HCV is a hepatophilic single-stranded positive-stranded RNA virus, and HCV infection can cause acute and chronic hepatitis with progressive liver damage, leading to cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). The World Health Organization estimates that there were 71 million chronic HCV infections worldwide in 2015, and 399,000 died from cirrhosis or HCC caused by HCV infection. In 2019, there were 58 million chronic HCV infections worldwide, 290,000 deaths from liver cirrhosis or HCC caused by HCV infection, and about 1.5 million new infections worldwide in 2019. Due to the large global HCV infection population, HCV-related end-stage liver disease and HCC remain the leading indications for liver transplantation.
With the advent of the pangenotype era of direct-acting antiviral drugs (DAAs), interferon-free pangenotypic protocols achieve more than 90% sustained virologic response (SVR) in HCV-infected patients with known major genotypes and major genotypes, including HCV-infected patients after organ transplantation, therefore, it can be assumed that HCV infection no longer affects the accessibility of organ transplantation and the outcome of organ transplantation. Despite the increasing proportion of organ donation and transplantation in recent years, the demand for transplanted organs still far exceeds the supply, coupled with the increasing availability and number of anti-HCV-positive donors, more and more ideas and research data consider the use of HCV viremia organs in HCV-negative recipients. This article will review HCV infection and organ transplantation.
1HCV-infected transplant recipient
1.1 肝移植
In 2016, the World Health Organization called for the elimination of HCV infections as a public health threat by 2030. Despite some progress, the World Health Organization estimates that 58 million people still have chronic hepatitis C, with about 1.5 million new infections and about 300,000 deaths each year. Several guidelines recommend that liver transplantation be considered first for patients with cirrhosis decompensation, especially those with a Model for End-Stage Liver Disease (MELD) score ≥ 18~20. Liver transplantation is also one of the curative treatments for HCC, especially for patients with small liver cancer who are decompensated and not suitable for surgical resection and ablation treatment.
DAAs currently used to treat chronic HCV infection are effective in both patients with advanced cirrhosis and post-liver transplantation. Data suggest that SVR significantly reduces the risk of progressive liver disease, cirrhosis decompensation, HCC, liver-related mortality, and all-cause mortality. Achieving SVR in patients with cirrhosis improves MELD scores.
In a modeling study by Chhatwal et al., the long-term prognosis of patients with MELD scores of 10~40 before and after liver transplantation was simulated using comprehensive data from the United Network for Organ Sharing and the SOLAR 1 and SOLAR 2 trials. The results of the study suggest that treatment of HCV prior to liver transplantation can increase life expectancy if the MELD score is ≤ 27, but life expectancy may be lower in patients with higher MELD scores. The International Liver Transplantation Society has also issued a consensus statement on the management of HCV in liver transplant candidates, indicating that patients with HCV-associated cirrhosis awaiting liver transplantation with a Child-Turcotte-Pugh grade B and/or MELD score of < 20 and no refractory portal hypertension can receive antiviral therapy, while a Child-Turcotte-Pugh grade C and/or MELD score is >Patients over 30 percent should not be treated with antiviral therapy. There are several additional factors that must be considered from the perspective of the liver transplant program and the patient. These factors include the projected transplant wait times in the region, the availability of HCV viremia donors, the availability of living donors, and the availability of DAA treatments. Therefore, the guidelines recommend that patients with liver cirrhosis who are waiting for liver transplantation and have a MELD score of <18~20 should start anti-HCV therapy as soon as possible before transplantation and complete the full course of treatment before transplantation. After treatment, the patient is further evaluated for improvement in liver function after obtaining an SVR, and may even be removed from the transplant waiting list if the improvement in liver function is significant. Patients waiting for liver transplantation with a MELD score of ≥18~20 should undergo liver transplantation first, followed by anti-HCV therapy after transplantation, but if the waiting time is more than 6 months, anti-HCV therapy can be given before transplantation on a case-by-case basis.
Decisions about the timing of HCV treatment are also complex in patients with HCV-associated HCC awaiting liver transplantation. Prenner et al. studied 421 patients with HCV cirrhosis, 33% of whom had active HCC or a history of HCC. The SVR rate was only 79% in patients with HCC compared with 88% in patients without HCC. Of the 29 HCC patients who did not achieve SVR, 93% had active tumor at the time of treatment. DAA treatment in patients with inactive tumors or after tumor resection/liver transplantation has a better SVR rate. These findings suggest that the primary predictor of DAA failure is the presence of active HCC at the time of treatment. The consensus statement of the International Liver Transplantation Society on HCV management indicates that HCV-infected patients with HCC combined with compensated cirrhosis or decompensated cirrhosis should receive antiviral therapy if they do not undergo liver transplantation within 3~6 months. Only those patients with HCV-related HCC and decompensated diseases who are expected to receive liver transplantation within 3~6 months are recommended to postpone DAA treatment.
After liver transplantation, cure of HCV is associated with a significant reduction in morbidity and mortality. For HCV reinfection or recurrence in patients after liver transplantation, timely antiviral therapy is closely related to all-cause mortality of patients. Due to the need for long-term use of immunosuppressants after transplantation, HCV recurrence or reinfection can significantly accelerate liver fibrosis, leading to cirrhosis and even liver failure in the transplanted liver. Therefore, patients with liver transplantation should be treated with antiviral therapy once they are HCV RNA positive. Serum levels of immunosuppressants should be monitored during or after anti-HCV therapy. Several studies have recommended that ledipavir/sofosbuvir (genotypes 1, 4, 5, 6) or sofosbuvir/velpatasvir (pan-genotype) can be used for HCV recurrence or reinfection after transplantation, without adjusting the dose of immunosuppressants.
In summary, patients with decompensated hepatitis C cirrhosis should receive anti-HCV therapy to prolong survival if liver transplantation is contraindicated or liver transplantation is not available. However, in order to optimize the prognosis of liver transplant candidates, the severity of liver disease must first be measured by the MELD score and the presence and stage of HCC must be considered. In addition, the expected wait time at the transplant center, the patient's prior treatment, and access to DAA therapy, remain important determinants of the timing of HCV treatment.
1.2 Non-hepatic solid organ transplantation
The proportion of HCV-infected patients with chronic kidney injury (CKD) is much higher than that of the general population, with 8.5% of HCV-infected patients aged 20~64 and 26.5% of HCV-infected patients over 65 years old co-occurring with CKD. The anti-HCV positivity rate in patients with CKD is also significantly higher than in the general population, and patients with HCV and CKD are at significantly increased risk of disease from other systems.
In a study of factors influencing the 10-year post-transplant survival of patients undergoing kidney transplantation, it was found that HCV infection was an independent prognostic factor affecting the 10-year post-transplant survival rate of kidney transplant patients, and chronic HCV infection was associated with a significant decrease in the survival rate of patients and grafts at 10 years after kidney transplantation. However, even in the pre-DAA era, transplantation had a clear survival advantage over continued dialysis for patients with chronic HCV infection. A systematic review and meta-analysis conducted by Ingsathit et al. showed that patients who continued dialysis had a higher risk of death compared with patients with chronic HCV infection who underwent kidney transplantation. In the wake of the era of DAA therapy, multiple studies in patients with end-stage renal disease and HCV infection after kidney transplantation have shown that multiple DAA regimens are safe and effective in this group of patients. Clinical trials and multiple real-world studies on the post-kidney transplant regimen have shown excellent efficacy and safety with several DAA regimens. In a phase II, open-label study, 114 kidney transplant recipients with genotype 1 or 4 HCV infection were randomized to receive DAA for 12 or 24 weeks, and all patients achieved SVR and treatment was well tolerated. In a Spanish cohort study, 103 kidney transplant recipients were treated with DAA after transplantation with an SVR of 98%. Several other cohort studies reported good outcomes after DAA treatment in kidney transplant recipients, with SVRs comparable to those in the non-transplant population.
The prevalence of HCV infection in thoracic organ transplant candidates has not been studied. Short-term results of DAA therapy have shown benefit of antiviral therapy in case reports of thoracic organ transplantation and in small case studies. All three patients after lung transplantation achieved SVR on sofosbuvir-based regimens, and had good drug tolerability, with no major adverse reactions or immunosuppressive drug dose adjustment requirements. Similar results were observed with DAA treatment in a group of 12 heart transplant recipients with chronic HCV infection. One patient with end-stage lung disease with chronic HCV infection also achieved HCV clearance after double lung transplantation. Although data are limited, the cure rate of DAA therapy in thoracic transplant recipients is expected to be similar to that of the general population and liver or kidney transplant patients, with higher cure rates.
As with liver transplantation, an important unresolved issue is the optimal timing of HCV therapy in patients who are candidates for kidney and other non-hepatic solid organ transplantation. Several studies have recommended early antiviral therapy in patients with renal failure awaiting kidney transplantation, as immunosuppressants given after transplantation can exacerbate and accelerate the progression of liver disease. For any recipient receiving DAA after transplantation, drug interactions and risk of rejection must be considered. Drug-drug interactions are an important factor to consider when choosing a DAA regimen. Overall, there are few significant drug interactions between immunosuppressants and DAAs. Patients with CKD stage 1~5 after kidney transplantation can choose ledipavir/sofosbuvir (genotypes 1, 4, 5, 6) or sofosbuvir/velpatasvir (pan-genotype) without adjusting the dose of immunosuppressants. The treatment regimen for patients after other solid organ transplantation is the same as that for patients after kidney transplantation.
2HCV-infected transplant donors
Although the proportion of organ donations and transplants has increased over the past few decades, the demand for organs still far exceeds the supply. Several strategies have been implemented to increase the donor pool: public health advocacy to increase organ donation, and increased utilization of high-risk donors. For high-risk donors, there is a good precedent for prophylactic therapy to prevent infection and/or post-breakthrough infection with the use of organs exposed to viral infections (e.g., cytomegalovirus or HBV); HCV-positive organ transplantation to anti-HCV positive recipients with HCV viremia is possible with approval by health authorities and signed informed consent by the recipient. Anti-HCV-positive donor transplantation has been used for chronic HCV recipients since the early 90s of the 20th century, however, the use of these organs in anti-HCV-negative recipients prior to DAA treatment resulted in high HCV transmission rates and reduced survival rates for patients and grafts. Over the past decade, the development of highly effective DAAs has made the treatment of HCV safe and successful, reducing the number of patients with chronic hepatitis C. The high safety and efficacy of DAAs in all genotypes, transplant recipients, and patients with renal failure, coupled with the increasing availability of anti-HCV-positive donors, have led some global transplant centers to employ various strategies for transplantation of HCV-infected organs into non-viral-infected recipients. Given that donors who die of drug overdose are often younger and have better organ function, this has the potential to significantly increase transplant rates and reduce organ transplant waiting list mortality;
2.1 肝移植
Two recent studies prospectively followed 80 HCV nonviremia recipients who underwent anti-HCV-positive nonviremia liver transplantation. HCV viremia was detected in 9 (11.5%) recipients after transplantation, and 7 received DAA, of which 6 patients acquired SVR (SRV12) at 12 weeks of treatment (2 patients who did not receive anti-HCV therapy died from non-HCV infection-related causes before antiviral therapy, and 1 patient who received DAA without SVR12 only completed treatment at the end of the observation period). These encouraging results lay the groundwork for the use of HCV viremia livers in non-viremia receptors. In a prospective study, 10 patients received a non-viraemic receptor from HCV viremia liver, followed by nucleic acid testing and, if positive, DAA therapy. As with kidney transplantation without DAA prophylaxis, HCV viremia is detectable after transplantation in 100% of patients. However, short-term results were excellent, with SVR12 of 100% and patient and graft survival of 100% at a median follow-up of 12.7 months. Similarly, two other prospective studies included a total of 16 HCV nonviremia liver transplant recipients, all of whom underwent liver transplantation in patients with HCV viremia, and viremia was detectable in 94% of post-transplant recipients. All patients were treated with DAA, and 13/16 of them reached SVR12 (3 patients were in different stages of treatment at the time of publication of the article), the survival rate of patients and grafts was 100%, and the median follow-up was 8~11 months. At the same time, a prospective, multicenter observational study included 34 HCV seronegative liver transplant recipients who received transplantation from HCV seropositive donors (20 HCV viremias and 14 nonviremias). Six patients underwent concurrent liver and kidney transplantation (SLK) and four patients underwent repeat liver transplantation. HCV viremia developed in HCV recipients who did not receive a nonviremia transplant. All 20 patients who received HCV viremia transplantation were diagnosed with HCV viremia within 3 days of liver transplantation. The median duration of DAA treatment was 27.5 days. All (20/20) patients completed treatment and achieved SVR12. The treatment was well tolerated and there were few adverse events.
Based on the above studies, the authors believe that liver transplantation of HCV seronegative recipients using HCV seropositive grafts is effective and well tolerated with antiviral therapy. Careful ongoing evaluation of patient and graft selection, as well as complications, and prompt initiation of antiviral therapy is recommended.
2.2 Elbow transplantation
A 2017 prospective trial conducted by THINKER and subsequent THINKER-2 in HCV viremia-negative kidney transplant recipients receiving kidneys from donors with genotype 1 HCV viremia included 20 kidney transplant patients. All patients had detectable HCV viremia after transplantation and were subsequently started with DAAs for 12 weeks (n=17) and DAAs plus ribavirin (RBV) for 16 weeks if NS5A resistance-associated loci (RAS) were present (n=3). All patients obtained SVR12, and allogeneic transplant kidney function at 6 months was better than that of the matched control group. SUBSEQUENT TRIALS (EXPANDERS) INCLUDE HCV GENOTYPE 1~3 AND PROPHYLACTIC TREATMENT REGIMENS. Patients were treated with DAAs for 12 weeks prior to transplantation, all patients achieved SVR12, and only 30% of patients developed detectable viremia after transplantation. In the DAPPeR trial, patients were treated with 1 DAA before transplantation and then continued 1 or 3 DAA treatments after transplantation: 17/50 (34%) patients developed detectable viremia 14 days after transplantation, and only 6/50 (12%) patients required treatment because 11 of these patients had self-limiting low-level viremia. Of these 6 patients, 5 achieved SVR12, 1 required increased RBV in week 2 due to resistance, and 2 relapsed and required re-second-line DAA therapy. The sixth patient failed second-line therapy and refused further treatment. The two most recent prospective studies achieved SVR12 with 10/10 (100%) and 30/30 (100%) prophylactic DAAs for 4 and 8 weeks, respectively.
In a prospective, real-world study of 77 HCV nonviremia recipients who received HCV viremia organs, including 64 kidneys, recipients were subjected to post-transplant nucleic acid testing to determine the need for treatment. Sixty-one patients (95 percent) developed HCV viremia after transplantation, 41 patients achieved SVR at the end of the study, and only one patient did not respond to initial treatment due to NS5A resistance-related loci. At a median follow-up of 8 months, the survival rate for patients and grafts was 98%. A review of data from the Organ Procurement and Transplantation Network registry from 2015 to 2019 compared patients with anti-HCV-positive viremia (n = 196) and non-viraemic patients (n = 349) with anti-HCV-negative non-viraemic donors, confirming the excellent short-term outcomes seen in these prospective trials, including better allograft function at 6 months, and no difference in 1-year graft survival or frequency of acute cell rejection (ACR).
2.3 Cardio-hypochronicular transplantation
The world's first prospective study using HCV viremia donor hearts included 11 patients with non-viremia recipients, 9 (85%) patients with detectable HCV viremia after transplantation, and DAA therapy was initiated at a median 33 days post-transplantation, achieving SVR12 in 100%. Several subsequent research centers reported their experiences with similar strategies. A total of 165 HCV nonviremia recipients were included, all of whom received hearts from HCV viremia donors, followed by nucleic acid testing, and if positive, were treated with various DAA regimens. 158/165 (96%) patients had HCV viremia with SVR12 after transplantation (4 patients died without viremia before completion of treatment, and 37 patients were in different stages of treatment at the time of publication). The reported 1-year survival rate is 91%~95%, with 8%~20% ACR, 1.5%~10% antibody-mediated rejection, and 0~43% of heart transplant vascular disease. No studies reported significant adverse events related to HCV or DAA. Similarly, analysis of an analysis of the Organ Sharing Joint Network from 2014 to 2018 showed no difference in primary transplant failure, acute rejection, post-transplant dialysis need, or 1-year survival among HCV viremia donors compared with non-HCV viremia donors. A recent retrospective analysis of adult heart transplant lists evaluated by the Joint Network for Organ Sharing database showed that the use of HCV-positive donor allografts can help optimize donor use and reduce wait-list mortality without affecting early survival. Ongoing evaluation is essential to ensure the long-term safety and efficacy of using HCV-positive donors.
The DONATE-HCV trial included eight HCV nonviremia recipients who received hearts from HCV viraemic donors immediately followed by four weeks of DAA therapy, while another single-center trial included 20 HCV nonviremia recipients who received one DAA prior to HCV viremia heart transplantation and eight weeks of DAA therapy after transplantation. Although HCV viremia was detectable after transplantation in 100% of patients, SVR12 was achieved in 27/28 patients (96%) (1 patient without viremia but had not reached SVR12 at the time of publication), and the 6-month survival rate for patients and grafts was 100%. Another trial evaluated the effects of a very short course of DAA, with 1 DAA treatment before transplantation and 7 days of DAA treatment after transplantation. The trial included 30 HCV nonviremia recipients who received organ transplantation from HCV viremia donors, including 13 lungs, 10 kidneys, 6 hearts, and 1 kidney-pancreas. HCV viremia was detected in 21/30 patients (67%) immediately after transplantation, however, no virus was detected in all patients 12 weeks after transplantation, suggesting that 7 days of treatment with a pan-genotype DAA after a prophylactic dose may be sufficient to prevent chronic HCV infection.
2.4 Lung transplantation
In a study of five lung transplants from HCV nonviremia recipients with rapidly deteriorating lung disease and HCV viremia donors, HCV viremia was detectable after transplantation in all patients and SVR was obtained after 12 weeks of DAA treatment. The median time to start treatment was 28 days, with no interruption of treatment and no adverse events related to HCV or DAA treatment.
Several studies of prophylaxis and shortening of the duration of DAA have been aimed at reducing the high rate of HCV transmission. The DONATE-HCV trial included 36 HCV nonviremia recipients who received lung transplantation from HCV viremia donors who were treated with DAA for 4 weeks. Viremia was detected in 34/36 (94%) patients after transplantation, and 28/28 patients achieved SVR at 6 months follow-up. Another single-center trial included 16 HCV nonviremia recipients who received 8 weeks of DAA treatment within 3 days of lung transplantation from an HCV viremia donor. Viremia was detectable after transplantation in 11/16 patients (69%) and achieved SVR12 in 100%. Another single-center trial compared in vitro lung perfusion of HCV nonviremia recipients who underwent HCV viraemic lung transplantation with or without UV irradiation: 11/11 (100%) and 9/11 (82%) patients had detectable viremia after transplantation, respectively, and 18 of these patients achieved SVR after 12 weeks of DAA therapy. Two other patients relapsed 8 and 12 weeks after completion of treatment, and one patient presented with fibrotic cholestatic hepatitis. In the end, both patients achieved SVR12 after receiving DAA combined with RBV.
2.5 HCV-positive donor selection
For HCV nucleic acid positive kidney donors, some pilot trials used cut-offs for the Kidney Donor Profile Index (KDPI), which is a measure of organ quality, but in the DAA era, HCV-infected donor kidneys were matched to non-HCV-infected donor kidneys on other KDPI metrics, with similar results. Similarly, for liver transplantation, a donor liver with fibrosis stage ≤2 on pre-transplant liver biopsy is acceptable, regardless of the donor's age. It is unclear whether other clinical factors influence donor selection and recipient outcomes, including duration of HCV infection, HCV viral load, HCV genotype, and prior HCV therapy.
2.6 Timing and regimen selection of anti-HCV therapy for HCV-negative recipients receiving HCV-positive donor organs
A cost-benefit analysis suggests that deferring HCV treatment and receiving HCV-infected kidneys is preferable to pre-transplant HCV treated and receiving HCV-non-viral kidneys, unless the additional waiting time for non-viral infected kidneys < 161 days. For patients with decompensated cirrhosis and chronic HCV infection, the decision to treat HCV before or after transplantation depends on the degree of liver dysfunction, as some patients may have liver function that improves enough to no longer require liver transplantation. Based on the comprehensive consideration of multiple studies, it is recommended that patients with a MELD score of <15 receive HCV treatment on the waiting list (except for refractory ascites), and patients with a MELD score of 25 > postpone HCV treatment until post-transplantation to increase their chances of transplantation. For patients with a MELD score of 15~25, a case study should be conducted taking into account the overall organ bank, expected waiting time, waiting list mortality, possibility of clinical improvement, and quality of life.
Pre-transplant prophylactic DAA therapy and a shortened post-transplant course of DAA appear to be as effective as standard DAA courses in preventing chronic HCV infection and can be cost-effective, but this remains an obstacle in practical application. Considering that DAA regimens initiated and given for 12 weeks or more after transplantation can achieve almost 100% SVR12, and that many patients require second-line DAA retreatment in short-term prophylaxis, some studies recommend waiting until patients transition to HCV viremia after transplantation and proceeding with a full 12-week course of treatment based on genotype and resistance testing.
3 Summary
Considering the significant incidence and mortality of HCV-associated liver disease, liver transplantation remains the top priority in HCV treatment. HCV was previously thought to have a negative long-term effect on both patients and graft survival in non-hepatic solid organ transplant recipients, and with the advent of the DAA era, liver and non-hepatic solid organ transplant recipients can be safely and effectively treated with new DAA regimens. This is expected to essentially eliminate the risk of liver and non-hepatic complications after hepatitis C transplantation.
The use of anti-HCV-positive organs can minimize discarded organs and significantly expand the available donor pool, reducing transplant waiting list time and increasing the chances of transplant access for patients on waiting lists, especially in areas with long waiting lists, which may significantly reduce overall waiting list morbidity and case fatality. In the era of DAA, this application has proven to be safe and effective. However, current research data on this application and long-term prognostic data for recipients are insufficient. Therefore, it is critical to determine the capacity of DAA therapy prior to transplantation, post-transplant drug interactions, and to ensure that patients are fully aware of the associated risks and transplant costs.
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引证本文 Citation
ZHANG Li, HU Peng . Hepatitis C virus infection and organ transplantation[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(4): 665-671
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