Are Hepatitis C-Infected Hearts and Lungs Safe to Transplant?

-Study suggests yes, thanks to direct-acting antivirals



Questions Addressed:

• Could hearts and lungs from patients with HCV viremia be safely transplanted into uninfected recipients?

• What was the benefit/risk profile of prompt, post-transplantation treatment of recipients with a pan-genotypic, direct-acting antiviral regimen?

Study Synopsis and Perspective:

Prompt post-transplantation prophylaxis with a 4-week, pan-genotypic, direct-acting antiviral regimen enabled the safe transplantation of HCV-infected hearts and lungs into uninfected recipients, with an undetectable viral load and generally excellent patient and allograft outcomes in the short term, according to pilot study results.

Although organ donation has increased by 20% in the last 5 years – mainly due to more donors having died from a drug overdose -- HCV-positive donated organs are usually discarded because of concerns about infection spread, explained Ann E. Woolley, MD, of Brigham and Women's Hospital in Boston, and colleagues, writing online in the New England Journal of Medicine.

Approximately 2.7 million to 3.9 million people in the U.S. have chronic hepatitis C, making HCV the most common chronic bloodborne infection in the country. If hearts and lungs from HCV+ donors could successfully be used, it could expand the donor pool by at least 25%, Woolley said.

Every day an estimated 20 people die waiting for a transplant. In 2018 alone, only 36,528 transplants were performed in spite of the fact that the waiting list exceeded 113,000 patients. In addition, heart failure cases have risen rapidly in the U.S., while the number of annual heart transplants has remained constant over the last decade.

Treatment of HCV infection early after transplantation with potent direct-acting antiviral agents proved feasible in early data on patients who had received liver and kidney transplants from HCV+ donors. Because of the need for organs in patients with advanced heart or lung failure, the researchers conducted the Donors of Hepatitis C NAT (nucleic acid amplification test) Positive Thoracic Allografts for Transplantation Evaluation in Non-HCV Recipients (DONATE HCV) trial.

Of 44 eligible patients screened from 2017 through 2018, a total of 36 received lung transplants and eight had heart transplants; median follow-up was 284 days. A total of 35 patients had at least 6 months of follow-up and 16 patients had at least 1 year of follow-up.

Median viral load in HCV+ donors was 890,000 IU/mL, and the researchers were able to identify genotype 3 in 17% of donors and genotypes 1 and 2, respectively, in 61% and 17% of the donors. Shortly after transplantation, viral load was detectable in 95% of patients at a median viral load of 1,800 IU/mL.

Sustained virologic response 12 weeks after completion of a 4-week course of therapy with sofosbuvir (at a dose of 400 mg)-velpatasvir (at a dose of 100 mg; regimen given once-daily to block viral replication) was met in all 35 patients with at least 6 months of follow-up. Viral load decreased to undetectable levels after 2 weeks and remained undetectable thereafter. Excellent graft function was observed for all 35 patients at 6 months.

Positive HCV-antibody tests were recorded for 27 of the 35 recipients within 1 week of transplantation, and 17 of the 35 recipients continued to have positive HCV-antibody tests 6 months after transplantation.

Graft survival was also observed in 15 of 16 recipients at 12 months. One patient died 8 months after a heart transplantation from a disseminated bacterial infection that was not deemed to be related to HCV infection.

There were no treatment-related serious adverse events, the researchers reported, adding that the recipient's initial HCV load was not significantly linked with the occurrence of acute cellular rejection for which treatment was indicated.

Study limitations, the team said, include the inherent concerns about an open-label, pilot study conducted at one center with assessments of small numbers of HCV genotypes. In addition, short follow-up times did not allow for longer-term assessments of chronic lung allograft dysfunction or cardiac allograft vasculopathy, and the direct-acting antiviral regimen has not been studied in patients with clinically significant renal dysfunction (creatinine clearance <30 mL/min).

Source Reference: New England Journal of Medicine, online April 3, 2019; DOI: 10.1056/NEJMoa1812406

Editorial: New England Journal of Medicine, online April 3, 2019; DOI: 10.1056/NEJMe1901957

Study Highlights: Explanation of Findings

The new study, which built on earlier studies of kidney and lung transplantation, and a case series in heart transplantation, showed that hearts and lungs from HCV-infected donors can be safely transplanted into uninfected recipients, despite transmission of HCV in nearly all recipients.

HCV viremia in recipients can be cleared after 2 weeks through prompt post-transplantation treatment for 4 weeks with a pan-genotypic, direct-acting antiviral regimen. Woolley and colleagues said they considered this treatment to be analogous to post-exposure prophylaxis, rather than the 8-12 weeks needed for treatment of established infection. Viral responses were sustained irrespective of baseline viral loads. Adherence to the treatment was 100%, and the researchers did not mention any identifiable toxic effects.

Passive transfer of donor antibodies within a clinical setting (detected by ultra-sensitive antibody detection tests) or transfer of passenger lymphocytes in the transplanted grafts were two possible reasons given by the authors for the emergence of HCV antibodies in the recipients.

Given the 5% mortality among patients on the transplant waiting list during the trial period and within the context of study limitations, it was reassuring that hearts and lungs were safely transplanted with excellent graft function at both 6 and 12 months.

"There was a 100% success rate in terms of HCV treatment and 6-month graft survival," noted Woolley in an article in a Brigham and Women's publication. "Direct-acting antivirals have revolutionized the field of hepatitis C treatment and have also created an opportunity to transplant organs from hepatitis C-positive donors."

"This study provided a unique opportunity to explore the utilization of thoracic organs from hepatitis C positive donors for transplantation, which to date have been underutilized despite being relatively common in the current donor population," added study co-author Hilary Goldberg, MD, MPH, medical director of the Lung Transplant Program at Brigham and Women's hospital. "This may allow us to provide successful transplantation to many recipients who might otherwise never have access to it."

In an accompanying editorial, Emily A. Blumberg, MD, of the University of Pennsylvania in Philadelphia, noted the relative youth of the HCV+ and HCV- donors and the fact that transplants occurred in recipients who were probably lower down on the donor waiting list and likely had relatively preserved renal function. Nevertheless, Blumberg said, the results are encouraging, and provide "further consideration of the use of organs from HCV+ donors, even for candidates for heart and lung transplantation."

Regarding the next steps, Blumberg said consideration should be given to the incidence of cardiovascular disease as a possible late complication following transplantation of HCV+ organs. Sustained viral responses may also need to be qualified in light of a recent anecdote of a mismatched lung transplant recipient who had a severe relapse after treatment for transplant-related HCV infection; Blumberg added, however, that a longer course of effective treatment at relapse might mitigate the effects.

Successful outcomes in HCV-mismatched organ transplantation, with cure of HCV infection, will also depend on educating patients about HCV and figuring out who will bear the cost of these expensive drugs outside of a trial setting.

"These are exciting times for the field of transplantation," Blumberg said. Using organs from HCV+ donors could "substantially increase the donor pool and thus increase access of organs to patients who might otherwise have died while waiting."

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