S. Cocchi

Performance of tests for latent tuberculosis in different groups of immunocompromised patients.

BACKGROUND Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their management is hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-gamma release blood assays T-SPOT.TB (TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy for latent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown. METHODS AND RESULTS Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneously performed, their results were compared, and intertest agreement was evaluated. Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p < 0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (kappa = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (kappa = 0.16) or QFT-IT (kappa = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001). CONCLUSIONS Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based on these results, we recommend tailoring application of the new blood IFN-gamma assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

Hepatocellular Carcinoma in HIV-Infected Patients: Check Early, Treat Hard

PURPOSE Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. The aims of this study were to describe HCC tumor characteristics and different therapeutic approaches, to evaluate patient survival time from HCC diagnosis, and to identify clinical prognostic predictors in patients with and without HIV infection. PATIENTS AND METHODS A multicenter observational retrospective comparison of 104 HIV-infected patients and 484 uninfected patients was performed in four Italian centers. HCC was staged according to the Barcelona Clinic Liver Cancer (BCLC) criteria. RESULTS Tumor characteristics of patients with and without HIV were significantly different for age, Eastern Cooperative Oncology Group performance status (PS) score ≤1, and etiology of chronic liver disease. Despite the similar potentially curative option rate and better BCLC stage at diagnosis, the median survival time was significantly shorter in HIV(+) patients. HIV(+) patients were less frequently retreated at relapse. Independent predictors of survival were: BCLC stage, potentially effective HCC therapy, tumor dimension ≤3 cm, HCC diagnosis under a screening program, HCC recurrence, and portal vein thrombosis. Restricting the analysis to HIV(+) patients only, all positive prognostic factors were confirmed together with HAART exposure. CONCLUSION This study confirms a significantly shorter survival time in HIV(+) HCC patients. The less aggressive retreatment at recurrence approach does not balance the benefit of younger age and better BCLC stage and PS score of HIV(+) patients. Thus, considering the prognosis of HIV(+) HCC patients, effective screening techniques, programs, and specific management guidelines are urgently needed.

HHV-6A in Syncytial Giant-Cell Hepatitis

Syncytial giant-cell hepatitis is a rare but severe form of hepatitis that is associated with autoimmune diseases, drug reactions, and viral infections. We used serologic, molecular, and immunohistochemical methods to search for an infectious cause in a case of syncytial giant-cell hepatitis that developed in a liver-transplant recipient who had latent infection with variant B of human herpesvirus 6 (HHV-6B) and who had received the organ from a donor with variant A latent infection (HHV-6A). At the onset of the disease, the detection of HHV-6A (but not HHV-6B) DNA in plasma, in affected liver tissue, and in single micromanipulated syncytial giant cells with the use of two different polymerase-chain-reaction (PCR) assays indicated the presence of active HHV-6A infection in the patient. Expression of the HHV-6A-specific early protein, p41/38, but not of the HHV-6B-specific late protein, p101, was demonstrated only in liver syncytial giant cells in the absence of other infectious pathogens. The same markers of HHV-6A active infection were documented in serial follow-up samples from the patient and disappeared only at the resolution of syncytial giant-cell hepatitis. Neither HHV-6B DNA nor late protein was identified in the same follow-up samples from the patient. Thus, HHV-6A may be a cause of syncytial giant-cell hepatitis.

Outcome, incidence, and timing of infectious complications in small bowel and multivisceral organ transplantation patients.

Background. Infectious complications still represent a major cause of morbidity and mortality in patients with organ transplantation. In particular, small bowel or multivisceral transplantation is complicated to a greater extent than other grafts as a consequence of infectious complications including sepsis. Methods. This prospective study assessed outcome, incidence, and timing of infections in sequential patients undergoing small bowel or multivisceral transplantation (SB/MVTx) performed at a university transplant center between January 2001 and October 2003. Nineteen patients underwent transplantation during this period, 13 of whom (68%) undergoing isolated SB and 6 (32%) MV grafts with or without liver. Results. The median follow up was 524 days (interquartile range=252–730) with an overall 24.4 person/year of observation. Postoperative mortality rate was 0.1 death/person/year; all patients, except one who died intraoperatively, were alive 6 months postsurgery. There were 100 documented infections including: 59 bacterial (2.4 events/person/year), 35 viral (1.4 events/person/year) and 6 fungal (0.2 events/person/year). Patients developed at least one episode of bacterial infection in 94% of the cases, viral infection in 67%, and fungal infection in 28%. Conclusions. This cohort describes the very common and complex nature of infectious complications in this challenging group of transplantation patients. Larger cohorts are needed to specifically address infection risk factors and longer term outcomes.

Fusarium verticillioides fungemia in a liver transplantation patient: successful treatment with voriconazole ☆

Fusarium is an opportunistic fungal pathogen which is emerging as a significant cause of morbidity and mortality in immunocompromised hosts. We present a rare case of F. verticillioides fungemia that occurred in a patient who underwent a second orthotopic liver transplantation for chronic rejection and completely responded to treatment with voriconazole.

University of Modena Experience in HIV-Positive Patients Undergoing Liver Transplantation

INTRODUCTION Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC). PATIENTS AND METHODS From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin. RESULTS The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively. DISCUSSION LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

GH response to GHRH plus arginine is impaired in lipoatrophic women with human immunodeficiency virus compared with controls.

OBJECTIVE GH secretion is impaired in lipodystrophic human immunodeficiency virus (HIV) patients and inversely related to lipodystrophy-related fat redistribution in men. Less is known about the underlying mechanisms involved in reduced GH secretion in HIV-infected women. DESIGN A case-control, cross-sectional study comparing GH/IGF1 status, body composition, and metabolic parameters in 92 nonobese women with HIV-related lipodystrophy and 63 healthy controls matched for age, ethnicity, sex, and body mass index (BMI). METHODS GH, IGF1, IGF binding protein 3 (IGFBP3), GH after GHRH plus arginine (GHRH+Arg), several metabolic variables, and body composition were evaluated. RESULTS GH response to GHRH+Arg was lower in HIV-infected females than in controls. Using a cutoff of peak GH ≤ 7.5 μg/l, 20.6% of HIV-infected females demonstrated reduced peak GH response after GHRH+Arg. In contrast, none of the control subjects demonstrated a peak GH response ≤ 7.5 μg/l. Bone mineral density (BMD), quality of life, IGF1, and IGFBP3 were lowest in the HIV-infected females with a GH peak ≤ 7.5 μg/l. BMI was the main predictive factor of GH peak in stepwise multiregression analysis followed by age, with a less significant effect of visceral fat in the HIV-infected females. CONCLUSIONS This study establishes that i) GH response to GHRH+Arg is lower in lipoatrophic HIV-infected women than in healthy matched controls, ii) BMI more than visceral adipose tissue or trunk fat influences GH peak in this population, and iii) HIV-infected women with a GH peak below or equal to 7.5 μg/l demonstrate reduced IGF1, IGFBP3, BMD, and quality of life.

A pilot study on the efficacy, pharmacokinetics and safety of atazanavir in patients with end-stage liver disease

OBJECTIVES Antiretroviral combinations including atazanavir are currently not recommended in HIV-infected patients with end-stage liver disease (ESLD). The objective of our study was to evaluate efficacy, pharmacokinetics and safety of unboosted atazanavir in HIV-infected patients with ESLD screened for orthotopic liver transplantation (OLT(x)). Patients and methods Single-arm, 24 week pilot study. Atazanavir-naive patients undergoing highly active antiretroviral therapy were switched to atazanavir 400 mg/day plus two non-thymidine nucleoside reverse transcriptase inhibitors. Results Fifteen patients (10 males and 5 females) were included. In the study period, 2 patients were transplanted and 10 completed 24 weeks of atazanavir treatment. Median area under the concentration-time curve at week 4 was 19 211 ng.h/mL (IQR = 8959-27 500). At week 24, median atazanavir trough concentrations (C(trough)) per patient calculated across the study were above the minimum effective concentration (MEC = 100 ng/mL) in 8 of 10 subjects. Atazanavir C(trough) time-point values were always above the MEC in five patients. The other three subjects experienced only one determination below the MEC, with median atazanavir C(trough) levels across the study being above the MEC in two of them. At 8 of 11 time-points when atazanavir and proton pump inhibitors (PPIs) were co-administered and at 16 of 19 time-points in which patients had a concomitant tenofovir association, atazanavir C(trough) was above the MEC. Conclusions Unboosted atazanavir showed a favourable pharmacokinetic profile and was able to maintain or gain immuno-virological eligibility for OLT(x) in all patients. Limited biochemical toxicities (including unconjugated hyperbilirubinaemia) and allowance of concomitant administration of tenofovir and PPIs were observed.

Differential dose adjustments of immunosuppressants after resuming boosted versus unboosted HIV-protease inhibitors postliver transplant.

Pharmacokinetic (PK) interactions between protease inhibitors (PIs) and immunosuppressive agents (IS) are critical elements in the management of HIV‐infected patients who undergo liver transplantation (LTx). The primary objective of this study was to evaluate the decreases in IS dosages necessary to maintain an appropriate therapeutic window (TW) after initiating PI‐based antiretroviral therapy regimens post‐LTx. Single‐center, PK cross‐sectional study of consecutive HIV‐infected adult patients who underwent LTx was done. Blood trough concentrations (Ct) of IS were obtained using a commercial MEIA test; plasma Ct of PIs were measured using HPLC. Twelve consecutive HIV‐infected adult patients (11 males, 1 female) were enrolled. More rapid increases in IS plasma Ct were observed 48 h after initiating ritonavir (RTV)‐boosted PI therapy post‐LTx than when using unboosted PIs. Seven patients developed acute renal failure. The median fold decrease in IS dosages required to regain IS concentrations that were in the TW was 7.5 (range 6–14) after resuming boosted PIs and 2.9 (range 2–4) after unboosted PIs. The overall median time necessary to reach IS TW after dose adjustment was 3.5 days (range 0–15). Unboosted PIs exhibited lesser PK interactions with IS than did RTV‐boosted PIs and were thus more amenable to use in the post‐LTx setting.

Brucellosis in a patient with end-stage liver disease undergoing liver transplantation: successful treatment with tigecycline.

Brucellosis is a common zoonotic disease caused by Brucella spp. In humans, it causes a wide range of clinical manifestations involving various body systems. It is a rare condition in advanced liver cirrhosis, and so far, only a few cases have been reported in this context with a more severe presentation. Antimicrobial therapy of brucellosis is difficult because of relatively high relapse rates and treatment failure. Tigecycline has recently shown promising results in vitro, but up to now, no data on its clinical efficacy for the treatment of brucellosis have been available. We describe a case of brucellosis successfully treated with tigecycline in a hepatitis C virus–infected patient suffering from cirrhosis who underwent liver transplantation. The patient was a 41-year-old Caucasian man with hepatitis C virus cirrhosis complicated by relapsing multifocal hepatocellular carcinoma. ln March 2008, he was admitted to the hospital with complaints of fever, ascites, and hepatic encephalopathy. Laboratory data revealed anemia and pancytopenia. Brucella melitensis grew in blood cultures, and the standard agglutination test (SAT) was positive at a titer of 1:1280. Because of the risk of worsening liver function, the patient was treated with a second-line antibiotic regimen consisting of oral ciprofloxacin (500 mg every 12 hours) and oral doxycycline (100 mg every 12 hours). In the following days, his fever persisted, and after 2 weeks, repeated blood cultures remained positive with an increase in the SAT titer to 1:40,960. His ascites and hepatic encephalopathy as well as his fever slowly resolved. After 6 weeks of treatment, the patient recovered, and his blood cultures became negative. The SAT titer progressively decreased. In June 2008, he was admitted again to the hospital with fever, fatigue, and anemia. SAT was repeated and showed a titer of 1:1280; bone marrow puncture was performed. B. melitensis grew in a bone marrow culture. Because of his liver failure, the patient was started on intravenous gentamicin (240 mg every 24 hours for 10 days) and intravenous tigecycline at a loading dose of 100 mg initially and then at a dose of 50 mg every 12 hours for 15 days; this was followed by oral doxycycline (100 mg every 12 hours for 2 additional weeks). The treatment was well tolerated, and no side effects occurred. At the end of the antibiotic therapy, the blood cultures, bone marrow cultures, and bone marrow cytological examination were negative, whereas the SAT titer decreased to 1:400. In November 2008, he underwent liver transplantation, and perioperative prophylaxis against brucellosis (oral doxycycline at 100 mg every 12 hours and intramuscular streptomycin at 1 g every 24 hours for 14 days) was administered. The SAT titer remained stable at 1:640, and the patient did not develop any clinical symptoms. In February 2009, because the SAT titer had increased to 1:1280, the blood cultures, bone marrow cultures, and bone marrow cytological examination were repeated, and they were negative. Afterwards, the SAT titer spontaneously decreased; 17 months after the recrudescence of brucellosis, the titer was 1:160, and the patient was clinically well without documented relapses, despite retransplantation in May 2009 for chronic cellular rejection. In conclusion, we believe that tigecycline is a promising treatment option for brucellosis in patients in whom the use of conventional antibiotics is contraindicated or limited because of the presence of severe comorbidities or a high risk of drug-drug pharmacokinetic interactions.