Hepatitis C Virus Treatment in Non-Liver Organ Transplantation Programs

Purpose of Review

Solid organ transplantation is the treatment of choice for many patients with end organ damage. Hepatitis C (HCV) infection is prevalent among solid organ candidates and recipients and remains to be a significant source of morbidity and mortality for this population. New therapies are currently available for this population. In the following review, we will outline HCV treatment strategies in non-liver transplantation candidates and recipients.

Recent Findings

Direct-acting antivirals (DAAs) have drastically modified the treatment landscape of HCV. New DAA agents have been studied in patients with chronic diseases, transplantation candidates, and transplantation recipients.

Summary

The safety and efficacy of DAAs in patients awaiting liver transplantation and liver transplantation recipients has provided us with guidance on how to use them effectively for patients who received or are awaiting non-liver solid organ transplantations.

     

Considerations When Treating Hepatitis C in a Cirrhotic Transplant Candidate

Purpose of Review

This review examines the issues in determining the decision to treat a HCV-positive patient who is a liver transplant (LT) candidate with highly effective and well-tolerated direct-acting antiviral (DAA) therapies.

Recent Findings

Cure of HCV with DAA can improve liver function and allow delisting in some patients. Beyond a threshold of hepatic impairment (likely MELD score >?16 to 20), patients may experience a decline in MELD score with HCV cure without improvement in liver-related complications resulting in decreased opportunity to receive a LT. Eradicating HCV from patients who need LT regardless also deprives them of the option of receiving HCV-positive donor organs. Patients with MELD >?16 or Child-Pugh B/C may also have reduced cure rates of HCV, increased risk of hepatic decompensation, and adverse events with DAA pre-LT compared to post-LT DAA therapy. Preliminary data demonstrates increase risk of hepatocellular carcinoma (HCC) recurrence after treatment with DAA with subsequent studies raising doubts about this association.

Summary

Patients with HCV cirrhosis on the LT waiting list with MELD score >?16, CTP-B/C, and HCC are best treated after LT with better response, tolerability, and the ability to receive organs from a larger donor pool that includes HCV-positive donors. Larger, prospective studies are needed to assess whether increased HCC recurrence after DAA is a true effect.

     

Ultra-Deep Genomic Sequencing of HCV NS5A Resistance-Associated Substitutions in HCV/HIV Coinfected Patients

Background and Aims

The prevalence of naturally occurring HCV-NS5A resistance-associated substitutions (RAS) to DAA drugs might affect the response to treatment in HCV/HIV coinfected subjects. There are limited data on the frequency of HCV-NS5A naturally occurring drug-RAS at baseline in HCV/HIV coinfected patients when ultra-deep sequencing methodologies are applied.

Methods

HCV-NS5A-RAS were evaluated among 25 subjects in each group. Patients were matched by age, gender, and hepatic fibrosis stage category to control for selection bias.

Results

Within subtype 1a, RAS were observed in 28% of HCV monoinfected and 48% of HCV/HIV coinfected subjects. More patients in the HCV/HIV coinfected group had clinically relevant mutations to DAA directed at NS5A.

Conclusion

While the clinical significance of this observation may be limited in highly drug adherent populations, some HCV/HIV coinfected persons may be at greater risk of viral resistance if suboptimal dosing occurs.

     

Chikungunya,Dengue, and Zika in Immunocompromised Hosts

Purpose of Review

Describe the characteristics of chikungunya, dengue, and Zika in transplant recipients and immunocompromised hosts.

Recent Findings

Stem cell/bone marrow grafts, organs, and blood transfusions can transmit CHIKV/DENV/ZIKV infections, which are clinically similar, resembling influenza-like illness. Laboratory confirmation is necessary. In the acute phase, RT-PCR is preferred. DENV and ZIKV serology may cross-react. Delayed engraftment and extended viruria is observed in ZIKV+/HSCT recipients, while longer viremia is observed in DENV+/HSCT patients. Arbovirus persistence in organ tissues is generally unknown. Vaccine development is in early stages for CHIKV/ZIKV. No data is available to recommend the licensed DENV vaccine in transplant recipients.

Summary

In endemic areas, the assessment of epidemiological risk is mandatory. Donor deferral for 120 days in suspected or confirmed ZIKV+ has been recommended, while CHIKV+ donors should wait 30 days. No deferral is recommended for DENV+ donors. CHIKV/DENV/ZIKV tests should be included in the differential of febrile neutropenia and other transplant syndromes. Reassessment of DENV serology is urgently needed. Prospective studies are necessary to determine the impact of CHIKV/DENV/ZIKV in this special population.

     

Non-tuberculous Mycobacterial Infections in Thoracic Transplant Candidates and Recipients

Purpose of Review

To review and discuss the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of non-tuberculous mycobacteria (NTM) in thoracic transplantation.

Recent Findings

Non-tuberculous mycobacteria are ubiquitous but are an uncommon cause of disease after solid organ transplantation. The incidence of infection is higher in thoracic transplant recipients than in abdominal transplant recipients, with most cases seen after lung transplantation. It is associated with increased morbidity and, occasionally, mortality. Infection in the pre-transplant setting can occur in lung transplant candidates, often posing a dilemma regarding transplant listing. Disease manifestations are diverse, and pulmonary disease is the most common. Diagnosis requires a high index of suspicion. Treatment requires a multiple-drug combination and is limited by drug-drug interactions and tolerability. Mycobacterium abscessus is a challenge in lung transplant recipients, due to its intrinsic resistance and propensity to relapse even after prolonged therapy. Mycobacterium chimaera is an emerging pathogen associated with contamination of heater-cooler units and is described to cause disease months after cardiothoracic surgery.

Summary

NTM infections in thoracic organ transplant recipients are uncommon but are associated with substantial morbidity and mortality. Data from larger multicenter studies is needed to better define the epidemiology of NTM in thoracic transplantation, best treatment options, and the management of infected transplant candidates.

     

Donor Diabetes Mellitus Is an Independent Risk Factor for Graft Loss in HCV Positive but Not HCV Negative Liver Transplant Recipients

Background and Aims

Graft survival in HCV (hepatitis C virus) infected recipients is worse than those transplanted for other liver diseases. We studied whether several donor cardiovascular risk factors (including advanced age, smoking, hypertension, and diabetes mellitus) contribute to worse outcomes for HCV positive and HCV negative liver transplant recipients.

Methods

We obtained data from the United Network for Organ Sharing on all adult liver transplants performed in the United States between January 1, 1998 and December 31, 2003. In total, 27,033 transplant cases were evaluated. Independent predictors of graft survival were determined using Cox proportional hazards regression analysis after controlling for factors previously found to be associated with differences in transplant outcomes.

Results

Donor diabetes was a strong independent risk factor for graft failure [hazard ratio (HR) = 1.20, p = 0.006] only in HCV positive recipients. Neither donor smoking status nor hypertension predicted graft loss in either cohort. Consistent with previous studies, advanced donor age, donation after cardiac death, height, and African American donor all predicted graft loss amongst both cohorts.

Conclusion

Accounting for donor diabetes in relation to recipient HCV status in the selection of liver recipients may result in improved graft survival.

     

Effects of a Video on Organ Donation Consent Among Primary Care Patients: A Randomized Controlled Trial

BACKGROUND

Low organ donation rates remain a major barrier to organ transplantation.

OBJECTIVE

We aimed to determine the effect of a video and patient cueing on organ donation consent among patients meeting with their primary care provider.

DESIGN

This was a randomized controlled trial between February 2013 and May 2014.

SETTING

The waiting rooms of 18 primary care clinics of a medical system in Cuyahoga County, Ohio.

PATIENTS

The study included 915 patients over 15.5 years of age who had not previously consented to organ donation.

INTERVENTIONS

Just prior to their clinical encounter, intervention patients (n?=?456) watched a 5-minute organ donation video on iPads and then choose a question regarding organ donation to ask their provider. Control patients (n?=?459) visited their provider per usual routine.

MAIN MEASURES

The primary outcome was the proportion of patients who consented for organ donation. Secondary outcomes included the proportion of patients who discussed organ donation with their provider and the proportion who were satisfied with the time spent with their provider during the clinical encounter.

KEY RESULTS

Intervention patients were more likely than control patients to consent to donate organs (22 % vs. 15 %, OR 1.50, 95%CI 1.10–2.13). Intervention patients were also more likely to have donation discussions with their provider (77 % vs. 18 %, OR 15.1, 95%CI 11.1–20.6). Intervention and control patients were similarly satisfied with the time they spent with their provider (83 % vs. 86 %, OR 0.87, 95%CI 0.61–1.25).

LIMITATION

How the observed increases in organ donation consent might translate into a greater organ supply is unclear.

CONCLUSION

Watching a brief video regarding organ donation and being cued to ask a primary care provider a question about donation resulted in more organ donation discussions and an increase in organ donation consent. Satisfaction with the time spent during the clinical encounter was not affected.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT01697137

     

Treatment of acute hepatitis C: recommendations from an expert panel of the Italian Society of Infectious and Tropical Diseases

Aim

This paper is aimed at providing practical recommendations for the management of acute hepatitis C (AHC).

Methods

This is an expert position paper based on the literature revision. Final recommendations were graded by level of evidence and strength of the recommendations.

Results

Treatment of AHC with direct-acting antivirals (DAA) is safe and effective; it overcomes the limitations of INF-based treatments.

Conclusions

Early treatment with DAA should be offered when available.

     

Intensive Pharmacy Care Improves Outcomes of Hepatitis C Treatment in a Vulnerable Patient Population at a Safety-Net Hospital

Background

Treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) regimens has resulted in high rates of sustained virologic response (SVR). Treatment of vulnerable populations may be improved by incorporating an on-site intensive specialty pharmacy (ON-ISP).

Aims

To describe outcomes of HCV treatment at a safety-net hospital and proportion of subjects achieving SVR for those using the ON-ISP compared to an off-site pharmacy (OFF-SP).

Methods

A retrospective cohort study of 219 subjects treated for HCV with DAA at Boston Medical Center was conducted. Subject characteristics, virologic response, and pharmacy services used were recorded. We used multivariable logistic regression to test the association between ON-ISP and SVR after adjusting for covariates.

Results

SVR occurred in 71% of subjects by intention-to-treat (73% among ON-ISP users vs 57% among OFF-SP users) and 95% completing treatment per-protocol (96% among ON-ISP users vs 87% among OFF-SP users). Adjustment for age, sex, ethnicity, insurance, fibrosis, prior treatment, and MELD revealed an increased likelihood of SVR among users of ON-ISP: OR 6.0 (95% CI 1.18–31.0). No significant difference in treatment delay or adverse events was seen among users of either pharmacy type.

Conclusions

HCV treatment with DAA was well tolerated, but the rate of SVR was low (71%) compared to trials. This was due to loss to follow-up, as the per-protocol rate of SVR was much higher (95%). Use of ON-ISP was associated with an increase in SVR and may be valuable for improving care for vulnerable populations.

     

Similar Sustained Virologic Response in Real-World and Clinical Trial Studies of Hepatitis C/Human Immunodeficiency Virus Coinfection

Background

Clinical trials evaluating efficacy of direct-acting antiviral (DAA) therapies demonstrate sustained virologic response (SVR) rates greater than 90% in patients infected with hepatitis C (HCV) and human immunodeficiency virus (HIV). However, generalizability of this data to real-world coinfected populations is unknown.

Aim

We aim to compare efficacy data from clinical trials to effectiveness data of real-world observational studies that evaluate oral interferon-free HCV treatment regimens in patients infected with HIV and HCV.

Methods

We included English-language studies on PubMed and MEDLINE databases from inception until October 2017. Eight clinical trials and 11 observational studies reporting on efficacy data and effectiveness data, respectively, of interferon-free oral DAA regimens in HCV/HIV coinfected patients, were included.

Results

Of patients in the eight clinical trials evaluated, 93.1% (1218/1308) achieved SVR12; of the 11 real-world observational studies, 90.8% (2269/2499) achieved SVR12. Relative risk between those treated in clinical trials versus observational studies was 0.98. Patients with genotype 1 infection, African-American patients, cirrhotic patients, and patients with prior HCV treatment experience had similar rates of SVR in real-world and clinical trial cohorts.

Conclusion

SVR among real-world HCV/HIV coinfected populations treated with DAA regimens is similar to SVR of patients studied in clinical trials. Historically negative predictors of achieving SVR during the era of interferon-based treatments, such as those with cirrhosis, prior HCV treatment failure, GT1 infection, and African-American race, are not associated with a significantly lower SVR in real-world populations treated with various DAA regimens.

     

Post-transplantation Development of Food Allergies

Purpose of Review

The development of food allergies is increasingly being recognized as a post-solid organ transplant complication. In this article, we review the spectrum of post-transplant food allergy development and the proposed mechanisms for de novo food allergies and the clinical significance they pose.

Recent Findings

The development of new food allergies is disproportionately associated with pediatric liver transplants, where it occurs in up to 38% of select populations. The mechanism of food allergy development is not completely understood; however, it is likely promoted by unbalanced immune suppression.

Summary

De novo food allergy development is a common complication of solid organ transplants with the highest risk occurring in pediatric liver transplant recipients. There are likely multiple mechanisms for food allergy development including passive transfer of membrane-bound IgE and lymphocytes from donor to recipient, as well as loss of food tolerance and active development of new food allergies. The optimal management of food allergies following organ transplants has not been well researched but may include changing the immune suppression regimen if the food allergy does not resolve without intervention.

     

Impact of endoscopic ultrasound-guided fine-needle aspiration in prospective liver transplant recipients with hepatocellular carcinoma and lymphadenopathy

Background

Diagnosis of metastatic disease is important in patients with cirrhosis and hepatocellular carcinoma (HCC) to prevent futile liver transplantation. Some of these patients have metastatic lymphadenopathy; however, it is difficult to perform percutaneous fine-needle aspiration due to presence of collateral and anatomic location. Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of lymph nodes offers several advantages like real-time vision, proximity to target, and avoidance of collaterals.

Aim

The aim of this study was to look for metastatic lymphadenopathy by EUS-guided FNA (EUS-FNA) in prospective liver transplant recipients with HCC.

Methods

A prospective study was conducted from January 2013 to January 2016 at a tertiary care center. All prospective liver transplant recipients with HCC had PET-CT and bone scan to look for metastatic disease. EUS-FNA was done in patients with abdominal or mediastinal lymphadenopathy and no evidence of extrahepatic disease. Data is shown as median (25–75 interquartile range).

Results

EUS-guided FNA was done for 50 patients (42 abdominal and 8 mediastinal lymph nodes), age 57 (53–62) years, Child-Turcotte-Pugh 7 (6–9), and model for end-stage liver disease 10 (7–16). FNA material was adequate in 92% patients, metastasis in 15 (30%), granulomatous lymphadenopathy in 4 (8%), and reactive change in 27 patients (54%). The material was inadequate for diagnosis in 4 (8%) patients. Thus, EUS-guided FNA precluded transplantation in 30% of patients with lymphadenopathy, and 4 (8%) patients received anti-tubercular therapy before liver transplantation.

Conclusion

In patients with HCC and lymphadenopathy, EUS-guided FNA detected metastatic disease and precluded liver transplantation in approximately one third of patients.

     

Proton Pump Inhibitors Independently Protect Against Early Allograft Injury or Chronic Rejection After Lung Transplantation

Background

Acid reflux has been associated with poor outcomes following lung transplantation. Unlike surgical fundoplication, the role of noninvasive, pharmacologic acid suppression remains uncertain.

Aims

To assess the relationship between post-transplant acid suppression with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) and onset of early allograft injury or chronic rejection following lung transplantation.

Methods

This was a retrospective cohort study of lung transplant recipients at a tertiary center in 2007–2014. Patients with pre-transplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess acid suppression therapy and onset of acute or chronic rejection, defined histologically and clinically. Subgroup analyses were performed to assess PPI versus H2RA use.

Results

A total of 188 subjects (60% men, mean age 54, follow-up 554 person-years) met inclusion criteria. During follow-up, 115 subjects (61.5%) developed rejection, with all-cause mortality of 27.6%. On univariate analyses, acid suppression and BMI, but not other patient demographics, were associated with rejection. The Kaplan–Meier curve demonstrated decreased rejection with use of acid suppression therapy (log-rank p = 0.03). On multivariate analyses, acid suppression (HR 0.39, p = 0.04) and lower BMI (HR 0.67, p = 0.04) were independently predicted against rejection. Subgroup analyses demonstrated that persistent PPI use was more protective than H2RA or no antireflux medications.

Conclusions

Post-lung transplant exposure to persistent PPI therapy results in the greatest protection against rejection in lung transplant recipients, independent of other clinical predictors including BMI, suggesting that PPI may have antireflux or anti-inflammatory effects in enhancing allograft protection.

     

Serum cystatin C is a determinant of central pressure augmentation index measured by oscillometric method in renal transplant recipients

Background

Serum cystatin C (ScysC) may help predicting cardiovascular outcome not only through its ability to detect renal dysfunction but also through its potential connection to others factors that are directly related to cardiovascular diseases. We explored the potential association of ScysC with arterial stiffness - a major contributor to cardiovascular disease - in renal transplant recipients (RTR).

Methods

Traditional and non-traditional cardio-vascular risk factors were collected from 215 stable RTR whom arterial stiffness was evaluated by the measure of the augmentation index of central pressure (AIx) determined by the arteriograph device. Serum creatinine and ScysC were measured the same day using standardized methods. Association between ScysC and AIx was examined in univariate and multivariate linear regression analysis.

Results

In univariate analysis, ScysC was strongly associated with AIx. This relationship was not confounded by age, gender, length of time spent on dialysis and transplantation vintage. Adjustment on the level of GFR estimated by the MDRD Study equation attenuated but did not abolish the association between ScysC and AIx.

Conclusions

In conclusion, ScysC is an independent predictor of AIx in RTR. Our data suggest that arterial stiffness may partially mediate the association between ScysC and cardiovascular risk in renal transplantation.

     

Should Sarcopenia Increase Priority for Transplant or Is It a Contraindication?

Purpose of Review

The purpose of this review is to discuss the current evidence regarding the impact of sarcopenia on patients with cirrhosis awaiting liver transplantation and to determine if its presence should be considered a criterion for expedited transplantation or a contraindication for transplantation.

Recent Findings

Sarcopenia is a negative predictor of survival in patients on a waiting list and after liver transplant. The gut-liver axis and the liver-muscle axis have been explored to understand the complex pathophysiology of sarcopenia.

Summary

Sarcopenia is a frequent finding in patients with cirrhosis. The diagnosis is ideally based on cross-sectional image analysis (CT or MRI) and treatment consists of optimization of caloric and protein intake. To date, prioritizing tools for liver transplantation have not included nutrition or sarcopenia parameters. Patients with a low Model for End-Stage Liver Disease (MELD) or MELD-Na score and sarcopenia would benefit from prioritization for transplant in order to reduce time on waiting list and therefore mortality.

     

Sedation with Propofol for Bronchoscopy in Cystic Fibrosis Lung Transplant Recipients

Introduction

Flexible fiberoptic bronchoscopy (FFB) plays an important role in the surveillance of cystic fibrosis (CF) patients after lung transplantation (LTx). With rapid onset and clearance, propofol provides a safe and efficient method for sedation during FFB, yet sedation requirements for CF patients are not well described.

Objectives

Due to pharmacokinetic differences for other classes of drugs in CF patients, this study was performed to examine propofol requirements for sedation during bronchoscopy in lung transplant recipients with CF.

Methods

A single-center retrospective cohort study was performed to examine propofol sedation requirements during outpatient surveillance. FFB procedures with transbronchial biopsy (TBB) in post-LTx recipients between 2009 and 2014 were conducted.

Results

A total of 40 FFB procedures with TBB were performed 20 CF (11 females), 20 non-CF (11 females). Mean (±?SD) age was 25.6?±?9.2 (range 13–42) years and 22.2?±?10.8 (range 11–39) years for the CF and non-CF groups, respectively. Propofol requirements were significantly higher in the CF patients compared to the non-CF patients. Mean (±?SD) propofol dose for CF patients was 334?±?86 versus 214?±?88 mg for non-CF patients (p?<?0.001). Mean (±?SD) propofol dose per weight (mg/kg) was 6.5?±?2.1 for CF patients versus 3.8?±?1.6 for non-CF patients (p?<?0.001).

Conclusions

Compared to a non-CF cohort, CF lung transplant recipients required higher dosages of propofol for sedation during FFB with TBB.

     

BK-Polyomavirus-Reaktivierung nach Nierentransplantation

Background

Reactivation of the BK polyomavirus(BKPyV) leads to polyomavirus-associated nephropathy (PyVAN) in up to 10?% of renal transplantion patients and is associated with transplant failure in up to 50?%. The main risk factor for BKPyV reactivation is immunosuppressive therapy due to its immunosuppressive effect and drug-dependent influence on virus replication. So far there is no antiviral causal therapy for PyVAN.

Aim

This review article discusses the current diagnostic steps and therapies recommended for BKPyV reactivation after renal transplantation.

Conclusion

The possibility for early intervention and prevention of PyVAN progression depends on a thorough screening for BKPyV replication after renal transplantation. Transplant function can be preserved and progression of viral replication can be prevented by early adjustment of the immunosuppressive therapy determined by the viral load.

     

High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study

Background

As treatment for chronic hepatitis C (HCV) virus has evolved to all-oral, interferon-free directly acting antiviral (DAA) therapy, the impact of these improvements on patient adherence has not been described.

Methods

Medication adherence was measured in 60 HCV, genotype-1, treatment-naïve participants enrolled in a phase 2a clinical trial at the National Institutes of Health and community clinics. Participants received either ledipasvir/sofosbuvir (LDV/SOF) (90 mg/400 mg) (one pill) daily for 12 weeks, LDV/SOF + GS-9451 (80 mg/day) (two pills) daily for 6 weeks, or LDV/SOF + GS-9669 (500 mg twice daily; three pills, two in the morning, one in the evening) for 6 weeks. Adherence was measured using medication event monitoring system (MEMS) caps, pill counts and patient report.

Results

Overall adherence to DAAs was high. Adherence declined over the course of the 12-week treatment (p = 0.04). While controlled psychiatric disease or symptoms of depression did not influence adherence, recent drug use was a risk factor for non-adherence to 12-week (p = 0.01), but not 6-week regimens. Adherence as measured by MEMS was lower than by patient report.

Conclusions

Adherence to short courses of DAA therapy with 1–3 pills a day was excellent in an urban population with multiple risk factors for non-adherence.

     

Immune Monitoring for CMV in Transplantation

Purpose of Review

Immune monitoring to determine when and how the recovery of cytomegalovirus (CMV)-specific T-cells occurs post-transplantation may help clinicians to risk stratify individuals at risk of complications from CMV. We aimed to review all recent clinical studies using CMV immune monitoring in the pre- and post-transplant setting including the use of recently developed standardized assays (Quantiferon-CMV and the CMV ELISPOT) to better understand in whom, when, and how immune monitoring is best used.

Recent Findings

Pre-transplant assessment of CMV immunity in solid-organ transplant recipients where CMV seropositive recipients had undetectable cell-mediated responses despite past immunity has shown that they are at a much higher risk of developing CMV reactivation. Post-transplant CMV immune monitoring can guide (shorten or prolong) the duration of antiviral prophylaxis, identify recipients at risk of post-prophylaxis CMV disease, and predict recurrent CMV reactivation.

Summary

Thus, CMV immune monitoring, in addition to current clinical and DNA-based monitoring for CMV, has the potential to be incorporated into routine clinical care to better improve CMV management in both the stem and solid-organ transplant population.

     

Fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection

Purpose

We report on a kidney transplant recipient treated with fecal microbiota transplantation (FMT) for recurrent urinary tract infections.

Methods

FMT was administered via frozen capsulized microbiota. Before and after FMT, urinary, fecal and vaginal microbiota compositions were analyzed.

Results

The patient remained without symptoms after FMT.

Conclusions

Underlying mechanisms of action need to be addressed in depth by future research.