Hepatitis C Virus Infection In Recipients Research Articles

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

An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.

154-P: ASSOCIATION OF HLA CLASS I AND II WITH HEPATITIS C VIRUS INFECTION IN HIGH-RISK HEMODIALYSIS PATIENTS AWAITING KIDNEY TRANSPLANTATION

Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation, considered at high-risk to infection due to protracted hemodialysis treatment. This case-control study included 1404 of 3000 total chronic kidney diseases patients on dialysis, in waiting list for transplantation, enrolled at the Laboratory of Transplantation Immunology of Second University of Naples, Italy. Particularly, we consecutively considered 301 patients with HCV infection and we randomly selected 1103 HCV-negative as control group. None of the patients carried hepatitis B surface antigen or had human immunodeficiency virus antibody to exclude additional viral factors that could affect our results. All patients were tested for HCV antibody detection by serological Chemiluminescent Microparticle Immunoassay (CMIA, Abbott, Italy). All kidney recipients were tested for HLA class I (HLA-A and -B) and class II (-DR) antigens by serological and molecular HLA typing. In our case-control study, HLA-A26 is positively associated with HCV infection, while HLA-A29, -B40 and -DR1 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR=1.02; 95% CI=1.01-1.04; p < 0.00), HLA-A26, -A29, -B40 and -DR1 [(OR=1.54; 95% CI=1.03-2.30; p=0.03); (OR=0.50; 95% CI=0.26-0.99 p=0.05); (OR=0.42; 95% CI=0.23-0,7 p=0.01); (OR=0.62; 95% CI=0.41-0,94 p=0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.

Association between human leukocyte antigen class I and II alleles and hepatitis C virus infection in high-risk hemodialysis patients awaiting kidney transplantation

Recent evidences have shown that several host genetic factors influence susceptibility or protection to hepatitis C virus (HCV) infection. There are controversial data regarding the associations of human leukocyte antigens (HLA) and the clearance or progression of HCV. The aim of this study was to investigate whether particular HLA molecules were associated with HCV infection in recipients awaiting kidney transplantation considered at high-risk to infection due to protracted hemodialysis treatment. To this purpose, 301 kidney recipients with HCV infection and 1103 uninfected recipients were examined for HLA class I and II molecules. In our case-control study, HLA-A*26 is positively associated with HCV infection while HLA-A*29, -B*40 and -DRB1*01 are negatively associated with HCV infection. Multiple logistic regression analysis demonstrated that age (OR=1.02; 95% CI=1.01–1.04; p<0.00), HLA-A*26, -A*29, -B*40 and -DRB1*01 [(OR=1.54; 95% CI=1.03–2.30; p=0.03); (OR=0.50; 95% CI=0.26–0.99; p=0.05); (OR=0.42; 95% CI=0.23-0, 7; p=0.01); (OR=0.62; 95% CI=0.41-0, 94; p=0.03); respectively] are independent predictors of HCV infection. Our results suggest that particular HLA molecules, as host genetic factors, may have a relationship with susceptibility or protection to HCV infection also in recipients awaiting kidney transplantation.

Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy

Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

Outcome of de novo hepatitis C virus infection in heart transplant recipients.

The outcome of de novo hepatitis C virus (HCV) infection in heart transplant recipients of HCV-antibody positive organs is not known. The aim of the study was to determine the short-term outcome of de novo HCV infection in recipients of HCV-positive donor organs. HCV-antibody negative recipients of HCV-antibody positive hearts were identified from January 1, 1991 to February 28, 1998. Control patients matched for year of transplantation were also identified. Twenty-eight patients (22 males, mean age of 56 +/- 11 SD) received hearts from HCV-antibody-positive donors. The control group was similar to the patients in all clinical and demographic aspects. Twenty-three patients had detectable viremia by reverse-transcription polymerase chain reaction (RT-PCR). Of these 23 patients with de novo HCV infection, 7 (30%) developed HCV-related liver disease. Three patients (13%) had chronic hepatitis and 4 patients (17%) developed severe acute cholestatic hepatitis (ACH). Mycophenolate mofetil (MMF) use (P =.04) and high viral load at onset of acute liver disease (P =.02) were associated with ACH. Overall survival was similar between patients with de novo HCV infection and controls (P =.20). Development of ACH (P =.02) and MMF use (P =.0009) were associated with decreased survival in patients with de novo HCV infection. The present study showed that survival of patients with de novo HCV infection was similar to a matched control group. HCV-related severe ACH is associated with a poor short-term outcome in patients with de novo HCV infection. MMF use may be associated with a higher incidence of HCV-related severe ACH and a poor short-term outcome.

Transmission Rates of Hepatitis C Virus by Different Batches of a Contaminated Anti–D Immunoglobulin Preparation

Background and Objectives: The aim of this study was to determine the hepatitis C virus (HCV) infection rate of recipients of different batches of anti–D immunoglobulin associated with an outbreak of HCV infection which occurred in 1977 and its relationship to the polymerase chain reaction (PCR) status of the implicated batches. This study was undertaken to determine the predictive value of HCV genome detection and quantification for subsequent infection in recipients of an HCV–contaminated anti–D immunoglobulin product for intravenous use. Materials and Methods: Sera from recipients of anti–D were tested by HCV enzyme immunoassay and if found positive were subsequently tested by recombinant immunoblot assay and HCV PCR in a national HCV anti–D screening programme set up in 1994. The HCV status of 1,342 known recipients of infectious or potentially infectious batches has been compared to the amount of HCV RNA in the anti–D batch they received so as to determine the value of PCR in the prediction of infectivity in immunoglobulin preparations. Results: It has been demonstrated that HCV–infected plasma derived from batches of anti–D showing levels of viral genome in excess of 10⁴ genomes per millilitre led to infection of up to 60% of recipients. In contrast, batches with undetectable levels of HCV genome very rarely transmitted infection. Conclusions: The presence of HCV RNA in intravenous immunoglobulin preparations which have not undergone a specific viral inactivation step is a predictor of HCV infection in recipients.

Transmission Rates of Hepatitis C Virus by Different Batches of a Contaminated Anti‐D Immunoglobulin Preparation

Abstract Background and Objectives: The aim of this study was to determine the hepatitis C virus (HCV) infection rate of recipients of different batches of anti‐D immunoglobulin associated with an outbreak of HCV infection which occurred in 1977 and its relationship to the polymerase chain reaction (PCR) status of the implicated batches. This study was undertaken to determine the predictive value of HCV genome detection and quantification for subsequent infection in recipients of an HCV‐contaminated anti‐D immunoglobulin product for intravenous use. Materials and Methods: Sera from recipients of anti‐D were tested by HCV enzyme immunoassay and if found positive were subsequently tested by recombinant immunoblot assay and HCV PCR in a national HCV anti‐D screening programme set up in 1994. The HCV status of 1,342 known recipients of infectious or potentially infectious batches has been compared to the amount of HCV RNA in the anti‐D batch they received so as to determine the value of PCR in the prediction of infectivity in immunoglobulin preparations. Results: It has been demonstrated that HCV‐infected plasma derived from batches of anti‐D showing levels of viral genome in excess of 104 genomes per millilitre led to infection of up to 60% of recipients. In contrast, batches with undetectable levels of HCV genome very rarely transmitted infection. Conclusions: The presence of HCV RNA in intravenous immunoglobulin preparations which have not undergone a specific viral inactivation step is a predictor of HCV infection in recipients.

Laboratory diagnosis and molecular epidemiology of an outbreak of hepatitis C virus infection among recipients of human intravenous immunoglobulin in Spain.

Passive transfer of antibody to hepatitis C virus (HCV) has been thought to occur after infusion of human intravenous immunoglobulin (IVIG), as anti-HCV and/or HCV RNA was commonly found in that product. Recently, however, HCV RNA was detected in the serum of recipients of IVIG. Establishment of a causal relationship between IVIG therapy and HCV infection in recipients was attempted. Anti-HCV and HCV RNA sequences were investigated in serum samples from 39 persons who received a human IVIG product in seven different hospitals in Spain. HCV RNA was also investigated in two batches of the IVIG shared by some recipients. All the viral RNA detected were characterized with a line probe assay, restriction fragment length polymorphism analysis of the 5'-noncoding and core regions, and sequencing of the nonstructural 5 region. On the basis of both clinical and laboratory data, a relationship could be established between the IVIG therapy and the acquisition of the HCV infection by the recipients. Several HCV strains were detected among the recipients, with most of the recipients coming from the same hospital presenting with closely related strains. Moreover, an HCV strain almost identical to the main strain detected among the recipients was found in one batch of the IVIG that probably was shared by most of them. Follow-up studies and evaluation of low-avidity anti-HCV IgG suggested that both acute primary infections and reinfections were produced. In one case, direct evidence of reinfection by a different HCV strain was obtained. The results did not exclude the possibility that a second HCV strain associated with a further, unidentified batch of the IVIG could have contributed to this outbreak.