Lisa A. Clough

Efficacy and Safety of Maribavir Dosed at 100 mg Orally Twice Daily for the Prevention of Cytomegalovirus Disease in Liver Transplant Recipients: A Randomized, Double-Blind, Multicenter Controlled Trial

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double‐blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV‐seronegative liver transplant recipients with CMV‐seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)‐confirmed CMV disease within 6 months of transplantation. In a modified intent‐to‐treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: −0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC‐confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non‐CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well‐tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.

Evidence of a Source of HIV Type 1 within the Central Nervous System by Ultraintensive Sampling of Cerebrospinal Fluid and Plasma

Defining the source of HIV-1 RNA in cerebrospinal fluid (CSF) will facilitate studies of treatment efficacy in the brain. Four antiretroviral drug-naive adults underwent two 48-hr ultraintensive CSF sampling procedures, once at baseline and again beginning on day 4 after initiating three-drug therapy with stavudine, lamivudine, and nelfinavir. At baseline, constant CSF HIV-1 RNA concentrations were maintained by daily entry of at least 10(4) to 10(6) HIV-1 RNA copies into CSF. Change from baseline to day 5 ranged from -0.38 to -1.18 log(10) HIV-1 RNA copies/ml in CSF, and from -0.80 to -1.33 log(10) HIV-1 RNA copies/ml in plasma, with no correlation between CSF and plasma changes. There was no evidence of genotypic or phenotypic viral resistance in either CSF or plasma. With regard to pharmacokinetics, mean CSF-to-plasma area-under-the-curve (AUC) ratios were 38.9% for stavudine and 15.3% for lamivudine. Nelfinavir and its active M8 metabolite could not be accurately quantified in CSF, although plasma M8 peak level and AUC(0-8hr) correlated with CSF HIV-1 RNA decline. This study supports the utility of ultraintensive CSF sampling for studying HIV-1 pathogenesis and therapy in the CNS, and provides strong evidence that HIV-1 RNA in CSF arises, at least in part, from a source other than plasma.

Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection

To characterize steady‐state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration‐time profile calculated over the interval 0 to 8 hours [AUC(0‐8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L · h, respectively. The cerebrospinal fluid‐to‐plasma AUC(0‐8) ratio for free indinavir was 14.7% ± 2.6% and did not correlate with indexes of blood‐brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid‐to‐plasma AUC(0‐8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood‐cerebrospinal fluid barrier, perhaps by P‐glycoprotein–mediated efflux. (Clin Pharmacol Ther 2000;68:367‐74.)

Factors That Predict Incomplete Virological Response to Protease Inhibitor—Based Antiretroviral Therapy

Many patients infected with human immunodeficiency virus type 1 (HIV-1) have suboptimal responses to protease inhibitor-based therapy. We retrospectively evaluated a cohort of 104 HIV-positive adults, most of whom had previously received antiretrovirals, to identify the frequency and clinical predictors of incomplete response to potent HIV-1 protease inhibitors. Sixty-two (60%) of the patients had an incomplete response, defined as a plasma HIV-1 RNA level of >400 copies/mL after 20 weeks of therapy. Logistic regression analysis identified the following independent risk factors for incomplete response: elevated baseline plasma HIV-1 RNA level (P = .03), low baseline weight (P = .01), chemoprophylaxis for Pneumocystis carinii pneumonia (P = .04), and active illicit drug use (P = .04). Regular prescription of narcotics or benzodiazepine anxiolytics (P = .01) and use of any Internet site (P = .01) predicted a more favorable response. Identifying factors that predict suboptimal response to protease inhibitors improves our understanding of interpatient variability in response to therapy and should foster strategies that enhance the effectiveness of current and future regimens.

Proinflammatory Cytokine and Human Immunodeficiency Virus RNA Levels during Early Mycobacterium avium Complex Bacteremia in Advanced AIDS

The relationship between Mycobacterium avium complex (MAC) bacteremia and proinflammatory cytokine and human immunodeficiency virus type 1 (HIV-1) RNA levels in AIDS was investigated. During a prospective study, blood samples were drawn monthly for mycobacterial cultures. Sera were available at baseline and onset of MAC bacteremia from 20 cases and at corresponding times from 19 controls. Mean interleukin-6 (IL-6) levels were 154% greater at the time of MAC bacteremia in cases than in controls. The IL-6 levels correlated with body temperature, serum tumor necrosis factor (TNF-alpha) levels, and alkaline phosphatase levels (P < or = .004 for each). Although TNF-alpha levels tended to rise more in MAC patients than in controls, the difference was not significant. However, among both cases and controls, serum TNF-alpha levels rose significantly from baseline to the time of last sample, irrespective of MAC infection (P = .015). Bacteremia was not associated with increased serum HIV-1 RNA levels. Thus, early MAC bacteremia is associated with increases in serum IL-6 levels, while TNF-alpha levels rise over time during advanced AIDS.

Comparison of Roche MONITOR and Organon Teknika NucliSens Assays To Quantify Human Immunodeficiency Virus Type 1 RNA in Cerebrospinal Fluid

ABSTRACT We compared Roche MONITOR and Organon Teknika NucliSens assays for human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid (CSF). Results of 282 assays were highly correlated (r = 0.826), with MONITOR values being 0.29 ± 0.4 log10copies/ml (mean ± standard deviation) values. Both assays can reliably quantify HIV-1 RNA in CSF.

Mycobacterium bovis Osteomyelitis of the Thoracic Spine Mimicking a Metastatic Lytic Lesion in a Patient Exposed to Intravesicular Bacille Calmette-Guérin Treatment☆

An 80-year-old man with previous intravesicular bacille Calmette-Guérin therapy developed mass lesions of the lower thoracic spine. Metastatic disease was suspected. The patient underwent a course of radiation; however, biopsy later demonstrated fibrosis and cultures grew Mycobacterium bovis. The patient was treated with a course of isoniazid, rifampin, and ethambutol.

Retrospective evaluation of fidaxomicin versus oral vancomycin for treatment of Clostridium difficile infections in allogeneic stem cell transplant

OBJECTIVE/BACKGROUND Clostridium difficile infection (CDI) is a potential complication during hematopoietic stem cell transplantation (HSCT), and no specific recommendations exist regarding treatment of CDI in allogeneic SCT patients. Use of metronidazole and oral vancomycin has been associated with clinical failure. Fidaxomicin has previously been found noninferior to the use of oral vancomycin for the treatment of CDI, and no studies have compared the use of oral vancomycin with fidaxomicin for the treatment of CDI in allogeneic SCT. METHODS This retrospective chart review included 96 allogeneic SCT recipients who developed CDI within 100 days following transplantation. Participants were treated with oral vancomycin (n = 52) or fidaxomicin (n = 44). The primary outcome was clinical cure, defined as no need for further retreatment 2 days following completion of initial CDI treatment. Secondary outcomes were global cure, treatment failure, and recurrent disease. RESULTS No differences in clinical cure were observed between patients receiving oral vancomycin or fidaxomicin (75% vs. 75%, p = 1.00). Secondary outcomes were similar between oral vancomycin and fidaxomicin in regards to global cure (66% vs. 67%, p = .508), treatment failure (28% vs. 27%, p = .571), and recurrent disease (7% vs. 5%, p = .747). In a subanalysis of individuals that developed acute graft-versus-host disease following CDI, the difference in mean onset of acute graft-versus-host disease was 21.03 days in the oral vancomycin group versus 32.88 days in the fidaxomicin group (p = .0031). CONCLUSION The findings of this study suggest that oral vancomycin and fidaxomicin are comparable options for CDI treatment in allogeneic SCT patients within 100 days following transplant.

1580Sexual Health of HIV Infected Patients Attending KUMC ID Clinic

Background. The aim of this study was to identify overall sexually transmitted diseases (STD) burden in HIV infected patients and determine compliance with sexual health screening and treatment based on CDC 2010 Guideline in our HIV clinic. Methods. This is a retrospective cohort study of all adult patients attending at least 2 visits at the University of Kansas Medical Center outpatient infectious diseases clinic between October 1, 2010 and August 15, 2013. Syphilis, gonorrhea, chlamydia, genital warts, genital herpes, hepatitis A, B, C testing frequency, diagnoses and treatments were abstracted from the charts. Period prevalence, compliance with screening methods, frequency, and treatment were measured. Percentages below are calculated out of the total cohort. Results. Of 241 patients included in the analysis, 197 (81.74%) were male, 43 (17.84%) were female, 1 (0.41%) was transgender, 136 (56.43%) were men who have sex with men, and mean age was 42.07 years. During the study period, 3 (1.24%) patients were diagnosed with gonorrhea, 3 (1.24%) had chlamydia, 34 (14.1%) had a positive syphilis test (RPR or EIA), 22 (9.13%) had positive hepatitis B surface antigen, 20 (8.3%) had positive hepatitis C antibodies, 26 (10.8%) had genital warts, 6 (2.5%) had genital herpes, and 4/43 (9.3%) women had positive cervical HPV DNA. At study entry, mean CD4 count was 403 cells/uL, and mean HIV viral load was 282,529 copies/mL. At STD diagnosis, mean CD4 was 352 cells/uL, and mean HIV viral load was 45,132 copies/mL. Testing per guideline occurred in 95.83% of patients for syphilis, 43.75% for chlamydia, 45% for gonorrhea, 90% for hepatitis A, 99.58% for hepatitis B and 96.25% for hepatitis C. Testing frequency per guideline occurred in 81.25% of patients for syphilis, 37.92% for chlamydia, 38.33% for gonorrhea. When STD was diagnosed, treatment was according to guideline for most patients. Conclusion. Compliance with screening methods and frequency was adequate for syphilis and hepatitis, but screening for chlamydia and gonorrhea is suboptimal and can be improved. Disclosures. All authors: No reported disclosures.

Massive Polymicrobial Suppurative Pancreatic Pseudocyst Originating From Cyst-Enteric Fistula Involving the Ileum

t a a A man presented with 3 months of progressive diffuse abdominal pain, 40-pound weight loss, and fever. On evaluation e was afebrile, with cachexia and abdominal distention with diffuse enderness. White cell count was 10.7 K/UL. Hepatic transaminases nd lipase were normal, alkaline phosphatase was 121 U/L, and lbumin was 1.6 g/dL. Contrast-enhanced computed tomography emonstrated a large fluid collection (23 cm transverse 14 cm nterior-posterior 30 cm craniocaudal) filling the peritoneal cavity nd containing air, fluid, and debris with peritoneal enhancement Figures A and B). Ultrasound-guided aspiration was performed. Culure grew vancomycin-resistant Enterococcus faecium, Enterobacter cloaae, Klebsiella pneumoniae, and mixed aerobic flora. A repeat culture also rew Candida albicans. Echinococcus, amebiasis, and human immunodeciency virus serologies were negative. Amylase of fluid was greater han 24,000 U/L, suggesting the collection formed as a pancreatic seudocyst. The patient was treated with fluconazole, linezolid, and rtapenem. After clinical failure of percutaneous drainage, he underent exploratory laparotomy with resection of the suppurative panreatic pseudocyst and right hemicolectomy. The large thick-walled seudocyst contained more than 4 L of feculent fluid. There was vidence of ileal perforation resulting in cyst-enteric fistula. Pathology eport revealed no malignancy. He was discharged home on hospital ay 40 on fluconazole, levofloxacin, doxycycline, and metronidazole; he final diagnosis was polymicrobial suppurative pancreatic pseudoyst originating from cyst-enteric fistula involving the ileum. Pancreatic and peripancreatic fluid collections (APFCs) repesent a complex clinical dilemma. Collections may be sterile or nfected.1 APFCs can occur in up to 30%–50% of patients with acute pancreatitis, usually within 48 hours. More than 50% of APFCs resolve spontaneously within several weeks, whereas 30%–50% persist and form pseudocysts, similar to the clinical course in our patient.1 Many pseudocysts will resolve without intervention; however, expected course depends on many anatomic factors including cyst size.2 Reviews suggest that 73% of cysts that are more than 10 cm will require surgical drainage.3 Endoscopic therapies have replaced many indications for surgical intervention; however, surgery may still be required with pseudocysts refractory to endoscopic therapy.4 Because many pancreatic pseudocysts will self-resolve, imageguided aspiration on a routine basis is not recommended and may lead to secondary infection.1 Diagnosis of an infected pseudocyst may be challenging, and history, examination, presence of fever, and white blood cell count should be considered. Although imaging can define persistent peripancreatic fluid collections, aspiration of cyst contents is required for diagnosis of suppurative pseudocyst. The most common bacteria cultured include enteric microorganisms, including Escherichia coli, Bacteroides species, Enterobacter species, Klebsiella species, and Streptococcus faecalis.4 Antimicrobial treatment should be directed oward normal enteric flora until definitive microbiological data are vailable. There is no consensus regarding appropriate length of therpy; thus, treatment must be determined on an individual basis.