RESUMEN
Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxic effects resulting in multiple organ disorders. Liver involvement has been associated mainly with severe lactic acidosis and massive steatosis. However, patients with HIV infection who are receiving antiretroviral treatment frequently have mildly abnormal liver test results that, to date, have not been linked unambiguously to the toxic effects of NRTIs. Thirteen patients with HIV infection treated with NRTI-based regimens had low-grade abnormal liver test results associated with digestive and nonspecific general symptoms. Histologic examination of liver samples showed diffuse steatosis in only 6 cases and mild steatosis in the remaining cases, associated with megamitochondria, mild lobular inflammation and necrosis, Mallory bodies, and perisinusoidal fibrosis. In all cases, ultrastructural study disclosed mitochondrial abnormalities. Our work demonstrates that NRTI-induced toxic effects in the liver may occur as indolent nonspecific disease with variable histologic features and emphasizes the diagnostic value of electron microscopy, particularly when diffuse steatosis is absent.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Hígado/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Adulto , Hígado Graso/inducido químicamente , Hígado Graso/patología , Femenino , Humanos , Hígado/patología , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Mitocondrias/ultraestructuraAsunto(s)
Adenina/análogos & derivados , Adenina/efectos adversos , Fármacos Anti-VIH/efectos adversos , Síndrome de Fanconi/inducido químicamente , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Organofosfonatos , Compuestos Organofosforados/efectos adversos , Lesión Renal Aguda/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , TenofovirRESUMEN
OBJECTIVE: The objective was to compare the safety and cellular immunogenicity of intradermal versus intramuscular immunization with an HIV-lipopeptide candidate vaccine (LIPO-4) in healthy volunteers. METHODOLOGY: A randomized, open-label trial with 24 weeks of follow-up was conducted in France at six HIV-vaccine trial sites. Sixty-eight healthy 21- to 55-year-old HIV-uninfected subjects were randomized to receive the LIPO-4 vaccine (four HIV lipopeptides linked to a T-helper-stimulating epitope of tetanus-toxin protein) at weeks 0, 4 and 12, either intradermally (0.1 ml, 100 microg of each peptide) or intramuscularly (0.5 ml, 500 microg of each peptide). Comparative safety of both routes was evaluated. CD8+ T-cell immune responses to HIV epitopes (ELISpot interferon-gamma assay) and tetanus toxin-specific CD4+ T-cell responses (lymphoproliferation) were assessed at baseline, two weeks after each injection, and at week 24. RESULTS AND CONCLUSION: No severe, serious or life-threatening adverse events were observed. Local pain was significantly more frequent after intramuscular injection, but local inflammatory reactions were more frequent after intradermal immunization. At weeks 2, 6, 14 and 24, the respective cumulative percentages of induced CD8+ T-cell responses to at least one HIV peptide were 9, 33, 39 and 52 (intradermal group) or 14, 20, 26 and 37 (intramuscular group), and induced tetanus toxin-specific CD4+ T-cell responses were 6, 27, 33 and 39 (intradermal), or 9, 46, 54 and 63 (intramuscular). In conclusion, intradermal LIPO-4 immunization was well tolerated, required one-fifth of the intramuscular dose, and induced similar HIV-specific CD8+ T-cell responses. Moreover, the immunization route influenced which antigen-specific T-cells (CD4+ or CD8+) were induced. TRIAL REGISTRATION: ClinicalTrials.gov NCT00121121.
Asunto(s)
Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Inmunidad Celular/inmunología , Vacunas contra el SIDA/efectos adversos , Adulto , Secuencia de Aminoácidos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Femenino , Infecciones por VIH/inmunología , Humanos , Inyecciones Intradérmicas , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Péptidos/genética , Péptidos/inmunología , Proteínas Virales/genética , Proteínas Virales/inmunología , Adulto JovenRESUMEN
Liver mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTI) in human immunodeficiency virus (HIV) patients has been associated with a wide range of liver involvement ranging from low-grade hepatotoxicity, asymptomatic lactacidemia to severe liver insufficiency, with massive steatosis and life-threatening lactic acidosis. Considerable efforts have been made in the last few years to establish clinical guidelines to avoid life-threatening NRTI-associated lactic acidosis. However, the important issue of low-grade NRTI-associated hepatotoxicity still needs to be unravelled since its natural history is largely unknown. We have recently reported a series of 13 monoinfected HIV patients with low-grade NRTI-associated toxicity. Our results outlined the heterogeneity of NRTI-induced hepatotoxicity and raised the question of its diagnosis. The present study evaluates the expression of cytochrome oxidase (COX) subunits I and IV, encoded by mitochondrial and nuclear DNA, respectively, in NRTI hepatotoxicity. The aim of our study was to compare the detection rate of mitochondrial abnormalities of immunohistochemistry for COX subunit I with electron microscopy. COX subunit I and IV labeling was performed together with light microscopy and ultrastructural analysis in a series of 55 liver biopsies from HIV monoinfected and HIV-hepatitis C virus coinfected patients. Clinical data were also recorded. Our major findings were: (i) decreased COX subunit I labeling is associated with severe ultrastructural mitochondrial alterations and may represent overt NRTI-induced mitochondrial cytopathy; (ii) mild ultrastructural damage associated with normal COX subunit I labeling is of unknown clinical significance. The results of the study suggest that COX subunit I labeling may be a valuable tool for the diagnosis of mitochondrial liver disease in HIV patients.
Asunto(s)
Complejo IV de Transporte de Electrones/metabolismo , Infecciones por VIH/tratamiento farmacológico , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/enzimología , Enfermedades Mitocondriales/enzimología , Inhibidores de la Transcriptasa Inversa/efectos adversos , Adulto , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hígado Graso/inducido químicamente , Hígado Graso/enzimología , Femenino , Humanos , Inmunohistoquímica , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/enzimología , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Mitocondrias Hepáticas/ultraestructura , Enfermedades Mitocondriales/inducido químicamente , Enfermedades Mitocondriales/patología , Subunidades de Proteína/metabolismo , Estudios RetrospectivosRESUMEN
Enterocytozoon bieneusi is an agent of intestinal microsporidiosis leading to chronic diarrhoea in AIDS patients. Pulmonary involvement may occur but remains rare with only 4 cases reported in the literature. We report here the fifth case of pulmonary localization of E. bieneusi in a severe immunocompromized HIV-infected patient with intestinal and pulmonary symptoms.