ObjectiveNoninvasive tests that can be used in place of liver biopsy to diagnose fibrosis have major limitations. They either leave a significant proportion of patients without a definitive diagnosis or produce inaccurate results. Moreover, the performance of these tests is lower in HIV/hepatitis C virus (HCV) coinfection. Against this background, we examined the utility of serum matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 1 (TIMP-1) measurements in combination with routine clinical data to predict fibrosis in HIV/HCV-coinfected patients. MethodsPatients with a liver biopsy who had not received anti-HCV therapy were included in the study. A model including variables independently associated with fibrosis was constructed. Diagnostic accuracy was determined by measuring the area under the receiver operating characteristic curve (AUROC). Positive (PPV) and negative (NPV) predictive values were calculated. ResultsNinety patients were included in the study. Aspartate aminotransferase (AST), platelet count and MMP-2 were predictors of significant fibrosis (F ! 2) and cirrhosis (F4). A score constructed using these variables yielded an AUROC of 0.76 for F ! 2 and 0.88 for F4. Score cut-offs detected (value ! 3.5) and excluded (value 1.5) F ! 2 with a PPV of 87% and an NPV of 88%. Thirty-one patients (34%) were correctly diagnosed using these cut-offs, with four (13%) incorrect classifications. Cirrhosis was excluded with a certainty of 98% and diagnosed with a probability of 83%. Two (17%) of 12 patients were misclassified as having cirrhosis. The AST to platelet count index and MMP-2 levels were sequentially applied to detect F ! 2. Forty-one patients (46%) were identified with this approach, with six (15%) misclassifications. ConclusionMMP-2 levels can be used in combination with AST and platelet count to aid the diagnosis of liver fibrosis in HIV/HCV-coinfected patients.Keywords: aspartate aminotransferase to platelet count index, hepatitis C virus, liver fibrosis, matrix metalloproteinase 2, noninvasive diagnosis of fibrosis IntroductionThe extent of liver fibrosis has prognostic and management implications in chronic hepatitis C. The diagnosis of fibrosis has traditionally relied on liver biopsy. However, this procedure is invasive, limited because of variability issues [1,2] and difficult to apply sequentially. Because of these issues, noninvasive tests that can be used in place of liver biopsy are needed. Among such tests, those employing simple blood indexes, based on routinely available data, and transient elastometry (TE) have been validated in patients with chronic hepatitis C virus (HCV) and HIV coinfection [3][4][5][6].Simple indexes are easy to implement and cost-effective. However, the diagnostic yield of these indexes is lower in HIV/HCV-coinfected patients [3,4]. In particular, the DOI: 10.1111/j.1468-1293.2010.00836.x HIV Medicine (2011 r 2010 British HIV Association 14 diagnosis of cirrhosis cannot be established confidently [3]. TE seems a promising technique for ...

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A considerable number of patients undergoing methadone maintenance treatment (MMT) are not considered for treatment against hepatitis C virus (HCV) infection due to a possible lower adherence and efficacy in this population. We aimed to compare the response rates to HCV treatment in patients with or without MMT. HCV-infected patients who initiated pegylated interferon plus ribavirin were included in this prospective cohort study. The relation between sustained virologic response (SVR) and MMT was analyzed. A total of 214 patients were included in the study [81 (37.9%) with and 133 (62.1%) without MMT]. No differences in HCV and interleukin 28B (rs12979860) genotype distribution were observed between the two groups. Of these patients, 103 (48.1%) achieved SVR. Among the patients who received MMT, 39 (48.1%) reached SVR compared to 64 (48.1%) subjects without MMT (p = 0.99). The frequency of voluntary drop-out and treatment discontinuations due to adverse events was comparable between the patients with and without MMT [10 (12.3%) versus 14 (10.5%), p = 0.68, and 4 (4.9%) versus 9 (6.8%), p = 0.59, respectively]. The efficacy of HCV therapy in MMT patients is similar to that found in subjects not taking methadone. MMT patients should be equally considered for treatment with pegylated interferon plus ribavirin in HCV-infected patients.

Hepatitis C virus (HCV)/human immunodefficiency virus (HIV) coinfection is a major health problem, affecting mostly to individuals with exposure to blood products, as hemophiliacs or intravenous drug users, or those exposed to high-risk sexual practices. Genotyping of interleukin 28B (IL-28B) rs12979860 polymorphism is a useful tool for guiding therapeutic decisions in this disease. On the contrary, there is not enough information on the pathogenic role of this polymorphism in the natural history of the disease. The objective of this study is to describe the relationships between the CT/TT genotype of this polymorphism with viral loads and also with a number of biomarkers of liver function in coinfected patients naïve for treatment for HCV. Seventy-five HCV/HIV coinfected patients were retrospectively recruited in our Hospital from 2010 to 2011. Logistic regression analysis adjusting by [Age], [Sex], [HCV viral genotype], [HCV viral load], [HIV viral load], and [CD4 T cells levels] revealed the IL-28B rs12979860 (CT/TT) genotype as a protective factor against alanine aminotransferase (ALT) levels (>100 IU/L), aspartate aminotransferase (AST) levels (>75 IU/L), and AST-to-platelet ratio index (APRI) score for liver fibrosis (>1.5) [OR, (95% CI), p]: ALT [0.026 (0.001-0.576) 0.021]; AST [0.001 (0.000-0.297) 0.019]; APRI [0.031 (0.002-0.41) 0.008]. Stepwise regression analysis considering the same adjusting variables showed the same results. In consequence, the IL-28B rs12979860 (CT/TT) genotype, which is a marker of poor response to HCV treatment, could be mediating on the contrary a certain protective effect against the hepatic damage caused by this virus in patients coinfected by HIV.

Widespread shutoff of host gene expression through RNA degradation is an advantageous way for many viruses to block antiviral responses. However, viruses need to maintain expression of their own genes and host genes necessary for replication despite the RNA degradation. The influenza A virus host shutoff endoribonuclease PA-X solves this problem by discriminating between RNAs and sparing viral mRNAs and some host RNAs. To understand how PA-X distinguishes between RNAs, we identified and characterized PA-X cut sites transcriptome-wide. This analysis shows that PA-Xs from multiple influenza strains cleave RNAs at GCUG tetramers in hairpin loop structures. Importantly, GCUG tetramers are enriched in the human but not the influenza transcriptome. This finding suggests that PA-X evolved these cleavage characteristics to target host but not viral mRNAs. Our study reveals a new layer of PA-X specificity, and shows how viral endoribonuclease cleavage specificity plays a functional role to selectively target the host.

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