2.6, and 6.8, respectively, for 0.1-0.4, 0.5-1.4, and 1.5+ yr vs. 0 yr; P trend = 0.004). Although serum globulin levels were elevated compared with the general population, NHL risk was unrelated to this B-cell activation marker (P = 0.39). Among HIV-infected individuals in the HAART era, NHLs are linked to immunosuppression and extended periods of uncontrolled HIV viremia. The association with high-level viremia could reflect detrimental effects on immune function related to incompletely effective HAART or direct effects on B cells.

Tobacco use and nicotine dependence among HIV-infected and uninfected injection drug users

INTRODUCTION Urban U.S. populations are burdened by intersecting epidemics of HIV infection, injection drug use, and cigarette smoking. Given the substantial morbidity attributable to tobacco in these populations, we characterized smoking behaviors, nicotine addiction, and tobacco exposure among HIV-infected and HIV-uninfected injection drug users (IDUs) in Baltimore, Maryland. METHODS Smoking behaviors among participants in the ALIVE Study were assessed using interviewer-administered questionnaires. Smoking history and nicotine dependence (Fagerstrom Index scores) were compared by HIV and drug injecting status. Serum cotinine (a nicotine metabolite) was measured for a sample of participants by enzyme immunoassay. RESULTS Among 1052 participants (29.7% HIV-infected, 39.8% active injectors), 85.2% were current smokers and 9.3% were former smokers. Smoking prevalence, age at smoking initiation, and cumulative tobacco exposure were similar by HIV status. Median Fagerstrom scores of 4 for HIV-infected and HIV-uninfected smokers indicated moderate nicotine dependence. Daily cigarette consumption was identical by HIV status (median 10 cigarettes), although HIV-infected participants were less likely to smoke 1+ pack daily compared to HIV-uninfected participants (18.0% vs. 26.9%, p=0.001). Compared to former injectors, active injectors had higher smoking prevalence (90.5% vs. 81.7%, p=0.0001), greater daily cigarette consumption (30.7% vs. 19.6% smoked 1+ pack daily, p=0.0001), and slightly higher Fagerstrom scores (median 5 vs. 4). Cotinine levels paralleled self-reported cigarette consumption. DISCUSSION Tobacco use is extremely common among inner-city IDUs. Smoking behavior and nicotine dependence did not materially differ by HIV status but were associated with active drug injection. Cessation efforts should target the dual dependence of cigarettes and drugs experienced among this population.

Incidence and risk factors for hepatocellular carcinoma after solid organ transplantation.

Background. Solid organ transplant recipients commonly are infected with hepatitis viruses, are immunosuppressed, and have other potential hepatocellular carcinoma (HCC) risk factors. Methods. We studied de novo HCC incidence arising after transplant using U.S. registry data (223,660 recipients, 1987–2005). We used proportional hazards regression to identify HCC risk factors and calculated standardized incidence ratios (SIRs) to compare HCC risk with that in the general population. Results. Based on 74 cases reported by transplant centers to the registry, HCC incidence was 6.5 per 100,000 person-years among kidney, heart, and lung (non-liver) recipients and 25 per 100,000 person-years among liver recipients. Hepatocellular carcinoma incidence among non-liver recipients was independently associated with hepatitis B surface antigenemia (hazard ratio [HR] 9.7, 95% confidence interval [CI] 2.8–33), hepatitis C virus (HCV) infection (HR 6.9, 95% CI 2.5–19), and diabetes mellitus (HR 2.8, 95% CI 1.2–6.6). Among liver recipients, HCC incidence was associated with advancing age (P<0.001), male sex (HR 4.6, 95% CI 1.4–16), HCV infection (HR 3.1, 95% CI 1.3–7.2), and diabetes mellitus (HR 2.7, 95% CI 1.2–6.2). Among non-liver recipients, overall HCC incidence was similar to the general population (SIR 0.8) but elevated among those with HCV (3.4) or hepatitis B surface antigenemia (6.5). Hepatocellular carcinoma incidence among liver transplant recipients was elevated overall (SIR 3.4) and especially among those with HCV (5.0) or diabetes mellitus (6.2). Conclusions. Hepatocellular carcinoma incidence is elevated among liver transplant recipients and subsets of non-liver recipients. These risk factors indicate the need for improved control of viral hepatitis after solid organ transplantation.

Cross sectional analysis of respiratory symptoms in an injection drug user cohort: the impact of obstructive lung disease and HIV

BackgroundInjection drug use is associated with an increased risk of human immunodeficiency virus (HIV) infection and with obstructive lung diseases (OLD). Understanding how HIV and OLD may impact respiratory symptoms among injection drug users (IDUs) is important to adequately care for this high-risk population. We characterized the independent and joint effects of HIV and OLD on respiratory symptoms of a cohort of inner-city IDUs.MethodsDemographics, risk behavior and spirometric measurements were collected from a cross-sectional analysis of the Acquired Immunodeficiency Syndrome Link to the IntraVenous Experience study, an observational cohort of IDUs followed in Baltimore, MD since 1988. Participants completed a modified American Thoracic Society respiratory questionnaire and the Medical Research Council (MRC) dyspnea score to assess respiratory symptoms of cough, phlegm, wheezing and dyspnea.ResultsOf 974 participants, 835 (86%) were current smokers and 288 (29.6%) were HIV-infected. The prevalence of OLD (FEV1/FVC ≤ 0.70) was 15.5%, and did not differ by HIV status. OLD, but not HIV, was associated with increased frequency of reported respiratory symptoms. There was a combined effect of OLD and HIV on worsening of MRC scores. OLD and HIV were independently associated with an increased odds of reporting an MRC ≥ 2 (OR 1.83 [95%CI 1.23-2.73] and 1.50 [95%CI 1.08-2.09], respectively). COPD, but not HIV, was independently associated with reporting an MRC ≥ 3 (OR 2.25 [95%CI 1.43-3.54] and 1.29 [95%CI 0.87-1.91], respectively).ConclusionsWhile HIV does not worsen cough, phlegm or wheezing, HIV significantly increases moderate but not severe dyspnea in individuals of similar OLD status. Incorporating the MRC score into routine evaluation of IDUs at risk for OLD and HIV provides better assessment than cough, phlegm and wheezing alone.