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Paul Calès,
Philippe Halfon, Dominique Batisse,
Fabrice Carrat,
Philippe Perré,
Guillaume Penaranda,
Dominique Guyader,
Louis d'Alteroche,
Isabelle Fouchard-Hubert,
Christian Michelet,
Pascal Veillon,
Jérôme Lambert,
Laurence Weiss,
Dominique Salmon,
Patrice Cacoub
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ABSTRACT: We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection.
Four hundred and sixty-seven patients were included into derivation (n=183) or validation (n=284) populations. Within these populations, the diagnostic target, significant fibrosis (Metavir F > or = 2), was found in 66% and 72% of the patients, respectively. Two new fibrosis tests, FibroMeter HICV and HICV test, were constructed in the derivation population.
Unadjusted AUROCs in the derivation population were: APRI: 0.716, Fib-4: 0.722, Fibrotest: 0.778, Hepascore: 0.779, FibroMeter: 0.783, HICV test: 0.822, FibroMeter HICV: 0.828. AUROCs adjusted on classification and distribution of fibrosis stages in a reference population showed similar values in both populations. FibroMeter, FibroMeter HICV and HICV test had the highest correct classification rates in F0/1 and F3/4 (which account for high predictive values): 77-79% vs. 70-72% in the other tests (p=0.002). Reliable individual diagnosis based on predictive values > or = 90% distinguished three test categories: poorly reliable: Fib-4 (2.4% of patients), APRI (8.9%); moderately reliable: Fibrotest (25.4%), FibroMeter (26.6%), Hepascore (30.2%); acceptably reliable: HICV test (40.2%), FibroMeter HICV (45.6%) (p<10(-3) between tests). FibroMeter HICV classified all patients into four reliable diagnosis intervals (< or =F1, F1+/-1, > or =F1, > or =F2) with an overall accuracy of 93% vs. 79% (p<10(-3)) for a binary diagnosis of significant fibrosis.
Tests designed for HCV infections are less effective in HIV/HCV infections. A specific test, like FibroMeter HICV, was the most interesting test for diagnostic accuracy, correct classification profile, and a reliable diagnosis. With reliable diagnosis intervals, liver biopsy can therefore be avoided in all patients.
Journal of Hepatology 08/2010; 53(2):238-44. · 9.26 Impact Factor
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ABSTRACT: Integrase positions 148 and 155 represent main determinants of resistance to integrase inhibitors. We assessed the prevalence of minority variants harboring such mutations in integrase-naive HIV-infected patients.
Two groups of patients were studied: 40 heavily antiretroviral-experienced patients, initiating a raltegravir-based therapy and 51 antiretroviral-naive patients. Allele-specific real-time PCR (AS-PCR) systems, developed for Q148H, Q148R and N155H mutations, were performed at baseline for antiretroviral-experienced patients. Samples from antiretroviral-naive patients were tested with the Q148R AS-PCR assay.
The limits of detection of AS-PCR systems were 0.10, 0.10 and 0.05% for Q148H, Q148R and N155H mutations, respectively. AS-PCR systems were successful in 79 of 91 samples. In antiretroviral-experienced patients, Q148R minority variants were frequently detected (26/32 patients, 81%) at low-level frequency (median = 0.40%), whereas no minority variants exhibiting Q148H or N155H mutation were found. Twenty-four of 26 patients exhibiting Q148R variants were virological responders but four of them displayed a delayed virological response occurring between W18 and W36. Two patients exhibited virological failure under raltegravir, both harboring Q148R minority variants at baseline. However, we did not find any association between the presence of Q148R minority variants and an increased risk of virological failure. Q148R minority variants were also found in 86% of antiretroviral-naive patients, a prevalence significantly higher than that of K103N minority variants (26%).
Q148R variants were frequently detected, always at low-level, in antiretroviral-experienced and naive patients. Although their presence was not consistently associated with virological failure, their impact on long-term viral suppression needs to be further investigated.
AIDS (London, England) 02/2010; 24(6):867-73. · 4.91 Impact Factor
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ABSTRACT: Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.
Modern Pathology 11/2006; 19(10):1277-88. · 4.79 Impact Factor
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ABSTRACT: A new device allowing recording capacitance images of the skin surface was recently presented. Parameters, extracted from the gray-level histogram of the images, are tested for a new approach of skin surface hydration measurement in comparison with the classical capacitance method. Illustration of the interest of having both images and parameters for studying the homogeneity and the level of skin surface hydration are presented.
Software for selecting a region of interest from an image and measuring the parameters derived from its gray-level histogram was used to characterize skin hydration.
There is a very close correlation between a Corneometer and the parameters extracted from the SkinChip measurements. The importance of having capacitance images of skin is demonstrated in case of non-homogeneity of the skin hydration, either because of photoaging or following an inflammation process.
Capacitance imaging is a necessary tool for both completely describing and quantifying skin surface hydration.
Skin Research and Technology 06/2006; 12(2):99-104. · 1.71 Impact Factor
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Jeanne Serpaggi,
Marie-Laure Chaix, Dominique Batisse,
Caroline Dupont,
Anaïs Vallet-Pichard,
Hélène Fontaine,
Jean-Paul Viard,
Christophe Piketty,
Elisabeth Rouveix,
Christine Rouzioux,
Laurence Weiss,
Stanislas Pol
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ABSTRACT: Recent studies have suggested an increased risk of acute hepatitis C (HCV) infection in homosexual HIV-infected men and that early treatment with standard or pegylated interferon-alfa, alone or associated with ribavirin, significantly reduces the risk of chronic evolution in HIV-infected patients.
A retrospective analysis of 12 HIV-infected patients who were consecutively diagnosed as developing acute HCV infection, defined by both seroconversion of anti-HCV antibodies and detection of serum HCV RNA in those with previous negative results. Ten of these patients received early antiviral treatment with standard or pegylated interferon-alfa, alone or associated with ribavirin.
The only risk factor in these patients was unprotected sexual intercourse with men. Acute HCV infection was asymptomatic in 10 patients, and the HCV genotype was 4d in 10 patients. The 10 genotype 4d viruses formed a monophylogenetic group and clustered separately from other local sequences of HCV genotype 4d, suggesting a common source of infection. None of the 10 patients who were treated early with antiviral therapy had a sustained virological response, as defined by undetectable HCV RNA 6 months after therapy.
There is a risk of sexual transmission of HCV in HIV-infected men who have sex with men; the cluster of HCV genotype 4d suggested a common source of infection and a failure in prevention counselling. Early treatment with standard interferon-alfa failed to prevent chronic evolution of HCV infection in this particular group of HIV-infected patients who had acquired this peculiar cluster of genotype 4 strains.
AIDS 02/2006; 20(2):233-40. · 6.24 Impact Factor
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ABSTRACT: Highly active antiretroviral therapy (HAART) has become the gold standard treatment of HIV/AIDS infection. NRTI-related mitochondrial toxicity has been recognized as a serious adverse effect of HAART. The mechanisms underlying NRTI-induced mitochondriopathy involve the inhibition of the human DNA polymerase gamma mtDNA mutations and oxidative stress. The clinical spectrum of NRTI-related toxicity ranges from a subclinical disease e.g. mild hepatic abnormalities, to a rare life-threatening condition with lactic acidosis and hepatic insufficiency. In the latter, liver histology shows massive steatosis. Ultrastructural assessment of mitochondrial abnormalities may be of help to address the NRTI toxicity in poorly symptomatic patients. Efforts have been recently made to assess the clinical relevance of non-invasive tests including the evaluation of mtDNA or mitochondrial functions in peripheral blood mononuclear cells for the diagnosis of NRTI-associated toxicity.
Annales de Pathologie 10/2005; 25(4):299-308. · 0.25 Impact Factor
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ABSTRACT: Peginterferon is now the gold standard of therapy in patients with chronic hepatitis C virus infection. Extrahepatic manifestations of HCV are usually treated with interferon alfa. Here we report on a patient with HCV-related cirrhosis and cryoglobulinaemia who presented with an acute and long-lasting exacerbation of vasculitis during treatment with peginterferon. To our knowledge this is the first report of an acute exacerbation of cryoglobulinaemia-related vasculitis involving skin, peripheral nerve and kidney in a patient treated with peginterferon for HCV-related cirrhosis. The long half-life of peginterferon might explain the long-lasting symptoms of vasculitis. Clinicians should be aware of possible sustained flare of cryoglobulinaemia-associated vasculitis in patients receiving peginterferon.
European Journal of Gastroenterology & Hepatology 08/2004; 16(7):701-3. · 1.76 Impact Factor
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ABSTRACT: Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxic effects resulting in multiple organ disorders. Liver involvement has been associated mainly with severe lactic acidosis and massive steatosis. However, patients with HIV infection who are receiving antiretroviral treatment frequently have mildly abnormal liver test results that, to date, have not been linked unambiguously to the toxic effects of NRTIs. Thirteen patients with HIV infection treated with NRTI-based regimens had low-grade abnormal liver test results associated with digestive and nonspecific general symptoms. Histologic examination of liver samples showed diffuse steatosis in only 6 cases and mild steatosis in the remaining cases, associated with megamitochondria, mild lobular inflammation and necrosis, Mallory bodies, and perisinusoidal fibrosis. In all cases, ultrastructural study disclosed mitochondrial abnormalities. Our work demonstrates that NRTI-induced toxic effects in the liver may occur as indolent nonspecific disease with variable histologic features and emphasizes the diagnostic value of electron microscopy, particularly when diffuse steatosis is absent.
American Journal of Clinical Pathology 05/2003; 119(4):546-55. · 2.60 Impact Factor
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ABSTRACT: This paper presents a computational model for studying the mechanical properties of skin with aging. In particular, attention is given to the folding capacity of skin, which may be manifested as wrinkles. The simulation provides visual results demonstrating the form and density of folds under the various conditions. This can help in the consideration of proper measures for a cosmetic product for the skin.
IEEE Transactions on Information Technology in Biomedicine 01/2003; 6(4):317-23. · 1.68 Impact Factor
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ABSTRACT: Comparisons of clinical assessment with measurement of physical parameters are rare.
To standardize the horizontal wrinkling of the skin in order to define a reference chart of the different wrinkling grades and to propose an interpretation of the clinical pattern in terms of skin layers thickness and mechanical parameters.
A device allowing reproducible wrinkling of the skin was made. The skin folds created in this way were clinically assessed on women of different ages. Measurements of the mechanical properties of the skin were carried out by using a Torquemeter. Skin layers' thicknesses were measured by using in vivo Confocal Microscopy (CM) and Ultrasound Imaging (B mode).
Skin wrinkling grades increase versus age. Skin elasticity, extensibility and echogenicity decrease also versus age and the wrinkling grade. Wrinkling appears to be related to skin rigidification (for both stratum corneum and dermis) coupled to a certain weakening of the upper dermis (loss of echogenicity).
This study points out the key role of the age-related alterations of the upper dermis in skin wrinkling capacities.
Skin Research and Technology 09/2002; 8(3):148-54. · 1.71 Impact Factor
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ABSTRACT: Background: We have assessed the long-term efficacy and safety of a combination therapy of interferon alpha-2b (IFN) and ribavirin (RBV) for the treatment of severe chronic hepatitis C in co-infected HIV-seropositive patients in an open prospective study.
Methods: Fifty-one patients were treated for 12 months. Mean baseline CD4 cell count, alanine aminotransferase and aspartate aminotransferase were 412 ± 232 × 106/l, 113 ± 75 IU/l and 111 ± 84 IU/l respectively. The mean Knodell score was 11.5 ± 2.1 with 28 patients (55%) exhibiting histological evidence of active cirrhosis.
Results: Fifteen (29%) patients discontinued the treatment prematurely because of adverse events. An end of treatment response (ETR) as defined by the lack of detectable hepatitis C virus (HCV) RNA in plasma at the end of treatment was achieved in 15 patients (29%). A sustained virological response (SVR), defined by the lack of detectable HCV RNA in plasma 6 months after completion of combination therapy, was achieved in 11 patients (21%). The HCV genotype 3a was associated with ETR and SVR (P = 0.002 and P = 0.003, respectively). HCV viraemia at baseline was lower in patients who achieved SVR and ETR than in those who did not (6.7 ± 7.8 versus 24 ± 26.7 × 106 genome equivalents/ml, P = 0.03 and 14.3 ± 28.7 versus 22.5 ± 23, P = 0.05, respectively).
Conclusion: Our results indicate that combination therapy with IFN and RBV is effective in approximately 20% of co-infected patients with severe liver disease.
AIDS 11/2001; 15(16):2149-2155. · 6.24 Impact Factor
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ABSTRACT: Objectives: To evaluate the efficacy and safety of a combination therapy of interferon-α2b (IFN) and ribavirin for the treatment of chronic hepatitis C in HIV-seropositive patients.
Design: Open prospective trial.
Methods: Twenty patients co-infected with hepatitis C virus (HCV) and HIV, with a mean CD4 cell count of 350 ± 153 × 106/l were treated with IFN (3 MU three times per week) in combination with ribavirin (500 mg or 600 mg twice a day) for 6 months. Tolerance and efficacy were monitored at weeks 12 (month 3) and 24 (month 6). The primary endpoint was a complete virological response, as defined by the lack of detectable HCV RNA in serum.
Results: Baseline values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 121 ± 72 IU/l and 75 ± 67 IU/l, respectively. The total Knodell score was 10.4 ± 2.4, with nine patients showing histological evidence of active cirrhosis (45%). All patients exhibited circulating HCV RNA. The treatment was well tolerated, with no impact on the course of HIV infection. After 6 months of combination therapy with IFN and ribavirin, 10 patients (50%) exhibited no further detectable HCV RNA viraemia, seven of whom achieved undetectable viraemia at month 3. Levels of ALT and AST decreased after 6 months of treatment from a mean of 121 ± 72 to 51 ± 40 IU/l and from a mean of 129 ± 58 IU/l to 68 ± 61 IU/l, respectively (P < 0.0002 and P < 0.0001).
Conclusion: Our results indicate that combination therapy with IFN and ribavirin is effective in 50% of cases in clearing serum HCV RNA and may thus provide effective means of therapy in HIV-HCV-coinfected patients as initial treatment or in patients who have previously failed IFN monotherapy.
AIDS 05/2000; 14(7):839-844. · 6.24 Impact Factor
