RESUMEN

OBJECTIVE: To evaluate the safety and efficacy of shortened 8-week regimen of ledipasvir/sofosbuvir (LED/SOF) combination therapy in treatment-naïve children without cirrhosis aged 4-10 years of age with chronic hepatitis C virus (HCV) infection. STUDY DESIGN: This observational single arm prospective study included 30 treatment-naïve children (20 males) with proved chronic HCV fulfilling inclusion criteria. Their body weights ranged from 17 to 26 kg. Four patients were excluded from the study. All the included children received a single oral dose of LED/SOF 45/200 mg for 8 weeks. Body weight, HCV-RNA, complete blood count, and liver function tests were monitored at 0, 2, 4, and 8 weeks and sustained virologic response was evaluated after 12 weeks after treatment (SVR12). The emergence of any side effects was also monitored. RESULTS: The most common risk factor (53.3%) was an parent or sibling with HCV infection. Twenty-nine patients (96.7%) were negative for HCV-RNA by week 2 of treatment and 1 patient became negative by week 4. The end of treatment response and SVR12 were 100%. Transaminases levels declined and returned to normal levels by week 2. Major side effects were fatigue in 90% (27/30) and headache in 76.7% (23/30). Side effects were minimal, tolerable, and did not interfere with daily activity or necessitate treatment discontinuation. CONCLUSIONS: A shortened 8-week regimen of LED/SOF (45/200 mg) is safe and effective with 100% SVR12 in treatment-naïve children with cirrhosis aged 4-10 years with chronic HCV infection genotype 4.

Asunto(s)

Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Niño , Preescolar , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/virología , Humanos , Masculino , Estudios Prospectivos , Sofosbuvir , Factores de Tiempo , Resultado del Tratamiento , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/efectos adversos

RESUMEN

INTRODUCTION AND OBJECTIVES: Four regimens are recommended for treating hepatitis C (HCV) genotype 1 infection. Study aims were to (1) compare frequencies of contraindicated drug interactions (XDDIs) when each HCV regimen is added to medication profiles of HCV-monoinfected patients, (2) quantify the proportion of patients with XDDIs to all four regimens and (3) determine covariates independently associated with having a XDDI to all four regimens. MATERIALS AND METHODS: A cross-sectional study was performed within Upstate New York Veterans Healthcare Administration. INCLUSION CRITERIA: (1) age ≥18 years, (2) HCV monoinfection and (3) available medication list. Data extracted were: demographics, comorbidities, and medication list. Primary outcome was XDDIs involving patient's home medications and each HCV regimen. University of Liverpool drug interaction website was used to define XDDIs. Two-way comparisons of regimens were performed using McNemar's test where p<0.0083 was considered statistically significant. Multivariate regression analyses were performed to determine predictors. RESULTS: Of the 4047 subjects, mean±standard deviation age was 59.8±7.6. Median (interquartile range) number of medications used was 7 [4-11]. Frequencies of XDDIs after the addition of each regimen ranged from 2.8% to 17.8% and were mostly statistically different from one another. There were 95 (2.3%) patients with XDDIs to all four regimens. Predictors of having XDDIs to all four regimens were ≥6 medications and HCV infection ≥10 years. CONCLUSION: The frequencies of XDDIs varied between HCV regimens. Number of medications and duration of HCV infection were predictors of having XDDIs to all four regimens.

Asunto(s)

Antivirales/efectos adversos , Contraindicaciones de los Medicamentos , Interacciones Farmacológicas , Hepatitis C Crónica/tratamiento farmacológico , Anciano , Ansiolíticos/efectos adversos , Antiasmáticos/efectos adversos , Anticoagulantes/efectos adversos , Anticonvulsivantes/efectos adversos , Antidepresivos/efectos adversos , Antieméticos/efectos adversos , Antihipertensivos/efectos adversos , Antipsicóticos/efectos adversos , Bencimidazoles/efectos adversos , Benzofuranos/efectos adversos , Carbamatos/efectos adversos , Estudios Transversales , Suplementos Dietéticos/efectos adversos , Combinación de Medicamentos , Femenino , Fluorenos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Polifarmacia , Pirrolidinas/efectos adversos , Quinoxalinas/efectos adversos , Sofosbuvir/efectos adversos , Sulfonamidas/efectos adversos , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/análogos & derivados , Veteranos , Vitaminas/efectos adversos

RESUMEN

INTRODUCTION AND AIM: Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited. OBJECTIVE: Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF. MATERIAL AND METHODS: Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed. RESULTS: Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred. CONCLUSIONS: Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment.

Asunto(s)

Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Ribavirina/uso terapéutico , Simeprevir/uso terapéutico , Sofosbuvir/uso terapéutico , Uridina Monofosfato/análogos & derivados , Anciano , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Ribavirina/efectos adversos , Simeprevir/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/uso terapéutico , Carga Viral

RESUMEN

INTRODUCTION: Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival. MATERIALS AND METHODS: We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant. RESULTS: Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock. CONCLUSION: Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.

Asunto(s)

Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Cirrosis Hepática/cirugía , Trasplante de Hígado , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Respuesta Virológica Sostenida , Anciano , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/mortalidad , Hepatitis C/virología , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Cirrosis Hepática/virología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Carga Viral

RESUMEN

ABSTRACT Background and aim. The combination of Sofosbuvir (SOF) and Ledipasvir (LDV) has been lead to considerable enhancement of treatment of hepatitis C virus (HCV) genotype 1 infection. A meta-analysis of the currently available studies was undertaken with the aim to evaluate the antiviral efficacy of SOF/LDV therapy for 12 or 24 weeks with or without Ribavirin (RBV) in patients with HCV genotype 1 infection. Material and methods. In this meta-analysis, we searched databases including PubMed, Scopus, Science Direct and Web of Science using appropriate keywords. All papers which evaluated the efficacy of combination therapy of SOF/LDV with or without RBV for 12 or 24 weeks among patients with HCV genotype 1 infection were included. Results. The 20 published articles were assessed for eligibility and finally 10 articles pooling 2248 participants were included in this meta-analysis. Pooled SVR12 for four SOF/LDV regimens were 95% (95%CI = 93%-97%) for 12 weeks of treatment with SOF/LDV, 97% (95%CI = 95%-98%) for 24 weeks of treatment with SOF/LDV, 96% (95%CI = 94%-97%) for 12 weeks of treatment with SOF/ LDV/RBV and 98% (95%CI = 97%-99%) for 24 weeks of treatment with SOF/LDV/RBV. Only in treatment regimen of SOF/LDV for 12 weeks, cirrhosis had a significant effect on the SVR12 (OR = 0.21, 95%CI = 0.07-0.66). Furthermore, NS5A resistance-associated substitutions at baseline were associated with decrease in the rate of SVR (OR = 0.31, 95%CI = 0.2-0.5). Conclusions. The Interferon-free regimen of SOF/LDV for 12 or 24 weeks with or without RBV is highly effective for treatment of patients with HCV genotype 1 infection.

Asunto(s)

Humanos , Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Hepatitis C/tratamiento farmacológico , Hepacivirus/efectos de los fármacos , Fluorenos/uso terapéutico , Sofosbuvir/uso terapéutico , Antivirales/efectos adversos , Ribavirina/uso terapéutico , Factores de Tiempo , Bencimidazoles/efectos adversos , Distribución de Chi-Cuadrado , Oportunidad Relativa , Resultado del Tratamiento , Hepatitis C/diagnóstico , Hepatitis C/virología , Hepacivirus/genética , Quimioterapia Combinada , Fluorenos/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Genotipo

Asunto(s)

Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Distribución de Chi-Cuadrado , Quimioterapia Combinada , Femenino , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Ribavirina/uso terapéutico , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven

RESUMEN

BACKGROUND AND AIM: Ledipasvir with sofosbuvir (LED/SOF) for the treatment of patients infected with genotype 1 hepatitis C virus can be used with or without ribavirin (RBV). RBV is well known to promote significant adverse events (AE). The aim of this study was to compare the efficacy and safety of treatment with LED/SOF, with or without RBV, in patients infected with hepatitis C virus genotype 1. METHODS: We performed a systematic review followed by a pairwise meta-analysis including randomized controlled trials that reported efficacy (rapid virological response, sustained virological response at 4 and 12 weeks post-treatment (SVR4 and 12), and viral relapse) and safety outcomes (any AE, serious AE, discontinuation owing to AE, anemia, and rash). It was performed a subgroup analysis evaluating the SVR12 including only cirrhotic patients. Results were reported as risk ratios (RR) and with 95% confidence intervals (95% CI). RESULTS: Seven randomized controlled trials were analyzed. LED/SOF with RBV showed a worse safety profile when compared with LED/SOF without RBV for the following outcomes: any AE (RR 0.56 [95% CI 0.46-0.69]), anemia (RR 0.08 [95% CI 0.04-0.17]), and rash (RR 0.35 [95% CI 0.19-0.65]). No significant differences were observed regarding serious AE, rapid virological response, SVR4, SVR12, or viral relapse. The subgroup analysis did not show significant differences between either treatment groups. CONCLUSION: Administration of LED/SOF + RBV to treatment-naïve patients with or without cirrhosis, and non-cirrhotic treatment-experienced patients, did not promote significant additional benefits. Furthermore, it is still unclear whether cirrhotic treatment-experienced patients could benefit from combined therapy.

Asunto(s)

Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Bases de Datos Bibliográficas , Quimioterapia Combinada , Fluorenos/efectos adversos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Resultado del Tratamiento

RESUMEN

UNLABELLED: Patients with hepatitis C virus (HCV) infection and cirrhosis are underrepresented in clinical trials of interferon-free regimens of direct-acting antiviral agents, making it difficult to optimize therapy. We performed a post-hoc analysis of data from seven clinical trials to evaluate the efficacy and safety of the fixed-dose combination of ledipasvir (LDV) and sofosbuvir (SOF), with and without ribavirin (RBV), in 513 treatment-naïve and previously treated patients with genotype 1 HCV and compensated cirrhosis. All patients received LDV-SOF for 12 or 24 weeks with or without RBV. We determined the rates of sustained virological response (SVR) 12 weeks after treatment (SVR12) overall and for subgroups. Of the 513 patients analyzed, 69% were previously treated and 47% had failed previous treatment with a protease-inhibitor regimen. Overall, 493 patients (96%; 95% confidence interval [CI]: 94%-98%) achieved SVR12, 98% of treatment-naïve and 95% of previously treated patients. SVR12 rates did not vary greatly by treatment duration (95% of patients receiving 12 weeks and 98% of patients receiving 24 weeks of treatment), nor by addition of RBV (95% of patients receiving LDV-SOF alone and 97% of those who received LDV-SOF plus RBV), although previously treated patients receiving 12 weeks of LDV-SOF without RBV had an SVR12 rate of 90%. One patient discontinued LDV-SOF because of an adverse event (AE). The most common AEs were headache (23%), fatigue (16%-19%), and asthenia (14%-16%). One patient (<1%) of those receiving LDV-SOF alone, and 4 (2%) of those receiving LDV-SOF plus RBV had treatment-related serious AEs. CONCLUSIONS: This analysis suggests that 12 weeks of LDV-SOF is safe and effective for treatment-naïve patients with HCV genotype 1 and compensated cirrhosis. The relatively lower SVR in treatment-experienced patients treated with 12 weeks of LDV-SOF raises the question of whether these patients would benefit from adding RBV or extending treatment duration to 24 weeks.

Asunto(s)

Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Fluorenos/efectos adversos , Hepatitis C Crónica/tratamiento farmacológico , Ribavirina/efectos adversos , Uridina Monofosfato/análogos & derivados , Adulto , Anciano , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Sofosbuvir , Resultado del Tratamiento , Uridina Monofosfato/efectos adversos , Adulto Joven

RESUMEN

In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) children<15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau (from 2003 to 2012). The pfcrt K76T and pfmdr1 N86Y frequencies were stable, and seasonal changes were not seen from 2003 to 2007. Since 2007, the mean annual frequencies increased (P<0.001) for pfcrt 76T (24% to 57%), pfmdr1 N86 (72% to 83%), and pfcrt 76+pfmdr1 86 TN (10% to 27%), and pfcrt 76T accumulated during the high transmission season (P=0.001). The pfmdr1 86+184 NF frequency increased from 39% to 66% (from 2003 to 2011; P=0.004). One sample had two pfmdr1 gene copies. pfcrt 76T was associated with a lower parasite density (P<0.001). Following the discontinuation of an effective chloroquine regimen, probably highly artemether-lumefantrine-susceptible P. falciparum (with pfcrt 76T) accumulated, possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).

Asunto(s)

Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Etanolaminas/uso terapéutico , Fluorenos/uso terapéutico , Quinina/uso terapéutico , Adolescente , Antimaláricos/efectos adversos , Niño , Preescolar , Cloroquina/efectos adversos , Etanolaminas/efectos adversos , Femenino , Fluorenos/efectos adversos , Guinea Bissau , Humanos , Lumefantrina , Malaria Falciparum/tratamiento farmacológico , Masculino , Quinina/efectos adversos

RESUMEN

INTRODUCTION: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemether-lumefantrine treatments. METHODS: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28‑day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: - treatment failures defined per the World Health Organization. Safety: assessed through adverse events. RESULTS: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI - Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). CONCLUSIONS: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemether-lumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.

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INTRODUÇÃO: Na Colômbia não existem estudos publicados sobre o tratamento da malária não complicada por Plasmodium falciparum comparando as terapias combinadas com artemisinina. Destarte, quer se demonstrar a não inferioridade dos perfis de eficácia/segurança dos tratamentos com artesunato+amodiaquina versus artemeter-lumefantrina. MÉTODOS: Foi realizado um estudo clínico de não inferioridade (∆≤5%), aleatório, controlado, aberto, em adultos com malária não complicada por P. falciparum usando o desenho validado de 28 dias e os desenhos validados/definidos pela Organização Mundial da Saúde. Os pacientes foram aleatorizados (1:1) para ambos artesunato+amodiaquina ou artemeter-lumefantrina orais. Critérios primários de eficácia: resposta clínica e parasitológica adequada; Criterios de eficácia secundários: as falhas de tratamento definidos pela Organização Mundial da Saúde. A segurança: avaliada através de eventos adversos. RESULTADOS: Foram incursos 105 pacientes em cada grupo: zero observações censuradas. As taxas médias da resposta clínica e parasitológica adequada (95% IC - intervalo de confiança): 100% para artesunato+amodiaquina e 99% para artemeter-lumefantrina; atingiu-se o critério de não inferioridade (∆=1.7%). Houve uma falha terapêutica parasitológica tardia (1%; grupo artemeter-lumefantrina), caracterizada mediante reação em cadeia da polimerase como o alelo MAD20 MSP1. Tempo de remissão da febre (grupo artesunato+amodiaquina), foi significativamente mais curto (p=0.002). Dor abdominal, para artesunato+amodiaquina e artemeter-lumefantrina, respectivamente, 1.9% e 3.8% (p=0.68) na linha de base, 1% e 13.3% pós-tratamento (p<0.001). CONCLUSÕES: O tratamento com artesunato+amodiaquina da malária não complicada por P. falciparum é não inferior ao tratamento normal com artemeter-lumefantrina. Os perfis de eficácia/segurança justificam estudos adicionais nesta e outras populações semelhantes.

Asunto(s)

Adulto , Femenino , Humanos , Masculino , Amodiaquina/administración & dosificación , Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Etanolaminas/administración & dosificación , Fluorenos/administración & dosificación , Malaria Falciparum/tratamiento farmacológico , Amodiaquina/efectos adversos , Antimaláricos/efectos adversos , Artemisininas/efectos adversos , Colombia , Combinación de Medicamentos , Quimioterapia Combinada/métodos , Etanolaminas/efectos adversos , Fluorenos/efectos adversos , Resultado del Tratamiento

RESUMEN

The safety of artemether-lumefantrine in patients with acute, uncomplicated Plasmodium falciparum malaria was investigated prospectively using the auditory brainstem response (ABR) and pure-tone thresholds. Secondary outcomes included polymerase chain reaction-corrected cure rates. Patients were randomly assigned in a 3:1:1 ratio to either artemether-lumefantrine (N = 159), atovaquone-proguanil (N = 53), or artesunate-mefloquine (N = 53). The null hypothesis (primary outcome), claiming that the percentage of patients with a baseline to Day-7 ABR Wave III latency increase of > 0.30 msec is ≥ 15% after administration of artemether-lumefantrine, was rejected; 2.6% of patients (95% confidence interval: 0.7-6.6) exceeded 0.30 msec, i.e., significantly below 15% (P < 0.0001). A model-based analysis found no apparent relationship between drug exposure and ABR change. In all three groups, average improvements (2-4 dB) in pure-tone thresholds were observed, and polymerase chain reaction-corrected cure rates were > 95% to Day 42. The results support the continued safe and efficacious use of artemether-lumefantrine in uncomplicated falciparum malaria.

Asunto(s)

Antimaláricos/efectos adversos , Artemisininas/efectos adversos , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Fluorenos/efectos adversos , Malaria Falciparum/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Combinación Arteméter y Lumefantrina , Artemisininas/administración & dosificación , Artemisininas/uso terapéutico , Artesunato , Atovacuona/administración & dosificación , Atovacuona/efectos adversos , Atovacuona/uso terapéutico , Audiometría , Niño , Colombia , Combinación de Medicamentos , Quimioterapia Combinada , Etanolaminas , Femenino , Fluorenos/administración & dosificación , Fluorenos/uso terapéutico , Humanos , Malaria Falciparum/parasitología , Masculino , Mefloquina/administración & dosificación , Mefloquina/efectos adversos , Mefloquina/uso terapéutico , Persona de Mediana Edad , Plasmodium falciparum/efectos de los fármacos , Proguanil/administración & dosificación , Proguanil/efectos adversos , Proguanil/uso terapéutico , Estudios Prospectivos , Resultado del Tratamiento , Adulto Joven

RESUMEN

INTRODUCTION: In Colombia, there are no published studies for the treatment of uncomplicated Plasmodium falciparum malaria comparing artemisinin combination therapies. Hence, it is intended to demonstrate the non-inferior efficacy/safety profiles of artesunate + amodiaquine versus artemether-lumefantrine treatments. METHODS: A randomized, controlled, open-label, noninferiority (Δ≤5%) clinical trial was performed in adults with uncomplicated P. falciparum malaria using the 28-day World Health Organization validated design/definitions. Patients were randomized 1:1 to either oral artesunate + amodiaquine or artemether-lumefantrine. The primary efficacy endpoint: adequate clinical and parasitological response; secondary endpoints: - treatment failures defined per the World Health Organization. SAFETY: assessed through adverse events. RESULTS: A total of 105 patients was included in each group: zero censored observations. Mean (95%CI - Confidence interval) adequate clinical and parasitological response rates: 100% for artesunate + amodiaquine and 99% for artemether-lumefantrine; the noninferiority criteria was met (Δ=1.7%). There was one late parasitological therapeutic failure (1%; artemether-lumefantrine group), typified by polymerase chain reaction as the MAD20 MSP1 allele. The fever clearance time (artesunate + amodiaquine group) was significantly shorter (p=0.002). Respectively, abdominal pain for artesunate + amodiaquine and artemether-lumefantrine was 1.9% and 3.8% at baseline (p=0.68) and 1% and 13.3% after treatment (p<0.001). CONCLUSIONS: Uncomplicated P. falciparum malaria treatment with artesunate + amodiaquine is noninferior to the artemether-lumefantrine standard treatment. The efficacy/safety profiles grant further studies in this and similar populations.

Asunto(s)

Amodiaquina/administración & dosificación , Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Etanolaminas/administración & dosificación , Fluorenos/administración & dosificación , Malaria Falciparum/tratamiento farmacológico , Adulto , Amodiaquina/efectos adversos , Antimaláricos/efectos adversos , Arteméter , Artemisininas/efectos adversos , Colombia , Combinación de Medicamentos , Quimioterapia Combinada/métodos , Etanolaminas/efectos adversos , Femenino , Fluorenos/efectos adversos , Humanos , Lumefantrina , Masculino , Resultado del Tratamiento

RESUMEN

A quantitative structure-activity relationship (QSAR) study of twenty flavonoid derivatives with antimutagenic activity against 3-nitrofluoranthene (3-NFA) was performed by Partial Least Squares (PLS), using Ordered Predictors Selection (OPS) algorithm for variable selection. Four descriptors (PJI2, Mor27m, G1e and R4u+) were selected and a good model (n = 19; R(2) = 0.747; SEC = 0.332; PRESS(cal) = 1.768; F((2,27)) = 23.585; Q(LOO)(2) = 0.590; SEV = 0.388; PRESS(val) = 2.858; R(pred)(2) = 0.591; SEP = 0.394; ARE(pred) = 5.230%; k = 1.005; k' = 0.990; |R(02) - R'(02)| = 0.109) was built with two latent variables describing 83.410% of the original information. Leave-N-out cross validation (LNO) and y-randomization were performed in order to confirm the robustness of the model. The topological descriptors selected indicate that the antimutagenic activity against 3-NFA depends on molecular size, shape and Sanderson electronegativity of flavonoids. The proposed model may provide a better understanding of the antimutagenic activity of flavonoids and can be used as a guidance for proposition of new chemopreventive agents.

Asunto(s)

Antimutagênicos/química , Antimutagênicos/farmacología , Flavonoides/química , Flavonoides/farmacología , Fluorenos/efectos adversos , Mutágenos/efectos adversos , Salmonella typhimurium/efectos de los fármacos , Algoritmos , Fluorenos/metabolismo , Análisis de los Mínimos Cuadrados , Modelos Biológicos , Modelos Moleculares , Mutágenos/metabolismo , Relación Estructura-Actividad Cuantitativa , Salmonella typhimurium/genética