Resumen

Para el tratamiento del virus de la inmunodeficiencia humana tipo 1 (VIH-1), los programas financiados con fondos públicos tienden a seguir las guías de la Organización Mundial de la Salud (OMS) para utilizar un inhibidor no nucleosídico de la transcriptasa reversa (INNTR) combinado con dos inhibidores nucleosídicos de la transcriptasa reversa (INTR) como terapia antirretroviral (TAR) de primera línea; sin embargo, se necesitan más datos sobre las mejores opciones de tratamiento para personas con VIH-1 que presentan fracaso virológico con este régimen de primera línea. El número de pacientes que fracasan en su régimen de primera línea está aumentando, lo que requiere un cambio a tratamiento de segunda línea para reducir la acumulación de mutaciones de resistencia a los fármacos, la progresión de la enfermedad, la transmisión del VIH y la muerte. Las guías de la OMS recomiendan terapia antirretroviral de segunda línea para adultos que consista en dos INTR + un inhibidor de la proteasa (IP) potenciado con ritonavir; atazanavir (ATV) más ritonavir (RTV) o lopinavir (LPV)/RTV son las opciones preferidas de IP potenciado. Este estudio se realiza para demostrar la actividad antiviral no inferior a las 48 semanas de un régimen que contiene dolutegravir (DTG) en comparación con un régimen estándar de tratamiento recomendado por la OMS para segunda línea, LPV/RTV + dos INTR, en pacientes infectados por VIH-1 que fracasan en el tratamiento de primera línea. Este estudio comprende una fase de selección (aproximadamente 28 a 42 días), una fase aleatorizada (día 1 a semana 48 más una extensión de tratamiento de 4 semanas) y una fase de continuación. Aproximadamente 612 sujetos serán aleatorizados 1:1 para recibir DTG 50 mg una vez al día o LPV/RTV (800/200 mg una vez al día o 400/100 mg dos veces al día, según decisión del investigador e indicación local), cada uno añadido a un régimen de base de dos INTR seleccionados por el investigador, al menos uno de los cuales debe ser completamente activo según las pruebas de resistencia viral en la selección. Los sujetos aleatorizados al brazo de LPV/RTV (i) continuarán recibiendo LPV/RTV y completarán el estudio después de la extensión de tratamiento de 4 semanas en la semana 52, o (ii) cambiarán al brazo de DTG antes de completar el estudio en la semana 52 y continuarán teniendo acceso a DTG en la fase de continuación. Los sujetos aleatorizados a recibir DTG que completen exitosamente 52 semanas de tratamiento y los sujetos originalmente aleatorizados a recibir LPV/RTV pero que cambiaron a DTG antes de la semana 52 continuarán teniendo acceso a DTG hasta que sea aprobado localmente y los suministros comerciales estén disponibles para los pacientes, o el paciente ya no obtenga beneficio clínico, o el paciente cumpla un motivo definido por protocolo para la interrupción.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

HIV-1 infected subjects \>=18 years of age.
A female subject may be eligible to enter and participate in the study if she:
is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and \>=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the protocol-defined methods of contraception to avoid pregnancy throughout the study and for at least 2 weeks after discontinuation of all study medication.
HIV-1 infection as documented by HIV-1 RNA \>=400 c/mL at Screening.
Subject has been on a first-line treatment regimen consisting of an NNRTI plus two NRTIs for at least 6 months and is currently experiencing virologic failure to this first-line regimen defined as two consecutive (\>=7 days apart) HIV-1 RNA results of \>=400 c/mL.
Subjects must receive at least one fully active agent within the dual-NRTI background regimen for second line treatment. Fully active is defined by the Screening genotypic resistance report of the central laboratory (or a laboratory contracted by the central laboratory) showing no evidence of full or of partial resistance for a given NRTI which will be taken on study.
Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or current exposure to any PI or INI.
Subject or the subject's legal representative is willing and able to understand and provide signed and dated written informed consent prior to screening.

Criterios de exclusión

Women who are breastfeeding.
Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic or current CD4+ cell levels \<200 cells per cubic millimeter
Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification
Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of the study.
History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial neoplasia; other localized malignancies require agreement between the investigator and the Study medical monitor for inclusion of the subject.
Subjects who in the investigator's judgment, poses a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, systemically administered immunomodulators.
Treatment with any agent, other than licensed ART as allowed above with documented activity against HIV-1 in vitro/vivo within 28 days of first dose of IP. The exception is use of entecavir, in appropriate clinical situations, for treatment of hepatitis B \[e.g. prior intolerance to Tenofovir (TDF), viral resistance to lamivudine (3TC) / Emtricitabine (FTC)\] after discussion and agreement between the investigator and the medical monitor.
Exposure to an experimental drug or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
Any evidence of primary viral resistance to PIs or INIs based on the presence of any major resistance-associated mutation.
The subject's virus does not yield results using genotype at Screening (assay data is essential for eligibility determination).
Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a result.
Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound.
Alanine aminotransferase (ALT) \>=5 times the upper limit of normal (ULN) or ALT \>=3xULN and bilirubin \>=1.5xULN (with \>35% direct bilirubin)

Intervenciones

drug

DTG

DTG is supplied as 50 mg tablets

drug

LPV/RTV

LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV

drug

Two NRTIs

Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC

Ubicaciones

GSK Investigational Site

Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

Ciudad de Buenos Aires, Buenos Aires, Argentina

GSK Investigational Site

Rosario, Santa Fe Province, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Buenos Aires, Argentina

GSK Investigational Site

Córdoba, Argentina

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

DTG

LPV/RTV

Two NRTIs

Ubicaciones

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

GSK Investigational Site

Patrocinadores