Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) after switching from a stable regimen consisting of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC) plus a third antiretroviral (ARV) agent in participants harboring the archived nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance mutation M184V and/or M184I in human immunodeficiency virus (HIV) -1 reverse transcriptase. This is a two part study. If the rate of virologic failure in Part 1 is deemed acceptable, once the internal data monitoring committee officially completes the interim review, the study will continue to Part 2.

Official Title
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A Phase 3b Open-Label Pilot Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adult Subjects Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: E/C/F/TAF


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented historical genotype report showing mutation M184V and/or M184I (mixtures are acceptable) in reverse transcriptase. Individuals must not have any primary integrase strand transfer inhibitor (INSTI) or primary protease inhibitor (PI) resistance mutations present on historical genotype; non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations are allowed. Proviral deoxyribonucleic acid (DNA) test must not have additional exclusion resistance mutations against PIs, NRTIs and INSTIs Part 1: Historical genotype report must show mutation M184V and/or M184I in reverse transcriptase WITHOUT any other NRTI resistance mutation (including thymidine analogue-associated mutations [TAMs] [TAMs are: M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E/N/R], K65R, K70E, T69 insertion, and Q151M mutation complex [A62V, V75I, F77L, F116Y, Q151M]) Part 2 (after the interim efficacy review): Historical genotype report must show M184V and/or M184I in reverse transcriptase WITH or WITHOUT 1 or 2 TAMs. Evidence of K65R, K70E, T69 insertion and/or Q151M mutation complex will not be eligible Currently receiving an ARV regimen consisting of FTC/TDF or ABC/3TC in combination with one third ARV agent for ≥ 6 consecutive months preceding the screening visit Documented plasma HIV-1 ribonucleic acid (RNA) levels < 50 copies/mL for ≥ 6 months preceding the screening visit Plasma HIV-1 RNA levels < 50 copies/mL at screening visit Estimated glomerular filtration rate (GFR) ≥ 30 mL/min according to the Cockcroft-Gault formula for creatinine clearance A female individual is eligible to enter the study if it is confirmed that she is: not pregnant of non-childbearing potential stopped menstruating for ≥ 12 months of childbearing potential and agrees to utilize the protocol-specified method of contraception or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following discontinuation of study drugs Male individuals must agree to use the protocol-specified method(s) of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from screening throughout the study period and for 30 days following the last study drug dose Male individuals must agree to refrain from sperm donation from first dose until at least 30 days after the last study drug dose Key Exclusion Criteria: Individuals will have no evidence of previous virologic failure on a PI/r or INSTI-based regimen (with or without resistance to either class of ARV). Individuals may have evidence of prior virologic failure on only an NNRTI plus 2 NRTI-based regimen Individuals on a current PI/r-based regimen will have no evidence of previous use of any approved or experimental integrase strand transfer inhibitor (INSTI) (for any length of time) Hepatitis C infection that would require therapy during the study Hepatitis B surface antigen (HBsAg) positive Individuals with clinical evidence of decompensated cirrhosis (eg, ascites, encephalopathy, variceal bleeding) Have an implanted defibrillator or pacemaker A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non invasive cutaneous squamous carcinoma. Individuals with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 and must not be anticipated to require systemic therapy during the study Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: E/C/F/TAF<br>Participants with M184V and/or M184I mutations in reverse transcriptase and without any other NRTI resistance mutation switched from their current human immunodeficiency virus (HIV) treatment regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF (150/150/200/10 mg) FDC tablet orally once daily for 48 weeks. Allowed third agents include: lopinavir/ritonavir (LPV/r), atazanavir + ritonavir (ATV+RTV), atazanavir+cobicistat (ATV+COBI), darunavir + ritonavir (DRV+RTV), darunavir + cobicistat (DRV+COBI), fosamprenavir + ritonavir (FPV + RTV), saquinavir + ritonavir (SQV + RTV), atazanavir (ATV) (no booster) efavirenz (EFV), rilpivirine (RPV), nevirapine (NVP), etravirine (ETR), raltegravir (RAL) or dolutegravir (DTG). | Drug: E/C/F/TAF<br>* 150/150/200/10 mg FDC tablets administered orally once daily<br>* Other names: Genvoya®;|
| Experimental: Part 2: E/C/F/TAF<br>Participants with M184V and/or M184I mutations in reverse transcriptase and with or without 1 or 2 TAMs switched from their current HIV treatment regimen consisting of FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF (150/150/200/10 mg) FDC tablet orally once daily for 48 weeks. Allowed third agents include: LPV/r, ATV+RTV, ATV+COBI, DRV+RTV, DRV+COBI, FPV + RTV, SQV + RTV, ATV (no booster) EFV, RPV, NVP, ETR, RAL or DTG. | Drug: E/C/F/TAF<br>* 150/150/200/10 mg FDC tablets administered orally once daily<br>* Other names: Genvoya®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/mL at Week 12 as Defined by Pure Virologic Response (PVR) | The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 12 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values ≥ 50 copies/mL or the last available HIV-1 RNA value ≥ 50 copies/mL during the study followed by premature discontinuation from the study. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Emergence of New Mutations in HIV-1 Reverse Transcriptase and Integrase | Development of new resistance mutations was assessed in participants who developed virologic failure, defined as 2 consecutive HIV-1 RNA result ≥ 50 copies/mL at any point in the study or with HIV-1 RNA ≥ 50 copies/mL at last visit. | Day 1 up to 48 weeks | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using PVR | The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 24 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values ≥ 50 copies/mL or the last available HIV-1 RNA value ≥ 50 copies/mL during the study followed by premature discontinuation from the study. | Week 24 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using PVR | The percentage of participants with PVR for HIV-1 RNA cutoff at 50 copies/mL at Week 48 was summarized. PVR was the percentage of participants who did not have a confirmed virologic rebound. Virologic rebound was defined as 2 consecutive HIV-1 RNA values ≥ 50 copies/mL or the last available HIV-1 RNA value ≥ 50 copies/mL during the study followed by premature discontinuation from the study. | Week 48 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 71 and 98 (inclusive). | Week 12 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 24 window was between Day 141 and 210 (inclusive). | Week 24 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 295 and 378 (inclusive). | Week 48 | 
| Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 12 Using the FDA Snapshot Analysis | The percentage of participants with HIV-1 RNA < 20 copies/mL at Week 12 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 71 and 98 (inclusive). | Week 12 | 
| Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 24 Using the FDA Snapshot Analysis | The percentage of participants with HIV-1 RNA < 20 copies/mL at Week 24 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 24 window was between Day 141 and 210 (inclusive). | Week 24 | 
| Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 48 Using the FDA Snapshot Analysis | The percentage of participants with HIV-1 RNA < 20 copies/mL at Week 48 was also analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Week 12 window was between Day 295 and 378 (inclusive). | Week 48 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Failure (M = F) Approach | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was analyzed using the M = F approach. In this approach, all missing data was treated as HIV-1 RNA ≥ 50 copies/mL. | Week 12 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = F Approach | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was analyzed using the M = F approach. In this approach, all missing data was treated as HIV-1 RNA ≥ 50 copies/mL. | Week 24 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = F Approach | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the M = F approach. In this approach, all missing data was treated as HIV-1 RNA ≥ 50 copies/mL. | Week 48 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the Missing = Excluded (M = E) Approach | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12 was also analyzed using the M = E approach. In this approach, all missing data was excluded in the computation of the proportions. | Week 12 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the M = E Approach | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 24 was also analyzed using the M = E approach. In this approach, all missing data was excluded in the computation of the proportions. | Week 24 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the M = E Approach | The percentage of participants with HIV-1 RNA < 50 copies/mL at Week 48 was also analyzed using the M = E approach. In this approach, all missing data was excluded in the computation of the proportions. | Week 48 | 
| Change From Baseline in Cluster Determinant 4+ (CD4+) Cell Count at Week 12 |  | Baseline (Day 1); Week 12 | 
| Change From Baseline in CD4+ Cell Count at Week 24 |  | Baseline (Day 1); Week 24 | 
| Change From Baseline in CD4+ Cell Count at Week 48 |  | Baseline (Day 1); Week 48 | 
| Change From Baseline in CD4 Percentage (%) at Week 12 |  | Baseline (Day 1); Week 12 | 
| Change From Baseline in CD4 % at Week 24 |  | Baseline (Day 1); Week 24 | 
| Change From Baseline in CD4 % at Week 48 |  | Baseline (Day 1); Week 48 |