Successful treatment of donor‐derived hepatitis C infection in a lung transplant recipient

Data are limited regarding the use of direct‐acting antivirals for treatment of hepatitis C infection post lung transplant, especially in a donor‐derived infection. We present a case of a lung transplant recipient with donor‐derived hepatitis C that was successfully treated with a 12‐week regimen of simeprevir and sofosbuvir. This case reiterates the importance of screening recipients of increased‐risk donor organs for disease transmission and the value of early therapy.     

A cluster of donor‐derived Cryptococcus neoformans infection affecting lung,liver, and kidney transplant recipients: Case report and review of literature

Donor‐derived infections (DDIs) are a very rare but potentially devastating complication of solid organ transplantation. Here we present a cluster of proven donor‐derived cryptococcal infection in the kidney, liver, and lung recipients from a single donor. Remarkably, the onset of illness in the kidney and liver recipients occurred more than 8‐12 weeks after transplantation, which is beyond the incubation period previously reported for donor‐derived cryptococcosis. DDI should always be considered in the differential diagnosis of transplant recipients admitted with febrile illness, even when presenting beyond the first month post‐transplant. Communication between reference laboratories, transplant centers, and organ procurement organizations is critical to improve outcomes.     

Interferon‐lambda4 genetic polymorphism is associated with the therapy response for hepatitis C virus recurrence after a living donor liver transplant

The standard therapy against hepatitis C virus (HCV) recurrence postliver transplantation includes interferon (IFN)α and ribavirin. IFNL4 ss469415590 polymorphism has been reported as a novel predictor of the response to IFN therapy for chronic HCV infection. We examined the impact of IFNL4 polymorphism on the responsiveness to IFN therapy after liver transplantation. Tissue specimens were collected from 80 HCV‐infected recipients and 78 liver donors, and their IFNL4 ss469415590 genotype, hepatic IFNL4 and interferon‐stimulated genes' mRNA expression levels were examined. The association of the polymorphism and expression levels in terms of the IFN therapy response to HCV recurrence was analysed. Most individuals who had rs8099917 risk alleles also had ss469415590 risk alleles (R² = 0.9). Sustained virological response (SVR) rates were higher in both liver graft recipients and transplants with ss469415590 TT/TT alleles than in those with the risk ΔG allele (P = 0.003 and P = 0.005, respectively). In recipients with ss469415590 TT/TT, IFNL4 TT mRNA levels showed no significant differences between livers of patients who responded to therapy and those who did not (P = 0.4). In recipients with the risk ΔG allele, IFNL4 ΔG mRNA expression levels were significantly lower in SVR patients than in non‐SVR patients (P = 0.02). Hepatic interferon stimulable genes and IFNL4 mRNA expression were correlated. Our findings suggest that analysing the ss469415590 genotype and IFNL4 ΔG expression provides a novel prediction strategy for the possible response to IFN therapy after liver transplantation.     

Rapid immunoassay alone is insufficient for the detection of hepatitis C virus infection among high‐risk population

Rapid testing for HCV has become a routine practice in resource‐limited settings for initial screening. The objective of this study was to evaluate the performance of rapid immunoassay diagnostic test kits for specific and accurate diagnosis of HCV infection among different patient groups in clinical settings of Kolkata, India. Two hundred and fifty‐four randomly selected serum samples of 612 samples reported as HCV nonreactive by rapid immunodiagnostic tests were evaluated for HCV antibody, ELISA and HCV RNA testing for confirmatory diagnosis. 15.74% were HCV seropositive by ELISA, and 11.02% were RNA positive by nested RT‐PCR. Additionally, 15 HCV‐seronegative chronic liver disease patients with high ALT and AST values were screened for HCV RNA, of which five were positive whose viral load ranged from 1.2 × 10² to 4.4 × 10⁶ IU/mL, and the samples belonged to IVDUs and HIV‐co‐infected individuals. The results showed that HCV rapid immunoassay test cannot be solely relied on as an absolute and accurate diagnostic tool for screening infection of HCV particularly in high‐risk group patients such as IVDUs, haemodialysis, thalassaemic and HIV‐co‐infected patients who need HCV screening frequently.     

Hepatitis C virus treatment and survival in patients with hepatitis C and human immunodeficiency virus co‐infection and baseline anaemia

The impact of pretreatment anaemia on survival in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co‐infection is not known. Moreover, HCV treatment is offered less frequently to individuals with anaemia, due to haematological side effects of the treatment regimen. This study aimed to determine the effect of HCV treatment on survival among HCV/HIV co‐infected individuals with pretreatment anaemia using the Electronically Retrieved Cohort of HCV‐Infected Veterans (ERCHIVES). Individuals with HCV/HIV co‐infection were included in current analyses. Participants were considered treated if they were prescribed ≥4 weeks of HCV treatment. All‐cause mortality data were obtained using record linkage. Survival analyses were performed using Cox proportional hazard models. Among 5000 HCV/HIV co‐infected individuals, 1671 (33.4%) had pretreatment anaemia. In a follow‐up period of up to 7 years (19 500 person‐years), individuals with anaemia had significantly higher mortality rate compared with those without anaemia [144.2 (95% CI: 134.5–154.7) vs 47.5 (44.0–51.2) per 1000 person‐years, respectively]. Among individuals with anaemia, HCV treatment was associated with significantly lower mortality rate [66.6 (44.3–100.2) vs 149.6 (139.2–160.5) per 1000 person‐years, for treated vs untreated, respectively]. Treatment remained associated with substantial survival benefit after taking into account the effect of multiple comorbidities (hazards ratio: 0.34, 95% CI: 0.21–0.62). These data suggest that HCV/HIV co‐infected individuals with pretreatment anaemia have significantly higher mortality compared with those without anaemia. HCV treatment is associated with substantial survival benefit in this group. Additional studies are needed to determine strategies to improve HCV treatment rates among this group.     

Analysis of resistance‐associated substitutions in acute hepatitis C virus infection by deep sequencing across six genotypes and three continents

Several direct‐acting antivirals (DAAs) have been approved for the treatment of chronic hepatitis C virus (HCV) infections, opening the door to highly effective interferon‐free treatment regimens. Resistance‐associated substitutions (RASs) have been reported both in treatment‐naïve patients and following treatment with protease (NS3), phosphoprotein (NS5A) and polymerase (NS5B) inhibitors. The prevalence of naturally occurring RASs in untreated HCV‐infected individuals has mostly been analysed in those infected with genotype 1 (GT1), in the late phase of infection, and only within limited regions of the genome. Furthermore, the geographic distribution of RASs remains poorly characterized. In this study, we used next‐generation sequencing to analyse full‐length HCV genomes for the prevalence of RASs in acute HCV infections identified in nine international prospective cohorts. RASs were analysed in 179 participants infected with all six major HCV genotypes (GT1‐GT6), and the geographic distribution of RASs was assessed in 107 GT1a and GT3a samples. While RASs were detected at varied frequencies across the three genomic regions, and between genotypes, RASs relevant to multiple DAAs in the leading IFN‐free regimens were rarely detected in combination. Low‐frequency RASs (<10% of the viral population) were also shown to have a GT‐specific distribution. The main RASs with geographic associations were NS3 Q80K in GT1a samples and NS5B N142T in GT3a. These data provide the backdrop for prospective surveillance of RASs during DAA treatment scale‐up.     

Treatment with direct‐acting antiviral agents of hepatitis C virus infection in injecting drug users: A prospective study

In this prospective study, we evaluated the effectiveness and tolerability of novel therapies against hepatitis C virus (HCV) in a cohort of PWID enrolled at our centre from April 2015 to July 2016. In this analysis, a total of 174 patients were included: eleven (6.3%) were treated with pegylated interferon (PEG‐IFN) and ribavirin (RBV) containing regimens, 163 (93.7%) with IFN‐free treatments. RBV has been used in 70 patients (40.2%); 59 (33.9%) patients were in opioid substitution therapy (OST) with methadone or buprenorphine. Overall, sustained virological response (SVR) has been observed in 162 subject (93.1%), breakthrough (BT) in three (1.7%), relapse in one (0.6%) and dropout in eight (4.6%). Treatment was interrupted for clinical conditions in seven patients: six (3.4%) had hepatic decompensation and one died for hepatocellular carcinoma (HCC). In multivariate analysis, predictive factors of treatment failure were as follows: albumin level below 3 g/dL (OR=7.190; 95% IC=1.236‐41.837; P<.001), MELD score >10 (OR=5.886; 95% IC=1.411‐35.994; P<.001) and years of HCV infection >20 (OR=1.286; 95% IC=0.556‐9.455; P=.016). In conclusion, treatment with DAAs was effective and well tolerated in PWID; cirrhotic subjects with MELD > 10 and albumin low level showed a higher risk of developing serious adverse events and treatment failure.     

Hepatitis C virus NS3/4A quasispecies diversity in acute hepatitis C infection in HIV‐1 co‐infected patients

The growing number of cases of acute hepatitis C (AHC) infections among human immunodeficiency virus type 1 (HIV‐1)‐positive men who have sex with men (MSM) in the last 10 years has promoted the search for predictors of AHC clearance as well as for epidemiological networks of viral transmission. We characterized the diversity and catalytic efficiency of HCV NS3/4A protease quasispecies in AHC patients coinfected with HIV‐1. Plasma samples obtained at HCV diagnosis from 18 MSM HIV‐coinfected patients with AHC were studied. Five HCV monoinfected patient samples with AHC were also investigated. An average of 39 clones from each sample was analysed. The catalytic efficiency of the dominant quasispecies (i.e. the most abundant) from each quasispecies was also assayed for mitochondrial antiviral signalling protein (MAVS) cleavage. Phylogenetic analysis identified two clusters of patients with highly related viruses, suggesting a common source of HCV infection. None of the 18 MSM HIV‐coinfected patients spontaneously cleared HCV, although 78% of the treated patients achieved a sustained virological response after early treatment with pegylated interferon (pegIFN) plus ribavirin (RBV). The synonymous‐nonsynonymous (ds/dn) mutation ratio, a marker of selective pressure, was higher in AHC compared to 26 HIV‐1‐infected men with genotype 1a chronic hepatitis C (CHC) (P < 0.0001). NS3/4A proteases from AHC patients also exhibited higher catalytic efficiency compared to CHC patients (P < 0.0001). No differences were found when ds/dn mutation ratios and NS3/4A protease catalytic efficiencies from AHC HIV‐coinfected patients were compared with AHC monoinfected patients. The presence of epidemiological networks of HCV transmission was confirmed among HIV‐1‐positive MSM. In addition, substantial genetic diversity was demonstrated in AHC. NS3/4A protease efficiency cleaving MAVS may be associated with virus transmission and response to pegIFN/RBV treatment.