OPTN/SRTR 2018 Annual Data Report: Hepatitis C

Abstract

Direct acting antivirals (DAAs) have fundamentally changed the treatment of hepatitis C virus (HCV) infection and reduced the discard rate of HCV-infected organs by offering a treatment option with a high likelihood of cure posttransplant. This has spurred increased interest in transplanting organs from HCV-positive donors into recipients both with and without HCV. In this chapter, we examine data from 2007 to 2018 to determine trends in HCV (+) donor transplants across various organ types. Since 2015, willingness to accept HCV (+) organs increased for candidates waitlisted for kidney, lung, heart, and pancreas transplant, but decreased for those listed for intestine transplant. For candidates listed for liver transplant, willingness to accept HCV (+) organs decreased from 2007 to 2017, but began increasing in 2017. Willingness to accept was not concentrated in a single US geographic area, and there was substantial variation among transplant programs and donation service areas. Numbers of anti-HCV (+) donor kidney, heart, lung, and liver transplants have increased considerably in the past few years. Short-term allograft survival for kidney and liver transplant recipients of anti-HCV (+) organs appears to be comparable to that for recipients of anti-HCV (-) organs in an unadjusted analysis. However, an unadjusted analysis indicates that long-term allograft survival may be worse. Kidney transplant between HCV-infected donors and uninfected recipients with posttransplant DAA treatment is an emerging area. Short-term data are promising, with similar 1-year allograft survival compared with HCV-uninfected donor to HCV-uninfected recipient kidney transplants in unadjusted analyses. However, long-term data are lacking and close monitoring in the future is warranted.

Introduction

Chronic hepatitis C virus (HCV) infection is a major public health problem affecting millions of people worldwide. Historically, organs from deceased donors infected with HCV were rarely transplanted due to the risk of transmission of the virus through the allograft. Likewise, recipients with chronic HCV who underwent solid organ transplant had worse outcomes than their HCV (-) counterparts. In kidney transplant recipients, chronic HCV infection was associated with increased risk of complications, including transplant glomerulopathy, de novo glomerular disease, and new onset diabetes after transplant. In liver transplant recipients, recurrence of HCV increased the risk of cirrhosis and allograft failure.

The lack of an effective and well-tolerated treatment for HCV has historically limited the usability of HCV (+) organs in the general population, and the ability to perform transplants in HCV-infected patients. Pegylated interferon and ribavirin, the standard treatment prior to 2014, was associated with incapacitating side effects and low response rates. The vast majority of patients were not treated for HCV either before or after transplant because the regimen was contraindicated in patients with end-stage renal disease or decompensated cirrhosis, and interferon was associated with increased risk of acute allograft rejection.

The advent of direct acting antivirals (DAAs) revolutionized the treatment of chronic HCV. The first DAAs, approved by the US Food and Drug Administration in 2011, were protease inhibitors used in conjunction with pegylated interferon and ribavirin. In 2014, second-generation DAAs arrived, allowing a combination of an NS5B polymerase inhibitor and protease inhibitors without the need for interferon. Subsequently, several additional DAAs have become available, and DAAs have become increasingly effective over time, allowing more than 90% of patients to achieve sustained virological response (SVR, absence of detectable viremia 12 weeks after therapy completion), which has been equated with HCV cure. Although the cumulative experience with DAAs has been relatively brief, patients to date have experienced few adverse effects. With the latest regimens, some of which are effective against all HCV genotypes, high rates of SVR are achievable with treatment duration as short as 8 weeks.

Relevant to the transplant setting, modern DAAs remain highly effective even in previously difficult-to-treat populations, such as dialysis patients or kidney transplant recipients. Due to a persistent organ supply/demand mismatch, access to transplant remains limited and waiting times unacceptably long for all organ types. Thus, the availability of DAAs has sparked interest in the transplant community in increasing use of organs from HCV (+) donors for both HCV-infected and HCV-uninfected recipients in an effort to decrease waiting times. In this chapter, we report general trends in transplant for HCV (+) donors and recipients for all solid organs, with particular emphasis on kidney and liver transplants. Nomenclature is important here. A donor who is anti-HCV (+) may or may not be infected. In general, approximately two-thirds of anti-HCV (+) donors are nucleic acid test (NAT) positive. A donor who is HCV NAT (+) is viremic and infectious.

Trends in candidate willingness to accept an organ from an anti-HCV (+) donor

Distributions of adult waitlisted candidates willing to accept an organ from an anti-HCV (+) donor are shown by organ type from 2007 to 2018 (Figure HEP 1, Figure HEP 2, Figure HEP 3, Figure HEP 4, Figure HEP 5, Figure HEP 6). The proportion of kidney transplant candidates willing to accept a kidney from an anti-HCV (+) donor increased from 3.1% in 2007 to 14.2% in 2018. This increase began in 2014, coinciding with the arrival and expanded use of second-generation DAAs for HCV. Pancreas, heart, and lung transplant candidates showed parallel increases in willingness to accept organs from anti-HCV (+) donors, and approximately one-third of listed heart and lung candidates in 2018 consented to their use. Conversely, willingness to accept organs from anti-HCV (+) donors decreased among waitlisted liver and intestine transplant candidates. The proportion of willing liver transplant candidates declined from 48.3% in 2007 to a nadir of 20.7% in 2016 before increasing to 29.6% in 2018. Reasons for reduced interest among intestine and liver candidates are unclear, but we speculate that they might relate to shorter waiting times for intestine transplants compared with waiting times for other organs and concern about potentially infecting liver transplant recipients with HCV.

Willingness to accept an organ from an anti-HCV (+) donor varied substantially across transplant programs, donation service areas (DSAs), Organ Procurement and Transplantation Network (OPTN) regions, and states. Geographic heat maps displaying adult waitlisted candidate willingness to accept anti-HCV (+) organs by candidate’s DSA and OPTN region are shown for kidney and liver for 2012 and 2018. (Figure HEP 7, Figure HEP 8, Figure HEP 9, Figure HEP 10, Figure HEP 11, Figure HEP 12, Figure HEP 13, Figure HEP 14)

Kidney

Some areas across the US report high willingness to accept anti-HCV (+) kidneys (Ohio, Michigan, Illinois, New York, Arizona, Oregon, and portions of the central and southeastern United States). Among OPTN regions, willingness to accept ranged from 2.7% to 30.1% in 2018. In 2018, 27 transplant programs reported that more than 50% of waitlisted candidates were willing to accept an anti-HCV (+) kidney. Across all programs, willingness ranged from 0% to 100%, and was more common in 2017-2018 than in 2007-2008 (Figure HEP 15). Even across Department of Veterans Affairs transplant programs, willingness patterns were heterogeneous, ranging from 67.8% to 0%. Program kidney transplant volume had at best only a weak correlation with willingness to accept an anti-HCV (+) kidney, depending on year.

Characteristics of adult waitlisted candidates willing to accept anti-HCV (+) donor kidneys are shown in Table HEP 1. Given that a primary benefit of accepting an anti-HCV (+) kidney is substantially reduced waiting time, candidates with long anticipated waiting times, for example due to blood type or minimal accrued waiting time, would theoretically derive the most benefit from accepting anti-HCV (+) kidneys. As expected, kidney transplant candidates willing to accept anti-HCV (+) kidneys were more likely to have waited less than 1 year (76.9% vs. 55.0%), to be pre-dialysis (21.9% vs. 18.6%) or have less than 3 years of dialysis time (73.5% vs. 60.1%), to be of black race (39.2% vs. 30.1%), or to have blood type B (15.9% vs. 15.3%) or O (51.0% vs. 49.9%), compared with unwilling candidates.

Liver

Liver transplant programs reported candidate willingness to accept anti-HCV (+) donor livers ranging from 0% to 100% in 2018. Willingness to accept was less common in 2017-2018 than in 2007-2008 (Figure HEP 3, Figure HEP 16). Variability was substantial across DSAs and OPTN regions, similar to variability in willingness to accept anti-HCV (+) kidneys. These observations suggest that willingness to accept an anti-HCV (+) kidney or liver is not dependent on geographic location but is heavily influenced by the particular transplant program where candidates are listed.

Fewer differences were noted between liver transplant candidates willing and unwilling to accept anti-HCV (+) organs than among kidney transplant candidates (Table HEP 2). Willing candidates were more likely to be aged older than 50 years (83.0% vs. 76.0%) or to be of black race (10.3% vs. 7.5%). In contrast to kidney candidates, there was virtually no difference in willingness to accept by ABO blood type. A greater proportion of unwilling candidates had model for end-stage liver disease scores 35 or higher, compared with willing candidates (14.2% vs. 12.1%).

Trends in use of HCV (+) donors

Distributions of transplants by donor HCV status (anti-HCV [+] or NAT[+]) are shown for kidney, liver, heart, and lung (Figure HEP 17, Figure HEP 18, Figure HEP 19, Figure HEP 20, Figure HEP 21, Figure HEP 22, Figure HEP 23, Figure HEP 24). Graphs for pancreas and intestine are not shown because for each only one transplant from an anti-HCV (+) donor occurred. Data are shown from 2007 to 2018 for anti-HCV (+) but only from 2015 to 2018 for NAT (+) as NAT profiles are available only after 2015, when United Network for Organ Sharing mandated that organ procurement organizations check and report donor NAT status.

Kidney

Kidney transplants using anti-HCV (+) donors have steadily increased since 2014, from 290 that year to 977 in 2018. Similarly kidney transplants using HCV NAT (+) donors also increased, from 275 in 2015 to 570 in 2018; 59.2% of HCV NAT (+) kidneys in 2018 were transplanted into HCV (-) recipients. While use of kidneys from HCV (+) donors is increasing, transplants of these organs still comprise a small fraction of all kidney transplants performed each year. In 2018, 6.9% and 4.0% of all kidney transplants were from anti-HCV (+) and NAT (+) donors, respectively. From 2016 to 2018, nationally 1151 donor anti-HCV (+) to recipient anti-HCV (+) (D+/R+) and 979 donor anti-HCV (+) to recipient anti-HCV (-) (D+/R-) kidney transplants were performed. Only 58% of anti-HCV (+) kidney donors in 2018 were NAT (+) and truly infected, illustrating the importance of using NAT instead of anti-HCV when classifying donors. The number of HCV NAT (+) donor to anti-HCV (-) recipient kidney transplants also increased across most OPTN regions, even from 2017 to 2018. (Figure HEP 25, Figure HEP 26).

Similar to willingness to accept, practice patterns related to use of anti-HCV (+) kidneys varied widely by transplant program, DSA, OPTN region, and state (Figure HEP 25, Figure HEP 27). The states with the highest use of anti-HCV (+) kidneys were California, Florida, Maryland, New York, Ohio, Pennsylvania, and Tennessee, each of which transplanted over 100 such kidneys from 2016 to 2018. Conversely, 15 states performed 10 or fewer kidney transplants using anti-HCV (+) donors. Geographic variation in prevalence of HCV infection in the US may account for this geographic difference in use of anti-HCV (+) kidneys. State-level variation in HCV infection prevalence may also explain the imperfect correlation between percentages of programs willing to accept HCV (+) kidneys and actual numbers of anti-HCV (+) donor kidney transplants performed. Transplant programs located in states with low prevalence of HCV infection likely receive fewer anti-HCV (+) offers than programs in states with high prevalence, regardless of how many waitlisted candidates have agreed to receive an HCV (+) kidney.

Liver

Although the proportion of patients willing to accept anti-HCV (+) livers had decreased until recently, the number of liver transplants using anti-HCV (+) or NAT (+) donors actually increased, with a sharp rise in 2015 similar to that seen for anti-HCV (+) kidneys. In 2018, 644 liver transplants were performed from anti-HCV (+) donors, compared with 308 in 2014. A total of 418 liver transplants used HCV NAT (+) donors in 2018, compared with 236 in 2015 (Figure HEP 19, Figure HEP 20).

From 2016 to 2018, a total of 1272 D+/R+ liver transplants were performed (Figure HEP 28), the highest numbers in California, Maryland, New York, Ohio, and Pennsylvania. As with kidneys, reported willingness to accept an anti-HCV (+) liver did not necessarily correlate with the number of anti-HCV (+) donor liver transplants performed. Less common were the 458 D+/R- liver transplants performed between 2016 and 2018.

Lung/Heart

Lung and heart transplants using anti-HCV (+) donors have been much less common than kidney and liver transplants, and almost never performed in the pre-DAA era except under extraordinary circumstances. Prior to 2016, only 11 anti-HCV (+) donor heart transplants and 5 anti-HCV (+) donor lung transplants were performed. Although heart and lung transplant programs have increased their use of anti-HCV (+) and HCV NAT (+) donors in recent years, the increase began in 2017, later than at kidney and liver programs. Given that so few lung and heart transplants using anti-HCV (+) donors have been performed, trends in geographic variation are not yet evident.

Allograft survival using anti-HCV (+) organs

Kidney

Studies conducted prior to the availability of DAAs indicated that transplanting kidneys from anti-HCV (+) donors was associated with worse allograft outcomes compared with transplanting kidneys from HCV (-) donors. Data from recipients who underwent transplant in 2013 appear to support these reports. Although early allograft survival of anti-HCV (+) donor allografts was similar or even slightly better than survival of anti-HCV (-) donor allografts (95.1% vs. 93.3% at 1 year), 5-year allograft survival was worse (73.3% vs. 79.1%) in an unadjusted analysis (Figure HEP 29). When stratified by donor and recipient hepatitis status, 1-year allograft survival for anti-HCV (-) recipients who received anti-HCV (+) donor organs again was better than for other donor/recipient pairings (D+/R+ 94.9% vs. D+/R- 96.2% vs. D-/R+ 89.9% vs. D-/R- 93.5%) in an unadjusted analysis, but 5-year allograft survival was worse (D+/R+ 74.1% vs. D+/R- 69.2% vs. D-/R+ 74.1% vs. D-/R- 79.4%) (Figure HEP 30). However, these transplants occurred during the infancy of the DAA era. The majority of these patients were likely not treated for their HCV infection or were treated several years after the transplant, and the well-described adverse effects of chronic HCV infection posttransplant likely contributed to the worse long-term allograft survival.

Data from transplant recipients in 2016 to 2017, which more likely reflect current practice and stratify donors by NAT status so viremic donors are identified, show better 1-year unadjusted allograft survival for D+/R- kidney transplant recipients than for the other pairings, similar to the 2013 data (D+/R- 95.8% vs. D-/R- 94.7% vs. D+/R+ 93.5% vs. D-/R+ 93.6%) (Figure HEP 31). Allograft survival was worst for HCV-infected recipients, regardless of donor HCV status, which may suggest that the recipient’s HCV status is more important than the donor’s. Data regarding which NAT (+) donor kidney transplant recipients were treated with DAAs posttransplant are not available in the SRTR database; however, most were likely treated with DAAs. It is plausible that long-term allograft survival will be better for patients undergoing transplant in the post-DAA era than for the older cohort, but this should be closely monitored.

Liver

In an unadjusted analysis, 5-year allograft survival was slightly worse for patients who received a liver from an anti-HCV (+) donor than for those who received a liver from an anti-HCV (-) donor in 2013 (74.9% vs. 76.7%), and 1-year allograft survival was slightly better (90.7% vs. 89.1%) (Figure HEP 32). Using a more recent cohort of recipients from 2013 to 2017, the 1-year unadjusted allograft survival differential increased to 92.2% vs. 89.9% for donor anti-HCV (+) vs. donor anti-HCV (-). When the same cohort was stratified by donor/recipient grouping, 1-year unadjusted allograft survival was better for HCV-infected recipients who received an anti-HCV (+) liver than for the other pairings (D+/R+ 92.5% vs. D+/R- 89.9% vs. D-/R- 89.8% vs. D-/R+ 89.8%) (Figure HEP 33). Overall, unadjusted allograft survival was better at 1 year for 2017 liver transplants from HCV NAT (+) donors than from uninfected donors (92.3% vs. 91.1%). The highest unadjusted 1-year allograft survival was for HCV NAT (+) donor to HCV NAT (-) recipient in 2017 (D+/R- 94.6% vs. D+/R+ 93.4% vs. D-/R+ 91.1% vs D-/R- 90.4%), but these data are limited, as few D+/R- transplants were performed (Figure HEP 34). Differences in donor and recipient factors likely affected the observed allograft survival; adjusting for these characteristics is an important future investigation.

Conclusion

In the past few years, waitlisted candidates across all organ types except intestine have been more willing to accept organs from anti-HCV (+) donors, and use of anti-HCV (+) donors has increased across kidney, heart, lung, and liver transplant. Both of these observations are likely due to the increasing availability of DAAs, which have been shown to be highly effective in curing HCV infection. Short-term kidney and liver allograft survival in recipients of anti-HCV (+) organs is similar to that in recipients of anti-HCV (-) organs in unadjusted analyses. While long-term HCV (+) allograft outcomes are yet to be determined, increasing use of these organs, including NAT (+) organs, increases the pool of available organs and improves access for all candidates awaiting a life-saving transplant.

Figure List

Waiting list

Figure HEP 1. Distribution of adults waiting for kidney transplant by willingness to accept an HCV+ organ
Figure HEP 2. Distribution of adults waiting for pancreas transplant by willingness to accept an HCV+ organ
Figure HEP 3. Distribution of adults waiting for liver transplant by willingness to accept an HCV+ organ
Figure HEP 4. Distribution of adults waiting for intestine transplant by willingness to accept an HCV+ organ
Figure HEP 5. Distribution of adults waiting for heart transplant by willingness to accept an HCV+ organ
Figure HEP 6. Distribution of adults waiting for lung transplant by willingness to accept an HCV+ organ
Figure HEP 7. Percent willing to accept HCV+ kidney in listing DSA, 2012
Figure HEP 8. Percent willing to accept HCV+ kidney in listing DSA, 2018
Figure HEP 9. Percent willing to accept HCV+ kidney in listing region, 2012
Figure HEP 10. Percent willing to accept HCV+ kidney in listing region, 2018
Figure HEP 11. Percent willing to accept HCV+ liver in listing DSA, 2012
Figure HEP 12. Percent willing to accept HCV+ liver in listing DSA, 2018
Figure HEP 13. Percent willing to accept HCV+ liver in listing region, 2012
Figure HEP 14. Percent willing to accept HCV+ liver in listing region, 2018
Figure HEP 15. Percent willing to accept HCV+ kidney by listing center, 2007-2008 vs 2017-2018
Figure HEP 16. Percent willing to accept HCV+ liver by listing center, 2007-2008 vs 2017-2018

Transplant

Figure HEP 17. Kidney-alone transplants from anti-HCV+ donors
Figure HEP 18. Kidney-alone transplants from HCV NAT+ donors
Figure HEP 19. Liver transplants from anti-HCV+ donors
Figure HEP 20. Liver transplants from HCV NAT+ donors
Figure HEP 21. Heart transplants from anti-HCV+ donors
Figure HEP 22. Heart transplants from HCV NAT+ donors
Figure HEP 23. Lung transplants from anti-HCV+ donors
Figure HEP 24. Lung transplants from HCV NAT+ donors
Figure HEP 25. HCV NAT+ donor transplants to anti-HCV- kidney recipients by recipient region, 2017
Figure HEP 26. HCV NAT+ donor transplants to anti-HCV- kidney recipients by recipient region, 2018
Figure HEP 27. HCV NAT+ donor transplants to anti-HCV- kidney recipients by recipient DSA, 2016-2018
Figure HEP 28. HCV NAT+ donor transplants to anti-HCV- liver recipients by recipient DSA, 2016-2018

Outcomes

Figure HEP 29. Graft survival among adult kidney transplant recipients, 2013, by donor HCV Ab status
Figure HEP 30. Graft survival among adult kidney transplant recipients, 2013, by donor and recipient HCV Ab status
Figure HEP 31. Graft survival among adult kidney transplant recipients, 2016-2017, by donor HCV NAT and recipient HCV Ab status
Figure HEP 32. Graft survival among adult liver transplant recipients, 2013, by donor HCV Ab status
Figure HEP 33. Graft survival among adult kidney transplant recipients, 2016-2017, by donor and recipient HCV Ab status
Figure HEP 34. Graft survival among adult liver transplant recipients, 2016-2017, by donor HCV NAT and recipient HCV Ab status

Table List

Waiting list

Table HEP 1. Demographic characteristics of adult candidates on the kidney transplant waiting list by willingness to accept an HCV+ kidney
Table HEP 2. Demographic characteristics of adult candidates on the liver transplant waiting list by willingness to accept an HCV+ liver

Table HEP 1. Demographic characteristics of adult candidates on the kidney transplant waiting list by willingness to accept an HCV+ kidney
Adult candidates waiting for kidney transplant at any time in the given year. Excludes kidney-pancreas listings. Candidates listed concurrently at multiple centers are counted once. Age is determined at the later of listing date or January 1 of the given year. Active and inactive candidates are included.

Characteristic	Will Accept HCV+, N	Will Accept HCV+, Percent	Will Not Accept HCV+, N	Will Not Accept HCV+, Percent
Age: 18-34 years	1975	9.1%	20,701	10.5%
Age: 35-49 years	5372	24.8%	50,711	25.7%
Age: 50-64 years	10,290	47.4%	85,153	43.1%
Age: ≥ 65 years	4056	18.7%	40,994	20.8%
Race/ethnicity: White	8640	39.8%	79,119	40.0%
Race/ethnicity: Black	8501	39.2%	59,448	30.1%
Race/ethnicity: Hispanic	3221	14.8%	38,766	19.6%
Race/ethnicity: Asian	1004	4.6%	16,803	8.5%
Race/ethnicity: Other/unknown	327	1.5%	3423	1.7%
Blood type: A	6547	30.2%	61,730	31.2%
Blood type: B	3458	15.9%	30,223	15.3%
Blood type: AB	628	2.9%	6990	3.5%
Blood type: O	11,060	51.0%	98,616	49.9%
Wait time: < 1 year	16,672	76.9%	108,571	55.0%
Wait time: 1-< 2 years	1808	8.3%	23,621	12.0%
Wait time: 2-< 3 years	1251	5.8%	19,672	10.0%
Wait time: 3-< 4 years	750	3.5%	14,614	7.4%
Wait time: 4-< 5 years	446	2.1%	10,482	5.3%
Wait time: ≥ 5 years	766	3.5%	20,599	10.4%
Dialysis time: None	4749	21.9%	36,811	18.6%
Dialysis time: < 1 year	3790	17.5%	26,925	13.6%
Dialysis time: 1-< 3 years	7409	34.2%	54,992	27.8%
Dialysis time: 3-< 5 years	2787	12.8%	32,636	16.5%
Dialysis time: ≥ 5 years	2958	13.6%	46,195	23.4%

Table HEP 2. Demographic characteristics of adult candidates on the liver transplant waiting list by willingness to accept an HCV+ liver
Adult candidates waiting for liver transplant at any time in the given year. Candidates listed concurrently at multiple centers are counted once. Age is determined at the later of listing date or January 1 of the given year. Active and inactive candidates are included.

Characteristic	Will Accept HCV+, N	Will Accept HCV+, Percent	Will Not Accept HCV+, N	Will Not Accept HCV+, Percent
Age: 18-34 years	579	3.8%	2823	6.3%
Age: 35-49 years	1997	13.2%	7949	17.7%
Age: 50-64 years	9572	63.3%	24,626	54.9%
Age: ≥ 65 years	2982	19.7%	9461	21.1%
Race/ethnicity: White	10,054	66.5%	31,541	70.3%
Race/ethnicity: Black	1552	10.3%	3383	7.5%
Race/ethnicity: Hispanic	2528	16.7%	7211	16.1%
Race/ethnicity: Asian	702	4.6%	2146	4.8%
Race/ethnicity: Other/unknown	294	1.9%	578	1.3%
Blood type: A	5742	38.0%	16,817	37.5%
Blood type: B	1785	11.8%	5550	12.4%
Blood type: AB	470	3.1%	1702	3.8%
Blood type: O	7133	47.1%	20,790	46.3%
Wait time: < 1 year	12,039	79.6%	35,366	78.8%
Wait time: 1-< 2 years	1010	6.7%	3433	7.7%
Wait time: 2-< 3 years	502	3.3%	1687	3.8%
Wait time: 3-< 4 years	373	2.5%	1172	2.6%
Wait time: 4-< 5 years	256	1.7%	832	1.9%
Wait time: ≥ 5 years	950	6.3%	2369	5.3%
Medical urgency: Status 1A	332	2.2%	1037	2.3%
Medical urgency: MELD ≥ 35	1830	12.1%	6376	14.2%
Medical urgency: MELD 30-34	1264	8.4%	4181	9.3%
Medical urgency: MELD 15-29	7152	47.3%	21,422	47.8%
Medical urgency: MELD < 15	3456	22.8%	10,333	23.0%
Medical urgency: Unknown	1096	7.2%	1510	3.4%