Dominique Batisse

DISCREPANT RESPONSES TO TRIPLE COMBINATION ANTIRETROVIRAL THERAPY IN ADVANCED HIV DISEASE

Objectives:To determine the clinical, virological and immunological outcome in a cohort of unselected patients receiving triple combination therapy for more than 1 year. Methods:Prospective follow-up of a cohort of 162 unselected, protease inhibitor-naive, antiretroviral-experienced patients with advanced HIV disease, treated with indinavir combined with two nucleoside analogues. Results:The mean CD4 cell count and plasma HIV RNA level in the study group at baseline were 69 ± 5 × 106/l and 4.75 ± 0.07 log10 copies/ml, respectively. Five per cent of patients died prematurely or were lost to follow-up. Fifty-seven per cent of patients responded to therapy, as assessed by a sustained increase in CD4 cell counts above 50 × 106/l and a decrease in plasma HIV RNA greater than 1 log10 copies/ml, throughout 12.1 months of follow-up. Seventeen per cent of patients were immunological and virological non-responders. Twenty-one per cent of patients exhibited discrepant virological and immunological responses to treatment, of whom one-half failed to exhibit significant increases in CD4 cells despite a virological response to therapy and one-half exhibited increased CD4 cell counts in the absence of significant decrease in plasma viral load. The incidence of AIDS-defining events in the latter group of patients was similar to that of responder patients, whereas their incidence was higher in patients who failed to exhibit a virological and immunological response and those who failed to increase CD4 cells despite a significant decrease in viral load. Conclusion:Our observations of discrepant immunological and virological responses to treatment raise the issue of the significance of persistent elevated levels of plasma HIV RNA and of the relevance of measurements of plasma viral load for assessing the efficacy of antiretroviral therapy in patients whose CD4 cell counts increase despite the absence of significant decrease in plasma HIV viral load.

Efficacy and safety of combination therapy with interferon-alpha2b and ribavirin for chronic hepatitis C in HIV-infected patients.

OBJECTIVES To evaluate the efficacy and safety of a combination therapy of interferon-alpha2b (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 x 10(6)/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.

Long-term efficacy of combination therapy with interferon-α2b and ribavirin for severe chronic hepatitis C in Hiv-infected patients

BackgroundWe 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. MethodsFifty-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. ResultsFifteen (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). ConclusionOur results indicate that combination therapy with IFN and RBV is effective in approximately 20% of co-infected patients with severe liver disease.

Toxic Effects of Nucleoside Reverse Transcriptase Inhibitors on the Liver Value of Electron Microscopy Analysis for the Diagnosis of Mitochondrial Cytopathy

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.

High frequency of integrase Q148R minority variants in HIV-infected patients naive of integrase inhibitors.

Background: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. Methods: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. Results: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%). Conclusion: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.

Comparison of liver fibrosis blood tests developed for HCV with new specific tests in HIV/HCV co-infection

BACKGROUND & AIMS We compared 5 non-specific and 2 specific blood tests for liver fibrosis in HCV/HIV co-infection. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Telaprevir for HIV/Hepatitis C Virus–Coinfected Patients Failing Treatment With Pegylated Interferon/Ribavirin (ANRS HC26 TelapreVIH): An Open-Label, Single-Arm, Phase 2 Trial

BACKGROUND Retreatment with pegylated interferon (peg-IFN) and ribavirin (RBV) results in poor sustained virological response (SVR) rates in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. There are limited data regarding the use of telaprevir plus peg-IFN/RBV in this population. METHODS HIV type 1-infected patients who previously failed ≥12 weeks of peg-IFN/RBV for HCV genotype 1 coinfection were enrolled in a single-arm, phase 2 trial. Patients with cirrhosis and previous null response were excluded. Authorized antiretrovirals were tenofovir, emtricitabine, efavirenz, atazanavir, and raltegravir. All patients received peg-IFN alfa-2a (180 µg/week) plus RBV (1000-1200 mg/day) for 4 weeks, followed by telaprevir (750 mg or 1125 mg every 8 hours with efavirenz) plus peg-IFN/RBV for 12 weeks and peg-IFN/RBV for 32-56 weeks according to virological response at week 8. The primary endpoint was the SVR rate at 24 weeks after the end of treatment (SVR24). RESULTS Sixty-nine patients started treatment; SVR24 was achieved in 55 (80% [95% confidence interval, 68%-88%). SVR24 was not influenced by baseline fibrosis stage, IL28B genotype, antiretroviral regimen, HCV subtype, CD4 cell count, previous response to HCV treatment, HCV RNA level, or HCV RNA decline at week 4. HCV treatment was discontinued for adverse events (AEs) in 20% of patients, including cutaneous (4%), psychiatric (4%), hematological (6%), and other AEs (6%). Peg-IFN or RBV dose reduction was required in 23% and 43% of patients, respectively. Seventy percent of patients required erythropoietin, blood transfusions, or RBV dose reduction for anemia. Two patients died during the study. No HIV breakthrough was observed. CONCLUSIONS Despite a high discontinuation rate related to toxicity, a substantial proportion of treatment-experienced HIV-coinfected patients achieved SVR24 with a telaprevir-based regimen. Clinical Trials Registration. NCT01332955.

Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients

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.

Toxicité hépatique des anti-rétroviraux chez les patients VIH : Étude ultra structurale et de l’expression immunohistochimique du complexe IV de la phosphorylation oxydative mitochondriale

La toxicite mitochondriale hepatique des anti-retroviraux demeure un probleme majeur de la prise en charge therapeutique des patients infectes par le VIH. Le principal risque est la survenue d’une acidose lactique, evenement rare, aigu et bruyant. Nous avons ainsi recemment decrit les anomalies ultrastructurales mitochondriales hepatiques chez 13 patients mono-infectes VIH. Cependant, peu d’informations existent : –– 1 chez les patients co-infectes VIH-VHC ; –– 2 sur les repercussions hepatiques d’une toxicite meme minime mais au long cours chez ces patients. Ceci nous a conduit a etudier les ponctions-biopsies hepatiques (PBH) d’une serie de 55 patients VIH suivis dans un centre hospitalier unique : 39 patients etant co-infectes par le VHC et 42 recevant un traitement antiretroviral. L’expression des sous-unites I (codee par l’ADN mitochondrial : OxPhox IV/I) et IV (codee par l’ADN nucleaire : OxPhox IV/IV) du complexe IV de la phosphorylation oxydative mitochondriale a ete evaluee par immunohistochimie (IHC) et confrontee a l’histologie standard, a la microscopie electronique (ME), puis aux donnees cliniques et biologiques. Pour le diagnostic de cytopathie mitochondriale, l’histologie hepatique standard n’etait que peu informative, exceptee en cas d’exceptionnelle acidose lactique grave ou il existait une steatose majeure. Des anomalies ultrastructurales isolees sans modification de l’expression IHC de OxPhox IV/I (ME+/OxPhox IV/I conservee) etaient frequemment observees chez les patient VHC co-infectes VIH, meme en l’absence de traitement par HAART ou de suspicion clinique de cytopathie. Un tableau complet (ME+ / perte d’expression de OxPhox IV/I) definissait une cytopathie « morphologiquement significative » et etait retrouvee chez des patients VIH (VHC ou non) presentant une biologie hepatique tres perturbee et chez qui une cytopathie etait le plus souvent cliniquement suspectee. Chez les patients mono-infectes VIH traites, une absence de perte d’expression de la OxPhox IV/I meme si il existait des anomalies ultra structurales moderee n’etait pas associee a des cytopathies cliniquement severes. Nos resultats permettent : - 1 de rediscuter la place de la ME dans le diagnostic positif de cytopathie mitochondriale hepatique, en particulier chez le patient co-infecte ; - 2 de valoriser l’etude de l’expression par IHC du complexe IV de la phosphorylation oxydative mitochondriale ; - 3 de souligner que le diagnostic final de cytopathie « significative » doit reposer sur un faisceaux d’arguments et necessite une collaboration entre pathologiste et clinicien.