Keith Sigel

HIV as an Independent Risk Factor for Incident Lung Cancer

Background:It is unclear whether the elevated rate of lung cancer among HIV-infected persons is due to biological effects of HIV, surveillance bias, or excess smoking. We compared the incidence of lung cancer between HIV-infected and demographically similar HIV-uninfected patients, accounting for smoking and stage of lung cancer at diagnosis. Design:Data from the Veterans Aging Cohort Study Virtual Cohort were linked to data from the Veterans Affairs Central Cancer Registry, resulting in an analytic cohort of 37 294 HIV-infected patients and 75 750 uninfected patients. Methods:We calculated incidence rates of pathologically confirmed lung cancer by dividing numbers of cases by numbers of person-years at risk. We used Poisson regression to determine incidence rate ratios (IRRs), adjusting for age, sex, race/ethnicity, smoking prevalence, previous bacterial pneumonia, and chronic obstructive pulmonary disease. Results:The incidence rate of lung cancer in HIV-infected patients was 204 cases per 100 000 person-years [95% confidence interval (CI) 167–249] and among uninfected patients was 119 cases per 100 000 person-years (95% CI 110–129). The IRR of lung cancer associated with HIV infection remained significant after multivariable adjustment (IRR 1.7; 95% CI 1.5–1.9). Lung cancer stage at presentation did not differ between HIV-infected and uninfected patients. Conclusion:In our cohort of demographically similar HIV-infected and uninfected patients, HIV infection was an independent risk factor for lung cancer after controlling for potential confounders including smoking. The similar stage distribution between the two groups indicated that surveillance bias was an unlikely explanation for this finding.

An Epidemic of Coccidioidomycosis in Arizona Associated with Climatic Changes, 1998–2001

BACKGROUND Reports of coccidioidomycosis cases in Arizona have increased substantially. We investigated factors associated with the increase. METHODS We analyzed the National Electronic Telecommunications System for Surveillance (NETSS) data from 1998 to 2001 and used Geographic Information Systems (GIS) to map high-incidence areas in Maricopa County. Poisson regression analysis was performed to assess the effect of climatic and environmental factors on the number of monthly cases; a model was developed and tested to predict outbreaks. RESULTS The overall incidence in 2001 was 43 cases/100,000 population, a significant (P<.01, test for trend) increase from 1998 (33 cases/100,000 population); the highest age-specific rate was in persons > or =65 years old (79 cases/100,000 population in 2001). Analysis of NETSS data by season indicated high-incidence periods during the winter (November-February). GIS analysis showed that the highest-incidence areas were in the periphery of Phoenix. Multivariable Poisson regression modeling revealed that a combination of certain climatic and environmental factors were highly correlated with seasonal outbreaks (R2=0.75). CONCLUSIONS Coccidioidomycosis in Arizona has increased. Its incidence is driven by seasonal outbreaks associated with environmental and climatic changes. Our study may allow public-health officials to predict seasonal outbreaks in Arizona and to alert the public and physicians early, so that appropriate preventive measures can be implemented.

Survival of patients with stage IV lung cancer with diabetes treated with metformin.

RATIONALE Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer. OBJECTIVES To compare overall survival of patients with diabetes with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin. METHODS Using data from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 750 patients with diabetes 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders. MEASUREMENTS AND MAIN RESULTS Overall, 61% of patients were on metformin at the time of lung cancer diagnosis. Median survival in the metformin group was 5 months, compared with 3 months in patients not treated with metformin (P < 0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio, 0.80; 95% confidence interval, 0.71-0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment. CONCLUSIONS Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect. Further research should evaluate plausible biologic mechanisms and test the effect of metformin in prospective clinical trials.

Cancer Screening in Patients Infected with HIV

Non–AIDS-defining cancers are a rising health concern among HIV-infected patients. Cancer screening is now an important component of health maintenance in HIV clinical practice. The decision to screen an HIV-infected patient for cancer should include an assessment of individualized risk for the particular cancer, life expectancy, and the harms and benefits associated with the screening test and its potential outcome. HIV-infected patients are at enhanced risk of several cancers compared to the general population; anal cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, and lung cancer all have good evidence demonstrating an enhanced risk in HIV-infected persons. A number of cancer screening interventions have shown benefit for specific cancers in the general population, but data on the application of these tests to HIV-infected persons are limited. Here we review the epidemiology and background literature relating to cancer screening interventions in HIV-infected persons. We then use these data to inform a conceptual model for evaluating HIV-infected patients for cancer screening.

High rates of anal dysplasia in HIV-infected men who have sex with men, women, and heterosexual men.

Objective:To determine rates of anal dysplasia in a cohort of HIV-infected men who have sex with men (MSM), women, and heterosexual men with abnormal anal cytology. Design/methods:We evaluated histologic findings in 728 HIV-infected MSM, women, and heterosexual men referred for high-resolution anoscopy (HRA) after abnormal anal cytology in a single-center cohort study. Using multivariable logistic regression, we evaluated predictors of high-grade squamous intraepithelial lesion (HSIL) histology or invasive carcinoma including age, sexual behavior, receptive anal intercourse (RAI), anogenital warts, smoking status, antiretroviral therapy, CD4+ T-cell count, and HIV-1 plasma viral load. Results:A total of 2075 HIV-positive patients were screened with anal cytology and 62% of MSM, 42% of women, and 29% of heterosexual men had abnormal findings (P <0.001). Of the 728 HIV-infected patients with abnormal anal cytology who underwent HRA, 71% were MSM, 23% women, and 6% heterosexual men. HSIL/cancer was found in 32% of MSM, 26% of women, and 23% of heterosexual men (P = 0.3). There were five cases of anal squamous cell carcinoma (0.7%), four in MSM and one in a heterosexual man. In a multivariable adjusted analysis, biopsy-proven HSIL/cancer was associated with RAI [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.3–3.7]. CD4+ T-cell counts more than 500/&mgr;l conferred a lower risk of HSIL/cancer (OR 0.5; 95% CI 0.3–0.9). Conclusion:Rates of anal HSIL histology are high in HIV-infected patients of all sexual risk groups with abnormal anal cytology. Consequently, all HIV-infected patients may warrant anal cancer screening.

Findings in asymptomatic HIV-infected patients undergoing chest computed tomography testing: implications for lung cancer screening.

Background:HIV-infected persons have a two-fold to five-fold increased unadjusted risk of lung cancer. In the National Lung Screening Trial (NLST), computed tomography (CT) screening was associated with a reduction in lung cancer mortality among high-risk smokers. These results may not generalize to HIV-infected persons, particularly if they are more likely to have false-positive chest CT findings. Methods:We utilized data including standardized chest CT scans from 160 HIV infected and 139 uninfected Veterans enrolled between 2009 and 2012 in the multicenter Examinations of HIV Associated Lung Emphysema (EXHALE) Study. Abnormal CT findings were abstracted from clinical interpretations of the scans and classified as positive by NLST criteria vs. other findings. Clinical evaluations and diagnoses that ensued were abstracted from the medical record. Results:There was no significant difference by HIV in the proportion of CT scans classified as positive by NLST criteria (29% of HIV infected and 24% of HIV uninfected, P = 0.3). However, HIV-infected participants with CD4+ cell counts less than 200 cells/&mgr;l had significantly higher odds of positive scans, a finding that persisted in multivariable analysis. Evaluations triggered by abnormal CT scans were also similar in HIV-infected and uninfected participants (all P > 0.05). Conclusion:HIV status was not associated with an increased risk of abnormal findings on CT or increased rates of follow-up testing in clinically stable outpatients with CD4+ cell count more than 200. These data reflect favorably on the balance of benefits and harms associated with lung cancer screening for HIV-infected smokers with less severe immunodeficiency.

Prognosis in HIV-infected patients with non-small cell lung cancer

Background:We conducted a population-based study to evaluate whether non-small cell lung cancer (NSCLC) prognosis was worse in HIV-infected compared with HIV-uninfected patients.Methods:Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare claims, we identified 267 HIV-infected patients and 1428 similar controls with no evidence of HIV diagnosed with NSCLC between 1996 and 2007. We used conditional probability function (CPF) analyses to compare survival by HIV status accounting for an increased risk of non-lung cancer death (competing risks) in HIV-infected patients. We used multivariable CPF regression to evaluate lung cancer prognosis by HIV status adjusted for confounders.Results:Stage at presentation and use of stage-appropriate lung cancer treatment did not differ by HIV status. Median survival was 6 months (95% confidence interval (CI): 5–8 months) among HIV-infected NSCLC patients compared with 20 months (95% CI: 17–23 months) in patients without evidence of HIV. Multivariable CPF regression showed that HIV was associated with a greater risk of lung cancer-specific death after controlling for confounders and competing risks.Conclusion:NSCLC patients with HIV have a poorer prognosis than patients without evidence of HIV. NSCLC may exhibit more aggressive behaviour in the setting of HIV.

Time trends in cancer incidence in persons living with HIV/AIDS in the antiretroviral therapy era: 1997-2012

Objective:Utilizing the Veterans Aging Cohort Study, the largest HIV cohort in North America, we conducted one of the few comprehensive comparisons of cancer incidence time trends in HIV-infected (HIV+) versus uninfected persons during the antiretroviral therapy (ART) era. Design:Prospective cohort study. Methods:We followed 44 787 HIV+ and 96 852 demographically matched uninfected persons during 1997–2012. We calculated age-, sex-, and race/ethnicity-standardized incidence rates and incidence rate ratios (IRR, HIV+ versus uninfected) over four calendar periods with incidence rate and IRR period trend P values for cancer groupings and specific cancer types. Results:We observed 3714 incident cancer diagnoses in HIV+ and 5760 in uninfected persons. The HIV+ all-cancer crude incidence rate increased between 1997–2000 and 2009–2012 (P trend = 0.0019). However, after standardization, we observed highly significant HIV+ incidence rate declines for all cancer (25% decline; P trend <0.0001), AIDS-defining cancers (55% decline; P trend <0.0001), nonAIDS-defining cancers (NADC; 15% decline; P trend = 0.0003), and nonvirus-related NADC (20% decline; P trend <0.0001); significant IRR declines for all cancer (from 2.0 to 1.6; P trend <0.0001), AIDS-defining cancers (from 19 to 5.5; P trend <0.0001), and nonvirus-related NADC (from 1.4 to 1.2; P trend = 0.049); and borderline significant IRR declines for NADC (from 1.6 to 1.4; P trend = 0.078) and virus-related NADC (from 4.9 to 3.5; P trend = 0.071). Conclusion:Improved HIV care resulting in improved immune function most likely contributed to the HIV+ incidence rate and the IRR declines. Further promotion of early and sustained ART, improved ART regimens, reduction of traditional cancer risk factor (e.g. smoking) prevalence, and evidence-based screening could contribute to future cancer incidence declines among HIV+ persons.

High Rates of Anal High-Grade Squamous Intraepithelial Lesions in HIV-Infected Women Who Do Not Meet Screening Guidelines

Background. Human immunodeficiency virus (HIV)–infected women have a higher burden of anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) compared with HIV-uninfected women. Guidelines for AC screening in this population are heterogeneous. Here we report outcomes and risk factors for anal HSIL following implementation of universal AC screening offered to all HIV-infected women. Methods. Data from women who underwent AC screening with anal cytology from April 2009 to July 2014 were analyzed. Routine clinical data included anal and cervical cytology, demographic/behavioral data, and high-resolution anoscopy (HRA) results. We evaluated the association of cytology with HRA results, and predictors of HSIL pathology, and compared rates of HSIL pathology among women meeting screening guidelines to those who did not. Results. Seven hundred forty-five HIV-infected women were screened with anal cytology. Thirty-nine percent had abnormal anal cytology on initial screen and 15% on secondary screen; 208 women underwent HRA following abnormal anal cytology. HSIL was found in 26% and 18% of anal biopsies following initial and secondary screening, respectively. One woman had AC. Cigarette smoking more than doubled HSIL risk. Among women who underwent AC screening despite not meeting existing guideline criteria, 21% and 10%, respectively, were found to have HSIL on biopsy. Neither meeting criteria for screening nor history of receptive anal sex was significantly associated with HSIL. Conclusions. Anal HSIL is common in HIV-infected women. Substantial numbers of HSIL would have been missed by strictly adhering to existing AC screening guidelines. These results support routine screening of all HIV-infected women regardless of human papillomavirus history or sexual practices.

Chronic Obstructive Pulmonary Disease Illness and Medication Beliefs are Associated with Medication Adherence

Abstract Almost half of patients with COPD do not adhere to their medications. Illness and medication beliefs are important determinants of adherence in other chronic diseases. Using the framework of the Common Sense Model of Self-Regulation (CSM), we determined associations between potentially modifiable beliefs and adherence to COPD medications in a cohort of English- and Spanish-speaking adults with COPD from New York and Chicago. Medication adherence was assessed using the Medication Adherence Report Scale. Illness and medication beliefs along CSM domains were evaluated using the Brief Illness Perception Questionnaire (B-IPQ) and the Beliefs about Medications Questionnaire (BMQ). Unadjusted analysis (with Cohens d effect sizes) and multiple logistic regression were used to assess the relationship between illness and medication beliefs with adherence. The study included 188 participants (47% Black, 13% Hispanics); 109 (58%) were non-adherent. Non-adherent participants were younger (p < 0.001), more likely to be Black or Hispanic (p = 0.001), to have reported low income (p = 0.02), and had fewer years of formal education (p = 0.002). In unadjusted comparisons, non-adherent participants reported being more concerned about their COPD (p = 0.011; Cohens d = 0.43), more emotionally affected by the disease (p = 0.001; Cohens d = 0.54), and had greater concerns about COPD medications (p < 0.001, Cohens d = 0.81). In adjusted analyses, concerns about COPD medications independently predicted non-adherence (odds ratio: 0.52, 95% confidence interval: 0.36–0.75). In this cohort of urban minority adults, concerns about medications were associated with non-adherence. Future work should explore interventions to influence patient adherence by addressing concerns about the safety profile and long-term effects of COPD medications.