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Hepatitis C Viremic Organs for Transplantation to Non-Viremic Patients

Policy Number: MP-731

Latest Review Date: July 2021

Category: Surgical                                                     

Policy Grade: B

POLICY:

Effective for dates of service on or after August 8, 2019:

The transplantation of HCV-viremic solid organs (kidney, lung, heart, liver, small bowel, pancreas) to a HCV non-viremic recipient combined with direct acting antiviral treatment for HCV is considered investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

In patients with end-stage organ failure, donor organ shortage is a growing concern and there is increasing consideration of use of augmented infectious risk, as well as otherwise medically marginal, donors. Hepatitis C virus (HCV)-infected donor organs are typically discarded. The availability of direct-acting antiviral agents (DAA) has made it possible to effectively treat most hepatitis C-infected patients including those who develop acute hepatitis infection after receiving an organ transplant from a hepatitis C viremic donor.

Direct-acting antiviral (DAA) HCV drugs achieve cure rates greater than 95% with well-tolerated side effects, which has prompted an investigation into approaches to increase organ allocation and decrease discard rates of potentially viable donor organs. Although organs from HCV-infected donors have historically been transplanted only into recipients with preexisting HCV infection. The extensive wait times for solid organ transplant and the high-risk of mortality while on the transplant waiting list for a kidney, thoracic organ, liver, and other solid organs has led to possible consideration of the acceptance of HCV-infected organs into non-HCV viremic recipients.

KEY POINTS:

This evidence review was created in May 2019 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 15, 2021.

Summary of Evidence

For individuals who require a kidney transplant, are HCV non-viremic, and receive a kidney transplant from an HCV viremic donor combined with DAA, the evidence consists of multiple single-arm prospective and retrospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, treatment-related mortality, treatment-related morbidity, morbid events, quality of life and resource utilization. These studies reported outcomes for 252 recipients who received a kidney transplant from an HCV viremic donor. Most prospectively conducted studies in which DAA were initiated early in the course of transplant or immediately post-transplant for a duration of 8 to 12 weeks report SVR12 rates approaching 100% and stable organ function during 1 year of follow-up. There is considerable heterogeneity between the studies in whether donor kidneys were genotyped in advance of transplantation, use of DAA pangenotypic or specific regimens chosen to match genotype were used, and differences in the timing and duration of the DAA regimen. Use of ultra-short course therapy (2 to 4 days) was associated with treatment failures whereas the delayed treatment approach has been associated with increased risks of cytomegalovirus and BK virus, and several cases of FCH. Current treatment recommendations include initiating treatment within the first month after kidney transplant, preferably within the first week when the patient is clinically stable with a pangenotypic DAA regimen that includes daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) or sofosbuvir (400 mg)/velpatasvir (100 mg) for 8 weeks. While the published studies enrolled a limited number of subjects as they intended to examine the feasibility of transplanting kidneys from HCV viremic donors into HCV non-viremic recipients and are informative in concluding that such a strategy is feasible; multicenter trials with standardized protocols, and rigorous adjudication of outcomes and adverse events are needed to confirm these promising results and demonstrate their generalizability to settings outside of academic centers. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who require a lung transplant, are HCV non-viremic, and receive a lung transplant from an HCV viremic donor combined with DAA, the evidence consists of three single-arm prospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, treatment-related mortality, treatment-related morbidity, morbid events, quality of life and resource utilization. The three studies reported outcomes for 61 recipients who received a lung transplant from an HCV viremic donor. While the studies by Wooley et al (2019) and Cypel et al (2020) used a pangenotypic DAA regimen consisting of sofosbuvir/velpatasvir, the duration and initiation of treatment were markedly different. In Wooley et al (2019), treatment duration was 4 weeks initiated immediately after transplant while in Cypel et al (2020), treatment duration was 12 weeks initiated 2 weeks after transplant. Feld et al (2020) also used a pangenotypic DAA treatment of glecaprevir/pibrentasvir for a total duration of 8 days along with single dose ezetemibe as well as use of ex-vivo lung perfusion plus ultraviolet-C radiation delivered to the circulating perfusate as an additional measure to lower HCV viral load. All three studies reported SVR12 rates of 100%. Reported rate of graft survival at 6 months available for 28 participants in the first study was 100%. The primary endpoint of survival and HCV-free status at 6 months after transplantation was 86% in the second study. Two patients presented with HCV relapse within 3 months after sofosbuvir/velpatasvir completion and required retreatment in the second study. Acute rejection requiring treatment was reported in 23% of recipients in the third study. The 3 published studies enrolled a limited number of subjects since they intended to examine the feasibility of transplanting lungs from HCV viremic donors into HCV non-viremic recipients and are informative in concluding that such a strategy is feasible; multicenter trials with standardized protocols, and rigorous adjudication of outcomes and adverse events are needed to confirm these promising results and demonstrate their generalizability to settings outside of academic centers. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who require a heart transplant, are HCV non-viremic, and receive a heart transplant from an HCV viremic donor combined with DAA, the evidence consists of four single-arm prospective studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, treatment-related mortality, treatment-related morbidity, morbid events, quality of life and resource utilization. These four studies reported outcomes for 44 recipients who received a heart transplant from an HCV viremic donor. The timing, duration and specific DAA regimens used in the four published studies were different. Except for the first study published by McLean et al (2019) that used a non-pangenotypic DAA regimen of grazoprevir/elbasvir, the remaining three studies used a pan-genotypic DAA regimen of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir. SVR12 rates were 100% in the three studies that used a pangenotypic DAA regimen while it was 90% in the study that used a non-pangenotypic DAA regimen. The 4 published studies enrolled a limited number of subjects as they intended to examine the feasibility of transplanting hearts from HCV viremic donors into HCV non-viremic recipients and are informative in concluding that such a strategy is feasible; multicenter trials with standardized protocols, and rigorous adjudication of outcomes and adverse events are needed to confirm these promising results and demonstrate their generalizability to settings outside of academic centers. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who require a liver transplant, are HCV non-viremic, and receive a liver transplant from an HCV viremic donor combined with DAA, the evidence consists of one prospective and three retrospective cohort studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, treatment-related mortality, treatment-related morbidity, morbid events, quality of life and resource utilization. The timing, duration and specific DAA regimens used in the published studies were different. The single prospective study that enrolled nine recipients who received livers from HCV viremic donors were treated with a 12-week course of pangenotypic DAA within 5 days of transplant and reported SVR12 rates of 100%. The two retrospective studies reported findings from a combined 25 recipients who received livers from HCV viremic donors but not treated with DAA immediately post-transplant reported 100% SVR12 rates. Additionally, a retrospective analysis from a transplant registry reported similar 1- and 3-year graft survival among recipients who received liver transplant from HCV viremic donors versus those who received organs from HCV non-viremic donors. These studies enrolled a limited number of subjects as they intended to examine the feasibility of transplanting liver from HCV viremic donors into HCV non-viremic recipients and are informative in concluding that such a strategy is feasible; multicenter trials with standardized protocols, and rigorous adjudication of outcomes and adverse events are needed to confirm these promising results and demonstrate their generalizability to settings outside of academic centers. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are HCV non-viremic who have end-stage organ disease and are candidates for a solid organ transplant such as for small bowel or pancreas, evidence for the use of HCV viremic donor organs as an alternative to continuing appropriate medical treatment and remaining on the transplant wait-list has not been reported in the published literature. Relevant outcomes are overall survival, disease-specific survival, change in disease status, treatment-related mortality, treatment-related morbidity, morbid events, quality of life and resource utilization. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

The American Society of Transplantation (2017) convened a consensus conference of experts to address issues related to the transplantation of hepatitis C virus (HCV) viremic solid organs into HCV non-viremic recipients. Key findings and recommendations are summarized in Table 1.

Table 1. American Society of Transplantation Consensus Conference - Use of HCV Viremic Donors

Content Area

Key Point

Definition of HCV positive

HCV –viremic reflecting a positive NAT should be adopted

Data interpretation

HCV antibody status alone limits interpretation of outcomes of transplantation of HCV “positive” organs

Transmission and Treatment

Highest risk for unexpected HCV transmission is associated with organ donation from a person who injected drugs within the eclipse or pre-viremic period

OPTN policy

No current policies prevent transplantation of HCV-viremic organs into HCV non-viremic recipients

Ethical considerations

Transplantation of HCV-viremic organs into HCV non-viremic recipients should be conducted under site-specific IRB approved protocols with multi-step informed consent.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

kidney transplant, lung transplant, heart transplant,  liver transplant , solid organ transplant, thoracic organ transplant, HCV, non-viremic HCV recipient; DAA, direct‐acting antiviral agent; hepatitis C virus; NAT, nucleic acid testing; IRB, institutional review board.

APPROVED BY GOVERNING BODIES:

Solid organ transplant represents donor and recipient surgical procedures and, as such, is not subject to regulation by the U.S. Food and Drug Administration (FDA).

Direct-Acting Antiviral Treatment

There are several drug combinations approved by the FDA for the treatment of chronic HCV infection. Drug regimen choice and duration of treatment are centered on the HCV genotype as well as the degree of liver cirrhosis.

The FDA (2016) approved a fixed-dose combination tablet containing sofosbuvir, a drug previously approved in 2013, and velpatasvir, which was the first DAA to treat HCV genotypes 1-6. (Epclusa - Gilead Sciences)

In 2017, the FDA approved two pangenotypic products. A once-daily single tablet containing the nucleotide analog nonstructural protein NS5B polymerase inhibitor sofosbuvir, the HCV NS5A inhibitor velpatasvir, and pangenotypic HCV NS3/4A protease inhibitor voxilaprevir was approved to treat adults with chronic HCV genotypes 1 through 6 without cirrhosis or with mild cirrhosis. This product is also indicated in patients who have been previously treated with the DAA drug sofosbuvir or other drugs for HCV that inhibit NS5A. (Vosevi - Gilead Sciences).

The combination of glecaprevir and pibrentasvir was approved for the treatment of adults with chronic HCV infection across all genotypes 1-6 without cirrhosis or with compensated cirrhosis, including patients with moderate to severe kidney disease and those who are on dialysis. The products are also approved for patients with HCV genotype 1 infection who have been previously treated with a regimen containing an NS5A inhibitor or an NS3/4A protease inhibitor but not both. (Mavyret - AbbVie)

There is no specific labeling of DAA treatment for post-exposure prophylaxis for persons exposed to HCV blood or contaminated body fluids.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply.  Refer to member’s benefit plan.

CURRENT CODING:

CPT Codes:

50300-50365 and 50547

 Kidney Transplant codes

48550-48554

 Pancreas Transplant codes

44120-44121 44132-44136 44715-44721

 Small Bowel Transplant codes

47133-47147

 Liver Transplant codes

32850-32856

 Lung Transplant codes

33930-33935

 Heart Lung Transplant codes

33940-33945

 Heart Transplant codes

HCPCS:

S2065

Simultaneous pancreas kidney transplantation

S2053

Transplantation of small intestine, and liver allografts

S2054-S2055

Transplantation of multi-visceral organs

S2060-S2061

Lung Transplant codes

REFERENCES:

  1. American Association for the Study of Liver Disease. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Treatment of HCV-Uninfected Transplant Recipients Receiving Organs From HCV-Viremic Donors. Accessed on April 30, 2021.Available at https://www.hcvguidelines.org/unique-populations/organs-from-hcv-viremic-donors.
  2. Bethea E, Arvind A, Gustafson J, et al. Immediate administration of antiviral therapy after transplantation of hepatitis C-infected liversinto uninfected recipients: Implications for therapeutic planning. Am J Transplant. Jun 2020; 20(6): 1619-1628.
  3. Bethea ED, Gaj K, Gustafson JL, et al. Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study. Lancet Gastroenterol Hepatol. Oct 2019; 4(10): 771-780.
  4. Campos-Varela I, Agudelo EZ, Sarkar M, et al. Use of a hepatitis C virus (HCV) RNA-positive donor in a treated HCV RNA-negative liver transplant recipient. Transpl Infect Dis. Feb 2018; 20(1).
  5. Cotter TG, Paul S, Sandikci B, et al. Increasing Utilization and Excellent Initial Outcomes Following Liver Transplant of Hepatitis C Virus(HCV)-Viremic Donors Into HCV-Negative Recipients: Outcomes Following Liver Transplant of HCV-Viremic Donors. Hepatology. Jun2019; 69(6): 2381-2395.
  6. Cypel M, Feld JJ, Galasso M, et al. Prevention of viral transmission during lung transplantation with hepatitis C-viremic donors: an open-label, single-centre, pilot trial. Lancet Respir Med. Feb 2020; 8(2): 192-201.
  7. Durand CM, Bowring MG, Brown DM, et al. Direct-Acting Antiviral Prophylaxis in Kidney Transplantation From Hepatitis C Virus-Infected Donors to Noninfected Recipients: An Open-Label Nonrandomized Trial. Ann Intern Med. Apr 17 2018; 168(8):533-540.
  8. Feld JJ, Cypel M, Kumar D, et al. Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study. Lancet Gastroenterol Hepatol. Jul 2020; 5(7): 649-657.
  9. Franco A, Moreso F, Merino E, et al. Renal transplantation from seropositive hepatitis C virus donors to seronegative recipients in Spain: a prospective study. Transpl Int. Jul 2019; 32(7): 710-716.
  10. Goldberg DS, Abt PL, Blumberg EA, et al. Trial of Transplantation of HCV-Infected Kidneys into Uninfected Recipients. N Engl J Med. Jun 15 2017; 376(24):2394-2395.
  11. Gottlieb RL, Sam T, Wada SY, et al. Rational Heart Transplant From a Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan Horse. J Card Fail. Oct 2017; 23(10):765-767.
  12. Gupta G, Yakubu I, Bhati CS, et al. Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients. Am J Transplant. Mar 2020; 20(3): 739-751.
  13. Jawad K, Feder S, Barten M, et al. Curative therapy of a hepatitis C infection due to an infected heart donor: 5-year outcomes after heart transplantation. Eur J Cardiothorac Surg. Aug 1 2018; 54(2):400-401.
  14. Kapila N, Menon KVN, Al-Khalloufi K, et al. Hepatitis C Virus NAT-Positive Solid Organ Allografts Transplanted Into Hepatitis C Virus-Negative Recipients: A Real-World Experience. Hepatology. Jul 2020; 72(1): 32-41.
  15. Kwong AJ, Wall A, Melcher M, et al. Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors. Am J Transplant. Oct 31 2018.
  16. Kwong AJ, Wall A, Melcher M, et al. Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors. Am J Transplant. May 2019; 19(5): 1380-1387.
  17. Levitsky J, Formica RN, Bloom RD, et al. The American Society of Transplantation Consensus Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation. Am J Transplant. Nov 2017; 17(11):2790-2802.
  18. Luckett K, Kaiser TE, Bari K, et al. Use of Hepatitis C Virus Antibody-Positive Donor Livers in Hepatitis C Nonviremic Liver Transplant Recipients. J Am Coll Surg. Apr 2019; 228(4):560-567.
  19. McLean RC, Reese PP, Acker M, et al. Transplanting hepatitis C virus-infected hearts into uninfected recipients: A single-arm trial. Am J Transplant. Feb 15 2019.
  20. McLean RC, Reese PP, Acker M, et al. Transplanting hepatitis C virus-infected hearts into uninfected recipients: A single-arm trial. Am J Transplant. Sep 2019; 19(9): 2533-2542.
  21. Moayedi Y, Gulamhusein AF, Ross HJ, et al. Accepting hepatitis C virus-infected donor hearts for transplantation: Multistep consent, unrealized opportunity, and the Stanford experience. Clin Transplant. Jul 2018; 32(7):e13308.
  22. Molnar MZ, Nair S, Cseprekal O, et al. Transplantation of kidneys from hepatitis C-infected donors to hepatitis C-negative recipients: Single center experience. Am J Transplant. Nov 2019; 19(11): 3046-3057.
  23. Ortiz J, Gunselman J, Javed I, et al. Are hepatitis C-positive allografts in simultaneous pancreas-kidney transplantation underutilized? Ann Transplant. Dec 31 2012; 17(4):39
  24. Radzi Y, Shezad MF, Danziger-Isakov L, et al. Using hepatitis C and B virus-infected donor organs for pediatric heart transplantation. J Thorac Cardiovasc Surg. Feb 19 2019.
  25. Reese PP, Abt PL, Blumberg EA, et al. Twelve-Month Outcomes After Transplant of Hepatitis C-Infected Kidneys Into Uninfected Recipients: A Single-Group Trial. Ann Intern Med. Sep 4 2018; 169(5):273-281.
  26. Saberi B, Hamilton JP, Durand CM, et al. Utilization of hepatitis C virus RNA-positive donor liver for transplant to hepatitis C virus RNA-negative recipient. Liver Transpl. Jan 2018; 24(1):140-143.
  27. Sise ME, Goldberg DS, Kort JJ, et al. Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC): An Open-Label Study of Combined Glecaprevir and Pibrentasvir to Treat Recipients of Transplanted Kidneys from Deceased Donors with Hepatitis C Virus Infection. J Am Soc Nephrol. Nov 2020; 31(11): 2678-2687.
  28. Sobotka LA, Mumtaz K, Wellner MR, et al. Outcomes of hepatitis C virus seropositive donors to hepatitis C virus seronegative liver recipients: A large single center analysis. Ann Hepatol. Jan 27 2021; 24: 100318.
  29. Watson J, Mulvihill MS, Cox ML, et al. Early experience with the use of hepatitis C antibody-positive, nucleic acid testing-negative donors in lung transplantation. Clin Transplant. Mar 2019; 33(3):e13476.
  30. Woolley AE, Singh SK, Goldberg HJ, et al. Heart and Lung Transplants from HCV-Infected Donors to Uninfected Recipients. N Engl J Med. Apr 3 2019.

POLICY HISTORY:

Medical Policy Panel, May 2019

Medical Policy Group, June 2019 (3):  Policy created with literature review through April 19, 2019. The transplantation of HCV-viremic solid organs (kidney, lung, heart, liver, small bowel, and pancreas) to a HCV non-viremic recipient combined with direct acting antiviral treatment for HCV is considered investigational. This policy was posted as DRAFT for 45 days for comment with effective date of August 8, 2019.

Medical Policy Panel, May 2020

Medical Policy Group, July 2020 (3): 2020 Updates to Key Points. No changes to policy statement or intent.

Medical Policy Panel, June 2021

Medical Policy Group, July 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements, and References. The title of the policy was changed from "Hepatitis C Positive Organs for Transplantation to Non-Viremic Patients" to "Hepatitis C Viremic Organs for Transplantation to Non-Viremic Patients". Policy statement updated to remove “not medically necessary, “no other changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.