Hepatitis: Mira JA

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.

Rivero A, Mira JA, Pineda JA. · Sección de Enfermedades Infecciosas, Hospital Universitario Reina Sofía, Cordoba, Spain. · J Antimicrob Chemother. · Pubmed #17255142 links to  free full text

Abstract: Liver toxicity is one of the most relevant adverse effects of antiretroviral therapy. Within the non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz can be considered a safer drug for the liver than nevirapine. In fact, the frequency of severe increased liver enzymes in patients on efavirenz ranges from 1 to 8%, whereas in patients treated with nevirapine, it ranges from 4 to 18%. Likewise, nevirapine is more commonly associated than efavirenz with early acute hepatitis, which is produced by a hypersensitivity mechanism and has a defined risk profile that often makes it avoidable. Despite the fact that most cases of NNRTI-induced liver toxicity are asymptomatic, the rates of symptomatic events in patients treated with nevirapine are greater than in subjects on efavirenz. In any case, it is unusual for an NNRTI to be suspended due to liver toxicity.

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.

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.

Vispo E, Barreiro P, Pineda JA, Mira JA, Maida I, Martín-Carbonero L, Rodríguez-Nóvoa S, Santos I, López-Cortes LF, Merino D, Rivero A, Soriano V. · Hospital Carlos III, Madrid, Spain. · Antivir Ther. · Pubmed #18572756 No free full text.

Abstract: BACKGROUND: There is little information about the influence of antiretroviral drugs on the antiviral activity of pegylated interferon (PEG-IFN) plus ribavirin (RBV) against hepatitis C virus (HCV). METHODS: All HIV-infected patients with chronic hepatitis C who received first-line PEG-IFN plus RBV were retrospectively analyzed. Only patients in whom virological stopping rules were applied and who did not change their antiretrovirals were chosen. Plasma RBV concentrations were measured at week 4. RESULTS: A total of 493 patients (78% males, mean age 41 years, 78% on antiretroviral therapy, mean CD4+ T-cell count 561 cells/microl) fit the study inclusion criteria. Mean baseline serum HCV RNA was 5.89 log10 IU/ml, 65% were infected by genotypes 1 or 4 and 40% had advanced liver fibrosis (Metavir F3F4). The overall rate of sustained virological response (SVR) was 38%. Factors associated with lack of SVR in the multivariate analyses (odds ratio [95% confidence interval], P-value) were higher baseline serum HCV RNA (2.42 per log10 IU/ml [1.31-4.46], 0.005), HCV genotypes 1 or 4 (5.95 [2.50-14.29], < 0.001) and lower RBV plasma trough concentrations (1.74 per microg/ml [1.15-2.63], 0.009). Interestingly, a trend was noticed for abacavir use (2.22 [0.91-5.40], 0.08), which become significant when only considering the subset of patients with RBV plasma levels < 2.3 microg/ml (7.63 [1.39-41.67], 0.02). CONCLUSIONS: The use of abacavir might interfere with the anti-HCV activity of PEG-IFN plus RBV. As both antivirals are guanosine analogues, an inhibitory competition between abacavir and RBV might explain this observation, which is more prominent in patients with lower RBV exposure.

Crespo M, Mira JA, Pineda JA, Van den Eynde E, Ríos-Villegas MJ, Collado A, Girón-González JA, López-Cortés LF, González-Serrano M, Rivero A, Merino D, Esteban JI. · Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain. · J Antimicrob Chemother. · Pubmed #18567911 No free full text.

Abstract: BACKGROUND: Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment for HCV infection in HIV co-infected patients. However, data available on the efficacy of this therapy in co-infected patients who failed a former interferon-based regimen are limited. METHODS: We analysed the efficacy and safety of the Peg-IFN alfa-2a or alfa-2b plus ribavirin combination in a multicentre observational cohort study including 54 HCV/HIV co-infected patients who had failed to respond to or relapsed on interferon-based treatment. The primary efficacy endpoint was the proportion of patients who achieved a sustained virological response (SVR), defined as HCV RNA <50 IU/mL 24 weeks after completion of therapy. RESULTS: By intention-to-treat analysis, 30% of the patients achieved an SVR. Viral eradication by genotype was 18.9% (7/37) genotype 1; 57.1% (8/14) genotype 3 and 33.3% (1/3) genotype 4. The only independent predictor of SVR was genotype 3 (odds ratio: 5.3; 95% confidence interval: 1.4-19.8). Fourteen (38%) patients with genotype 1 had undetectable viral load at week 48 of treatment. Nevertheless, 50% of them relapsed during the follow-up period. Severe adverse events or progression of HIV infection did not occur during the study; however, 39% of the patients required Peg-IFN dose reduction because of intolerance or haematological toxicity. CONCLUSIONS: Combined Peg-IFN and ribavirin achieved a substantial rate of SVR in HCV/HIV co-infected patients who failed a prior standard interferon-based regimen. The decision to retreat any co-infected patient should be individual-based. More aggressive strategies may be necessary to avoid the high relapse rate observed among patients with genotype 1.

del Valle J, Mira JA, de los Santos I, López-Cortés LF, Merino D, Rivero A, Girón JA, Ríos-Villegas MJ, González-Serrano M, Collado A, García-García JA, Pineda JA. · Infectious Diseases Unit, Hospital Universitario de Valme, Sevilla, Spain. · AIDS. · Pubmed #18453851 No free full text.

Abstract: BACKGROUND: High levels of serum low-density lipoprotein cholesterol are associated with better response to pegylated interferon and ribavirin in hepatitis C virus monoinfected patients. There are no data concerning this topic in HIV/hepatitis C virus coinfected patients in whom lipid disorders are particularly common. OBJECTIVE: To assess the association between baseline lipid levels and sustained virologic response to pegylated interferon and ribavirin in coinfected patients. METHODS: A total of 260 HIV/hepatitis C virus coinfected patients under treatment with pegylated interferon and ribavirin and who had a baseline serum lipid profile were included in this retrospective study. RESULTS: Thirty-eight (24%) patients with genotypes 1-4 and 64 (63%) with genotypes 2-3 achieved sustained virologic response. Forty-nine (44%) patients with serum low-density lipoprotein cholesterol levels 100 mg/dl or more showed sustained virologic response compared with 53 (36%) with lower values [adjusted odds ratio: 2.51; 95% confidence interval: 1.40-4.87; P = 0.003]. This association was independent of the remaining predictors of sustained virologic response which were genotypes 2-3, plasma hepatitis C virus RNA 600,000 IU/ml or less, exposure to at least 80% of the planned therapy and lack of concomitant antiretroviral therapy. The rate of sustained virologic response in patients with genotype 1 and low-density lipoprotein cholesterol at least 100 mg/ml was 31% compared with 17% in those with lower values (adjusted odds ratio: 2.19; 95% confidence interval: 1.04-4.66; P = 0.040). The corresponding figures in subjects with genotypes 2-3 were 73 and 58% [2.71 (0.99-7.46); P = 0.054]. No other lipid was associated with response. CONCLUSION: Higher low-density lipoprotein cholesterol levels predict sustained virologic response to pegylated interferon and ribavirin in HIV/hepatitis C virus coinfected patients. This might be used to improve the rate of sustained virologic response in this setting.

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.

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.

Pineda JA, Mira JA, Gil Ide L, Valera-Bestard B, Rivero A, Merino D, Girón-González JA, Ríos-Villegas MJ, González-Serrano M, Collado A, García-García JA, Carrillo-Gómez R, López-Cortés LF, Gómez-Mateos J. · Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Sevilla, Spain. · J Antimicrob Chemother. · Pubmed #17938129 links to  free full text

Abstract: OBJECTIVES: To investigate whether concomitant antiretroviral therapy (ART) is a predictor of sustained virological response (SVR) in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients treated with pegylated interferon plus ribavirin. METHODS: Three hundred and ten HIV/HCV-coinfected patients on pegylated interferon plus ribavirin treatment, 258 of them with concurrent ART, were included in this retrospective multicentre study. The predictors of SVR were evaluated. RESULTS: SVR was shown by 114 (37%) subjects. HCV genotype 2 or 3, plasma HCV-RNA load lower than 600 000 IU/mL, an exposure to the therapy against HCV infection > or =80% of the planned dose and baseline CD4 cell counts higher than or equal to 300/mm(3) were predictors of SVR. Likewise, patients without ART and those receiving a combination including tenofovir or stavudine plus lamivudine plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) showed a higher SVR rate than the subjects who were on other ART strategies at baseline [44%, 44% and 29%, respectively; adjusted odd ratio (95% CI) for no ART = 1.96 (1.07-4.76), P = 0.025, and for ART including tenofovir or stavudine plus lamivudine plus a PI or a NNRTI = 2.08 (1.16-3.70), P = 0.014]. CONCLUSIONS: The ART strategy on starting therapy with pegylated interferon plus ribavirin is a predictor of SVR in HIV/HCV-coinfected patients. Subjects without ART and those receiving combinations of a PI or a NNRTI with a nucleos(t)ide backbone of tenofovir or stavudine plus lamivudine respond better than those who receive other regimens.

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.

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.

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.

Macias J, Japón MA, Sáez C, Palacios RB, Mira JA, García-García JA, Merchante N, Vergara S, Lozano F, Gómez-Mateos J, Pineda JA. · Servicio de Medicina Interna, Hospital Universitario de Valme, Seville, Spain. · J Infect Dis. · Pubmed #16206071 No free full text.

Abstract: BACKGROUND: Chronic hepatitis C disease (CHC) follows an accelerated course in human immunodeficiency virus (HIV) coinfection. The reasons for this are unclear. Fas-mediated hepatocyte apoptosis is involved in the pathogenesis of hepatitis C virus (HCV) infection. We sought to compare the expression of Fas on hepatocytes and irreversible apoptosis of hepatocytes among patients with CHC with and without HCV/HIV coinfection. METHODS: Fas-immunostained hepatocytes were semiquantified, and apoptotic hepatocytes were detected by staining caspase-cleaved cytokeratin 18 filaments and counted across the entire section of liver-biopsy specimens from HCV-infected patients with and without HCV/HIV coinfection. RESULTS: One hundred thirty-four HCV/HIV-coinfected and 100 HCV-infected patients were included. HCV/HIV coinfection was associated with both diffuse distribution of Fas-stained hepatocytes (adjusted odds ratio [AOR], 7.4 [95% confidence interval {CI}, 3.8-14.4]) and with apoptotic hepatocyte counts greater than the median (AOR, 2.5 [95% CI, 1.5-4.5]). In HCV/HIV-coinfected patients, CD4+ cell nadir<200 cells/mL was associated with both Fas expression (AOR, 2.9 [95% CI, 1.3-6.8]) and hepatocyte apoptosis (AOR, 2.3 [95% CI, 1.1-4.9]). CONCLUSION: HCV/HIV-coinfected patients show higher levels of hepatocytes expressing Fas and undergoing irreversible apoptosis than do HCV-infected patients. However, low CD4+ cell nadirs in coinfected patients are associated with hepatocyte Fas expression and apoptosis.

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.

de La Rosa R, Pineda JA, Delgado J, Macías J, Morillas F, Mira JA, Sánchez-Quijano A, Leal M, Lissen E. · Viral Hepatitis and AIDS Study Group, Servicio de Medicina Interna, Hospital Universitario Virgen del Rocío Servicio de Medicina Interna, Hospital Universitario de Valme, Seville, Spain. · J Clin Microbiol. · Pubmed #11880390 links to  free full text

Abstract: The way in which the extensive use of highly active antiretroviral therapy (HAART) has influenced the incidence of visceral leishmaniasis (VL) among human immunodeficiency type 1 (HIV-1)-infected patients is not yet understood. The present study assessed whether the incidence of symptomatic VL in HIV-infected patients has decreased since the introduction of HAART. Likewise, the role of other potential risk factors for VL was also analyzed. Therefore, 479 HIV-1-infected patients receiving antiretroviral treatment, according to the available drugs at each moment, were prospectively followed from April 1989 to June 2000 in two university hospitals in southern Spain. A bone marrow aspiration was performed when patients showed symptoms suggestive of kala-azar. A diagnosis of VL was made when Leishmania amastigotes were seen in Giemsa-stained samples or promastigotes were cultured in specific media. The median follow-up time was 1,380 [8 to 4,536] days. Twenty-one patients were diagnosed with symptomatic VL. The density of incidence of VL has decreased 64.8% as of January 1997, when HAART began to be used extensively in our area. The use of HAART was the main independent factor associated with VL; this therapy was a protective factor (adjusted hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.02 to 0.15). CDC clinical category C at entry in the cohort (HR, 4.08; 95% CI, 1.46 to 11.35) and CD4(+) cell counts below 300 cells/mm(3) during the follow-up (HR, 3.96; 95% CI, 1.56 to 10.01) were also independently associated with kala-azar. A VL diagnosis prior to follow-up and low compliance with antiretroviral therapy were not independently associated with symptomatic VL, although statistical significance was almost reached (P = 0.1 and P = 0.08, respectively). In summary, the use of HAART has led to a fall in the incidence of symptomatic VL in HIV-infected patients. The main risk factor associated with kala-azar emergence in patients infected with HIV is deep immunosuppression.

Pineda JA, Palacios R, Rivero A, Abdel-kader L, Márquez M, Cano P, Mira JA, Torre-Cisneros J, Lozano F, Santos J. · No affiliation provided · J Antimicrob Chemother. · Pubmed #16556636 links to  free full text

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Macías J, Mira JA, Vergara S, Pineda JA. · No affiliation provided · Hepatology. · Pubmed #15880585 No free full text.

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Merchante N, Macías J, Palacios RB, Mira JA, García-García JA, Lozano F, Pineda JA. · No affiliation provided · AIDS. · Pubmed #15280793 No free full text.

This publication has no abstract.