The Impact of Direct-Acting Antiviral Agents on Liver and Kidney Transplant Costs and Outcomes

D. A. Axelrod; M. A. Schnitzler; T. Alhamad; F. Gordon; R. D. Bloom; G. P. Hess; H. Xiao; M. Nazzal; D. L. Segev; V. R. Dharnidharka; A. S. Naik; N. N. Lam; R. Ouseph; B. L. Kasiske; C. M. Durand; K. L. Lentine

Disclosures

American Journal of Transplantation. 2018;18(10):2473-2482. 

In This Article

Discussion

Introduction of DAAs has markedly improved care for LT and KT recipients with chronic HCV infection. Among LT recipients, our data support findings from smaller clinical studies that suggest that DAAs in the posttransplant setting improve posttransplant outcomes. In the pre-DAA era, HCV reinfection after LT was universal and treatment was generally reserved only for recipients with early aggressive recurrence resulting in fibrosing cholestatic hepatitis C or other complications. Treatment was often ineffective, resulting in accelerated graft loss and death, as confirmed in this analysis. DAAs, by contrast, are well tolerated and recommended for all actively infected patients.[7,9,28] Based on national data and early follow-up, there is a consistent pattern of improved outcomes in LT recipients with HCV treated with DAAs. In KT recipients, treatment of HCV is less common than in LT recipients. However, a similar protective effect is noted in D+/R+ KT recipients, who have reduced mortality and, likely, graft loss if they receive posttransplant DAAs. Access to these expensive medications, however, appears limited, as <20% of D+/R+ LT and KT recipients receive them, and DAA treatment rates appear to be even lower among privately insured patients.

The availability of effective posttransplant HCV treatment allows LT and KT recipients to time treatment to achieve the greatest benefit.[24,29] Pretransplant patients who are precirrhotic or who have well-compensated disease may benefit from early HCV treatment with stabilization or regression of chronic liver disease, potentially avoiding LT entirely. Ahmed et al recently reported a Markov analysis comparing delayed or immediate HCV treatment among patients waiting for LT.[30] The benefit of HCV treatment varied according to clinical condition. Among patients with decompensated liver disease, pre-LT treatment was associated with improved survival (9.3 vs 8.7 quality-adjusted life-years) but higher costs ($304 800 USD vs $283 789 USD). Results were sensitive to MELD score at evaluation, such that pre-LT treatment was of less benefit to patients with greater decompensation. Decompensated patients may be further disadvantaged by pre-LT treatment, because the availability of HCV-infected donor organs has historically been significantly greater, allowing earlier transplant. Among patients with stable liver disease who undergo transplant due to hepatocellular carcinoma, immediate HCV treatment was associated with a gain of 11.5 quality-adjusted life-years vs 10.4 for delayed treatment; however, healthcare expenditures were increased by $82 000 USD per patient. Our data suggest that HCV treatment after transplant is no longer associated with a decrement in graft or patient survival, and may in fact be protective. In light of the organ shortage, reserving treatment of patients with decompensated cirrhosis until after LT may be clinically and economically beneficial, provided they have access to DAAs after transplant.

Dialysis patients infected with HCV are frequently encouraged to seek DAA treatment before transplant despite demonstrated efficacy of DAA in the posttransplant setting.[13,31] In recipients with available, compatible live donors, this strategy can be justified as it allows viral clearance prior to transplant, thereby avoiding potential posttransplant drug-drug interactions and mitigating risk of any early HCV-related complications (for example, new-onset diabetes). However, patients who are waiting for deceased donor organs may delay HCV treatment until after transplant to allow greater access to HCV+ donor organs, which is associated with a marked reduction in expected waiting times.[32] Importantly, these data are the first to suggest improved patient and allograft survival among HCV+ KT patients who are treated with DAAs early posttransplant, yet <15% of patients who receive a HCV D+ organ received timely DAA treatment.

The cost of HCV therapy with DAAs increased markedly compared with interferon and ribavirin. The cost of care is further increased for HCV patients with co-existing organ dysfunction. Patients with CKD or ESRD who require HCV treatment incur fourfold higher per member per month costs than HCV patients without ESRD ($5481 USD vs $1922 USD, P < .001). Despite these high costs, DAA treatment in the majority of patients has been found to be generally cost effective, with some regimens characterized as cost saving in the nontransplant population.[33,34] While early treatment regimens, such as those identified in this data set, were very expensive, competition from newly released agents has dramatically reduced the cost of treatment in an effort to increase market share. Treatment costs have also been reduced after shorter durations of care and have been demonstrated to be equally effective. A recent meta-analysis assessing the cost effectiveness of pretransplant treatment revealed that 71% of analyses found second-generation DAAs to be cost saving and 22% cost effective, while only 7% were not cost effective. Further savings may be expected through reduced graft loss and need for retransplantation (LT) and HCV-related kidney disease. Because use of kidneys from HCV-infected donors can markedly reduce wait times for transplant for HCV-infected kidney candidates, the cost-saving realized by a shorter dialysis burden in these patients must be accounted for as well, especially in regions associated with lengthy waiting times.[35] It is therefore unclear why access to treatment with DAAs should be limited for transplant recipients, who are even more likely to benefit from treatment than dialysis patients.[24,36]

This analysis has several key limitations. First, we lack information regarding viral load and genotype in both the pre- and posttransplant setting. Therefore, it is impossible to determine definitively which patients were actively infected at the time of transplant. This is particularly important in the current era, as HCV seropositivity in the absence of a positive NAT is consistent with virological cure, either related to prior administration of efficacious therapy or spontaneous clearance. This may account for the lower rate of utilization of HCV treatment in the post-DAA era among D-/R+ recipients. Second, the price of HCV medications has fallen since 2016 as new medications have been developed and marketed. This competition has resulted in somewhat lower costs for treatment regimens than reported in this analysis. Therefore, the reduced treatment access for privately insured patients that we found may have improved, as insurance companies start to develop new policies relating to DAAs. Third, despite our assembling the largest cohort reported of treatment in HCV+ recipients, the number of presumptively viremic patients (D+/R+) is still limited in this national study. This may limit inferences about the impact of treatment and comparisons of treatments. Additional data with longer periods of follow-up may provide important insight into the benefits of these treatments. Finally, among KT patients, the severity of HCV-related liver disease, an important outcome determinant, was unknown. However, in this large-scale analysis, it is unlikely to have differed between eras.

In conclusion, HCV treatment patterns have changed with the introduction of highly effective DAAs. Fewer HCV D-/R+ LT patients are treated in the posttransplant setting, because many may have been treated prior to transplant, while rates have increased for D+/R+ patients. In contrast to the reduced survival observed in LT patients treated in the pre-DAA era, HCV treatment with DAAs was not associated with poor outcomes in D+/R+ HCV+ LT recipients. Future studies capturing larger samples may demonstrate improved survival following DAA treatment. In KT patients, HCV treatment remains rare, but is more common in the DAA era and appears to improve outcomes in HCV+ KT recipients. Finally, DAAs were associated with a 10-fold increase in the cost of HCV treatment after LT and KT compared with medications in the pre-DAA era. These data suggest that patients with private insurance have reduced access to DAAs, which may result in higher rates of graft failure and death in patients who receive HCV+ donor organs or remain viremic at the time of transplant. Further study is needed to determine the optimal time and treatment strategy for transplant candidates and recipients infected with HCV.

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