Paolo Grossi

Antifungal prophylaxis in liver transplant patients: A systematic review and meta-analysis†

We performed a meta‐analysis to determine whether antifungal prophylaxis decreases infectious morbidity and mortality in liver transplant patients. We searched for randomized trials dealing with prophylaxis with systemic antifungal agents. We used a fixed effect model, with risk ratio (RR) and 95% confidence interval (CI); we assessed study quality for heterogeneity and publication bias. Six studies (5 double‐blind), for a total of 698 patients, compared fluconazole, itraconazole, or liposomal amphotericin to placebo (5 studies) or oral nystatin. Prophylaxis reduced colonization (RR, 0.45; CI, 0.37‐0.55), total proven fungal infections (RR, 0.31; CI, 0.21‐0.46), which included both superficial (RR, 0.27; CI, 0.16‐0.45) and invasive (RR, 0.33; CI, 0.18‐0.59) infections, and mortality attributable to fungal infection (RR, 0.30; CI, 0.12‐0.75). Prophylaxis did not affect overall mortality (RR, 1.06; CI, 0.69‐1.64) or empiric treatment for suspected fungal infection (RR, 0.80; CI, 0.39‐1.67). The beneficial effect of antifungal prophylaxis was predominantly associated with the reduction of Candida albicans infection and mortality attributable to C. albicans. Compared to controls, however, patients receiving prophylaxis experienced a higher proportion of episodes of non–albicans Candida, and in particular of C. glabrata. No beneficial effect on invasive Aspergillus infection was observed. In conclusion, our analysis shows a clear, though limited, beneficial effect of antifungal prophylaxis in liver transplant patients. Concerns about the selection of triazole‐resistant Candida strains, however, are realistic, and the potential disadvantages of prophylaxis should be weighed against the established benefits. Liver Transpl 12:850–858, 2006.

Cytomegalovirus PP65 antigenemia monitoring as a guide for preemptive therapy: a cost effective strategy for prevention of cytomegalovirus disease in adult liver transplant recipients.

BACKGROUND The aim of the study was to assess the incidence of cytomegalovirus (CMV) infection and disease in adult liver transplant recipients, using routine preemptive therapy guided by the pp65 antigenemia test. METHODS Antigenemia was monitored weekly after liver transplantation (OLTX) for the first 3 months, and once a month for another 3 months. CMV seronegative recipients were treated preemptively for the first positive antigenemia. Seropositive recipients were treated only when their antigenemia count reached a threshold of > or =100 positive cells per 200,000 leukocytes. RESULTS A total of 144 patients were included between June 1994 and April 1995, of which 137 (95%) were primary OLTX. The percentage of positive antigenemia and CMV disease was 55 and 8%, respectively. Seventy-eight (54%) patients were protocol-monitored for the entire follow-up (group 1) and received appropriate preemptive therapy, although 66 (46%) patients had protocol violation by having missed blood samples or blood drawn at unscheduled times (group 2). Using Coxs proportional hazards model, patients with a first antigenemia count of >11 leukocytes had a significantly higher rate of CMV disease compared to patients with an antigenemia count < or =11 leukocytes (RR = 7.3, 95% confidence interval = 2.2 to 24.5). In a multivariate Cox regression analysis, adjustments were made to control for: group 1 versus group 2, use of OKT3, and serology risk categories. This analysis showed that the relative rate of CMV disease was still significantly higher among patients with antigenemia count >11 leukocytes (adjusted RR = 4.9, 95% confidence interval = 1.3 to 18.1). The estimated cost of preemptive therapy was less than that of prophylaxis with i.v. (14-day course) or oral (90-day course) ganciclovir. CONCLUSIONS Preemptive therapy guided by pp65 antigenemia is a useful and cost effective strategy for prevention of CMV disease.

In-Hospital and 1-Year Mortality in Patients Undergoing Early Surgery for Prosthetic Valve Endocarditis

IMPORTANCE There are limited prospective, controlled data evaluating survival in patients receiving early surgery vs medical therapy for prosthetic valve endocarditis (PVE). OBJECTIVE To determine the in-hospital and 1-year mortality in patients with PVE who undergo valve replacement during index hospitalization compared with patients who receive medical therapy alone, after controlling for survival and treatment selection bias. DESIGN, SETTING, AND PARTICIPANTS Participants were enrolled between June 2000 and December 2006 in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), a prospective, multinational, observational cohort of patients with infective endocarditis. Patients hospitalized with definite right- or left-sided PVE were included in the analysis. We evaluated the effect of treatment assignment on mortality, after adjusting for biases using a Cox proportional hazards model that included inverse probability of treatment weighting and surgery as a time-dependent covariate. The cohort was stratified by probability (propensity) for surgery, and outcomes were compared between the treatment groups within each stratum. INTERVENTIONS Valve replacement during index hospitalization (early surgery) vs medical therapy. MAIN OUTCOMES AND MEASURES In-hospital and 1-year mortality. RESULTS Of the 1025 patients with PVE, 490 patients (47.8%) underwent early surgery and 535 individuals (52.2%) received medical therapy alone. Compared with medical therapy, early surgery was associated with lower in-hospital mortality in the unadjusted analysis and after controlling for treatment selection bias (in-hospital mortality: hazard ratio [HR], 0.44 [95% CI, 0.38-0.52] and lower 1-year mortality: HR, 0.57 [95% CI, 0.49-0.67]). The lower mortality associated with surgery did not persist after adjustment for survivor bias (in-hospital mortality: HR, 0.90 [95% CI, 0.76-1.07] and 1-year mortality: HR, 1.04 [95% CI, 0.89-1.23]). Subgroup analysis indicated a lower in-hospital mortality with early surgery in the highest surgical propensity quintile (21.2% vs 37.5%; P = .03). At 1-year follow-up, the reduced mortality with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (27.9% vs 50.0%; P = .007) quintiles of surgical propensity. CONCLUSIONS AND RELEVANCE Prosthetic valve endocarditis remains associated with a high 1-year mortality rate. After adjustment for differences in clinical characteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in the overall cohort. Further studies are needed to define the effect and timing of surgery in patients with PVE who have indications for surgery.

Donor-Derived Infections in Solid Organ Transplantation

Summary of potential donor-derived infectious diseasetransmissions reported to the United States organ procurementand transplantation network 2005–2011 (2)Number of Number ofNumber recipients with DDI-attributableInfection of donor confirmed recipienttype reports transmission deathsViruses 1 166 48 16Bacteria 2 118 34 9Fungi 3 75 31 10Mycobacteria 4 53 10 3Parasites 5 35 22 7 1 Viruses: adenovirus, HBV, HCV, HEV, HIV, HTLV, herpes simplex,influenza, LCMV, parainfluenza (PIV)-3, parvovirus B19, rabies,West Nile virus. 2 Bacteria: Acinetobacter, Brucella, Enterococcus (including VRE),Ehrlichiaspp,E.coli,Gram-positivebacteria,Klebsiella,Legionella,Listeria, Borrelia burgdorferi, Nocardia, Pseudomonas, RockyMountain Spotted Fever, Serratia, S. aureus (MRSA), Streptococ-cus spp, Treponema pallidum, Veillonella;bacterialmeningitis&bacterial emboli. 3 Fungi: Aspergillus spp, Candida spp, Coccidioides imitis, Cryp-tococcus neoformans, Histoplasma capsulatum, Scopulariopsis,zygomyces. 4 Mycobacteria: tuberculosis, non-TB mycobacteria.

Interruption of highly active antiretroviral therapy in HIV clinical practice: results from the Italian Cohort of Antiretroviral-Naive Patients.

Objectives:To investigate the frequency of a first therapy interruption (TI) ≥12 weeks, to identify the factors associated with TI and with therapy resumption, and to compare the risk of developing clinical events during TI and during continuous therapy. Methods:Observational study of 3142 patients who started a first highly active antiretroviral therapy (HAART) regimen. End points were time to (1) first TI of ≥12 weeks, (2) subsequent therapy resumption, and (3) development of new AIDS-related events or death. Results:Over a median follow-up period of 41 months (interquartile range: 18-60 months), 721 patients (22.9%) interrupted HAART for ≥12 weeks, with a probability of 28.6% (95% confidence interval [CI]: 26.7-30.6) by 4 years from the date of therapy initiation. Patient decision (47.4%) and toxicity (24.0%) were the main reasons for TI. Women, injection drug users, and patients with a higher current CD4 cell count were more likely to interrupt. The median time to therapy resumption was 12 months (95% CI: 11-14). The higher the current CD4 count, the slower was the rate of resuming therapy; conversely, patients who stopped because of failure and those with a pre-HAART viral load >100,000 copies/mL resumed therapy sooner. Two hundred eighty-one patients experienced clinical progression at a rate of 2.6 per 100 person-years (pys) (95% CI: 2.3-3.0) while patients were on therapy and 3.5 per 100 pys (95% CI: 2.4-4.8) during TI. The adjusted relative hazard of clinical progression associated with TI was 2.75 (95% CI: 1.14-6.65; P = 0.03). Conclusions:TI occurring in clinical practice is associated with an increased risk of clinical progression; hence, it should be discouraged outside strictly experimental settings.

High-Dose Daptomycin Therapy for Left-Sided Infective Endocarditis: a Prospective Study from the International Collaboration on Endocarditis

ABSTRACT The use of daptomycin in Gram-positive left-sided infective endocarditis (IE) has significantly increased. The purpose of this study was to assess the influence of high-dose daptomycin on the outcome of left-sided IE due to Gram-positive pathogens. This was a prospective cohort study based on 1,112 cases from the International Collaboration on Endocarditis (ICE)-Plus database and the ICE-Daptomycin Substudy database from 2008 to 2010. Among patients with left-sided IE due to Staphylococcus aureus, coagulase-negative staphylococci, and Enterococcus faecalis, we compared those treated with daptomycin (cohort A) to those treated with standard-of-care (SOC) antibiotics (cohort B). The primary outcome was in-hospital mortality. Time to clearance of bacteremia, 6-month mortality, and adverse events (AEs) ascribable to daptomycin were also assessed. There were 29 and 149 patients included in cohort A and cohort B, respectively. Baseline comorbidities did not differ between the two cohorts, except for a significantly higher prevalence of diabetes and previous episodes of IE among patients treated with daptomycin. The median daptomycin dose was 9.2 mg/kg of body weight/day. Two-thirds of the patients treated with daptomycin had failed a previous antibiotic regimen. In-hospital and 6-month mortalities were similar in the two cohorts. In cohort A, median time to clearance of methicillin-resistant S. aureus (MRSA) bacteremia was 1.0 day, irrespective of daptomycin dose, representing a significantly faster bacteremia clearance compared to SOC (1.0 versus 5.0 days; P < 0.01). Regimens with higher daptomycin doses were not associated with increased incidence of AEs. In conclusion, higher-dose daptomycin may be an effective and safe alternative to SOC in the treatment of left-sided IE due to common Gram-positive pathogens.

Donor‐Derived Infections in Solid Organ Transplant Recipients

Viral, bacterial, parasitic, prion and fungal infections havebeen transmitted via organ and tissue allografts (1). De-spite screening programs utilizing serologic testing and ona review of the potential donor’s medical records and be-havioral history, clusters of donor-derived infections in re-cipients persist although these are uncommon. Recent im-provements in the microbiologic screening of donors havereduced this risk. However, requirements for microbiologictesting of organ donors are nonuniform. Behavioral defini-tions of the ‘high-risk donor’ designed to reduce the riskfor HIV transmission are dated (1994) but, coupled withmicrobiologic screening, have resulted in a low incidenceof disease transmission through exclusion of donors withrecent intravenous drug use, incarceration and certain sex-ual contacts. However, the accuracy of exposure historymay be suspect. The availability of viral nucleic acid testing(NAT) has the capacity to reduce the risk of disease trans-mission by detecting early stages of many infections in-cluding those due to human immunodeficiency virus (HIV),hepatitis B virus (HBV) and hepatitis C virus (HCV) in the‘window’ period before antibody seroconversion develops(II-2).Despite the development of new policies and the use ofhighly sensitive assays, reports of the transmission of in-fection to organ transplantation recipients remain uncom-mon but occur with sufficient frequency to suggest thatcurrent approaches to screening of donors are inadequate.The role of geographically restricted microorganisms hasalso increased as a consequence of travel and migrationof populations. The commercialization of transplantationin some regions may also minimize the incentive to testand exclude potentially infected donors. Recent clusters oforgan-associated viral transmissions illustrate the vulnera-bility of immunosuppressed recipients to infections dueto organisms of limited native virulence for normal indi-viduals (2–4). Many potential exposures are too commonor too nonspecific to allow appropriate decision-makingregarding the risk of transmission. Furthermore, in someclusters of documented transmissions (e.g. due to lym-phocytic choriomeningitis, LCMV), no clear exposure orevidence of donor infection could be demonstrated evenin retrospective investigation (2).In contrast with solid organ screening, blood and tissuescreening policies have adopted more consistent labora-tory testing of donors for a wider array of pathogens withthe flexibility to introduce additional assays when indicatedby changing epidemiologic patterns. However, any strategyadopted for organ donors must be cost-effective, highlysensitive and specific and available at all times with rapidturn around times. The selection of the ‘list’ of pathogensfor screening of organ donors might be shaped by a seriesof specific questions: (1) Is the pathogen prevalence suffi-ciently high in the general population for the positive pre-dictive value of the screening test to be useful? (2) Is thereevidence that the pathogen can be transmitted by organtransplantation? (3) Does transmission result in significantmorbidityandmortality?and(4)Isthereareliableandlogis-tically applicable test available for screening? (II-3). For themajority of recent transmission events, including LCMV,other reported arenaviruses and rabies, the above criteriaare not fulfilled. Therefore while disease transmission byorgan transplantation may lead to serious morbidity andmortality, there are no currently available diagnostic testsfor these pathogens that could be readily applied to donorscreening. The inability to detect potential pathogens re-flects the low level of viremia in immunologically normaldonors compared with the rapid amplification of infectionin the immunosuppressed recipients. Thus, given the levelof viremia and the low frequency of these agents in thegeneral population, it is unlikely that a sufficiently rapid,sensitive and specific screening test could be developedand applied in the short term. Even for a pathogen such asWest Nile virus (WNV) for which disease outbreaks may be

Practice guidelines for the treatment of hepatitis C: Recommendations from an AISF/SIMIT/SIMAST expert opinion meeting

It is increasingly clear that a tailored therapeutic approach to patients with hepatitis C virus infection is needed. Success rates in difficult to treat and low-responsive hepatitis C virus patients are not completely satisfactory, and there is the need to optimise treatment duration and intensity in patients with the highest likelihood of response. In addition, the management of special patient categories originally excluded from phase III registration trials needs to be critically re-evaluated. This article reports the recommendations for the treatment of hepatitis C virus infection on an individual basis, drafted by experts of three scientific societies.

Solid Organ Transplantation From Hepatitis B Virus–Positive Donors: Consensus Guidelines for Recipient Management

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non‐liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti‐HBc+) donors. Organs from anti‐HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non‐liver recipients but is not recommended in immune non‐liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost‐effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

Role of hepatitis C virus (HCV) viremia and HCV genotype in the immune recovery from highly active antiretroviral therapy in a cohort of antiretroviral-naive HIV-infected individuals.

BACKGROUND The roles of hepatitis C virus (HCV) viremia and HCV genotype in the immune response to highly active antiretroviral therapy (HAART) are poorly understood. Our aim was to assess the CD4+ cell count recovery after HAART in human immunodeficiency virus (HIV)-infected patients with HCV viremia and HIV-infected patients who tested negative for HCV antibody (HCV-Ab). We also aimed to assess whether the response to HAART in these patients varied according to HCV genotype. METHODS The analysis focused on 1219 HCV-Ab-negative patients and 284 HCV-viremic patients from a cohort of HIV-infected subjects that includes persons who were antiretroviral naive before initiating HAART after cohort enrollment. HCV RNA load and HCV genotype were determined in plasma specimens obtained and stored during the 6-month period preceding the initiation of HAART. RESULTS The chance of achieving a CD4+ cell count increase of > or = 100 cells/microL from the pre-HAART level tended to be poorer in HCV-viremic patients than in patients who tested negative for HCV-Ab (adjusted relative hazard [RH], 0.82; 95% confidence interval [CI], 0.66-1.01; P = .06). In contrast, a comparison of patients who had a HCV RNA load >1 x 10(6) IU/mL with patients who had a HCV RNA load of 5-1 x 10(6) IU/mL revealed no significant association between HCV RNA load and achievement of an increased CD4+ cell count (adjusted RH, 0.97; 95% CI, 0.75-1.27; P = .83). There was no clear association between HCV genotype and the probability of achieving a CD4+ cell count increase. CONCLUSIONS An association between the presence of HCV-Ab and immune reconstitution after HAART has been shown elsewhere. Results of our large, prospective study support a direct role of HCV viremia in the CD4+ cell count response to HAART. Moreover, our results underline the fact that, in individuals coinfected with HIV and HCV, the goal of treating HCV infection is to eradicate HCV, to both slow the rate of HCV progression and limit potential interference with the response to HAART.