Long-term evolution in liver fibrosis and immune profile after direct-acting antivirals therapy in hepatitis C virus-human immunodeficiency virus co-infected patients

ObjectiveHepatitis C virus (HCV) therapy with direct-acting antivirals (DAA) achieves high rates of sustained virological response in people living with human immunodeficiency virus (HIV) (PLWH). Information on its long-term clinical impact is scarce. The aim of this study was to analyse liver fibrosis and immune response evolution after DAA treatment.MethodsRetrospective, single centre cohort study of HIV-HCV co-infected patients treated with DAA between June 2013 and June 2018. We analysed the changes during follow up in liver fibrosis (assessed by transient elastography (TE), aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 scores) and immunity (CD4 and CD8 cells counts and CD4/CD8 ratio).ResultsWe included 410 patients; 75% (308/407) men with a mean age of 50 years (SD 8); 78% (318/410) had long chronic HCV infection (median 21 years, interquartile range (IQR) 6–27 years) and 27% (107/393) had liver cirrhosis. Liver fibrosis improvement based on the decrease in TE value compared with the baseline occurred in 43% (131/302) of patients and 31% of patients based on biological scores (APRI: 124/398; FIB-4: 104/398) (p < 0.0001), being more frequent in those with advanced baseline fibrosis (83/144). The higher decrease was observed at 6 months after DAA therapy (–0.23; 95% CI –0.29 to –0.18), but a continuum in fibrosis regression of at least 30% from baseline value of TE was observed along the follow up (32% of patients at month 6, 51% at month 24 and 55% at month 48). Regarding the immunological profile, there was a significant decrease in CD8 counts at month 48 (–62.38; 95% CI –106.77 to –17.99; p 0.0001) and a progressive rise in the CD4/CD8 ratio after 24 months of follow up reaching an increment of +0.07 (95% CI 0.03–0.10, p 0.0001) at month 48.ConclusionsHCV treatment with DAA in PLWH is associated with significant progressive improvement in liver fibrosis and recovery of the immune system with an increase in the CD4/CD8 ratio in long-term follow up.     

Liver histopathology in patients with concurrent chronic hepatitis C and HIV infection

To investigate the influence of human immunodeficiency virus (HIV) coinfection on preexisting long-term chronic C hepatitis (HCV) 68 liver biopsies from 22 HIV/HCV-coinfected, 13 HIV and 33 HCV-monoinfected patients and 71 livers obtained at autopsy from 26 HIV/HCV-coinfected and 45 HIV-monoinfected patients were studied by histo- and immunohistochemistry. All HIV patients had reached the advanced stage of immunodeficiency (stage III CDC), except for 3 haemophiliacs (stage II CDC). HCV infection was associated with a higher degree of portal, periportal and lobular inflammation — regardless of whether there was concurrent HIV infection. HIV/HCV coinfection was associated with a significantly higher rate of granulocytic cholangiolitis than HCV and HIV monoinfection (P < 0.05), a histological feature uncommon in C hepatitis. In HIV/HCV coinfection cholestasis was a predominant histological feature. HCV monoinfection and HCV/HIV coinfection were associated with the highest fibrosis index. In HIV/HCV coinfection centrilobular fibrosis was significantly more marked than in HCV monoinfection (P < 0.05), suggesting an HIV associated fibrogenic effect. Patients with chronic C hepatitis showed a significantly increased rate of posthepatitic cirrhosis compared with the patients without HCV infection (P < 0.05). At autopsy, 10 of the 20 HIV/HCV-coinfected haemophiliacs had developed cirrhosis because of chronic C hepatitis, whereas cirrhosis was found in only 2 of 6 HIV/HCV-coinfected non-haemophiliacs (1 case of chronic B and C hepatitis, and 1 case of chronic alcohol abuse). No cirrhosis was observed in the 45 autopsy patients with HIV monoinfection. The findings suggest that HIV coinfection aggravates the course of preceding long-term chronic C hepatitis by a more marked (centrilobular) fibrosis. HIV/HCV-coinfected patients are threatened by a higher rate of posthepatitic cirrhosis —particularly in multitransfused haemophiliacs — and cholestatic hepatopathy.     

Liver Enzyme Elevation During Darunavir-Based Antiretroviral Treatment in HIV-1–Infected Patients With or Without Hepatitis C Coinfection: Data from the ICONA Foundation Cohort

Objectives: To investigate differences in liver enzyme elevation (LEE) between HIV-infected patients with and without HCV coinfection who start a darunavir/ritonavir-containing regimen. Methods: HIV-infected patients enrolled in the Italian Cohort of Naïve to Antiretrovirals (ICONA) Foundation Study were included if they started darunavir/ritonavir for the first time. Patients were classified as not HCV coinfected, HCV active coinfected (HCV RNA positive), and HCV nonactive coinfected (HCV-Ab positive/HCV RNA negative). Time to LEE endpoint was defined using the ACTG toxicity scale, based on changes relative to baseline. Kaplan-Meier was used to estimate 1-year and 2-year probability of LEE. The incidence rate ratios (IRRs) of LEEs were estimated until the last follow-up (intention-to-treat analysis [ITT]) and up to darunavir/ritonavir discontinuation (on-treatment analysis [OT]). Results: Overall, 703 patients were included. Ninety-one were HCV-Ab positive; of those, 68 (9.7%) had active HCV coinfection. In 879 person-years of follow-up, 101 LEEs occurred (ITT). No severe hepatotoxicity event was registered in active HCV coinfected patients. HCV active coinfection was predictive of LEE in the overall population (OT: adjusted incidence rate ratio (IRR), 2.25; 95% CI, 0.70–7.24; P = .17; ITT: adjusted IRR, 3.62; 95% CI, 1.67–7.83; P .001) and in naïve patients (OT: adjusted IRR, 6.29; 95% CI, 2.54–15.55; P = .00; ITT: adjusted IRR, 3.87; 95% CI, 0.99–15.16; P = .05). Conclusions: No grade 3–4 LEEs occurred in HCV active coinfected patients. HCV active coinfected patients experienced low grade LEEs more frequently than HCV-Ab negative patients. Darunavir/ritonavir seems to be safe whatever the HCV status, when liver enzymes are carefully monitored.     

Association of torque teno virus (TTV) and torque teno mini virus (TTMV) with liver disease among patients coinfected with human immunodeficiency virus and hepatitis C virus

Torque teno virus (TTV) and torque teno mini virus (TTMV) have been potentially related to liver diseases. The aim of the study was to quantify TTV and TTMV in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients to study the relationship between the TTV and TTMV viral loads and the severity of liver disease. We carried out a cross-sectional study in 245 patients coinfected with HIV and HCV (HIV/HCV-group), 114 patients monoinfected with HIV (HIV-group), and 100 healthy blood donors (Control-group). Plasma samples were tested for TTV and TTMV by quantitative real-time polymerase chain reaction (PCR). The prevalences of TTV and TTMV infections in the HIV/HCV-group and the HIV-group were significantly higher than the Control-group (p?<?0.05). Furthermore, TTV and TTMV coinfections were found in 92.2 % (226/245) in the HIV/HCV-group, 84.2 % (96/114) in the HIV-group, and 63 % (63/100 %) in the Control-group (p?≤?0.05). HIV/HCV-coinfected patients with HIV viral load ≥50 copies/mL and patients with severe activity grade had the highest viral loads of TTV and TTMV (p?≤?0.05). HIV/HCV-coinfected patients with high TTV load (>2.78 log copies/μL) had increased odds of having advanced fibrosis or severe necroinflammatory activity grade in the liver biopsy. Moreover, HIV/HCV-coinfected patients with high TTMV load (>1.88 log copies/μL) had decreased odds of having no/minimal fibrosis and no/mild activity grade, and increased odds of having a high fibrosis progression rate. In conclusion, TTV and TTMV might play a role in the development of liver disease in immunodeficiency patients, such as the patients coinfected with HIV and HCV.     

HIV replication is associated with increased severity of liver biopsy changes in HIV-HBV and HIV-HCV co-infection

Histological parameters were assessed in liver biopsies (n = 48) performed in patients co‐infected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in order to evaluate factors which were associated with significant liver disease. Necroinflammation and fibrosis was scored by the Ishak classification system, and binary logistic regression analysis was used to assess HIV and antiretroviral‐related determinants of necroinflammation and fibrosis. A total of 46 biopsies were included; 33 were from HIV‐positive patients co‐infected with HCV and 15 biopsies were from HIV‐positive patients co‐infected with HBV. One HIV‐positive patient was co‐infected with HBV and HCV. Median biopsy inflammatory grade for the cohort was 8.5 (IQR 6–10), the median fibrosis Stage 2 (IQR 1.8–4), and the median steatosis score was 1 (IQR 0–2). At the univariate level, HIV‐related variables that were significantly associated with more severe biopsy changes were higher HIV RNA at the time of biopsy (associated with inflammatory Grade 10+; P = 0.018) and any exposure to didanasine (ddI) or stavudine (D4T; associated with fibrosis Stage 3+; P = 0.022). HIV RNA at the time of biopsy remained significant at the multivariate level. Patients with HIV hepatitis co‐infection in this cohort had surprisingly mild changes in liver histology, and there were no statistically significant differences between biopsy results in HBV compared to HCV co‐infection. The association between HIV RNA and necroinflammation supports current recommendations for earlier initiation of HAART in patients with HIV‐hepatitis co‐infection. J. Med. Virol. 84: 993–1001, 2012. © 2012 Wiley Periodicals, Inc.     

Human platelet antigens polymorphisms; association to the development of liver fibrosis in patients with chronic hepatitis C

Recently, human platelet antigens (HPAs) polymorphisms are found to play a role in susceptibility to hepatitis C virus (HCV) infection and fibrosis progression. The aim of the current study was to evaluate the possible association between the HPAs polymorphisms with liver fibrosis progression in HCV patients. HPAs polymorphisms genotyping was performed in HCV patients (n = 71) by Sequence-specific primers-polymerase chain reaction. Fibrosis progression was evaluated using the Metavir scoring system and liver biopsy, and the patients were assigned to two groups, namely, G1 (n = 35) that included patients with F1 (portal fibrosis without septa) or F2 (few septa) and G2 (n = 36) that comprised patients with F3 (numerous septa) or F4 (cirrhosis). The data analyses were performed using Pearson's χ² test. The genotype frequency of HPA-3ab was significantly higher in G1 patients than in G2 patients (P = 0.015). No statistically significant differences were found between the patient groups (G1 and G2) regarding the distributions of the allelic and genotypic frequencies of the HPA-1, -2, -4, -5, and -15 systems. Multivariate logistic regression showed an independent association between the genotype HPA-3aa/BB and severe fibrosis (F3-F4), when compared with genotype HPA-3ab, independent of the viral genotype, high alanine transaminase, sex, age, time of infection, diabetes, and high cholesterol as risk factors. The present study suggested that the HPA-3ab genotype could be noticed as a potential protecting factor against hepatic fibrosis. Therefore, the antigenic variation of integrins might be considered as a part of the coordinated inflammatory process involved in the progression of liver fibrosis.     

Dysregulation of toll‐like receptor (TLR) 2 expression on monocytes and upregulation of the frequency of T cells expressing TLR2 in patients with chronic hepatitis C virus infection

Toll‐like receptors (TLRs) initiate inflammatory responses that may play a role in disease progression in patients infected with hepatitis C virus (HCV). TLR2 and TLR4 surface expression were assessed on CD14⁺ monocytes, CD4⁺ and CD8⁺ T cells in treatment naïve patients with chronic HCV infection with fibrosis, without fibrosis, co‐infected with human immunodeficiency virus (HIV), and in healthy controls. Increased expression of TLR2 was found on monocytes in HCV‐infected patients with fibrosis (p < 0.01), co‐infected with HIV (p = 0.03), and possibly in patients without fibrosis (p = 0.07) when compared to controls. TLR2 positive CD4⁺ and CD8⁺ T cells were upregulated in patients with fibrosis only (p < 0.01). However, expression of TLR2 was not associated with T cell activation. TLR4 expression was similar in patients and healthy controls. In conclusion, TLR2 expression on monocytes and the frequency of T cells expressing TLR2 may contribute to disease progression in chronic HCV infection.     

CD4(+) and CD8(+) Regulatory T Cells (Tregs) are Elevated and Display an Active Phenotype in Patients with Chronic HCV Mono-Infection and HIV/HCV Co-Infection

The aim of this study was to examine regulatory T cells (Tregs) in peripheral blood and liver tissue in patients with chronic hepatitis C virus (HCV) mono‐infection and in patients with HIV/HCV co‐infection. In a cross‐sectional study were included 51 patients with chronic HCV infection, 24 patients with HIV/HCV co‐infection and 24 healthy individuals. CD4⁺ and CD8⁺ Tregs were determined using flow cytometry. Fibrosis was examined by transient elastography. Inflammation, fibrosis and Tregs were determined in liver biopsies from 12 patients. Increased frequency of CD4⁺ and CD8⁺ Tregs was found in HIV/HCV co‐infected patients [median: 6.4% (IQR: 5.7–6.9) and 1.0% (0.7–1.2), respectively] compared to HCV mono‐infected patients [5.6% (4.2–6.3), P = 0.01 and 0.5% (0.3–0.7), P < 0.001, respectively]. Furthermore, HCV mono‐infected patients had increased frequencies of Tregs compared with healthy controls (P < 0.05). However, no associations between the frequency of Tregs and fibrosis were found. Furthermore, characterization of CD4⁺ Tregs using CD45RA demonstrated a higher frequency of activated Tregs in both HCV mono‐infected and HIV/HCV co‐infected patients compared with healthy controls. Finally, number of intrahepatic Tregs was associated with both peripheral CD8⁺ Tregs and intrahepatic inflammation. In conclusion, HCV mono‐infected patients and particularly HIV/HCV co‐infected patients have increased the frequency of CD4⁺ and CD8⁺ Tregs compared with healthy controls. Furthermore, CD4⁺ Tregs in infected patients displayed an active phenotype. Tregs were not associated with fibrosis, but a positive correlation between intrahepatic Tregs and inflammation was found. Taken together, these results suggest a role for Tregs in the pathogenesis of chronic HCV infection.     

Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

Hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfected patients demonstrate accelerated progression to severe liver injury in comparison to HCV monoinfected patients, although the underlying mechanisms are unclear owing to infection of separate tissue compartments with two distinct viral pathogens. Microarray analysis of paired liver biopsy and peripheral blood mononuclear cell (PBMC) specimens from HCV/HIV coinfected and HCV monoinfected patients identified a gene expression signature associated with increased inflammation and immune activation that was present only in liver and PBMC samples from coinfected patients. We also identified in these samples liver- and PBMC-specific signatures enriched with fibrogenic/hepatic stellate activation and proinflammatory genes, respectively. Finally, Bayesian networks were constructed by assimilating these data with existing data from liver and PBMC samples from other cohorts, augmenting enrichment of biologically important pathways and further indicating that chronic immune activation in HCV/HIV coinfection may exacerbate liver disease progression in coinfected patients.     

Proapoptotic IL-18 in patients with chronic hepatitis C treated with pegylated interferon-alpha

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. In mainland of China, It was estimated the population of 1.3 billion infected with HCV. HCV is not cytopathic. Immune response that is essentially conducted by cytokines may play an important role in the pathogenesis of HCV infection. Interleukin (IL)-18, mainly produced by monocytes/macrophages, plays an important role in the immune system by enhancing T cell responses, regulating interferon-gamma (IFN-γ) production and promoting the development of T helper cell Th1 immune responses. Raised serum levels of IL-18 have recently been reported in patients with chronic hepatitis C before antiviral therapy. Herein we report the IL-18 sequential changes in patients with hepatitis C during the period of pegylated interferon (PEG-IFN) alpha treatment for 48 weeks. We established the correlation of plasma IL-18 level and alanine aminotransferase (r = 0.77, P < 0.05). Hepatic inflammatory activity in chronic hepatitis C was shown to be closely associated with an increased amount of IL-18. HCV-infected patients had raised IL-18 levels (93.67 ± 23.58 pg/ml versus 59.73 ± 24.06 pg/ml; P < 0.001) comparing donor negativity for HCV. PEG-IFN alpha-2a treatment induces a marked decline in IL-18 and remission of hepatic inflammatory in responders at week 24 and week 48 follow-up time point, while increased levels persist in those in whom the HCV infection was not eliminated by the therapy. We proposed declined IL-18 levels favor for virus solution, while persistent raised IL-18 associated with PEG-IFN treatment failure.     

Prevalence of hepatitis B virus,hepatitis C virus,and human immunodeficiency virus among blood donors of Mekelle blood bank,Northern Ethiopia: A three‐year retrospective study

Blood transfusion services are a vital and integral part of modern healthcare services. However, the risk of transfusion transmittable infections (TTI) has been a major handicap. Therefore, this study was aimed at determining the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) among blood donors. A retrospective study was conducted to collect data about the blood donors who consecutively donated blood from October 2011 to 2014. A three‐year retrospective study was conducted in Mekelle Blood Bank. A data abstraction format was used to collect the sociodemographic and clinical data, and the prevalence of HBV, HCV, and HIV was determined. Data were analyzed using STATA version 10 analytical software. P value less than 0.05 was considered significant in all the analyses. A total of 10 728 blood donors, median (interquartile range) of age 30 (23‐45) years and 3750 (34.9%) males were enrolled in this study. Of the participants 407(3.79%), 143(1.33%), and 111(1.03%) blood donors were positive for HBV, HCV, and HIV, respectively. HBV‐HIV coinfections were found 10 (1.93%) blood donors, followed by HBV‐HCV and HIV‐HCV. A significant association between sex and marital status with HBV and HIV infection was found. However, significant association of HCV was observed among sex ( X ² = 33.18, P < 0.001) and occupational ( X ² = 84.33, P < 0.001). A significant percentage of HBV, HCV, and HIV among blood donors was observed. To select a donor and collect safe blood risk factors exposing blood donor should be studied, and community‐based prevalence studies on TTI are also required.     

Changes of FibroScan,APRI, and FIB-4 in chronic hepatitis B patients with significant liver histological changes receiving 3-year entecavir therapy

Noninvasive fibrosis tests have been used widely for evaluation of liver fibrosis in patients with chronic hepatitis B (CHB). We aimed to investigate the influence of antiviral treatment on FibroScan, APRI, and FIB-4 in CHB patients with significant liver histological changes (SLHC) defined as inflammatory grade ≥ A2 and/or fibrosis stage ≥ F2. A total of 104 CHB patients with SLHC at the baseline were included. FibroScan, APRI, and FIB-4 values were compared before and after 3-year entecavir (ETV) treatment. Liver stiffness measurement values decreased significantly after 3-year ETV treatment in cirrhosis group (from 13.6 to 9.6 kPa, p = 0.018), significant fibrosis group (from 8.4 to 5.8 kPa, p = 0.001), and mild fibrosis group (from 5.5 to 4 kPa, p < 0.001). APRI decreased significantly after 3-year ETV treatment in patients with cirrhosis (from 0.80 to 0.25, p < 0.001), patients with significant fibrosis (from 0.54 to 0.24, p < 0.001), and those with mild fibrosis (from 0.35 to 0.23, p < 0.001). FIB-4 decreased significantly after 3-year ETV treatment in patients with cirrhosis (from 1.27 to 0.81, p = 0.007) and significant fibrosis (from 1.12 to 0.78, p < 0.001), while did not decrease significantly in patients with mild fibrosis (from 0.90 to 0.80, p = 0.389). FibroScan, APRI, and FIB-4 values decreased significantly after 3-year ETV treatment in CHB patients, which indicates that these noninvasive fibrosis tests might be useful for monitoring regression of liver fibrosis and assessing treatment efficacy during long-term ETV treatment.     

Lack of anti-GOR antibody among subjects with GB virus C/hepatitis G virus RNA

Homologies were sought between the putative amino acid sequences of GB virus C/hepatitis G virus (GBV-C/HGV) and the GOR epitope or the liver/kidney microsome-1 (LKM-1) epitope, which share partial sequence identity with the hepatitis C virus (HCV) polyprotein. Anti-GOR antibody (anti-GOR) was assayed among 100 subjects with GBV-C/HGV RNA. Twenty-one and 25 subjects were coinfected with hepatitis B virus (HBV) or HCV, respectively. Homologies were found between the NS5 or E2 polyproteins of GBV-C/HGV and the GOR epitope or the LKM-1 epitope, respectively. These segments of GBV-C/HGV polyproteins sharing identity with the GOR or the LKM-1 epitope were well conserved among three genotypes of GBV-C/HGV. However, only 1 of 55 subjects (1.8%) with GBV-C/HGV RNA, but not with HBV or HCV, was positive for anti-GOR. The positivity for anti-GOR among the group with GBV-C/HGV RNA alone was significantly lower than that among the groups with HCV RNA (P < 0.01 and P < 0.05, respectively). Only 2 of 55 subjects (3.6%) with GBV-C/HGV RNA alone exhibited elevation of alanine aminotransferase. The incidence of liver dysfunction among the group with GBV-C/HGV RNA alone was significantly lower than the incidence among the groups with GBV-C/HGV RNA and hepatitis B surface antigen (HBsAg) or HCV RNA (P < 0.01 and P < 0.01, respectively). These data indicate that 1) there is no association between GBV-C/HGV infection and the presence of anti-GOR, and 2) GBV-C/HGV infection is not related to chronic liver dysfunction. J. Med. Virol. 55:129–133, 1998. © 1998 Wiley-Liss, Inc.     

Comparison of Hepatitis C Viral Loads in Patients with or without Human Immunodeficiency Virus

A better understanding of how human immunodeficiency virus (HIV) coinfection affects the course of hepatitis C virus (HCV) infection is required to select patients with HIV who would benefit from current HCV therapy. Between June 1996 and March 2000, HCV RNA levels were quantified for 1,279 patients at the Louisiana State University Health Sciences Center; 28 of these patients were coinfected with HIV. HCV loads were quantified by the Bayer branched-DNA assay with a lower limit of detection of 0.2 Meq/ml. We compared the median HCV RNA levels of for patients coinfected with HIV and HCV and patients infected only with HCV who were in the same age range (23 to 55 years). The median HCV load for the 28 patients coinfected with HCV and HIV (17.8 Meq/ml) was significantly greater (P < 0.05) than that for similarly aged patients infected only with HCV (6.1 Meq/ml). The HCV load did not correlate with age or sex for either group of patients. A significant (R = −0.4; P < 0.05) negative correlation was observed between HCV load and CD4 count in the coinfected group, for whom the CD4 counts at the time of HCV load analysis ranged from 6 to 1,773/mm³. The increased HCV load in patients coinfected with HCV and HIV compared to that in patients infected only with HCV and the inverse relationship of the HCV load to the CD4 count indicate that immunosuppression results in decreased control of HCV replication. In addition, we report significantly higher HCV loads among coinfected African Americans than Caucasians.     

Hepatitis C (HCV) genotype and viral titer distribution among Argentinean hemophilic patients in the presence or absence of human immunodeficiency virus (HIV) co-infection

Hepatits C (HCV) infection is frequent among hemophilic patients treated with non-inactivated factor-concentrates. Both HCV genotype and viral load have been suggested to be important prognostic markers of disease progression and treatment outcome. In addition, co-infection with the human immunodeficiency virus (HIV) has been associated with increased level of HCV replication and higher risk of developing liver failure. Thus, HCV genotype, viral load, and HIV co-infection are important factors in HCV infection. Using restriction fragment length polymorphism analysis (RFLP) and the branched-DNA (bDNA) assay, we retrospectively investigated the HCV genotypes and viral loads present in 59 Argentinean hemophiliacs, in the presence or absence of HIV infection. HCV genotype 1 was the predominant viral variant detected among HIV-negative (HIV⁻) (76%) and HIV-positive (HIV⁺) (82.5%) patients, followed by genotypes 3 (10.4%), 2(2%) and a small proportion of multiply co-infected patients including genotypes 4 and 5 (6.25%). HIV⁺ patients had higher plasma HCV RNA levels than HIV⁻ patients (88.4 ± 16.5 × 10⁵ Eq/ml vs. 24.7 ± 5.8 × 10⁵ Eq/ml) (P < 0.001); however, no correlation between HCV replication and level of immune suppression, evaluated by CD4⁺ T-cell measurement, was observed among HIV⁺ patients (r = 0.017). Abnormal and higher ALT levels were more frequently detected among HIV⁺ (93%; 123.6 ± 15.7 U/liter) than HIV⁻ (41%; 70.2 ± 24.2 U/liter) patients (P < 0.001; P < 0.05). Although we were able to confirm previous reports suggesting the existence of increased HCV replication in HIV/HCV co-infected hemophiliacs, our data did not support the conclusion that HIV-induced immune suppression is directly responsible for this phenomena. It is possible that other factors induced by HIV are responsible for the increased levels in HCV replication observed. J. Med. Virol. 52:219–225, 1997. © 1997 Wiley-Liss, Inc.     

Mortality due to Liver Failure and Impact on Survival of Hepatitis Virus Infections in HIV-Infected Patients Receiving Potent Antiretroviral Therapy

The aim of the present study was to examine the causes of death, the mortality attributable to liver failure, and the impact of hepatitis virus infections on the survival of a cohort of HIV-infected patients before and after the extensive use of highly active antiretroviral therapy (HAART). Liver disease associated with hepatitis C virus (HCV) seems to be accelerated in patients infected with the human immunodeficiency virus (HIV). On the other hand, the effect of HCV on HIV progression was controversial before the introduction of HAART. However, the last study to report changes in mortality due to liver failure was published in 1997, and the impact of HCV carriage on the survival of HIV-infected patients receiving HAART needs to be clarified. In this investigation, 492 patients who were prescribed antiretroviral drugs between April 1989 and September 2000 were included in the study cohort. The median duration of follow-up of the cohort was 1,392 days. HCV infection was present in 323 (68%). Mortality attributable to AIDS decreased from 4.5 to 1.8 per 100 persons per year. Mortality due to liver failure increased from 0.3 to 0.5 per 100 persons per year (P<0.01). The survival of patients with and without HCV infection was similar (P=0.8). Although liver failure is an increasing cause of death among HIV-infected patients receiving HAART, HCV infection has still no impact on the survival of HIV-infected patients. Electronic Publication     

Systematic Review and Meta–Analysis of the Diagnostic Accuracy of Fibrosis Marker Panels in Patients with HIV/Hepatitis C Coinfection

Abstract

Background: Accurately staging hepatitis C virus (HCV)–related fibrosis is crucial for treatment decisions and prognostication. Our objective was to systematically review studies describing the accuracy of serum marker panels for predicting fibrosis in HIV/HCV–coinfected patients. Method: Studies comparing serum marker panels with biopsy in HIV/HCV-coinfected patients were identified. Random effects meta-analyses and areas under summary receiver operating characteristics curves (AUC) examined test accuracy for detecting significant fibrosis (F2–4) and cirrhosis. Heterogeneity was explored using meta-regression. Results: Five studies (n = 574) including four fibrosis measures (APRI [n = 4 studies], Forns’ [n = 2], FibroTest [n = 1], SHASTA [n = 1]) met the inclusion criteria. The prevalence of significant fibrosis and cirrhosis were 51% and 16%, respectively. For the prediction of significant fibrosis, the summary AUC was 0.82 (95% CI 0.78–86) and diagnostic odds ratio was 7.8 (5.1–11.9). For cirrhosis, these figures were 0.83 (0.69–0.97) and 11.0 (4.6–26.2), respectively. Meta–regression including study factors (methodological quality and biopsy adequacy), patient characteristics (age, gender, CD4 count), and fibrosis measure failed to identify important predictors of accuracy. Conclusion: Available fibrosis marker panels have acceptable performance for identifying significant fibrosis and cirrhosis in HIV/HCV–coinfected patients but are not yet adequate to replace liver biopsy. Additional studies are necessary to identify the optimal measure.     

Effects of hepatitis C and B viruses infection on the development of hepatocellular carcinoma

A case control study consisting of 102 patients with HCC, 102 sex-matched and age-matched patients with nonhepatic disease, and 204 matched healthy controls was carried out to investigate the effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection on the development of hepatocellular carcinoma (HCC). The prevalence of antibody to HCV (anti-HCV) in HCC (34.3%) was higher than in nonhepatic disease (10.7%, P< 0.001) or in healthy controls (2.4%, P< 0.001). The prevalence of hepatitis B surface antigen (HBsAg) in HCC (77.4%) was higher than in nonhepatic disease (16.6%, P< 0.001) or in healthy controls (19.6%, P< 0.001). Anti-HCV positivity in nonhepatic disease was higher than in healthy controls (P<0.01). Using patients with nonhepatic disease as controls, stepwise logistic regression analysis indicated that both anti-HCV (odds ratio, 3.4; 95% confidence interval, 2.1-5.6) and HBsAg (odds ratio, 5.6; 95% confidence interval, 3.6–8.5) are independent risk factors for HCC. Using healthy controls, the development of HCC was also strongly associated with anti-HCV (odds ratio, 8.0; 95% confidence interval, 4.3–14.6) and HBsAg (odds ratio, 5.5; 95% confidence interval, 3.7–8.2). Calculation of incremental odds ratio indicated that there is no interaction between HBV and HCV. In conclusion, HBV and HCV are risk factors of HCC. They act independently and without interaction. © 1994 Wiley-Liss, Inc.     

Apoptosis markers related to pathogenesis of pediatric chronic hepatitis C virus infection: M30 mirrors the severity of steatosis

Apoptosis involvement in liver damage related to hepatitis C virus (HCV) chronic infection has been suggested. Although liver biopsy represents the gold standard for evaluating disease severity, non‐invasive tests are a growing medical need. The aim of this study was to detect apoptosis markers in liver and serum from pediatric HCV‐infected patients and to assess its utility to predict liver damage progression. Twenty‐three patients were included. Liver biopsies were used for histological analysis as well as for immunodetection of a viral protein (NS3) and apoptosis markers (activated caspase‐3 [casp‐3a], caspase‐generated CK‐18 fragment [M30] and TUNEL). M30 was quantified in paired serum and biopsy samples. NS3 correlated both with casp‐3a (r = 0.83, P < 0.0001) and TUNEL (r = 0.61, P < 0.0017). Casp‐3a and TUNEL also displayed a correlation (r = 0.56, P = 0.005). Both NS3 and casp‐3a were associated with fibrosis stage (P = 0.03). Serum M30 [median: 122.15 UL‐1 (86.68–794.58)] was higher in patients than in controls [median: 81.44 UL‐1 (41.17–129.30)], (P < 0.0001). M30 showed a correlation with steatosis, and indeed it was linked to severe grade (P = 0.004). In children, HCV would be involved in liver damage through apoptosis induction. The apoptosis markers detected reflect liver injury. Serum M30 might be useful as a marker to detect the extent of liver steatosis. J. Med. Virol. 82:949–957, 2010. © 2010 Wiley‐Liss, Inc.     

Matrix Metalloproteinase-9 and Tissue Inhibitors of Matrix Metalloproteinase-1 in Plasma of Patients Co-Infected with HCV and HIV

Abstract

Background: Accelerated progression of hepatic fibrosis has been shown in patients co-infected with hepatitis C virus (HCV) and HIV. Liver fibrosis is a dynamic process in which the altered balance between matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) may play a major role. Method: The involvement of MMP-9 and TIMP-1 in HCV liver disease progression in patients co-infected with HIV was evaluated. Plasma concentrations of human MMP-9 and TIMP-1 were assessed in 76 HIV-infected patients; 27 were co-infected with HCV and 49 were HCV negative. 18 healthy donors were included as controls. Results: Patients with HIV infection exhibited a striking increase in TIMP-1 levels; this is more evident in patients with advanced CD4 depletion. There was no elevation in the plasma concentrations of the MMP-9. The highest levels of TIMP-1 were found in the HIV/HCV co-infected patients. The values of TIMP-1 in HIV-infected patients with chronic HCV hepatitis were significantly higher than in HIV-positive individuals without HCV infection, even including those with low CD4 count. No significant differences were seen in the MMP-9 levels. Conclusion: These findings suggest that the altered balance between circulating MMP-9 and TIMP-1 during HIV infection may play an important role in exacerbating liver fibrosis progression in patients co-infected with HCV.