RESUMEN
Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immunodeficiency virus type 1 (HIV) DNA level. However, the short-term impact of IFN alfa on persistent HIV and its effects on immune activation after antiretroviral therapy remain unknown. Our study showed that the cell-associated HIV RNA level and CD4(+) T-cell activation decreased in the IFN group (n = 10). No changes were detected in levels of residual plasma viremia, replication-competent reservoirs, proviral DNA, or 2-long-terminal repeat circles, although APOBEC3G, TRIM5α, BST2, and TRIM22 were upregulated in the IFN group. These data suggest that short-term treatment with IFN alfa combined with RBV decreases HIV expression, in part through inhibition of HIV transcription by TRIM22 and decrease in T-cell activation.
Asunto(s)
Antivirales/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Hepatitis C/complicaciones , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Antivirales/administración & dosificación , Biomarcadores , Linfocitos T CD4-Positivos/clasificación , Linfocitos T CD4-Positivos/fisiología , Coinfección , Femenino , Regulación Viral de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/complicaciones , Hepacivirus , Humanos , Interferón-alfa/administración & dosificación , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Ribavirina/administración & dosificación , Ribavirina/uso terapéuticoRESUMEN
Triple combination therapy with pegylated interferon, ribavirin and telaprevir is currently considered the gold standard for the treatment of chronic hepatitis C virus (HCV) infection. The most important features are an increase in rates of sustained viral response (74-79% vs 46% with pegylated interferon and ribavirin), as well as the possibility of early cessation of ineffective therapy due to the application of futility rules at weeks 4 and 12 (HCV-RNA > 1,000 UI/ml), and the possibility of selecting candidates for the shortest treatments due to the clinical significance of extended rapid viral response (undetectable HCV-RNA at weeks 4 and 12 of triple therapy). Treatment length is mainly based on the stage of fibrosis and prior response to pegylated interferon and ribavirin. Thus, in both treatment-naïve patients and patients with recurrence after pegylated interferon therapy, the duration of treatment is 24 or 48 weeks (unless cirrhosis is present), depending on the presence of extended rapid viral response, while in cirrhotic patients and null responders, treatment length is 48 weeks. The main adverse effects of telaprevir therapy are anemia and skin rash. If these effects occur, the main measures that should be adopted are reduction of the ribavirin dose in anemia, and close monitoring and treatment cessation in skin rash, depending on its spread and severity.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Oligopéptidos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Anemia/inducido químicamente , Antivirales/administración & dosificación , Antivirales/efectos adversos , Ensayos Clínicos como Asunto , Erupciones por Medicamentos/etiología , Exantema/inducido químicamente , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/complicaciones , Humanos , Interferones/administración & dosificación , Interferones/uso terapéutico , Interleucinas/genética , Cirrosis Hepática/etiología , Inutilidad Médica , Estudios Multicéntricos como Asunto , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/uso terapéutico , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/efectos adversos , ARN Viral/sangre , ARN Viral/aislamiento & purificación , Ribavirina/administración & dosificación , Ribavirina/uso terapéutico , Síndrome de Stevens-Johnson/etiología , Carga ViralRESUMEN
The role of the hepatitis C virus (HCV) NS3/4A protease in ablating the signaling pathway involved in the production of alpha/beta interferon (IFN-α/ß) suggests a relationship between NS3/4A proteolytic activity and a patient's response to IFN-based therapy. To identify viral factors associated with the HCV treatment response, we analyzed the pretreatment NS3/4A protease gene quasispecies composition of 56 HCV genotype 1-HIV-1-coinfected patients treated in our clinic with pegylated IFN (pegIFN) plus ribavirin (RBV). The catalytic efficiency of the dominant (i.e., the most abundant) quasispecies was also assayed for Cardif cleavage and correlated with treatment outcome. A total of 1,745 clones were isolated and sequenced. Significantly less nucleotide quasispecies heterogeneity and lower Shannon entropy values were detected within the responder group (P < 0.05). A correlation was also found between the efficiency of NS3/4A protease Cardif cleavage and therapy outcome. Proteases from sustained responder patients were more efficient at processing Cardif (mean ± standard error of the mean [SEM], 0.8960 ± 0.05568; n = 19) than proteases from nonresponders (mean ± SEM, 0.7269 ± 0.05306; n = 37; P < 0.05). Finally, the amino acid p distance (the proportion [p] of nucleotide sites at which two sequences being compared are different) was significantly shorter in patients with an interleukin-28B (IL-28B) risk allele (P < 0.01), suggesting that IL-28B risk allele carriers exert a lower positive selection pressure on the NS3/4A protease. NS3/4A protease efficiency in cleaving Cardif may be associated with the pegIFN-RBV treatment response, as shown in our cohort of HIV-HCV-coinfected patients. Greater NS3/4A nucleotide heterogeneity and higher Shannon entropy values in nonresponders suggest that less HCV quasispecies complexity may favor a better response to pegIFN-RBV.
Asunto(s)
Antivirales/uso terapéutico , Proteínas Portadoras/genética , Infecciones por VIH/complicaciones , Hepacivirus/enzimología , Hepatitis C/tratamiento farmacológico , Proteínas no Estructurales Virales/genética , Adulto , Secuencia de Aminoácidos , Proteínas Portadoras/química , Proteínas Portadoras/aislamiento & purificación , Catálisis , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1 , Hepacivirus/clasificación , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Interferón-alfa/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Análisis de Secuencia de ADN , Resultado del Tratamiento , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/aislamiento & purificación , Adulto JovenRESUMEN
UNLABELLED: Although two pegylated interferons (Peg-IFN) are available to treat chronic hepatitis C virus (HCV) infection, no head-to-head comparative studies have been published. We aim to compare the efficacy and safety of PEG IFN alfa-2b (PEG 2b) versus PEG IFN alfa-2a (PEG 2a), plus ribavirin (RBV). A prospective, randomized, multi-center, open-label clinical trial including 182 human immunodeficiency virus (HIV)-hepatitis C virus (HCV) patients naïve for HCV therapy was performed. Patients were assigned to PEG 2b (80-150 mug/week; n = 96) or PEG 2a (180 mug/week; n = 86), plus RBV (800-1200 mg/day) for 48 weeks. The primary endpoint was sustained virological response (SVR: negative HCV-RNA 24 weeks after completion of treatment). At baseline, both groups were well balanced: 73% male; 63% HCV genotype 1 or [corrected] 4; 29% had fibrosis index of 3 or greater. The overall SVR was 44% (42% PEG 2b versus 46% PEG 2a, P = 0.65). Among genotypes 1 or [corrected] 4, SVRs were 28% versus 32% (P = 0.67) and 62% versus 71% (P = 0.6) in genotypes 2 or [corrected] 3 for PEG 2b and PEG 2a, respectively. Early virological response (EVR; >or=2 log reduction from baseline or negative HCV-RNA at week 12) was 70% in the PEG 2b group and 80% in the PEG 2a group (P = 0.13), reaching a positive predictive value of SVR of 64% and a negative predictive value of 100% in both arms. Side effects were present in 96% of patients but led to treatment discontinuation in 10% of patients (8% on PEG 2b and 13% on PEG 2a, P = 0.47). CONCLUSION: In patients with HIV, HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Polietilenglicoles/administración & dosificación , Ribavirina/administración & dosificación , Adulto , Quimioterapia Combinada , Femenino , Infecciones por VIH/complicaciones , Hepatitis C Crónica/etiología , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Proteínas RecombinantesRESUMEN
BACKGROUND: Suboptimal doses of ribavirin have been suggested to explain the diminished efficacy of pegylated interferon (PEG-IFN) plus ribavirin in hepatitis C virus (HCV)-HIV-coinfected patients. METHODS: A cohort of 104 coinfected patients and an age-, sex- and genotype-matched cohort of HCV-monoinfected patients (n = 104) were compared. All patients received PEG-IFN-alpha2a 180 microg/week plus ribavirin 800-1,200 mg daily (HCV genotype 2/3 patients received 800 mg daily and those with genotype 1/4 received 1,000-1,200 mg daily) for 48 weeks (24 weeks for monoinfected patients with genotypes 2/3). HCV RNA levels were determined qualitatively at weeks 4, 12, 24, 48 and 72 and quantified monthly until week 12. RESULTS: The coinfected cohort had more advanced liver disease and lower body weight. HCV genotype 1 patients coinfected with HIV showed higher levels of HCV RNA than monoinfected patients. A significantly higher proportion of coinfected patients interrupted the prescribed treatment period prematurely (84% versus 98%). During the first 12 weeks, smaller decreases in HCV RNA levels were observed in coinfected patients. Among patients with HCV genotype 1, coinfected patients achieved lower rates of early virological response (64% versus 87%), end-of-treatment response (47.3% versus 80%) and sustained virological response (SVR; 27.3% versus 56.4%), but not rapid virological response (RVR). HCV-HIV-coinfected patients with HCV genotype 2/3 achieved significantly lower rates of RVR (52% versus 88%). Multivariate analysis identified RVR, gender and liver fibrosis as independent predictors of SVR. CONCLUSIONS: Differences in efficacy of PEG-IFN-alpha2a plus ribavirin treatment between HCV-HIV-coinfected and HCV-monoinfected patients were maintained despite optimized ribavirin dose.
Asunto(s)
Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Estudios de Cohortes , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Masculino , Polietilenglicoles/administración & dosificación , Estudios Prospectivos , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/administración & dosificaciónRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Ribavirina/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Adulto , Sangre/virología , Estudios de Cohortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Didesoxinucleósidos/uso terapéutico , Emtricitabina , Femenino , Estudios de Seguimiento , VIH-1/aislamiento & purificación , Hepacivirus/aislamiento & purificación , Humanos , Interferón alfa-2 , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Organofosfonatos/uso terapéutico , Polietilenglicoles , Proteínas Recombinantes , Tenofovir , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVE: To identify baseline characteristics predictive of a sustained virological response (SVR) in patients with HIV-hepatitis C virus (HCV) co-infection treated with interferon-based therapy. DESIGN/METHODS: A stepwise multiple logistic regression analysis was used to explore the prognostic factors associated with SVR [undetectable HCV-RNA (< 50 IU/ml) at the end of untreated follow-up in week 72]. RESULTS: In all patients (n = 853), in addition to the HCV therapy received, the factors most predictive of SVR were baseline HCV-RNA [< or = versus > 400 000 IU/ml; odds ratio (OR) 4.77; 95% confidence interval (CI) 3.15-7.22; P < 0.0001] and HCV genotype (OR 2.87; 95% CI 2.00-4.12; P < 0.0001). HIV treatment (with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor; P = 0.034), race (P = 0.027), and body mass index (P = 0.039) were also weak predictors of HCV treatment response. CONCLUSIONS: In the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT), the predictors of SVR among HIV-HCV co-infected patients treated with peginterferon alfa-2a plus ribavirin were similar to those in patients with HCV mono-infection. The HCV genotype and pretreatment HCV-RNA level had the greatest influence on SVR.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/complicaciones , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Pronóstico , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/uso terapéutico , Resultado del Tratamiento , Carga ViralRESUMEN
Human papillomavirus (HPV) types are associated with squamous cell cancers. HIV infection is linked with a higher prevalence of anal HPV infection. It is important to assess whether HPV is present in other body parts involved in sexual practices to establish a cancer prevention program. A high prevalence of high-risk HPV types was present in the anus, penis and mouth (78, 36 and 30%, respectively) in a cohort of HIV-infected males (men who have sex with men and heterosexual), without evidence of pathology in these areas.
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Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adolescente , Adulto , Enfermedades del Ano/virología , Estudios Transversales , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Boca/virología , Papillomaviridae/clasificación , Infecciones por Papillomavirus/virología , Enfermedades del Pene/virología , Factores de Riesgo , Conducta SexualRESUMEN
OBJECTIVE: To assess the efficacy and safety of an extended treatment period in HIV/hepatitis C virus (HCV)-coinfected patients without early virological response (EVR). METHODS: Patients received pegylated interferon (peg-INF)-alpha2a 180 microg/week plus ribavirin 800 mg/d for 12 weeks. Patients achieving EVR at week 12 continued under therapy for an additional 12 or 36 weeks depending on genotype. Patients without EVR were randomized to complete the standard treatment or treatment lasting 72 weeks (extension arm). RESULTS: One hundred and ten patients were included (mean age 38.7 years, mean weight 68 kg, 74% males, 74% on highly active antiretroviral therapy, mean CD4+ T-cell count 564 cells/mm3). Fifty-one patients harboured genotype 1, 44 genotype 2/3, and 15 genotype 4. Fifty-three had an HCV load >800,000 IU/ml. Premature interruptions occurred in 32.7%. EVR was achieved in 63.6% (51% in genotype 1, 88.6% in genotype 2/3, 33.3% in genotype 4). End-of-treatment response was 52.7% (47.2% in genotype 1, 68.2% in genotype 2/3, 26.7% in genotype 4). Sustained virological response (SVR) was achieved in 41.8% (37.3% in genotype 1, 54.6% in genotype 2/3, 20% in genotype 4). Only one patient allocated to the extended arm achieved SVR. The rate of drop-outs in the extension arm was 68%. The negative predictive value of EVR was 97.5%. CONCLUSIONS: This study shows no benefit of extending therapy in patients without EVR at week 12. Measures to improve adherence to HCV antiviral therapy should be considered when new approaches based on extended periods of treatment are investigated.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por VIH/complicaciones , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Antivirales/efectos adversos , Quimioterapia Combinada , Femenino , VIH-1 , Hepacivirus/fisiología , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Polietilenglicoles/efectos adversos , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To assess the baseline factors associated with haematological toxicity that lead to ribavirin or pegylated interferon (peginterferon) dosage reductions in hepatitis C and human immunodeficiency virus (HCV/HIV)-coinfected patients. DESIGN: Multicentre, prospective, observational study. SETTING: Eleven hospitals in Spain during the period 2002-2003. SUBJECTS AND METHODS: One-hundred and forty-two HIV/HCV-coinfected patients received peginterferon-alpha2a plus ribavirin. Baseline characteristics and haematological parameters were recorded at baseline, week 4, 8, 12, 24 and 48. Cox's regression model was used to study the factors associated with the appearance of a haemoglobin level below 10g/dl (haemoglobin-endpoint), a neutrophil count below 750/mm(3) (neutrophil-endpoint) and a platelet count below 50,000/mm(3) (platelet-endpoint). RESULTS: Nineteen patients (13.4%) reached the haemoglobin-endpoint, 22.5% the neutrophil-endpoint and 7% the platelet-endpoint. Mean time of follow-up was 8 months (+/-3.5). A baseline haemoglobin level below 14g/dl [hazard ratio (HR): 3.65; 95% confidence interval (CI): 1.46-9.06] and treatment with zidovudine (HR: 3.25; 95% CI: 1.31-8.11) were the independent factors associated with the appearance of the haemoglobin-endpoint. A baseline neutrophil below 2050/mm(3) (HR: 3.59; 95% CI: 1.77-7.28) and baseline weight <60 kg (HR: 2.21; 95% Cl: 1.04-4.56) were independently associated with the appearance of the neutrophil-endpoint. Baseline platelet count (x1000/mm(3) decrease) (HR: 1.074; 95% CI: 1.04-1.11) was independently associated with the appearance of the platelet-endpoint. CONCLUSIONS: Baseline factors allow the identification of a subset of HIV/HCV-coinfected patients who are prone to experience haematological toxicity during HCV antiviral therapy.
Asunto(s)
Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Ribavirina/administración & dosificación , Ribavirina/efectos adversos , Adulto , Antivirales/administración & dosificación , Antivirales/efectos adversos , Femenino , Humanos , Interferón alfa-2 , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes , Factores de RiesgoRESUMEN
OBJECTIVE: Faldaprevir is a potent, once-daily hepatitis C virus (HCV) NS3/4A protease inhibitor. STARTVerso4 assessed the efficacy and safety of faldaprevir and response-guided pegylated interferon α-2a/ribavirin (PegIFN/RBV) in individuals with HCV/HIV co-infection. DESIGN: A phase 3 open-label study (NCT01399619). METHODS: Individuals (Nâ=â308) co-infected with HCV genotype 1 (treatment-naive or prior interferon relapsers) and HIV [96% on antiretroviral therapy (ART)] received faldaprevir 120âmg (Nâ=â123) or 240âmg (Nâ=â185) and PegIFN/RBV. Those receiving a protease inhibitor or efavirenz ART were assigned to faldaprevir 120 or 240âmg, respectively. Individuals achieving early treatment success (ETS; HCV RNA <25âIU/ml at week 4 and undetectable at week 8) were randomized to 24 or 48 weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: SVR12 was achieved in 221 (72%) individuals, and the rates were comparable across faldaprevir doses. ETS was achieved in 80%, and of these 86% achieved SVR12, with comparable rates with 24 and 48 weeks of PegIFN/RBV (87 and 94%, respectively). In multivariate analysis, age below 40 years, IL28B CC genotype, and baseline HCV RNA below 800â000âIU/ml were associated with SVR12 (Pâ=â0.027, Pâ<â0.0001, and Pâ=â0.0002, respectively), whereas treatment (ART regimen and faldaprevir dose), liver cirrhosis, and genotype 1 subtype were not. The safety profile was comparable to that of faldaprevir in HCV-monoinfected individuals. CONCLUSIONS: High SVR12 rates were achieved with faldaprevir and PegIFN/RBV in HIV/HCV co-infected individuals, regardless of faldaprevir dose and background ART, HCV genotype 1 subtype, or cirrhosis status. SVR rates mirrored those obtained with similar regimens in HCV monoinfected individuals.
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Antivirales/uso terapéutico , Infecciones por VIH/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Oligopéptidos/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Tiazoles/uso terapéutico , Adolescente , Adulto , Anciano , Ácidos Aminoisobutíricos , Antirretrovirales/uso terapéutico , Quimioterapia Combinada/métodos , Humanos , Leucina/análogos & derivados , Persona de Mediana Edad , Prolina/análogos & derivados , Quinolinas , Proteínas Recombinantes/uso terapéutico , Resultado del Tratamiento , Carga Viral , Viremia/diagnóstico , Adulto JovenRESUMEN
OBJECTIVES: To describe the 28-day hepatitis C virus (HCV) kinetics under Pegylated-interferon (Peg-IFN) + ribavirin (RBV) therapy in HIV/HCV co-infected patients. To evaluate the predictive value of early virological response (EVR) of achieving a sustained virological response (SVR). To investigate the baseline mutations in the interferon sensitivity determining region (ISDR)2209-2248 in the non-structural 5A protein of HCV according to genotype. METHODS: Open, prospective trial including 28 co-infected patients with directly observed treatment with Peg-IFN + RBV. We assessed the predictive values of EVR (> or = 2 log10 of HCV decay or a negative qualitative test) at days 1, 7, 28 and in week 12 of the SVR. RESULTS: The SVR in an intention-to-treat analysis was 28.6% (genotype 1, 1/13; genotype 3, 6/10; genotype 4, 1/5). Patients who reached SVR presented a significantly faster HCV plasma viral load reduction compared to non-responders from the first 24 h [-1.06 log10 (interquartile range, -1.7 to -0.4) versus -0.05 log10 (interquartile range, -0.4 to +0.14) respectively; P = 0.002]. The median HCV viral load at week 12 was significantly different from that at baseline in responder and transient responders but not in non-responder patients. The positive predictive value was 100% within the first month and the best negative predictive value was 92% and 88.8% at weeks 4 and 12 respectively. The only genotype 1 responder patient had eight mutations in ISDR2209-2248. CONCLUSIONS: A very early HCV viral decay is observed in responder patients. An early virological response assessment at week 4 and 12 might be a useful tool in the clinical management of the co-infected population.
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Antivirales/uso terapéutico , Infecciones por VIH/complicaciones , Hepacivirus/fisiología , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles , Ribavirina/uso terapéutico , Adulto , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/virología , Humanos , Interferón alfa-2 , Hígado/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Proyectos Piloto , Pronóstico , Estudios Prospectivos , ARN Viral/sangre , Proteínas Recombinantes , Sensibilidad y Especificidad , Carga Viral , Proteínas no Estructurales Virales/genética , Replicación Viral/fisiologíaRESUMEN
BACKGROUND: It has been suggested that the addition of ribavirin (RBV) as a part of the treatment for chronic hepatitis C virus (HCV) in HIV co-infected patients on didanosine (ddI) or stavudine (d4T) might increase the nucleoside-induced impairment of mitochondrial function. DESIGN: Comparative study to investigate the impact on mitochondrial function of adding RBV to a long-term treatment with ddI, d4T or both in HCV/HIV non-cirrhotic, asymptomatic patients. We included 26 patients: 16 continued with their current antiretroviral therapy (control group) and 10 patients received a concomitant 24-week course of RBV plus pegylated interferon (PEG-IFN) alpha-2b therapy (HCV-treated group). METHODS: We assessed peripheral blood mononuclear cells mitochondrial DNA (mtDNA) content and mitochondrial respiratory chain (MRC) function at baseline and at 24 weeks of follow-up. In the HCV-treated group we performed additional determinations at 12 weeks during anti-HCV therapy and 24 weeks after finishing anti-HCV therapy. RESULTS: Times on ddI or d4T exposure were 194 +/- 54.9 and 131 +/- 66.5 weeks in the HCV-treated and control groups, respectively. There were no differences either in mtDNA content, the enzyme activity of MRC complexes or clinical parameters at baseline. Throughout the study, mitochondrial measurements remained stable within groups and without differences when we compared HCV-treated and control groups. CONCLUSIONS: In our study, the addition of RBV and PEG-IFN during a 24-week period in HCV/HIV non-cirrhotic, asymptomatic patients on long-term ddI, d4T or both had no impact on mitochondrial function. These findings could suggest that additional triggers are required to achieve a critical threshold in the degree of mitochondrial damage needed for symptoms to develop.
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Antivirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Mitocondrias/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Antivirales/administración & dosificación , Antivirales/farmacología , ADN Mitocondrial/genética , Didanosina/administración & dosificación , Didanosina/uso terapéutico , Quimioterapia Combinada , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacología , Masculino , Persona de Mediana Edad , Mitocondrias/fisiología , Polietilenglicoles , Proteínas Recombinantes , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Ribavirina/administración & dosificación , Ribavirina/farmacología , Estavudina/administración & dosificación , Estavudina/uso terapéutico , Factores de TiempoRESUMEN
BACKGROUND: It is uncertain whether a 4-week induction period of pegylated interferon and ribavirin increases early virological response (EVR) in HIV-HCV-coinfected patients. METHODS: HIV and HCV genotype 1- and 4-coinfected subjects were randomized to receive pegylated interferon-α2a 270 µg/week plus ribavirin 1,600 mg daily and epoetin-ß for 4 weeks, followed by pegylated interferon-α2a at standard dosages plus weight-based ribavirin (WBR) dosage for 8 weeks (induction arm [IA]), or pegylated interferon-α2a plus WBR for 12 weeks (standard therapy arm [SA]). HCV RNA was determined at weeks 0, 1, 2, 3, 4, 8 and 12. Ribavirin plasma trough concentrations were determined at weeks 4 (RBV-C(4)) and 12 (RBV-C(12)). RESULTS: A total of 67 patients were included; 33 in the SA and 34 in the IA. Overall, 25% received nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens. More patients achieved an HCV RNA decrease ≥1 log(10) at week 4 in the IA than in the SA (62% versus 38%; P=0.017), but EVR rates were similar in the two groups (74% versus 59% in the IA and SA, respectively; P=0.15). Independent predictors of faster HCV RNA decrease at 12 weeks were higher RBV-C(4) and younger age. RBV-C(4) were higher in patients allocated in the IA and in those receiving NRTIs (P=0.039). CONCLUSIONS: A 4-week induction with pegylated interferon-α2a plus ribavirin was associated with a greater decrease in HCV RNA at week 4; however, this did not translate into higher EVR rates. Higher RBV doses and avoidance of NRTI-sparing antiretroviral regimens might improve HCV treatment efficacy.
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Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Infecciones por VIH/complicaciones , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Antivirales/efectos adversos , Coinfección/virología , Femenino , VIH/genética , Hepacivirus/genética , Hepatitis C/virología , Humanos , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Ribavirina/efectos adversos , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND: We evaluated the effect of different doses of pegylated interferon (PEG-IFN)-alpha2a/ribavirin (RBV) on several T-cell activation markers in HIV-HCV-coinfected patients and their relationship with changes in plasma HCV RNA. METHODS: Frozen peripheral blood mononuclear cells (PBMCs) from 22 patients receiving two different PEG-IFN-alpha2a schedules were analysed by six-colour flow cytometry. Cell-surface expression of CD38 was quantified. HIV and HCV viral loads, as well as absolute CD4+ and CD8+ T-cell counts, were recorded during the follow up (72 weeks). RESULTS: PEG-IFN-alpha2a/RBV treatment decreased the absolute numbers of CD8+ and CD4+ T-cells. The decrease in CD8+ T-cells was more pronounced, resulting in increased percentages of CD4+ T-cells. Percentages of naive/memory CD4+ T-cell subsets remained unchanged, although the percentage of CD38+CD45RO+ cells significantly increased. By contrast, the CD8+ T-cell compartment significantly reduced the percentage of CD45RO+ cells and HLA-DR+ cells, whereas the percentage of CD38 expressing cells was increased because of a significant increase in cell-surface CD38 expression. Changes in CD8+ T-cells were similar for both PEG-IFN-alpha2a/RBV doses, but high doses induced more severe perturbations in CD4+ T-cells. All changes returned to baseline levels after treatment cessation and, except for the loss of naive CD4+ T-cells, were not associated with virological response. CONCLUSIONS: Transient lymphopaenia induced by PEG-IFN-alpha2a/RBV differentially affects T-cell subsets. Activated HLA-DR+ and CD45RO+ cells were selectively reduced in peripheral blood, whereas CD38 expression was up-regulated mainly in memory cells. Increasing PEG-IFN-alpha2a/RBV doses mainly affect CD4+ T-cells but failed to modify clinical outcome.
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Antivirales , Infecciones por VIH , Hepatitis C , Interferón-alfa , Polietilenglicoles , Ribavirina , Subgrupos de Linfocitos T/efectos de los fármacos , ADP-Ribosil Ciclasa 1/metabolismo , Antivirales/administración & dosificación , Antivirales/farmacología , Antivirales/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Quimioterapia Combinada , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Hepatitis C/inmunología , Hepatitis C/virología , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacología , Polietilenglicoles/uso terapéutico , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/administración & dosificación , Ribavirina/farmacología , Ribavirina/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Resultado del Tratamiento , Carga ViralRESUMEN
OBJECTIVE: Guidelines recommendation to extend treatment duration in genotype 1 hepatitis C virus (HCV)/HIV-coinfected patients who clear the virus later than treatment week 4 is not evidence-based. Our main objective was to study the ability of week 12 viral response [early virologic response (EVR)] to predict long-term outcome in patients treated for 48 weeks. DESIGN: Multicenter retrospective cohort analysis. METHODS: Genotype 1 HCV treatment-naive, HIV-coinfected adult patients with compensated liver disease who started combination therapy with fixed-dose pegylated-interferon (pegIFN) alfa-2a or weight-based pegIFN alfa-2b plus ribavirin were included. Univariate and forward stepwise logistic regression analysis were used to identify predictors of sustained viral response (SVR) and relapse. RESULTS: By intention-to-treat analysis, 31.3% (87/278) of patients achieved an SVR. SVR rate was more than three-fold higher in patients who cleared the virus by week 12 of treatment compared with late responders. Among 123 end-of-treatment responders, 36 (29.3%) relapsed. Relapse risk increased in patients with cirrhosis, in those with ribavirin dose reductions and in late responders: more than 65% of patients who cleared the virus between weeks 12 and 24 relapsed following 48 weeks of treatment compared with 10% of those attaining a complete EVR (<15 IU/ml) at treatment week 12 (risk ratio 6.4, 95% confidence interval 2.9-14.4). CONCLUSION: Viral response at treatment week 12 is a strong predictor of long-term outcome. Genotype 1 HCV/HIV-coinfected patients who achieve a complete EVR (<15 IU/ml) are at low risk of viral relapse after completing the standard 48 weeks of therapy.