Study of Novel Antiretrovirals in Participants With HIV-1

An Umbrella Phase 1b, Open-label, Multi-Cohort Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Novel Antiretrovirals in Participants With HIV-1

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05585307

Enrollment

Registered

2022-10-18

Start date

2022-10-26

Completion date

2024-03-18

Last updated

2025-05-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV-1-infection

Brief summary

Master protocol: The goal of this master clinical trial study is to learn how novel antiretrovirals (medicines that stop the virus from multiplying) affect the human immunodeficiency virus-1 (HIV-1) infection in people living with HIV (PWH). Substudy-01 (GS-US-544-5905-01) will evaluate bavtavirine in PWH. Substudy-02 (GS-US-544-5905-02) will evaluate GS-1720 in PWH. Substudy-03 (GS-US-544-5905-03) will evaluate GS-6212 in PWH.

Detailed description

This umbrella study will begin with a substudy of bavtavirine (Substudy-01), and later substudies GS-1720 (Substudy-02) and GS-6212 (Substudy-03) will be added. Substudies evaluating additional study drugs will be added in a staggered manner when relevant nonclinical and/or clinical data become available. * Substudy-01 enrollment closed, actual enrollment is 13. * Substudy-02 enrollment closed, actual enrollment is 28. * Substudy-03 enrollment closed, actual enrollment is 8.

Interventions

DRUGBavtavirine

Administered orally

DRUGB/F/TAF

Administered orally

DRUGStandard of Care (Substudy 01)

Antiretroviral therapy, administered orally Non-NNRTIs, examples: ABC/DTG/3TC; DTG plus (TAF or TDF) plus (FTC or 3TC)

DRUGGS-1720

Administered orally

DRUGStandard of Care (Substudy 02)

Antiretroviral therapy, administered orally Example INSTIs: DTG/ABC/3TC or DTG/3TC

DRUGGS-6212

Administered orally

DRUGStandard of Care (Substudy 03)

Antiretroviral therapy, administered orally

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

The Substudies were conducted in parallel. However, the cohorts within the Substudies received drug assignment sequentially.

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: All Substudies: * Plasma human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) ≥ 5000 copies/mL but ≤ 400,000 copies/mL at screening. * Cluster of differentiation 4 (CD4) cell count \> 200 cells/mm\^3 at screening. * Antiretroviral (ARV) treatment-naive or treatment-experienced but naive to the investigational ARV drug class being investigated in the given substudy and have not received any ARV within 12 weeks of screening, including medications received for pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) (note that current or prior receipt of long acting (LA) parenteral ARVs such as monoclonal antibodies (mAbs) targeting HIV-1, injectable cabotegravir (CAB), or injectable rilpivirine (RPV) is exclusionary). * Have adequate renal function (estimated glomerular filtration rate (eGFR) ≥ 70 mL/min/1.73 m\^2) * No clinically significant abnormalities in electrocardiogram (ECG) at screening. Substudy-01, Substudy-02, and Substudy-03: * Participants in substudy-01 should be willing to initiate a non-NNRTI based SOC ART on Day 11. * Participants in substudy-02 and Substudy-03 should be willing to initiate any SOC ART on Day 11. * Willing and able to comply with meal requirements on dosing days. Key

Exclusion criteria

All Substudies: * Known historical genotypic or phenotypic resistance to 4 major ARV classes (nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), integrase strand-transfer inhibitor (INSTI)). * History of an AIDS-defining condition including present at the time of screening. * Active, serious infections (other than HIV-1) requiring therapy and including active tuberculosis infection \< 30 days prior to randomization. * History of or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding). * Any other serious or active clinical condition or prior therapy that, in the opinion of the investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements. * Hepatitis C virus (HCV) antibody positive and detectable HCV RNA. * Chronic hepatitis B virus (HBV) infection, as determined by either: * Positive HBV surface antigen and negative HBV surface antibody, regardless of HBV core antibody status, at the screening visit, or * Positive HBV core antibody and negative HBV surface antibody, regardless of HBV surface antigen status, at the screening visit. * Hepatic transaminases (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) \> 5 x upper limit of normal (ULN). * Current alcohol or substance use judged by the investigator to potentially interfere with individual study compliance. * Positive serum pregnancy test at screening or a positive pregnancy test prior to Day 1. * Individuals with plan to breastfeed during the study period including the protocol-defined follow-up period. * Requirement for ongoing therapy with or prior use of any prohibited medications listed in the protocol. Any prescription medications or over the counter medications, including herbal products, within 28 days prior to start of study drug dosing must be reviewed and approved by the sponsor, with the exception of vitamins and/or acetaminophen and/or ibuprofen. * Any current or prior receipt of LA parenteral ARVs such as mAbs targeting HIV-1, injectable CAB, or injectable RPV, for treatment or prophylaxis (PrEP, PEP). Substudy-01, Substudy-02, Substudy-03: * Requirement for ongoing therapy with any prohibited medications listed in protocol. Note: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame
Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline, Day 11

Secondary

Measure	Time frame	Description
Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25)	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as any AEs with an onset date on or after the study drug start date. Percentages were rounded-off.
Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25)	Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any time postbaseline. Laboratory abnormalities were graded using Division of AIDS (DAIDS) scale with grade 0 to 4 where 0 = no grade; 1 = mild, 2 = moderate, 3 = severe; 4 = potentially life-threatening. Participants with at least a 1 grade increased from baseline for an individual laboratory test where the maximum post baseline laboratory abnormality was 1) grade 1 or higher and 2) grade 3 or higher were reported. The maximum postbaseline toxicity grade across all tests for an individual participant was used in analysis. Percentages were rounded-off.
Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine	Cohorts 1, 2 and 3 (Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose); Cohort 3: Day 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, and 8 hours postdose	Cmax was defined as the maximum observed concentration of drug.
Substudy 01: PK Parameter: AUC of Bavtavirine	Day 1 up to Day 11	AUC was defined as the area under the concentration versus time curve.
Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Days 8 and 11	—
Substudy 02: PK Parameter: Cmax of GS-1720	Days 1 and 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and (optional) 12 hours postdose	Cmax was defined as the maximum observed concentration of drug.
Substudy 02: PK Parameter: AUC of GS-1720	Day 1 up to Day 11	AUC was defined as the area under the concentration versus time curve.
Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Days 8 and 11	—
Substudy 03: PK Parameter: Cmax of GS-6212	Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose)	Cmax was defined as the maximum observed concentration of drug.
Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline, Day 8	—
Substudy 03: PK Parameter: AUCtau of GS-6212	Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose)	AUCtau was defined as the area under the curve from time zero to end of dosing interval.
Substudy 03: PK Parameter: Plasma Concentration of GS-6212	Days 1 and 10: 8 hours postdose	—
Substudy 03: PK Parameter: Ctrough of GS-6212 (Day 10)	Day 10 (Parameter estimated based on observed data from 0 to 8 hours postdose)	Ctrough was defined as concentration at the end of the dosing interval.
Substudy 03: PK Parameter: Cavg of GS-6212 (Day 10)	Day 10 (predose to 8 hours postdose)	Cavg was defined as average plasma concentration during dose administration.
Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	Up to Day 11	Percentages were rounded-off.
Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	Up to Day 11	The antiretroviral (ARV) class of given drugs would be BVY or NNRTIs (Substudy 01) or INSTIs (Substudy 02) or INSTIs (Substudy 03). Percentages were rounded-off.
Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11	Up to Day 11	Inhibitory quotient was calculated as the ratio of bavtavirine in vivo exposure to in vitro plasma concentration. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.
Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11	Day 11	Inhibitory quotient was calculated as the ratio of GS-1720 in vivo exposure to in vitro plasma concentration. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.
Substudy 03: Inhibitory Quotient (IQ) of GS-6212 by Ctrough at Day 11	Day 11	Ctrough is the plasma concentration of the drug just before the next dose. Inhibitory quotient was calculated as the ratio of GS-1720 in vivo exposure to in vitro Ctrough. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.
Substudy 03: PK Parameter: AUC0-8h of GS-6212	Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose)	AUC0-8h was defined as the area under the concentration versus time curve spanning from 0 to 8 hours post dose.

Countries

Dominican Republic, Thailand, United States

Participant flow

Recruitment details

100 participants were screened. Participants were enrolled at study sites in the United States, Thailand, and Dominican Republic.

Pre-assignment details

Efficacy outcome measures (OM) included an additional cohort of Placebo. In this study, none of the participants received placebo. Placebo arm included 21 participants with HIV-1 from 3 other Gilead Phase 1b studies (GS-US-120-0104, GS-US-141-1219 (NCT02275065), and GS-US-200-4072 (NCT03739866)). Each bavtavirine, GS-1720, and GS-6212 cohort was compared to the pooled placebo cohort in the efficacy OMs #1, 2, and 17.

Participants by arm

Arm	Count
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal) Participants received a single dose of bavtavirine 675 mg tablet, orally, with a high-fat meal on Day 1. After assessments on Day 11 or upon early termination (ET), the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 39.	6
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal) Participants received a single dose of bavtavirine 1200 mg tablet, orally, with a low-fat meal on Day 1. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 39.	6
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal) Participants received a single dose of bavtavirine 900 mg tablet, orally, with a high-fat meal on Days 1 and 2. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 39.	1
Substudy 02: Cohort 1: GS-1720 450 mg Participants received a single dose of GS-1720 450 mg tablet, orally, on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 60.	7
Substudy 02: Cohort 2: GS-1720 150 mg Participants received a single dose of GS-1720 150 mg tablet, orally, on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 60.	7
Substudy 02: Cohort 3: GS-1720 30 mg Participants received a single dose of GS-1720 30 mg tablet, orally, on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 60.	7
Substudy 02: Cohort 4: GS-1720 900 mg Participants received a single dose of GS-1720 900 mg tablet, orally, on both Days 1 and 2 in fasted condition. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 60.	7
Substudy 03: Cohort 1: GS- 6212 100 mg Participants received GS-6212 100 mg tablet, orally, twice daily on Days 1 through 10. After assessments on Day 11 or upon ET, the participants initiated an oral regimen of B/F/TAF, or an alternative SOC ART regimen (example INSTI + NRTIs: DTG/ABC/3TC or DTG/3TC), orally up to Day 25.	8
Total	49

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007
Overall Study	Lost to Follow-up	0	0	0	0	0	0	1	0

Baseline characteristics

Characteristic	Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: Cohort 2: GS-1720 150 mg	Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: Cohort 3: GS-1720 30 mg	Substudy 02: Cohort 4: GS-1720 900 mg	Substudy 03: Cohort 1: GS- 6212 100 mg	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	2 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	6 Participants	1 Participants	7 Participants	7 Participants	5 Participants	6 Participants	7 Participants	8 Participants	47 Participants
Age, Continuous	38 years STANDARD_DEVIATION 13.9	31 years	35 years STANDARD_DEVIATION 13.9	42 years STANDARD_DEVIATION 13.5	34 years STANDARD_DEVIATION 9.5	39 years STANDARD_DEVIATION 13	32 years STANDARD_DEVIATION 6.5	33 years STANDARD_DEVIATION 11.9	36 years STANDARD_DEVIATION 11.6
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	0 Participants	2 Participants	2 Participants	2 Participants	4 Participants	5 Participants	2 Participants	19 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	1 Participants	5 Participants	5 Participants	4 Participants	3 Participants	2 Participants	6 Participants	30 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	2 Participants	1 Participants	3 Participants
Race (NIH/OMB) Black or African American	3 Participants	1 Participants	0 Participants	3 Participants	3 Participants	3 Participants	0 Participants	3 Participants	16 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	2 Participants	0 Participants	1 Participants	2 Participants	3 Participants	0 Participants	8 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	3 Participants	0 Participants	3 Participants	3 Participants	2 Participants	1 Participants	2 Participants	4 Participants	18 Participants
Region of Enrollment Dominican Republic	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	2 Participants	3 Participants	0 Participants	5 Participants
Region of Enrollment Thailand	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	2 Participants
Region of Enrollment United States	6 Participants	1 Participants	7 Participants	7 Participants	6 Participants	5 Participants	3 Participants	7 Participants	42 Participants
Sex: Female, Male Female	1 Participants	1 Participants	1 Participants	1 Participants	2 Participants	1 Participants	0 Participants	1 Participants	8 Participants
Sex: Female, Male Male	5 Participants	0 Participants	6 Participants	6 Participants	4 Participants	6 Participants	7 Participants	7 Participants	41 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6	0 / 1	0 / 7	0 / 7	0 / 7	0 / 7	0 / 8
other Total, other adverse events	3 / 6	0 / 6	1 / 1	3 / 7	6 / 7	6 / 7	5 / 7	6 / 8
serious Total, serious adverse events	0 / 6	1 / 6	0 / 1	0 / 7	1 / 7	0 / 7	0 / 7	0 / 8

Outcome results

Primary

Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data

Time frame: Baseline, Day 11

Population: Participants in the Full Analysis Set with data available were analyzed. The Full Analysis Set included all participants who were enrolled and received full dose(s) of study drugs bavtavirine, GS-1720 and GS-6212 in these substudies.~The placebo arm included pooled data from participants who received placebo in 3 historical Gilead HIV-1 phase 1b studies (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) for HIV-1 efficacy parameters only.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.68 log10 copies/mL	Standard Deviation 0.517
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-1.40 log10 copies/mL	Standard Deviation 0.454
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.68 log10 copies/mL	Standard Deviation 0.488
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-1.46 log10 copies/mL	Standard Deviation 0.69
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.27 log10 copies/mL	—
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-1.54 log10 copies/mL	—
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	5.16 log10 copies/mL	Standard Deviation 0.562
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-2.44 log10 copies/mL	Standard Deviation 0.425
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.72 log10 copies/mL	Standard Deviation 0.362
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-2.18 log10 copies/mL	Standard Deviation 0.199
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-1.74 log10 copies/mL	Standard Deviation 0.766
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.52 log10 copies/mL	Standard Deviation 0.565
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-2.37 log10 copies/mL	Standard Deviation 0.509
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.93 log10 copies/mL	Standard Deviation 0.366
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.41 log10 copies/mL	Standard Deviation 0.85
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	-2.43 log10 copies/mL	Standard Deviation 0.698
Placebo	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Baseline	4.43 log10 copies/mL	Standard Deviation 0.508
Placebo	Substudies 01, 02 and 03: Change From Baseline in Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) (log10 Copies/mL) at Day 11 Relative to Historical Placebo Data	Change from Baseline at Day 11	0.01 log10 copies/mL	Standard Deviation 0.338

p-value: <0.0001t-test, 2 sided

p-value: 0.0013t-test, 2 sided

p-value: <0.0001t-test, 2 sided

Secondary

Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data

Time frame: Baseline, Day 8

Population: Participants in the Full Analysis Set with available data were analyzed. The placebo arm included pooled data from participants who received placebo in 3 historical Gilead HIV-1 phase 1b studies (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) for HIV-1 efficacy parameters only.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.68 log10 copies/mL	Standard Deviation 0.517
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-1.49 log10 copies/mL	Standard Deviation 0.239
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.68 log10 copies/mL	Standard Deviation 0.488
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-1.54 log10 copies/mL	Standard Deviation 0.497
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.27 log10 copies/mL	—
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-1.51 log10 copies/mL	—
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	5.16 log10 copies/mL	Standard Deviation 0.562
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-2.04 log10 copies/mL	Standard Deviation 0.346
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.72 log10 copies/mL	Standard Deviation 0.362
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-1.76 log10 copies/mL	Standard Deviation 0.185
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-1.67 log10 copies/mL	Standard Deviation 0.326
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.52 log10 copies/mL	Standard Deviation 0.565
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-1.98 log10 copies/mL	Standard Deviation 0.249
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.93 log10 copies/mL	Standard Deviation 0.366
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.41 log10 copies/mL	Standard Deviation 0.85
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	-2.10 log10 copies/mL	Standard Deviation 0.417
Placebo	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Baseline	4.43 log10 copies/mL	Standard Deviation 0.508
Placebo	Substudies 01, 02 and 03: Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Day 8 Relative to Historical Placebo Data	Change from Baseline at Day 8	0.01 log10 copies/mL	Standard Deviation 0.297

p-value: <0.0001t-test, 2 sided

Secondary

Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level

Percentages were rounded-off.

Time frame: Up to Day 11

Population: Participants in the Full Analysis Set were analyzed. The placebo arm included pooled data from participants who received placebo in 3 historical Gilead HIV-1 phase 1b studies (GS-US-120-0104, GS-US-141-1219, and GS-US-200-4072) for HIV-1 efficacy parameters only.

Arm	Measure	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	28.6 percentage of participants
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	37.5 percentage of participants
Placebo	Substudies 01, 02 and 03: Percentage of Participants at Any Measurement Achieving HIV-1 RNA < 50 Copies/mL by Day 11 at Each Dose Level	0 percentage of participants

Secondary

Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug

The antiretroviral (ARV) class of given drugs would be BVY or NNRTIs (Substudy 01) or INSTIs (Substudy 02) or INSTIs (Substudy 03). Percentages were rounded-off.

Time frame: Up to Day 11

Population: Participant in the Full Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	33.0 percentage of participants
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	16.6 percentage of participants
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	0 percentage of participants
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	0 percentage of participants
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	0 percentage of participants
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	0 percentage of participants
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	0 percentage of participants
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Percentage of Participants With Emergence of Viral Resistance to the ARV Class of the Given Drug	0 percentage of participants

Secondary

Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities

Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any time postbaseline. Laboratory abnormalities were graded using Division of AIDS (DAIDS) scale with grade 0 to 4 where 0 = no grade; 1 = mild, 2 = moderate, 3 = severe; 4 = potentially life-threatening. Participants with at least a 1 grade increased from baseline for an individual laboratory test where the maximum post baseline laboratory abnormality was 1) grade 1 or higher and 2) grade 3 or higher were reported. The maximum postbaseline toxicity grade across all tests for an individual participant was used in analysis. Percentages were rounded-off.

Time frame: First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25)

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	16.7 percentage of participants
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	66.7 percentage of participants
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	0 percentage of participants
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	0 percentage of participants
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	14.3 percentage of participants
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	14.3 percentage of participants
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	0 percentage of participants
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	100 percentage of participants
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 1 or Higher	87.5 percentage of participants
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Percentage of Participants With Graded Laboratory Abnormalities	Grade 3 or Higher	0 percentage of participants

Secondary

Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as any AEs with an onset date on or after the study drug start date. Percentages were rounded-off.

Time frame: First dose up to last dose (Substudy 01: Up to Day 39; Substudy 02: Up to Day 60; Substudy 03: Up to Day 25)

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	50.0 percentage of participants
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	16.7 percentage of participants
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	100 percentage of participants
Substudy 02: Cohort 1: GS-1720 450 mg	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	42.9 percentage of participants
Substudy 02: Cohort 2: GS-1720 150 mg	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	85.7 percentage of participants
Substudy 02: Cohort 3: GS-1720 30 mg	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	85.7 percentage of participants
Substudy 02: Cohort 4: GS-1720 900 mg	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	71.4 percentage of participants
Substudy 03: Cohort 1: GS- 6212 100 mg	Substudies 01, 02 and 03: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	75.0 percentage of participants

Secondary

Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11

Inhibitory quotient was calculated as the ratio of bavtavirine in vivo exposure to in vitro plasma concentration. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.

Time frame: Up to Day 11

Population: The PK/PD Analysis Set included all participants who were in the Full Analysis Set and have both nonmissing Ct (and/or AUC) of study drug and the change from baseline at Day 11 in plasma HIV-1 RNA (log10 copies/mL).

Arm	Measure	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11	5 ratio
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11	5 ratio
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: Maximum Inhibitory Quotient (IQ) of Bavtavirine by Mean Plasma Concentration (Ct) up to Day 11	5 ratio

Secondary

Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine

Cmax was defined as the maximum observed concentration of drug.

Time frame: Cohorts 1, 2 and 3 (Day 1: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose); Cohort 3: Day 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, and 8 hours postdose

Population: Participants in PK Analysis Set in Substudy 01 were analyzed. The PK Analysis Set included all participants who were enrolled in the study, received at least 1 dose of study drug, and had at least 1 non-missing post baseline concentration value for bavtavirine. Per pre-specified analysis, Cmax at Day 2 was calculated only for Cohort 3.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine	Cmax (Day 1)	685 ng/mL	Standard Deviation 172
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine	Cmax (Day 1)	700 ng/mL	Standard Deviation 364
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine	Cmax (Day 1)	565 ng/mL	—
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: Pharmacokinetic (PK) Parameter: Cmax of Bavtavirine	Cmax (Day 2)	1160 ng/mL	—

Secondary

Substudy 01: PK Parameter: AUC of Bavtavirine

AUC was defined as the area under the concentration versus time curve.

Time frame: Day 1 up to Day 11

Population: Participants in the PK Analysis Set in Substudy 01 were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 01: PK Parameter: AUC of Bavtavirine	AUC (Days 1-8)	33,300 h*ng/mL	Standard Deviation 10300
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 01: PK Parameter: AUC of Bavtavirine	AUC (Days 1-11)	38,800 h*ng/mL	Standard Deviation 11800
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: PK Parameter: AUC of Bavtavirine	AUC (Days 1-8)	24,300 h*ng/mL	Standard Deviation 13700
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: PK Parameter: AUC of Bavtavirine	AUC (Days 1-11)	28,300 h*ng/mL	Standard Deviation 16100
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: PK Parameter: AUC of Bavtavirine	AUC (Days 1-8)	71,400 h*ng/mL	—
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: PK Parameter: AUC of Bavtavirine	AUC (Days 1-11)	89,100 h*ng/mL	—

Secondary

Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine

Time frame: Days 8 and 11

Population: Participants in the PK Analysis Set in Substudy 01 with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Day 8	94.5 ng/mL	Standard Deviation 36.8
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Day 11	61.2 ng/mL	Standard Deviation 26
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Day 8	64.8 ng/mL	Standard Deviation 44.7
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Day 11	44.6 ng/mL	Standard Deviation 32.8
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Day 8	250 ng/mL	—
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 01: PK Parameter: Plasma Concentration of Bavtavirine	Day 11	202 ng/mL	—

Secondary

Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11

Inhibitory quotient was calculated as the ratio of GS-1720 in vivo exposure to in vitro plasma concentration. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.

Time frame: Day 11

Population: Participants in the PK/PD Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11	4.5 ratio
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11	3 ratio
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11	0.8 ratio
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: Inhibitory Quotient (IQ) of GS-1720 by Mean Plasma Concentration (Ct) at Day 11	9.5 ratio

Secondary

Substudy 02: PK Parameter: AUC of GS-1720

AUC was defined as the area under the concentration versus time curve.

Time frame: Day 1 up to Day 11

Population: Participants in the PK Analysis Set in Substudy 02 were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 8)	2790 h*µg/mL	Standard Deviation 1060
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 11)	3540 h*µg/mL	Standard Deviation 1330
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 11)	2160 h*µg/mL	Standard Deviation 1020
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 8)	1670 h*µg/mL	Standard Deviation 780
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 8)	503 h*µg/mL	Standard Deviation 134
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 11)	648 h*µg/mL	Standard Deviation 169
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 8)	4960 h*µg/mL	Standard Deviation 1360
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: PK Parameter: AUC of GS-1720	AUC (Day 11)	6430 h*µg/mL	Standard Deviation 1740

Secondary

Substudy 02: PK Parameter: Cmax of GS-1720

Cmax was defined as the maximum observed concentration of drug.

Time frame: Days 1 and 2: Predose, 0.5, 1, 2, 3, 4, 5, 6, 8 and (optional) 12 hours postdose

Population: Participants in the PK Analysis Set in Substudy 02 with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 1)	17.2 µg/mL	Standard Deviation 8.37
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 2)	30.8 µg/mL	Standard Deviation 10.7
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 2)	15.6 µg/mL	Standard Deviation 5.59
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 1)	9.77 µg/mL	Standard Deviation 3.09
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 1)	3.00 µg/mL	Standard Deviation 0.691
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 2)	5.39 µg/mL	Standard Deviation 1.48
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 1)	33.7 µg/mL	Standard Deviation 11.6
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: PK Parameter: Cmax of GS-1720	Cmax (Day 2)	48.3 µg/mL	Standard Deviation 9.85

Secondary

Substudy 02: PK Parameter: Plasma Concentration of GS-1720

Time frame: Days 8 and 11

Population: Participants in the PK Analysis Set in Substudy 02 were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 8	12.2 µg/mL	Standard Deviation 4.21
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 11	8.78 µg/mL	Standard Deviation 4.15
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 11	5.87 µg/mL	Standard Deviation 2.98
Substudy 01: Cohort 2: Bavtavirine 1200 mg (Low-Fat Meal)	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 8	7.44 µg/mL	Standard Deviation 3.65
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 11	1.64 µg/mL	Standard Deviation 0.376
Substudy 01: Cohort 3: Bavtavirine 900 mg (High-Fat Meal)	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 8	2.59 µg/mL	Standard Deviation 0.868
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 8	22.7 µg/mL	Standard Deviation 4.94
Substudy 02: Cohort 1: GS-1720 450 mg	Substudy 02: PK Parameter: Plasma Concentration of GS-1720	Day 11	18.4 µg/mL	Standard Deviation 4.75

Secondary

Substudy 03: Inhibitory Quotient (IQ) of GS-6212 by Ctrough at Day 11

Ctrough is the plasma concentration of the drug just before the next dose. Inhibitory quotient was calculated as the ratio of GS-1720 in vivo exposure to in vitro Ctrough. IQ is defined as paEC95. paEC95 = protein-adjusted effective concentration to achieve 95% effective inhibition. The IQ ≥ 2 indicated higher reduction in viral load with less rebound.

Time frame: Day 11

Population: Participants in the PK/PD Analysis Set with available data were analyzed.

Arm	Measure	Value (NUMBER)
Substudy 01: Cohort 1: Bavtavirine 675 mg (High-Fat Meal)	Substudy 03: Inhibitory Quotient (IQ) of GS-6212 by Ctrough at Day 11	6.5 ratio

Secondary

Substudy 03: PK Parameter: AUC0-8h of GS-6212

AUC0-8h was defined as the area under the concentration versus time curve spanning from 0 to 8 hours post dose.

Time frame: Days 1 and 10 (Predose, 0.25, 0.5, 1, 2, 3, 4, 6, 8 and (optional) 12 hours postdose)