aThe determination of efficacy was based on interim analyses when 50% of randomized participants completed 52 weeks of follow-up. Based on the results, the study arms were unblinded, and this interim analysis became the primary analysis.
Both phase 3 trials evaluated the efficacy of YEZTUGO by comparing the incidence of HIV with the estimated bHIV in the screened population and evaluated the efficacy and safety of YEZTUGO compared with FTC/TDF.2,3
bN values represent the modified intention-to-treat analyses that excluded participants with HIV at baseline.
YEZTUGO was studied across the most age-, gender-, and racially inclusive, phase 3, PrEP clinical trials to date1-5
The first phase 3 HIV prevention clinical trial to study pregnant and lactating women1,2,4,c
cThe first phase 3 HIV prevention clinical trial to allow individuals to stay enrolled and continue on study drug if they became pregnant or started lactating.
dEligible individuals had sexual encounters without recent HIV testing and had unknown HIV status.
eThe determination of efficacy was based on interim analyses when 50% of randomized participants completed 52 weeks of follow-up. Based on results, the study arms were unblinded, and this interim analysis became the primary analysis.
Baseline characteristics2
characteristics
N=2138
N=1070
| Median—yr (range) | 21 (16–25) | 21 (16–25) | |
| 16 or 17 yr—no. (%) | 56 (2.6) | 23 (2.1) |
| Black race— no. (%)f |
2135 (99.9) | 1068 (99.8) |
| Chlamydia trachomatis | 520 (24.3) | 263 (24.6) |
|
| Neisseria gonorrhoeae | 197 (9.2) | 90 (8.4) | |
| Trichomonas vaginalis | 154 (7.2) | 82 (7.7) | |
| Syphilis | 57 (2.7) | 29 (2.7) |
fRace was reported by the participants. All non-Black participants were multiracial.
The first phase 3 HIV prevention study to intentionally include gender-diverse individuals1,3,5
gEligible individuals had condomless sex, no recent HIV testing, and had unknown HIV status.
hThe determination of efficacy was based on interim analyses when 50% of randomized participants completed 52 weeks of follow-up. Based on results, the study arms were unblinded, and this interim analysis became the primary analysis.
Baseline characteristics3
characteristics
N=2138
N=1088
| Median—yr (range) | 28 (17–74) | 29 (17–73) | |
| 16 to ≤25 yr—no. (%) | 752 (34.4) | 344 (31.6) |
| Argentina | 161 (7.4) | 64 (5.9) | |
| Brazil | 769 (35.2) | 396 (36.4) | |
| Mexico | 8 (0.4) | 4 (0.4) | |
| Peru | 309 (14.2) | 138 (12.7) | |
| South Africa | 246 (11.3) | 112 (10.3) | |
| Thailand | 250 (11.5) | 139 (12.8) | |
| United States | 440 (20.2) | 235 (21.6) |
| Asian | 269/2175 (12.4) | 144/1086 (13.3) | |
| Black | 811/2175 (37.3) | 420/1086 (38.7) | |
| Indigenous or Indigenous ancestry | 341/2175 (15.7) | 156/1086 (14.4) | |
| White | 722/2175 (33.2) | 344/1086 (31.7) | |
| Other and other multiracial | 32/2175 (1.5) | 22/1086 (2.0) | |
| Hispanic or Latine | 1378/2182 (63.2) | 675/1088 (62.0) |
| Cisgender man | 1697 (77.7) | 846 (77.8) | |
| Transgender woman | 315 (14.4) | 161 (14.8) | |
| Transgender man | 29 (1.3) | 14 (1.3) | |
| Gender nonbinaryj | 136 (6.2) | 63 (5.8) | |
| Otherk | 6 (0.3) | 4 (0.4) |
| No previous HIV testing—no. (%) | 597 (27.3) | 306 (28.1) | |
| Median time since last HIV test—mo (range)l | 7.2 (2.6–149.4) | 7.1 (1.2–274.2) |
| Any previous use of PrEP—no. (%) | 515 (23.6) | 249 (22.9) | |
| Median time since last use of PrEP—mo (range)m | 13.0 (0.7–103.9) | 10.8 (0.7–274.5) |
| Condomless receptive anal sex with ≥2 partners in previous 12 wks—no. (%) | 2128 (97.5) | 1049 (96.4) |
| Chlamydia trachomatis | 253 (11.6) | 126 (11.6) | |
| Neisseria gonorrhoeae | 193 (8.8) | 115 (10.6) | |
| Syphilis | 84 (3.8) | 43 (4.0) |
| Use of gender-affirming hormone therapy—no. (%)o | 253 (11.6) | 131 (12.0) |
iRace and ethnic group were reported by the participants. The “Black” category included all of the participants who identified as being Black or as being of Black ancestry and included the terms “Black,” “Black/White,” “Black/Pardo” (Brazilian term for a specific racial category), “Black/Brown” (Brazil), “Black/Colored” (South African term for a specific racial category), “Black/American Indian or Alaska Native,” “Black/Asian,” and “Black/Native Hawaiian or Pacific Islander.” The “Indigenous or Indigenous ancestry” category included the terms “American Indian or Alaska Native,” “Native Hawaiian or Pacific Islander,” “Asian/Native Hawaiian or Pacific Islander,” “White/Native Hawaiian or Pacific Islander,” and “White/American Indian or Alaskan Native.” The “other and other multiracial” category included the terms “Asian/White,” “Colored” (South Africa), “Pardo” (Brazil), “White/Brown” (Brazil), “multiracial any other,” and “not multiracial other.”
jAmong the participants who identified as gender nonbinary, 122 (89.7%) in the YEZTUGO group and 53 (84.1%) in the FTC/TDF group were assigned male at birth.
kThe “other” category included participants who identified as “Travesti” (3 participants in the YEZTUGO group and 3 in the FTC/TDF group) or as an “other” gender (3 in the YEZTUGO group and 1 in the FTC/TDF group).
lData are included for 1585 participants in the YEZTUGO group and 782 in the FTC/TDF group.
mIncluded are participants who were not taking PrEP at baseline (449 in the YEZTUGO group and 215 in the FTC/TDF group).
nChlamydia trachomatis and Neisseria gonorrhoeae diagnoses were based on testing of pharyngeal, rectal, and urethral (urine) samples, performed by central and local laboratories. Blood testing for syphilis was performed locally with the use of local testing protocols.
oUse of gender-affirming hormone therapy included concomitant use with the trial regimen during the randomized, blinded phase.
Proven HIV prevention across the broadest range of individuals1-5
YEZTUGO showed superior efficacy compared to FTC/TDF1,2
PURPOSE 1 included cisgender adolescent girls and young women.1,2
Efficacy endpoint: HIV incidence rate/100 PY
- Primary efficacy analysis: HIV incidence rate with YEZTUGO (0/100 PY) was significantly lower than bHIV (2.41/100 PY), IRR (95% CI): 0.000 (0.000, 0.042), p<0.00012
- Secondary efficacy analysis: HIV incidence rate with YEZTUGO (0/100 PY) was significantly lower than FTC/TDF (1.69/100 PY), IRR (95% CI): 0.000 (0.000, 0.101), p<0.00011,2
pThe determination of efficacy was based on interim analyses when 50% of randomized participants completed 52 weeks of follow-up. Based on results, the study arms were unblinded, and this interim analysis became the primary analysis.
YEZTUGO showed superior efficacy compared to FTC/TDF1,3
PURPOSE 2 included cisgender men, transgender men and women, and nonbinary persons.1,3
Efficacy endpoint: HIV incidence rate/100 PY
- Primary efficacy analysis: HIV incidence rate with YEZTUGO (0.1/100 PY) was significantly lower than bHIV (2.37/100 PY), IRR (95% CI): 0.043 (0.010, 0.182), p<0.00013
- Secondary efficacy analysis: HIV incidence rate with YEZTUGO (0.1/100 PY) was significantly lower than FTC/TDF (0.93/100 PY), IRR (95% CI): 0.111 (0.024, 0.513), p=0.002451,3
qThe determination of efficacy was based on interim analyses when 50% of randomized participants completed 52 weeks of follow-up. Based on results, the study arms were unblinded, and this interim analysis became the primary analysis.
Safety and tolerability data1-3
Review the safety profile for YEZTUGO, including adverse reactions and injection site reactions (ISRs), and see how the frequency of ISRs decreased with subsequent doses.
The only twice-yearly dosing1,4
The first-and-only HIV prevention option that is 2 subcutaneous injections every 6 months, done in office within a ±2-week continuation dosing window from the scheduled injection date.
bHIV=background HIV; CI=confidence interval; DHHS=US Department of Health and Human Services; FTC/TAF=emtricitabine/tenofovir alafenamide fumarate; FTC/TDF=emtricitabine/tenofovir disoproxil fumarate; INSTI=integrase strand transfer inhibitor; IRR=incidence rate ratio; NRTI=nucleoside/nucleotide reverse transcriptase inhibitor; PY=person-years; SC=subcutaneous.
Important Safety Information
BOXED WARNING: RISK OF DRUG RESISTANCE WITH USE OF YEZTUGO IN UNDIAGNOSED HIV-1 INFECTION
- Individuals must be tested for HIV-1 infection prior to initiating YEZTUGO, and with each subsequent injection of YEZTUGO, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of YEZTUGO by individuals with undiagnosed HIV-1 infection. Do not initiate YEZTUGO unless negative infection status is confirmed. Individuals who acquire HIV-1 while receiving YEZTUGO must transition to a complete HIV-1 treatment regimen.
Contraindications
- YEZTUGO is contraindicated in individuals with unknown or positive HIV-1 status.
Warnings and precautions
- Comprehensive risk management:
- Use YEZTUGO to reduce the risk of HIV-1 acquisition as part of a comprehensive prevention strategy including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs).
- HIV-1 acquisition risk includes behavioral, biological, or epidemiologic factors including, but not limited to, condomless sex, past or present STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high-prevalence area or network. Counsel individuals on the use of other prevention methods to help reduce their risk.
- Use YEZTUGO only in individuals confirmed to be HIV-1 negative. Evaluate for current or recent signs or symptoms consistent with HIV-1 infection. Confirm HIV-1 negative status prior to initiating, prior to each subsequent injection, and as clinically appropriate.
- Potential risk of resistance:
- There is a potential risk of developing resistance to YEZTUGO if an individual acquires HIV-1 before or when receiving YEZTUGO, or following discontinuation. HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection taking only YEZTUGO, because YEZTUGO alone is not a complete regimen for HIV-1 treatment.
- To minimize this risk, it is essential to test before each injection and additionally as clinically appropriate. Individuals confirmed to have HIV-1 must immediately begin a complete HIV-1 treatment regimen.
- Alternative forms of PrEP should be considered after discontinuation of YEZTUGO for those who are at continuing risk of HIV-1 acquisition and should be initiated within 28 weeks of the last YEZTUGO injection.
- Long-acting properties and potential associated risks:
- Residual concentrations of YEZTUGO may remain in systemic circulation for up to 12 months or longer after the last injection.
- Select individuals who agree to the required injection dosing schedule because nonadherence or missed doses could lead to HIV-1 acquisition and development of resistance.
- Serious injection site reactions: Improper administration (intradermal injection) has been associated with serious injection site reactions, including necrosis and ulcer. Only administer YEZTUGO subcutaneously.
Adverse reactions
- Most common adverse reactions (≥5%) in YEZTUGO clinical trials were injection site reactions, headache, and nausea.
Drug interactions
- Strong or moderate CYP3A inducers may significantly decrease YEZTUGO concentrations. Dosage modifications are recommended when initiating these inducers.
- It is not recommended to use YEZTUGO with combined P-gp, UGT1A1, and strong CYP3A inhibitors.
- Coadministration of YEZTUGO with sensitive substrates of CYP3A or P-gp may increase their concentrations and result in the increased risk of their adverse events. YEZTUGO may increase the exposure of drugs primarily metabolized by CYP3A initiated within 9 months after the last injection of YEZTUGO.
Dosage and administration
- HIV screening: Test for HIV-1 infection prior to initiating, prior to each subsequent injection, and as clinically appropriate using an approved or cleared test for the diagnosis of acute or primary HIV-1 infection.
- Dosage: Initiation dosing (injections and tablets) followed by once-every-6-months continuation injection dosing. Tablets may be taken with or without food.
- Initiation: Day 1: 927 mg by subcutaneous injection (2 x 1.5-mL injections) and 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally.
- Continuation: 927 mg by subcutaneous injection every 6 months (26 weeks) from date of last injection ±2 weeks.
- Anticipated delayed injections: If scheduled 6-month injection is anticipated to be delayed by more than 2 weeks, YEZTUGO tablets may be taken on an interim basis (for up to 6 months) until injections resume. Dosage is 300 mg orally (1 x 300-mg tablet) once every 7 days. Resume continuation injections within 7 days of the last oral dose.
- Missed injections: If more than 28 weeks have elapsed since the last injection and YEZTUGO tablets have not been taken, restart with initiation dosing if clinically appropriate.
- Dosage modifications of YEZTUGO are recommended when initiating with strong or moderate CYP3A inducers. Consult the full Prescribing Information for recommendations.
Indication
YEZTUGO is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents (≥35 kg) who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating YEZTUGO.
Please see full Prescribing Information for YEZTUGO, including BOXED WARNING.
References:
- YEZTUGO. Prescribing information. Gilead Sciences, Inc.; 2025.
- Bekker LG, Das M, Abdool Karim Q, et al; PURPOSE 1 study team. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. 2024;391(13):1179-1192.
- Kelley CF, Acevedo-Quiñones M, Agwu AL, et al; PURPOSE 2 study team. Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. N Engl J Med. 2025;392(13):1261-1276.
- Full efficacy and safety results for Gilead investigational twice-yearly lenacapavir for HIV prevention presented at AIDS 2024. News release. Gilead Sciences, Inc.; July 24, 2024. Accessed January 6, 2025. https://www.gilead.com/news/news-details/2024/full-efficacy-and-safety-results-for-gilead-investigational-twice-yearly-lenacapavir-for-hiv-prevention-presented-at-aids-2024
- Gallardo-Cartagena J, Phanuphak N, Ndlovu N, et al. Global racial, ethnic, and gender diversity among participants enrolled in the PURPOSE 2 trial of lenacapavir for pre-exposure prophylaxis. Paper presented at: 5th HIV Research for Prevention Conference (HIVR4P); October 6-10, 2024; Lima, Peru.
- Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Clinicalinfo. Updated September 12, 2024. Accessed May 13, 2025. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/adult-adolescent-arv/guidelines-adult-adolescent-arv.pdf