Kristina Crothers

HIV Infection and the Risk of Acute Myocardial Infarction

IMPORTANCEnWhether people infected with human immunodeficiency virus (HIV) are at an increased risk of acute myocardial infarction (AMI) compared with uninfected people is not clear. Without demographically and behaviorally similar uninfected comparators and without uniformly measured clinical data on risk factors and fatal and nonfatal AMI events, any potential association between HIV status and AMI may be confounded.nnnOBJECTIVEnTo investigate whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care.nnnDESIGN AND SETTINGnParticipants in the Veterans Aging Cohort Study Virtual Cohort from April 1, 2003, through December 31, 2009.nnnPARTICIPANTSnAfter eliminating those with baseline cardiovascular disease, we analyzed data on HIV status, age, sex, race/ethnicity, hypertension, diabetes mellitus, dyslipidemia, smoking, hepatitis C infection, body mass index, renal disease, anemia, substance use, CD4 cell count, HIV-1 RNA, antiretroviral therapy, and incidence of AMI.nnnMAIN OUTCOME MEASUREnAcute myocardial infarction.nnnRESULTSnWe analyzed data on 82 459 participants. During a median follow-up of 5.9 years, there were 871 AMI events. Across 3 decades of age, the mean (95% CI) AMI events per 1000 person-years was consistently and significantly higher for HIV-positive compared with uninfected veterans: for those aged 40 to 49 years, 2.0 (1.6-2.4) vs 1.5 (1.3-1.7); for those aged 50 to 59 years, 3.9 (3.3-4.5) vs 2.2 (1.9-2.5); and for those aged 60 to 69 years, 5.0 (3.8-6.7) vs 3.3 (2.6-4.2) (P < .05 for all). After adjusting for Framingham risk factors, comorbidities, and substance use, HIV-positive veterans had an increased risk of incident AMI compared with uninfected veterans (hazard ratio, 1.48; 95% CI, 1.27-1.72). An excess risk remained among those achieving an HIV-1 RNA level less than 500 copies/mL compared with uninfected veterans in time-updated analyses (hazard ratio, 1.39; 95% CI, 1.17-1.66).nnnCONCLUSIONS AND RELEVANCEnInfection with HIV is associated with a 50% increased risk of AMI beyond that explained by recognized risk factors.

HIV Infection and Risk for Incident Pulmonary Diseases in the Combination Antiretroviral Therapy Era

RATIONALEnIn aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era.nnnOBJECTIVESnTo determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons.nnnMETHODSnWe analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%).nnnMEASUREMENTS AND MAIN RESULTSnIncident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline.nnnCONCLUSIONSnPulmonary diseases among HIV-infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non-AIDS-defining and chronic conditions, many of which are associated with aging.

The Impact of Cigarette Smoking on Mortality, Quality of Life, and Comorbid Illness Among HIV‐Positive Veterans

AbstractBACKGROUND: The impact of smoking on outcomes among those with HIV infection has not been determined in the era of highly active antiretroviral therapy (HAART).n STUDY OBJECTIVE: Determine the impact of smoking on morbidity and mortality in HIV-positive patients post-HAART.n DESIGN: Prospective observational study.n PARTICIPANTS: Eight hundred and sixty-seven HIV-positive veterans enrolled in the Veterans Aging Cohort 3 Site Study.n MEASUREMENTS: Clinical data were collected through patient questionnaire, International Classification of Diseases—9th edition codes, and standardized chart extraction, and laboratory and mortality data through the national VA database. Quality of life was assessed with the physical component summary (PCS) of the Short-Form 12.n RESULTS: Current smokers had increased respiratory symptoms, chronic obstructive pulmonary disease (COPD), and bacterial pneumonia. In analyses adjusted for age, race/ethnicity, CD4 cell count, HIV RNA level, hemoglobin, illegal drug and alcohol use, quality of life was substantially decreased (β=−3.3, 95% confidence interval [CI] −5.3 to −1.4) and mortality was significantly increased (hazard ratio 1.99, 95% CI 1.03 to 3.86) in current smokers compared with never smokers.n CONCLUSIONS: HIV-positive patients who currently smoke have increased mortality and decreased quality of life, as well as increased respiratory symptoms, COPD, and bacterial pneumonia. These findings suggest that smoking cessation should be emphasized for HIV-infected patients.

Medical disease and alcohol use among veterans with human immunodeficiency infection: A comparison of disease measurement strategies.

Background:Many people with human immunodeficiency (HIV) infection drink alcohol. We asked whether level of exposure to alcohol is associated with medical disease in a linear or nonlinear manner, whether the association depends upon the proximity of alcohol use, and whether it varies by source used to measure disease (chart review vs. ICD-9 Diagnostic Codes). Methods:The Veterans Aging 3 Site Cohort Study (VACS 3) enrolled 881 veterans, 86% of all HIV-positive patients seen, at 3 VA sites from June 23, 1999, to July 28, 2000. To maximize the sensitivity for alcohol exposure, alcohol use was measured combining data from patient self-report, chart review, and ICD-9 codes. We assigned the greatest exposure level reported from any source. Alcohol use within the past 12 months was considered current. Data on comorbid and AIDS-defining medical diseases were collected via chart review and ICD-9 diagnostic codes. The association of alcohol use (level and timing) and disease was modeled only for diseases demonstrating ≥10% prevalence. Linearity was compared with nonlinearity of association using nested multivariate models and the likelihood ratio test. All multivariate models were adjusted for age, CD4 cell count, viral load, intravenous drug use, exercise, and smoking. Results:Of 881 subjects enrolled, 866 (98%) had sufficient data for multivariate analyses, and 876 (99%) had sufficient data for comparison of chart review with ICD-9 Diagnostic Codes. Of the 866, 42 (5%) were lifetime abstainers; 247 (29%) were past drinkers; and 577 (67%) were current users. Among the 824 reporting past or current alcohol use, 341 (41%) drank in moderation, 192 (23%) drank hazardously, and 291 (35%) carried a diagnosis of abuse or dependence. ICD-9 codes showed limited sensitivity, but overall agreement with chart review was good for 15 of 20 diseases (kappa >0.4). The following diseases demonstrated a ≥10% prevalence with both measures (hepatitis C, hypertension, diabetes, obstructive lung disease, candidiasis, and bacterial pneumonia). All of these were associated with alcohol use (P < 0.05). Hepatitis C, hypertension, obstructive lung disease, candidiasis, and bacterial pneumonia demonstrated linear associations with level of alcohol use (P < 0.03). Past alcohol use increased the risk of hepatitis C and diabetes after adjustment for level of exposure (P < 0.01). With the exception of candidiasis, the associations between level and timing of alcohol use were similar when measured by ICD-9 codes or by chart review. Conclusions:Past and current use of alcohol is common among those with HIV infection. Estimates of disease risk associated with alcohol use based upon ICD-9 Diagnostic Codes appear similar to those based upon chart review. After adjustment for level of alcohol exposure, past use is associated with similar (or higher) prevalence of disease as among current drinkers. Finally, level of alcohol use is linearly associated with medical disease. We find no evidence of a “safe” level of consumption among those with HIV infection.

Role of Cathepsin S-Dependent Epithelial Cell Apoptosis in IFN-γ-Induced Alveolar Remodeling and Pulmonary Emphysema

Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethyl-ketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.

IL-18 Is Induced and IL-18 Receptor α Plays a Critical Role in the Pathogenesis of Cigarette Smoke-Induced Pulmonary Emphysema and Inflammation

Th1 inflammation and remodeling characterized by local tissue destruction coexist in pulmonary emphysema and other diseases. To test the hypothesis that IL-18 plays an important role in these responses, we characterized the regulation of IL-18 in lungs from cigarette smoke (CS) and room air-exposed mice and characterized the effects of CS in wild-type mice and mice with null mutations of IL-18Rα (IL-18Rα−/−). CS was a potent stimulator and activator of IL-18 and caspases 1 and 11. In addition, although CS caused inflammation and emphysema in wild-type mice, both of these responses were significantly decreased in IL-18Rα−/− animals. CS also induced epithelial apoptosis, activated effector caspases and stimulated proteases and chemokines via IL-18Rα-dependent pathways. Importantly, the levels of IL-18 and its targets, cathepsins S and B, were increased in pulmonary macrophages from smokers and patients with chronic obstructive lung disease. Elevated levels of circulating IL-18 were also seen in patients with chronic obstructive lung disease. These studies demonstrate that IL-18 and the IL-18 pathway are activated in CS-exposed mice and man. They also demonstrate, in a murine modeling system, that IL-18R signaling plays a critical role in the pathogenesis of CS-induced inflammation and emphysema.

Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

We review studies of dihydropteroate synthase gene mutations in Pneumocystis jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.

Severity and outcome of HIV-associated Pneumocystis pneumonia containing Pneumocystis jirovecii dihydropteroate synthase gene mutations.

Background:The impact of Pneumocystis jirovecii (formerly P. carinii) dihydropteroate synthase (DHPS) gene mutations on morbidity and mortality of Pneumocystis pneumonia (PCP) in HIV-positive patients is unclear. Objective:To determine whether severity and outcome of HIV-associated PCP differes according to DHPS genotype. Setting:A prospective, observational study in a university-affiliated county hospital. Patients:The study included 197 patients with 215 microscopically confirmed PCP episodes and successfully sequenced DHPS genotypes; 175 (81%) episodes displayed mutant genotypes. Main outcome measure:All-cause mortality within 60 days. Results:The majority of patients (86%) with PCP containing Pneumocystis DHPS mutations survived. Although severity of PCP was comparable, there was a trend for more patients with mutant genotypes than patients with wild-type to require mechanical ventilation (14.3% versus 2.5%; P = 0.056) and to die (14.3% versus 7.5%, P = 0.31). Independent predictors of mortality at baseline were low serum albumin levels [odds ratio (OR), 4.62; 95% confidence interval (CI), 1.63–13.1; P = 0.004] and requiring intensive care within 72 h of hospitalization (OR, 5.06; 95% CI, 1.43–18.0; P = 0.012). Conclusion:The majority of HIV-infected patients with PCP containing mutant Pneumocystis DHPS genotypes survived. Mortality was related primarily to the underlying severity of illness. However, a trend towards increased mortality in episodes of PCP containing mutant DHPS genotypes was observed and this warrants further study.

A Prospective, Blinded Study of Quantitative Touch-Down Polymerase Chain Reaction Using Oral-Wash Samples for Diagnosis of Pneumocystis Pneumonia in HIV-Infected Patients

Oral-wash samples obtained during 113 episodes of suspected Pneumocystis pneumonia (PCP) in human immunodeficiency virus-infected patients were tested by use of a quantitative touch-down PCR (QTD PCR) assay. QTD PCR had a sensitivity of 88% and a specificity of 85%. Treatment for PCP prior to oral wash collection had an impact on the sensitivity, and PCR-positive oral-wash samples obtained within < or =1 day of treatment from patients without PCP had significantly fewer copies per tube than did those from patients with PCP; thus, application of a post hoc cut-off value of 50 copies/tube increased the specificity to 100%. QTD PCR of oral-wash samples can be an accurate and noninvasive method for diagnosis of PCP.

Impact of cigarette smoking on mortality in HIV-positive and HIV-negative veterans.

It is unknown whether smoking confers similar mortality risk in HIV-positive as in HIV-negative patients. We compared overall mortality stratified by HIV and smoking of 1,034 HIV-positive block-matched to 739 HIV-negative veterans, enrolled 2001-2002 in the Veterans Aging Cohort 5 Site Study. Adjusted incidence rate ratios (IRR) for mortality were calculated using Poisson regression. Mortality was significantly increased in HIV-positive veterans according to both smoking status and pack-years in unadjusted and adjusted analyses (adjusted IRR 2.31, 95% confidence interval [CI] 1.53-3.49 for HIV-positive current smokers and IRR 1.32, 95% CI 0.67-2.61 for HIV-negative current smokers). Comorbid diseases were also significantly increased according to smoking status and pack-years. Current smoking is associated with poor outcomes; even lower levels of exposure appear to be detrimental in HIV-infected veterans. These findings support the need for improvements in smoking cessation and for studies of mechanisms and diseases underlying increased mortality in smokers with HIV.