Some studies that had preliminary results presented as published abstracts at the 2019 ISHLT meeting represent important recent work, and a large number of patients who have been successfully treated. Though not suitable for our primary analysis, they provide important information about this topic and will be invaluable once the studies are fully completed. Four of them were integrated into the analysis of sustained viral response after 12 weeks (SVR-12). The summary of ongoing studies is shown in Table 2.
The 16 included studies consisted of 2 abstracts (Congress abstract/presentation), 7 case reports, 3 case series, and 4 cohort studies. The completeness of data provided was rated as sufficient in 5 (31%) publications and as good in the remaining 11 (69%).
Eleven out of 16 publications (68%) were written by research groups working in institutions in the United States.
Selected epidemiological and descriptive characteristics of the transplant recipients are described in Table 3. Four patients (8%) underwent a multiorgan transplantation, 3 of these patients (6%) received a combined heart-kidney transplant38,40,45 and 1 patient (2%) received a heart-liver transplant.34 The majority of patients (n = 16, 47%) received basiliximab as induction. The most commonly used maintenance immunosuppression was a combination containing tacrolimus (91%). Most centers used the same induction and maintenance immunosuppression protocol as per their usual practice without changing the dose or the timing of the immunosuppressive drugs.44
Eight different DAA regimes were used. A pan-genotypic regimen was used in 15 (21%) of all treated patients. Forty-five (80%) were treated for 12 weeks. In 7 patients (13%), 4 weeks of treatment was used.11
All patients treated with a complete course of DAA achieved RNA clearance between 1 and 12 weeks of therapy (Table 5).
Median time to clearance was 4 weeks. All surviving patients with available data achieved as SVR-12, which is an accepted criterion to determine HCV cure.47 One patient failed to reach viral clearance after cessation of the DAA drug in the context of a medication induced hepatitis.45 The longest follow-up was 18 months after DAA therapy with persistently negative RNA. No relapses were documented.
The presence of non-life-threatening complications was not systematically reported. In the publications that did report non-life threatening morbidity data, the adverse event rate was ~60% of patients,35 which is slightly lower than the adverse event rates reported in the Phase 3 DAA treatment studies.48
One study reported an interaction between ledipasvir/sofosbuvir and everolimus that required a dose reduction of the everolimus.35 Another study reported an interaction between daclatasvir/sofosbuvir(DCV/SOF) and both mycophenolate and tacrolimus resulting in a slightly decreased level of tacrolimus and an increased level of mycophenolate without requiring any dose adjustments.36
There were no documented cases of an interaction between DAA and the induction regime in our series.
In the setting of transplantation, DAA therapy appears to be safe and effective for the treatment of HCV. Despite the heterogeneity of the studies, there was no reported HCV relapse following complete DAA therapy. Nevertheless, it is worth noting that continued monitoring of viral loads posttreatment was reported in most series. In the THINKER trial that reported on kidney transplants from HCV-viremic donors to HCV-negative recipients, 1 patient had increased HCV viral loads on follow-up measurements during therapy because of DAA resistance and required a change in his DAA therapy.
Due to geographic variations in the prevalence of HCV genotypes, differences exist in national guidelines on the use of DAA for HCV. American guidelines recommend the use of a genotype-guided therapy,49 whereas in Australia a pan-genotypic combination is recommended as first-line treatment.50 Despite the differences in choice of DAA combinations, timing of initiation and duration of DAA therapy between studies, all studies reported 100% cure rate. None of the studies identified in this review reported prophylactic administration of DAA (commencing pretransplant) and only 1 study reported the use of a preemptive protocol in the first week posttransplant. Most studies documented HCV infection of the recipient (by NAT testing) before commencement of DAA therapy. This likely reflects the high cost of DAA therapy and the reimbursement arrangements that exist in countries where there is a requirement to prove HCV infection before commencing DAA therapy.
In the case of transplantation the use of a pan-genotypic is probably the optimal approach for prophylactic and preemptive treatment because of the expected delay in obtaining the genotype of the donor. It is worth noting that a pan-genotypic treatment is being utilized in 2 ongoing studies of DAA after transplantation as well as the most recent publication on the topic.11,12,16,24
The data regarding pharmacokinetic interactions between DAA and immunosuppression are also reassuring. Initiation of the DAA resulted in a significant change to biochemical drug levels in only 2 of 62 patients (3%); however, neither of these patients developed rejection. In an abstract addressing this question, no adjustment of immunosuppression was needed after DAA therapy was started.51 A recently published review on immunosuppression levels in patients undergoing DAA therapy confirmed this probable lack of interaction. No change in the drug levels were observed retrospectively when DAA were started.51
Moreover, if DAA therapy is administered early after transplantation, the risk of persistent sub- or supra-therapeutic levels of immunosuppression drugs is greatly reduced as immunosuppressive drug levels are routinely checked and titrated at regular intervals during this time period.
In this series, most of the patients (16 patients, 47%) received basiliximab as induction and no interaction between induction and DAA were reported, but it is worth mentioning that most of the patients (n = 33, 66%) did not receive DAA during the first week after transplantation. With the half-life of 30 days for Anti-thymocyte globulin (ATG)52 and 7 days for basiliximab, the absence of interaction between DAA and induction regime must be reviewed with some caution.
The risk of rejection due to the HCV viral load or treatment with DAA cannot be formally determined from published studies due to the heterogeneity of the data. However, 6 (14%) patients suffered from acute cellular or antibody-mediated rejection over the course of the DAA therapy. The rate of acute rejections in these studies is comparable with the available data on rejection in the absence of HCV or DAA.53
In a cohort of 25 patients, there was no significant difference in the observed rate of rejection (ISHLT grad >1R) between patients with DDHC and a control group. No correlation between viral load and rejection could be found.18 The long-term risk of chronic rejection is for the moment mostly unknown. One group has shown that patients who are viremic before initiation of DAA treatment have more marked intimal thickening shown on intravascular ultrasound of the left anterior descending coronary artery.46
The optimal timing of initiation of DAA and the duration of the therapy in the setting of transplantation of a noninfected patient with a HCV-infected heart is still not established.
In the patients reported in this review, most commenced treatment at first documentation of viremia. Seven patients (14%) received preemptive therapy (first day after transplantation) and none received prophylactic treatment as has been described in a recently published kidney transplant protocol9,10 and ongoing heart transplant study.24 As seen in the current review, the success of DAA therapy does not seem to be affected by the timing of initiation. Nevertheless, the long-term consequences of the initial viremic period are unknown, particularly the risk of hepatitis C-induced coronary arteriosclerosis,46,54 and the possibility of accidental transmission to medical staff should also be considered. In the context of immunosuppression, initial viremia may be extremely high and this could have negative consequences. Some data suggest a deleterious effect of the viremic load on the incidence of ISHLT-1R mild rejection (but not moderate and severe rejection)18 and there are 2 case reports of possible DDHC-associated pancreatitis in patient with high viral load before commencing DAA therapy.22
As demonstrated with kidney transplantation in the same setting, a prophylactic dose or a preemptive dose (given few h after transplant) could diminish or even completely suppress viral load.9-11
Regarding duration of therapy, international guidelines on DAA for HCV treatment recommend a duration of 8–12 weeks depending on the DAA regimen.55,56 The most recently published study on heart (and lung) transplantation from HCV-infected donors utilized a 4-week protocol of preemptive therapy with a pan-genotype combination commencing within hours of transplantation.11 Interestingly, nearly all recipients had detectable hepatitis C viremia immediately posttransplant but all patients achieved sustained viral clearance with no late relapses. While this study suggests that preemptive initiation of treatment may allow a shorter course of DAA to be administered, only 8 heart transplants were included in the study. A confirmatory study in a larger cohort of patients would be desirable before routinely advocating this regimen.
Given the observational nature of all the studies included in this review, there is a possible publication bias in favor of studies with positive outcomes. Nonetheless, the highly consistent conclusions of all published studies in relation to the efficacy of DAA and favorable clinical outcomes of heart transplant recipients with DDHC provides compelling evidence to support the use of NAT-positive hepatitis C donors for heart transplantation. Our review did not address the safety of heart transplantation from NAT-negative hepatitis C–seropositive donors; however, published data show that the risk of transmission of hepatitis C from these donors is very low.57
Based on this systematic review, we make the following conclusions and propose the following recommendations regarding protocols for heart transplantation from HCV viremic donors to HCV-negative recipients:
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