Kirk M. Chan-Tack

Meta-Analysis of Gender Differences in Efficacy Outcomes for HIV-Positive Subjects in Randomized Controlled Clinical Trials of Antiretroviral Therapy (2000–2008)

Women are often underrepresented in randomized clinical trials (RCT) of HIV-1 drugs. As a result, determining whether women have different virologic outcomes compared to men is not always possible because the gender-related analyses usually lack statistical power. To address this important public health concern, the Food and Drug Administrations (FDA) Division of Antiviral Products (DAVP) created a database including 20,328 HIV-positive subjects from 40 RCTs in 18 New Drug Applications (NDAs) submitted to the FDA between 2000 and 2008. These RCTs were conducted for at least 48 weeks in duration and were used to support approval of new molecular entity, new formulation, or major label change. To delineate potential gender differences in antiretroviral treatment (ART), we evaluated the percentage of subjects with HIV RNA less than 50 copies per milliliter at 48 weeks. Analyses of the database represent the most systematic review of gender-related ART efficacy data to date. Overall, the meta-analyses did not demonstrate statistically or clinically significant gender differences in virologic outcome at week 48. However, the corresponding subgroup analyses appear to show several statistically significant gender differences favoring males.

Failure of interferon alpha-2b in a patient with West Nile virus meningoencephalitis and acute flaccid paralysis

WNV infection can cause meningoencephalitis (MNE) and acute flaccid paralysis (AFP). Both syndromes are associated with high morbidity and mortality. Interferon alpha-2b (IFN-α-2b) inhibits WNV replication in vitro. To date, 5 patients with WNV-CNS disease have recovered neurologic function with IFN-α-2b. We report the first failure of IFN-α-2b in the treatment of WNV-MNE-AFP.

Intracranial Hemorrhage and Liver-Associated Deaths Associated with Tipranavir/Ritonavir: Review of Cases from the FDA's Adverse Event Reporting System

Tipranavir (TPV), a protease inhibitor, has box warnings for intracranial hemorrhage (ICH) and hepatotoxicity (including hepatic failure and death). A box warning is a labeling statement about serious adverse events leading to significant injury and/or death. A box warning is the most serious warning placed in the labeling of a prescription medication. As a result of the respective morbidity and mortality associated with ICH and hepatic failure, the Food and Drug Administrations (FDAs) Adverse Event Reporting System (AERS) was searched for reports of these adverse events in HIV-infected patients receiving a tipranavir/ritonavir (TPV/r)-based regimen. This search comprised part of the FDAs safety analysis for traditional approval. From July 2006 to March 2007, 10 cases of ICH were identified in AERS. From June 2005 to March 2007, 12 cases of liver-associated deaths were identified. One patient experienced liver failure and fatal ICH. Most patients with these events had additional risk factors. Among patients with liver-associated deaths, 3 had HIV-RNA less than 400 copies per milliliter at the time of hepatic failure. Among 10 patients who discontinued TPV/r when hepatic failure developed, median number of days post-TPV/r to death was 23 (range, 2-69 days). Review of AERS did not identify new safety concerns regarding ICH. Among most patients with liver-associated deaths, death appears to occur soon after hepatic failure develops. If considering TPV/r, careful assessment of risk/benefit is suggested for patients at risk for ICH and hepatic failure.

Central venous catheter-associated fungemia secondary to mucormycosis

Mucormycosis can cause fatal infections in immunocompromized persons. Rhinocerebral and pulmonary disease predominate. Diagnosis is challenging, dissemination frequent, and mortality high. Positive blood cultures are rare. We report the first case of central venous catheter-associated mucormycosis fungemia (Mucor circinelloides). Early diagnosis and multi-modal therapy led to clinical and microbiological cure.

Acute renal failure and nephrotic range proteinuria due to amyloidosis in an HIV-infected patient.

Amyloidosis is an uncommon cause of renal disease in HIV-positive patients. Diagnosis is challenging, treatment options are limited, and prognosis remains poor. We discuss an HIV-positive patient with acute renal failure and nephrotic range proteinuria. The differential diagnosis included nephropathy due to trimethoprim/sulfamethoxazole, tenofovir, HIV, hepatitis C, heroin, or multifactorial causes. Serum and urine study findings were inconclusive. Rapid clinical deterioration ensued and a renal biopsy was performed. Pathologic examination revealed eosinophilic, amorphous material in the glomerular tufts that stained red-orange with Congo red stain. Immunohistochemical analysis confirmed amyloid A (AA) amyloidosis. AA amyloidosis occurs as a complication of chronic infection or chronic inflammatory disease. It has been reported in intravenous or subcutaneous drug abusers, some of whom were HIV-positive. This case underscores the importance of tissue diagnosis to determine the cause of renal disease in HIV-positive patients. Clinical diagnosis, based on CD4 count, viral load, and degree of proteinuria, may not predict the pathological diagnosis in HIV-positive patients.

Original Research: Risk Factors for Mortality from Primary Cryptococcosis in Patients with HIV

Abstract Cryptococcosis continues to have a high mortality rate in human immunodeficiency virus (HIV)-positive patients despite advances made in antifungal treatment, intracranial pressure management, and antiretroviral therapy. This retrospective chart review was conducted at the University of Maryland Medical Center and Baltimore VA Medical Center from 1993 to 2004. We reviewed all inpatient cases of cryptococcal infections to assess predictors of inpatient mortality among HIV-positive patients. Data collected included patient demographics, presenting symptoms and CD4 counts, lumbar puncture (LP) results including opening pressure (OP), cryptococcal antigen (CAg) levels, sites of infection, and drug therapy. Multivariate and survival analyses were performed. We identified 202 patients with primary cryptococcosis. The main sites of infection included blood (72%), central nervous system (85%), and lower respiratory tract (34%). Overall 30-day mortality was 14%. Predictors of mortality included syncope (P = 0.039; OR, 4.5), concomitant pneumonia (P = 0.001; OR, 3.5), respiratory failure (P < 0.001; OR, 10.5), and admission into the intensive care unit (P < 0.001; OR, 8). Amphotericin dose, OP ≥ 250 mm H2O, and number of LPs were not found to be predictive of mortality. Mortality attributable to cryptococcosis remains high. Our study findings suggest that syncope, respiratory failure, pneumonia, and admission to the intensive care unit are independently associated with an increased risk of death within 30 days after cryptococcosis diagnosis.

A filamentous foe.

A 65-year-old man who was HIV-positive (CD4 count, <20 cells/mm; viral load, 59 552 copies/mL) presented from a long-term care facility with 5 days of fever and lethargy. A ventriculoperitoneal shunt (VPS) had been placed 2 weeks previously for management of hydrocephalus owing to a massive hemorrhagic stroke. HIV infection had been diagnosed 3 weeks previously, at the time of the stroke. His medical history was negative for any opportunistic infections or central nervous system infections. Medications were narcotics and laxatives. At the request of his family, the patient was not receiving any antiretroviral or prophylactic medications for opportunistic infections. They had based their decision on his overall poor prognosis owing to the stroke, hydrocephalus, residual neurologic status (nonverbal but responsive to some simple commands), and debilitation. On examination, the patient was febrile (39.3°C), hypotensive, and obtunded. There was no erythema, drainage, or fluctuance at the VPS site. Results of admission blood, urine, and sputum cultures were negative. Cerebrospinal fluid (CSF) analysis after lumbar puncture (LP) showed 18 600 white blood cells/mm (normal, 4000 to 11 000/mm) with 100% neutrophils; 519 red blood cells/mm (normal, 0 to 5 cells/mm); glucose, 12 mg/dL (normal, 40 to 70 mg/dL); protein, 1150 mg/dL (normal, 15 to 40 mg/dL). A CSF gram stain demonstrated gram-negative rods, and CSF cultures grew Escherichia coli. No minimum inhibitory concentration levels were determined. A review of the microbiologic data confirmed sensitivity to amikacin, cefepime, ceftriaxone, imipenem, and piperacillin-tazobactam. The E coli strain was resistant to ampicillin-sulbactam, gentamicin, and trimethoprimsulfamethoxazole. Ceftriaxone (2 grams intravenously every 12 hours) was initiated on admission. The VPS remained intact. His fevers persisted. White blood cell count was 4300 cells/mm (normal, 4000 to 11 000 cells/mm) with 94% neutrophils, 2% lymphocytes, and 4% monocytes. Results of hemoglobin, platelets, electrolytes, and liver function tests were normal. Results of repeat blood (aerobic, anaerobic, mycobacterial, fungal), sputum, and urine cultures were negative, as were serum cryptococcus antigen and urine histoplasma antigen. A computed tomography (CT) scan of the head was unchanged from previous studies. The result of a CT of the sinuses, chest, abdomen, and pelvis were negative. Transthoracic and transesophageal echocardiograms showed no valvular vegetations. On hospital day 4, a repeat LP showed 273 white blood cells/mm with 94% neutrophils; 1 red blood cell/mm; glucose level, 18 mg/dL; and protein level, 242 mg/dL. A Gram stain of the CSF showed gramnegative filamentous organisms (Figure 1). This combination of an unusual microbiologic finding in a severely immunocompromised patient with ongoing fevers led to an evaluation by the infectious disease service. Filamentous organisms are typically fungi, but also include some bacteria (eg, Nocardia spp, Actinomyces spp), and mycobacteria (eg, Mycobacterium chelonae). However, none of these organisms produce gramnegative stain on microbiologic analysis. Penicillinbinding protein 3 (PBP3) is a key enzyme involved in cell septation for E coli. β-Lactam antibiotics, including ceftriaxone, can inhibit PBP3, prevent cell septation, and create filamentous E coli. In this patient, it is