Hepatitis: Macías J

Neukam K, Macías J, Mira JA, Pineda JA. · Hospital Universitario de Valme, Unidad Clínica de Enfermedades Infecciosas, 41014 Seville, Spain. · Expert Opin Pharmacother. · Pubmed #19191679 No free full text.

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection remains a serious health problem worldwide. The current standard treatment of HCV infection is pegylated interferon-alpha plus ribavirin, but this is clearly not sufficiently effective and tolerable. OBJECTIVE: To review current HCV treatment strategies and future options. METHODS: Review of major clinical trials or observational studies when no trial is available. RESULTS/CONCLUSION: Rates of sustained virologic response are widely variable, approximately 40-80%, depending on genotype, and even lower when HIV coinfection occurs. New agents, like small molecules that specifically target the HCV life cycle, may improve response rates; but safety is a concern.

Pineda JA, Macías J. · Service of Internal Medicine, Unit of Infectious Diseases, Hospital Universitario de Valme, Seville, Spain. · J Antimicrob Chemother. · Pubmed #15731202 links to  free full text

Abstract: As the immunosuppression caused by human immunodeficiency virus (HIV) accelerates the progression of hepatitis C virus (HCV)-related liver fibrosis, the immune reconstitution associated with highly active antiretroviral therapy (HAART) may have the opposite effect. However, hepatotoxicity related to HAART could enhance the progression of liver fibrosis. Some retrospective studies have shown that therapy with the protease inhibitors may be associated with less severe liver fibrosis, whereas nevirapine use seems to correlate with faster progression. Low-grade liver toxicity associated with nevirapine could account for this effect. However, other studies have not confirmed these findings. Long-term prospective studies are needed to analyse the impact of antiretroviral drugs on the progression of HCV-related liver disease. Meanwhile, no specific recommendations can be made on the use of individual drugs or drug classes in HIV/HCV-coinfected patients. Most importantly however, the inherent benefits of HAART largely outweigh the risk of enhancing fibrosis progression. Additionally, in coinfected patients, other factors that promote fibrogenesis, such as alcohol consumption, should be avoided. Antiviral treatment of chronic hepatitis C could also reduce the risk of liver damage associated with HAART.

Macías J, Recio E, Vispo E, Rivero A, López-Cortés LF, Ríos MJ, Merino D, González M, Barreiro P, de Lédinghen V, Quereda C, Pineda JA. · Clinical Unit of Infectious Diseases, Department of Internal Medicine, Seville, Spain. · J Hepatol. · Pubmed #18929426 No free full text.

Abstract: BACKGROUND/AIMS: Transient elastometry (TE) is accurate for detecting cirrhosis (F=4) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) co-infected patients. However, this procedure is less precise to differentiate mild (F < or = 1) from moderate to severe (F > or = 2) fibrosis using the cut-off value of 7.2kPa, a level previously proposed by some authors. Because of this, we elaborated and validated cut-off values of liver stiffness (LS) to better discriminate F < or = 1 from F > or = 2 in HIV/HCV co-infected subjects to aid therapy decisions. METHODS: One hundred and ninety-seven co-infected patients with liver biopsy and TE measurement, without prior therapy against HCV infection, were included. RESULTS: To diagnose F < or = 2, a cut-off of 9.0kPa showed a positive predictive value of 87%. To discard F > or = 2, a cut-off of 6.0kPa showed a negative predictive value of 90%. Considering all the patients, 61 (31%) patients yielded LS values < or = 6.0kPa and 81 (41%) patients showed LS values > or = 9.0kPa. There were no severe classification errors as the NPV of L < or = S6.0kPa for F > or = 3 was 100% and the NPV LS > or = 9.0kPa for F=0 was also 100%. CONCLUSIONS: The usefulness of TE can be enhanced using two different cut-off values to identify patients with F < or = 1 and F > or = 2.

Mira JA, López-Cortés LF, Barreiro P, Tural C, Torres-Tortosa M, de Los Santos Gil I, Martín-Rico P, Ríos-Villegas MJ, Hernández-Burruezo JJ, Merino D, López-Ruz MA, Rivero A, Muñoz L, González-Serrano M, Collado A, Macías J, Viciana P, Soriano V, Pineda JA. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla, Spain. · J Antimicrob Chemother. · Pubmed #18854330 No free full text.

Abstract: OBJECTIVES: To compare the response to hepatitis C virus (HCV) therapy among human immunodeficiency virus (HIV)/HCV co-infected patients receiving a nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] backbone consisting of abacavir plus lamivudine with that observed in subjects who receive tenofovir plus lamivudine or emtricitabine. METHODS: A total of 256 subjects, enrolled in a cohort of 948 HIV-infected patients who received pegylated interferon and ribavirin from October 2001 to January 2006, were included in this study. All patients were taking one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor and abacavir plus lamivudine or tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone during HCV therapy. Sustained virological response (SVR) rates in both backbone groups were compared. RESULTS: In an intention-to-treat analysis, 20 out of 70 (29%) individuals under abacavir and 83 out of 186 (45%) under tenofovir showed SVR (P = 0.02). N(t)RTI backbone containing tenofovir was an independent predictor of SVR in the multivariate analysis [adjusted odds ratio (95% CI), 2.6 (1.05-6.9); P = 0.03]. The association between abacavir use and lower SVR was chiefly seen in patients with plasma HCV-RNA load higher than 600 000 IU/mL and genotype 1 or 4. Among patients treated with ribavirin dose <13.2 mg/kg/day, 3 (20%) of those under abacavir versus 22 (52%) under tenofovir reached SVR (P = 0.03), whereas the rates were 31% and 38% (P = 0.4), respectively, in those receiving >/=13.2 mg/kg/day. CONCLUSIONS: HIV-infected patients who receive abacavir plus lamivudine respond worse to pegylated interferon plus ribavirin than those who are given tenofovir plus lamivudine or emtricitabine as N(t)RTI backbone, especially in those receiving lower ribavirin doses.

Palacios R, Vergara S, Rivero A, Aguilar I, Macías J, Camacho A, Lozano F, García-Lázaro M, Pineda JA, Torre-Cisneros J, Márquez M, Santos J. · Hospital Virgen de la Victoria, Málaga. · HIV Clin Trials. · Pubmed #17197379 links to  free full text

Abstract: OBJECTIVES: To analyze the incidence of severe liver events in HIV patients treated with lopinavir/ritonavir and the role of coinfection in the development of this toxicity. METHOD: This was a retrospective, multicenter, cohort study of all HIV-positive patients who started a regimen of HAART that included lopinavir/ritonavir (LPV/r). The main outcome variable was the emergence of a severe liver event, defined as decompensation of pre-existing chronic liver disease and grade 3-4 hypertransaminasemia (HT), that is, plasma AST or ALT values >5 times above the upper limit of normality, if baseline levels were normal, or >3.5 times the baseline values when they were abnormal. RESULTS: 388 HIV-infected patients were included, with a median follow-up of 25.6 months. Coinfection with HCV was present in 61% of the patients and with HBV in 6.7%. There were 6 cases of severe liver events, all involving patients who were coinfected with HCV and all within the first 6 months. This represents 0.72 events per 100 patient-years (95% confidence interval [CI] 0.36-2.98) and 1.21 events per 100 patient-years (95% CI 0.60-5.86) in coinfected patients. The only factors associated with severe liver events at 6 months were baseline HT and HCV coinfection. CONCLUSION: The incidence of severe hepatic events in HIV-positive patients receiving a HAART regimen including LPV/r was very low, even in coinfected patients. HCV coinfection and baseline HT were the only factors associated with severe liver events. LPV/r can be considered a safe and well-tolerated option in HIV patients with hepatotropic virus coinfections.

García-García JA, Mira JA, Fernández-Rivera J, Ramos AJ, Vargas J, Macías J, Pineda JA. · Departamento de Medicina Interna, Hospital Universitario de Valme, Carretera de Cádiz s/n, 41014, Sevilla, Spain. · Eur J Clin Microbiol Infect Dis. · Pubmed #12649720 No free full text.

Abstract: The influence of hepatitis C virus (HCV) coinfection on the kinetics of serum beta2microglobulin levels in HIV-infected patients undergoing highly active antiretroviral therapy was analyzed. After 96 weeks of therapy, beta2microglobulin levels declined significantly both in 24 HCV seronegative and 16 HCV-infected individuals. Throughout the follow-up period, HCV-infected patients showed higher beta2microglobulin values than non-HCV-infected patients. These results show that HCV infection precludes immune deactivation in HIV-infected patients undergoing highly active antiretroviral therapy.

Pineda JA, Recio E, Camacho A, Macías J, Almodóvar C, González-Serrano M, Merino D, Tellez F, Ríos MJ, Rivero A, Anonymous00075. · Unit of Infectious Diseases, Hospital Universitario de Valme, Seville, Spain. · J Acquir Immune Defic Syndr. · Pubmed #19487952 No free full text.

Abstract: BACKGROUND: Liver stiffness (LS) measured by transient elastometry is associated with portal pressure in hepatitis C virus (HCV)-monoinfected patients and could predict the presence of esophageal varices in these subjects. The aim of this study was to assess the ability of LS to predict esophageal varices requiring preventive therapy for bleeding in HIV/HCV-coinfected patients. METHODS: One hundred two HIV/HCV-coinfected patients with liver cirrhosis (LS >or= 14 kPa) underwent an upper gastrointestinal endoscopy (UGE) examination. The diagnostic performance of LS for esophageal varices requiring therapy (>or=F2 or F1 with red signs or Child-Pugh-Turcotte class C) was assessed by receiver operating receptor characteristic curves. RESULTS: Nineteen patients (19%) harbored varices requiring therapy. LS in patients with and without varices needing treatment was 48 (33-71) kPa and 32 (18-48) kPa (P = 0.004). The area under the receptor operating characteristic curve (95% confidence interval) of LS for the occurrence of varices that should be treated was 0.71 (0.60 to 0.82). There was no cutoff level of LS with good positive predictive value for the presence of varices requiring therapy, but LS of 21 kPa had a negative predictive value of 100%. Twenty-six percent of patients with LS measurement and UGE showed LS <21 KPa. CONCLUSIONS: LS is higher in HIV/HCV-coinfected patients with cirrhosis who show esophageal varices requiring therapy than in those who do not. A cutoff value of LS of 21 kPa could be useful to identify patients with very low probability of varices at risk for bleeding. UGE for screening could be spared in these patients until LS increases above 21 kPa.

Vispo E, Barreiro P, Del Valle J, Maida I, de Ledinghen V, Quereda C, Moreno A, Macías J, Castera L, Pineda JA, Soriano V. · Infectious Diseases Department, Hospital Carlos III, Madrid, Spain. · Antivir Ther. · Pubmed #19430093 No free full text.

Abstract: BACKGROUND: Transient elastography (TE) is a non-invasive method that allows liver fibrosis staging on the basis of hepatic stiffness measurements. Little is known about the influence of chronic liver inflammation on the stiffness of hepatic tissue. METHODS: A total of 112 patients with chronic hepatitis C underwent a liver biopsy and TE. RESULTS: Mean values of liver stiffness (in kPa) by inflammation strata were 4.8, 6.4, 9.4 and 12.6 for A0, A1, A2 and A3, respectively, in hepatitis C virus (HCV)-monoinfected individuals (P=0.018). These figures were 8.0, 10.4, 12.9 and 12.6 for A0, A1, A2 and A3, respectively, in HIV-HCV-coinfected patients (P=0.35). In HCV-monoinfected patients with fibrosis staging F3-F4, mean liver stiffness was greater if inflammation was > or =A2 versus A0-A1 (14.6 versus 6.2 kPa; P=0.04). By contrast, no differences in liver stiffness according to inflammation were seen in HCV-monoinfected patients with <F3 or in HIV-HCV-coinfected patients regardless of liver fibrosis staging. Among HCV-monoinfected patients, mean liver stiffness was greater for alanine aminotransferase >100 versus <100 IU/l (10.5 versus 8.5 kPa; P=0.04). CONCLUSIONS: The extent of liver inflammation might affect the accuracy of TE for staging liver fibrosis, particularly in HCV-monoinfected patients with advanced fibrosis on liver biopsy and/or increased alanine aminotransferase levels.

Macías J, Orihuela F, Rivero A, Viciana P, Márquez M, Portilla J, Ríos MJ, Muñoz L, Pasquau J, Castaño MA, Abdel-Kader L, Pineda JA, Anonymous00264. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain. · J Antimicrob Chemother. · Pubmed #18952618 No free full text.

Abstract: OBJECTIVES: The aim of this study was to evaluate the incidence and risk factors of severe liver events among HIV-infected patients treated with drug combinations including tipranavir boosted with ritonavir (TPV/r). METHODS: One hundred and fifty patients were selected because they started a regimen that included TPV/r (500/200 mg twice a day) and had clinical visits at least every 3 months. Patients who discontinued TPV/r before their first visit were included. RESULTS: Twelve (8%) individuals developed grade>or=3 transaminase elevation (G>or=3TE). Nine (6%) patients discontinued TPV/r due to liver events. Six (8.6%) of 70 hepatitis C virus (HCV) co-infected patients and 6 (7.5%) of 80 subjects without HCV co-infection developed G>or=3TE (P=1). Liver fibrosis was evaluable in 48 (63%) of 76 individuals with hepatitis B virus and/or HCV infection. Four (13%) of 30 subjects with moderate-to-severe fibrosis and none of 18 with mild fibrosis showed G>or=3TE (P=0.3). None of nine patients with cirrhosis showed G>or=3TE. CONCLUSIONS: Liver tolerability of TPV/r was generally good in a cohort of patients with a high proportion of HCV co-infection, including subjects with advanced fibrosis. The presence of HCV co-infection was not associated with an increased risk of severe transaminase elevations.

Macías J, Palacios RB, Claro E, Vargas J, Vergara S, Mira JA, Merchante N, Corzo JE, Pineda JA. · Servicio de Medicina Interna, Hospital Universitario de Valme, Seville, Spain. · Liver Int. · Pubmed #18312289 No free full text.

Abstract: BACKGROUND: Most of the prevalent cases of hepatitis C virus (HCV) infection are attributable to intravenous drug using. However, a substantial number of individuals, particularly noninjecting drug users (NIDU), report no identifiable source of HCV exposure. This may be interpreted as inaccurate reporting of past intravenous exposure or as the presence of an unidentified source of HCV infection. Because of this, we evaluated the prevalence of and factors associated with HCV infection among NIDU. METHODS: One hundred and eighty-two individuals who were attended from 2003 to 2004 in a drug addiction facility because of noninjecting drug use were included. RESULTS: HCV infection was detected in 23 (12.6%) participants. Sharing the inhalation tube of crack cocaine [adjusted odds ratio (AOR) 3.6, 95% confidence interval (CI) 1.3-9.8, P=0.01], presence of tattoos (AOR 3.5, 95% CI 1.3-9.1, P=0.02) and age >or=34 years (AOR 3.9, 95% CI 1.3-11.6, P=0.01) 3.9 were independently associated with HCV infection. CONCLUSION: The prevalence of HCV infection in NIDU is higher than in general population. HCV infection is more likely among older drug users, those with tattoos and crack cocaine users that share the inhalation implements.

Pineda JA, Santos J, Rivero A, Abdel-Kader L, Palacios R, Camacho A, Lozano F, Macías J, Anonymous00166. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain. · J Antimicrob Chemother. · Pubmed #18276600 links to  free full text

Abstract: OBJECTIVES: To appraise the rate of grade 3-4 transaminase elevations (TEs) and grade 4 total bilirubin elevation (TBE) in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C or hepatitis B virus (HCV or HBV, respectively) who receive atazanavir/ritonavir. Moreover, the relationship between these events and the degree of prior liver fibrosis was evaluated. METHODS: A cohort of 189 HIV-infected patients, 175 co-infected with HCV, 4 with HBV and 10 with both, receiving atazanavir/ritonavir, was analysed. Baseline liver fibrosis was assessed in 113 (60%) patients. Twenty-four patients had cirrhosis, whereas such a diagnosis was ruled out in 58 patients. RESULTS: Twelve (6%) and 28 (15%) patients developed grade 3-4 TEs and grade 4 TBE, respectively. Eight (10%) of 84 patients with fibrosis >/=F2 versus 1 of 29 (3%) with F0-F1 (P = 0.51) developed grade 3-4 TEs. The frequencies of grade 3-4 TEs in patients with and without cirrhosis were 8% and 5% (P = 0.63), respectively. Grade 4 TBE was more common among patients with cirrhosis (35% versus 13%, P = 0.05) in the univariate analysis. In the multivariate study, the only predictor of grade 3-4 TEs was baseline CD4 cell count <300 cells/mm(3) [adjusted OR (AOR) (95% CI) = 8.77 (1.07-71.42), P = 0.04]. The factors independently associated with grade 4 TBE were baseline total bilirubin >1 mg/dL [AOR (95% CI) = 3.2 (1.21-8.45), P = 0.01] and age >40 years [AOR (95% CI) = 2.98 (1.19-7.47), P = 0.02]. CONCLUSIONS: Prior significant liver fibrosis or cirrhosis do not increase substantially the risk of severe TE associated with atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses.

Mira JA, López-Cortés LF, Merino D, Arizcorreta-Yarza A, Rivero A, Collado A, Ríos-Villegas MJ, González-Serrano M, Torres-Tortoso M, Macías J, Valera-Bestard B, Fernández-Fuertes E, Girón-González JA, Lozano F, Pineda JA, Anonymous00098. · Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain. · Antivir Ther. · Pubmed #18240862 No free full text.

Abstract: BACKGROUND: Haematological adverse events related to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy could affect the patients' quality of life; however, the risk factors for severe haematological toxicity associated with this therapy in patients coinfected with hepatitis C virus (HCV) and HIV are unclear. The objective of this study was to identify predictors of severe haematological toxicity among HIV-HCV-coinfected patients treated with PEG-IFN plus RBV. METHODS: This retrospective multicentric study included 237 HIV-HCV-coinfected patients on PEG-IFN plus RBV. Predictors of severe anaemia, neutropenia, thrombocytopenia and overall haematological toxicity were analyzed. RESULTS: Eighty (34%) individuals showed an episode of severe haematological toxicity. Severe anaemia, neutropenia and thrombocytopenia occurred in 32 (13%), 42 (18%) and 26 (11%) patients, respectively. In the multivariate analysis, zidovudine use (adjusted odds ratio [AOR] 3.3; 95% confidence interval [CI] 1.6-10; P = 0.001), baseline body weight < 65 kg (AOR 2.5; 95% CI 1.1-5; P = 0.024), cirrhosis (AOR 5; 95% CI 1.6-16.6; P = 0.006), PEG-IFN-alpha2a (AOR 2.7; 95% CI 1.1-6.6; P = 0.029) and pretreatment haemoglobin level < 14 g/dl (AOR 2.7; 95% CI 1.3-5.5; P = 0.005) were associated with any kind of severe haematological toxicity. Likewise, haemoglobin level < 13 g/dl, neutrophil counts < 2,500 cells/mm3 and platelet counts < 175,000 cells/mm3 were independent predictors of severe anaemia, neutropenia and thrombocytopenia, respectively. CONCLUSIONS: Zidovudine treatment, cirrhosis, baseline low body weight, use of PEG-IFN-alpha2a, and baseline haemoglobin level < 14 g/dl are predictors of overall severe haematological toxicity secondary to PEG-IFN plus RBV in HIV-infected individuals. Low pretreatment levels of each haematological series predict a significant decrease of their values during therapy.

Vergara S, Macías J, Rivero A, Gutiérrez-Valencia A, González-Serrano M, Merino D, Ríos MJ, García-García JA, Camacho A, López-Cortés L, Ruiz J, de la Torre J, Viciana P, Pineda JA, Anonymous00035. · Clinical Unit of Infectious Diseases, Department of Internal Medicine, Hospital Universitario de Valme, Seville, Spain. · Clin Infect Dis. · Pubmed #17879910 No free full text.

Abstract: BACKGROUND: Transient elastometry (TE) is accurate for detecting significant liver fibrosis and cirrhosis in hepatitis C virus (HCV)-monoinfected patients. However, this procedure has been insufficiently validated in patients with human immunodeficiency virus (HIV) and HCV coinfection. The purpose of this study was to validate reported cutoff values of TE that discriminate significant liver fibrosis and cirrhosis in HIV-HCV-coinfected subjects. METHODS: Liver stiffness measurements were obtained for 169 HIV-HCV-coinfected adult patients who had undergone a liver biopsy or who had received a nonhistologic diagnosis of cirrhosis within 12 months before or after a liver stiffness measurement. Patients had received no prior therapy for HCV infection. RESULTS: TE measurements ranged from 3.6 kPa to 75 kPa. The area under the receiver operating characteristic curve was 0.87 (95% confidence interval, 0.84-0.93) for significant liver fibrosis and 0.95 (95% confidence interval, 0.92-0.99) for cirrhosis. To diagnose significant liver fibrosis, a cutoff value of 7.2 kPa was associated with a positive predictive value of 88% and a negative predictive value of 75%. Thirty-four patients (20%) were misclassified when this cutoff value was used. Thirteen (24%) of 54 patients with liver stiffness values <7.2 kPa had significant liver fibrosis detected by liver biopsy. To diagnose cirrhosis, a cutoff value of 14.6 kPa was associated with a positive predictive value of 86% and a negative predictive value of 94%. Thus, 13 patients (10%) had disease that was misclassified using this cutoff value. CONCLUSIONS: We found that the diagnostic accuracy of TE was high for detecting cirrhosis and good for diagnosis of significant liver fibrosis. However, the performance of TE was low for discriminating mild fibrosis from significant liver fibrosis, which might limit the applicability of this technique in clinical practice.

Mira JA, Valera-Bestard B, Arizcorreta-Yarza A, González-Serrano M, Torre-Cisneros J, Santos I, Vergara S, Gutiérrez-Valencia A, Girón-González JA, Macías J, López-Cortés LF, Pineda JA. · Hospital Universitario de Valme, Sevilla, Spain. · Antivir Ther. · Pubmed #17668561 No free full text.

Abstract: INTRODUCTION: The clinical applicability of early viral kinetics at week 4 in predicting sustained virological response (SVR) of pegylated interferon (peg-IFN) plus ribavirin (RBV) in HIV/HCV-coinfected patients is unclear. Our objective was to determine if rapid virological response (RVR) at week 4 of therapy with peg-IFN and RBV could predict SVR among HIV/HCV-coinfected patients. METHODS: HIV/HCV-coinfected patients in whom an HCV viral load determination had been carried out at week 4 of therapy were included in the study. The positive predictive value (PPV) and the negative predictive value (NPV) of RVR (undetectable serum HCV RNA at 4 week) for SVR were calculated in the study population. Receiver operating characteristic curves were calculated to determine the best cutoff of HCV RNA decrease to predict treatment failure. RESULTS: A total of 101 HIV/HCV-coinfected patients were included. RVR and SVR were observed in 39 (39%) and in 49 (48%) individuals, respectively. Of patients with RVR, 37/39 patients achieved SVR (PPV: 95%), whereas 50/62 individuals without RVR did not show SVR (NPV: 81%). The highest NPV (96%) was reached by using a cutoff level of HCV RNA decrease of 0.6 log10. By applying this cutoff level, treatment could have been discontinued in 25 (25%) patients. CONCLUSIONS: An undetectable serum HCV RNA determination at week 4 of treatment with peg-IFN plus RBV is a reliable predictor of SVR in HIV/HCV-coinfected patients. In addition, a decrease of HCV RNA less than 0.6 log10 at this point of treatment could identify an appreciable proportion of individuals who will fail to achieve SVR.

Pineda JA, García-García JA, Aguilar-Guisado M, Ríos-Villegas MJ, Ruiz-Morales J, Rivero A, del Valle J, Luque R, Rodríguez-Baño J, González-Serrano M, Camacho A, Macías J, Grilo I, Gómez-Mateos JM, Anonymous00041. · Unidad Clínica de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain. · Hepatology. · Pubmed #17659577 No free full text.

Abstract: Little is known about the natural history of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected subjects under highly active antiretroviral therapy (HAART). The objectives of this study were to obtain information about the mortality, the incidence of hepatic decompensations, and the predictors thereof in this population. In a multicenter cohort study, the time to the first hepatic decompensation and the survival of 1,011 antiretroviral naïve, HIV/HCV-coinfected patients who started HAART and who were followed prospectively were analyzed. After a median (Q1-Q3) follow-up of 5.3 (2.9-7.1) years, 59(5.83%) patients developed a hepatic decompensation and 69 (6.82%) died, 30 (43%) of them because of liver disease. The factors independently associated [HR (95% CI)] with the occurrence of hepatic decompensations were age older than 33 years [2.11 (1.18-3.78)], female sex [2.11 (1.07-4.15)], Centers for Disease Control stage C [2.14 (1.24-3.70)], a diagnosis of cirrhosis at baseline [10.86 (6.02-19.6)], CD4 cell gain lower than 100/mm3 [4.10 (2.18-7.69)] and less than 60% of the follow-up with undetectable HIV viral load [5.23 (2.5-10.93)]. Older age [2.97 (1.18-7.50)], lack of HCV therapy [11.32 (1.44-89.05)], hepatitis D virus coinfection [16.15 (2.45-106.48)], a diagnosis of cirrhosis at recruitment [13.69 (5.55-34.48)], hepatic encephalopathy [62.5 (21.27-200)] and lower CD4 cell gain [3.63 (1.45-9.09)] were associated with mortality due to liver failure. CONCLUSION: End-stage liver disease is the primary cause of death in HIV/HCV-coinfected patients under HAART. Higher increase of CD4 cell counts, lack of markers of serious liver disease and therapy against HCV are factors associated with better hepatic outcome.

Macías J, Mira JA, López-Cortés LF, Santos I, Girón-González JA, González-Serrano M, Merino D, Hernández-Quero J, Rivero A, Merchante N, Trastoy M, Carrillo-Gómez R, Arizcorreta-Yarza A, Gómez-Mateos J, Pineda JA. · Hospital Universitario de Valme, Seville, Spain. · Antivir Ther. · Pubmed #17302246 No free full text.

Abstract: Cohort studies have shown that highly active antiretroviral therapy (HAART) can improve liver-related mortality in HIV/hepatitis C virus (HCV)-coinfected patients. A reduction in the accelerated liver fibrosis progression observed in HIV infection induced by HAART could explain these findings. A few studies have assessed the impact of HAART on liver fibrosis, but with contradictory results. Therefore, we evaluated the associations between the use of different antiretroviral drug classes and HAART combinations, and liver fibrosis in HIV-infected patients with chronic hepatitis C. Six hundred and eighty-three HIV/HCV-coinfected patients, who underwent a liver biopsy and who had not received anti-HCV treatment were included. Age at HCV infection < 23years (adjusted odds ratio [AOR] = 0.7, 95% confidence interval [95% CI] = 0.3-0.9, P = 0.05) and protease inhibitor (PI)-based HAART versus no use of HAART (AOR = 0.5, 95% CI = 0.3-0.9, P = 0.01) were negatively associated with advanced fibrosis (> or = F3). PI-based HAART versus no use of HAART (AOR = 0.4, 95% CI = 0.2-0.7, P = 0.001) was negatively associated with fibrosis progression rate > or = 0.2 units/year and independently of age at HCV infection and CD4+ T-cell counts. Fifteen (17%) patients treated only with PIs and zidovudine plus lamivudine showed > or = F3, compared with 65 (37%) patients without HAART (P = 0.001). Forty (31%) patients on PI and stavudine plus lamivudine showed > or = F3 (P = 0.3, when compared with patients with no HAART). The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis. The nucleoside analogue backbone in a HAART regimen may influence this association.

García-García JA, Romero-Gómez M, Girón-González JA, Rivera-Irigoin R, Torre-Cisneros J, Montero JL, González-Serrano M, Andrade RJ, Aguilar-Guisado M, Grilo I, Martín-Vivaldi J, Salmerón J, Caballero-Granado FJ, Macías J, Vergara-López S, Pineda JA, Anonymous00083, Anonymous00084. · Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain. · AIDS Res Hum Retroviruses. · Pubmed #17209765 No free full text.

Abstract: We compared the incidence of and factors associated with hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-monoinfected subjects and human immunodeficiency virus (HIV)/HCV-coinfected individuals, both with decompensated cirrhosis. In a retrospective study, a cohort of 180 individuals with HIV coinfection and 1037 HCV-monoinfected patients with decompensated HCV-related cirrhosis from eight centres in Spain were analyzed. HCC was found in 234 (23%) HCV-monoinfected subjects and in four (2%) HIV-coinfected subjects (p<0.001). At the time of the first hepatic decompensation, 188 (17%) and 4 (2%) (p<0.001) patients in the former and in the latter group, respectively, showed HCC. Fifty-four (11%) patients without HCC at baseline developed such a disease during follow-up. There were no incident cases among the HIV-coinfected population. The density of incidence (95% IC) of HCC in HIV/HCV-coinfected and HCV-monoinfected patients was 0 (0-1.70) and 3.31 (2.70-4.64) cases per 100 person-years (p<0.001), respectively. Lack of HIV infection [adjusted odds risk (AOR) (95% IC)=16.7 (3.9-71.1)] and high alanine aminotransferase levels [AOR (95% IC)=2.5 (1.1-5)] were the only two independent predictors of the emergence of HCC. In the group of patients in whom the date of HCV infection could be estimated, the time elapsed until HCC diagnosis was shorter among HIV-coinfected subjects. The incidence of HCC in patients with HCV-related cirrhosis after the first hepatic decompensation is lower in HIV-coinfected patients. This is probably due to the fact that HIV infection shortens the survival of HCV-coinfected patients with end-stage liver disease to such an extent that HCC not had a chance to emerge.

Vergara S, Macías J, Mira JA, García-García JA, Merchante N, del Valle J, Abdel-Kader L, Lozano F, Gómez-Mateos JM, Pineda JA. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain. · J Antimicrob Chemother. · Pubmed #17095528 links to  free full text

Abstract: OBJECTIVES: To assess the association between non-severe liver enzyme elevations (LEEs) during antiretroviral treatment and liver fibrosis in HIV/HCV-coinfected patients. METHODS: All co-infected patients from an Infectious Disease Unit who had received treatment with highly active antiretroviral therapy (HAART) for at least 12 months before undergoing a liver biopsy were included in the study. RESULTS: One-hundred and sixteen patients met the inclusion criteria of the study. Advanced liver fibrosis was observed in 32 (38%) of 84 patients who developed non-severe LEEs and in 11 (34%) of 32 subjects who developed severe (grade > or = 3) LEEs, (P = 0.7). Seven (6%) of 116 patients showed grade 3 or 4 LEEs for at least 30% of the follow-up. Advanced liver fibrosis was observed in five (71%) of these patients and in 38 (35%) of the 109 subjects who did not develop long-term severe LEEs (P = 0.05). Eight (10%) of 84 patients showed grade 2 LEEs for at least 30% of the follow-up. Advanced liver fibrosis was observed in 28 (37%) of 76 subjects who did not develop long-term grade 2 LEEs and in three (38%) of eight patients who developed them (P = 0.9). CONCLUSIONS: In HIV/HCV-coinfected patients, non-severe LEEs, whether persistent or not, are not associated with advanced liver fibrosis. On the other hand, long-term severe LEEs are associated with more severe liver fibrosis in this population.

Merchante N, Macías J, Ramayo E, Vergara S, García-García JA, Mira JA, Corzo JE, Gómez-Mateos JM, Lozano F, Pineda JA. · Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain. · J Viral Hepat. · Pubmed #16792538 No free full text.

Abstract: Insulin resistance (IR) is a common condition in chronic hepatitis C. Recent studies have reported that IR is associated with liver fibrosis progression in these patients. However, there is no information available on this issue in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients. For these reasons, we investigate the relationship between IR and liver fibrosis in patients with HIV and HCV infections. This was a cross-sectional study where patients from an Infectious Diseases Unit with HIV/HCV coinfection who underwent a liver biopsy, with available frozen sera samples at the time of biopsy and a known or estimated date of infection were included. IR was determined by the homeostasis model assessment (HOMA-IR) method. The relationship between histological findings and several variables, including HOMA-IR values, was examined. Seventy-nine patients fulfilled the inclusion criteria. Age at HCV infection >21 years was the only variable independently associated with advanced liver fibrosis (stages F3 and F4) [adjusted odds ratio (AOR) 4.15; 95% confidence interval (CI) 1.5-11.3]. The variables associated with a fibrosis progression rate above the median were age at HCV infection >21 years (AOR 6.41; 95% CI 2.16-27.96) and previous exposure to nevirapine (AOR 8.9; 95% CI 2.01-39.36). There was no association between HOMA-IR values and the presence of advanced fibrosis or a faster fibrosis progression. Thus IR is not associated with liver damage or fibrosis progression in HIV/HCV-coinfected individuals.

Mira JA, Macías J, Girón-González JA, Merino D, González-Serrano M, Jiménez-Mejías ME, Caballero-Granado FJ, Torre-Cisneros J, Terrón A, Becker MI, Gómez-Mateos J, Arizcorreta-Yarza A, Pineda JA, Anonymous00224. · Servicio de Medicina Interna, Hospital Universitario de Valme Sevilla, Spain. · J Antimicrob Chemother. · Pubmed #16720565 links to  free full text

Abstract: OBJECTIVES: To determine the incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients with known stage of liver fibrosis. METHODS: All HIV/HCV-coinfected patients were monitored for a period of 12 months after starting nelfinavir-containing regimens and, with an available liver biopsy, were included in a retrospective study. RESULTS: A total of 82 patients were included in the study. Nine (10.9%) HIV/HCV-coinfected patients showed an episode of severe hepatotoxicity during the study period. Eight (9.8%) individuals showed grade 3 or 4 change in levels of serum alanine aminotransferase and one subject presented with an event of decompensated liver cirrhosis. Six (18.2%) of 33 patients with advanced liver fibrosis and three (6%) of 49 individuals without advanced liver fibrosis showed an episode of severe hepatotoxicity (P = 0.1). In the multivariate analysis, only nevirapine use during nelfinavir therapy [adjusted odds ratio (AOR) 8.9; 95% confidence interval (CI), 1.4-54.1; P = 0.01] was independently associated with risk of development of severe liver toxicity. CONCLUSIONS: The incidence of severe hepatotoxicity of nelfinavir-containing regimens is low among HIV/HCV-coinfected patients with known stage of liver fibrosis. In addition, our findings show that concomitant nevirapine use is associated with an increased risk of severe hepatotoxicity in these subjects. Likewise, the proportion of severe liver toxicity tended to be higher in individuals with advanced liver fibrosis.

Merchante N, Girón-González JA, González-Serrano M, Torre-Cisneros J, García-García JA, Arizcorreta A, Ruiz-Morales J, Cano-Lliteras P, Lozano F, Martínez-Sierra C, Macías J, Pineda JA, Anonymous00016. · Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario de Valme, Sevilla, Spain. · AIDS. · Pubmed #16327319 No free full text.

Abstract: OBJECTIVE: To find the survival and the predictors of death of HIV-infected patients with hepatitis C virus (HCV)-related end-stage liver disease (ESLD). DESIGN AND METHODS: A prospective cohort study set in the infectious diseases units of four tertiary care public hospitals in Andalucía, Spain. From a multicentric cohort of 2664 HIV/HCV-co-infected patients, all consecutive patients with HCV-related cirrhosis who presented with the first hepatic decompensation from January 1997 to June 2004 were followed-up and 153 patients were included. The survival and the demographic, HIV-related and liver-related factors associated with death were evaluated. RESULTS: Ninety-five (62%) patients died during the follow-up. In 79 (85%) individuals, the cause of death was liver related. The median survival time was 13 months. Independent predictors of survival were Child score [hazard ratio (HR), 1.2; 95% confidence interval (CI), 1.08-1.37; P = 0.001], CD4+ cell count at decompensation lower than 100 cells/microl (HR, 2.48; 95% CI, 1.52-4.06; P < 0.001) and hepatic encephalopathy as the first hepatic decompensation (HR, 2.45; 95% CI, 1.41-4.27; P = 0.001). HAART was prescribed to 101 (66%) patients. The cumulative probability of survival in patients under HAART was 60% at 1 year and 40% at 3 years, versus 38 and 18%, respectively, in patients not treated with HAART (P < 0.0001). The HR (95% CI) of death in patients on HAART was 0.5 (0.3-0.9), (P = 0.03). CONCLUSIONS The survival of HIV/HCV-co-infected patients with ESLD is extremely poor. Immunosuppression and markers of severe liver disease predict liver-related mortality in these patients. HAART seems to be associated with a reduced liver-related mortality.

Macías J, Girón-González JA, González-Serrano M, Merino D, Cano P, Mira JA, Arizcorreta-Yarza A, Ruíz-Morales J, Lomas-Cabeza JM, García-García JA, Corzo JE, Pineda JA. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Ctra de Cádiz s/n, 41014 Seville, Spain. · Gut. · Pubmed #16118349 links to  free full text

Abstract: BACKGROUND: Liver biopsy is an invasive technique with associated major complications. There is no information on the validity of five non-invasive indexes based on routinely available parameters, estimated and validated in hepatitis C virus (HCV) monoinfected patients, in human immunodeficiency virus (HIV)/HCV coinfected patients. AIM: To validate these predictive models of liver fibrosis in HIV/HCV coinfected patients. PATIENTS: A total of 357 (90%) of 398 patients from five hospitals were investigated, who underwent liver biopsy and who had complete data to validate all of the models considered. METHODS: The predictive accuracy of the indexes was tested by measuring areas under the receiver operating characteristic curves. Diagnostic accuracy was calculated by estimating sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values. RESULTS: The models performed better when liver biopsies>or=15 mm were used as reference. In this setting, the Forns and Wai indexes, models aimed at discriminating significant fibrosis, showed PPV of 94% and 87%, respectively. Using these models, 27-34% of patients could benefit from exclusion of liver biopsy. If both models were applied sequentially, 41% of liver biopsies could be spared. The indexes aimed at predicting cirrhosis achieved NPV of up to 100%. However, they showed very low PPV. CONCLUSIONS: The diagnostic accuracy of these models was lower in HIV/HCV coinfected patients than in the validation studies performed in HCV monoinfected patients. However, simple fibrosis tests may render liver biopsy unnecessary in deciding anti-HCV treatment in over one third of patients with HIV infection and chronic hepatitis C.

Macías J, Castellano V, Merchante N, Palacios RB, Mira JA, Sáez C, García-García JA, Lozano F, Gómez-Mateos JM, Pineda JA. · Servicio de Medicina Interna, Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain. · AIDS. · Pubmed #15075511 No free full text.

Abstract: BACKGROUND: The hepatotoxicity of highly active antiretroviral therapy (HAART) could enhance liver fibrosis in HIV/Hepatitis C virus (HCV)-coinfected patients. Moreover, HAART-related immune restoration could lessen HCV-associated liver damage. The data on the effect of protease inhibitors (PI) on liver fibrosis are scant and contradictory. No information is available on the relationship between non-nucleoside analogue therapy and liver fibrosis in co-infected patients. OBJECTIVE: To investigate the associations between the use of different antiretroviral drugs and the liver fibrosis in patients with HIV and HCV infections. DESIGN: Cross-sectional study. METHODS: All HIV/HCV co-infected patients with an available liver biopsy and known or estimated duration of HCV infection seen at a Infectious Diseases Unit were included in the study. The fibrosis stage and the fibrosis progression rate were evaluated. RESULTS: The inclusion criteria were fulfilled by 152 patients. Age at HCV infection < 20 years [adjusted odds ratio (AOR), 0.39; 95% confidence interval (CI), 0.19-0.82], PI-based HAART (AOR, 0.39; 95% CI, 0.19-0.78) and nevirapine-based HAART (AOR, 2.56; 95% CI, 1.02-6.58) were associated with fibrosis stage >or= F3. The variables associated with fibrosis progression rate > 0.2 units/year were age at HCV infection < 20 years (AOR, 0.23; 95% CI, 0.1-0.52), CD4 cell counts < or = 250 x 10/l at liver biopsy (AOR, 2.8; 95% CI, 1.1-7.1), PI-based HAART (AOR, 0.39; 95% CI, 0.2-0.8) and nevirapine-based HAART (AOR, 3.82; 95% CI, 1.9-7.6). CONCLUSIONS: HAART regimens including nevirapine are associated with faster liver fibrosis progression in HIV-infected patients with chronic hepatitis C. In contrast, patients on PI as the backbone of potent antiretroviral therapy are more likely to show less liver fibrosis.

Macías J, Pineda JA, Lozano F, Corzo JE, Ramos A, León E, García-García JA, Fernández-Rivera J, Mira JA, Gómez-Mateos J. · Servicio de Medicina Interna, Hospital Universitario de Valme, Carretera de Cádiz s/n, 41014 Seville, Spain. · Eur J Clin Microbiol Infect Dis. · Pubmed #14574616 No free full text.

Abstract: Coinfection with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) is highly prevalent in southern Europe. However, there are few and contradictory data about the effect of HCV carriage on the response to highly active antiretroviral therapy (HAART). In this study, the recovery of CD4+ T cells following HAART among antiretroviral-naïve patients seropositive for HIV with and without HCV coinfection was investigated. Two hundred one HIV-infected patients without previous exposure to antiretroviral drugs were included in the study. HCV coinfection was detected in 123 (61%) patients. The time to recover 200 CD4+ cells/ microl was longer in the HCV-positive group ( P<0.001). In a Cox model, HCV infection and lack of persistent HIV viremia (defined as <200 copies/ml) were associated with the time to recover 200 CD4+ cells/ microl. The mean increase in CD4+ cell counts was lower in the HCV-positive group during the first year of therapy. HIV/HCV-coinfected patients naïve for antiretroviral therapy show a delayed recovery of CD4+ cell counts after starting HAART.

Macías J, Melguizo I, Fernández-Rivera FJ, García-García A, Mira JA, Ramos AJ, Rivera JM, Pineda JA. · Servicio de Medicina Interna, Hospital Universitario de Valme, Ctra Cádiz, s/n, 41014 Seville, Spain. · Eur J Clin Microbiol Infect Dis. · Pubmed #12461586 No free full text.

Abstract: 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.