Systematic Review

Hepatitis C Viraemic Allografts to Hepatitis C-negative Recipients in Solid Organ Transplantation

Taaj Raasikh; Taher Jamali; Avegail Flores; Ronald T. Cotton; Venkat Ramanathan; Henkie P. Tan; Ruben Hernaez


Aliment Pharmacol Ther. 2021;54(5):571-582. 

In This Article


Our initial search terms resulted in a set of 2186 articles, of which 35 studies satisfied the inclusion and exclusion criteria (Figure 1),[13–46] including one paper identified with reference search.[47] There were 852 SOTs, which included 343 kidney, 233 heart, 204 liver and 72 lung transplants.

Figure 1.

Flow chart of the systematic review (1 January 2007–17 April 2021)

Kidney Transplantation Outcomes of Viraemic Allografts to Negative Recipients

We included 15 studies or a total of 343 kidney transplant recipients.

Prophylactic/Pre-emptive Studies. Of these 15 studies, six studies (107 transplants) started DAA treatment before confirmation of viraemia. For these prophylactic/pre-emptive studies, three were non-randomized clinical trials and three were observational studies. The median follow-up ranged from 6 to 28 months. SVR12 was achieved in 100% of the recipients who were eligible for SVR12 check. There were no complications from HCV infection reported. Only three deaths across these studies, which were deemed not to be related to HCV (Table 1).[17,35,38] Two patients had graft failure[17,36] five had acute cellular rejection[17,38] and three recipients had acute antibody-mediated rejection.[17] There were two cases out of 107 of viral relapse after completion of treatment with DAA (Table S6). For the Gupta study,[17] 50 patients received HCV viraemic kidneys, transmission rate 6/50; SVR12 5/6. Two of the patients had a viral relapse but subsequently obtained SVR12 after the second treatment. One patient from this study with reported questionable medication adherence did not achieve SVR12, and had persistent HCV viraemia.

Reactive Studies. There were nine reactive treatment studies; three were non-randomized trials and the other six studies were observational, for a total of 236 kidney transplants. The median follow-up ranged from 6 to 12 months post-transplant. Two hundred and thirty patients developed viraemia after transplantation. Of the 193 patients who were eligible for SVR12 check, 100% achieved SVR12. There were 37 patients who were not eligible for SVR12 check due to not receiving DAA treatment, still undergoing treatment or awaiting 12 weeks post-treatment to measure SVR (Table S2). One case of viral relapse was successfully treated[37] and there was one case of a patient with persistent viraemia who was undergoing second-line treatment at the time of publication (Table 2).[18] One patient had graft failure[37] and five had acute cellular rejection (Table S6).[19,21] Complications included three patients developing fibrosing cholestatic hepatitis (with all cases treated successfully with DAA),[17] three patients developed hypertension,[16] one patient had proteinuria[14] and one patient had focal segmental glomerulosclerosis.[47] There was only one death across the nine studies, with the patient passing away at an outside hospital with an unknown cause of death.[18]

Insurance Data and Access to DAA Therapy. Of the 15 kidney transplant studies, only seven reported detailed information regarding insurance coverage for DAAs. Five studies used patient insurance and waited for insurance approval before initiating transplantation. The remaining two studies had the hospital cover the cost of DAA treatment if personal insurance was unable to,[47] and the other study had costs of DAAs covered through research funds (Table S3).[44]

Heart Transplantation Outcomes of Viraemic Allografts to Negative Recipients

A total of 233 heart transplants across 12 studies were included in our review.

Prophylactic/Pre-emptive Studies. Two studies implemented prophylactic/pre-emptive treatment with DAAs. Both studies were non-randomized clinical trials and had a total of 28 individuals who received an HCV viraemic organ. Follow-up median was 10.7 and 9.4 months.[23,27] SVR12 was achieved in 100% of recipients who were eligible for SVR12 (27 recipients eligible). Only one patient had completed DAA therapy but had not reached the 12-week time interval post-treatment for SVR12 check.[27] There were no complications reported from DAA therapy or HCV infection. Acute cellular rejection occurred in three patients. There was only one patient who died from a disseminated bacterial infection which was deemed not to be due to HCV infection (Table S7, Table 1).[27]

Reactive Studies. For the 10 reactive studies or 205 recipients of HCV viraemic hearts, two studies were non-randomized control trials,[22,24] and eight observational studies. The median follow-up ranged from 7.3 to 12 months. Of the 205 recipients, 97% (199/205) developed viraemia. Of the 199 patients with documented viraemia, 137 were eligible for SVR 12 check with SVR12 achieved in 100% of patients (137/137). There was one case of viral relapse, successfully retreated and achieved SVR12 (Table 2).[25] A total of 12 deaths occurred. Five deaths were from primary graft failure, one death from graft dysfunction,[45] one from a pulmonary embolism,[26] one from disseminated bacteremia,[27] one from heart failure,[22] two deaths from necrotizing pancreatitis[39,46] and one death from multi-organ failure with antibody-mediated rejection.[24] None of the causes of death was reported to be specifically related to or associated with HCV transmission. There were six graft failures/dysfunctions (which ultimately led to patients' deaths), 31 cases of acute cellular rejection and 5 cases of antibody-mediated rejection (Table S7).

Insurance Data and Access to DAA Therapy. Of the 12 studies that studied HCV viraemic donor heart transplants to negative recipients, only seven studies reported detailed information regarding coverage of costs for DAA treatment. Four studies relied solely on patient insurance, with the remaining studies receiving funding from grants or the hospital. The study by Morris et al. did not wait for insurance approval before transplantation and experienced significant delays in initiating treatment despite confirmed viraemia (Table S3).[25]

Liver Transplantation Outcomes of Viraemic Allografts to Negative Recipients

We included a total of 204 liver transplant recipients from 11 studies.

Prophylactic/Pre-emptive Studies. We identified one open-label non-randomized clinical trial by Bethea et al. which implemented prophylactic DAA treatment before checking HCV viral transmission with nine total transplant recipients.[29] The median follow-up time was 11.5 months. This study reported 100% SVR12 in all nine recipients with no episodes of viral relapse. One recipient developed acute cellular rejection. There were no patient deaths in this study (Table 1).

Reactive Studies. The remaining 10 studies with 195 recipients implemented reactive DAA treatment after documentation of HCV viraemic transmission. Of these 10 studies, eight were observational and two were non-randomized trials. Of these 195 recipients, approximately 193 recipients developed detectable HCV viraemia post-transplant. The median follow-up ranged from 6 to 16 months in the studies that reported this data. Among the 165 recipients who were eligible for SVR12, 100% achieved SVR12. Only one patient across all the studies had reported viral relapse, with appropriate treatment and achievement of SVR12 subsequently.[34] Acute cellular rejection was reported in 21 recipients, and antibody-mediates rejection was reported in three recipients. There were six reported cases of graft failure. There were 11 post-transplant deaths reported across the 10 studies, with no deaths reported to be related to HCV transmission. Two recipients developed potential complications of HCV infection, with one recipient developing acute membranous nephropathy and the other developing intrahepatic biliary sclerosis (Table 2 and Table S8).

Insurance Data and Access to DAA Therapy. Of the 11 liver transplant studies, ten had documented insurance data. Only three of these studies reported not waiting for insurance approval prior to initiating DAA therapy. Insurance issues were reported in six studies, with appeal problems in four. The study by Terrault et al. was unique because DAA treatment was paid for by internal funding/allocated study funds[44] (Table S3).

Lung Transplantation Outcomes of Viraemic Allografts to Negative Recipients

There were 72 total recipients of HCV viraemic lung allografts among three studies.

Prophylactic/Pre-emptive Studies. Two of these studies—one observational and one non-randomized clinical trial—implemented prophylactic DAA treatment with 52 total recipients of HCV viraemic allografts.[27,39] Median follow-up was approximately 9 months for both studies. Among the 46 recipients who were eligible for SVR12 from these two studies, 100% achieved SVR12. There were no cases of viral relapse. There were seventeen total cases of acute cellular rejection and three cases of antibody-mediated rejection. There were no reports of graft failure. One recipient died of a pulmonary embolism in the Smith et al. study.[39] There were no complications of HCV infection reported (Table 1).

Reactive Studies. One study designed as a non-randomized clinical trial implemented reactive DAA treatment with 20 total recipients of HCV viraemic lung allografts. All 20 recipients achieved SVR12 in this study, including two patients who had a viral relapse with successful post-relapse treatment.[31] There were 11 cases of acute cellular rejection and one reported case of antibody-mediated rejection. There were no reported cases of graft failure. One patient death was reported due to pseudomonas sepsis. One recipient developed fibrosing cholestatic hepatitis, a known complication of HCV infection(Table 1 and Table S9).[31]

Insurance Data and Access to DAA Therapy. Of the three lung transplant studies, two reported information about funding for DAA treatment. Woolley et al. reported hospital funding, and Cypel et al. reported assistance grant funding for DAA treatment (Table S3).[27,31]

Quality Assessment of Studies

Observational Studies. We included a total of 22 observational studies with data from 25 SOT recipient cohorts, including eight kidneys, one lung, eight heart, eight liver transplant recipient cohorts (Kapila et al. included data on kidney, heart and lung transplant recipient cohorts; Smith et al. included data on both heart and lung transplant recipients cohorts).[18,31] Fourteen of these studies were retrospective and eight were prospective. For observational studies assessing all 25 cohorts, we found the median quality as 7 (range 4–8), suggestive of a robust methodological quality among most studies. The studies with the lowest score (≤4) were mainly because they (a) did not have guaranteed 6 months of follow-up post-transplant to assess patient and graft outcomes, (b) did not demonstrate confirmation of HCV-NAT negativity in all recipients or (c) did not have HCV-positive/NAT-negative donor comparator group or demonstrate confirmation that SVR12 was checked in all recipients (Tables S4 and S5).

Controlled Trials. We included a total of 13 open-label non-randomized control trials with data from 15 SOT recipient study groups, including six kidney, two lung, four heart and three liver transplant recipient study groups (Terrault et al[44] included data on both liver and kidney transplant groups. Woolley et al[27] included data on both heart and lung transplant groups). For non-randomized clinical trials assessing all 15 SOT recipient study groups, we found the median quality as 6 (range 5–8), suggestive of moderately strong methodological quality. The quality of many of these studies was found to be significantly affected by the absence of an HCV-positive/NAT-negative comparator group. Aqel et al. (liver)[33] and Bethea et al. (heart)[23] were the only two studies that did have this comparator group which elevated these two trials to a maximum quality assessment score of 8 (Tables S4 and S5).