Inhibidores de la integrasa: eficacia y seguridad en el tratamiento de pacientes con infección por VIH

Programa Oficial de Doutoramento en Ciencias da Saúde. 5007V01[Resumen] El virus de la inmunodeficiencia humana (VIH) utiliza diferentes tipos de células como blanco de infección siendo los linfocitos T CD4+ su principal diana. La infección por VIH es capaz de producir un deterioro progresivo del sistema inmunológico que conduce a la aparición de enfermedades definitorias del síndrome de inmunodeficiencia humana adquirida (SIDA). La introducción de la terapia antirretroviral (TAR) de alta eficacia ha cambiado drásticamente el pronóstico de la infección por VIH, con una disminución significativa de la morbilidad y la mortalidad relacionada con el SIDA y convirtiéndola en una patología crónica. La evolución de la infección por el VIH en países con acceso a tratamiento está condicionada por diferentes factores: relacionados con el paciente (ejemplos son los factores epidemiológicos, situación inmunológica, adherencia al tratamiento), con el virus (ejemplos son la carga viral plasmática, presencia de mutaciones de resistencia) o con los fármacos antirretrovirales (ejemplos son la eficacia, tolerabilidad, resistencias, interacciones). En la actualidad las guías clínicas nacionales e internacionales recomiendan tratar a todos los pacientes infectados por el VIH independientemente de su estado inmunológico. Las pautas recomendadas en el momento actual para el tratamiento de inicio en la infección por el VIH consisten en una combinación de tres fármacos que incluyen dos inhibidores de la transcriptasa inversa análogos de nucleósidos o nucleótidos (ITIAN) asociados a un inhibidor de la integrasa (INI) o un inhibidor de la transcriptasa inversa no análogo de nucleósido (ITINN) o un inhibidor de la proteasa potenciado (IP). Basándose en el buen perfil de eficacia y seguridad demostrado en ensayos clínicos, los INI (raltegravir, elvitegravir, dolutegravir y bictegravir) se han posicionado como opciones preferentes frente al resto de familias, adquiriendo gran relevancia su uso en la práctica clínica. Por lo tanto, es importante conocer las características epidemiológicas, clínicas y virológicas, así como el perfil de eficacia y tolerabilidad de tratamientos antirretrovirales basados en inhibidores de la integrasa en nuestra área sanitaria para establecer y optimizar las estrategias de manejo clínico de los pacientes con infección por VIH. En la presente tesis se desarrollan tres estudios: - Estudio 1. Describió las características epidemiológicas, clínicas e inmunovirológicas y analizó la eficacia y tolerabilidad del tratamiento antirretroviral en los pacientes con infección por VIH en los que fueron prescritos los INI Dolutegravir (DTG) y Elvitegravir/cobicistat (EVG/c) en el área sanitaria de A Coruña durante el período Enero 2015 a Enero 2017. Más del 90% de los pacientes naïve y pretratados tuvieron supresión virológica a las 48 semanas del inicio del tratamiento. Durante el seguimiento, se observó un alto porcentaje de abandonos por efectos adversos, no descritos previamente en ensayos clínicos, especialmente con DTG (10.2%). Concretamente, el sexo femenino y recibir tratamiento con DTG se identificaron como factores de riesgo para la interrupción por efectos adversos en la población estudiada. En el caso de DTG las interrupciones de tratamiento se relacionaron principalmente con alteraciones neuropsiquiátricas (70.4%) y para EVG/c con molestias gastrointestinales (50.0%). Se identificaron como factores de riesgo de suspensión de tratamiento debido a efectos adversos neuropsiquiátricos las terapias basadas en DTG, especialmente en combinación con los ITIAN abacavir/lamivudina. - Estudio 2. Evaluó la respuesta virológica en pacientes VIH naïve que iniciaron tratamiento antirretroviral basado en INI desde enero de 2015 hasta febrero de 2017 y que estaban infectados con los dos subtipos genéticos más frecuentes en nuestra población, el subtipo B (54.4%) y el subtipo F (27.2%). La tasa de supresión virológica fue significativamente menor en los pacientes infectados por el subtipo F del VIH en comparación con los pacientes infectados por el subtipo B en la semana 12 (25.0% vs. 75.0%) y 24 (59.1% vs. 95.0%) de tratamiento. La infección por subtipo F fue el único factor predictor independiente de una peor respuesta al tratamiento con INI en la semana 24. - Estudio 3. Evaluó las modificaciones en el perfil lipídico de los pacientes VIH naïve y pretratados que iniciaron tratamiento con EVG/c/FTC/TAF y EVG/c/FTC/TDF desde enero 2015 hasta enero 2018. Los pacientes que iniciaron tratamiento con EVG/c/FTC/TAF tuvieron un empeoramiento de los valores de colesterol total, LDL-C y triglicéridos tras 48 semanas de tratamiento; no hubo cambios significativos en estos parámetros en el grupo a tratamiento con EVG/c/FTC/TDF. En el seguimiento de los pacientes del grupo con EVG/c/FTC/TAF se comprobó que un alto porcentaje tuvo niveles de lípidos por encima del rango normal a las 48 semanas (un 63.1% niveles por encima del rango normal de colesterol total y un 56.2% de LDL-C) y un 11.9% de los pacientes en este grupo tuvieron que recibir fármacos hipolipemiantes. En el análisis multivariante realizado en este grupo, el cociente colesterol total/HDL-C durante las primeras 48 semanas de tratamiento, se asoció con una mayor probabilidad de prescripción de hipolipemiantes [OR 1.6 (95% CI 1.12–2.52); p=0.011]. En resumen, los resultados obtenidos durante el desarrollo de esta tesis han permitido un conocimiento detallado de la eficacia y seguridad de los fármacos antirretrovirales basados en INI en nuestra área sanitaria. Entre los principales hallazgos encontrados hay que destacar el alto porcentaje de abandonos por efectos adversos no descritos previamente en ensayos clínicos, especialmente con DTG (10.2%), la peor respuesta virológica de los pacientes infectados por el subtipo F del VIH a los INI, en comparación con el subtipo B, y el empeoramiento del perfil lipídico cuando los pacientes reciben EVG/c/FTC/TAF.[Resumo] O virus da inmunodeficiencia humana (VIH) utiliza diferentes tipos de células como branco de infección sendo os linfocitos T CD4+ a súa principal diana. A infección por VIH é capaz de producir un deterioro progresivo do sistema inmunolóxico que conduce á aparición de enfermidades definitorias do síndrome de inmunodeficiencia humana adquirida (SIDA). A introdución da terapia antirretroviral (TAR) de alta eficacia cambiou drasticamente o prognóstico da infección por VIH, con unha diminución significativa da morbilidade e a mortalidade relacionada co SIDA e converténdoa nunha patoloxía crónica. A evolución da infección polo VIH en países con acceso ó tratamento está condicionada por diferentes factores: relacionados co paciente (exemplos son factores epidemiolóxicos, situación inmunolóxica, adherencia ó tratamento), co virus (exemplos son a carga viral plasmática, presenza de mutacións de resistencia) ou cos fármacos antirretrovirales (exemplo son a eficacia, tolerabilidade, resistencias, interaccións). Na actualidade as guías clínicas nacionais e internacionais recomendan tratar a todos os pacientes infectados polo VIH independentemente de seu estado inmunolóxico. As pautas recomendadas no momento actual para o tratamento de inicio na infección polo VIH consisten na combinación de tres fármacos que inclúen dous inhibidores da transcriptasa inversa análogos de nucleósidos ou nucleótidos (ITIAN) asociados a un inhibidor da integrasa (INI) ou un inhibidor da transcriptasa inversa non análogo de nucleósido (ITINN) ou un inhibidor da proteasa potenciado (IP). Baseándose no bo perfil de eficacia y seguridade demostrado nos ensaios clínicos, os INI (raltegravir, elvitegravir, dolutegravir e bictegravir) posicionáronse como opcións preferentes fronte ó resto de familias, adquirindo gran relevancia o seu uso na práctica clínica. Resumen 12 Polo tanto, é importante coñecer as características epidemiolóxicas, clínicas e virolóxicas, así como o perfil de eficacia e tolerabilidade da terapia antirretroviral baseada en INI na nosa área sanitaria para establecer e optimizar as estratexias de manexo clínico dos pacientes con infección por VIH. Na presente tese desenrólanse tres estudos: - Estudo 1. Analizáronse as características epidemiolóxicas, clínicas e inmunovirolóxicas e a eficacia e tolerabilidade do tratamento antirretroviral nos pacientes con infección por VIH nos que foron prescritos os INI Dolutegravir e Elvitegravir/cobicistat na área sanitaria da Coruña durante o período xaneiro 2015 a xaneiro 2017. Mais do 90% dos pacientes naïve e pretratados tiveron supresión virolóxica ás 48 semanas de iniciar o tratamento. Durante o seguimento, observouse un alto porcentaxe de abandonos por efectos adversos non descritos previamente nos ensaios clínicos, especialmente con DTG (10.2%). Concretamente, o sexo feminino e o tratamento con DTG se identificaron como factores de risco para a interrupción por efectos adversos. No caso de DTG, as interrupcións de tratamento se relacionaron principalmente con alteracións neuropsiquiátricas (70.4%) e EVG/c con molestias gastrointestinais (50.0%). Identificáronse como factores de risco de suspensión do tratamento debido a efectos adversos neuropsiquiátricos as terapias baseadas en DTG, especialmente en combinación cos ITIAN abacavir/lamivudina. - Estudo 2. Avaliouse a resposta virolóxica en pacientes VIH naïve que iniciaron tratamento antirretroviral baseado en INI desde xaneiro de 2015 hasta febreiro de 2017 e que estaban infectados cos dous subtipos xenéticos mais frecuentes na nosa poboación, o subtipo B (54.4%) e o subtipo F (27.2%). A taxa de supresión virolóxica foi significativamente menor nos pacientes infectados polo subtipo F do VIH en comparación cos pacientes infectados polo subtipo B na semana 12 (25.0% vs. 75.0%) e 24 (59.1% vs. 95.0%) do tratamento. A infección polo subtipo F foi o único factor predictor independente de unha peor resposta ó tratamento con INI na semana 24. - Estudo 3. Avaliaronse as modificacións no perfil lipídico dos pacientes VIH naïve e pretratados que iniciaron tratamento con EVG/c/FTC/TAF e EVG/c/FTC/TDF dende xaneiro 2015 ata xaneiro 2018. Os pacientes que iniciaron tratamento con EVG/c/FTC/TAF tiveron un empeoramento dos valores de colesterol total, LDL-C e triglicéridos tras 48 semanas de tratamento; non houbo cambios significativos nestes parámetros no grupo a tratamento con EVG/c/FTC/TDF. No seguimento dos pacientes do grupo con EVG/c/FTC/TAF comprobouse que un alto porcentaxe tivo niveles de lípidos por encima do rango normal ás 48 semanas (63.1% niveis por encima do rango normal de colesterol total e 56.2% de LDL-C) e un 11.9% dos pacientes neste grupo tiveron que recibir fármacos hipolipemiantes. No análise multivariante realizado neste grupo, o cociente colesterol total/HDL-C durante as primeiras 48 semanas de tratamento asociouse con una maior probabilidade de prescrición de hipolipemiantes [OR 1.6 (95% CI 1.12–2.52); p=0.011]. En resumo, os resultados obtidos durante o desenrolo desta tese permitiron un coñecemento detallado da eficacia e seguridade dos tratamentos antirretrovirais baseados en INI nos pacientes tratados de nosa área sanitaria. Entre os principais achados hai que destacar o alto porcentaxe de abandonos por efectos adversos non descritos previamente en ensaios clínicos, especialmente con DTG (10.2%), a peor resposta virolóxica dos pacientes infectados polo subtipo F do VIH ós inhibidores da integrasa en comparación co subtipo B e o empeoramento do perfil lipídico cando os pacientes reciben EVG/c/FTC/TAF.[Abstract] Human immunodeficiency virus (HIV) uses different types of cells as a target of infection, with CD4+ T lymphocytes being the main target. HIV infects cells of the immune system, destroying or impairing their function. Infection with the virus results in progressive deterioration of the immune system, leading to the appearance of diseases defining the acquired immune deficiency syndrome (AIDS). The introduction of high-efficacy antiretroviral therapy (ART) has drastically changed the prognosis of HIV infection, with a significant reduction in AIDS-related morbidity and mortality, making HIV infection a chronic disease. The evolution of HIV infection in countries with access to treatment is conditioned by several factors: related to the patient (i.e. epidemiological factors, immunological status, adherence to treatment), to the virus (i.e. plasma viral load, presence of drug resistance mutations) or to antiretroviral drugs (i.e. efficacy, tolerability, interactions). Nowadays, national and international clinical guidelines recommend treating all HIV-infected patients regardless of their immunological status. National and international guidelines for initial treatment of HIV-infected patients recommend the use of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) plus a third active drug: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a boosted protease inhibitor (PI). Based on the good efficacy and safety profile demonstrated in clinical trials, the INSTI (raltegravir, elvitegravir, dolutegravir and bictegravir) have been positioned as preferred options compared to the rest of families, acquiring great relevance its use in clinical practice. Therefore, it is important to know the epidemiological, clinical and virological characteristics, as well as the efficacy and tolerability of antiretroviral therapy based on INI in our health area to establish and optimize the clinical management strategies of HIV patients. In this thesis, three studies have been developed: - Study 1. Epidemiological, clinical and immunovirological characteristics, and efficacy and tolerability of antiretroviral treatment in HIV patients with Dolutegravir and Elvitegravir/cobicistat prescription in the health area of A Coruña during the period January 2015 to January 2017 were described. More than 90% of naïve and experienced patients had virological suppression after 48 weeks of treatment. During follow-up, a high percentage of adverse events discontinuations not previously described in clinical trials has been observed, especially with DTG (10.2%). Female gender and DTG treatment were identified as risk factors for AE discontinuation. In the case of DTG, treatment interruptions were mainly related to neuropsychiatric disturbances (70.4%) and EVG/c with gastrointestinal discomfort (50.0%). DTG-based therapies, especially in combination with the NRTI abacavir/lamivudine, were associated with an increased risk of treatment discontinuation due to neuropsychiatric adverse events. - Study 2. Virological response in HIV naïve patients who initiated antiretroviral treatment based on INSTI from January 2015 to February 2017 and who were infected with the two most frequent genetic subtypes in our population, subtype B (54.4%) and subtype F (27.2%), were evaluated. Virological response rates to antiretroviral therapy based on integrase inhibitor were significantly lower among F subtypes compared with B subtypes at weeks 12 (25.0% vs. 75.0%) and 24 (59.1% vs. 95.0%). Subtype F was independently associated with poor virological response to INI-based regimens at 24 weeks. - Study 3. Changes in the lipid profile of naïve and experienced HIV patients who started treatment with EVG/c/FTC/TAF and EVG/c/FTC/TDF from January 2015 to January 2018 were evaluated. A significantly negative influence in the lipid profile parameters were observed after 48 weeks of treatment with EVG/c/FTC/TAF, while these parameters remained stable in the EVG/c/FTC/TDF group. During follow-up, a greater proportion of patients had lipid levels above the normal range (63.1% TC, 56.2% LDL-C) and new lipid-modifying drugs were prescribed (11.9%) in the EVG/c/FTC/TAF group. In this group, the mean total cholesterol to HDL-C ratio in the first 48 weeks of the study treatment was associated with a higher likelihood of lipid-lowering prescription in multivariate analysis [OR 1.6 (95% CI 1.12–2.52); p=0.011]. In summary, the results obtained during the development of this thesis have allowed a detailed knowledge of the efficacy and safety of INSTI-based regimens in patients of our health area. Among the main findings, we must highlight the high percentage of discontinuations due to adverse events not previously described in clinical trials, especially with DTG (10.2%), the worst response to the INSTI in subtype F HIV infected patients compared with subtype B and the worsening of lipid profile when patients receive EVG/c/FTC/TAF

Late HIV Diagnosis but Earlier Antiretroviral Treatment Initiation in Northwest Spain: Impact of Current Treatment Guidelines

[Abstract] Background: Current HIV treatment guidelines recommend antiretroviral treatment (ART) initiation for all HIV-infected individuals regardless of CD4 count. This study evaluates the immunological and virological status and the clinical characteristics of patients who have started ART in the last 8 years in the Northwest of Spain. Methods: All HIV-infected patients who have started ART between January 2009 and December 2016 at a reference hospital in the Northwest of Spain were included in this retrospective observational study. Epidemiological, clinical, and immunovirological features and antiretroviral drugs used for initiation were recorded. A statistical analysis was performed using SPSS version 19 software. Categorical and continuous variables were compared by the specific statistical tests, and a logistic regression model was used to identify time associated with Center for Disease Control and Prevention (CDC) categories change. Results: A high proportion of HIV-infected patients (66.7%) had initiated ART with CD4 counts <350 cells/mm3 in the last 8 years. From these, most of them (68.3%) had <350 CD4 counts at first contact with HIV specialist medical team, 12.2% had no indications for ART initiation in the last clinic visit before ART initiation according to the national guidelines at that moment, 11.0% were lost to follow-up because of lack of compliance with scheduled visits and 8.5% of patients refused treatment. A logistic regression model showed that a delay of one month since the first contact with HIV specialist medical team to ART initiation involves a risk of worsening in the CDC clinical category (odds ratio: 1.02 [95% confidence interval: 1.012-1.029]; P < .001). A trend towards an earlier start of ART was observed during 2015 and 2016, likely influenced by the last treatment guidelines recommendations. Conclusion: High proportion of HIV-infected patients (66.7%) had initiated ART with CD4 counts <350 cells/mm3 in the last 8 years. The main reasons for this problem were analyzed and an important rate of late diagnosis was identified. However, a trend towards an earlier start of ART was observed during 2015 and 2016, likely influenced by the last treatment guidelines recommendations. These findings highlight the need to promote and facilitate HIV testing to reduce the late diagnosis as well as counseling on HIV prevention, treatment, and linkage care

Influence of drug–drug interactions on effectiveness and safety of direct-acting antivirals against hepatitis C virus

[Abstract] Objectives Direct-acting antivirals are the recommended treatment for hepatitis C-infected patients. Drug–drug interactions with concomitant treatments can cause lack of effectiveness and/or safety. The objective of this study is to characterise drug–drug interactions of direct-acting antivirals and to analyse their influence both on the effectiveness of antiviral treatment and on the overall safety of pharmacological treatment in hepatitis C-infected patients. Methods Observational and prospective cohort study for 3 years in the pharmaceutical care outpatient consultation of a general hospital, undertaking detection, evaluation and management of drug–drug interactions by clinical pharmacists and physicians. The main outcome measures were sustained virologic response at week 12 for effectiveness and serious drug-related adverse events for safety. Multivariate statistical analysis applied to: (a) patient basal characteristics related to presence of drug–drug interactions; (b) previous antiviral treatments, viral genotype, cirrhosis, decompensations and presence of drug–drug interactions related to the effectiveness of direct-acting antivirals. Results Of a total of 1092 patients, the majority of them were men, around 60 years old and HCV-genotype 1 mono-infected, with a high basal viral load, naive to antiviral treatment, treated with ledipasvir/sofosbuvir and without cirrhosis. 24.5% had drug–drug interactions. Proton pump inhibitors were the concomitant drugs that caused the most drug–drug interactions. Age ≥65 years and direct-acting antivirals based on protease inhibitors were independently related to the presence of drug-drug interactions (p≤0.012). All (100%) of the therapeutic recommendations based on detected drug–drug interactions were implemented; 97.7% of patients with interactions versus 99.0% without them reached sustained virologic failure (p=0.109). The serious adverse events rates were 1.5% and 1.3% in patients with and without drug-drug interactions, respectively (p=0.841). Conclusions Drug–drug interactions are frequent among hepatitis C-infected patients receiving treatment with direct-acting antivirals. However, the collaboration between physicians and clinical pharmacists makes it possible to detect, evaluate, avoid or clinically manage these drug–drug interactions, in order to maintain whole treatment therapeutic safety and the effectiveness of direct-acting antivirals

Liver-related events and mortality among elderly patients with advanced chronic hepatitis C treated with direct-acting antivirals

Research article[Abstract] BACKGROUND: Direct-acting antivirals (DAAs) are effective in patients aged ≥65 years. However, little is known about the effects of DAAs on survival, liver decompensation and development of hepatocellular carcinoma (HCC). OBJECTIVE: To compare the incidence of liver-related events and mortality between patients aged ≥65 and <65 years. METHODS: Prospective study comparing patients aged ≥65 and <65 years treated with DAAs. The incidence of liver-related events and mortality, and HCC was compared between age groups. RESULTS: Five hundred patients (120 aged ≥65 and 380 aged <65 years) were included. The incidence of liver-related events was 2.62 per 100 patient-years (py) in older and 1.41/100 py in younger patients. All-cause mortality was 3.89 and 1.27/100 py in older and younger patients, respectively. The respective liver-related mortality rates were 1.12 and 0.31/100 py. In patients with cirrhosis (stage F4), all-cause mortality (P = 0.283) and liver-related mortality (P = 0.254) did not differ between groups. All five liver-related deaths were related to multifocal HCC. The incidence of HCC was 1.91 and 1.43 per 100 py in the older and younger groups, respectively (P = 0.747). The diagnosis of HCC was 8 months after the end of treatment. CONCLUSIONS: The incidence of liver-related events and liver-related mortality was low in older people treated with DAAs and was similar to that in younger patients. The extra mortality in people aged ≥65 years treated with DAAs seems to be secondary to non-liver-related causes. These results support the utilization of DAAs in patients aged ≥65 years.Instituto de Salud Carlos III; JR17/0002

Clinical experience with the integrase inhibitors Dolutegravir and Elvitegravir in HIV-infected patients: efficacy, safety and tolerance

[Abstract] Two integrase inhibitors (INSTIs), dolutegravir (DTG) and elvitegravir/cobicistat (EVG/COBI), have joined recently the pharmacotherapy arsenal against HIV. This study evaluated the efficacy and tolerability of these INSTIs in the last two years. A retrospective observational study in patients who started DTG or EVG/COBI from January 2015 to January 2017 at a reference hospital in north-western Spain was done. Epidemiological, clinical and immunovirological data were recorded. A statistical analysis was performed with SPSS software. A total of 542 DTG (n = 275)- or EVG/COBI (n = 267)-based therapies were initiated during the study period. Overall, more than 90% of naïve and pre-treated patients had virological suppression in both groups after 48 weeks of initiation of treatment per-protocol snapshot analysis. During follow-up, 10.2% of patients were treated with DTG and 4.5% of those treated with EVG discontinued due to adverse events (AE). In the case of DTG mainly related to neuropsychiatric disturbances (70.4%) and for EVG/COBI with gastrointestinal discomfort (50%). Female sex [HR 2.255 (95%CI 1.121–4.535), p = 0.023] and DTG treatment [HR 2.453 (95%CI 1.221–4.931), p = 0.012] were associated with AE discontinuations. Specifically for neuropsychiatric events, DTG treatment [HR 5.906 (95%CI 1.954–17.846), p = 0.002] and receiving abacavir/lamivudine/DTG [HR 4.380 (95%CI 1.348–14.233), p = 0.014] were identified as predictive risk factors for treatment discontinuations in two different multivariate analyses. A high percentage of AE discontinuations not previously described in clinical trials has been observed, especially with DTG. Female gender and DTG treatment were identified as risk factors for AE discontinuation. DTG-based therapies, especially in combination with abacavir/lamivudine, were associated with an increased risk of treatment discontinuation due to neuropsychiatric AE.Instituto de Salud Carlos III; CPII14/00014Instituto de Salud Carlos III; PI10/02166Instituto de Salud Carlos III; PI13/02266Instituto de Salud Carlos III; CM13/00328Instituto de Salud Carlos III; CM15/00233Instituto de Salud Carlos III; PI16/0215

Efectividad y seguridad de daclatasvir/ sofosbuvir con o sin ribavirina en pacientes infectados por el genotipo 3 del virus de la hepatitis C: resultados en práctica clínica real

[Abstract] OBJECTIVE: Direct-acting antivirals have shown high efficacy in all hepatitis C virus (HCV) genotypes, but genotype 3 (G3) treatments continue to be a challenge, mainly in cirrhotic patients. The aim of this study is to analyse effectiveness and safety of daclatasvir associated with sofosbuvir with or without ribavirin in G3-HCV infected patients in real clinical practice. METHODS: An observational, prospective, cohort study over 2.5 years, in G3-HCV infected adult patients, in all fibrosis stages including patients with decompensated cirrhosis. Treatment was a combination of sofosbuvir 400 mg/day + daclatasvir 60 mg/day, with or without a weight-adjusted dosing of ribavirin for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response rates 12 weeks after therapy (SVR12). The primary safety endpoint was treatment withdrawal rates secondary to severe adverse events. RESULTS: A total of 111 patients were enrolled, 32.4% cirrhotics and 29.9% treatment-experienced. The global SVR12 rate was 94.6%, while the SVR12 rate in F3-4 fibrosis stage patients was 90.8% versus 100% in patients with F0-2 fibrosis (p=0.03). In cirrhotic patients, SVR12 was 100% versus 40% depending on whether ribavirin was added or not to daclatasvir/sofosbuvir (p=0.001). No other patient or treatment basal variables influenced the treatment effectiveness. No patient treatment withdrawal secondary to severe adverse events was observed. CONCLUSIONS: Daclatasvir/sofosbuvir ± ribavirin is highly effective in G3-HCV infected patients. Advanced degrees of fibrosis significantly decrease the effectiveness of this treatment, which motivates the need for the addition of ribavirin in cirrhotic patients. The regimen was safe and well tolerated.[Resumen] OBJETIVOS: Los antivirales de acción directa han demostrado una alta eficacia en todos los genotipos del virus de la hepatitis C (VHC), pero los tratamientos para el genotipo 3 (G3) siguen siendo un desafío, principalmente en pacientes cirróticos. El objetivo de este estudio es analizar la efectividad y la seguridad del daclatasvir asociado con sofosbuvir con o sin ribavirina en pacientes infectados por G3-VHC en la práctica clínica real. PACIENTES Y MÉTODOS: Estudio observacional, prospectivo, de cohorte de más de 2,5 años, en pacientes adultos infectados con G3-VHC, en todos los estadios de fibrosis, incluidos los pacientes con cirrosis descompensada. El tratamiento fue una combinación de sofosbuvir 400 mg / día + daclatasvir 60 mg / día, con o sin una dosis de ribavirina ajustada por peso durante 12 o 24 semanas. El criterio de valoración principal de eficacia fue la tasa de respuesta virológica sostenida 12 semanas después del tratamiento (RVS12). La variable principal de seguridad fue la tasa de suspensiones de tratamiento secundaria a eventos adversos graves. RESULTADOS: Se incluyeron 111 pacientes, 32.4% cirróticos y 29.9% con experiencia previa de tratamiento antiviral. La tasa global de RVS12 fue del 94,6%, mientras que la tasa de RVS12 en pacientes con estadio de fibrosis F3-4 fue del 90,8% frente al 100% en pacientes con fibrosis F0-2 (p = 0,03). En pacientes cirróticos, la RVS12 fue del 100% en comparación con el 40%, dependiendo de si se agregó o no ribavirina a daclatasvir / sofosbuvir (p = 0,001). Ninguna otra variable basal del paciente o del tratamiento influyó en la efectividad del tratamiento. No se observó ninguna suspensión del tratamiento secundario a eventos adversos graves. CONCLUSIONES: Daclatasvir / sofosbuvir ± ribavirina es altamente efectivo en pacientes infectados por G3-VHC. Los grados avanzados de fibrosis disminuyen significativamente la efectividad de este tratamiento, lo que motiva la necesidad de la adición de ribavirina en pacientes cirróticos. El régimen fue seguro y bien tolerado

Teleconsultation for the pharmaceutical care of HIV outpatients in receipt of home antiretrovirals delivery: clinical, economic, and patient-perceived quality analysis

Observational study[Abstract] Background/Introduction: Pharmacist teleconsultations, combined with home drug delivery or mail-order pharmacy (MOP), can help hospital outpatients with difficulties accessing treatment. The objectives of this study are to describe a teleconsultation protocol and to evaluate clinical, economic, and patient-perceived quality results. Materials and Methods: A cohort observational study was carried out for 3 years on HIV outpatients. Clinical variables were adherence, plasma HIV-RNA, and CD4+ levels. A pharmacoeconomic analysis was carried out through a cost-minimization study. Patient-perceived quality was assessed through a satisfaction survey. Simple random sampling was performed for 95% safety, accuracy ±1%, and losses ±20%. Results: The 38 participants (sample size) consisted of 82% male patients, aged 44.7 ± 8.4 years. There were 854 teleconsultations and 100% treatment adherence. All HIV outpatients kept virally suppressed (p = 1.00) and maintained a controlled immunological level (p = 0.87). The economic evaluation revealed 137 ± 23 € patient/year costs-saved and 18.5 ± 7.2 h/patient/year working time gained. Patient-perceived quality average score was >9.4 out of 10 in all items; the most valued factors were the saving of direct costs and reconciliation with work commitments (45%) and the least valued attributes were making the payment for the shipment and having to adjust to a telephone appointment (41%). Discussion/Conclusions: A teleconsultation protocol associated with home antiretrovirals delivery or MOP obtains a high degree of satisfaction from the HIV hospital outpatients receiving treatment, without repercussions on the therapeutic objectives and with the saving of important direct costs for the patient and indirect costs in relation to labor productivity

Darunavir/cobicistat maintains the effectiveness of darunavir/ritonavir in HIV-infected patients under mono or dual therapy

[Abstract] OBJECTIVES: Darunavir/ritonavir (DRV/r) in mono or dual therapy has proven efficacy in selected patients. The aim of this study was to evaluate the efficacy of switching from DRV/r to DRV/cobicistat (DRV/c) in patients under mono or dual therapy. METHODS: This was a prospective multicenter cohort study of patients using DRV/r under mono or dual therapy plus lamivudine who changed to DRV/c maintaining the previous regimen. All patients had a controlled HIV viral load (<50 copies/ml) when switched and were examined every 12 weeks. The primary end-point was the percentage of participants without virological failure (VF) at week 48 in the intent-to-treat analysis. The CD4 cell count and concentrations of cholesterol, triglyceride, and creatinine were measured from baseline to week 48. RESULTS: A total of 162 patients were included: 68.5% were men, and their mean age was 46 ± 12 years. Seventy (43.2%) patients were treated with DRV/r monotherapy, and 92 (56.8%) were treated with DRV/r plus lamivudine. The efficacy at week 48 was 95.1% (95% CI: 90.6%-97.5%) in the intent-to-treat analysis and 98.7% (95.5-99.6%) in the on-treatment analysis. Two VFs were documented but without development of resistance mutations. No significant changes were found in the lipid profile. Creatinine concentration increased significantly by 0.07 mg/dl (0.04-0.10, P < 0.001). CONCLUSIONS: Switching from DRV/r to DRV/c in patients under mono or dual therapy is safe and effective.Instituto de Salud Carlos III; JR17/0002

Effectiveness and Safety of Sofosbuvir/Velpatasvir ± Ribavirin vs Glecaprevir/Pibrentasvir in Genotype 3 Hepatitis C Virus Infected Patients

[Abstract] Objectives. Sofosbuvir/velpatasvir±ribavirin (SOF/VEL±RBV) and glecaprevir/pibrentasvir (GLE/PIB) are the drug combinations of choice for treating individuals with genotype 3 hepatitis C virus (G3-HCV) infection. The objective of this study was to evaluate the effectiveness and safety of SOF/VEL±RBV compared with GLE/PIB for treating G3-HCV infection under routine clinical practice conditions. Methods. We conducted a prospective observational cohort study of individuals with G3-HCV infection who initiated treatment with SOF/VEL +/-RBV or GLE/PIB between April 2017 and July 2018. Prisoners and children were excluded. The outcome variable of effectiveness was sustained virological response 12 weeks after completing treatment (SVR12). The safety variable was withdrawal secondary to severe adverse events (SAEs). Covariates included sex, age, HIV co-infection, previous liver transplant, cirrhosis, hepatic fibrosis and previous antiviral treatment. Statistical significance was calculated using Fisher’s exact test or the Mann–Whitney U-test. Results. A total of 76 patients were included in the analysis, of whom 46 were treated with SOF/VEL±RBV and 30 were treated with GLE/PIB. No baseline differences were observed between treatment groups with respect to age, sex, HIV co-infection, fibrosis stage, cirrhosis and previous antiviral treatment. Of the patients treated with SOF/VEL±RBV and GLE/PIB, 95.7% and 96.7% reached SVR12, respectively (P=0.7). Of patients with and without cirrhosis, 83.3% and 98.4% reached SVR12, respectively (P=0.09). Of the patients with low-grade hepatic fibrosis (F0-2) and advanced fibrosis (F3-4), 100% and 85.7% reached SVR12, respectively (P=0.03). In treatment-naïve and treatment-experienced patients, 95.7% and 100% reached SVR12, respectively (P=0.57), without significant differences independent of the treatment group (P=0.28 for SOF/VEL±RBV; P=0.18 for GLE/PIB). The incidence of AEs was 21.1% (95% CI 11.3% to 30.9%). None of the patients developed an SAE or required antiviral treatment withdrawal. Conclusions. SOF/VEL±RBV or GLE/PIB are safe and effective for treating G3-HCV-infections, with a lower effectiveness in patients with advanced fibrosis F3-4

Real life experience with direct-acting antivirals agents against hepatitis C infection in elderly patients

Short communication[Abstract] Background. New direct-acting antivirals agents (DAAs) are very safe and well tolerated. Objectives. The purpose of this study is to analyse the efficacy and safety of DAAs in elderly patients, who have co-morbidities and are on chronic medications. Study design. All HCV-infected patients over 65 years old in clinical follow-up at two Hospitals in Spain who initiated anti-HCV therapy were included (August 2012–October 2015). Results. A total of 120 HCV mono-infected patients were recorded. Mean age of patients was 72.6 ± 7.4 years. There were 53.3% women and GT1b was the most frequent (83.3%); 64.2% had cirrhosis and 42.5% were treatment experienced. Ombitasvir + Paritaprevir/r ± Dasabuvir ± Ribavirin (RBV) and sofosbuvir/ledipasvir ± RBV were the most frequently used regimens. Weight-adjusted dosing of RBV was included in 61.7% and 43.6% of them required a dose reduction. Most of the patients (86.7%) had concomitant chronic medication and in 35.8% adjustment was necessary. Adverse events (AE) were seen in 65% of the patients; more frequent when a protease inhibitor (PI) was being used. The sustained virological response (SVR12) per ITT was 88.3%. Only 3 patients discontinued treatment and 2 patients died. Conclusions. High rates of SVR12 (88.3%) were observed among elderly patients with DAAs-based regimens. The presence of AE was frequent (65%). The majority of these patients (86.7%) had concomitant medication that required adjustment in 1/3 of them. These findings highlight the high rates of response to DAAs in the elderly HCV-population. However, special caution must be taken when using RBV and a PI.Instituto de Salud Carlos III; CPII14/00014Instituto de Salud Carlos III; PI10/02166Instituto de Salud Carlos III; PI13/02266Instituto de Salud Carlos III; CM15/0023