SNPMiner Trials (Home Page)
Report for Mutation Y181I
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
There are 4 clinical trials
Clinical Trials
1 A Phase 2b Study to Select a Once Daily Oral Dose of GSK2248761 in HIV-1 Infected Antiretroviral Therapy Experienced Adults With Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI) Resistance
This 48 week, phase 2b study in 150 HIV-1 infected antiretroviral therapy experienced adult subjects consists of a dose-ranging evaluation of GSK2248761 at blinded doses of 100 mg and 200 mg once daily with a control arm of open-label etravirine (ETV) 200 mg twice daily. The background ART for all three arms will be darunavir/ritonavir (DRV/r) 600 mg/100 mg twice daily plus raltegravir (RAL) 400 mg twice daily. Antiviral activity, safety, PK, and development of viral resistance will be evaluated.
NCT01199731 Infection, Human Immunodeficiency Virus Drug: GSK2248761 100 mg once daily Drug: GSK2248761 200 mg once daily Drug: Etravirine MeSH:Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome
In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled - HIV-1 genotype results with any of the following will be excluded: (1)Any screening genotype with virus showing a Y181 mutation in combination with any other NNRTI resistance-associated mutations, (2) Any screening genotype with virus showing a Y181I or Y188L alone or in combination with any other NNRTI resistance-associated mutations - HIV-1 phenotype results with any of the following will be excluded: (1) Any screening phenotype with virus showing etravirine fold change >10, (2) Any screening phenotype with virus showing darunavir fold change > 20, (3) Any screening phenotype with virus showing raltegravir fold change >1.5 - 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. --- Y181I ---
Primary Outcomes
Description: Plasma for quantitative HIV-1 RNA was collected. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 16 has been presented. A 2 ml plasma was assayed with the real-time NucliSens EasyQ HIV-1 assay (bioMerieux) capable of quantifying as low as 2.5 c/mL by using three modifications to the standard assay: 15 microliters (µl) of extracted eluate, 20 µl of primer, and 5 µl of 2X enzyme in place of standard kit volumes. The validated assay incorporated molecular beacons for detection.
Measure: Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies Per Milliliter (/mL) at Week 16 Time: At Week 16Secondary Outcomes
Description: An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.
Measure: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Time: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)Description: A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of IP). Division of acquired immunodeficiency syndrome (AIDS) toxicity scale for Grading the Severity of Adult and Pediatric Adverse Events Version 1.0 was used for grading i.e. Grade 3=severe and Grade 4=potentially life threatening. Categories with values have been presented. No toxicity-related dose reductions of IP was allowed. IP and background antiretroviral therapy (ART) was restarted as soon as medically appropriate; in general, this was no longer than 14] days after discontinuation (unless Grade 3 or 4 toxicities persisted).
Measure: Number of Participants With Abnormal Clinical Chemistry Laboratory Data With Grade 3 or 4 Treatment-Emergent (TE) Toxicities Time: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)Description: A toxicity was considered to be TE if it was greater than the Baseline grade, and if it had developed or increased post-Baseline in intensity (and prior to the last dose of IP). The hematology parameters included hemoglobin, total neutrophils, and white blood cells (WBC) count. Categories with values has been presented. Grade 3=severe and Grade 4=potentially life threatening. No toxicity-related dose reductions of IP was allowed. IP and background ART was restarted as soon as medically appropriate; in general, this was no longer than 14] days after discontinuation (unless Grade 3 or 4 toxicities persisted).
Measure: Number of Participants With Abnormal Hematology Laboratory Data With Grade 3 or 4 TE Toxicities Time: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)Description: A switch was defined as any ART substitution or addition in the participant's ART regimen. Any ART switch permitted per protocol that was determined necessary and documented prior to the first on-treatment visit where HIV-1 RNA was assessed could occur without penalty. However, any participants with an ART switch not permitted per protocol or ART switch permitted per protocol with a viral load >=50 copies/mL at the time of the decision to switch was made was counted as a non-responder from that point onward for all assessment windows without a viral load measurement collected prior to the switch. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1. The unit is log10 copies per milliliter (log10 copies/mL).
Measure: Change From Baseline in Plasma HIV-1 RNA Prior to Switch of GSK2248761 Time: Baseline (Day 1) and Week 2, 4, 8, 12 and 16Description: A switch was defined as any ART substitution or addition in the participant's ART regimen. Any ART switch permitted per protocol that was determined necessary and documented prior to the first on-treatment visit where HIV-1 RNA was assessed could occur without penalty. However, any participants with an ART switch not permitted per protocol or ART switch permitted per protocol with a viral load >=50 copies/mL at the time of the decision to switch was made was counted as a non-responder from that point onward for all assessment windows without a viral load measurement collected prior to the switch. Change from Baseline was calculated as (observed value - Baseline value ). Baseline was Day 1.
Measure: Change From Baseline in Plasma HIV-1 RNA After Switch of GSK2248761 Time: Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and follow-up Week 4, 8, 12Description: Clinical DP was defined as progression from Baseline HIV disease status:Category A at Baseline to Centers for Disease Control and Prevention(CDC) category B event, category A at Baseline to CDC category C event, category B at Baseline to CDC category C event, category C at Baseline to new CDC category C event or category A, B or C at Baseline to death. Category A consisted of one or more of the conditions like asymptomatic HIV infection, persistent generalized lymphadenopathy and acute (primary) HIV infection with accompanying illness in an adolescent or adult(>13 years) with documented HIV infection. Category B consisted like Bacillary angiomatosis, Candidiasis, oropharyngeal (thrush), Candidiasis, vulvovaginal; persistent, frequent, oral, Herpes zoster etc. Category C included clinical conditions listed like Candidiasis of bronchi, trachea, or lungs, Candidiasis, esophageal, Cervical cancer, Coccidioidomycosis, disseminated or extrapulmonary etc in AIDS surveillance case definition.
Measure: Number of Participants Who Experienced Disease Progression (HIV-associated Conditions, AIDS and Death) Time: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)Description: CD4 is a receptor for the HIV virus. Most of the damage to an AIDS participant's immune system was done by the virus' destruction of CD4+ lymphocytes. Absolute values of CD4+ cell counts after Switch of GSK2248761 has been presented.
Measure: Absolute Values of CD4+ Cell Counts After Switch of GSK2248761 Time: Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and Follow-up Week 4, 8, 12Description: CD4 is a receptor for the HIV virus. Most of the damage to an AIDS patient's immune system is done by the virus' destruction of CD4+ lymphocytes. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1 value.
Measure: Change From Baseline in CD4+ Cell Counts Prior to Switch of GSK2248761 Time: Baseline (Day 1) and Week 2, 4, 8, 12 and 16Description: CD4 is a receptor for the HIV virus. Most of the damage to an AIDS patient's immune system is done by the virus' destruction of CD4+ lymphocytes. Change from Baseline was calculated as (observed value - Baseline value). Baseline was Day 1 value.
Measure: Change From Baseline in CD4+ Cell Counts After Switch of GSK2248761 Time: Baseline (Day 1) and post switch Week 1, 2, 4, withdrawal and Follow-up Week 4, 8, 12Description: An AE is defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
Measure: Number of Participants Who Discontinued Treatment Due to AEs Time: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)Description: Number of participants with ECG of PCI above 480 has been presented. ECG was be performed twice on Day 1 at least 5 minutes apart and following 5 minutes of rest in a semi supine position at ∼1 hour prior to first dose. ECG evaluations at other visits was obtained after dosing, preferably at 2 hours post dosing. An ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and corrected QT (QTc) intervals was used.
Measure: Number of Participants With Electrocardiograph (ECG) With Values of Potential Critical Concern (PCI) Time: Up to follow-up i.e. 2-4 weeks after the last study visit (due to early termination the last visit was on 19 July 2011)2 A Multicenter, Single Arm, Open-Label Study of the Once Daily Combination of Etravirine and Darunavir/Ritonavir As Dual Therapy in Early Treatment-Experienced Patients
This study is a Phase II single arm, open-label, multicenter, study of 50 human immunodeficiency virus-1 (HIV) infected adult patients, all of whom will receive etravirine (ETR) 400mg and DRV/r 800/100mg each given orally once daily. This trial is designed to evaluate the efficacy of the aforementioned ARV regimen, as measured by the percentage of patients with HIV RNA <50 copies/mL at 48 weeks, in early treatment-experienced HIV-infected patients. In addition to general safety parameter measurements, this trial will also assess changes in metabolic, inflammatory, immune restoration, and bone markers. Screening will occur over a 6-week period. The primary endpoint will be assessed at Week 48, and the treatment period is 48 weeks. The end of study endpoint will be met by either completing the Week 48 visit, or by early termination from the study for any reason.
NCT01199939 Human Immunodeficiency Virus (HIV) Drug: Etravirine Drug: Ritonavir Drug: Darunavir MeSH:Acquired Immunodeficiency Syndrome HIV Infections Immunologic Deficiency Syndromes
HPO:Immunodeficiency
Inclusion Criteria: - Male or female patients, aged 18 years or above - Patients with documented HIV-1 infection - On current HAART regimen for at least 12 weeks continuous duration at screening, and with an HIV-1 plasma viral load above 500 HIV-1 RNA copies/mL by site's currently utilized viral load assay (Note: For the purposes of this study, HAART is defined as treatment with a combination of 3 or more HIV antiretroviral medications from at least 2 different classes of medications (NRTIs, NNRTIs, PIs, integrase inhibitors, CCR5 antagonists, fusion inhibitors)) - No more than 2 previous virologic failures while on PI-containing HAART regimens where virologic failure is generally defined as either a lack of suppression of the subjects' viral load to lower limit of quantification (per standard assay historically used in care) after 24 weeks of treatment or, rebound of a previously suppressed viral load (undetectable per investigator's standard of care) to detectable limits and without demonstrated re-suppression on the same regimen - Demonstrated phenotypic sensitivity to both etravirine and darunavir based on resistance testing at Screening (FC= 2.9 for etravirine and FC = 10.0 for darunavir using the PhenoSense GT) - The absence of all of the following Resistance Associated Mutations (RAMS) at baseline: For Darunavir: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, L89V - For Etravirine: L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, G190S - 7. CD4 count = 50 cells/mm3. --- V11I --- --- V32I --- --- L33F --- --- I47V --- --- I50V --- --- I54L --- --- T74P --- --- L76V --- --- I84V --- --- L89V --- --- L100I --- --- E138A --- --- I167V --- --- V179D --- --- V179F --- --- Y181I ---
Primary Outcomes
Description: CVR is defined as confirmed plasma Viral Load of less than 50 human immunodeficiency virus - type 1 (HIV-1) ribonucleic acid (RNA) copies/mL.
Measure: Number of Participants With Confirmed Virologic Response (CVR) at Week 48 Time: Week 48Secondary Outcomes
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 4 Time: Baseline (Day 1) and Week 4Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 8 Time: Baseline (Day 1) and Week 8
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 12 Time: Baseline (Day 1) and Week 12
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 16 Time: Baseline (Day 1) and Week 16
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 20 Time: Baseline (Day 1) and Week 20
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 24 Time: Baseline (Day 1) and Week 24
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 30 Time: Baseline (Day 1) and Week 30
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 36 Time: Baseline (Day 1) and Week 36
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 42 Time: Baseline (Day 1) and Week 42
Measure: Change From Baseline in Log10 Plasma Human Immunodeficiency Virus - Type 1 (HIV-1) Viral Load at Week 48 Time: Baseline (Day 1) and Week 48
Description: CVR is defined as confirmed plasma Viral Load of less than 50 human immunodeficiency virus - type 1 (HIV-1) ribonucleic acid (RNA) copies/mL.
Measure: Time to Reach First Confirmed Virologic Response Time: Baseline (Day 1) to Week 48Description: Virologic Failure is defined as participant who is a rebounder or a non-responder. Rebounder participant is defined as a participant who is still in the study at Week 12 and first achieves 2 consecutive virologic responses (<50 copies/mL) followed by 2 consecutive non-responses or a discontinued participant (any reason) for which the last observed time point shows a non-response. Non responder participant is defined as a participant who is still in the study at Week 12 and never achieves 2 consecutive responses.
Measure: Number of Participants With Virologic Failure Time: Baseline (Day 1) to Week 48Measure: Change From Baseline in Cluster of Differentiation 4 (CD4+) and Cluster of Differentiation 8 (CD8+) Cell Counts at Week 48 Time: Baseline (Day 1) and Week 48
3 A Phase IV, Open-label Single-arm Study Investigating the Pharmacokinetics and Pharmacodynamics of the Antiretroviral Combination of Rilpivirine and Ritonavirboosted Darunavir in Therapy-naive HIV-1 Infected Patients.
For patients who are starting to take antiretroviral medication (to treat HIV) for the first time, there are now a variety of different medicines which may be taken together as a combination in order to form an effective treatment which suppresses the virus for prolonged periods of time. Currently, national guidelines recommend the use of two different drugs of one type (the nucleoside/ nucleotide reverse transcriptase inhibitors, NRTI often known as "nukes") with a third drug from one of two other types (either a nonnucleoside reverse transcriptase inhibitor, known as an NNRTI or "nonnuke", or a protease inhibitor, known as a PI) to form a treatment regime of three active drugs. In the UK and Europe, all PIs are given in combination with a small dose of a second PI, ritonavir, which has the effect of boosting the levels of the active PI in the bloodstream. The investigators know from both research studies and patient experience in clinic that a combination of a ritonavirboosted PI with an NNRTI achieves similar results in suppressing the HIV virus, compared to the use of either a PI or NNRTI with 2 NRTI as described above. In this study, the investigators will observe the combination of two licensed antiretroviral medications, ritonavirboosted darunavir(DRV/r) and rilpivirine (RPV), in suppressing virus when given to patients who are commencing treatment for HIV infection for the first time. Both of these drugs are licensed for treatment of patients with HIV in the UK and Europe, and are currently in standard clinical use. The study will monitor this treatment over the first 48 weeks. The investigators will also examine the levels of both drugs in the bloodstream during the first 4 weeks of starting this regimen, to confirm that they remain at levels which the investigators know to be effective against the virus.
NCT01736761 HIV Drug: Darunavir, Ritonavir and Rilpivirine
- Disallowed concomitant medication as per the summary of product characteristics for darunavir or rilpivirine (see section 5.2). - Any genotypic resistance mutations on screening or prior tests to darunavir (V11I, V32I, L33F, I47V, I50V, I54M, I54L, T74P, L76V, I84V and L89V) or rilpivirine (K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, H221Y, F227C, M230I, and M230L). --- V11I --- --- V32I --- --- L33F --- --- I47V --- --- I50V --- --- I54M --- --- I54L --- --- T74P --- --- L76V --- --- I84V --- --- L89V --- --- K101E --- --- K101P --- --- E138A --- --- E138G --- --- E138K --- --- E138R --- --- E138Q --- --- V179L --- --- Y181C --- --- Y181I ---
Primary Outcomes
Description: To describe the rate of virologic suppression after 48 weeks of therapy with the study regime. This will be measured by the proportion of patients with HIV-1 RNA ≤ 40 copies/mL at week 48
Measure: Virologic suppression after 48 weeks of therapy with the study regime Time: 48 weeksSecondary Outcomes
Description: The proportion of enrolled patients with a reduction from baseline in HIV-1 RNA >1 log10 copies /mL at weeks 4, 8, 12 and proportion with HIV-1 RNA ≤400 copies/mL at week 24.
Measure: To explore the virologic response to this combination rilpivirine and ritonavir-boosted darunavir at weeks 4, 8, 12 and 24 of therapy. Time: 24 weeksOther Outcomes
Description: The PK parameters (Cmax, C24, AUC0-24, and t1/2) for darunavir, rilpivirine and ritonavir at steady-state on day 28
Measure: To investigate the plasma pharmacokinetics of darunavir, ritonavir and rilpivirine when given in combination Time: Day 284 A Phase IV 48 Week, Open Label, Pilot Study of Darunavir Boosted by Cobicistat in Combination With Rilpivirine to Treat HIV+ Naïve Subjects (PREZENT)
Current HIV treatment guidelines recommend the use of triple-drug therapy (two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or an integrase inhibitor) for the treatment of antiretroviral (ARV)-naïve patients. With the introduction of highly active antiretroviral therapy (HAART), patients with HIV are living much longer. With the increasing lifespan of persons with HIV, long-term complications from therapy as well as the occurrence of co-morbidities with aging have prompted HCPs to re-think the current treatment paradigm and consider novel combinations of ARVs. All of the currently approved HIV antiretrovirals have been implicated in causing long-term toxicities; however the greatest body of evidence for long-term metabolic effects has implicated the nucleoside reverse transcriptase (NRTI) class. By utilizing a non-NRTI treatment regimen, it is hypothesized that many of these long-term metabolic effects (renal toxicity, bone loss, body fat changes) can be delayed or avoided altogether. The clinical data on novel combinations is currently limited but rapidly growing and has included several combinations that have utilized darunavir. This study will be the first of its kind using the unique combination of darunavir/cobicistat and rilpivirine. Currently, this drug combination is not a recommended option for first time treatment of HIV
NCT02404233 HIV Positive Drug: darunavir/cobicistat Drug: rilpivirine MeSH:HIV Seropositivity
Exclusion Criteria 1. Patient with active AIDS-defining opportunistic infection or disease according to the 1993 CDC AIDS surveillance definition (Clinical Category C) in the 30 days prior to baseline and that, in the opinion of the investigator, would preclude the patient from participating in the study (See Appendix C). 2. Patient has none of the following darunavir-associated RAMs: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V 3. Having documented genotypic evidence of NNRTI resistance at screening or from historical data available in the source documents, i.e. at least one of the NNRTI rams from the following list; K101E, K101P, E138A, E138G, E138K, E138R, E138Q, , V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, or the combination of the K103N and L100I. --- V11I --- --- V32I --- --- L33F --- --- I47V --- --- I50V --- --- I54L --- --- I54M --- --- T74P --- --- L76V --- --- I84V --- --- L89V --- --- K101E --- --- K101P --- --- E138A --- --- E138G --- --- E138K --- --- E138R --- --- E138Q --- --- V179L --- --- Y181C --- --- Y181I ---
Primary Outcomes
Measure: Proportion of patients with plasma HIV-1 RNA <50 copies/mL Time: up to weeks 48Secondary Outcomes
Measure: Proportion of patients with plasma HIV-1 RNA <400 copies/mL at each time point evaluated Time: At week 4, week 12, week 24, week 36, week 48Measure: Number of weeks until HIV RNA <400 copies/mL and <50 copies/mL, respectively Time: At week 4, week 12, week 24