ResearchPad - hepatitis-c-virus https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[The prevalence of hepatitis C virus in hemodialysis patients in Pakistan: A systematic review and meta-analysis]]> https://www.researchpad.co/article/elastic_article_14616 Hepatitis C virus (HCV) infection is one of the most common bloodborne viral infections reported in Pakistan. Frequent dialysis treatment of hemodialysis patients exposes them to a high risk of HCV infection. The main purpose of this paper is to quantify the prevalence of HCV in hemodialysis patients through a systematic review and meta-analysis.MethodsWe systematically searched PubMed, Medline, EMBASE, Pakistani Journals Online and Web of Science to identify studies published between 1 January 1995 and 30 October 2019, reporting on the prevalence of HCV infection in hemodialysis patients. Meta-analysis was performed using a random-effects model to obtain pooled estimates. A funnel plot was used in conjunction with Egger’s regression test for asymmetry and to assess publication bias. Meta-regression and subgroup analyses were used to identify potential sources of heterogeneity among the included studies. This review was registered on PROSPERO (registration number CRD42019159345).ResultsOut of 248 potential studies, 19 studies involving 3446 hemodialysis patients were included in the meta-analysis. The pooled prevalence of HCV in hemodialysis patients in Pakistan was 32.33% (95% CI: 25.73–39.30; I2 = 94.3%, p < 0.01). The subgroup analysis showed that the prevalence of HCV among hemodialysis patients in Punjab was significantly higher (37.52%; 95% CI: 26.66–49.03; I2 = 94.5, p < 0.01) than 34.42% (95% CI: 14.95–57.05; I2 = 91.3%, p < 0.01) in Baluchistan, 27.11% (95% CI: 15.81–40.12; I2 = 94.5, p < 0.01) in Sindh and 22.61% (95% CI: 17.45–28.2; I2 = 78.6, p < 0.0117) in Khyber Pukhtoonkhuwa.ConclusionsIn this study, we found a high prevalence (32.33%) of HCV infection in hemodialysis patients in Pakistan. Clinically, hemodialysis patients require more attention and resources than the general population. Preventive interventions are urgently needed to decrease the high risk of HCV infection in hemodialysis patients in Pakistan. ]]> <![CDATA[Toward precision prescribing for methadone: Determinants of methadone deposition]]> https://www.researchpad.co/article/N51499fe4-a854-40f2-ac0e-5bd2b114360f

Background

Despite the World Health Organization listing methadone as an essential medication, effective dose selection is challenging, especially in racial and ethnic minority populations. Subtherapeutic doses can result in withdrawal symptoms while supratherapeutic doses can result in overdose and death. Although CYP3A4 was conventionally considered the principal methadone metabolizing enzyme, more recent data have identified CYP2B6 as the principal enzyme. CYP2B6 has ethnically-associated polymorphisms that affect the metabolic rate. Our objective was to investigate the effects of genetic and nongenetic factors on methadone metabolism.

Methods

We measured trough plasma methadone levels in 100 participants with opioid use disorder. We assessed methadone metabolism by calculating the metabolite ratio (major metabolite: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine [EDDP] divided by methadone concentration). We assessed hepatic fibrosis and steatosis by transient elastography and CYP2B6 alleles, principally responsible for methadone metabolism. Mixed effects models modeled the data in 97 participants.

Results

Participants were largely male (58%), minority (61% African American) and non-Hispanic (68%). Forty percent were HCV mono-infected, 40% were uninfected, and 20% were HCV/HIV co-infected. Female sex had significant effects on (R)- and (S)-methadone metabolism (p = 0.016 and p = 0.044, respectively). CYP2B6 loss of function (LOF) alleles significantly affected (S)-methadone metabolism (p = 0.012). Body mass index (BMI) significantly affected (R)-methadone metabolism (p = 0.034). Methadone metabolism appeared to be lower in males, in individuals with LOF alleles, and elevated BMI.

Conclusions

Genetic analysis, especially in minority populations, is essential to delivering individualized treatments. Although the principal methadone metabolizing enzyme remains controversial, our results suggest that sex, CYP2B6 genotype, and BMI should be incorporated into multivariate models to create methadone dosing algorithms. Methadone dosing algorithms should facilitate medication delivery, improve patient satisfaction, and diminish overdose potential.

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<![CDATA[Chronic Human Pegivirus 2 without Hepatitis C Virus Co-infection]]> https://www.researchpad.co/article/N10c54614-aecc-4774-9184-dd59d3723654

Most human pegivirus 2 (HPgV-2) infections are associated with past or current hepatitis C virus (HCV) infection. HPgV-2 is thought to be a bloodborne virus: higher prevalence of active infection has been found in populations with a history of parenteral exposure to viruses. We evaluated longitudinally collected blood samples obtained from injection drug users (IDUs) for active and resolved HPgV-2 infections using a combination of HPgV-2–specific molecular and serologic tests. We found evidence of HPgV-2 infection in 11.2% (22/197) of past or current HCV-infected IDUs, compared with 1.9% (4/205) of an HCV-negative IDU population. Testing of available longitudinal blood samples from HPgV-2–positive participants identified 5 with chronic infection (>6 months viremia in >3 timepoints); 2 were identified among the HCV-positive IDUs and 3 among the HCV-negative IDUs. Our findings indicate that HPgV-2 can establish chronic infection and replicate in the absence of HCV.

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<![CDATA[Dynamics of leukocyte telomere length in pregnant women living with HIV, and HIV-negative pregnant women: A longitudinal observational study]]> https://www.researchpad.co/article/5c897779d5eed0c4847d2db4

Background

HIV-mediated inflammation and immune activation can accelerate telomere attrition. In addition, antiretrovirals can inhibit telomerase, possibly shortening telomeres. We examined the longitudinal dynamics of leukocyte telomere length (LTL) during pregnancy in a unique cohort of women living with HIV (WLWH) treated with combination antiretroviral therapy (cART), and HIV-negative control women.

Methods

Blood was collected at three visits during pregnancy, at 13–23, >23–30, and >30–40 weeks of gestation, and for WLWH only, at 6 weeks post-partum. LTL was measured by qPCR and both cross-sectional and longitudinal (MANOVA) models were used to examine possible predictors of LTL among participants who attended all three visits during pregnancy.

Results

Among WLWH (n = 64) and HIV-negative women (n = 41), within participant LTL were correlated throughout pregnancy (p<0.001). LTL was shorter among WLWH at first visit, but this difference waned by the second visit. WLWH who discontinued cART post-partum experienced a decrease in LTL. Longitudinally, LTL was similar in both groups and increased as gestation progressed, a change that was more pronounced among women under 35 years. Among WLWH, both smoking throughout pregnancy (p = 0.04) and receiving a ritonavir-boosted protease inhibitor-based regimen (p = 0.03) were independently associated with shorter LTL.

Conclusions

LTL increases as pregnancy progresses; the reasons for this are unknown but may relate to changes in blood volume, hormones, and/or cell subset distribution. While our observations need confirmation in an independent cohort, our data suggest that although some cART regimens may influence LTL, being on cART appears overall protective and that stopping cART post-partum may negatively impact LTL. The effect of smoking on LTL is clearly negative, stressing the importance of smoking cessation.

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<![CDATA[HCV transmission in high-risk communities in Bulgaria]]> https://www.researchpad.co/article/5c882406d5eed0c4846395b0

Background

The rate of HIV infection in Bulgaria is low. However, the rate of HCV-HIV-coinfection and HCV infection is high, especially among high-risk communities. The molecular epidemiology of those infections has not been studied before.

Methods

Consensus Sanger sequences of HVR1 and NS5B from 125 cases of HIV/HCV coinfections, collected during 2010–2014 in 15 different Bulgarian cities, were used for preliminary phylogenetic evaluation. Next-generation sequencing (NGS) data of the hypervariable region 1 (HVR1) analyzed via the Global Hepatitis Outbreak and Surveillance Technology (GHOST) were used to evaluate genetic heterogeneity and possible transmission linkages. Links between pairs that were below and above the established genetic distance threshold, indicative of transmission, were further examined by generating k-step networks.

Results

Preliminary genetic analyses showed predominance of HCV genotype 1a (54%), followed by 1b (20.8%), 2a (1.4%), 3a (22.3%) and 4a (1.4%), indicating ongoing transmission of many HCV strains of different genotypes. NGS of HVR1 from 72 cases showed significant genetic heterogeneity of intra-host HCV populations, with 5 cases being infected with 2 different genotypes or subtypes and 6 cases being infected with 2 strains of same subtype. GHOST revealed 8 transmission clusters involving 30 cases (41.7%), indicating a high rate of transmission.

Four transmission clusters were found in Sofia, three in Plovdiv, and one in Peshtera. The main risk factor for the clusters was injection drug use. Close genetic proximity among HCV strains from the 3 Sofia clusters, and between HCV strains from Peshtera and one of the two Plovdiv clusters confirms a long and extensive transmission history of these strains in Bulgaria.

Conclusions

Identification of several HCV genotypes and many HCV strains suggests a frequent introduction of HCV to the studied high-risk communities. GHOST detected a broad transmission network, which sustains circulation of several HCV strains since their early introduction in the 3 cities. This is the first report on the molecular epidemiology of HIV/HCV coinfections in Bulgaria.

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<![CDATA[Modulation of calcium signaling pathway by hepatitis C virus core protein stimulates NLRP3 inflammasome activation]]> https://www.researchpad.co/article/5c803c6cd5eed0c484ad893f

Hepatitis C virus (HCV) infection remains a major cause of hepatic inflammation and liver disease. HCV triggers NLRP3 inflammasome activation and interleukin-1β (IL-1β) production from hepatic macrophages, or Kupffer cells, to drive the hepatic inflammatory response. Here we examined HCV activation of the NLRP3 inflammasome signaling cascade in primary human monocyte derived macrophages and THP-1 cell models of hepatic macrophages to define the HCV-specific agonist and cellular processes of inflammasome activation. We identified the HCV core protein as a virion-specific factor of inflammasome activation. The core protein was both necessary and sufficient for IL-1β production from macrophages exposed to HCV or soluble core protein alone. NLRP3 inflammasome activation by the HCV core protein required calcium mobilization linked with phospholipase-C activation. Our findings reveal a molecular basis of hepatic inflammasome activation and IL-1β release triggered by HCV core protein.

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<![CDATA[A novel point-of-care oral anti-HCV assay: Is it reliable for screening hepatitis C virus infection in the era of direct-acting antivirals?]]> https://www.researchpad.co/article/5c6c75cfd5eed0c4843d01fd

Recent advance in the direct-acting antivirals (DAAs) offers the potentials to eradicate hepatitis C virus (HCV) worldwide and makes universal screening more urgent. A point-of-care (POC) oral anti-HCV assay, the Fortune assay, was developed and its performance was evaluated. Individuals with or without HCV infection were recruited in three Centers. Paired oral and serum samples were tested using the Fortune and InTec anti-HCV assays. The Kehua serum anti-HCV assay served as a supplemental test to verify the discordant results. Some oral samples were also tested using the OraQuick anti-HCV assay. Furthermore, the Fortune assay results were compared with the documented RNA results. Sensitivity, specificity, and accuracy of the Fortune assay was 93.11%, 98.48%, and 96.58%, respectively (n = 1,022). Consistency between the Fortune and OraQuick assays was 96.35% (264/274); the Fortune assay detected additional 8 positive oral samples missed by the OraQuick assay. The Fortune assay demonstrated a 97.46% (115/118) positivity among the viremic patients. Furthermore, its sensitivity was HCV genotype independent. In conclusion, the Fortune assay was highly specific and accurate. It had comparable sensitivity as the serum assays for the diagnosis of active HCV infection. It provides a completely non-invasive and reliable tool for HCV screening in the DAA era.

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<![CDATA[Psychological distress mediated the effects of self-stigma on quality of life in opioid-dependent individuals: A cross-sectional study]]> https://www.researchpad.co/article/5c648cd9d5eed0c484c8193c

Background

Both stigma and psychological distress affect quality of life (QOL). This study is an attempt to determine the effects of these two factors on QOL and to explore possible mediation effects between psychological distress and self-stigma in opioid-dependent individuals.

Methods

This cross-sectional study comprised 268 consecutive, treatment-seeking opioid-dependent individuals who were interviewed using the brief version of the World Health Organization Quality of Life instrument (WHOQOL-BREF), the Self-Stigma Scale-Short (SSS-S), the Chinese Health Questionnaire-12 (CHQ-12), and the Opiate Treatment Index (OTI). A series of regression models were constructed to determine if the SSS-S and CHQ-12 predict the WHOQOL-BREF scores. Moreover, a comparison of the potential mediation effects of psychological distress (as assessed by the CHQ-12) was made between the SSS-S and the WHOQOL-BREF using the Baron and Kenny procedure (including three separate regressions), along with the Sobel test.

Results

The CHQ-12 score was predictive of the scores for the four domains and almost all facets of the WHOQOL-BREF except the item, “Dependence on medical aids.” Nonetheless, the SSS-S score predicted three of the four facets of the social QOL after adjustment of the CHQ-12 score. Psychological distress completely mediated the relation between self-stigma and the physical, psychological, and environmental domains, and partially mediated the relationship between self-stigma and social QOL (two-tailed Sobel test: p = 0.02 for each domain).

Conclusions

Psychological distress has a significant impact on the QOL of treated opioid users. It appears to be a core element in reducing the negative effects of self-stigma on aspects of QOL.

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<![CDATA[Phylogenetic analysis of hepatitis C virus among HIV/ HCV co-infected patients in Nigeria]]> https://www.researchpad.co/article/5c648d10d5eed0c484c81eb5

Hepatitis C virus (HCV) infection has been associated with liver disease including liver cirrhosis and hepatocellular carcinoma (HCC) in chronically-infected persons. However, in HIV/HCV co-infected patients, increased rate of progression to cirrhosis and HCC has been reported. Limited information exists regarding genetic variants of HCV circulating among co-infected patients, which could be important in the design of broadly protective vaccine and management of the disease. Here, we determined the genotypes of HCV isolates circulating among HIV/HCV co-infected patients in Ibadan, southwestern Nigeria. One hundred and twenty-five HIV/HCV IgM positive samples obtained from HIV laboratory, University of Ibadan were used for this study. HCV NS5B gene was amplified using polymerase chain reaction (PCR). The amplified NS5B gene was sequenced using gene specific primers. Twenty isolates were amplified, out of which 13 were successfully sequenced. Phylogenetic analysis of the 13 sequenced isolates showed three HCV subtypes 1a, 3a and 5a belonging to genotypes 1, 3 and 5 respectively. Ten isolates (77%) belong to subtype 5a, followed by 2 isolates (15%) subtype 1a and 1 isolate (8%) was subtype 3a. The predominant HCV genotype was 5, followed by genotype 1 (subtype 1a). The findings, as well as the observed mutations in NS5B gene, indicate the need for screening and monitoring of HIV/HCV co-infected patients. Further study to determine the phylogeny of isolates circulating in other parts of Nigeria will be carried out.

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<![CDATA[Mortality risk in the population of HIV-positive individuals in Southern China: A cohort study]]> https://www.researchpad.co/article/5c6b2637d5eed0c4842895b1

To evaluate the mortality risk in the HIV-positive population, we conducted an observational cohort study involving routine data collection of HIV-positive patients who presented at HIV clinics and multiple treatment centers throughout Guangxi province, Southern China in 2011. The patients were screened for tuberculosis (TB) and tested for hepatitis B (HBV) and C (HCV) virus infections yearly. Following the registration, the cohort was followed up for a 60-month period till the end-point (December 31, 2015). Univariable and multivariable Cox proportional hazards regression models were used to analyze the hazard ratio (HR) and 95% confidence interval (95% CI) for mortality after adjusting for confounding factors stratified by patients’ sociodemographic and behavioral characteristics. HRs were compared within risk-factor levels. With the median follow-up of 3.7-person years for each individual, 5,398 (37.8%) (of 14,293 patients with HIV/AIDS) died; among whom, 78.4% were antiretroviral therapy (ART)-naïve; 43.6% presented late; and 12.2% and 3.3% of patients had Mycobacterium tuberculosis (MTB) and HBV and HCV co-infection, respectively. Of individuals with CD4 counts, those with CD4 count >350 cells/μL formed 14.0% of those who died. Furthermore, gender [multivariable HR (95% CI):1.94 (1.68–2.25)], Han ethnicity [2.15 (1.07–4.32)], illiteracy [3.28 (1.96–5.5)], elementary education [2.91 (1.8–4.72)], late presentation [2.89 (2.46–3.39)], and MTB co-infection [1.28 (1.10–1.49)] strongly increased the all-cause mortality risk of HIV-positive individuals. The HR for ART-based stratification was 0.08 (0.07–0.09); and for HBV and HCV co-infection, HR was 1.02 (0.86–1.21). The findings emphasized that accessibility to HIV testing among high-risk populations and screening for viral hepatitis and TB co-infection are important for the survival of HIV-positive individuals. Initiating early ART, even for individuals with higher CD4 counts, is advisable to help increase the prolongation of lives within the community.

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<![CDATA[The association between inter-twin birth weight discordance and hepatitis C: The United States 2011–2015 twin birth registration data]]> https://www.researchpad.co/article/5c5b526bd5eed0c4842bc7c6

Background

Twins with discordant growth have increased risks of perinatal mortality and morbidity. Previous studies have identified a number of risk factors for inter-twin birth weight discordance, yet no study has examined the effect of maternal hepatitis C infection.

Methods

We used the twin birth records extracted from the 2011 to 2015 United States birth records created by the Centers for Disease Control and Prevention. The outcome variable of this study was inter-twin birth weight discordance, defined as [(birth weight of larger twin–birth weight of smaller twin) / birth weight of larger twin]. The independent association of hepatitis C infection with birth weight discordance was examined using the gamma regression or log binomial regression, adjusted by potential confounders.

Results

Of the 270,256 twin pairs included in the final analysis, 850 (0.31%) had positive hepatitis C. Compared to mothers without hepatitis C, mothers with hepatitis C positive tended to have higher risk of birth weight discordance, but with no statistical significance. After adjustment for potential confounding factors, hepatitis C positive became a significant risk factor for birth weight discordance >25% (relative risk 1.14, 95% confidence interval 1.02−1.29). Sensitivity analyses (by treating birth weight discordance as a continuous outcome or dichotomizing into by different cutoffs) yielded similar results, with relative risks ranging from 1.07 to 1.12 (all P<0.05).

Conclusion

Maternal hepatitis C positive is associated with inter-twin birth weight discordance, an important adverse infant outcome in twin pregnancies, although the effect size is small.

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<![CDATA[Increased liver stiffness is associated with mortality in HIV/HCV coinfected subjects: The French nationwide ANRS CO13 HEPAVIH cohort study]]> https://www.researchpad.co/article/5c57e6ecd5eed0c484ef4387

Background

The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study.

Methods

HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates.

Results

1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4–49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2–6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p<0.0001), history of HCV treatment (aHR = 0.53 [0.32; 0.90], p = 0.01) and smoking (past (aHR = 5.69 [1.56; 20.78]) and current (3.22 [0.93; 11.09]) versus never, p = 0.01) were associated with all-cause mortality independently of SVR, age, sex, alcohol use and metabolic disorders.

Conclusion

Any LSM >12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.

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<![CDATA[Early treatment of acute hepatitis C infection is cost-effective in HIV-infected men-who-have-sex-with-men]]> https://www.researchpad.co/article/5c40f79ed5eed0c4843864ac

Background

Treatment of hepatitis C virus infections (HCV) with direct acting antivirals (DAA) can prevent new infections since cured individuals cannot transmit HCV. However, as DAAs are expensive, many countries defer treatment to advances stages of fibrosis, which results in ongoing transmission. We assessed the epidemiological impact and cost-effectiveness of treatment initiation in different stages of infection in the Netherlands where the epidemic is mainly concentrated among HIV-infected MSMs.

Methods

We calibrated a deterministic mathematical model to the Dutch HCV epidemic among HIV-infected MSM to compare three different DAA treatment scenarios: 1) immediate treatment, 2) treatment delayed to chronic infection allowing spontaneous clearance to occur, 3) treatment delayed until F2 fibrosis stage. All scenarios are simulated from 2015 onwards. Total costs, quality adjusted life years (QALY), incremental cost-effectiveness ratios (ICERs), and epidemiological impact were calculated from a providers perspective over a lifetime horizon. We used a DAA price of €35,000 and 3% discounting rates for cost and QALYs.

Results

Immediate DAA treatment lowers the incidence from 1.2/100 person-years to 0.2/100 person-years (interquartile range 0.1–0.2) and the prevalence from 5.0/100 person-years to 0.5/100 person-years (0.4–0.6) after 20 years. Delayed treatment awaiting spontaneous clearance will result in a similar reduction. However, further delayed treatment to F2 will increases the incidence and prevalence. Earlier treatment will cost society €68.3 and €75.1 million over a lifetime for immediate and awaiting until the chronic stage, respectively. The cost will increase if treatment is further delayed until F2 to €98.4 million. Immediate treatment will prevent 7070 new infections and gains 3419 (3019–3854) QALYs compared to F2 treatment resulting in a cost saving ICER. Treatment in the chronic stage is however dominated.

Conclusions

Early DAA treatment for HIV-infected MSM is an excellent and sustainable tool to meet the WHO goal of eliminating HCV in 2030.

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<![CDATA[Modeling suggests that microliter volumes of contaminated blood caused an outbreak of hepatitis C during computerized tomography]]> https://www.researchpad.co/article/5c478c58d5eed0c484bd1b87

Background & aims

Acute hepatitis C (AHC) is not frequently identified because patients are usually asymptomatic, although may be recognized after iatrogenic exposures such as needle stick injuries, medical injection, and acupuncture. We describe an outbreak of AHC among 12 patients who received IV saline flush from a single multi-dose vial after intravenous contrast administration for a computerized tomography (CT) scan. The last patient to receive IV contrast with saline flush from a multi-dose vial at the clinic on the previous day was known to have chronic HCV genotype 1b (termed potential source, PS). Here we sought to confirm (via genetic analysis) the source of infection and to predict the minimal contaminating level of IV saline flush needed to transmit infectious virus to all patients.

Methods

In order to confirm the source of infection, we sequenced the HCV E1E2 region in 7 CT patients, in PS, and in 2 control samples from unrelated patients also infected with HCV genotype 1b. A transmission probabilistic model was developed to predict the contamination volume of blood that would have been sufficient to transmit infectious virus to all patients.

Results

Viral sequencing showed close clustering of the cases with the PS. The transmission probabilistic model predicted that contamination of the multi-dose saline vial with 0.6–8.7 microliters of blood would have been sufficient to transmit infectious virus to all patients.

Conclusion

Analysis of this unique cohort provides a new understanding of HCV transmission with respect to contaminating volumes and viral titers.

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<![CDATA[Validation of Multiplex Serology for human hepatitis viruses B and C, human T-lymphotropic virus 1 and Toxoplasma gondii]]> https://www.researchpad.co/article/5c3d012dd5eed0c484038f6b

Multiplex Serology is a high-throughput technology developed to simultaneously measure specific serum antibodies against multiple pathogens in one reaction vessel. Serological assays for hepatitis B (HBV) and C (HCV) viruses, human T-lymphotropic virus 1 (HTLV-1) and the protozoan parasite Toxoplasma gondii (T. gondii) were developed and validated against established reference assays. For each pathogen, between 3 and 5 specific antigens were recombinantly expressed as GST-tag fusion proteins in Escherichia coli and tested in Monoplex Serology, i.e. assays restricted to the antigens from one particular pathogen. For each of the four pathogen-specific Monoplex assays, overall seropositivity was defined using two pathogen-specific antigens. In the case of HBV Monoplex Serology, the detection of past natural HBV infection was validated based on two independent reference panels resulting in sensitivities of 92.3% and 93.0%, and specificities of 100% in both panels. Validation of HCV and HTLV-1 Monoplex Serology resulted in sensitivities of 98.0% and 95.0%, and specificities of 96.2% and 100.0%, respectively. The Monoplex Serology assay for T. gondii was validated with a sensitivity of 91.2% and specificity of 92.0%. The developed Monoplex Serology assays largely retained their characteristics when they were included in a multiplex panel (i.e. Multiplex Serology), containing additional antigens from a broad range of other pathogens. Thus HBV, HCV, HTLV-1 and T. gondii Monoplex Serology assays can efficiently be incorporated into Multiplex Serology panels tailored for application in seroepidemiological studies.

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<![CDATA[Machine learning models to predict disease progression among veterans with hepatitis C virus]]> https://www.researchpad.co/article/5c390bb0d5eed0c48491dd99

Background

Machine learning (ML) algorithms provide effective ways to build prediction models using longitudinal information given their capacity to incorporate numerous predictor variables without compromising the accuracy of the risk prediction. Clinical risk prediction models in chronic hepatitis C virus (CHC) can be challenging due to non-linear nature of disease progression. We developed and compared two ML algorithms to predict cirrhosis development in a large CHC-infected cohort using longitudinal data.

Methods and findings

We used national Veterans Health Administration (VHA) data to identify CHC patients in care between 2000–2016. The primary outcome was cirrhosis development ascertained by two consecutive aspartate aminotransferase (AST)-to-platelet ratio indexes (APRIs) > 2 after time zero given the infrequency of liver biopsy in clinical practice and that APRI is a validated non-invasive biomarker of fibrosis in CHC. We excluded those with initial APRI > 2 or pre-existing diagnosis of cirrhosis, hepatocellular carcinoma or hepatic decompensation. Enrollment was defined as the date of the first APRI. Time zero was defined as 2 years after enrollment. Cross-sectional (CS) models used predictors at or closest before time zero as a comparison. Longitudinal models used CS predictors plus longitudinal summary variables (maximum, minimum, maximum of slope, minimum of slope and total variation) between enrollment and time zero. Covariates included demographics, labs, and body mass index. Model performance was evaluated using concordance and area under the receiver operating curve (AuROC). A total of 72,683 individuals with CHC were analyzed with the cohort having a mean age of 52.8, 96.8% male and 53% white. There are 11,616 individuals (16%) who met the primary outcome over a mean follow-up of 7 years. We found superior predictive performance for the longitudinal Cox model compared to the CS Cox model (concordance 0.764 vs 0.746), and for the longitudinal boosted-survival-tree model compared to the linear Cox model (concordance 0.774 vs 0.764). The accuracy of the longitudinal models at 1,3,5 years after time zero also showed superior performance compared to the CS model, based on AuROC.

Conclusions

Boosted-survival-tree based models using longitudinal information are statistically superior to cross-sectional or linear models for predicting development of cirrhosis in CHC, though all four models were highly accurate. Similar statistical methods could be applied to predict outcomes in other non-linear chronic disease states.

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<![CDATA[Safety and efficacy of glecaprevir/pibrentasvir for the treatment of chronic hepatitis C in patients aged 65 years or older]]> https://www.researchpad.co/article/5c3667e9d5eed0c4841a68f0

Finding safe and effective treatments for chronic hepatitis C virus (HCV) infection in the elderly is of clinical interest given the comorbidities and associated polypharmacy in this population. However, the number of patients older than age 65 years enrolled into clinical trials of anti-HCV medications generally have been limited and thus reaching meaningful conclusions for this demographic has been difficult. Glecaprevir/pibrentasvir is a once-daily, all-oral, ribavirin-free, pangenotypic direct-acting antiviral (DAA) combination therapy that has demonstrated high sustained virologic response rates at post-treatment week 12 (SVR12) and a favorable safety profile in patients with chronic HCV infection. This analysis evaluated the safety and efficacy of glecaprevir/pibrentasvir in patients aged ≥65 years. Data were pooled for treatment-naïve and -experienced patients with chronic HCV genotype (GT) 1–6 infections who received glecaprevir/pibrentasvir for 8, 12, or 16 weeks in 9 Phase 2 and 3 trials. SVR12 and adverse events (AEs) were evaluated for patients aged ≥65 versus <65 years. Of the 2369 patients enrolled, 328 (14%) were aged ≥65 years. Among patients aged ≥65 years, 42% and 34% had GT1 and GT2, respectively; 40% were treatment-experienced and 20% had compensated cirrhosis. Glecaprevir/pibrentasvir treatment resulted in SVR12 rates of 97.9% (95% CI, 96.3–99.4; n/N = 321/328) for patients aged ≥65 years and 97.3% (95% CI, 96.6–98.0; n/N = 1986/2041) for patients aged <65 years. The rates were not significantly different between the two age groups (P = 0.555). DAA-related AEs leading to treatment discontinuation, or serious AEs were similarly rare (<0.5%) for patients ≥65 and <65 years old. Glecaprevir/pibrentasvir is an efficacious and well-tolerated treatment option for patients aged ≥65 years with chronic HCV infection.

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<![CDATA[Liver steatosis and dyslipidemia after HCV eradication by direct acting antiviral agents are synergistic risks of atherosclerosis]]> https://www.researchpad.co/article/5c26972cd5eed0c48470ed67

Aim

We comprehensively analyzed how hepatitis C virus (HCV) eradication by interferon (IFN)-free direct-acting-antiviral-agents (DAAs) affects liver steatosis and atherogenic risk.

Methods

Patients treated with IFN-free-DAAs who underwent transient elastography before and at 24-weeks post-treatment, including controlled attenuation parameter (CAP), and achieved sustained viral response (SVR) were enrolled. The association between changes in liver steatosis, lipid-metabolism, and genetic and clinical factors was analyzed.

Results

A total of 117 patients were included. The mean CAP and low-density lipoprotein cholesterol (LDL-C) levels were significantly elevated at SVR24. However, baseline LDL-C and CAP values were significantly negatively correlated with changes in these values after HCV eradication, indicating that in patients with high baseline values, the values generally decreased after HCV eradication. Mean small-dense LDL-C (sdLDL-C), which has greater atherogenic potential, was significantly elevated only in patients with both dyslipidemia (LDL-C >140 mg/dL) and liver steatosis (CAP >248 dB/m) at SVR24. Those patients had significant higher baseline BMI, LDL-C, and total-cholesterol levels.

Conclusions

Generally, successful HCV eradication by IFN-free-DAAs decreases CAP and LDL-C in patients with high baseline values. However, elevated LDL-C was accompanied with elevated sdLDL-C only in patients with liver steatosis and dyslipidemia at SVR24; therefore, those patients may require closer monitoring.

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<![CDATA[Distribution of HCV genotypes in Belgium from 2008 to 2015]]> https://www.researchpad.co/article/5c117b69d5eed0c484699195

Background

The knowledge of circulating HCV genotypes and subtypes in a country is crucial to guide antiviral therapy and to understand local epidemiology. Studies investigating circulating HCV genotypes and their trends have been conducted in Belgium. However they are outdated, lack nationwide representativeness or were not conducted in the general population.

Methods

In order to determine the distribution of different circulating HCV genotypes in Belgium, we conducted a multicentre study with all the 19 Belgian laboratories performing reimbursed HCV genotyping assays. Available genotype and subtype data were collected for the period from 2008 till 2015. Furthermore, a limited number of other variables were collected: some demographic characteristics from the patients and the laboratory technique used for the determination of the HCV genotype.

Results

For the study period, 11,033 unique records collected by the participating laboratories were used for further investigation.

HCV genotype 1 was the most prevalent (53.6%) genotype in Belgium, with G1a and G1b representing 19.7% and 31.6%, respectively. Genotype 3 was the next most prevalent (22.0%). Further, genotype 4, 2, and 5 were responsible for respectively 16.1%, 6.2%, and 1.9% of HCV infections. Genotype 6 and 7 comprise the remaining <1%. Throughout the years, a stable distribution was observed for most genotypes. Only for genotype 5, a decrease as a function of the year of analysis was observed, with respectively 3.6% for 2008, 2.3% for 2009 and 1.6% for the remaining years.

The overall M:F ratio was 1.59 and was mainly driven by the high M:F ratio of 3.03 for patients infected with genotype 3. Patients infected with genotype 3 are also younger (mean age 41.7 years) than patients infected with other genotypes (mean age above 50 years for all genotypes). The patients for whom a genotyping assay was performed in 2008 were younger than those from 2015.

Geographical distribution demonstrates that an important number of genotyped HCV patients live outside the Belgian metropolitan cities.

Conclusion

This national monitoring study allowed a clear and objective view of the circulating HCV genotypes in Belgium and will help health authorities in the establishment of cost effectiveness determinations before implementation of new treatment strategies.

This baseline characterization of the circulating genotypes is indispensable for a continuous surveillance, especially for the investigation of the possible impact of migration from endemic regions and prior to the increasing use of highly potent direct-acting antiviral (DAA) agents.

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<![CDATA[Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients]]> https://www.researchpad.co/article/5c0ed777d5eed0c484f141d9

Background & aims

Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients.

Methods

In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS.

Results

In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases.

Conclusions

A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.

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