Hepatitis: Clotet B

Rubio R, Berenguer J, Miró JM, Antela A, Iribarren JA, González J, Guerra L, Moreno S, Arrizabalaga J, Clotet B, Gatell JM, Laguna F, Martínez E, Parras F, Santamaría JM, Tuset M, Viciana P. · Hospital 12 Octubre, Madrid, Spain. · Enferm Infecc Microbiol Clin. · Pubmed #12084354 links to  free full text

Abstract: OBJECTIVE: To provide an update of recommendation on antiretroviral treatment (ART) in HIV-infected adults.Methods. These recommendations have been agreed by consensus by a committee of the spanish AIDS Study Group (GESIDA) and the National AIDS Plan. To do so, advances in the physiopathology of AIDS and the results on efficacy and safety in clinical trials, cohort and pharmacokinetics studies published in biomedical journals or presented at congresses in the last few years have been reviewed. Three levels of evidence have been defined according to the data source: randomized studies (level A), case-control or cohort studies (level B) and expert opinion (level C). Whether to recommend, consider, or not to recommend ART has been established for each situation. RESULTS: Currently, ART with combinations of at least three drugs constitutes the treatment of choice in chronic HIV infection. In patients with symptomatic HIV infection, initiation of ART is recommended. In asymptomatic patients initiation of ART should be based on the CD41/mL lymphocyte count and on the plasma viral load (PVL): a) in patients with CD41 lymphocytes < 200 cells/mL, initiation of ART is recommended; b) in patients with CD41 lymphocytes between 200 and 300 cells/mL, initiation of ART should, in most cases, be recommended; however, it could be delayed when the CD41 lymphocyte count remains close to 350 cells/mL and the PVL is low, and c) in patients with CD41 lymphocytes > 350 cells/mL, initiation of ART can be delayed. The aim of ART is to achieve an undetectable PVL. Adherence to ART plays a role in the durability of the antiviral response. Because of the development of cross-resistance, the therapeutic options in treatment failure are limited. In these cases, genotypic analysis is useful. Toxicity limits ART. The criteria for ART in acute infection, pregnancy and postexposure prophylaxis and in the management of coinfection with HIV and hepatitis C and B virus are controversial. CONCLUSIONS: The current approach to initiating ART is more conservative than in previous recommendations. In asymptomatic patients, the CD41 lymphocyte count is the most important reference factor for initiating ART. Because of the considerable number of drugs available, more sensitive monitoring methods (PVL) and the possibility of determining resistance, therapeutic strategies have become much more individualized.

Tural C, Clotet B. · No affiliation provided · Med Clin (Barc). · Pubmed #15498442 No free full text.

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Fuster D, Clotet B. · No affiliation provided · J Int Assoc Physicians AIDS Care (Chic Ill). · Pubmed #12961758 No free full text.

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Fuster D, Clotet B. · HIV Clinical Unit/Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. · Expert Opin Pharmacother. · Pubmed #16086644 No free full text.

Abstract: Atazanavir is a novel and potent protease inhibitor that differs from other protease inhibitors because of its good gastrointestinal tolerability, once-daily dosing, low pill burden and it does not seem to cause insulin resistance or lipid elevations in short-term use. Atazanavir produces an increase in indirect bilirubin levels, which is not related to hepatotoxicity. The incidence of atazanavir-related hyperbilirubinaemia does not seem to be increased in hepatitis B or C coinfection. I50L is atazanavir's signature mutation. It has been shown in previously treated patients that resistance is likely when three or more protease inhibitor resistance-related primary mutations are present.

Soriano V, Miró JM, García-Samaniego J, Torre-Cisneros J, Núñez M, del Romero J, Martín-Carbonero L, Castilla J, Iribarren JA, Quereda C, Santín M, González J, Arribas JR, Santos I, Hernández-Quero J, Ortega E, Asensi V, del Pozo MA, Berenguer J, Tural C, Clotet B, Leal M, Mallolas J, Sánchez-Tapias JM, Moreno S, Gatell JM, Téllez MJ, Rubio R, Ledesma E, Domingo P, Barreiro P, Pedreira J, Romero M, González-Lahoz J, Lissen E. · Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain. · J Viral Hepat. · Pubmed #14738553 No free full text.

Abstract: Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV-infected patients.

Tural C, Solà R, Rubio R, Santín M, Planas R, Quereda C, Berenguer J, Montes-Ramírez M, Clotet B, Anonymous00415. · HIV Clinical Unit, Hospital Germans Trias I Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain. · J Viral Hepat. · Pubmed #17875005 No free full text.

Abstract: To evaluate the safety and efficacy of an induction dose of pegylated interferon alpha 2a (IFN-alpha2a) on the 12-week hepatitis C virus (HCV) kinetics in human immunodeficiency virus (HIV) patients co-infected with HCV. One hundred sixteen HIV/HCV co-infected patients from nine hospitals in Spain were randomized to receive 270 microg/week of pegylated IFN-alpha2a for 4 weeks followed by 180 microg/week for 8 weeks or 180 microg/week for 12 weeks. Ribavirin was given at a daily dose of 1000 or 1200 mg. The main outcome measure was the percentage of patients achieving an HCV-RNA below 50 IU/mL or a decrease of 2 or more log(10) at week 12 (early virologic response, EVR). HCV-RNA was measured at baseline, weekly, for the first 4 weeks and monthly thereafter. We observed no difference in the percentage of patients achieving an EVR between arms (on-treatment, 74% in both arms; intention-to-treat, 70% in the induction arm and 67% in the control arm), nor were there differences in the percentage achieving an undetectable HCV qualitative polymerase chain reaction at any time points or in the decrease in HCV-RNA from baseline. No differences were found between arms in the percentage of dropouts (8% in the whole study population). Our study failed to find a benefit of an induction dose of 270 microg/week of pegylated IFN-alpha2a for 4 weeks on the EVR in co-infected patients who are treatment naive. Despite the lack of benefit with this regimen, induction therapy with this schedule was safe and well tolerated in co-infected patients.

Solà R, Galeras JA, Montoliu S, Tural C, Force L, Torra S, Montull S, Castro ER, Coll S, Fuster D, Barrufet P, Sirera G, Giménez MD, Clotet B, Planas R. · Liver Section, Hospital del Mar, Institut Municipal d'Investigació Médica, Universitat Autònoma de Barcelona, 08003 Barcelona, Spain. · AIDS Res Hum Retroviruses. · Pubmed #16706615 No free full text.

Abstract: The degree of adherence to anti-hepatitis C virus (HCV) therapy among HIV/HCV-coinfected patients is not known. A prospective cohort study was performed in two groups of patients: 79 HIV/HCV-coinfected patients (group 1) and 78-HCV-monoinfected patients (group 2). Patients were treated with interferon alpha-2a (3 million international units [MIU], three times per week) plus ribavirin (1000-1200 mg/day) for 48 weeks. Adherence to therapy was defined as having received +/-80% of both drug dosages for +/-80% of the expected duration of therapy. The degree of adherence to treatment was similar for patients with or without HIV coinfection (72.2 versus 80.8%). The overall sustained virological response (SVR) in patients with adherence to therapy was 41.7% as compared with only 8.1% (p = 0.0001) in patients without adherence. The difference in SVR rate according to adherence to treatment was also evident in patients of group 1 (29.8% versus 9.1%; p = 0.05) as well as in those of group 2 (52.4 versus 6.7%; p = 0.001). Adherence to anti-HCV therapy, which can be similar in mono- and coinfected patients, enhances the likelihood of achieving an increase in SVR rate. In addition to improved adherence, in coinfected patients more aggressive therapeutic strategies may be necessary to achieve SVR.

Fuster D, Huertas JA, Gómez G, Solà R, González García J, Vilaró J, Pedrol E, Force L, Tor J, Sirera G, Videla S, Planas R, Clotet B, Tural C, Anonymous00181. · HIV Clinical Unit/Fundació de la Lluita contra la SIDA/Internal Medicine Service and Hepatology Unit, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. · Antivir Ther. · Pubmed #16312180 No free full text.

Abstract: OBJECTIVE: To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients. DESIGN: Multicentre, prospective, observational study. Setting: Eleven hospitals in Spain during the period 2002-2003. SUBJECTS AND METHODS: One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-alpha2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm(3) (neutrophil-endpoint) and a platelet count below 50,000/mm(3) (platelet-endpoint). RESULTS: Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (+/-3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46-9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31-8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm(3) (HR: 3.59; 95% CI: 1.77-7.28) and baseline weight <60 kg (HR: 2.21; 95% Cl: 1.04-4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm(3) decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint. CONCLUSIONS: Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.

Ballesteros AL, Miró O, López S, Fuster D, Videla S, Martínez E, Garrabou G, Salas A, Côté H, Tor J, Rey-Joly C, Planas R, Clotet B, Tural C. · HIV Clinical Unit, Hospital Universitari Germans Trias i Pujol, Universitat Autónoma de Barcelona, Barcelona, Spain. · Antivir Ther. · Pubmed #15651755 No free full text.

Abstract: BACKGROUND: It has been suggested that the addition of ribavirin (RBV) as a part of the treatment for chronic hepatitis C virus (HCV) in HIV co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function. DESIGN: Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HCV/HIV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their current antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus pegylated interferon (PEG-IFN) alpha-2b therapy (HCV-treated group). Methods: We assessed peripheral blood mononuclear cells mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy. RESULTS: Times on ddI or d4T exposure were 194 +/- 54.9 and 131 +/- 66.5 weeks in the HCV-treated and control groups, respectively. There were no differences either in mtDNA content, the enzyme activity of MRC complexes or clinical parameters at baseline. Throughout the study, mitochondrial measurements remained stable within groups and without differences when we compared HCV-treated and control groups. CONCLUSIONS: In our study, the addition of RBV and PEG-IFN during a 24-week period in HCV/HIV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop.

Ribera E, Lopez RM, Diaz M, Pou L, Ruiz L, Falcó V, Crespo M, Azuaje C, Ruiz I, Ocaña I, Clotet B, Pahissa A. · Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d'Hebron, Paseo Vall Hebron 119-129, 08035 Barcelona, Spain. · Antimicrob Agents Chemother. · Pubmed #15504850 links to  free full text

Abstract: Management of treatment-experienced human immunodeficiency virus patients has become complex, and therapy may need to include two protease inhibitors at therapeutic doses. The objective of this study was to characterize the pharmacokinetics in serum of saquinavir (1,000 mg twice daily [b.i.d.]), lopinavir (400 mg b.i.d.), and ritonavir (100 mg b.i.d.) in a multidrug rescue therapy study and to investigate whether steady-state pharmacokinetics of lopinavir-ritonavir are affected by coadministration of saquinavir. Forty patients were included (25 given ritonavir, lopinavir, and saquinavir and 15 given ritonavir and lopinavir). The median pharmacokinetic parameters of lopinavir were as follows: area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 85.1 microg/ml . h; maximum concentration of drug in serum (C(max)), 10.0 microg/ml; trough concentration of drug in serum (C(trough)), 7.3 microg/ml; and minimum concentration of drug in serum (C(min)), 5.5 microg/ml. Lopinavir concentrations were similar in patients with and without saquinavir. The median pharmacokinetic parameters for saquinavir were as follows: AUC(0-12), 22.9 microg/ml . h; C(max), 2.9 microg/ml; C(trough), 1.6 microg/ml; and C(min), 1.4 microg/ml. There was a strong linear correlation between lopinavir and ritonavir and between saquinavir and ritonavir concentrations in plasma. The correlation between lopinavir and saquinavir levels was weaker. We found higher saquinavir concentrations in women than in men, with no difference in lopinavir levels. Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group. Ritonavir has a double-boosting function for both lopinavir and saquinavir, and in terms of pharmacokinetics, the drug doses selected seemed appropriate for combining these agents in a dual protease inhibitor-based antiretroviral regimen for patients with several prior virologic failures.

Negredo E, Moltó J, Muñoz-Moreno JA, Pedrol E, Ribera E, Viciana P, Galindos MJ, Miralles C, Burger D, Rodriguez Fumaz C, Puig J, Gel S, Rodríguez E, Videla S, Ruiz L, Clotet B. · Lluita Contra la SIDA Foundation, Germans Trias i Pujol Hospital, Badalona, Spain. · Antivir Ther. · Pubmed #15259896 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and safety of a once-daily antiretroviral regimen in HAART-experienced subjects with long-lasting viral suppression. METHODS: One-hundred-and-sixty-nine patients with chronically suppressed viral load (limit of detection <50 copies/ml) were recruited. Based on patient willingness to simplify treatment, 84 of them continued receiving their usual treatment (BID Group) and 85 switched to once-daily didanosine/tenofovir/nevirapine (QD Group) in a non-randomized fashion. RESULTS: At week 48, the proportion of patients with viral suppression in the QD and in the BID Group, respectively, was 97 vs 100% in the per-protocol analysis (P = 0.497), and 76 vs 86% for the intention-to-treat analysis (P = 0.176). Nevertheless, CD4 count decreased in the QD Group, with a mean decline of 95 cells/mm3 (95% CI: 45-145). Twelve subjects in the QD Group (14%) discontinued treatment due to adverse events, mainly nevirapine-related hepatitis (6%). No significant differences regarding the rate of acute pancreatitis or peripheral neuropathy were observed between both groups. A significant improvement in the lipid profile was only seen in the QD Group. High levels of adherence were observed in both groups during follow-up, as well as a good quality of life. At week 48, a reduction in effort to take medication (P < or = 0.001) and an increment in the satisfaction with the treatment (P < 0.001) was only seen in the QD group. No differences were observed in median nevirapine trough levels between patients on twice-daily nevirapine at baseline (4820 ng/ml) and subjects in the QD Group (6090 ng/ml, P = 0.30). CONCLUSION: Treatment simplification to a once-daily antiretroviral regimen based on didanosine, tenofovir and nevirapine may be a valid approach in HIV-infected subjects with long-lasting viral suppression. Combination of standard doses of didanosine and tenofovir may have contributed to the CD4 cell decline observed with this QD regimen.

Llibre JM, Falco V, Tural C, Negredo E, Pineda JA, Muñoz J, Ortega E, Videla S, Sirera G, Martinez E, Miralles C, Iribarren J, Galindo MJ, Domingo P, d'Arminio-Monforte A, Miro JM, Clotet B. · Lluita Contra la SIDA Foundation, University Hospital Germans Trias, Barcelona 08916, Spain. · Curr HIV Res. · Pubmed #19601771 No free full text.

Abstract: The spectrum of complications emerging in successfully treated HIV-infected patients has dramatically changed since the advent of HAART. Typical AIDS-defining illnesses have been substituted by new comorbid conditions that threaten even those patients who maintain virologic suppression. Proper management of cardiovascular risk, and early diagnosis of AIDS-related and, particularly, non-AIDS-related malignancies (including papilomavirus-related neoplasms) must be introduced into the routine of care. Hot areas of investigation include HIV-associated neurocognitive disorders, hepatitis B and C coinfection, non-alcoholic fatty liver disease, progressive multifocal leukoencephalopathy and tuberculosis. Bone and kidney long-term toxicities and lipoatrophy remain as issues of paramount importance. The identification and early treatment of immune reconstitution disease is also of major interest, specially in those patients starting their antiretroviral treatment with severe CD4 cell depletion. The present review focuses on these twelve areas of increasing interest for physicians currently facing successfully treated HIV+ patients.

Moltó J, Llibre JM, Ribera E, Mínguez C, del Río JS, Pedrol E, Vallecillo G, Cedeño S, Valle M, Miranda C, Negredo E, Clotet B, Anonymous00044. · 'Lluita contra la SIDA' Foundation, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · J Antimicrob Chemother. · Pubmed #19279052 No free full text.

Abstract: OBJECTIVES: The aim of this study was to assess the influence of hepatitis B virus or hepatitis C virus co-infection and the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics in HIV-infected subjects without liver function impairment. METHODS: A cross-sectional, comparative study enrolling HIV-infected adults receiving saquinavir/ritonavir 1000/100 mg twice daily or 1500/100 mg once daily was conducted. Patients with chronic viral hepatitis (HEP+) were grouped as having advanced liver fibrosis (HEP+/FIB+) or not (HEP+/FIB-) based on the FIB-4 index. Saquinavir and ritonavir trough concentrations (C(trough)) in plasma were determined by HPLC. The geometric mean ratio (GMR) was used to compare saquinavir and ritonavir C(trough) between HEP- and HEP+ patients, and the influence of the extent of liver fibrosis on saquinavir and ritonavir pharmacokinetics was explored using analysis of variance. RESULTS: One hundred and thirty-eight patients on twice-daily saquinavir/ritonavir (67 HEP-, 71 HEP+) and 36 patients on once-daily saquinavir/ritonavir (12 HEP-, 24 HEP+) were included. Saquinavir C(trough) was comparable between HEP- and HEP+ patients receiving either saquinavir/ritonavir 1000/100 mg twice daily [GMR 0.91, 95% confidence interval (CI) 0.60-1.37; P = 0.655] or 1500/100 mg once daily (GMR 0.88, 95% CI 0.39-1.97; P = 0.752). Similarly, ritonavir C(trough) was also comparable between HEP- and HEP+ patients. The extent of liver fibrosis was not significantly related to saquinavir or ritonavir C(trough) in patients receiving either of the two studied doses. CONCLUSIONS: Saquinavir C(trough) was not increased in HIV-infected patients with chronic viral hepatitis in the absence of liver function impairment. These results confirm that no specific dose modification of saquinavir/ritonavir should be recommended in this setting.

Sanvisens A, Serra I, Tural C, Tor J, Ojanguren I, Barluenga E, Rey-Joly C, Clotet B, Muga R. · Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma, Barcelona, Spain. · J Viral Hepat. · Pubmed #19200132 No free full text.

Abstract: Chronic hepatitis C virus (HCV) infection follows an accelerated course in patients co-infected with human immunodeficiency virus (HIV); establishing the extent of liver fibrosis is crucial for disease staging and determining treatment strategy in these patients. The utility of noninvasive markers of fibrosis as alternatives to liver biopsy has not been well-studied in these patients. We evaluated the predictive value of serum transforming growth factor-beta1 (TGF-beta1) and hyaluronic acid (HA) levels for determining the extent of liver fibrosis. Liver biopsies and blood samples were collected from 69 consecutive patients (74% male; median age, 41 years) between May 2005 and November 2006. Serum TGF-beta1 and HA were analysed using commercial kits. Aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase levels were elevated in 81%, 70% and 60% of patients, respectively. Fifty-three patients (90%) were on highly active antiretroviral therapy and the median CD4-positive cell count was 422 cells/microL. The extent of fibrosis according to Scheuer's scoring was 32% F0 (no fibrosis), 16.5% F1, 16.5% F2, 26% F3 and 7% F4 (cirrhosis). Mean serum TGF-beta1 was 36.1 +/- 14.4 ng/mL; mean serum HA was 75.2 +/- 85.0 microg/L. Serum HA was positively associated and significantly correlated with the stage of fibrosis (r = 0.56; P < 0.05). The area under the curve for discriminating mild (F0-F2) from significant (F3-F4) fibrosis in receiver operating analysis using HA was 0.83 (sensitivity, 87%; specificity, 70%). These data suggest that HA is clinically useful for predicting liver fibrosis and cirrhosis in patients co-infected with HCV/HIV. However, serum TGF-beta1 was not predictive of histological damage in co-infected individuals treated with HAART.

Tural C, Galeras JA, Planas R, Coll S, Sirera G, Giménez D, Salas A, Rey-Joly C, Cirera I, Márquez C, Tor J, Videla S, García-Retortillo M, Clotet B, Solà R. · HIV Clinical Unit, Internal Medicine Department, Fundació de la Lluita contra la SIDA, University Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain. · Antivir Ther. · Pubmed #19195330 No free full text.

Abstract: BACKGROUND: Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)-HIV-coinfected patients. METHODS: A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients (n = 104) were compared. All patients received PEG-IFN-alpha2a 180 microg/week plus ribavirin 800-1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000-1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12. RESULTS: The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV-HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR. CONCLUSIONS: Differences in efficacy of PEG-IFN-alpha2a plus ribavirin treatment between HCV-HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.

Tural C, Tor J, Sanvisens A, Pérez-Alvarez N, Martínez E, Ojanguren I, García-Samaniego J, Rockstroh J, Barluenga E, Muga R, Planas R, Sirera G, Rey-Joly C, Clotet B. · HIV Clinical Unit, Fundació de la Lluita contra la SIDA, Barcelona, Spain. · Clin Gastroenterol Hepatol. · Pubmed #19171202 No free full text.

Abstract: BACKGROUND & AIMS: We assessed the ability of 3 simple biochemical tests to stage liver fibrosis in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS: We analyzed liver biopsy samples from 324 consecutive HIV/HCV-positive patients (72% men; mean age, 38 y; mean CD4+ T-cell counts, 548 cells/mm(3)). Scheuer fibrosis scores were as follows: 30% had F0, 22% had F1, 19% had F2, 23% had F3, and 6% had F4. Logistic regression analyses were used to predict the probability of significant (>or=F2) or advanced (>or=F3) fibrosis, based on numeric scores from the APRI, FORNS, or FIB-4 tests (alone and in combination). Area under the receiver operating characteristic curves were analyzed to assess diagnostic performance. RESULTS: Area under the receiver operating characteristic curves analyses indicated that the 3 tests had similar abilities to identify F2 and F3; the ability of APRI, FORNS, and FIB-4 were as follows: F2 or greater: 0.72, 0.67, and 0.72, respectively; F3 or greater: 0.75, 0.73, and 0.78, respectively. The accuracy of each test in predicting which samples were F3 or greater was significantly higher than for F2 or greater (APRI, FORNS, and FIB-4: >or=F3: 75%, 76%, and 76%, respectively; >or=F2: 66%, 62%, and 68%, respectively). By using the lowest cut-off values for all 3 tests, F3 or greater was ruled out with sensitivity and negative predictive values of 79% to 94% and 87% to 91%, respectively, and 47% to 70% accuracy. Advanced liver fibrosis (>or=F3) was identified using the highest cut-off value, with specificity and positive predictive values of 90% to 96% and 63% to 73%, respectively, and 75% to 77% accuracy. CONCLUSIONS: Simple biochemical tests accurately predicted liver fibrosis in more than half the HIV/HCV co-infected patients. The absence and presence of liver fibrosis are predicted fairly using the lowest and highest cut-off levels, respectively.

Tedaldi E, Peters L, Neuhaus J, Puoti M, Rockstroh J, Klein MB, Dore GJ, Mocroft A, Soriano V, Clotet B, Lundgren JD, Anonymous00127. · Temple University School of Medicine, Philadelphia, Pennsylvania, USA. · Clin Infect Dis. · Pubmed #18959492 No free full text.

Abstract: BACKGROUND: In the Strategic Management of Antiretroviral Therapy (SMART) study, the risk of opportunistic disease (OD) and/or death due to any cause was elevated in the drug conservation (i.e., interrupt antiretroviral therapy until the CD4(+) cell count is <250 cells/microL) group, compared with the viral suppression (continued use of antiretroviral therapy) group. We assessed whether participants with concurrent hepatitis had an increased risk of the end points evaluated in the SMART study. METHODS: Participants were classified as being positive for hepatitis B virus (HBV) if they had positive hepatitis B surface antigen results for >6 months and positive for HCV if they tested HCV antibody positive. The rate and hazard ratio (HR) of OD and/or death and its 2 components were compared by hepatitis status and drug conservation versus the viral suppression group. RESULTS: Among 5472 participants enrolled from 8 January 2002 through 11 January 2006, 930 (17%) were HBV positive and/or HCV positive. The relative risk of non-OD death in participants randomized to the drug conservation group versus the viral suppression group was comparable regardless of hepatitis status (HR for coinfected and HIV-monoinfected participants, respectively, 1.9 [95% confidence interval {CI}, 1.0-3.9 and 1.8 [95% CI, 0.9-3.4]). The rate of OD or death was 3.9 events per 100 person-years in the coinfected group and 2.0 per 100 person-years in the HIV-monoinfected group. This excess risk was due to a higher risk of non-OD death among the coinfected participants (HR, 3.6; 95% CI, 2.3-5.6), whereas the risk of OD was comparable (HR, 1.1; 95% CI, 0.7-1.8). The 3 leading causes of non-OD death in coinfected participants were unknown cause, substance abuse, and non-acquired immunodeficiency disease cancer. CONCLUSIONS: Interruption of antiretroviral therapy is particularly unsafe in persons with hepatitis virus coinfection. Although HCV- and/or HBV-coinfected participants constituted 17% of participants in the SMART study, almost one-half of all non-OD deaths occurred in this population. Viral hepatitis was an unlikely cause of this excess risk.

Fumaz CR, Muñoz-Moreno JA, Moltó J, Ferrer MJ, López-Blázquez R, Negredo E, Paredes R, Gómez G, Clotet B. · Lluita contra la SIDA Foundation, Barcelona, Spain. · AIDS Care. · Pubmed #18728987 No free full text.

Abstract: The objective of this study was to assess adherence of HIV-1-infected patients who started treatment in the pre-HAART era and to determine variables associated with better adherence, including relevant attitudes and beliefs. This is a cross-sectional study enrolling patients who had received antiretroviral therapy for >or=10 years. Adherence was evaluated through self-reporting and plasma drug concentrations. Treatment variables, attitudes and beliefs were collected during structured interviews. The results show that for 87 patients the median (interquartile range) time on therapy was 13 (10-19) years; 80 were on therapy at the time of analysis. Adherence was >or=95% in 54 patients (67.5%), 90-94% in 22 (27.5%) and <90% in 4 (5%). Drug concentrations were below the lower limit of detection in five patients. Younger age (p=0.014), female gender (p=0.005), current substance abuse (p=0.004) and hepatitis C virus co-infection (p<0.001) were related to lower adherence. Adherence did not differ in relation to different drug families or once- or twice-daily regimens. Patients with adherence <95% were more likely to have interrupted treatment without doctor's recommendation (p=0.009). Adherent patients exhibited a higher perception of risk of developing the illness and of benefits of therapy, higher self-efficacy and intention to adhere and were more influenced by events that motivate medication intake. To conclude, adherence was >90% in most patients on antiretroviral therapy for >or=10 years. Adherence was more related to beliefs about health and illness than to the characteristics of medication or level of knowledge about treatment. Care adherence interventions should include assessment of health beliefs.

Opravil M, Sasadeusz J, Cooper DA, Rockstroh JK, Clumeck N, Clotet B, Montaner J, Torriani FJ, Depamphilis J, Dieterich DT. · Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland. · J Acquir Immune Defic Syndr. · Pubmed #18156990 No free full text.

Abstract: OBJECTIVE: The impact of baseline CD4 status on hepatitis C virus (HCV) treatment response among patients with HIV/HCV coinfection was investigated using data from a randomized study of peginterferon alfa-2a (40KD) + ribavirin (Peg-IFN/RBV). METHODS: Of 860 patients treated with conventional interferon alfa-2a + ribavirin (IFN/RBV), peginterferon alfa-2a (40KD) + placebo (Peg-IFN), or Peg-IFN/RBV for 48 weeks, 857 patients had baseline CD4 data available and were included in the analysis. Efficacy and safety were analyzed according to baseline CD4 status as absolute cell count and proportion of total lymphocytes. RESULTS: Sustained virologic response (SVR) rates were highest with Peg-IFN/RBV across all CD4 strata. With Peg-IFN/RBV, SVR rates were independent of baseline CD4 in genotype 2/3 patients, but in genotype 1 patients, they tended to be higher with higher CD4 or CD4%. Frequencies of adverse events (AEs) and serious AEs were similar among treatment arms and CD4 strata. Withdrawal and dose reduction rates attributable to safety were highest with CD4 <200 cells/muL. CONCLUSIONS: Peg-IFN/RBV could be effective and well tolerated in HIV/HCV-coinfected individuals with stable HIV. With Peg-IFN/RBV, response tended to increase with higher CD4 counts in genotype 1; however, because of the paucity of patients with CD4 <200 cells/muL, these data require corroboration.

Kuntzen T, Tural C, Li B, Feldmann G, Kupfer B, Nischalke HD, Clotet B, Sauerbruch T, Rockstroh JK, Spengler U. · Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA. · AIDS. · Pubmed #18097222 No free full text.

Abstract: OBJECTIVE: Liver disease is more progressive in HIV/hepatitis C virus (HCV) co-infection than in HCV infection alone. This accelerated pathogenesis is probably influenced by differences in the composition of infiltrating inflammatory cells and the local release of inflammatory and profibrogenic cytokines. METHODS: Using quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) we studied intrahepatic messenger RNA levels of cytokines and cellular markers defining distinct subsets of inflammatory cells in liver biopsies from 33 HCV-mono-infected and 40 HIV/HCV-co-infected patients. RESULTS: Despite their well preserved peripheral blood CD4 cell counts (median 598 cells/microl), HIV/HCV-co-infected patients displayed significantly lower CD4 mRNA levels than HCV-mono-infected patients, whereas increased mRNA levels of CD3epsilon, TCRalpha, CD8alpha and CD8beta suggested intrahepatic enrichment of CD8 T cells in HIV co-infection. Intrahepatic mRNA levels of the inflammatory cytokines interferon gamma (IFN-gamma), regulated upon activation, normal T-cell expressed and secreted (RANTES, CCL5), macrophage inflammatory protein 1 alpha (CCL3) and interferon-inducible protein 10 (CXCL10) were significantly higher in HIV-positive than in HIV-negative patients, whereas mRNA levels of the profibrogenic cytokines macrophage chemoattractant protein 1 (CCL2), secondary lymphochemokine (CCL21) and stroma-derived factor 1 (CXCL12) did not differ between the two groups. All changes were less pronounced in the subgroup of HIV-positive patients receiving antiretroviral treatment (HAART) than in untreated HIV-positive patients. CONCLUSION: The accelerated liver disease observed in HIV/HCV-co-infected patients might reflect enhanced intrahepatic inflammatory responses rather than increased local transcription of directly profibrogenic cytokines.

Franco S, Clotet B, Martínez MA. · Fundacio irsiCaixa, Universitat Autònoma de Barcelona (UAB), Spain. · Virus Res. · Pubmed #18037183 No free full text.

Abstract: The hepatitis C virus (HCV) NS3/4A protease acts as an antagonist of virus-induced interferon (IFN) regulatory factor (IRF)-3 activation and IFN-beta expression. The NS3/4A protease performs this function by cleaving Cardif and TRIF proteins to block retinoic-acid-inducible gen I (RIG-I) and toll-like receptor (TLR)-3 signaling, respectively. NS3/4A protease inhibition can prevent Cardif and/or TRIF inactivation during HCV infection, thereby maintaining the innate immune response. Thus, differences in NS3/4A protease catalytic efficiency could be related to viral pathogenicity. In this study, we analyzed the catalytic efficiency of the most abundant NS3/4A protease isolated from each of 12 individuals infected with HCV genotypes 1b, 1a, 3a, 4a or 4d. A diversity of NS3/4A protease catalytic efficiencies (up to a six-fold difference) was found in the analyzed samples. The genotype 1b NS3/4A proteases displayed the highest catalytic efficiencies. However, within this genotype up to three-fold differences were observed. Cross-genotypic interactions between the NS3 protease domain and the NS4A cofactor peptide were also investigated. Overall, catalytic efficiencies of NS3 proteases cross-interacting with NS4A cofactors from heterologous genotypes were as efficient as the homologous NS3/4A interactions. Of the 28 heterologous interactions tested, only 6 resulted in deleterious or nonfunctional enzymes. Nonfunctional interactions were not genotype-specific, suggesting that enhancement of NS3 catalytic efficiency by the NS4A cofactor depends on a few specific amino acid residues. Characterization of the proteolytic activities of individual NS3/4A proteases should provide clues for understanding HCV-host interactions, as well as assisting in the development of new classes of NS3/4A protease inhibitors.

Rachlis A, Clotet B, Baxter J, Murphy R, Lefebvre E. · Division of Infectious Disease, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. · HIV Clin Trials. · Pubmed #17720661 links to  free full text

Abstract: PURPOSE: This subanalysis examines the safety and efficacy of darunavir with low-dose ritonavir (DRV/r) in hepatitis B or C virus (HBV or HCV) co-infected patients in POWER 1 and 3 trials. METHOD: POWER 1 and 3 enrolled treatment-experienced, HIV-infected patients with > or =1 primary protease inhibitor (PI) mutation and HIV-1 RNA >1,000 copies/mL. All patients received an optimized background regimen plus either control PI (almost all ritonavir boosted) or one of four DRV/r doses (POWER 1) or DRV/r 600/100 mg bid (POWER 3). Patients with active HBV or HCV co-infection who did not require treatment for hepatitis were included. Safety parameters were evaluated. RESULTS: Of 634 DRV/r and 63 control (97% ritonavir boosted) patients assessed, 13% and 16%, respectively, had active co-infection. In both groups, more patients with active co-infection than without co-infection had liver-related adverse events (AEs). These AEs were mainly asymptomatic liver transaminase elevations, although changes were slightly less in the DRV/r group (DRV/r, 13% vs. 8%; control PI, 20% vs. 12%). Only two patients (one per treatment arm) discontinued therapy due to grade 3 or 4 alanine and aspartate transaminase elevations. CONCLUSION: DRV/r was generally well tolerated in treatment-experienced, HBV or HCV co-infected patients. No differences in liver-related AEs were observed between treatment groups.

Nattermann J, Vogel M, Berg T, Danta M, Axel B, Mayr C, Bruno R, Tural C, Klausen G, Clotet B, Lutz T, Grünhage F, Rausch M, Nischalke HD, Schewe K, Bienek B, Haerter G, Sauerbruch T, Rockstroh JK, Spengler U, Anonymous00347. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Hepatology. · Pubmed #17668881 No free full text.

Abstract: Hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection poses a difficult therapeutic problem. Response to HCV-specific therapy is variable but might be influenced by host genetic factors, including polymorphisms of cytokine genes. Here, we studied whether interleukin-6 (IL-6) C174G gene polymorphism affects the response to antiviral treatment in HCV-infected HIV-positive subjects. We determined IL-6 genotypes in HIV-positive patients with acute (n = 52) and chronic (n = 60) hepatitis C treated with pegylated interferon-alpha. Two hundred ten HCV monoinfected, 197 HIV monoinfected, and 100 healthy individuals were studied as controls. Patients were classified into high and low producers according to IL-6 genotypes. Rates of sustained virological responses (SVRs) were compared between the IL-6 genotypes. Signal transducer and activator of transcription three phosphorylation was analyzed by Western blot in HCV core-transfected human hepatoma cell line (HUH7) cells. Distribution of IL-6 genotypes did not differ significantly between the study groups. SVR was achieved in 63% of HIV/HCV coinfected patients. Carriers of the IL-6 high producer (HP) genotype had significantly higher SVR rates than patients with an IL-6 low producer genotype (70.1% versus 52%; P < 0.002). This effect was seen in both HIV-positive patients with acute (74% versus 33%; P < 0.05) and chronic (66% versus 33%; P < 0.05) hepatitis C. Multivariate analysis confirmed IL-6 HP carriage as an independent positive predictor for SVR (Odd's ratio 6.1; P = 0.004). This effect corresponds to the in vitro observation that in HCV core-transfected HUH7 cells, IL-6 overcomes the HCV core-mediated inhibition of STAT3 activation. CONCLUSION: Response rates to HCV-specific treatment are higher in HCV/HIV-positive patients carrying the IL-6 HP genotype, which might be because of IL-6 mediated STAT3 activation.

Moltó J, Valle M, Blanco A, Negredo E, DelaVarga M, Miranda C, Miranda J, Domingo P, Vilaró J, Tural C, Costa J, Barbanoj MJ, Clotet B. · Fundació Lluita contra la SIDA, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · Clin Pharmacokinet. · Pubmed #17201460 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. RESULTS: Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively). CONCLUSION: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Fumaz CR, Muñoz-Moreno JA, Ballesteros AL, Paredes R, Ferrer MJ, Salas A, Fuster D, Masmitjà E, Pérez-Alvarez N, Gómez G, Tural C, Clotet B. · Universitat Autònoma de Barcelona, Barcelona, Spain. · AIDS Care. · Pubmed #17129869 No free full text.

Abstract: This is a prospective observational comparative 48-week study to assess the impact of the different types of Peg-IFN on depressive and neuropsychiatric symptoms during treatment in HIV-HCV coinfected patients. Thirty-one patients treated with Peg-IFN alpha-2b 1.5 microg/kg/w plus ribavirine (RBV) (Peg-IFN alpha-2b Group) and 32 patients receiving Peg-IFN alpha-2a 180 microg/w plus RBV (Peg-IFN alpha-2a Group) were included. Depressive and neuropsychiatric symptoms, quality of life and adherence were assessed. Fifteen subjects (23%) discontinued therapy (p = 0.3, between groups). Overall, 37 patients presented mild to moderate depressive symptoms, 9 moderate to severe and 3 severe, without differences between groups. Patients in Peg-IFN alpha-2b reported higher fatigue and dizziness at weeks 12 (p < 0.05) and 24 (p < 0.05), and irritability and memory loss at week 24 (p < 0.05) with respect to Peg-IFN alpha-2a Group. At week 12, role functioning, general health perception, vitality, emotional role, mental health and the summary areas of physical health and mental health were lower in Peg-IFN alpha-2b Group (p < 0.05). The same was observed in physical functioning (p = 0.05) and role functioning, general health perception, emotional role and mental health (p < 0.001) at week 24. Three months after finishing treatment, no patient had depressive or neuropsychiatric symptoms, and quality of life improved. Antiretroviral adherence was low but adherence to anti-HCV therapy remained high in both groups. According to our data, Peg-IFN alpha-2a and Peg-IFN alpha-2b exert a similar impact on the overall rate of depressive symptoms, although patients treated with Peg-IFN alpha-2a experience less fatigue and fewer neuropsychiatric symptoms and a lower impairment in their physical and mental quality of life.