Pre-Exposure Prophylaxis of HIV Infection
Conditions
Brief summary
The goal of this study is to evaluate the efficacy of the study drugs, lenacapavir (LEN) in preventing HIV infection, in participants ≥ 16 years of age who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV-1 infection. The primary objective of this study is to evaluate the efficacy of LEN for HIV-1 pre-exposure prophylaxis (PrEP) in participants ≥ 16 years of age who have condomless receptive anal sex with partners assigned male at birth at risk of HIV-1 infection.
Interventions
Tablets administered orally without regard to food
DRUGF/TDF
Tablets administered orally
DRUGSub-cutaneous (SC) Lenacapavir (LEN)
Administered via SC injections
DRUGPlacebo SC LEN
Administered via SC injections
DRUGPTM F/TDF
Tablets administered orally
DRUGPTM Oral LEN
Tablets administered orally
DRUGF/TAF (for US participants only)
F/TAF tablets administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: Incidence Phase * CGM, TGW, TGM, and GNB who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV infection. * HIV-1 status unknown at screening and no prior HIV-1 testing within the last 3 months. * Sexually active with ≥ 1 partner assigned male at birth (condomless receptive anal sex) in the last 12 months and 1 of the following: * Condomless receptive anal sex with ≥ 2 partners in the last 12 weeks. * History of syphilis, rectal gonorrhea, or rectal chlamydia in the last 24 weeks. * Self-reported use of stimulants with sex in the last 12 weeks. Randomized Phase * Negative local rapid fourth generation HIV-1/2 Ab/Ag, central fourth generation HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative nucleic acid amplification testing (NAAT). * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min at screening according to the Cockcroft-Gault formula for creatinine clearance (CLcr). Key
Exclusion criteria
Incidence Phase * Prior use of HIV PrEP (including F/TDF or F/TAF) or HIV postexposure prophylaxis (PEP) in the past 12 weeks or any prior use of long-acting systemic PrEP (including cabotegravir or islatravir). * Prior recipient of an HIV vaccine or HIV broadly neutralizing antibody formulation. Randomized Phase * Acute viral hepatitis A, B or C or evidence of chronic hepatitis B or C infection. * Severe hepatic impairment or a history of or current clinical decompensated liver cirrhosis. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Phase: Recent Infection Testing Algorithm (RITA) Estimate of the Background Human Immunodeficiency-1 Virus Infection Incidence Rate (bHIV) Per 100 Person Years (PY) | Incidence Phase Screening Visit (Day 1) | bHIV per 100 PY in the Incidence Phase was calculated using RITA. The RITA incorporated HIV-1 testing results and recency assay testing results to estimate the bHIV. Recency assay testing was performed for participants in the All Screened Set found to have HIV-1 infection at the Incidence Phase Screening Visit as defined below. Participants were considered to have recent HIV-1 infection if the normalized optical density (ODn) was below 1.5 threshold using the Sedia limiting antigen avidity enzyme immunoassay (LAg-EIA) and the HIV-1 RNA (viral load) was \> 75 copies/mL of blood. HIV-1 infection was defined as participants having at least one of the following central lab results at the Incidence Phase screening visit: * Positive HIV-1/2 differentiation Ab, OR * Positive HIV-1 ribonucleic acid (RNA) qualitative test, OR * HIV-1 RNA quantitative test ≥200 copies/mL. |
| Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set) | Up to 149 weeks | HIV-1 incidence per 100 PY for LEN was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples. bHIV incidence per 100 PY in All Screened Set was estimated as described in outcome measure#1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF | Up to 149 weeks | HIV-1 incidence per 100 PY was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples. |
| Randomized Blinded Phase: HIV-1 Incidence Among Participants Adherent to LEN | Up to 149 weeks | A participant was defined as adherent to LEN if they have received all per-protocol administrations of LEN within 28 weeks since the previous administration. The incidence of HIV-1 infection per 100 PY calculation is defined in outcome measure #2. |
| Randomized Blinded Phase: Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | First dose date up to 184 weeks | An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a study drug that did not necessarily have a causal relationship with the treatment. TEAEs were defined as 1 or both of the following: Any AEs leading to premature discontinuation of study drug, or any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. |
| Randomized Blinded Phase: Percentage of Participants Experiencing Grade 3 or Higher Laboratory Abnormalities | First dose date up to 184 weeks | Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any post-baseline visit, up to and including the last exposure date for participants who permanently discontinued study drug, or the last available date in the database snapshot for participants who were still on treatment at the time of an analysis. The division of acquired immunodeficiency syndrome toxicity grading scale, Version 2.1 was used to assign toxicity grades (0 to 4) to laboratory results for analysis. Grade 0 included all values that do not meet the criteria for an abnormality of at least Grade 1. Grade 1 mild, Grade 2 moderate, Grade 3 severe, and Grade 4 potentially life-threatening. Percentages were rounded off. |
Countries
Argentina, Brazil, Mexico, Peru, Puerto Rico, South Africa, Thailand, United States
Contacts
STUDY_DIRECTORGilead Study Director
Gilead Sciences
Participant flow
Recruitment details
4807 participants were screened. Out of 4807, 4634 had at least 1 non-missing HIV-1 diagnosis based on HIV test results from a central laboratory. So, 4634 participants were considered for screening in Incidence Phase and were included in All Screened Set. Out of 4634, 3292 were enrolled and randomized in Randomized Blinded Phase. Incidence Phase refers to Screening Phase. Participants were enrolled in Argentina, Brazil, Mexico, Peru, Puerto Rico, South Africa, Thailand and the United States.
Pre-assignment details
Data submitted represent primary analysis performed on data collected by the Primary Completion Date (PCD) (Per pre-specified analysis, PCD is when at least 50% of the planned randomized participants were followed for at least 52 weeks in the study or prematurely discontinued from the study) as well as additional data through the end of Randomized Blinded Phase to Week 223 through 25 September 2025. Complete data will be submitted 1 year from Study Completion date.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Blinded Phase: LEN + Placebo-to-match (PTM) F/TDF Participants received lenacapavir (LEN) 927 mg subcutaneous (SC) injection, every 26 weeks, starting on Day 1 for up to approximately 52 weeks. Participants also received loading dose of LEN 600 mg tablet orally, once daily on Day 1 and Day 2. Participants received placebo to match (PTM) emtricitabine/tenofovir disoproxil fumarate (F/TDF) tablet orally, once daily, up to approximately 52 weeks. | 2,183 |
| Randomized Blinded Phase: Placebo LEN + F/TDF Participants received F/TDF tablet on Day 1 orally, once daily for up to approximately 52 weeks. Participants also received PTM LEN SC injection every 26 weeks starting on Day 1 up to approximately 52 weeks and PTM LEN tablet, orally, once daily on Day 1 and Day 2. | 1,088 |
| Total | 3,271 |
Baseline characteristics
| Characteristic | Total | Randomized Blinded Phase: Placebo LEN + F/TDF | Randomized Blinded Phase: LEN + Placebo-to-match (PTM) F/TDF |
|---|---|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 9 | 31 years STANDARD_DEVIATION 9.5 | 30 years STANDARD_DEVIATION 8.7 |
| Age, Customized 16 to <18 years | 4 Participants | 1 Participants | 3 Participants |
| Age, Customized 18 to ≤ 25 years | 1092 Participants | 343 Participants | 749 Participants |
| Age, Customized > 25 to < 35 years | 1335 Participants | 423 Participants | 912 Participants |
| Age, Customized 35 to < 50 years | 721 Participants | 267 Participants | 454 Participants |
| Age, Customized ≥ 50 years | 119 Participants | 54 Participants | 65 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 2053 Participants | 675 Participants | 1378 Participants |
| Race/Ethnicity, Customized Ethnicity Not Collected | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 1217 Participants | 413 Participants | 804 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 31 Participants | 12 Participants | 19 Participants |
| Race/Ethnicity, Customized Race Asian | 413 Participants | 144 Participants | 269 Participants |
| Race/Ethnicity, Customized Race Black or African American | 884 Participants | 301 Participants | 583 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Not Collected | 10 Participants | 2 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Other or More Than One Race | 863 Participants | 285 Participants | 578 Participants |
| Race/Ethnicity, Customized Race White | 1067 Participants | 344 Participants | 723 Participants |
| Region of Enrollment Argentina | 225 Participants | 64 Participants | 161 Participants |
| Region of Enrollment Brazil | 1165 Participants | 396 Participants | 769 Participants |
| Region of Enrollment Mexico | 12 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Peru | 447 Participants | 138 Participants | 309 Participants |
| Region of Enrollment Puerto Rico | 11 Participants | 2 Participants | 9 Participants |
| Region of Enrollment South Africa | 358 Participants | 112 Participants | 246 Participants |
| Region of Enrollment Thailand | 389 Participants | 139 Participants | 250 Participants |
| Region of Enrollment United States | 664 Participants | 233 Participants | 431 Participants |
| Sex: Female, Male Female | 67 Participants | 24 Participants | 43 Participants |
| Sex: Female, Male Male | 3204 Participants | 1064 Participants | 2140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 2,195 | 2 / 1,097 |
| other Total, other adverse events | 1,950 / 2,183 | 905 / 1,088 |
| serious Total, serious adverse events | 96 / 2,183 | 56 / 1,088 |
Outcome results
Primary
Incidence Phase: Recent Infection Testing Algorithm (RITA) Estimate of the Background Human Immunodeficiency-1 Virus Infection Incidence Rate (bHIV) Per 100 Person Years (PY)
bHIV per 100 PY in the Incidence Phase was calculated using RITA. The RITA incorporated HIV-1 testing results and recency assay testing results to estimate the bHIV. Recency assay testing was performed for participants in the All Screened Set found to have HIV-1 infection at the Incidence Phase Screening Visit as defined below. Participants were considered to have recent HIV-1 infection if the normalized optical density (ODn) was below 1.5 threshold using the Sedia limiting antigen avidity enzyme immunoassay (LAg-EIA) and the HIV-1 RNA (viral load) was \> 75 copies/mL of blood. HIV-1 infection was defined as participants having at least one of the following central lab results at the Incidence Phase screening visit: * Positive HIV-1/2 differentiation Ab, OR * Positive HIV-1 ribonucleic acid (RNA) qualitative test, OR * HIV-1 RNA quantitative test ≥200 copies/mL.
Time frame: Incidence Phase Screening Visit (Day 1)
Population: Participants in the All Screened Set were analyzed. The All Screened Set included all participants who were screened for HIV-1 in the Incidence Phase and had a non-missing HIV-1 diagnosis based on HIV test results at Incidence Phase screening. As the outcome measure was assessed prior to Randomized Blinded Phase, the data is reported in one arm consisting of all participants screened in Incidence Phase.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Incidence Phase: Recent Infection Testing Algorithm (RITA) Estimate of the Background Human Immunodeficiency-1 Virus Infection Incidence Rate (bHIV) Per 100 Person Years (PY) | 2.374 HIV-1 events per 100 person-years |
Primary
Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set)
HIV-1 incidence per 100 PY for LEN was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples. bHIV incidence per 100 PY in All Screened Set was estimated as described in outcome measure#1.
Time frame: Up to 149 weeks
Population: Participants in the LEN group in the Full Analysis Set (FAS) were analyzed. The FAS included all randomized participants who received at least 1 dose of any study drug and had not been diagnosed with HIV-1 on or prior to the first dose date. Per prespecified analysis, HIV-1 incidence for this outcome measure was reported only for participants who received LEN. The HIV-1 incidence was compared with participants in the All Screened Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set) | 0.103 HIV-1 events per 100 person-years |
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to Background HIV (bHIV, Participants in All Screened Set) | 2.374 HIV-1 events per 100 person-years |
Comparison: Null Hypothesis 01: LEN/bHIV\>= 1; Null hypothesis was to be rejected if HIV-1 incidence in LEN was significantly lower than bHIV.p-value: <0.000195% CI: [0.01, 0.182]Wald test
Comparison: Null Hypothesis 02: LEN/bHIV\>= 0.8; Null hypothesis was to be rejected if HIV-1 incidence in LEN was significantly and at least 20% lower than bHIV.p-value: <0.000195% CI: [0.01, 0.182]Wald test
Secondary
Percentage of Participants Experiencing Clinically Significant Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any post-baseline visit, up to and including the last exposure date for participants who permanently discontinued study drug, or the last available date in the database snapshot for participants who were still on treatment at the time of an analysis.
Time frame: Up to 4 years
Secondary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)
TEAEs were defined as 1 or both of the following: Any adverse events (AEs) leading to premature discontinuation of study drug, or Any AEs with an onset date on or after the study drug start date and no later than the last exposure date after permanent discontinuation of the study drug. An AE was any untoward medical occurrence in a clinical study participant administered a study drug that did not necessarily have a causal relationship with the treatment.
Time frame: Up to 4 years
Secondary
Randomized Blinded Phase: HIV-1 Incidence Among Participants Adherent to LEN
A participant was defined as adherent to LEN if they have received all per-protocol administrations of LEN within 28 weeks since the previous administration. The incidence of HIV-1 infection per 100 PY calculation is defined in outcome measure #2.
Time frame: Up to 149 weeks
Population: Participants in the Full Analysis Set who were adherent to LEN were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Among Participants Adherent to LEN | 0.125 HIV-1 events per 100 person-years |
Secondary
Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF
HIV-1 incidence per 100 PY was calculated as the number of participants who acquired HIV-1 divided by the total of a) for participants not diagnosed with HIV-1, sum of all duration of follow-up time in years, while at risk of HIV-1 infection (where a year is 365.25 days) and b) for participants diagnosed with HIV-1, sum of all duration of follow-up time up to confirmed HIV-1 diagnoses. HIV-1 diagnosis was determined by an HIV adjudication committee who reviewed potential HIV-1 infection events in the randomized participants. The committee, in a blinded, consistent, and unbiased manner, determined whether HIV test results confirmed HIV-1 infection and determined the date of diagnosis for each case, defined as the date of the earliest study visit with evidence of HIV infection considering both prospective HIV testing and back-testing of archived samples.
Time frame: Up to 149 weeks
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF | 0.103 HIV-1 events per 100 person-years |
| Incidence Phase: All Screened Participants With Non-missing HIV-1 Diagnosis | Randomized Blinded Phase: HIV-1 Incidence Reported Per 100 PY for LEN Compared to F/TDF | 0.931 HIV-1 events per 100 person-years |
p-value: <0.000195% CI: [-1.669, -0.255]Hybrid approach
Comparison: Null Hypothesis 04: LEN vs F/TDF\>= 1; Null hypothesis was to be rejected if HIV-1 incidence in LEN was significantly lower than F/TDF.p-value: 0.0024595% CI: [0.024, 0.513]Poisson model