在2017 and 2018, the pilot studiesTHINKERandEXPANDER-1introduced the practice of transplanting kidneys from donors infected with HCV (HCV D+) into uninfected recipients (HCV R-). By utilizing pre-emptive or early treatment initiation with DAA’s and a 12-week course of therapy, all recipients in these studies (N=30) were either cured of HCV or (in a few patients) HCV was not transmitted at all. Kidney function at 6 (EXPANDER-1) and 12 months（Thinker-2）很棒，没有重大的不利事件。在2020年，twootherstudies performed in a clinical trial setting were published, showing similar results. The table below summarizes these studies.
Research versus Real-World Setting
The promising results from these small clinical trials bring up the question as to whether this data is sufficient to implement HCV D+/R- kidney transplantation in a real-world or “standard of care” setting. Indeed, more than a handful of US transplant programs have adopted this practice outside of clinical trials or research studies. A研究检查美国注册表数据from April 2015 to March 2019 found that utilization of HCV+ kidneys increased over the study period, and there was a dramatic increase in the allocation of HCV+ kidneys to HCV- recipients, particularly in theSoutheast and Mid-AtlanticUnited Network for Organ Sharing regions. A对美国肾脏移植程序的调查发现对调查做出响应的112个计划（占美国计划的54％），有58％的计划提供了HCV D+/r-肾脏移植，而14％的计划则将其作为“护理标准”。
A big difference, however, with HCV D+/R- transplantation in the real-world setting versus in a clinical trial or research setting is that unlike in clinical trials or research studies, DAA therapy is usually not available prior to or early after transplantation unless it is provided (and paid for) by the transplant center. Third-party payers currently do not cover DAA therapy prior to transplantation. Therefore, assuming transplant centers are unwilling to incur the upfront cost of DAA therapy, the order of events are usually to:
- Perform the transplant
- Obtain third-party payer approval for DAA, and finally
The delay in DAA treatment in this scenario results in sustained recipient HCV viremia forat least a few weeks.为什么this a problem? Two major potential concerns have been raised:
- HCV-induced immunologic activationwith a resultant increased risk for acute rejection and infections with CMV and BK, and
- Risk of serious and life-threatening complications such asfibrosing cholestatic hepatitis(FCH).
Additional concernsthat have been brought up regarding HCV D+/R- transplantation in the real-world setting include the possibility of denial of DAA coverage by third party payers, and suboptimal oversight with regards to patient education and the consent process.
Last year,Molnar及其同事reported their single center real-world experience with 53 patients and 6-month outcomes. All patients in their cohort were able to access DAA and achieved SVR-12 after treatment, which is considered a cure. Patients were initiated on DAA therapy at a median of 76 days post-transplant. Among the 53 patients, one patient developed FCH, 60% of patients had documented CMV viremia and 34% of patients had BK viremia. In another single center real-world experience,卡皮拉和同事reported outcomes in 64 kidney transplant recipients. Among the 58 who had started or completed DAA therapy, only one patient did not respond to DAA due to nonstructural protein 5A resistance. The SVR-12 rate remained excellent, at 98%. The median time to initiation of DAA therapy post-transplant in this cohort was 72 days. Importantly, two patients developed FCH and there was one death.
在theircurrent AJKD article, Molnar and colleagues expand on their previous report and include 65 HCV- recipients of HCV+ kidneys in 2018 with 12-month follow-up data, focusing on kidney outcomes. Compared to 59 recipients at their center who received HCV- kidneys in 2018, they found no difference in post-transplant eGFR, acute rejection rates, and development of donor specific antibodies. One patient in the HCV+ group had biopsy-proven BK nephropathy. At 12 months after receipt of HCV+ kidneys, mean eGFR was 64 ml/min/1.73m2. In addition, all patients were able to access DAA and achieve SVR-12. The authors noted an improvement in timeliness to initiation of DAA treatment over the study period, and stated that their center’s current time between transplantation and treatment initiation is approximately 3-4 weeks.
Do Benefits Outweigh Risks in the Real-World?
Taken together, the published experiences of HCV D+/R- kidney transplantation in a real-world setting are certainly intriguing, and despite the 2 to 3 month delay in initiation of DAA treatment resulting in sustained HCV viremia, the outcomes appear promising. Molnar and colleagues’ current study provides some reassurance regarding the lack of any increased risk of adverse kidney outcomes, including acute rejection and graft loss. However, one must be cognizant that the number of participants in this study remains relatively small and that it carries the limitations of being a retrospective single-center study.
很容易说需要更多数据，因为这肯定是正确的（稍后再详细介绍）。但是，当我们等待未来的潜在多中心研究, is the available data sufficient to continue with this real-world practice? Of course, it boils down to weighing risks versus benefits, and weighing these risks versus “other risks”.
- 继续进行这种做法的最强烈的“好处”论点是，它使我们能够最大程度地利用HCV+肾脏，帮助减轻器官短缺，并增加移植的机会>90,000 patientswaiting on the deceased donor list.当然有空间，如研究OPTN数据这发现与HCV肾脏相比，2019年的HCV+肾脏仍被丢弃48％。
- What about risks? Based on Molnar and colleagues’ experience, the risks appear to be minimal with regards to kidney adverse events. However, there remains a signal forincreased rates of CMV and BK infectionand the rare possibility of developing FCH (cumulatively, 3 cases have been reported in the literature).
- As mentioned above, the risks associated with HCV D+/R- transplantation in the real-world must also be weighed against “other” risks, specifically those associated with delaying transplantation and prolonging a patient’s waiting time by turning down HCV+ kidneys.
病人对这个问题的看法如何？在一个conjoint analysisof 189 kidney transplant candidates conducted at 2 transplant centers where participants were presented with 12 hypothetical decisions about accepting HCV+ kidneys under varying scenarios, participants were more likely to accept a HCV+ kidney with higher cure rates, a younger donor, and a longer waiting time for a HCV- kidney. These are important parameters for transplant programs to consider when discussing risks and benefits with transplant candidates during the consent process and when selecting suitable HCV+ deceased donors.
It is worth mentioning that preliminary experience on a prophylactic approach to therapy with shorter courses of DAA have also been published? In a单中心试验试验利用泛基因型DAA，有10例患者在移植前接受了1剂Sofosbuvir/velpatasvir，并在术后第1天接受了另一种剂量。与此同时，40名患者在移植之前接受了1剂Sofosbuvir/velpatasvir，在移植之前和3天接受了3剂。3.总体病毒传播率为12％，为期4天的策略较低，为7.5％。那些患有病毒血症的人接受了为期12周的DAA课程。但是，2名患者需要第二个DAA和1例患者未达到SVR-12。在另一项研究的四周课程glecaprevir / brentasvir广告ministered to 10 patients, with the first dose given prior to transplant. All recipients had undetectable viremia by postoperative day 7. This study makes the argument that perhaps a 4-week (versus 12-week) pre-emptive or “prophylactic” course of DAA therapy is sufficient. This is important because a 4-week course would be less costly, and if outcomes are non-inferior to the standard 8-12 week course of DAA therapy, then transplant centers or third-party payers may be more willing to cover the upfront cost of DAAs prior to transplantation.
Many questions remain. Future studies will need to determine:
- The optimal duration of therapy
- How to optimize patient selection—are there patients who are more likely to benefit (eg, those with expected prolonged waiting time)? Are there those that are more likely to be harmed (eg, those with pre-existing liver disease, older patients)?
在the future, answering these questions and incorporating cost-effectiveness data (previously reviewed in anotherblog post) will likely form the basis of third-party payer’s approval for DAAs prior to transplantation.
The field of HCV and kidney transplantation continues to evolve rapidly. The practice of HCV D+/R- transplantation has been truly innovative, with an immediate and direct impact on numerous patients who have been awaiting transplantation. Efforts should continue to fine-tune this practice, and cumulative experience along with well-designed studies will ultimately allow us to provide our patients with the best possible outcomes.
Authors:Miklos Z. Molnar, Ambreen Azhar, Makoto Tsujita, Manish Talwar, Vasanthi Balaraman, Anshul Bhalla, Pradeep S.B. Podila, Jiten Kothadia, Uchenna A. Agbim, Benedict Maliakkal, Sanjaya K. Satapathy, Csaba P. Kovesdy, Satheesh Nair, James D. Eason