Hepatitis C and heart transplantation: An update.

There are limited data regarding heart transplantation in the setting of hepatitis C virus (HCV) infection in either recipients or donors, as the practice was infrequent, given concerns of worse post-transplant outcomes. This changed dramatically after the development of highly effective HCV therapies, namely direct-acting antivirals (DAAs). Additionally, nucleic acid testing currently in use establishes more precisely the risk of HCV transmission from donors. As a result, chronic HCV infection in itself is no longer a barrier for heart transplant candidates, and the use of HCV-positive organs for HCV-infected and non-infected transplant candidates has increased dramatically. A review of the literature revealed that in the pre-DAA era, HCV seropositive heart transplant patients had a higher mortality than their seronegative counterparts. However, short-term data suggest that the differences in survival have been erased in the DAA era. Heart transplantation from HCV-viremic donors to HCV-uninfected recipients has become increasingly common as the number of deceased donors with HCV viremia has increased over the past years. Preliminary outcome reports are very encouraging, although further data are needed with regard to long-term safety. New information continues to be incorporated to optimize protocols that guide this practice.

Delayed spontaneous hepatitis C virus elimination in a renal transplant patient following graft rejection.

While elimination of the hepatitis C virus (HCV) following acute infection is not uncommon, spontaneous clearance once the infection becomes chronic is extremely rare. The mechanisms involved in the clearance of chronic HCV infection without intervening antiviral therapy are not well known. Herein we describe a case of a renal transplant recipient who acquired HCV infection while immunosuppressed, experienced a rapid histological progression, and thereafter cleared the virus spontaneously long after withdrawal of immunosuppression following kidney graft rejection and failure. We review the literature and summarize the reports of spontaneous clearance of chronic HCV infection in various settings.

Drug-induced liver injury in hospitalized HIV patients: high incidence and association with drugs for tuberculosis.

BACKGROUND: The evaluation of liver disease in HIV patients is cumbersome because may result from a number of different causes. The aim of this retrospective study was to estimate the incidence of severe drug induced liver injury (DILI) in a group of HIV inpatients and investigate potential risk factors. MATERIAL AND METHODS: We performed a retrospective analysis of data from HIV-infected patients hospitalized between August 2010 and August 2011 in a tertiary hospital in São Paulo, Brazil. Severe hepatotoxicity was defined as grade 3 (5.1 to 10 x ULN) or 4 (> 10 x ULN) of ALT and AST levels. Factors analyzed included demographics, infection with hepatitis viruses, alcohol history and use of hepatotoxic drugs prior to or during hospital admission. RESULTS: A total of 149 patients with HIV were hospitalized during the study period. The majority were male over 42 years of age and 82 (55%) were taking HAART initiated prior to admission. Mean CD4 counts were 164 cells/mm3. Thirty three patients (22.1%) developed severe DILI during hospital stay, which had a mean duration of 26 days. Factors associated with severe DILI in the multivariate analysis were abnormal baseline ALT levels [OR 2.02 (95%CI 1.13-3.59); p = 0.017] and tuberculosis therapy [OR 2.31 (95% CI 1.27-4.19); p = 0.006]. In conclusion, in this group of HIV patients admitted to a tertiary hospital in Brazil, we found a high incidence (22.1%) of severe DILI. The use of anti-tuberculosis drugs and baseline liver injury were independent factors associated with severe DILI during hospital stay.

JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy.

Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.

Liver toxicity of antiretroviral drugs.

Drug-induced liver injury (DILI) associated with antiretroviral treatment has represented an important side effect since the beginning of the HAART era. The lack of standard definition and specific markers makes assessment of DILI very challenging. Several clinical syndromes of DILI have been described over the years; the pathogenic mechanisms are not fully understood. Better knowledge of DILI, identification of high-risk patients using pharmacogenetics, and the availability of antiretroviral agents with improved safety profile have all contributed to decrease the incidence of DILI and to ameliorate its effects. Nevertheless, with an aging human immunodeficiency virus- (HIV-) infected population and increased survival, DILI will probably continue to represent a relevant entity in e HIV therapeutic management.

Association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease.

Familial aggregation of non-diabetic end-stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in the high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2% of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared with one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated glomerular filtration rate (GFR; MDRD equation), and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.

Hepatitis C virus and kidney transplantation: Recent trends and paradigm shifts.

The management of HCV infection in kidney transplantation presents significant challenges. HCV, left untreated, worsens patient and graft survival after kidney transplantation through multiple mechanisms. The field has evolved significantly in recent years, due to the ability to effectively eliminate the virus with direct-acting antivirals. Limited data suggest that current HCV treatment improves outcomes of infected kidney transplant patients. Along with the ability to successfully treat HCV, the increased HCV prevalence among donors has led to transplantation of kidneys from HCV-viremic donors into uninfected recipients. The practice has become increasingly common, but optimization of protocols to guide this practice is currently under debate. We have searched the literature on HCV and kidney transplantation, and review here the epidemiology, clinical outcomes, HCV treatment, and studies on transplantation from positive donor to negative recipient. We also discuss the evolving clinical management paradigms and address unresolved questions, highlighting the need for additional data with longer follow up.

Multifocal Abdominal Pyomyositis From Subcutaneous Dissemination in an Immunocompetent Patient.

A 61-year-old woman presented to the emergency ward complaining of low back pain for a month. She had undergone several spinal surgeries and a right radical nephrectomy 30 years before. A few days earlier she was injected with an intramuscular painkiller in her right buttock. An abdominal CT scan revealed multiple abscesses in the psoas muscle and the right posterior abdominal wall, including cellulitis in the adjacent subcutaneous tissue and the injection site. A diagnosis of pyomyositis from subcutaneous dissemination was made, and intravenous cefazolin was initiated. After five days of favorable progress, treatment was switched to oral cefadroxil to complete four weeks, leading to full recovery.

Clinical syndromes and consequences of antiretroviral-related hepatotoxicity.

Highly active antiretroviral therapy (HAART)-related hepatotoxicity complicates the management of patients infected with human immunodeficiency virus (HIV), increases medical costs, alters the prescription patterns, and affects the guideline recommendations. Among the clinical consequences derived from HAART-related liver toxicity, hypersensitivity reactions and lactic acidosis are recognized as acute events with potential to evolve into fatal cases, whereas there seems to be other syndromes not as well characterized but of equal concern as possible long-term liver complications. Belonging to the latter category of syndrome, HAART-related nonalcoholic steatohepatitis, liver fibrosis, portal hypertension, and nodular regenerative hyperplasia are discussed in this review. Updated information on liver toxicity of current antiretroviral drugs, including the most recently licensed, is provided. Management and prevention of liver toxicity among HIV-infected patients treated with HAART are reviewed as well.

Diabetic Foot Infection and Select Comorbidities Drive Readmissions in Outpatient Parenteral Antimicrobial Therapy.

BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) facilitates early patient discharge, but readmissions prior to completion of therapy may offset its advantages. The objective of this study was to evaluate unplanned readmissions of patients undergoing OPAT at our institution and to identify risk factors. We hypothesized that host factors were most relevant. METHODS: We retrospectively identified all patients discharged to receive OPAT during 2017 who experienced at least one unplanned readmission to the hospital prior to its completion. We determined the proportion of patients readmitted, and the causes for readmission. Using a control group, we identified risk factors through multivariate logistic regression analysis. RESULTS: Out of 684 patients, 17% had an unplanned readmission while receiving OPAT. Causes included worsening infection in 18%, venous access problems in 11%, acute events unrelated to infection in 19%, treatment intolerance in 19%, progression of underlying comorbidity in 20%, and social and other problems in 13%. In multivariate analysis diabetic foot infection (OR 3.24; 95%CI 1.38-8.31; p = 0.01), the presence of chronic kidney disease, decubitus ulcer or heart failure (OR 2.65; 95% CI 1.51-4.70; p < 0.001), and narcotics prescribed at discharge (OR 1.93; 95% CI 1.06-3.60; p = 0.049) were independent risk factors for readmission. CONCLUSIONS: Unplanned hospital readmissions were frequent and due to very heterogeneous causes. Diabetic foot infection, selected comorbidities, and discharge on opioids were identified as independent risk factors. In the efforts to decrease readmissions among patients receiving outpatient parenteral antimicrobial a focus on these high-risk groups is a priority.

Virological rather than host factors are associated with transaminase levels among HIV/HCV-coinfected patients.

Alanine aminotransferase (ALT) is a routine parameter in the assessment and monitoring of chronic hepatitis C viral (HCV) infection. Hepatitis C virus-infected African Americans (AAs) have been reported to have lower ALT levels. In this retrospective, cross-sectional, multicenter study, host and virological factors possibly associated with ALT levels were analyzed by multivariate regression analyses among HIV/HCV-coinfected patients. Of the 289 patients included, 142 were African Americans and 144 Caucasians. In multivariate analysis, only HCV genotype 3 (B 0.2 [95% CI 13.39-52.33]; P = .001) and HCV RNA >500 000 IU/mL (B 3.1 [95% CI 7.67-34.75]; P = .002) were independent predictors of higher ALT levels. Per the American Association for the Study of Liver Disease (AASLD) definition, 18.2% had ALT levels within normal limits. Male sex and HCV RNA <500 000 IU/mL predicted ALT within normal limits. Hepatitis C viral factors rather than race were associated with ALT levels in this HIV/HCV-coinfected population. ALT were within normal limits in 18% of patients, who more often were male and had lower Hepatitis C viral load.

Acute Hepatitis B Surge: Opioid Epidemic Implication and Management Challenges.

We recognized a surge in acute hepatitis B at our institution and a link to the opioid epidemic since 2017. Among barriers to optimal management, we identified frequent deviations from national recommendations and patient noncompliance with follow-up.

More Frequent Premature Antibiotic Discontinuations and Acute Kidney Injury in the Outpatient Setting With Vancomycin Compared to Daptomycin.

Vancomycin and daptomycin are often used in outpatient parenteral antimicrobial therapy for gram-positive coverage. Vancomycin's narrow therapeutic window poses challenges. We retrospectively assessed acute kidney injury (AKI) and other adverse drug events in outpatient parenteral antimicrobial therapy patients receiving vancomycin or daptomycin at home after hospital discharge. Among 191 patients included, AKI was the most common adverse drug event. Early antibiotic discontinuation and AKI were more frequent in the vancomycin group. Vancomycin use (odds ratio [OR], 4.57; 95% confidence interval [CI], 1.02-20.51); p = 0.04], female sex (OR, 3.28; 95%CI, 1.41-7.67; P < .01), and longer hospitalization (OR, 1.06; 95%CI, 1.01-1.11; P = .02] independently predicted moderate-to-severe AKI. In the vancomycin group, trough concentrations increased after discharge, and were higher in female compared to male patients, and in those who developed moderate-to-severe AKI compared to those who did not. Female sex (OR, 8.37; 95%CI, 2.35-29.82; P < .01) and higher concentrations (OR, 1.12; 95%CI, 1.05-1.19; P < .01) predicted moderate-to-severe AKI in patients receiving vancomycin. In conclusion, premature antibiotic discontinuations and nephrotoxicity are more frequent in patients treated at home with vancomycin compared to daptomycin. Among patients receiving vancomycin, plasma concentrations increased after hospital discharge and predicted moderate-to-severe AKI. Women had higher vancomycin concentrations and higher risk for AKI.

Longer duration of HBV-active antiretroviral therapy is linked to favorable virological outcome in HIV-HBV co-infected patients.

BACKGROUND: HBV-HIV co-infection is associated with increased liver-related morbidity and mortality. Herein we analyzed HBV-related virologic and clinical outcomes in HBV-HIV patients in the HAART era. METHODS: HBsAg positive HIV-infected patients followed at a US academic center between 1990 and 2008 were assessed in a retrospective and longitudinal study. Factors associated with HBsAg and/or HBeAg clearance and with advanced liver disease were evaluated using logistic regression. RESULTS: 72 patients were evaluated. Their median time of follow-up and of adherence to HBV-active HAART were 3 and 1 years, respectively. HBeAg and HBsAg cleared in 17.6% and 5.5% of patients, respectively. More prolonged use of HBV-active HAART predicted clearance of HBeAg (odds ratio [OR] 2.66, 95% CI 1.15-6.16, p = .02) and of HBsAg (OR 1.54, 95% CI 1.02-2.31, p = .04). Patients clearing HBsAg tended to have higher baseline CD4 (mean CD4 counts: 550 vs. 246 cells/mm3; p = .06). Rate of diagnosis of liver-related complications and death were 24.6/1,000 and 10.5/1,000 patient-years, respectively. Higher ALT levels before HAART initiation were associated with the diagnosis of cirrhosis during follow-up (OR 1.02, 95% CI 1.002-1.03, p = .02). CONCLUSIONS: Prolonged use of HBV-active HAART favors HBsAg and HBeAg clearance in HIV-HBV co-infected patients. Those with higher ALT levels at presentation have higher risk of being diagnosed with cirrhosis during the first few years of follow-up.

First HAART in HIV-infected patients with high viral load: value of HIV RNA levels at 12 weeks to predict virologic outcome.

The aim of this study is to identify the role of incomplete suppression during the first months of highly active antiretroviral treatment (HAART) to predict virologic failure in patients with high levels of HIV replication. In a retrospective, longitudinal, and multicenter study, response to HAART was assessed in treatment-naive adults with HIV RNA >100 000 copies/mL, and factors predicting failure were analyzed through regression analyses. A total of 118 patients were included. Virologic failure occurred more often in patients with >500 copies/mL at week 12 (Cox regression: Exp (B) 3.22; P = .02). HIV RNA >500 copies/mL at week 12 predicted incomplete virologic response (odds ratio [OR] = 9.33; P = .002] but not viral rebound. Major antiretroviral resistant mutations were present in 11 of 14 patients. HIV RNA >500 copies/mL at week 12 of first HAART predicts incomplete virologic response in patients with high levels of replication at baseline. Most patients carried resistance mutations at the time of failure.

Double invasive fungal infection due to dematiaceous moulds in a renal transplant patient.

Alternaria and Verruconis are two dematiaceous moulds that occasionally cause disease in immunocompromised hosts. We present the case of a 58-year-old man with history of deceased donor renal transplantation 14 months prior, who presented with fevers and cough. He was found to have right upper lobe pneumonia and a non-healing eschar of his right knee. Dematiaceous fungi grew from bronchoalveolar lavage (BAL) and was sent to reference lab for identification. Meanwhile, the eschar on his right knee was biopsied and grew Alternaria spp. Pathology was consistent with invasive mould infection and he was treated as having disseminated Alternaria infection with voriconazole and amphotericin B lipid complex. Later on, the dematiaceous mould from a BAL specimen was identified as Verruconis gallopava The patient was discharged on voriconazole awaiting minimal inhibitory concentrations for V. gallopava but was readmitted 2 days later with high fevers and died from acute respiratory failure.

Evolution of T-cell responses to hepatitis C virus (HCV) during pegylated interferon plus ribavirin treatment in HCV-monoinfected and in HCV/HIV-coinfected patients.

BACKGROUND: The role of T-cell immunity in chronic hepatitis C virus (HCV) infection remains controversial. As in HIV infection, virus replication could drive or be contained by T-cell immunity. We have examined the effect of HIV coinfection and of suppression of HCV replication with therapy on HCV-specific T-cell responses. PATIENTS AND METHODS: Thirty-five patients with chronic hepatitis C (17 coinfected with HIV) initiating anti-HCV therapy were analysed. HCV-specific responses were assessed at different time points using intracellular interferon-gamma staining in response to a panel of overlapping peptides comprising E2, NS3, NS5a and NS5b HCV proteins. RESULTS: At baseline, HCV-specific responses were significantly lower in HIV-coinfected patients. At week 12 of therapy, CD8+ T-cell responses against all HCV proteins significantly decreased in HCV-monoinfected patients and this was maintained throughout the follow-up period. Although the same trend occurred in the HIV-coinfected group, differences were not significant. CD4+ T-cell responses against NS3 significantly diminished in the HCV-monoinfected group, whereas in coinfected patients CD4+ T-cell responses were low at baseline and did not experience any significant variation. CONCLUSIONS: HCV-specific T-cell responses are lower in HIV-coinfected patients and vanish following complete suppression of HCV replication under successful HCV therapy, suggesting that they are dependent on continuous antiqenic stimulation.

Premature treatment discontinuation in HIV/HCV-coinfected patients receiving pegylated interferon plus weight-based ribavirin.

BACKGROUND: Chronic hepatitis C therapy in HIV patients is often penalized by more frequent premature treatment discontinuations. It is unclear what the relative contribution of more adverse events and/or early virological failures are. METHODS: PRESCO was a prospective, multicentre, comparative trial, in which 389 HIV/HCV-coinfected patients with CD4+ T-cell counts >300 cells/ml and elevated aminotransferases received pegylated interferon-alpha2a (peg IFN-alpha2a) 180 mg per week plus ribavirin (RBV) 1,000-1,200 mg daily. Patients with HCV genotypes 1 or 4 were treated for 48 or 72 weeks while HCV genotypes 2 or 3 carriers were treated for 24 or 48 weeks. Use of didanosine was not allowed. RESULTS: Sustained virological response (SVR) was achieved by 193 (49.6%), and was significantly greater in HCV-2/3 than in HCV-1/4 patients (72.4% versus 35%; P<0.0001). Premature treatment discontinuations occurred in 174 patients (44.7%). This was due to early virological failure in 66 (17%), serious adverse events in 32 (8.2%), loss-to-follow-up in 12 (3.1%) and voluntary withdrawal in 64 (16.4%). Only 10 patients (2.6%) stopped HCV therapy due to severe anaemia. Two patients stopped HCV medication due to symptomatic mitochondrial toxicity. There were no episodes of hepatic decompensation. CONCLUSIONS: Treatment with RBV 1,000-1,200 mg/day plus peg IFN-alpha2a is relatively safe and provided SVR in nearly half of the HIV/HCV-coinfected patients, twice as many amongst the HCV-2/3 than HCV-1/4 carriers. Avoidance of didanosine, limited use of zidovudine and therapy restricted to patients with CD4+ T-cell counts >300 cells/ml most probably explains the lower and different spectrum of serious adverse events in PRESCO compared with prior trials conducted in coinfected patients.

Liver fibrosis stage and HCV genotype distribution in HIV-HCV coinfected patients with persistently normal transaminases.

Hepatitis C virus (HCV)-infected patients with normal transaminases may show significant liver damage. The proportion of subjects with alanine aminotransferase (ALT) levels within normal limits was examined in HIV-infected patients never exposed to interferon and with detectable plasma HCV-RNA on regular follow-up at one single institution. Liver fibrosis was evaluated using transient elastography (FibroScan). Out of 281 coinfected patients, 25 (8.9%) had persistently normal ALT levels. Patients with HCV genotypes 2 (1/5; 20%) and 4 (10/50; 20%), more often had significantly normal ALT than patients with HCV-1 (13/158; 8%) (p = 0.01) and HCV-3 (1/49; 2%) (p = 0.01). Liver fibrosis stages in these patients were as follows: F0-F1 in 13 (59.1%), F2 in 4 (18.2%), F3 in 2 (9.1%), and F4 in 3 (13.6%). Advanced liver fibrosis (F3-F4) tended to be more frequent in patients infected with HCV-4 than HCV-1 (33.3% versus 9.1%; p = 0.2). Of HIV-infected patients with chronic hepatitis C 8.9% show persistently normal ALT levels. Nearly 25% of HIV-HCV-coinfected patients with persistently normal ALT show advanced liver fibrosis. Therefore, HCV-HIV-coinfected patients with normal ALT levels should be closely monitored.

Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial.

The response to pegylated interferon (pegIFN) plus ribavirin (RBV) as treatment of chronic hepatitis C virus (HCV) infection is lower in HIV-coinfected than in HCV-monoinfected patients and could be due to suboptimal RBV dosing and/or insufficient duration of therapy in prior trials. In a prospective, multicenter, open, comparative trial, HCV/HIV-coinfected patients received pegIFN plus weight-based RBV for 48 or 72 weeks (HCV genotypes 1 and 4) and 24 or 48 weeks (HCV genotypes 2 and 3). Use of didanosine was not allowed. Out of 389 patients included in the trial, 61% were infected by HCV-1/4 and 67% had serum HCV-RNA >500,000 IU/ml. Sustained virological response (SVR) was achieved by 49.6%, significantly higher in HCV-2/3 than HCV-1/4 (72.4% vs. 35%; p < 0.0001). A high drop-out rate in the longer treatment arms precluded obtaining definitive conclusions about the efficacy of prolonging therapy. Premature treatment discontinuations due to serious adverse events occurred in 8.2%. Infection with HCV-2/3, lower baseline HCV-RNA, and negative HCV-RNA at week 12 were all independent predictors of SVR in the multivariate analysis. The use of RBV 1000-1200 mg/day plus pegIFN is relatively safe and provides SVR in nearly half of coinfected patients, twice as high in HCV-2/3 than HCV-1/4.