James Cutrell

The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health.

Background NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression. Methods In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48. Results Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP). Conclusion The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health. Trial Registration ClinicalTrials.gov NCT 00677300

Non-AIDS-defining cancers among HIV-infected patients

In the highly active antiretroviral therapy (HAART) era, the incidence of non-AIDS-defining cancers (NADC) has increased and contributes to a growing proportion of mortality in the aging HIV-infected population. The underlying pathogenic mechanisms of increased cancer risk are incompletely understood. Potential contributors include oncogenic effects of the HIV virus, immunosuppression, chronic inflammation and immune activation, exposure to HAART, higher rates of oncogenic viral coinfections and traditional cancer risk factors. HIV-infected patients often present with NADC at younger ages with more aggressive or advanced stage disease. However, when standard cancer therapy is given, treatment outcomes appear similar to the non-HIV population. These facts highlight the importance of clinicians’ maintaining a high index of suspicion, performing age-appropriate screening, and optimizing cancer therapy. Development of novel strategies for screening, prevention, and treatment of NADC will be required to reverse these epidemiologic trends and improve the survival of HIV-infected patients.

Mechanisms of bone disease in HIV and hepatitis C virus: impact of bone turnover, tenofovir exposure, sex steroids and severity of liver disease.

Objective:Both HIV and hepatitis C virus (HCV) infections are associated with higher osteoporotic fracture risk. Increased bone turnover, liver fibrosis, tenofovir (TDF) use or hormonal imbalances are possible underlying mechanisms. Design:This prospective, cross-sectional study assessed 298 male volunteers with either virologically suppressed HIV or untreated HCV mono-infections, HIV/HCV co-infection and noninfected controls. Methodology:Study participants underwent bone mineral density (BMD) by dual-energy x-ray absorptiometry and measurement of bone turnover markers [BTM: C-telopeptide (CTX) and osteocalcin (OC)], insulin-like growth factor-1 (IGF-1), the sex steroids testosterone (T) and estradiol (E2), and the aspartate aminotransferase-to-platelet ratio index (APRI). Impact of HIV and HCV status on BMD was evaluated in multivariate models adjusting for APRI score, BTM, TDF exposure, IGF-1, and sex steroids. Results:HIV and HCV status independently predicted lower BMD, controlling for age, race, BMI, and smoking (P = 0.017 and P = 0.010, respectively), whereas APRI did not (P = 0.84). HIV was associated with increased bone resorption (CTX: P < 0.001) and formation (OC: P = 0.014), whereas HCV infection was not associated with CTX (P = 0.30) or OC (P = 0.36). TDF exposure was associated with lower BMD (P < 0.01). IGF-1 was significantly decreased in HCV and increased in HIV. Tumor necrosis factor-&agr; (P = 0.98), IGF-1 (P = 0.80), bioavailable T (P = 0.45) and E2 (P = 0.27) were not associated with BMD and did not attenuate the impact of HIV or HCV on BMD. Conclusion:HIV and TDF exposure decrease BMD through increased bone turnover, although the lower BMD in HCV is not explained by a high turnover state. Neither virus’ effect on BMD is likely mediated through increased inflammation, liver fibrosis, IGF-1, or sex steroids.

Risk factors for deep sternal wound infection after cardiac surgery: Influence of red blood cell transfusions and chronic infection

BACKGROUND Deep sternal wound infection (DSWI) following cardiac surgery is a serious complication, but risk factors associated with DSWI have not been fully elucidated. METHODS We analyzed all DSWI cases at our institution from 2010-2013 in adult cardiac median sternotomy cases, based on Society of Thoracic Surgeons or National Healthcare Safety Network definitions, but with 1-year surveillance postsurgery. Controls were matched 3:1 per case for procedure, age, and year of surgery. Demographic and operative data were pulled from Society of Thoracic Surgeons database and chart review. Potential variables were evaluated using univariate and multivariate conditional logistic regression. RESULTS Out of 1,894 surgeries performed, 39 DSWI cases (2%) and 117 controls were identified. In univariate analyses, patients with red blood cell (RBC) transfusion ≥ 4 units, any platelet transfusion, previous infections, and chronic infections were associated with higher DSWI. RBC transfusion ≥ 4 units (P = .037) and chronic infections (P = .029) remained significant risk factors for DSWI in multivariate analysis. Preoperative anemia alone was not associated with more DSWI, but its interaction with RBC transfusion ≥ 4 units was significant. CONCLUSIONS High-volume RBC transfusions and chronic infections were strongly associated with DSWI in our population and represent potentially modifiable areas for improvement.

Current use of statins reduces risk of HIV rebound on suppressive HAART

Background Despite compelling evidence for activity against HIV-1 in vitro, a virologic effect of statins has not been shown in clinical studies. Given their short plasma half-lives, such an effect may be transient and only apparent during ongoing exposure. Methods We studied all HIV infected US-Veterans who started HAART 1995–2011, had a documented HIV viral load (VL) >1000 copies/mL, reached an undetectable VL on HAART, and had ≥1 follow-up VL within 13 months. We defined virologic failure (VF) as the first VL >1,000 copies/mL or the first of 2 consecutive VL >200 copies/mL. We built a time-updated drug exposure model for antiretrovirals (ARVs), statins, and other cardiovascular drugs (CVMs), investigating current use (yes/no), recent use (proportion of days used), and categorical use (ever/never). We used both multiply adjusted and inverse-probability-weighted (IPW) Cox models to explore the association between statin and CVM use and VF. Results 19,324 veterans met inclusion criteria. Median follow-up was 13 months (IQR: 5–32 months); 63% experienced VF after a median time of 9 months (IQR 4–21 months). Almost 1/3 patients ever used statins but exposure comprised only 41% of follow-up time covered after initial prescription. Unadjusted, current statin use was associated with a hazard ratio (HR) for VF of 0.60 (CI: 0.56–0.65). This remained statistically significant after multivariate adjustment (MVA) for demographics, HIV and HAART parameters [HR 0.81 (CI: 0.75–0.88), p<0.001] and IPW (truncation <1%/>99%) HR: 0.83 (CI: 0.75–0.92), p<0.001]. No independent association was observed for other CVMs. The association between categorical-statin use and VF after MVA was much weaker: HR 0.94 (CI: 0.88–1.00, p = 0.04). Conclusion Current statin exposure was associated with reduced risk of VF in univariate, multivariate, and inverse-probability-weighted models. Our results highlight the importance of time-updated medication exposure models for observational studies.

Brucellosis in Dallas, Texas: a Case Series

Abstract Background While the epidemiology of Brucellosis is well described in systematic reviews and retrospective analyses in endemic countries, there is a paucity of similar data in the United States (US). With a recent outbreak of Brucellosis reported in Dallas County in 2016, we sought to characterize cases of Brucellosis at two Dallas teaching hospitals over the past 10 years. Methods A retrospective chart review of electronic medical records at Parkland Health and Hospital System and Clements University Hospital was completed for all patients over 18 who were diagnosed with Brucellosis, as defined by ICD9/10 codes, problem lists, and/or positive microbiologic or serologic data, between 1/1/2007 - 2/6/2017. Demographic, epidemiologic, and clinical characteristics were collected. Results Out of 104 charts reviewed, 16 cases of Brucellosis (14 definite, 2 probable) were identified. Fifty-six percent were male, the mean age was 45, and 94% were of Hispanic ethnicity. Recent travel was reported in 6/16 cases (5 to Mexico, 1 to India) and exposure to unpasteurized cheeses was reported in 13/16 cases. The majority of cases were seen in the summer months, and a sharp increase in incidence was noted in 2016 (Figure 1). Common symptoms included fever (16/16), chills (8/16), diarrhea (4/16), headache (4/16), malaise (4/16), and body aches (4/16). Laboratory abnormalities included leukopenia, thrombocytopenia, and elevated liver function tests. Other complications included epididymitis and/or orchitis (2/16), hepatomegaly (5/16), splenomegaly (4/16), and other splenic abnormalities (2/16). Brucella discitis/osteomyelitis with spinal epidural abscess (1/16), possible neurobrucellosis (1/16) and recurrent disease (2/16) were also identified. The most common treatment regimen used was doxycycline/rifampin +/- gentamicin. Conclusion This case series represents one of the largest contemporary Brucella experiences described in the US. While not endemic in the US, the diagnosis of Brucellosis requires a high index of suspicion and should be considered in patients presenting with a febrile illness and a compatible travel history or exposure history, particularly to unpasteurized dairy products. Disclosures All authors: No reported disclosures.

Disseminated histoplasmosis presenting as multiple oral ulcers

A 61-year-old female with a history of advanced HIV disease and chronic hepatitis B was presented with an 8-week history of painful oral ulcers. She appeared systemically well but examination revealed multiple well-demarcated clean-based ulcers on the tongue and hard palate. Biopsy of one of the lesions showed numerous histiocytes containing intracellular yeast forms consistent with Histoplasma capsulatum var. capsulatum. Fungal blood cultures subsequently grew H. capsulatum var. capsulatum, confirming a diagnosis of disseminated histoplasmosis. She was treated with intravenous amphotericin B for 2 weeks followed by a prolonged course of oral itraconazole, with which her ulcers resolved completely and have not recurred. This case exemplifies how oral ulcers may be a manifestation of an underlying systemic disease and demonstrates the utility of biopsy in establishing a diagnosis.

1602Impact of IGF-1 and Sex Steroids on Bone Health in HIV- and HCV-Infected US Male Veterans

1. Young B, et al. Clin Infect Dis 2011; 52(8):1061-8. 2. Bedimo R, et al. AIDS 2012; 26(7): 825-31. 3. Maalouf NM, et al. JBMR 2013; 28 (12):2577-83. 4. Cutrell J, et al. Abstract 783. CROI 2014. 5. Sodergard R, et al. J Steriod Biochem 1982; 16:801-10. • Prospective, cross-sectional study of 298 male veterans with uninfected controls (n=107), HCV (n=79), HIV (n=81), and HIV/HCV co-infection (n=31). • Inclusion criteria: Age≥ 40; eGFR ≥ 60; no known osteoporosis • All HIV patients virologically suppressed on HAART • All HCV patients were HCV treatment-naive • Study Measurements: • BMD by DXA scan • BTMs: serum C-telopeptide (CTX), bone-specific alkaline phosphatase (BSAP) and osteocalcin (OC) • Hormones: IGF-1, Insulin-like growth factor binding protein 3 (IGFBP3), total T, total E2, sex hormone binding globulin (SHBG); Bioavailable T and E2 calculated from published equations5 • AST-to-platelet ratio index – APRI (as marker of liver fibrosis) • Statistical Analysis: • Group means for BMD and BTMs compared by ANOVA and by ANCOVA adjusting for age, race, smoking, and BMI in all models • Additional multivariate models controlling for IGF-1, bioavailable T and E2 levels • Correlation between hormones and BMD, BTMs, and severity of liver disease by Spearman’s correlation coefficient Impact of IGF-1 and Sex Steroids on Bone Health in HIVand HCV-Infected US Male Veterans

Surveillance of patients identified with fungal mold at a public academic medical center

BACKGROUND This study describes the epidemiology of patients with fungal mold infection or colonization at a large academic medical center during a period of ongoing construction of a new hospital building. METHODS This is an observational retrospective cohort study performed at a public academic hospital. We performed focused medical record review of all patients with fungal mold isolated on microbiologic culture over a 3-year period from May 2009 through April 2012. We established case definitions by modifying criteria used in previously published studies. We established 4 categories for invasiveness: proven invasive fungal disease (IFD), probable IFD, clinical infection not meeting IFD criteria, or colonization/contamination. We also established 3 categories for association with our health care facilities: health care-associated hospital onset (HO), health care-associated community onset (HACO), or community associated (CA). RESULTS Of the 188 cases included in the study, 15 (7.9%) and 23 (12.2%) met criteria for proven and probable IFD, respectively. Of the cases, 114 (60.6%) represented contamination or colonization, and 36 (19.1%) had clinical infection not meeting IFD criteria. Epidemiologically, 46 (24.5%) cases were HO, 42 (22.3%) cases were HACO, and 100 (53.2%) cases were CA. CONCLUSION The surveillance methods we established were helpful for characterizing and monitoring fungal mold infections at the study institution.