RESUMEN
BACKGROUND: We determined the prevalence and determinants of worsening fibrosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who were receiving anti-HCV therapy. METHODS: Among 383 HIV-HCV-coinfected patients who received at least 1 dose of anti-HCV treatment (weekly subcutaneous injections of 1.5 mug/kg pegylated interferon-alpha-2b plus daily ribavirin or thrice-weekly subcutaneous injections of 3 MU of interferon-alpha-2b plus daily ribavirin for 48 weeks), paired pretreatment and posttreatment liver biopsy specimens were available and interpretable for 198 cases. Hepatic necroinflammation and fibrosis were graded with Ishak's classification. Histological worsening of fibrosis was defined as a score increase of > or =2 points in patients with fibrosis stage of <4 and as a score increase of 1 point in patients with stage-5 fibrosis. RESULTS: The mean interval +/- standard deviation between the 2 biopsies was 109 +/- 34 weeks. Fibrosis worsened in 34 patients (17.1%). In univariate analysis, ongoing antiretroviral therapy, failure to achieve a sustained viral response, nucleoside reverse-transcriptase inhibitor therapy, didanosine therapy, and stavudine therapy were significantly associated with worsening of fibrosis. Didanosine (odds ratio, 3.34; 95% confidence interval, 1.39-7.96; P = .007) and failure to have a sustained viral response (odds ratio, 9.05; 95% confidence interval, 2.06-39.66; P = .003) remained significantly associated with worsening of fibrosis. CONCLUSION: The mitochondrial toxicity of antiretrovirals, such as didanosine, seems to play a major role in worsening of fibrosis during HCV therapy. Therefore, anti-HCV therapy should ideally be administered before antiretroviral treatment initiation. If anti-HCV and anti-HIV treatments have to be administered concomitantly, then nucleoside reverse-transcriptase inhibitors with the lowest mitochondrial toxicity should be preferred.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Interferones/uso terapéutico , Cirrosis Hepática/patología , Ribavirina/uso terapéutico , Adulto , Fármacos Anti-VIH/toxicidad , Progresión de la Enfermedad , Femenino , Humanos , Interferones/administración & dosificación , Hígado/patología , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Prevalencia , Ribavirina/administración & dosificación , Factores de RiesgoAsunto(s)
Infecciones por VIH/tratamiento farmacológico , Hiperlipidemias/inducido químicamente , Lipoproteínas LDL/sangre , Pirimidinonas/efectos adversos , Ritonavir/efectos adversos , Adulto , Terapia Antirretroviral Altamente Activa/efectos adversos , Arteriosclerosis/inducido químicamente , Inhibidores de la Proteasa del VIH/efectos adversos , Humanos , Lípidos/sangre , LopinavirRESUMEN
OBJECTIVES: Tubulopathy with hypophosphatemia have been observed in HIV-positive patients receiving a tenofovir-containing regimen. However, the real incidence and prevalence of hypophosphatemia and their relation to tubular reabsorption disorders in tenofovir-treated patients remain uncertain. The aim of our study was to explore the effect of tenofovir on phosphatemia and on tubular phosphate reabsorption. METHODS: In a first transversal study, 145 HIV-positive adults (44+/-9 years) receiving tenofovir 300 mg daily with a mean exposure of 11+/-9 months were included. In a second prospective study, 29 HIV-positive antiretroviral experienced adults (44+/-10 years) were evaluated before introduction of tenofovir 300 mg daily (M0) and at 3 months (M3) and 6 months (M6), thereafter. Phosphate, creatinine, glucose and protein levels were determined in plasma and urine. The ratio of maximal reabsorption capacity (TmPO4)/glomerular filtration rate (GFR) was determined by using the normogramm of Walton and Bijvoet. RESULTS: In the transversal study, 26% of patients had hypophosphatemia (<0.84 mmol/l) while 47% of patients had a decreased TmPO4/GFR (<0.8 mmol/l). In the prospective study, baseline prevalence of hypophosphatemia (<0.84 mmol/l) and decreased TmPO4/GFR (<0.8mmol/l) was 31 and 41%, respectively. Three and 6 months after starting tenofovir, there is no significant change in mean phosphate levels (M0:0.91 mmol/l, M3:0.97 mmol/l, M6:0.98 mmol/l) and mean TmPO4/GFR (M0:0.80 mmol/l, M3:0.88 mmol/l, M6:0.84 mmol/l). Moreover, prevalence of hypophosphatemia (M3:28%, M6:28%) and decreased TmPO4/GFR (M3:41%, M6:45%) remained stable. CONCLUSION: Hypophosphatemia linked to a decreased proximal tubular reabsorption was frequently observed in HIV-positive adults independently of the use of tenofovir. In this preliminary study, no worsening effect on phosphatemia and tubular phosphate reabsorption was observed 6 months after introduction of tenofovir in treatment experienced patients.
Asunto(s)
Adenina/análogos & derivados , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Hipofosfatemia/inducido químicamente , Túbulos Renales Proximales/efectos de los fármacos , Organofosfonatos/efectos adversos , Adenina/efectos adversos , Adenina/uso terapéutico , Adulto , Fármacos Anti-VIH/uso terapéutico , Estudios Transversales , Femenino , Humanos , Túbulos Renales Proximales/metabolismo , Masculino , Persona de Mediana Edad , Organofosfonatos/uso terapéutico , Fosfatos/metabolismo , TenofovirRESUMEN
CCR5 antagonists represent promising anti-HIV agents. Yet, if the CCR5 chemokine receptor plays a positive role in hepatitis C virus (HCV) infection, CCR5 antagonists might be contraindicated in HCV/HIV-coinfected subjects. Therefore, we tested the hypothesis that the level of T-cell surface CCR5 expression, which might determine the intensity of HCV-specific T-cell recruitment into the liver, and thereby the efficiency of the anti-HCV response, could determine HCV disease evolution. For this purpose, we compared CCR5 density, measured by quantitative flow cytometry at the surface of nonactivated (human leukocyte antigen-D-related [HLA-DR]-) T cells of 51 HCV/HIV patients, with HCV load, serum aminotransferase levels, and liver histology (inflammatory activity, fibrosis, and rate of fibrosis progression). DR-CD4+ T-cell surface CCR5 density, which correlated with DR-CD8+ T-cell surface CCR5 density and was stable over time in HCV/HIV-coinfected individuals, did not correlate with any of the biologic parameters of HCV infection analyzed and was not linked to the capacity to clear the virus. In conclusion, we failed to demonstrate any impact of interindividual variability in T-cell surface CCR5 density on HCV infection, which would have argued against the use of CCR5 antagonists in HIV/HCV-coinfected subjects.
Asunto(s)
Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Hepatitis C/inmunología , Receptores CCR5/análisis , Linfocitos T/inmunología , Adulto , Antagonistas de los Receptores CCR5 , Antígenos CD4/análisis , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/análisis , Linfocitos T CD8-positivos/inmunología , Femenino , Citometría de Flujo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Antígenos HLA-DR/análisis , Hepacivirus/aislamiento & purificación , Hepacivirus/fisiología , Hepatitis C/patología , Hepatitis C/virología , Humanos , Hígado/patología , Cirrosis Hepática/patología , Masculino , Persona de Mediana Edad , Transaminasas/sangre , Carga ViralRESUMEN
BACKGROUND: The antiviral efficacy of didanosine in patients experiencing virological failure is not well known. METHODS: A total of 168 patients (139 men and 29 women) receiving stable antiretroviral therapy with plasma human immunodeficiency virus type 1 (HIV-1) RNA levels of 1000-100,000 copies/mL were randomly assigned to have didanosine (n=111) or placebo (n=57) added to their currently failing regimen for 4 weeks. The primary efficacy end point was the change in HIV-1 RNA level from baseline to week 4. RESULTS: At baseline, the median HIV-1 RNA level was 3.8 log(10) copies/mL, the median CD4 cell count was 378 cells/mm(3), and the median number of nucleoside reverse-transcriptase inhibitor-associated mutations (NAMs) was 4. At week 4, a significant decrease in the median HIV-1 RNA level was observed in the didanosine group, compared with that in the placebo group (-0.56 vs. +0.07 log(10) copies/mL, respectively) (P<.0001). A total of 33 patients (31%) in the didanosine group, compared with 3 (6%) in the placebo group, had HIV-1 RNA levels <400 copies/mL (P<.001). Significant antiviral activity of didanosine was observed in patients with up to 5 NAMs at baseline. Diarrhea occurred in 5 patients (5%) in the didanosine group and 2 patients (4%) in the placebo group. CONCLUSIONS: In HIV-1-infected patients experiencing failure of antiretroviral therapy, didanosine retains short-term antiviral activity.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Didanosina/uso terapéutico , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Didanosina/efectos adversos , Método Doble Ciego , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Mutación , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/efectos adversos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
The factors that determine the emergence of X4 isolates in some HIV-1-infected subjects are unknown. As the level of expression of CXCR4 could favor an R5 to X4 switch, quantitative flow cytometry was used to measure CXCR4 density on CD4 T cells in 200 HIV-1-positive adults, and this was compared with CD4 counts, interleukin-7 (IL-7), and RANTES (regulated on activation, normal T expressed and secreted) plasma levels and the R5/X4 virus phenotype. CD4 T-cell surface CXCR4 densities were increased in infected subjects and inversely correlated with CD4 T-cell count (r=-0.548, P<0.001). Yet, in vitro infection with either R5 or X4 strains and in vivo increases in viral load following interruption of antiretroviral treatment did not induce CXCR4 overexpression. The plasma levels of IL-7 and RANTES, 2 cytokines able to induce CXCR4 expression, did not correlate with CXCR4 density. Finally, higher CXCR4 densities were observed in patients harboring X4 strains (3300, 95% CI 2431-4169 CXCR4 molecules per cell) than in patients harboring only R5 strains (2406, 95% CI 2135-2677, P=0.027). These data suggest that CXCR4 overexpression during the course of the disease in some patients could favor the emergence of X4 strains.
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Infecciones por VIH/sangre , Infecciones por VIH/virología , VIH-1/genética , Receptores CXCR4/biosíntesis , Adolescente , Adulto , Anciano , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/metabolismo , Quimiocina CCL5/sangre , Femenino , Expresión Génica , Humanos , Interleucina-7/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Receptores CXCR4/sangre , Carga Viral , Replicación ViralRESUMEN
Indinavir and nelfinavir plasma levels were studied in 407 patients having plasma HIV RNA <500 copies/mL after 4 months of treatment with these drugs. For each drug, an observed/predicted (O/P) ratio was calculated between individual and mean time-adjusted population plasma drug levels. The relationship between the O/P ratio and the risk of rebound of plasma HIV RNA >500 copies/mL beyond month 4 was studied using Cox proportional hazard models. Median follow-up was 20 months. There was no association between indinavir plasma levels and risk of virologic rebound, whereas low nelfinavir + M8 (active nelfinavir metabolite) plasma levels were associated with a higher risk of virologic rebound. In multivariate analysis, the adjusted relative hazard of virologic rebound for patients with an O/P ratio of nelfinavir + M8 metabolite <0.8 compared with others was 2.2 (P = 0.01). In some patients, plasma levels of nelfinavir sufficient to achieve early viral response may not be sufficient to maintain it in the long term. This may be related to insufficient compliance with dietary recommendations. Monitoring of nelfinavir plasma levels thus seems useful, even in patients having early virologic response.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , VIH/aislamiento & purificación , Indinavir/sangre , Indinavir/uso terapéutico , Nelfinavir/sangre , Nelfinavir/uso terapéutico , Biotransformación , Estudios de Cohortes , Estudios de Seguimiento , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , ARN Viral/sangre , ARN Viral/aislamiento & purificación , Factores de Tiempo , Insuficiencia del Tratamiento , Carga ViralRESUMEN
We describe 7 cases of renal tubular injury in HIV-infected patients receiving an antiretroviral regimen containing tenofovir. Our patients (5 women and 2 men) developed renal tubular dysfunction, with hypophosphatemia, normoglycemic glycosuria, proteinuria, and decrease of creatinine clearance. The first biologic signs of renal toxicity were observed after duration of tenofovir treatment from 5 weeks to 16 months, and they resolved less than 4 months after discontinuation of tenofovir. Six patients had a low body weight (<60 kg). Five patients received low doses of ritonavir, and 1 received didanosine. In 5 patients, the signs resolved with the discontinuation of only the tenofovir. A renal biopsy performed in 1 patient was consistent with tubulointerstitial injury. Proximal tubulopathy appears to be a rare adverse effect of long-term tenofovir therapy. In patients with low weight or mild preexisting renal impairment, regular monitoring of tubulopathy markers could lead to early detection of this dysfunction.