Behzad Hajarizadeh

EPIDEMIOLOGY AND NATURAL HISTORY OF HCV INFECTION

Worldwide, an estimated 130–170 million people have HCV infection. HCV prevalence is highest in Egypt at >10% of the general population and China has the most people with HCV (29.8 million). Differences in past HCV incidence and current HCV prevalence, together with the generally protracted nature of HCV disease progression, has led to considerable diversity in the burden of advanced liver disease in different countries. Countries with a high incidence of HCV or peak incidence in the recent past will have further escalations in HCV-related cirrhosis and hepatocellular carcinoma (HCC) over the next two decades. Acute HCV infection is difficult to detect because of the generally asymptomatic nature of the disease and the marginalization of at-risk populations. Around 25% of patients with acute HCV infection undergo spontaneous clearance, with increased rates among those with favourable IL28B genotypes, acute symptoms and in women. The remaining 75% of patients progress to chronic HCV infection and are subsequently at risk of progression to hepatic fibrosis, cirrhosis and HCC. Chronic hepatitis C generally progresses slowly in the initial two decades, but can be accelerated during this time as a result of advancing age and co-factors such as heavy alcohol intake and HIV co-infection.

The effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection.

Although 20%‐40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin‐28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty‐eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow‐up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non‐genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex‐based differences in HCV control. (Hepatology 2014;58:109–120)

Prevalence of hepatitis C virus infection and related risk factors among Iranian haemodialysis patients

SUMMARY:  Hepatitis C virus (HCV) infection is common among patients undergoing haemodialysis, and liver disease is an important cause of morbidity and mortality in this population. Management of HCV‐related liver disease is a major health concern in patients with end‐stage renal disease (ESRD) undergoing haemodialysis. To investigate the prevalence of HCV infection in patients on haemodialysis and its associated risk factors, we conducted a prospective case series study of 838 patients on haemodialysis in Tehran, Iran. Patients were selected randomly (cluster sampling) and all were screened for anti‐HCV antibodies, using ELISA 3rd generation and confirmed by using RIBA 2nd generation. We found that 111 patients (13.2%) were infected. By applying univariate analysis, longer duration on haemodialysis (P = 0.000), more weekly dialysis sessions (P = 0.03), history of blood transfusion (P = 0.03) and history of previous renal transplantation (P = 0.01) were found to be associated with a higher rate of HCV infection. Multivariate analysis revealed that only length of time on dialysis (P = 0.000) and history of blood transfusion (P = 0.02) were significantly associated with HCV infection. The more the units transfused, the higher the rate of HCV infection. Our results suggest that early transplantation and avoidance of blood transfusion, as much as possible, are the two most important practical interventions to reduce the HCV exposure rate in our patients on haemodialysis.

Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study.

Background Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection. Methods Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels≤120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression. Results Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P=0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83). Conclusions Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.

Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression

BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. The aims of this study were to compare the rate of HCC occurrence in patients with HCV-related cirrhosis, following DAA vs. interferon (IFN)-based cure, and to compare the rate of HCC recurrence in patients who received curative HCC treatment, following DAA vs. IFN-based cure. METHODS A search was conducted for reports published between January 2000 and February 2017. Studies were included if they assessed HCC outcomes by type and response to HCV therapy. Random-effects meta-analyses were undertaken to determine a combined estimate of HCC incidence rate per 100/person-years (py) among patients with a sustained virological response (SVR). RESULTS A total of 41 studies (n=13,875 patients), including 26 on HCC occurrence (IFN=17, DAA=9; prospective=19, retrospective=5, retrospective-prospective=2), and 17 on HCC recurrence (IFN=7, DAA=10; prospective=11, retrospective=5 and retrospective-prospective=1) were included. In studies assessing HCC occurrence, average follow-up was shorter (1.0 vs. 5.5years), and average age older (60 vs. 52years) in DAA studies. In studies assessing HCC recurrence, average follow-up was shorter (1.3 vs. 5.0years), but average age similar (64 vs. 66years) in DAA studies. HCC occurrence was 1.14/100 py (95% CI 0.86-1.52) and 2.96/100 py (95% CI 1.76-4.96) in IFN and DAA studies respectively. HCC recurrence was 9.21/100 py (95% CI 7.18-11.81) and 12.16/100 py (95% CI 5.00-29.58) in IFN and DAA studies respectively. In meta-regression adjusting for study follow-up and age, DAA therapy was not associated with higher HCC occurrence (RR 0.68; 95% CI 0.18-2.55; p=0.55) or recurrence (RR 0.62, 95% CI 0.11-3.45, p=0.56). CONCLUSION There is no evidence for differential HCC occurrence or recurrence risk following SVR from DAA and IFN-based therapy. LAY SUMMARY The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. We conducted a meta-analysis to compare occurrence and recurrence of HCC in patients receiving either DAA or interferon (IFN) therapy. There is no evidence that HCC occurrence or recurrence is different between patients receiving DAA or IFN therapy.

Non-alcoholic fatty liver disease prevalence among school-aged children and adolescents in Iran and its association with biochemical and anthropometric measures.

Objective: To investigate the prevalence of non‐alcoholic fatty liver disease (NAFLD) as well as the determination of associated metabolic abnormalities in Iranian school‐aged children and adolescents.

Pretransplant hepatitis C virus infection and its effect on the post-transplant course of living renal allograft recipients

Background: Hepatitis C virus infection (HCV) is a main health problem in end‐stage renal disease (ESRD) patients. The effect of pretransplant HCV infection on survival among ESRD patients who have undergone renal transplantation is controversial. We report the results of a large monocenter study that evaluated the effect of hepatitis C on the patient, and on graft survival in renal‐transplanted patients who received living donated allograft.

Hepatitis C virus reinfection and spontaneous clearance of reinfection - the InC3 study

BACKGROUND We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance. METHODS Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain). RESULTS Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021). CONCLUSIONS Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.

Case definitions for acute hepatitis C virus infection: a systematic review.

BACKGROUND & AIMS Case definitions for recent hepatitis C virus (HCV) infection vary considerably between studies. The aim of this systematic review was to characterize case definitions for recent HCV and explore the heterogeneity in studies performed to date. METHODS A systematic literature search of MEDLINE, SCOPUS, and ISI Web of Knowledge was performed covering all studies of recent HCV infection cited between January 2000 and June 2011. The criteria used by each study to define cases of recent HCV infection were extracted, structured, and analyzed. RESULTS Overall, 195 articles were included, with 87% (n=169) providing a clear case definition for recent HCV infection. The most frequently used individual criteria for defining a case included HCV antibody seroconversion (77%), alanine aminotransferase (ALT) elevation (68%), and HCV RNA detection (63%). In studies using HCV antibody seroconversion, the window period between the last negative and the first positive antibody test varied widely across studies (4 weeks to 4 years). Considerable diversity was also observed with respect to the ALT threshold used to characterize ALT elevations, ranging from 2 to 20 times the upper limit of normal. HCV antibody seroconversion was used as a single criterion in 41% of the studies, while all other studies used at least two criteria (range: 2-9). Epidemiology/surveillance studies mostly used a more sensitive case definition, whereas treatment studies, natural history studies, and diagnosis studies used more specific case definitions. CONCLUSIONS Marked heterogeneity in case definitions for recent HCV infection was observed. Although a single case definition for recent HCV is not warranted, a degree of standardization within specific study categories would enable improved cross-study comparison and more uniform evaluation of HCV prevention and management strategies.

Evaluation of the Xpert HCV Viral Load point-of-care assay from venepuncture-collected and finger-stick capillary whole-blood samples: a cohort study

BACKGROUND Point-of-care hepatitis C virus (HCV) RNA testing offers an advantage over antibody testing (which only indicates previous exposure), enabling diagnosis of active infection in a single visit. In this study, we evaluated the performance of the Xpert HCV Viral Load assay with venepuncture and finger-stick capillary whole-blood samples. METHODS Plasma and finger-stick capillary whole-blood samples were collected from participants in an observational cohort enrolled at five sites in Australia (three drug and alcohol clinics, one homelessness service, and one needle and syringe programme). We compared the sensitivity and specificity of the Xpert HCV Viral Load test for HCV RNA detection by venepuncture and finger-stick collection with the Abbott RealTime HCV Viral Load assay (gold standard). FINDINGS Of 210 participants enrolled between Feb 8, 2016, and July 27, 2016, 150 participants had viral load testing results for the three assays tested. HCV RNA was detected in 45 (30% [95% CI 23-38]) of 150 participants based on Abbott RealTime. Sensitivity of the Xpert HCV Viral Load assay for HCV RNA detection in plasma collected by venepuncture was 100·0% (95% CI 92·0-100·0) and specificity was 99·1% (95% CI 94·9-100·0). Sensitivity of the Xpert HCV Viral Load assay for HCV RNA detection in samples collected by finger-stick was 95·5% (95% CI 84·5-99·4) and specificity was 98·1% (95% CI 93·4-99·8). No adverse events caused by the index test or the reference standard were observed. IMPLICATIONS The Xpert HCV Viral Load test can detect active infection from a finger-stick sample, which represents an advance over antibody-based tests that only indicate past or previous exposure. FUNDING National Health and Medical Research Council (Australia), Cepheid, South Eastern Sydney Local Health District (Australia), and Merck Sharp & Dohme (Australia).