Incidence of Liver Damage of Uncertain Origin in HIV Patients Not Co-Infected with HCV/HBV

Background and Aims

Several studies have reported that a significant number of HIV patients not co-infected with HCV/HBV develop liver damage of uncertain origin (LDUO). The objective of our study was to evaluate the incidence of and risk factors for the development of LDUO in HIV infected patients not co-infected with HCV/HBV.

Methods

Prospective longitudinal study that included HIV-infected patients free of previous liver damage and viral hepatitis B or C co-infections. Patients were followed up at 6-monthly intervals. Liver stiffness was measured at each visit. Abnormal liver stiffness (ALS) was defined as a liver stiffness value greater than 7.2 kPa at two consecutive measurements. For patients who developed ALS, a protocol was followed to diagnose the cause of liver damage. Those patients who could not be diagnosed with any specific cause of liver disease were diagnosed as LDUO and liver biopsy was proposed.

Results

210 patients matched the inclusion criteria and were included. 198 patients completed the study. After a median (Q1–Q3) follow-up of 18 (IQR 12–26) months, 21 patients (10.6%) developed ALS. Of these, fifteen patients were diagnosed as LDUO. The incidence of LDUO was 7.64 cases/100 patient-years. Histological studies were performed on ten (66.6%) patients and all showed liver steatosis. A higher HOMA-IR value and body mass index were independently associated with the development of LDUO.

Conclusion

We found a high incidence of LDUO in HIV-infected patients associated with metabolic risk factors. The leading cause of LDUO in our study was non-alcoholic fatty liver disease.     

HIV/HCV共感染者抗逆转录病毒治疗后免疫恢复情况

由于具有相同的传播途径,人类免疫缺陷病毒(Human immunodeficiency virus,HIV)和丙型肝炎病毒(Hepatitis C virus,HCV)共感染非常普遍,但是关于合并感染的程度,两种病毒之间的相互关系,在艾滋病抗逆转录病毒治疗(Antiretroviral therapy,ART)前后,HCV合并感染对HIV患者免疫细胞恢复的影响仍不明确。为了通过分析CD4⁺和CD8⁺T淋巴细胞数的变化,以了解辽宁省HIV/HCV共感染者ART后免疫恢复的情况,本研究从辽宁省艾滋病抗病毒治疗数据库中筛选符合要求的HIV感染者和HIV/HCV共感染者,收集感染者基本人口学资料及HCV抗体检测结果、HIV/HCV共感染途径等资料。采用t检验或卡方检验进行组间比较,采用Kaplan-Meier乘积极限法绘制生存分析函数图。结果显示,本研究共纳入HIV感染者12742人,HIV/HCV共感染者340人。HIV感染者和HIV/HCV共感染者的不同人口学特征均差异显著(P<0.001)。HIV感染和HIV/HCV共感染者ART治疗后CD4⁺细胞数和CD4⁺/CD8⁺比值显著升高(P<0.05),CD8⁺细胞数比ART前显著下降(P<0.05)。HIV/HCV共感染者随着ART时长,CD4⁺T淋巴细胞数恢复情况始终显著低于HIV感染者(P<0.05)。生存分析曲线表明,HCV/HIV共感染者从艾滋病诊断开始随着ART的治疗CD4⁺细胞恢复情况显著低于HIV感染者,Log-Rank检验统计量为4.483(P=0.034)。本研究揭示,HCV感染对ART患者CD4⁺和CD8⁺T淋巴细胞的恢复有影响。ART后HIV/HCV共感染者中CD4⁺T淋巴细胞计数的改善低于HIV单一感染者,并且单一感染患者对ART的反应比合并感染患者更好。因此,建议在启动ART之前,对每个感染HIV的患者进行HCV抗体筛查。     

Immune Biomarker Differences and Changes Comparing HCV Mono-Infected,HIV/HCV Co-Infected,and HCV Spontaneously Cleared Patients

Background

Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response

Methods

Fifty immune biomarkers were analyzed at baseline(BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error

Results

Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment

Conclusions

Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets     

Liver Fibrosis,Host Genetic and Hepatitis C Virus Related Parameters as Predictive Factors of Response to Therapy against Hepatitis C Virus in HIV/HCV Coinfected Patients

Objective

To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism).

Patients and Methods

A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count.

Results

Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis.

Conclusions

In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients.     

Progression of Liver Fibrosis in HIV/HCV Co-Infection: A Comparison between Non-Invasive Assessment Methods and Liver Biopsy

Objectives

To evaluate the diagnostic performance of seven non-invasive tests (NITs) of liver fibrosis and to assess fibrosis progression over time in HIV/HCV co-infected patients.

Methods

Transient elastography (TE) and six blood tests were compared to histopathological fibrosis stage (METAVIR). Participants were followed over three years with NITs at yearly intervals.

Results

Area under the receiver operating characteristic curve (AUROC) for significant fibrosis (> = F2) in 105 participants was highest for TE (0.85), followed by FIB-4 (0.77), ELF-Test (0.77), APRI (0.76), Fibrotest (0.75), hyaluronic acid (0.70), and Hepascore (0.68). AUROC for cirrhosis (F4) was 0.97 for TE followed by FIB-4 (0.91), APRI (0.89), Fibrotest (0.84), Hepascore (0.82), ELF-Test (0.82), and hyaluronic acid (0.79). A three year follow-up was completed by 87 participants, all on antiretroviral therapy and in 20 patients who completed HCV treatment (9 with sustained virologic response). TE, APRI and Fibrotest did not significantly change during follow-up. There was weak evidence for an increase of FIB-4 (mean increase: 0.22, p = 0.07). 42 participants had a second liver biopsy: Among 38 participants with F0-F3 at baseline, 10 were progessors (1-stage increase in fibrosis, 8 participants; 2-stage, 1; 3-stage, 1). Among progressors, mean increase in TE was 3.35 kPa, in APRI 0.36, and in FIB-4 0.75. Fibrotest results did not change over 3 years.

Conclusion

TE was the best NIT for liver fibrosis staging in HIV/HCV co-infected patients. APRI-Score, FIB-4 Index, Fibrotest, and ELF-Test were less reliable. Routinely available APRI and FIB-4 performed as good as more expensive tests. NITs did not change significantly during a follow-up of three years, suggesting slow liver disease progression in a majority of HIV/HCV co-infected persons on antiretroviral therapy.     

Survival and HLA-B*57 in HIV/HCV Co-Infected Patients on Highly Active Antiretroviral Therapy (HAART)

Background and aims

HLA class I alleles, in particular HLA-B*57, constitute the most consistent host factor determining outcomes in untreated HCV- and HIV-infection. In this prospective cohort study, we analysed the impact of HLA class I alleles on all-cause mortality in patients with HIV-, HCV- and HIV/HCV- co-infection receiving HAART.

Methods

In 2003 HLA-A and B alleles were determined and patients were prospectively followed in 3-month intervals until 2013 or death. HLA-A and B alleles were determined by strand-specific oligonucleotide hybridisation and PCR in 468 Caucasian patients with HCV- (n=120), HIV- (n=186) and HIV/HCV-infection (n=162). All patients with HIV-infection were on HAART. In each patient group, HLA class I-associated survival was analysed by Kaplan-Meier method and Cox regression analysis.

Results

At recruitment the proportion of patients carrying a HLA-B*57 allele differed between HIV- (12.9%) and HCV-infection (4.2%). Kaplan Meier analysis revealed significantly increased mortality in HLA-B*57-positive patients with HIV-infection (p=0.032) and HIV/HCV-co-infection (p=0.004), which was apparently linked to non-viral infections. Cox logistic regression analysis confirmed HLA-B*57 (p=0.001), serum gamma-glutamyltranspeptidase (p=0.003), serum bilirubin (p=0.022) and CD4 counts (p=0.041) as independent predictors of death in HIV-infected patients.

Conclusion

Differences in the prevalence of HLA-B*57 at study entry between HIV- and HCV- infected patients may reflect immune selection in the absence of antiviral therapy. When patients were treated with HAART, however, HLA-B*57 was associated with increased mortality and risk to die from bacterial infections and sepsis, suggesting an ambiguous role of HLA-B*57 for survival in HIV/HCV infection depending on the circumstances.     

PRO-C3-Levels in Patients with HIV/HCV-Co-Infection Reflect Fibrosis Stage and Degree of Portal Hypertension

Background

Liver-related deaths represent the leading cause of mortality among patients with HIV/HCV-co-infection, and are mainly related to complications of fibrosis and portal hypertension. In this study, we aimed to evaluate the structural changes by the assessment of extracellular matrix (ECM) derived degradation fragments in peripheral blood as biomarkers for fibrosis and portal hypertension in patients with HIV/HCV co-infection.

Methods

Fifty-eight patients (67% male, mean age: 36.5 years) with HIV/HCV-co-infection were included in the study. Hepatic venous pressure gradient (HVPG) was measured in forty-three patients. The fibrosis stage was determined using FIB4 -Score. ECM degraded products in peripheral blood were measured using specific ELISAs (C4M, MMP-2/9 degraded type IV collagen; C5M, MMP-2/9 degraded type V collagen; PRO-C3, MMP degraded n-terminal propeptide of type III collagen).

Results

As expected, HVPG showed strong and significant correlations with FIB4-index (r_s = 0.628; p = 7*10⁻⁷). Interestingly, PRO-C3 significantly correlated with HVPG (r_s = 0.354; p = 0.02), alanine aminotransferase (r_s = 0.30; p = 0.038), as well as with FIB4-index (r_s = 0.3230; p = 0.035). C4M and C5M levels were higher in patients with portal hypertension (HVPG>5 mmHg).

Conclusion

PRO-C3 levels reflect liver injury, stage of liver fibrosis and degree of portal hypertension in HIV/HCV-co-infected patients. Furthermore, C4M and C5M were associated with increased portal pressure. Circulating markers of hepatic ECM remodeling might be helpful in the diagnosis and management of liver disease and portal hypertension in patients with HIV/HCV coinfection.     

乙肝患者血清标志物与肝纤维化血清学指标的相关性分析

目的:探讨乙肝患者血清标志物与肝纤维化血清学指标的相关性。方法:收集我院收治的136例乙型病毒肝炎患者,根据轻中重程度分为轻度组、中度组以及重度组,每组42例。观察并比较所有患者乙肝血清标志物、HBV-DNA水平、透明质酸(HA),血清Ⅲ型前胶原肽(PCⅢ),Ⅳ型胶原(CIV)水平以及层粘连蛋白(LN)水平。结果:三组患者的HBV-DNA水平依次升高,与轻度组相比,中度组、重度组患者HBV-DNA水平较高,与中度组患者相比,重度组患者HBV-DNA水平较高,差异具有统计学意义(P0.05)。与轻度组相比,中度组、重度组患者HA、PCⅢ、CIV、LN水平较高,与中度组患者相比,重度组患者HA、PCⅢ水平较高,差异具有统计学意义(P0.05);HBV-DNA水平与HA、PCⅢ、CIV、LN水平均呈显著正相关。结论:乙肝患者的血清学检测指标与血清肝纤维化测定有助于对乙肝的纤维化过程的进展情况进行评估。     

Predictors of Death during Tuberculosis Treatment in TB/HIV Co-Infected Patients in Malaysia

Background

Mortality among TB/HIV co-infected patients is still high particularly in developing countries. This study aimed to determine the predictors of death in TB/HIV co-infected patients during TB treatment.

Methods

We reviewed medical records at the time of TB diagnosis and subsequent follow-up of all newly registered TB patients with HIV co-infection at TB clinics in the Institute of Respiratory Medicine and three public hospitals in the Klang Valley between January 2010 and September 2010. We reviewed these medical records again twelve months after their initial diagnosis to determine treatment outcomes and survival. We analysed using Kaplan-Meier and conducted multivariate Cox proportional hazards analysis to identify predictors of death during TB treatment in TB/HIV co-infected patients.

Results

Of the 227 patients studied, 53 (23.3%) had died at the end of the study with 40% of deaths within two months of TB diagnosis. Survival at 2, 6 and 12 months after initiating TB treatment were 90.7%, 82.8% and 78.8% respectively. After adjusting for other factors, death in TB/HIV co-infected patients was associated with being Malay (aHR 4.48; 95%CI 1.73-11.64), CD4 T-lymphocytes count < 200 cells/µl (aHR 3.89; 95% CI 1.20-12.63), three or more opportunistic infections (aHR 3.61; 95% CI 1.04-12.55), not receiving antiretroviral therapy (aHR 3.21; 95% CI 1.76-5.85) and increase per 10³ total white blood cell count per microliter (aHR 1.12; 95% CI 1.05-1.20)

Conclusion

TB/HIV co-infected patients had a high case fatality rate during TB treatment. Initiation of antiretroviral therapy in these patients can improve survival by restoring immune function and preventing opportunistic infections.     

超声造影对肝硬化和肝纤维化的应用价值

目的：评估超声造影对于肝硬化和肝纤维化的I临床应用价值。方法：选取2011年5月至2013年5月在我院接受诊治的慢性病毒性肝炎患者32例,其中肝纤维化24例,肝硬化12例,均经过超声造影下的肝功能检测和肝穿刺病理证实。另选取10例到我院经检查身体健康的志愿者作为对照组,无任何肝脏病史。采用实时灰阶造影,经肘静脉注射造影SonoVue,记录测定造影剂进入肝静脉到达时间（HVAT）、肝动脉到达时间（HAAT）及肝动静脉渡越时间（HAVTT）。结果：肝纤维化组超声造影剂到达肝静脉的时间较对照组明显延长,肝硬化组较对照组和肝纤维化组的超声造影剂到达肝静脉的时间要明显缩短,差异符合统计学意义（P〈0．05）;造影剂到达肝动脉的时间组间比较无统计学差异;肝硬化组肝动静脉渡越时间（HAVTT）较对照组时间明显缩短,组间比较具有统计学差异（P〈0．05）;HAVTT随着肝纤维化程度的升高而缩短,中、重度肝纤维化患者的时间缩短较明显,差异具有统计学意义（P〈0．05）。结论：超声造影在肝硬化和肝纤维化诊断上具有一定的临床诊断价值,尤其是对于诊断肝纤维化程度具有重要的参考价值,可以更好地指导临床治疗,但是对于轻度的肝纤维化的诊断的准确性上有些缺陷。     

Predictive Value of Proteinuria in Adult Dengue Severity

Background

Dengue is an important viral infection with different presentations. Predicting disease severity is important in triaging patients requiring hospital care. We aim to study the value of proteinuria in predicting the development of dengue hemorrhagic fever (DHF), utility of urine dipstick test as a rapid prognostic tool.

Methodology and principal findings

Adult patients with undifferentiated fever (n = 293) were prospectively enrolled at the Infectious Disease Research Clinic at Tan Tock Seng Hospital, Singapore from January to August 2012. Dengue infection was confirmed in 168 (57%) by dengue RT-PCR or NS1 antigen detection. Dengue cases had median fever duration of 6 days at enrolment. DHF was diagnosed in 34 cases according to the WHO 1997 guideline. Dengue fever (DF) patients were predominantly younger and were mostly seen in the outpatient setting with higher platelet level. Compared to DF, DHF cases had significantly higher peak urine protein creatinine ratio (UPCR) during clinical course (26 vs. 40 mg/mmol; p<0.001). We obtained a UPCR cut-off value of 29 mg/mmol based on maximum AUC in ROC curves of peak UPCR for DF versus DHF, corresponding to 76% sensitivity and 60% specificity. Multivariate analysis with other readily available clinical and laboratory variables increased the AUC to 0.91 with 92% sensitivity and 80% specificity. Neither urine dipstick at initial presentation nor peak urine dipstick value during the entire illness was able to discriminate between DF and DHF.

Conclusions

Proteinuria measured by a laboratory-based UPCR test may be sensitive and specific in prognosticating adult dengue patients.     

The Impact of PNPLA3 rs738409 SNP on Liver Fibrosis Progression,Portal Hypertension and Hepatic Steatosis in HIV/HCV Coinfection

Background

Faster fibrosis progression and hepatic steatosis are hallmarks of HIV/HCV coinfection. A single nucleotide polymorphism (SNP) of the PNPLA3-gene is associated with development of non-alcoholic steatohepatitis and a worse outcome in alcoholic liver disease. However, the role of PNPLA3 rs738409 SNP on liver fibrosis and steatosis, portal hypertension, and virological response in HIV/HCV coinfection remains unclear.

Methods

In this cross-sectional study PNPLA3 (rs738409) and IL28B (rs12979860) SNPs were determined in 177 HIV/HCV coinfected patients. Liver fibrosis and steatosis—staged by liver biopsy and transient elastography using the Controlled Attenuation Parameter (CAP)–and portal hypertension (hepatic venous pressure gradient, HVPG) were compared across PNPLA3 genotypes.

Results

75 (42.4%) patients tested positive for a PNPLA3 minor/major risk allele (G/C:66; G/G:9) showed comparable fibrosis stages (median F2 vs. F2; p = 0.292) and similar amounts of hepatic steatosis (CAP: 203.5±41.9 vs. 215.5±59.7dB/m; p = 0.563) as compared to patients without a PNPLA3 risk allele. Advanced liver fibrosis was neither associated with PNPLA3 (p = 0.253) nor IL28B-genotype (p = 0.628), but with HCV-GT3 (p = 0.003), higher BMI (p = 0.008) and higher age (p = 0.007). Fibrosis progression rate (0.27±0.41 vs. 0.20±0.26 units/year; p = 0.984) and HVPG (3.9±2.6 vs. 4.4±3.0 mmHg; p = 0.472) were similar in patients with and without PNPLA3 risk alleles. SVR rates to PEGIFN/RBV therapy were similar across PNPLA3 genotypes.

Conclusions

The presence of a PNPLA3 risk allele had no independent impact on liver disease or virological response rates to PEGIFN/RBV therapy in our cohort of HIV/HCV coinfected patients.     

还原型谷胱甘肽联合多烯磷脂酰胆碱对急性药物性肝损伤患者肝功能、肝纤维化指标及血清炎性因子的影响

摘要 目的：探讨还原型谷胱甘肽联合多烯磷脂酰胆碱对急性药物性肝损伤（ADILI）患者肝功能、肝纤维化指标及血清炎性因子的影响。方法：选择2017年1月~2019年3月期间我院收治的ADILI患者100例,采用随机数字表法分为对照组和联合组,各50例。对照组给予多烯磷脂酰胆碱治疗,联合组给予还原型谷胱甘肽联合多烯磷脂酰胆碱治疗,对比两组疗效、肝功能指标[谷丙转氨酶（ALT）、谷草转氨酶（AST）、总胆红素（TBIL）和谷氨酰转肽酶（GGT）]、肝纤维化指标[层粘连蛋白（LN）、III型前胶原（PC-III）、IV型胶原（IV-C）、透明质酸酶（HA）]、血清炎性因子[白介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、白介素-2（IL-2）]及不良反应。结果：对照组的总有效率为76.00%（38/50）,联合组的总有效率为94.00%（47/50）,联合组的总有效率高于对照组（P<0.05）。治疗4周后,两组ALT、AST、TBIL、GGT、LN、PC-III、IV-C、HA、IL-2、TNF-α、IL-6水平均较治疗前下降,且联合组低于对照组（P<0.05）。两组治疗期间不良反应发生率比较无明显差异（P>0.05）。结论：在多烯磷脂酰胆碱基础上,联合还原型谷胱甘肽治疗ADILI患者,疗效较好,可改善肝功能和肝纤维化指标,减轻机体炎症反应,且安全可靠。     

Liver transplantation for patients infected with both HIV and HCV or HIV and HBV

Human immunodeficiency virus infection (HIV) has been considered until recently as a contraindication for liver transplantation. This was due to the poor spontaneous prognosis of HIV infection. The advent of highly active antiretroviral drugs (HAART) was a therapeutic breakthrough, and the prognosis has been dramatically improved. 30 % and 10 % of HIV infected patients are coinfected with hepatitis C virus (HCV) and with hepatitis B virus (HBV), respectively. The progression of chronic hepatitis B and C seems more rapid in coinfected patients, and a high number of patients will develop life-threatening liver cirrhosis. There are numerous potential problems raised by liver transplantation in HIV infected patients: (1) the potential risk of needlestick injury during this type of hemorrhagic surgery at high risk of bleeding; (2) the timing for liver transplantation; (3) the risk of interference between HAART and calcineurin inhibitors; (4) The risk of HBV and HCV recurrence post-transplant. Since 1999, a program of liver transplantation has been started in patients coinfected with HIV and HBV or HCV with the support of the Agence Nationale de Recherche contre le Sida et les Hépatites virales (ANRS). The first results showed that liver transplantation in HIV-HCV and HIV-HBV infected patients is feasible, achieving 2-year survival of 70 % and 100 %, respectively. There was no acceleration of HIV disease after transplantation. HBV recurrence was well prevented by the combination of anti-HBs immunoglobulins plus nucleoside and nucleotide analogues effective against HBV. The main problem is HCV recurrence, which is more rapid and more severe in HIV coinfected patients than in HCV monoinfected patients. Understanding HCV recurrence mechanisms, and preventing and treating of HCV recurrence are major future challenges.     

Performance of Two HCV RNA Assays during Protease Inhibitor-Based Triple Therapy in Patients with Advanced Liver Fibrosis and Cirrhosis

Introduction

On-treatment HCV RNA measurements are crucial for the prediction of a sustained virological response (SVR) and to determine treatment futility during protease inhibitor-based triple therapies. In patients with advanced liver disease an accurate risk/benefit calculation based on reliable HCV RNA results can reduce the number of adverse events. However, the different available HCV RNA assays vary in their diagnostic performance.

Aim

To investigate the clinical relevance of concordant and discordant results of two HCV RNA assays during triple therapy with boceprevir and telaprevir in patients with advanced liver fibrosis/cirrhosis.

Methods

We collected on-treatment samples of 191 patients with advanced liver fibrosis/cirrhosis treated at four European centers for testing with the Abbott RealTime (ART) and COBAS AmpliPrep/COBAS TaqMan HCV v2.0 (CTM) assays.

Results

Discordant test results for HCV RNA detectability were observed in 23% at week 4, 17% at week 8/12 and 9% at week 24 on-treatment. The ART detected HCV RNA in 41% of week 4 samples tested negative by the CTM. However, the positive predictive value of an undetectable week 4 result for SVR was similar for both assays (80% and 82%). Discordance was also found for application of stopping rules. In 27% of patients who met stopping rules by CTM the ART measured levels below the respective cut-offs of 100 and 1000 IU/ml, respectively, which would have resulted in treatment continuation. In contrast, in nine patients with negative HCV RNA by CTM at week 24 treatment would have been discontinued due to detectable residual HCV RNA by the ART assay. Importantly, only 4 of these patients failed to achieve SVR.

Conclusion

Application of stopping rules determined in approval studies by one assay to other HCV RNA assays in clinical practice may lead to over and undertreatment in a significant number of patients undergoing protease inhibitor-based triple therapy.     

Serum Cell Death Biomarkers for Prediction of Liver Fibrosis and Poor Prognosis in Primary Biliary Cirrhosis

The development of simple, noninvasive markers of liver fibrosis is urgently needed for primary biliary cirrhosis (PBC). This study examined the ability of several serum biomarkers of cell death to estimate fibrosis and prognosis in PBC. A cohort of 130 patients with biopsy-proven PBC and 90 healthy subjects were enrolled. We assessed the utility of the M30 ELISA, which detects caspase-cleaved cytokeratin-18 (CK-18) fragments and is representative of apoptotic cell death, as well as the M65 and newly developed M65 Epideath (M65ED) ELISAs, which detect total CK-18 as indicators of overall cell death, in predicting clinically relevant fibrosis stage. All 3 cell death biomarkers were significantly higher in patients with PBC than in healthy controls and were significantly correlated with fibrosis stage. The areas under the receiver operating characteristic curve for the M65 and M65ED assays for differentiation among significant fibrosis, severe fibrosis, and cirrhosis were 0.66 and 0.76, 0.66 and 0.73, and 0.74 and 0.82, respectively. In multivariate analysis, high M65ED (hazard ratio 6.13; 95% confidence interval 1.18–31.69; P = 0.031) and severe fibrosis (hazard ratio 7.45; 95% confidence interval 1.82–30.51; P = 0.005) were independently associated with liver-related death, transplantation, or decompensation. High serum M65ED was also significantly associated with poor outcome in PBC (log-rank test; P = 0.001). Noninvasive cell death biomarkers appear to be clinically useful in predicting fibrosis in PBC. Moreover, the M65ED assay may represent a new surrogate marker of adverse disease outcome.     

CD127 Expression,Exhaustion Status and Antigen Specific Proliferation Predict Sustained Virologic Response to IFN in HCV/HIV Co-Infected Individuals

Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in the HIV co-infected population. Interferon-alpha (IFN-α) remains a major component of anti-HCV therapy despite its deleterious effects on the immune system. Furthermore, IFN-α was recently shown to diminish the size of the latent HIV reservoir. The objectives of this study were to monitor the impact of IFN-α on T cell phenotype and proliferation of HIV and HCV-specific T cells during IFN therapy, and to identify immune markers that can predict the response to IFN in HICV/HIV co-infected patients. We performed longitudinal analyses of T cell numbers, phenotype and function in co-infected patients undergoing IFN-α therapy with different outcomes including IFN-α non-responders (NR) (n = 9) and patients who achieved sustained virologic response (SVR) (n = 19). We examined the expression of activation (CD38, HLA-DR), functional (CD127) and exhaustion markers (PD1, Tim-3, CD160 and CD244) on total CD4 and CD8 T cells before, during and after therapy. In addition, we examined the HIV- and HCV-specific proliferative responses against HIV-p24 and HCV-NS3 proteins. Frequencies of CD127⁺ CD4 T cells were higher in SVR than in NR patients at baseline. An increase in CD127 expression on CD8 T cells was observed after IFN-α therapy in all patients. In addition, CD8 T cells from NR patients expressed a higher exhaustion status at baseline. Finally, SVR patients exhibited higher proliferative response against both HIV and HCV antigens at baseline. Altogether, SVR correlated with higher expression of CD127, lower T cell exhaustion status and better HIV and HCV proliferative responses at baseline. Such factors might be used as non-invasive methods to predict the success of IFN–based therapies in co-infected individuals.     

Complementary Role of HCV and HIV in T-Cell Activation and Exhaustion in HIV/HCV Coinfection

Objectives

To investigate whether T-cell activation and exhaustion is linked to HCV- and HIV disease parameters in HIV/HCV infected individuals, we studied T-cell characteristics in HIV/HCV coinfected patients and controls.

Methods

14 HIV/HCV coinfected, 19 HCV monoinfected, 10 HIV monoinfected patients and 15 healthy controls were included in this cross-sectional study. Differences in expression of activation and exhaustion markers (HLA-DR, CD38, PD-1, Tim-3 and Fas) and phenotypic markers on CD4⁺ and CD8⁺ T-cells were analysed by flow cytometry and were related to HCV disease parameters (HCV-viremia, ALT and liver fibrosis).

Results

Frequencies of activated CD4⁺ and CD8⁺ T-cells were higher in HIV/HCV-coinfected compared to healthy controls and HCV or HIV mono-infected individuals. Coinfected patients also showed high expression of the exhaustion marker PD-1 and death receptor Fas. In contrast, the exhaustion marker Tim-3 was only elevated in HIV-monoinfected patients. T-cell activation and exhaustion were correlated with HCV-RNA, suggesting that viral antigen influences T-cell activation and exhaustion. Interestingly, increased percentages of effector CD8⁺ T-cells were found in patients with severe (F3–F4) liver fibrosis compared to those with no to minimal fibrosis (F0–F2).

Conclusions

HIV/HCV coinfected patients display a high level of T-cell activation and exhaustion in the peripheral blood. Our data suggest that T-cell activation and exhaustion are influenced by the level of HCV viremia. Furthermore, high percentages of cytotoxic/effector CD8⁺ T-cells are associated with liver fibrosis in both HCV monoinfected and HIV/HCV coinfected patients.