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Cost-Effectiveness of New Direct-Acting Antivirals to Prevent Post-Liver Transplant Recurrent Hepatitis
Abstract
Preliminary studies on HCV-cirrhotics listed for transplant suggest that sofosbuvir in combination with ribavirin is very effective in promoting viral clearance and preventing disease recurrence. Unfortunately, the high cost of such treatment (€46 500 per 12 weeks of treatment) makes its cost-effectiveness questionable. A semi-Markov model was developed to assess the cost-effectiveness of sofosbuvir/ribavirin treatment in cirrhotic patients without HCC (HCV-CIRRH) and with HCC (HCV-HCC) listed for transplant. In the base-case analysis, the incremental cost-effectiveness ratio for 24 weeks of sofosbuvir/ribavirin was €44 875 per quality-adjusted life-year gained in HCV-CIRRH and €60 380 in HCV-HCC patients. Both results were above the willingness to pay threshold of €37 000 per quality-adjusted life-year. Our data also show that in order to remain cost-effective (with a 24-week treatment), any novel interferon-free treatment endowed with ideal efficacy should cost less than €67 224 or €95 712 in HCV-cirrhotics with and without HCC, respectively. The results shows that sofosbuvir/ribavirin therapy, given to patients listed for transplant, is not cost-effective at current prices despite being very effective, and new, more effective treatments will have little economic margins to remain cost-effective. New interferon-free combinations have the potential to revolutionize the treatment and prognosis of HCV-positive patients listed for transplant; however, without sustainable prices, this revolution is unlikely to happen.
© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
... The others used either just chronic hepatitis C (10-15%), mild and moderate health states (6-9%) or just non-cirrhotic state (6-9%). Two studies did not report health states by name: one was a decision tree without any health states [21] and one did not consider early health states [23]. Fifty-five (82%) of the models considered liver transplant as a health state. ...
... Eleven studies found that the examined DAAs are cost-effective with some conditions as in only some of the examined stages or genotypes. One study [23] stated that the examined DAA cannot be cost-effective with the given price. ...
... While the analysed therapies were heterogeneous, they were almost always cost effective (or even dominant), although the strength of evidence (and risk of bias) could vary across economic evaluations as we did not assess the quality of the studies. Only one article [23] came to the conclusion that at the published price the studied therapy could not be cost-effective. ...
Background:
Our objectives were to review the economic modelling methods and cost-effectiveness of second-generation direct-acting antiviral agents for the treatment of chronic HCV infection.
Methods:
A systematic literature search was performed in February 2017 using Scopus and OVID to review relevant publications between 2011 to present. Two independent reviewers screened potential papers.
Results:
The database search resulted in a total of 1,536 articles; after deduplication, title/abstract and full text screening, 67 studies were included for qualitative analysis. The vast majority of studies were conducted in high-income countries (n=59) and used Markov-based modelling techniques (n=60). Most of the analyses utilized long-term time horizons; 58 studies calculated lifetime costs and outcomes. The examined treatments were heterogenic among the studies; seven analyses did not directly evaluate treatments (just with screening or genotype testing). The examined treatments (n=60) were either dominant (23%), or cost-effective at base case (57%) or in given subgroups (18%). Only one (2%) study reported that the assessed treatment was not cost-effective with the given setting and price.
Conclusions:
Despite their high initial therapeutic costs, second-generation direct-acting antiviral agents were found to be cost-effective to treat chronic HCV infection. Studies were predominantly conducted in higher income countries, although we have limited information on cost-effectiveness in low- and middle-income countries, where assessment of cost-effectiveness is even more essential due to more limited health-care resources and potentially higher public health burden due to unsafe medical interventions.
... 5 After almost 3 years of prescribing DAAs, the best timing for treating LT candidates is still unclear. 2,[5][6][7] The aim of this study was to compare the cost-effectiveness of the aforementioned three strategies in patients with decompensated cirrhosis (DCC) or with hepatocellular carcinoma (HCC) listed for LT. ...
... Based on a previously published model, 6 we developed a decision analytical Markov model to simulate the progression of a HCV-infected cirrhotic with or without HCC from the time of listing until death, and we used this model to study the cost-effectiveness of the three strategies proposed. The parameters were estimated to reflect two specific subgroups of HCV-positive LT candidates: patients listed for DCC and patients with a transplantable HCC. ...
... To be considered cost-effective, the ICER should be under the willingness to pay (WTP) threshold of 40,000 € per QALY gained, which is considered acceptable by leading regulatory agencies such as NICE-UK, AHRQ-USA and CADTH-Canada. 6 The SVR probability of PERI-LT was derived from a phase 2 clinical trial with only 16 patients, 3 due to the small sample size, the possible different efficacies of PERI-LT (88%) with POST-LT (96%) could be related to chance. Based on this uncertainty, an alternative scenario with a SVR probability of 96% for both POST-LT and PERI-LT strategies was tested, assuming 6-week treatment duration for PERI-LT strategy. ...
Different strategies of DAAs treatment are currently possible both pre and post liver-transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost-effectiveness. A decision-analytical model was created to simulate the progression of HCV-infected patients listed for decompensated cirrhosis (DCC) or for Hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12-week course of DAAs prior to transplantation (PRE-LT), (ii) a 4-week course of DAAs starting at the time of transplantation (PERI-LT), and (iii) a 12-week course of DAAs administered at disease recurrence (POST-LT). The population was sub-stratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness was estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE-LT treatment strategy was dominant for DCC patients with MELD<16 and cost-effective for those with MELD16-20, while POST-LT strategy emerged as cost-effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE-LT as the cost-effective strategy for patients with MELD≤20. In conclusion, PRE-LT treatment is cost-effective for patients with MELD≤20 without HCC, while treatments after LT are cost-effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant-related factors.
... cirrhosis only) would potentially eliminate a need for LT. 25 This cost-effective analysis was performed using the best estimates of all parameters and probabilities following the recommendations of the Panel on Cost-Effectiveness in Health and Medicine. 26 Model structure Based upon the study design, a Markov state-transition model was developed to simulate the progression of a hypothetical cohort of HCV-genotype 1 or 4 cirrhotic patients. ...
... Assuming each studied cohort received treatment (one prior to LT, one preemptively prior to HCV recurrence, and the other post-LT after HCV recurrence), the probability at each decision point was determined (Table 1). 10,25,[27][28][29][30][31][32][33][34][35][36][37] Using these assumptions, a final decision point was constructed based upon the varied decision tree. For each final end point, the total cost and quality-adjusted life years (QALYs) were determined. ...
... Costs were derived from published literature with cost estimated derived from the 2014 Centers for Medicare and Medicaid standardised hospital accounting reports (Tables 2 and 3). 25,[39][40][41][42][43][44][45] This charge information was representative of the amount that hospitals billed for services; however, it does not reflect the actual hospital services cost or the specific payment that care facilities received in total. From this, a cost-to-charge ratio was performed to remove the difference in mark-up costs as determined by the hospitals to account for differences in a mixed payer system, local competition, and price strategy. ...
Background:
Recurrence of hepatitis C virus (HCV) following liver transplantation (LT) is universal for those with ongoing viraemia and is associated with higher rates of allograft failure and death. However, the optimal timing of HCV treatment for patients awaiting transplant remains unclear.
Aim:
To evaluate the comparative cost-effectiveness of treating HCV pre-LT vs. post-LT (pre-emptive or after HCV recurrence).
Methods:
A Markov state-transition model was created to simulate the progression of a cohort of HCV-genotype 1 or 4 cirrhotic patients from the time of transplant listing until death. We then used this model to study the cost-effectiveness of ledipasvir-sofosbuvir (LDV/SOF) with ribavirin for 12 weeks, administered for three separate treatment strategies: (i) pre-LT; (ii) post-LT preemptively prior to HCV recurrence; or (iii) post-LT after HCV recurrence.
Results:
In the base-case analysis using a median model for end-stage liver disease (MELD) score <25 at the time of transplant, we found that pre-LT treatment of HCV led to more QALYs for fewer dollars compared to other strategies. Analysis limited to living donor LT recipients revealed that pre-LT treatment was also the most cost-effective strategy. When the analysis was repeated for MELD ≥25, decompensated disease (Child-Pugh class B or C), and hepatocellular carcinoma cases, preemptive post-LT strategy was more cost-effective.
Conclusions:
Treatment of HCV prior to liver transplantation appears to be the most cost-effective strategy for patients with a MELD score <25. For patients with a MELD ≥25 or decompensated cirrhosis, preemptive post-liver transplantation treatment before HCV recurrence is the most cost-effective strategy.
... (11) The costs of these life-saving therapies have sparked an intense debate that has even involved members of the US Senate who voiced concerns about revenue-driven drug pricing. (12) A number of studies have shown that DAA-based therapy is cost-effective, (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) although concerns were raised about the sustainability of these treatments. (28,(30)(31)(32)(33)(34) In fact, because of the combined effects of the high cost of the treatment and the high prevalence of hepatitis C viral (HCV) infection, in several countries access to cure has been slow and restricted to the most advanced cases. ...
... (6,35,36) The cohort Markov model is most frequently used in liver diseases because of its transparency, efficiency, and ease of debugging. (13,14,(17)(18)(19)(20)(21)(22)(23)(24)(25)(40)(41)(42)(43)(44)(45)(46) Alternatively, individual-level state transition models and individuallevel discrete event simulation models could be used where the decision problem is related to a liver condition that affects patients with a high heterogeneity (in the case of CHC, different METAVIR score, genotype, age, sex, treatment history, etc.) and when data on the relationship between individual patient characteristics and event probabilities are available (e.g., fibrosis stage progression related to patient characteristics). (26)(27)(28) Finally, dynamic modeling could be used in HCV populations with a high transmission rate (e.g., injecting drug users), (47,48) hepatitis vaccination or screening, (49)(50)(51) and transplant, (52) when interaction between subjects plays an important role. ...
... A number of cost-effectiveness analyses based on Markov models and individual-based models have been performed to evaluate the cost-effectiveness of treatment based on protease inhibitors and of DAAs for the therapy of CHC. (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(41)(42)(43)(44)(45)(46)59) DAA regimens are characterized by very high rates of sustained virological response even in advanced cases, a shorter treatment course, an acceptable side effect profile with little or no resistance-associated mutations, and, possibly, a pan-genotypic activity. (60) Although DAAs have revolutionized the treatment of hepatitis C infection, enthusiasm has been dampened by their high cost. ...
Unlabelled:
In the current context of rising health care costs and decreasing sustainability, it is becoming increasingly common to resort to decision analytical modeling and health economics evaluations. Decision analytic models are analytical tools that help decision makers to select the best choice between alternative health care interventions, taking into consideration the complexity of the disease, the socioeconomic context, and the relevant differences in outcomes. We present a brief overview of the use of decision analytical models in health economic evaluations and their applications in the area of liver diseases. The aim is to provide the reader with the basic elements to evaluate health economic analysis reports and to discuss some limitations of the current approaches, as highlighted by the case of the therapy of chronic hepatitis C. To serve its purpose, health economics evaluations must be able to do justice to medical innovation and the market while protecting patients and society and promoting fair access to treatment and its economic sustainability.
Conclusion:
New approaches and methods able to include variables such as prevalence of the disease, budget impact, and sustainability into the cost-effectiveness analysis are needed to reach this goal. (Hepatology 2016;64:1331-1342).
... Further, the probability of Sativex to be a cost-effective option at a WTP threshold of €40,000 per QALY gained was virtually 100%. The ICER estimated was under the WTP threshold of €40,000 per QALY gained that is considered acceptable by leading regulatory agencies such as NICE-UK, AHRQ-USA, and CADTH-Canada [29] and is under the WTP of €60,000 per QALY gained used in Italy [25,30]. ...
IntroductionMultiple sclerosis (MS) is a highly symptomatic disease, with a wide range of disabilities affecting many bodily functions, even in younger persons with a short disease history. The availability of a cannabinoid oromucosal spray (Sativex) for the management of treatment-resistant MS spasticity has provided a new opportunity for many patients.Objective
Our study aimed to assess the cost effectiveness of Sativex in Italian patients with treatment-resistant MS spasticity. The analysis was based on the real-world data of a large registry of Italian patients.MethodsA cost-utility analysis was conducted using data collected prospectively from an electronic registry of all patients who began to use Sativex for MS-resistant spasticity between January 2014 and February 2015 in 30 specialized MS units across Italy and were followed up for ≤ 6 months. Data on drug consumption and spasticity/utility were used to estimate the incremental cost-effectiveness ratio (ICER) of Sativex, as compared with no intervention. No costs or spasticity/utility changes were assumed for no treatment intervention. The ICER was expressed as quality-adjusted life-years (QALYs) gained, using the Italian NHS perspective and a 6-month time horizon.ResultsSativex effectiveness and consumption was estimated analyzing data of 1350 patients from the registry. These patients reported a mean (SD) utility increment of 0.087 (0.069) after 1 month of treatment, 0.118 (0.073) after 3 months’ treatment and 0.127 (0.080) after 6 months’ treatment. The 6-month cost of treating the entire population with Sativex was €1,361,266, with a €1008 cost and 0.0284 QALYs gained per patient. The estimated ICER was €35,516 per QALY gained, with little variability around the central estimate of cost-effectiveness, as shown by the cost-effectiveness acceptability curve.Conclusion
The use of Sativex could improve the quality of life of patients with a reasonable incremental cost resulting as a cost-effective option for patients with MS-resistant spasticity. These results could help clinicians and decision makers to develop improved management strategies for spasticity in patients with MS, optimizing the use of available resources.
... Fifty percent of these patients will subsequently decompensate if left untreated [33]. The use of DAAs during the peri-transplant period is cost effective [34]. DAAs may improve the patient clinical status to the point where they can even be delisted. ...
Purpose of Review
We aim to review the current guidelines and emerging data and compare the pros and cons for the use of HCV-positive organs.
Recent Findings
Some recent data suggests that the use of HCV-positive livers and kidneys safely increases the organ pool, additionally reducing wait list time, healthcare costs, and mortality.
Summary
Despite this therapeutic breakthrough, the demand for organs and waitlist mortality remains high. Every year, thousands of viable hepatitis C-positive organs are discarded. The emerging data regarding transplantation of HCV-positive organs is promising; however, further research is warranted with larger samples. A literature search was conducted using PubMed, using the keywords “transplant recipients,” “hepatitis C,” “kidney transplantation,” “liver transplantation,” “direct acting antivirals,” and “pre transplant.” Only articles in the English language were included.
... Currently, IFN has been reported to be cost-effective because it decreases liver disease-associated mortality (31), but it is more expensive compared with DAAs with borderline treatment benefits (32). If it becomes clear that there are a number of recurrences of HCC following DAA treatment, its cost-effectiveness may be very poor. ...
Interferon (IFN) has been identified to suppress carcinogenesis when used for treating hepatitis C virus (HCV) infections. Treatment with IFN-free direct-acting antiviral agents (DAAs) is an acceptable alternative, even in elderly patients or patients who have been treated for hepatocellular carcinoma (HCC), because it has a lower incidence of side effects and higher sustained virological response (SVR) rate compared with IFN treatment. However, the suppression of carcinogenesis by DAAs is unclear. In the present study, 19 patients who underwent DAA treatment following treatment for HCC between January 2015 and March 2017 were retrospectively investigated. The clinical data were compared between 9 patients with HCC recurrence following DAA treatment (recurrence group) and 10 patients without HCC recurrence (no-recurrence group). The 1-year cumulative recurrence rate of HCC following SVR was as high as 50.2%. Age and sex did not significantly differ between the two groups, and the average number of HCC treatments prior to DAA treatment was also not significantly different between the recurrence and no-recurrence groups (3.2 and 2.2, respectively). The median interval between the final HCC treatment and the commencement of DAA treatment was 88 days in the recurrence group, which was significantly less compared with 790 days in the no-recurrence group (P=0.018). An interval of 120 days or more from final HCC treatment to the commencement of DAA treatment was a significant independent factor of no HCC recurrence following DAA treatment (P=0.028). A high HCC recurrence rate was identified following DAA treatment in patients with a history of HCC treatment. Therefore, there should be at least a 4-month interval from the final HCC treatment to the commencement of DAA treatment to ensure no HCC recurrence.
... Furthermore, the high costs associated with DAA therapy warrant the pursuit of more cost-effective measures. 7 Novel strategies to address these limitations could increase the pool of donor organs available, improve transplant outcomes and reduce costs to further alleviate the medical burden of organ shortage. ...
Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion-associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naïve cells from virus-induced alterations. Combining entry inhibitors with direct-acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation. The role of DAAs in transplantation, while still under clinical investigation, carries the risk of recipient infection and HCV-induced disease, since DAAs act only after infection is established. Thus, entry inhibitors provide a perspective to improve patient outcomes during organ transplantation. Applying this approach for transplant of organs from HCV-positive donors to HCV-negative recipients may also contribute to alleviate the medical burden of organ shortage.
... Hence, transplant physicians should always consider a cost-benefit analysis if they want to continue an effective LT program [116,117] . Dialysis treatment, plasma exchange, blood derivatives, and direct-acting antivirals are very expensive [62,118,119] . Notably, attempts to perform blood transfusion and infusion of fraction products are illadvised because they are very detrimental to the medical economy [62,116,117,119] . ...
Advanced liver cirrhosis is usually accompanied by portal hypertension. Long-term portal hypertension results in various vascular alterations. The systemic hemodynamic state in patients with cirrhosis is termed a hyperdynamic state. This peculiar hemodynamic state is characterized by an expanded blood volume, high cardiac output, and low total peripheral resistance. Vascular alterations do not disappear even long after liver transplantation (LT), and recipients with cirrhosis exhibit a persistent systemic hyperdynamic state even after LT. Stability of optimal systemic hemodynamics is indispensable for adequate portal venous flow (PVF) and successful LT, and reliable parameters for optimal systemic hemodynamics and adequate PVF are required. Even a subtle disorder in systemic hemodynamics is precisely indicated by the balance between cardiac output and blood volume. The indocyanine green (ICG) kinetics reflect the patient's functional hepatocytes and effective PVF, and PVF is a major determinant of the ICG elimination constant (kICG) in the well-preserved allograft. The kICG value is useful to set the optimal PVF during living-donor LT and to evaluate adequate PVF after LT. Perioperative management has a large influence on the postoperative course and outcome; therefore, key points and unexpected pitfalls for intensive management are herein summarized. Transplant physicians should fully understand the peculiar systemic hemodynamic behavior in LT recipients with cirrhosis and recognize the critical importance of PVF after LT.
... In this issue of the American Journal of Transplantation, Dr. Cortesi et al present a cost-effectiveness analysis of pretransplant treatment with sofosbuvir and ribavirin in order to prevent posttransplant recurrent hepatitis C (HCV) (1). Using Markov modeling, they investigate the impact of pretransplant viral clearance on morbidity and mortality posttransplant from recurrent HCV. ...
New all-oral interferon-free therapies offer the ability to potentially eradicate hepatitis C, but the high cost of therapy is leading to critical questions about who and when to treat in the peritransplant period. See article by Cortesi et al on page 1817.
Infections caused by the Hepatitis C virus (HCV) affect around 70 million people worldwide, leading to serious liver problems such as fibrosis, steatosis, cirrhosis, in addition to progressing to hepatocellular carcinoma, and becoming globally the main cause of liver disease. Despite great therapeutic advances in obtaining pan-genotypic direct-acting antivirals (DAAs), around 5-10% of affected individuals are unable to eliminate the virus by their own immune system’s activity. Still, there are no licensed vaccines so far. In this context, the orchestrated process of virus entry into host cells is a crucial step in the life cycle and the infectivity capability of most viruses. In recent years, the entry of viruses has become one of the main druggable targets used for designing effective antiviral molecules. This goal has come to be widely studied to develop pharmacotherapeutic strategies against HCV, combined or not with DAAs in multitarget approaches. Among the inhibitors found in the literature, ITX 5061 corresponds to the most effective one, with EC50 and CC50 values of 0.25 nM and >10 µM (SI: 10,000), respectively. This SR-BI antagonist completed the phase I trial, constituting a promising compound against HCV. Interestingly, chlorcyclizine (an antihistamine drug) showed action both in E1 apolipoproteins (EC50 and CC50 values of 0.0331 and 25.1 µM, respectively), as well as in NPC1L1 (IC50 and CC50 values of 2.3 nM and > 15 µM, respectively). Thus, this review will be addressed to promising inhibitors targeting HCV entry, discussing their SAR analyzes, recent contributions and advances in this field.
Objective
This paper constitutes the first attempt to draw lessons from the recent uptake of health economic evaluation of innovative drugs in the French regulatory framework.
Study Design
Taking the example of new direct-acting antivirals against hepatitis C virus, the paper asks whether and how the cost-effectiveness (CE) opinions issued by the French National Health Authority improve the information available to support the pricing decisions.
Methods
The analysis compares the assessment of these drugs based on three different sources: CE opinions, clinical opinions, and the published cost-utility analyses (CUA) available in the literature and identified through a systematic review.
Results
The results show that CE opinions bring to the fore three issues prone to impact the incremental cost utility ratio and those were not available to the decision maker through clinical opinions or published CUA: the stage of treatment initiation, the modeling of the disease progression, and the uncertainty around the efficacy rates.
Conclusions
France has introduced the criterion of the cost per QALY gained in the pricing and regulation of innovative pharmaceuticals since 2013. Our analysis shows that the use of CUA does enhance the information available to the decision makers on the value of the treatments.
Antiviral therapy to eradicate hepatitis C virus (HCV) infection improves outcomes in patients undergoing liver transplantation (LT) for advanced chronic HCV with or without hepatocellular carcinoma. Traditionally, antiviral therapy focused on the use of interferon (IFN)‐based regimens, with antiviral treatment initiated in the post‐transplant period once recurrent HCV disease with fibrosis in the allograft was identified. The use of IFN‐based therapy was limited in pre‐transplant patients with advanced liver disease. Earlier intervention, either before transplantation or early after LT is now feasible with the advent of second‐generation direct‐acting antiviral agents (DAAs) with superior tolerability and efficacy to IFN‐based therapy. These agents have the potential to reduce the number of patients developing HCV‐related complications requiring LT and re‐transplantation, as well as reducing the demand for donor organs. We discuss the pros and cons of pre‐transplant, peri‐transplant and post‐transplant therapy with current DAAs, citing available data from clinical trials and real‐world experience.
This article is protected by copyright. All rights reserved.
Aim
Recently, elbasvir/grazoprevir combination therapy (EBR/GZR therapy) has been reported to have excellent antiviral effects for chronic genotype 1 hepatitis C virus (HCV) infection. However, it has not been recommended for patients with post‐liver transplant (LT) HCV re‐infections because of a lack of evidence for effectiveness and drug‐drug interactions.
Methods
We report the usage of EBR/GZR in five post‐LT HCV re‐infected patients with the kinetics of renal function and tacrolimus (Tac) trough levels during and after therapy. Further, to evaluate the antiviral effects, we examined the HCV kinetics during and after therapy and compared this with other IFN‐free therapy in post‐LT patients (n=19).
Results
All patients treated with EBR/GZR therapy obtained rapid virological response and sustained at 12 weeks post‐treatment. There was no evidence of worsening estimated glomerular filtration rates (eGFR). Three patients were administrated tacrolimus as immunosuppressive therapy and its trough levels were controllable with dosage adjustments. One patient developed grade 1 diarrhea 3 days after therapy induction. To evaluate the antiviral effects of EBR/GZR therapy for these patients, we compared them to the effects of daclatasvir/asunaprevir combination therapy (n=8) and sofosbuvir/ledipasvir combination therapy (n=11). EBR/GZR therapy was not inferior to other therapies in its early phase and late‐phase antiviral effects.
Conclusions
Although further studies with a larger number of patients are required, we suggest that EBR/GZR therapy is an alternative therapy for patients with post‐LT genotype 1 HCV re‐infections.
Background
Decisions about which subgroup of chronic hepatitis C (CHC) patients should be treated with direct acting anti-viral agents (DAAs) have economic importance due to high drug prices. Treat-all DAA strategies for CHC have gained acceptance despite high drug acquisition costs. However, there are also costs associated with the surveillance of CHC to determine a subgroup of patients with significant impairment. The aim of this systematic review was to describe the modelling methods used and summarise results in cost-effectiveness analyses (CEAs) of both CHC treatment with DAAs and surveillance of liver disease. Methods
Electronic databases including Embase and Medline were searched from inception to May 2015. Eligible studies included models predicting costs and/or outcomes for interventions, surveillance, or management of people with CHC. Narrative and quantitative synthesis were conducted. Quality appraisal was conducted using validated checklists. The review was conducted following principles published by NHS Centre for Research and Dissemination. ResultsForty-one CEAs met the eligibility criteria for the review; 37 evaluated an intervention and four evaluated surveillance strategies for targeting DAA treatment to those likely to gain most benefit. Included studies were of variable quality mostly due to reporting omissions. Of the 37 CEAs, eight models that enabled comparative analysis were fully appraised and synthesized. These models provided non-unique cost-effectiveness estimates in a specific DAA comparison in a specific population defined in terms of genotype, prior treatment status, and presence or absence of cirrhosis. Marked heterogeneity in cost-effectiveness estimates was observed despite this stratification. Approximately half of the estimates suggested that DAAs were cost-effective considering a threshold of US$30,000 and 73% with threshold of US$50,000. Two models evaluating surveillance strategies suggested that treating all CHC patients regardless of the staging of liver disease could be cost-effective. ConclusionsCEAs of CHC treatments need to better account for variability in their estimates. This analysis suggested that there are still circumstances where DAAs are not cost-effective. Surveillance in place of a treat-all strategy may still need to be considered as an option for deploying DAAs, particularly where acquisition cost is at the limit of affordability for a given health system.
Sofosbuvir plus ledipasvir (SOF-LDV) combination therapy is a promising therapy for post-transplant hepatitis C virus (HCV) reinfection. It is known that gastric pH elevation induces lower absorption of ledipasvir; therefore, the use of proton pump inhibitors (PPIs) should be considered regarding dose reduction after SOF-LDV therapy induction. Here, we report two patients who developed duodenal ulcers due to the discontinuation of PPIs after the induction of SOF-LDV therapy for post-transplant HCV reinfection. The first patient was a 71-year-old man who had undergone living donor liver transplantation due to HCV-related liver cirrhosis. Lansoprazole, 30 mg daily, was discontinued upon SOF-LDV therapy induction. Seven days after SOF-LDV therapy induction, gastrointestinal endoscopy revealed the presence of a duodenal ulcer. The second patient was a 54-year-old man who had undergone living donor liver transplantation due to HCV-related end-stage liver disease. Similar to the first patient, rabeprazole sodium was discontinued upon the induction of SOF-LDV therapy. Eighteen days after SOF-LDV therapy induction, gastrointestinal endoscopy revealed the presence of a duodenal ulcer. In both cases, these duodenal ulcers improved after the resumption of the administration of PPIs, and a sustained virologic response at 12 weeks was achieved by SOF-LDV therapy with PPI use. Thus, PPI use should be continued consistently during SOF-LDV therapy for post-transplant HCV reinfection.
All patients with chronic hepatitis C virus (HCV) infections can and should be treated.1-9 Though highly effective directacting antiviral therapies are costly, the price of a cure is a 1-time investment that is outweighed by future benefits. For clinicians caring for patients requiring liver transplant, the key question relates to the timing of treatment: before or after liver transplantation? On 1 hand, treating HCV often improves our patients' model for end-stage liver disease (MELD) score, decreasing costs, and potentially improving longevity by reducing our patients' risk of death and transplantation. On the other hand, there is a concern that the cured patient with decompensated cirrhosis will find themselves in MELD purgatory with nonprogressive liver disease but a poor quality of life. At the same time, some patients, such as those with hepatocellular carcinoma, will require liver transplant irrespective of theirMELD meaning that pretransplant therapy cannot reduce costs in such settings. These important tradeoffs are often difficult reconcile for clinicians who care for patients awaiting liver transplant. Fortunately, guidance for navigating these competing concerns can be obtained from cost-effectiveness analyses. Herein, we review the available data on this approach to HCV therapy before or after liver transplant.
Background:
HCV(+) donors represent an effective strategy to increase liver donor availability to HCV-infected recipients. However, many HCV(+) transplant candidates are now receiving treatment with direct acting anti-virals (DAA) that lower the risk of posttransplant HCV recurrence but could make the patient ineligible for HCV(+) livers.
Methods:
We compared pretransplant DAA treatment versus deferred DAA treatment using a cost-effectiveness decision analysis model to estimate incremental cost-effectiveness ratios (ICERs; cost per quality-adjusted life year [QALY] gained) from the societal perspective across a range of HCV(+) liver availability rates. For practical considerations, the population modelled was restricted to well-compensated HCV(+) cirrhotics listed for liver transplantation with HCC MELD exception points.
Results:
Under base case conditions, the deferred DAA treatment strategy was found to be the "dominant" strategy. That is, it provided superior health outcomes at cost savings compared to the pretransplant DAA treatment strategy. The pretransplant DAA treatment strategy trended towards cost-effectiveness as HCV(+) donor liver availability declined. However, only in 1 scenario that was highly optimized for favorable outcomes in the pretransplant DAA treatment arm (low availability of HCV(+) organs, low cost of DAA treatment, high cost of HCV recurrence) was the ICER associated with HCV DAA treatment before transplant <$150,000/QALY gained.
Conclusions:
Deferring HCV treatment until after liver transplant and maintaining access to the expanded pool of HCV(+) donors appears to be the most cost-effective strategy for well-compensated HCV-infected cirrhotics listed for liver transplantation with HCC, even in geographic areas of relatively low HCV(+) donor availability.
Background & aims:
Orthotopic liver transplant patients with recurrent hepatitis C (HCV) historically have had limited treatment options. Ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin (3D+R) was approved by the FDA in December 2014 for liver transplant recipients with recurrent genotype 1 HCV, in whom it is effective and well-tolerated.
Methods:
Using a two-phase Markov model, we analyzed the cost-effectiveness of 3D+3 in liver transplant recipients, the only HCV treatment with FDA approval in this population. As a sensitivity analysis, we also considered the cost effectiveness of pegylated interferon plus ribavirin, the only other therapy with data from Phase III trials in this population. Patients were given one of three options: 3D+R for 24 weeks, pegylated interferon and ribavirin for 48 weeks (PR48) or no treatment (NT). Patients were then followed through subsequent disease progression until death. Outcome measures analyzed were: lifetime risks of liver morbidity and mortality, treatment costs, non-treatment medical expenditures, and quality-adjusted life years.
Results:
Treatment with 3D+R was associated with a significantly lower lifetime risk of liver-related morbidity and mortality than treatment with PR48 or NT. 3D+R also was associated with a higher gain in quality-adjusted life years (11.3 compared to 8.25 with NT) and lower discounted overall costs ($423,585 compared to $724,757 with NT).
Conclusions:
The use of 3D+R for liver transplant recipients with recurrent HCV is an outcome-improving and cost-effective regimen for this population with limited treatment options and large unmet need. This article is protected by copyright. All rights reserved.
Background & aims:
Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.
Methods:
In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation.
Results:
Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%).
Conclusions:
Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.
State-transition modeling (STM) is an intuitive, flexible, and transparent approach of computer-based decision-analytic modeling, including both Markov model cohort simulation as well as individual-based (first-order Monte Carlo) microsimulation. Conceptualizing a decision problem in terms of a set of (health) states and transitions among these states, STM is one of the most widespread modeling techniques in clinical decision analysis, health technology assessment, and health-economic evaluation. STMs have been used in many different populations and diseases, and their applications range from personalized health care strategies to public health programs. Most frequently, state-transition models are used in the evaluation of risk factor interventions, screening, diagnostic procedures, treatment strategies, and disease management programs.
Royal Free Hospital, London, UKIntroductionBackground of the European Liver Transplant RegistrySince 1968 the European Liver Transplant Registry (ELTR) collectsprospectively the data of liver transplantation (LT) in 145 centersall over Europe. It represents more than 95% of the overallEuropean data compared to the published official figures [1]. Thiscollectionismadeprospectivelythroughastandardizedquestion-naire. The first part of the questionnaire includes items regardingdate andindicationfor LT,donor andrecipientdata, surgical tech-niqueofLT,andtheimmediatepostoperativeimmunosuppressiontherapy. The second part concerns graft and patient outcome, andimmunosuppressive regimen follow-up. Participation in the ELTRis voluntary and a standard computerized database is provided tocontributing centers with detailed instructions for the collectionof accurate and uniform information [2].Along with reports concerning LT for specific hepatic diseases[3–12],ELTRhasallowedthedevelopmentofriskmodelsforliver-transplantation mortality according to the characteristics of thedonor and recipient, and of the transplant procedure [13,14].Qualityofthedataisassessedroutinely.Aregularauditingpro-cessisconductedeachyeartoensurethereliabilityofthescientificanalysis of the data, a control of the good adequacy between ELTRquestionnaire and patient charts is performed by randomly con-ductedauditvisits.ResultsoftheseauditvisitshaveindicatedthatELTR data were reliable and the scientific results of ELTR can beconsidered credible and representative of LT in Europe [15–18].In addition, a control quality program has been developed inter-nally. The data are subjected to checks for completeness, consis-tency, and range. Comprehensive logical intra- and inter-updatesare performed. Moreover, the ELTR has established agreementswith the European Organ Sharing Organizations (OSO): UnitedKingdom Transplant Service Support Authority (UKTransplant),Spanish Organizacion Nacional de Transplantes (ONT), Scandina-vian Scanditransplant (SKT), Dutch Transplant Foundation (NTS),Eurotransplant (ET), French Agence de la Biomedecine (ABM) toexchangedatacollectedfromEuropeanCentersandtocrosscheckcommon data between OSO and ELTR.Patients and methodsWe have first considered all data since 1968 to show the evolu-tion of results of LT in Europe since its initial development. Therest of the analysis has been undertaken during two differentperiods: (a) from January 1988 to December 2009 (89,865 LT –80,347 patients), where the date from January 1988 was chosenJournal of Hepatology 2012 vol. 57
New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost-effectiveness analysis of boceprevir (BOC)- and telaprevir (TVR)-based triple therapy according to different patients’ selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1–F4 fibrosis, (ii) only F2–F4 and (iii) only F3–F4. For each strategy, TVR interleukin-28B-guided (IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio (ICER) for F1–F4 strategy relative to F3–F4 was €5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and €7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1–F4 strategy relative to F3–F4 was €1 818 679 (TVR IL28B-guided) and €1 866 437 (BOC RVR-guided) per end-stage liver disease or death (ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization.
Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug–drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV. There is a tide in the affairs of men. Which, taken at the flood, leads on to fortune(Shakespeare: J Caesar Act 4, scene 3)
Unlabelled:
Treatment guidance for chronic hepatitis C (CHC) released by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) offers two options for interferon (IFN)-ineligible/intolerant individuals with genotype 1 infection: sofosbuvir/ribavirin (SOF/RBV) for 24 weeks or sofosbuvir/simeprevir (SOF/SMV) for 12 weeks. A 24-week course of SOF/RBV costs approximately US$169,000, with sustained virologic response (SVR) rates ranging from 52% to 84%; 12 weeks of SOF/SMV costs approximately $150,000, with SVR between 89% and 100%. Because SOF/SMV is currently used off-label, debate exists among physicians and payers about whether it should be prescribed and covered. This article presents a cost-effectiveness analysis of these two treatment regimens accounting for costs of drugs, treatment-related medical care, retreatment for individuals who do not achieve SVR, and natural history of continued HCV infection after failed retreatment. Analysis uses a Markov model with a lifetime horizon and a societal perspective. In the base-case scenario, SOF/SMV dominated SOF/RBV in a modeled 50-year-old cohort of treatment-naïve and -experienced subjects, excluding those who failed earlier therapy with telaprevir or boceprevir. SOF/SMV yielded lower costs and more quality-adjusted life years (QALYs) for the average subject, compared to SOF/RBV ($165,336 and 14.69 QALYs vs. $243,586 and 14.45 QALYs, respectively). In base-case cost analysis, the SOF/SMV treatment strategy saved $91,590 per SVR, compared to SOF/RBV. Under all one-way sensitivity scenarios, SOF/SMV remained dominant and resulted in cost savings.
Conclusions:
These results suggest that a 12-week course of SOF/SMV is a more cost-effective treatment for genotype 1 CHC than 24 weeks of SOF/RBV among IFN-ineligible/intolerant individuals, supporting the AASLD/IDSA guidance and offering implications for both clinical and regulatory decision making as well as pharmaceutical pricing.
Liver diseases (LDs) have a high impact on morbidity, mortality and health-related quality of life (HRQoL). Different LDs may have different effects on patients' HRQoL. The aim of our study was to assess the reliability and benefit of using a generic HRQoL questionnaire to evaluate the health status of patients with the major liver conditions: hepatitis B (HBV), hepatitis C (HCV), cirrhosis, hepatocellular carcinoma (HCC), autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), NAFLD/NASH and patients in the liver transplant list. A naturalistic, prospective, multicenter study has been conducted to generate and validate a set of health care outcomes indicators for the major liver conditions. LDs patients (age>18 years) were enrolled in 3 major Italian medical centers and are still being followed up (median f-up: 13 months). Within this study, socio-demographic, clinical and HRQoL were collected using the EQ-5D-3L, a generic instrument that enables HRQoL to com
Within 5-10 years, 20-40% of hepatitis C virus (HCV)-infected liver transplant recipients can be expected to develop cirrhosis. Here, cost-effectiveness of antiviral therapy was assessed. A Markov model was developed to simulate disease progression and calculate outcome and costs of treatment. In the baseline analysis, Peg-IFN/RBV treatment prevented organ loss/death, gained quality-adjusted life-years (QALYs) and undercut the limit of cost-effectiveness of €50 000/QALY with an incremental cost-effectiveness ratio of approximately €40 400/QALY and €21 000/QALY for HCV genotype 1 and 2/3 patients, respectively. Furthermore, sensitivity analysis testing modified model parameters according to extreme data described in the literature confirmed cost-effectiveness for a lower or higher rate of fibrosis progression, increased non-HCV-related mortality, lower limits of utilities, a time horizon of 30 years, and additional costs in the year of death. On the other hand, cost-effectiveness was lost for patients with genotype 1 in case of doubled antiviral or life-time costs or an increased discount rate of 7%. New treatment strategies for HCV genotype 1 infected patients remained on the same level cost-effective, if additional costs did not exceed €10 774 per 10% sustained virologic response gain. We conclude that Peg-IFN/RBV treatment is cost-effective post transplant. This may support treatment decision in individual cases.
The appropriate development of a model begins with understanding the problem that is being represented. The aim of this article is to provide a series of consensus-based best practices regarding the process of model conceptualization. For the purpose of this series of papers, the authors consider the development of models whose purpose is to inform medical decisions and health-related resource allocation questions. They specifically divide the conceptualization process into two distinct components: the conceptualization of the problem, which converts knowledge of the health care process or decision into a representation of the problem, followed by the conceptualization of the model itself, which matches the attributes and characteristics of a particular modeling type to the needs of the problem being represented. Recommendations are made regarding the structure of the modeling team, agreement on the statement of the problem, the structure, perspective and target population of the model, and the interventions and outcomes represented. Best practices relating to the specific characteristics of model structure, and which characteristics of the problem might be most easily represented in a specific modeling method, are presented. Each section contains a number of recommendations that were iterated among the authors, as well as the wider modeling taskforce, jointly set up by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making.
The natural history of clinically compensated hepatitis C virus (HCV) cirrhosis after liver transplantation is unknown. This information is relevant to transplant centers to improve the management of these patients and decide the optimal timing for retransplantation. The aims of the study were (1) to describe the natural history of patients with HCV-cirrhosis transplants in a center with annual liver biopsies, and (2) to determine predictors for clinical decompensation, retransplantation, and mortality rates. A total of 49 patients with HCV-graft cirrhosis, 39 clinically compensated at histologic diagnosis of cirrhosis (post–liver transplantation cirrhosis) were included and followed up for 1 year (15 days-3.5 years). All patients tested were infected with genotype 1b. Predictive variables included histologic activity index (HAI) at post–liver transplantation cirrhosis, liver function tests, age, sex, and maintenance immunosuppression. Eighteen of 39 patients developed at least 1 episode of decompensation after a median of 7.8 months (4 days-2.6 years; 93% ascites). The cumulative probability of decompensation was 8%, 17%, and 42% at 1, 6, and 12 months, respectively. Graft and patient survival rates were 100%, 85%, and 71% and 100%, 92%, and 74% at 1, 6, and 12 months, respectively. Patient survival rates dropped significantly once decompensation developed (93%, 61%, and 41% at 1, 6, and 12 months, respectively). Variables associated with decompensation, retransplantation, and mortality rate included a high Child-Pugh score (>A), low levels of albumin at post–liver transplantation cirrhosis, and a short interval between liver transplantation and post–liver transplantation cirrhosis. The natural history of clinically compensated HCV-graft cirrhosis is shortened when compared with immunocompetent patients. If retransplantation is considered, it should be performed promptly once decompensation develops.
In financially constrained health systems across the world, increasing emphasis is being placed on the ability to demonstrate that health care interventions are not only effective, but also cost-effective. This book deals with decision modelling techniques that can be used to estimate the value for money of various interventions including medical devices, surgical procedures, diagnostic technologies, and pharmaceuticals. Particular emphasis is placed on the importance of the appropriate representation of uncertainty in the evaluative process and the implication this uncertainty has for decision making and the need for future research. This highly practical guide takes the reader through the key principles and approaches of modelling techniques. It begins with the basics of constructing different forms of the model, the population of the model with input parameter estimates, analysis of the results, and progression to the holistic view of models as a valuable tool for informing future research exercises. Case studies and exercises are supported with online templates and solutions. This book will help analysts understand the contribution of decision-analytic modelling to the evaluation of health care programmes. ABOUT THE SERIES: Economic evaluation of health interventions is a growing specialist field, and this series of practical handbooks will tackle, in-depth, topics superficially addressed in more general health economics books. Each volume will include illustrative material, case histories and worked examples to encourage the reader to apply the methods discussed, with supporting material provided online. This series is aimed at health economists in academia, the pharmaceutical industry and the health sector, those on advanced health economics courses, and health researchers in associated fields.
Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus.
Liver disease caused by the hepatitis C virus is the main indication for liver transplantation in Western countries. However, HCV re-infection post-transplantation is constant and recent data confirm that it significantly impairs patient and graft survival. Chronic HCV infection develops in 75-90% of patients, and 5-30% ultimately progress to cirrhosis within 5 years. Because of the impact of HCV recurrence on graft and patient survival, several treatment strategies have been evaluated. Antiviral therapy could be administered before transplantation to suppress viral replication and reduce the risk of recurrence. However, this approach is applicable in around 50% of patients and tolerance is poor, particularly in patients with decompensated cirrhosis. Pre-emptive therapy in the early post-transplant period is limited by the high rate of side effects. Frequently, antiviral therapy is initiated when HCV recurs to obtain viral eradication and/or reduce disease progression. Treatment of established graft lesions with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV) combination therapy results in a sustained virological response (SVR) in around 30% of patients. The new classes of potent and direct antiviral agents (DAA) will certainly improve the results of pre- and post-transplant antiviral therapy. However, at the present time, no data are available on the use of these drugs in patients with decompensated cirrhosis or post-transplant hepatitis.
The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation.
Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board.
The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant.
The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.
Recently developed German guidelines for antiviral treatment in patients with chronic hepatitis C recommend basing drug dosage, intended treatment duration and early stopping rules on the genotype of the hepatitis C virus and early viral responses to treatment.
To evaluate effectiveness and cost effectiveness of different antiviral treatment strategies including the German guidelines, for chronic hepatitis C.
A validated lifetime Markov model was used to project life expectancy, QALYs and lifetime costs for the following strategies: (i) no antiviral therapy (NoAVT); (ii) interferon-alpha-2b plus ribavirin for 48 weeks (IFN + R); (iii) peginterferon-alpha-2b plus weight-based ribavirin for 48 weeks (PEG + R); (iv) peginterferon-alpha-2b plus ribavirin according to German guidelines with genotype-dependent treatment duration, dosage and 12-week viral response evaluation (GUIDE). Clinical and resource utilization data were derived from a clinical trial, the published literature and a survey of German hepatologists. Incremental cost-effectiveness ratios (ICERs) were calculated adopting the German societal perspective. Costs (in euro, year 2005 values) and health outcomes were discounted at 3% annually. Uncertainty was assessed using deterministic and probabilistic sensitivity analyses.
Compared with NoAVT, PEG + R increased undiscounted life expectancy by 5.0 life-years (5.2 QALYs) and GUIDE increased undiscounted life expectancy by 4.9 years (5.1 QALYs). Compared with PEG + R, GUIDE saved 13% of hepatitis C virus-related lifetime costs per patient. GUIDE dominated IFN + R. Compared with NoAVT, discounted ICERs were euro1500 per QALY for GUIDE and euro3200 per QALY for PEG + R.
Administering GUIDE should allow tailoring treatment efficiently to genotype, bodyweight and early viral response in patients with chronic hepatitis C, and appears cost effective compared with other well accepted medical interventions.
Most studies evaluating chronic hepatitis C virus (HCV) natural history have taken the development of cirrhosis as an end-point.
To perform a systematic review of the literature to establish the outcome of compensated HCV cirrhosis.
A systematic literature review was performed. Only data regarding HCV mono-infected patients were included. Weighted mean annual percentage rates for death/transplantation, decompensation of cirrhosis and development of HCC were calculated.
Thirteen papers were included. Despite some heterogeneity, we extracted data relating to 2386 patients. In compensated HCV cirrhosis, the estimated annual rate of death/transplantation is 4.58%, that of decompensation is 6.37% per and that of HCC, 3.36%. When compared with studies of untreated patients, studies that included treated patients reported significantly lower mean annual percentage rates of HCC (2.52% vs. 4.79%, P = 0.02), but not decompensation (5.34% vs. 7.88%, P = 0.026) and death/transplantation (3.79% vs. 4.62%, P = 0.25).
These rates highlight the need for continued vigilance for the occurrence of HCC, while confirming the relatively slow progress of compensated HCV cirrhosis. Heterogeneity in reporting means that these data may underestimate the rate of disease progression, particularly HCC development. It will be important to ensure clearer distinction between treatment responses in future studies.
To analyze the characteristiscs, evolution and survival of patients included on the waiting list (WL) for liver transplantation (OLT).
Between February 2002 and April 2009, 254 patients were included on WL to receive a first graft. Two hundred twenty-two patients (87.4%) were transplanted (group T); 7 (2.8%) died on the WL and 25 (9.8%) were excluded, namely, 13 (52%) due to improvement (group IE) and 12, for other reasons (group OE). Data collected prospectively were analyzed retrospectively.
Indications for transplant were cirrhosis (58%), hepatocellular carcinoma (HCC; 29%) and other etiologies (13%.) Average time on the WL was 60.3 +/- 62.9 days. Significant differences were not observed among the groups with respect to age, gender, or indication for OLT. The probability for exclusion due to progression and/or death was not significantly greater among patients included for HCC than for other reasons (P = .6). Survivals at 1, 3, and 5 years after WL inclusion were 81.2%, 73.3%, and 68.6%, respectively, in the whole series; and 85,4%, 76,9%, and 71.7% in group T. All group OE patients died before the first year, while group IE showed a survival of 100%, 91.7% and 91.7% at 1, 3, and 5 years, respectively. Survival was not different between groups T and IE (P = .03), but was lower in group OE than in groups T or IE (P < .001).
The list mortality rate in our series was low, probably in relation to the short waiting time. The rate of exclusion from WL was 10%. Patient with hepatocellular carcinoma were not at an increased risk of WL exclusion. Patients excluded due to improvement displayed excellent survivals during the 5 years following exclusion.
The natural history of hepatitis C virus (HCV) infection following liver transplantation and predictors of disease severity remain controversial. The aims of the study were to assess in a homogeneous population of 81 cyclosporine-based HCV-infected liver transplant recipients mostly infected with genotype 1b and undergoing strict protocol annual biopsies: 1) the histological progression of posttransplantation HCV disease and, in particular, the incidence of HCV-related graft cirrhosis within the first 5 years after surgery; and 2) the relationship between progression to cirrhosis and i) rejection episodes and ii) first-year liver biopsy findings. We studied 81 consecutive HCV-RNA-positive patients (96% genotype 1b) undergoing liver transplantation between 1991 and 1996 with a minimum histological follow-up of 1 year. All patients received cyclosporine-based immunosuppression and underwent protocol yearly liver biopsies for the first 5 years. The mean histological follow-up was 32 months (range, 12-60 months). Biopsies were scored according to the histological activity index (HAI), with separate evaluation of grade (activity) and stage (fibrosis). Histological hepatitis, present in 97% of patients in the most recent biopsy, was moderate or severe in 64%. Twelve patients developed HCV-related cirrhosis at a median time of 24 months (range, 12-48 months), with an actuarial rate of HCV-cirrhosis of 3.7%, 8.5%, 16%, 28%, and 28% at 1, 2, 3, 4, and 5 years, respectively. Rejection was significantly more common among patients with cirrhosis versus those without (83% vs. 48%; P =.02), with an association between the incidence of cirrhosis and the number of rejection episodes: 5%, 15%, and 50% in patients without rejection, one and two episodes, respectively (P =.001). The degree of activity and fibrosis score in the first-year biopsy were higher in patients who developed cirrhosis than in those who did not (P =.008 and.18, respectively). In conclusion, HCV genotype 1b-infected liver recipients are at a high risk of developing graft cirrhosis in the first 4 to 5 years following transplantation, especially those with previous rejection episodes. First-year liver biopsies may help to sooner identify patients at the highest risk, improving further patient management.
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