DONATE-HCV

Published

Woolley AE, et al. "Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients". The New England Journal of Medicine. 2019. 380(17):1606-1617.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with end-stage heart or lung disease requiring transplantation who are negative for hepatitis C virus (HCV), does transplantation of an HCV positive organ with immediate anti-viral therapy result in similar allograft function and successful viral suppression compared to transplantation of HCV negative organs?

Bottom Line

In patients with end-stage heart or lung disease requiring transplantation who are HCV negative, transplantation of HCV positive organs followed by immediate viral suppression with sofosbuvir/velpatasvir is feasible. At 6 months, all of 35 individuals (28 lung and 7 heart) transplanted had intact allograft function and undetectable HCV viral loads. In limited post-hoc analyses, overall transplant outcomes were similar to those observed with HCV- organs.

Major Points

Mortality for patients with end-stage heart or lung disease awaiting transplantation remains a major public health problem. Many organs that are otherwise medically suitable for transplantation have traditionally been declined due to the presence of hepatitis C virus (HCV) in the donors. In the past, transplantation of these HCV+ organs into HCV naive recipients has led to acquired chronic HCV infection in the vast majority of recipients. Downstream effects of HCV acquisition have included increased mortality from liver disease and the development of accelerated graft damage due to cardiac allograft vasculopathy.

More recently, the development of direct-acting broad-spectrum antiviral agents has revolutionalized the approach to HCV treatment, resulting in durable cure rates after relatively short and well-tolerated treatment courses. Early data on HCV naive patients who have received HCV positive kidney and liver transplants have suggested that treatment of HCV infection early after transplantation is feasible. More robust data regarding the efficacy and safety of this approach for patients undergoing heart and lung transplantation was needed.

The 2019 Donors of Hepatitis C NAT [nucleic acid amplification test] Positive Thoracic Allografts for Transplantation Evaluation in Non-HCV Recipients (DONATE HCV) was an open-label, single-center pilot trial assessing the feasibility of HCV+ heart and lung transplantation into HCV naive recipients with the use of antiviral therapy immediately after transplantation. A total of 44 patients were enrolled (36 lung and 8 heart recipients). The primary outcome of the combination of sustained virological response at 12 weeks and allograft survival at 6 months was met in all 35 patients with at least 6 months of follow-up. A total of 42/44 (95%) of recipients had a detectable HCV viral load immediately after transplantation, and all had an undetectable viral load by 2 weeks, which subsequently remained undetectable. In exploratory analyses comparing graft outcomes in HCV+ versus HCV- donor organs, there was an increased odds of acute cellular rejection requiring therapy in lung transplant recipients receiving HCV+ organs, which was not statistically significant after adjustment for substantial differences in baseline comorbidity.

In summary, the results of DONATE HCV provide further evidence that donation of HCV+ organs into HCV naive recipients is feasible with the use of immediate antiviral therapy, resulting in complete virological suppression in all cases (despite initial transmission in 95% of individuals). Based on DONATE-HCV, the practice of heart and lung donation using HCV+ organs is likely to expand. Data assessing longer-term outcomes is needed to rule out an increase in delayed complications related to either recurrent HCV or legacy effects from transient HCV infection. Furthermore, randomized studies comparing outcomes observed using HCV- versus HCV+ organs would be required before the two approaches can be considered equivalent.

Guidelines

As of May 2019, no guidelines have been published that reflect the results of this trial.

Design

• Single-center, open-label, non-randomized pilot trial
• N=44
  • Lung transplant (n=36)
  • Heart transplant (n=8)
• Setting: 1 center in the US
• Enrollment: March 1, 2017 to July 31, 2018
• Median follow-up: 284 days
• Primary outcome: sustained virological response at 12 weeks and allograft survival at 6 months

Population

Inclusion Criteria

• Age ≥ 18
• On transplant list for heart or lung transplant
• Provides written informed consent to receive an organ from an increased-risk donor with known transmissible HCV infection

Exclusion Criteria

• Significant liver disease
• Seropositive for HIV, HBV, or HCV
• History of previous transplantation
• Creatinine clearance < 30 mL/min

Baseline Characteristics

Lung transplantation group, HCV+

• Demographics: age 61, male 39%, white 93%
• Transplant: median lung allocation score 33.31, list time 136 days, bilateral lung 96%
• Disease: restrictive 29%, obstructive 61%, cystic fibrosis 11%

Lung transplantation group, HCV-

• Demographics: age 63, male 66%, white 91%
• Transplant: median lung allocation score 38.16, list time 79 days, bilateral lung 86%
• Disease: restrictive 68%, obstructive 18%, cystic fibrosis 14%

Heart transplantation group, HCV+

• Demographics: age 51, male 86%, white 86%
• Transplant: UNOS 1A 14%, UNOS 1B 71%, UNOS 2 14%, list time 559 days, VAD 86%
• Disease: ischemic 29%, non-ischemic 71%

Heart transplantation group, HCV-

• Demographics: age 52, male 50%, white 83%
• Transplant: UNOS 1A 100%, UNOS 1B 0%, UNOS 2 0%, list time 183 days, VAD 58%
• Disease: ischemic 8%, non-ischemic 92%

Interventions

• All patients received 4-week regimen of sofosbuvir (400MG) plus velpatasvir (100MG) daily
  • Agent chosen because of its activity against all HCV genotypes and lack of interaction with immunosuppressive agents
• Treatment began a few hours after transplantation
• In exploratory, post-hoc analyses, possible differences in transplantation outcomes between the recipients of transplants from HCV-positive donors and the recipients of transplants occurring contemporaneously from HCV-negative donors were compared

Outcomes

Comparisons are HCV+ donor versus HCV- donor.

Lung transplantation

Primary Outcomes

Virological response at 12 weeks and allograft survival at 6 months

28/28 (100%)

Secondary Outcomes

Graft survival at 6 months

28 (100%) vs. 43 (98%); mean difference 0, 95% CI 0-61.23

Overall survival at 6 months

28 (100%) vs. 43 (98%); mean difference 0, 95% CI 0-61.23

Acute cellular rejection requiring treatment

15 (54%) vs. 13 (30%); OR 2.70, 95% CI 0.92-8.33

Heart transplantation

Primary Outcomes

Virological response at 12 weeks and allograft survival at 6 months

7/7 (100%)

Secondary Outcomes

Graft survival at 6 months

7 (100%) vs. 10 (83%); mean difference 0, 95% CI 0-9.25

Overall survival at 6 months

7 (100%) vs. 10 (83%); mean difference 0, 95% CI 0-9.25

Acute cellular rejection requiring treatment

3 (43%) vs. 4 (33%); OR 1.47, 95% CI 0.14-14.3

Adverse Events

• No adverse events or serious adverse events were considered by the investigators and the data and safety monitoring board to be related to trial medication
• No irreversible grade 3 or higher adverse events or serious adverse events were attributed by the investigators and the data and safety monitoring board to HCV infection
• The adverse events at 30 days and 6 months who received organs from HCV+ donors were similar to those of HCV- donors

Criticisms

• Small, single-center, pilot trial limits generalizability to other centers and populations
• Non-randomized nature limits ability to make conclusions regarding the relative efficacy and safety of HCV+ donor organ transplantation compared to HCV- donor organ transplantation
• Limited follow-up time does not allow for assessment of longer-term transplant complications (e.g., chronic allograft vasculopathy or dysfunction)

Funding

• Authors with multiple ties to industry