Hepatic fibrosis and immune phenotype vary by HCV viremia in HCV/HIV co-infected subjects: A Women's interagency HIV study.
ABSTRACT: HCV and HIV independently lead to immune dysregulation. The mechanisms leading to advanced liver disease progression in HCV/HIV coinfected subjects remain unclear.In this cross-sectional study, we assessed the association of HCV viremia, liver fibrosis, and immune response patterns in well-characterized HIV phenotypes: Elite controllers (Elites), HIV controlled (ARTc), and HIV uncontrolled (ARTuc) matched by age and race. Groups were stratified by HCV RNA status. Regulatory T-cell frequencies, T-cell activation (HLADR+CD38+), apoptosis (Caspase-3+), and intracellular cytokines (interferon-?, IL-2, IL-17) were assessed using multiparametric flow-cytometry. Liver fibrosis was scored by AST to platelet ratio index (APRI).We found liver fibrosis (APRI) was 50% lower in Elites and ARTc compared to ARTuc. Higher liver fibrosis was associated with significantly low CD4+ T cell counts (P?
Project description:Hepatitis C virus infection induces inflammation and while it is believed that HIV co-infection enhances this response, HIV control may reduce inflammation and liver fibrosis in resolved or viremic HCV infection. Measurement of systemic biomarkers in co-infection could help define the mechanism of inflammation on fibrosis and determine if HIV control reduces liver pathology. A nested case-control study was performed to explore the relationship of systemic biomarkers of inflammation with liver fibrosis in HCV viremic and/or seropositive women with and without HIV infection. Serum cytokines, chemokines, growth factors and cell adhesion molecules were measured in HIV uninfected (HIV-, n = 18), ART-treated HIV-controlled (ARTc, n = 20), uncontrolled on anti-retroviral therapy (ARTuc, n = 21) and elite HIV controllers (Elite, n = 20). All were HCV seroreactive and had either resolved (HCV RNA-; <50IU/mL) or had chronic HCV infection (HCV RNA+). In HCV and HIV groups, aspartate aminotransferase to platelet ratio (APRI) was measured and compared to serum cytokines, chemokines, growth factors and cell adhesion molecules. APRI correlated with sVCAM, sICAM, IL-10, and IP-10 levels and inversely correlated with EGF, IL-17, TGF-? and MMP-9 levels. Collectively, all HCV RNA+ subjects had higher sVCAM, sICAM and IP-10 compared to HCV RNA-. In the ART-treated HCV RNA+ groups, TNF-?, GRO, IP-10, MCP-1 and MDC were higher than HIV-, Elite or both. In ARTuc, FGF-2, MPO, soluble E-selectin, MMP-9, IL-17, GM-CSF and TGF-? are lower than HIV-, Elite or both. Differential expression of soluble markers may reveal mechanisms of pathogenesis or possibly reduction of fibrosis in HCV/HIV co-infection.
Project description:The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of -0.46% (-1.61% to 0.71%) in HIV mono-infected compared to 2.54% (-1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population.
Project description:HIV increases the risk of liver disease as do two common coinfections, hepatitis B and C viruses (HBV and HCV). However, whether combination antiretroviral therapy (cART) reverses or exacerbates hepatic fibrosis remains unclear.This was an observational retrospective study. cART-naïve HIV-infected subjects without a history of substance abuse (including alcohol) had liver disease stage determined by aspartate aminotransferase-to-platelet ratio indices (APRIs) and fibrosis-4 (FIB-4) before and 24 and 48 weeks after cART. All the data were retrieved from previously established cohorts. Values before and after cART were compared using Wilcoxon test for paired samples. Regression analyses were used to determine factors associated with moderate-to-severe liver disease.Of the 1105 HIV-infected subjects, 120 were HBV coinfected and 64 were HCV coinfected. About 20% of HIV monoinfected participants had APRI and FIB-4 scores consistent with moderate-to-significant fibrosis compared to ?36% of HIV-HBV coinfected and 67% to 77% of HIV-HCV coinfected participants. In adjusted analyses compared with HIV monoinfection, HBV coinfection was associated with 1.18-fold higher APRI (P?<?0.001) and a 1.12-fold higher FIB-4 (P?=?0.007) prior to cART; while HCV coinfection was associated with 1.94-fold higher APRI (P?<?0.001) and a 1.43-fold higher FIB-4 (P?<?0.001). After 48 weeks of cART, both fibrosis scores decreased in all subjects; however, HCV coinfection was still associated with higher fibrosis scores at week 48 compared to HIV monoinfection.cART was associated with improvement in hepatic fibrosis scores in the majority of HIV-hepatitis coinfected and HIV-monoinfected Chinese participants.
Project description: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.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.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.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.
Project description:Coinfection with hepatitis C virus (HCV) is a major cause of morbidity and mortality among individuals with HIV. Our objective was to assess the prognostic performance of noninvasive measures of liver fibrosis in predicting all-cause mortality in women with HIV/HCV coinfection.We studied HCV/HIV coinfected women enrolled in the prospective, multicenter Women's Interagency HIV Study. Aspartate aminotransferase to platelet ratio and FIB-4 were used to identify women without fibrosis at all visits and women who progressed to severe fibrosis.Enhanced liver fibrosis (ELF), which utilizes direct measures of fibrosis, hyaluronic acid, procollagen III aminoterminal peptide and tissue inhibitor of matrix metalloproteinase was performed.Included were 381 women with 2296 ELF measurements, with mean follow-up 8.3?±?3.3 years. There were 134 deaths (60% with severe liver fibrosis). Receiver operator characteristic curves at fixed time windows prior to death or at end of follow-up showed that ELF was best at predicting mortality when tested within a year of death (area under the curve for ELF 0.85 vs. APRI 0.69, P?<?0.0001 and vs. FIB-4 0.75, P?=?0.0036); and 1-3 years prior (ELF 0.71 vs. APRI 0.61, P?=?0.005 and vs. FIB-4 0.65, P?=?0.06). Use of all three measures did not improve on ELF alone. In multivariate logistic regression models controlling for CD4 cell count, HIV viral load, antiretroviral use and age, ELF continued to perform better than APRI and FIB-4.ELF predicted all-cause mortality and was superior to APRI and FIB-4 in HIV/HCV coinfected women.
Project description:Human leukocyte antigen (HLA) class I and II genotype is associated with clearance of hepatitis C virus (HCV) infection, but little is known regarding its relation with HCV viral load or risk of liver disease in patients with persistent HCV infection.High-resolution HLA class I and II genotyping was conducted in a prospective cohort of 519 human immunodeficiency virus (HIV)-seropositive and 100 HIV-seronegative women with persistent HCV infection. The end points were baseline HCV viral load and 2 noninvasive indexes of liver disease, fibrosis-4 (FIB-4), and the aspartate aminotransferase to platelet ratio index (APRI), measured at baseline and prospectively.DQB1*0301 was associated with low baseline HCV load (? = -.4; 95% confidence interval [CI], -.6 to -.3; P < .00001), as well as with low odds of FIB-4-defined (odds ratio [OR], .5; 95% CI, .2-.9; P = .02) and APRI-defined liver fibrosis (OR, .5; 95% CI, .3-1.0; P = .06) at baseline and/or during follow-up. Most additional associations with HCV viral load also involved HLA class II alleles. Additional associations with FIB-4 and APRI primarily involved class I alleles, for example, the relation of B*1503 with APRI-defined fibrosis had an OR of 2.0 (95% CI, 1.0-3.7; P = .04).HLA genotype may influence HCV viral load and risk of liver disease, including DQB1*0301, which was associated with HCV clearance in prior studies.
Project description:HIV-elite controllers are a minority group of HIV-infected patients with the ability to maintain undetectable HIV viremia for long time periods without antiretroviral treatment. A small group of HIV-controllers are also able to spontaneously clear the hepatitis C virus (HCV) whom we can refer to as "supercontrollers." There are no studies that explore immune correlates looking for the mechanisms implicated in this extraordinary phenomenon. Herein, we have analyzed HCV- and HIV-specific T-cell responses, as well as T, dendritic and NK cell phenotypes. The higher HCV-specific CD4 T-cell polyfunctionality, together with a low activation and exhaustion T-cell phenotype was found in supercontrollers. In addition, the frequency of CD8 CD161high T-cells was related with HIV- and HCV-specific T-cells polyfunctionality. Interesting features regarding NK and plasmacytoid dendritic cells (pDCs) were found. The study of the supercontroller's immune response, subjects that spontaneously controls both chronic viral infections, could provide further insights into virus-specific responses needed to develop immunotherapeutic strategies in the setting of HIV cure or HCV vaccination.
Project description:Liver fibrosis progresses faster in individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Interferon λ3 (IFN-λ3) has both antiviral and proinflammatory properties. Genotypes at IFNL single-nucleotide proteins (SNPs; rs12979860CC and rs8099917TT) are linked to higher HCV clearance, potentially via rs8103142. We examined the relationship between IFN-λ genotypes and significant liver fibrosis in HIV-HCV coinfection.From the prospective Canadian Co-infection Cohort (n = 1423), HCV RNA-positive participants in whom IFN-λ genotypes were detected and who were free of fibrosis, end-stage liver disease, and chronic hepatitis B at baseline (n = 485) were included. Time to significant fibrosis (defined as an aspartate transaminase level to platelet count ratio index [APRI] of ≥1.5) by IFN-λ genotypes was analyzed using Cox proportional hazards, with adjustment for age, sex, ethnicity, alcohol use, CD4(+) T-cell count, HCV genotype, γ-glutamyl transferase level, and baseline APRI. Haplotype analysis was performed, with adjustment for ethnicity.A total of 125 participants developed fibrosis over 1595 person-years (7.84 cases/100 person-years; 95% confidence interval [CI], 6.58-9.34 cases/100 person-years). Each genotype was associated with an increased fibrosis risk, with adjusted hazard ratios of 1.37 (95% CI, .94-2.02) for rs12979860CC, 1.34 (95% CI, .91-1.97) for rs8103142TT, and 1.79 (95% CI, 1.24-2.57) for rs8099917TT. Haplotype TCT was also linked with a higher risk (hazard ratio, 1.14 [95% CI, .73-1.77]).IFN-λ SNPs rs12979860, rs8099917, and rs81013142 were individually linked to higher rates of fibrosis in individuals with HIV-HCV coinfection. IFN-λ genotypes may be useful to target HCV treatments to people who are at higher risk of liver disease.
Project description:Liver diseases progress faster in human immunodeficiency virus (HIV)-hepatitis C virus (HCV)-coinfected persons than HIV-monoinfected persons. The aim of this study was to compare rates of liver fibrosis progression (measured by the aspartate-to-platelet ratio index [APRI]) among HIV-HCV-coinfected users of modern protease inhibitor (PI)- and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens with a backbone of tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC).Data from a Canadian multicenter cohort study were analyzed, including 315 HCV polymerase chain reaction-positive persons who initiated antiretroviral therapy with a PI or NNRTI and a backbone containing either TDF/FTC or ABC/3TC. Multivariate linear regression analyses with generalized estimating equations were performed after propensity score matching to balance covariates across classes of anchor agent.A backbone of TDF/FTC was received by 67% of PI users and 69% of NNRTI users. Both PI and NNRTI use was associated with increases in APRI over time when paired with a backbone of ABC/3TC: 16% per 5 years (95% confidence interval [CI], 4%, 29%) and 11% per 5 years (95% CI, 2%, 20%), respectively. With TDF/FTC use, no clear association was found among PI users (8% per 5 years, 95% CI, -3%, 19%) or NNRTI users (3% per 5 years, 95% CI, -7%, 12%).Liver fibrosis progression was more influenced by the backbone than by the class of anchor agent in HIV-HCV-coinfected persons. Only ABC/3TC-containing regimens were associated with an increase of APRI score over time, regardless of the class of anchor agent used.
Project description:Hepatic steatosis (HS) is common in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, but the independent contributions of HCV and HIV to HS are unclear. Magnetic resonance imaging and spectroscopy were used to measure visceral adipose tissue (VAT) and liver fat fraction (LFF) (total lipids/[total lipids?+?water]) in 356 adults: 57 with HCV monoinfection, 70 with HIV/HCV coinfection, 122 with HIV monoinfection, and 107 with neither infection. Participants who were infected with HCV genotype 3 were excluded because of the genotype's reported steatogenic effects. For prevalence estimates, HS was defined as LFF???0.05. We estimated the association of HIV and HCV status with LFF using multivariable linear regression, adjusting for demographics, lifestyle, and metabolic factors including the homeostasis model assessment estimate of insulin resistance (HOMA-IR) and liver fibrosis defined using the aspartate aminotransferase-to-platelet ratio index (APRI). The prevalence of HS was highest in the uninfected (33%) and HIV-monoinfected (28%), followed by the HCV-monoinfected (19%) and HIV/HCV-coinfected (11%) (P?=?0.003 across groups). Compared with uninfected participants-and after adjusting for demographics, lifestyle, and metabolic factors-HIV monoinfection, HCV monoinfection, and HIV/HCV coinfection were associated with 19% (95% confidence interval [CI], -39% to 6%), 38% (95% CI, -55% to -12%), and 42% (95% CI, -59% to -18%) lower LFF, respectively. HCV monoinfection and HIV/HCV coinfection remained strongly associated with lower LFF after further adjusting for APRI, and results were unchanged after excluding subjects with suspected cirrhosis. Among the entire cohort, Hispanic ethnicity, male sex, VAT, and HOMA-IR were independently associated with greater LFF.Contrary to expectations, HIV/HCV-coinfected and HCV-monoinfected adults had significantly less liver fat than uninfected adults, even after adjusting for demographics, lifestyle, metabolic factors, and hepatic fibrosis. Our findings suggest that non-genotype 3 HCV infection may be protective against HS. The mechanisms by which this occurs and the impact of HCV treatment on HS requires further investigation. (Hepatology 2017;65:853-863).