YEZTUGO - A Twice-Yearly PrEP Injection Transforming HIV Prevention

SUMMARY

This article summarizes the June 2025 FDA approval of Yeztugo, a long-acting HIV prevention drug for adults and adolescents. I review Yeztugo's mechanism of action, clinical trial data, and discuss potential impacts on HIV prevention.

BACKGROUND

Understanding HIV and AIDS

Human Immunodeficiency Virus (HIV) is mainly transmitted through bodily fluids such as blood, semen, vaginal fluids, and breast milk. It originated from a simian immunodeficiency virus (SIV) that infects chimpanzees. Through cross-species transmission, SIV is believed to have infected humans most likely through contaminated blood.

Once inside the human body, HIV targets CD4+ T cells that are crucial in fighting off common infections. Targeting occurs via the binding of viral glycoprotein called gp120 binds to CD4 receptors on CD4+ T cells. Once infected, the viral RNA is converted to DNA by an enzyme called reverse transcriptase (RT). Viral DNA can efficiently integrate into the host CD4+ T cell to facilitate replication to produce multiple viral copies. Over time, the CD4+ T cell count drops, increasing susceptibility to infections. If left untreated, this process can lead to acquired immunodeficiency syndrome (AIDS).

Prognosis Without Treatment 

Without medical intervention, the average lifespan of an HIV-positive person is about 11 years. However, with an AIDS diagnosis, the average lifespan of patients can decrease to just three years without treatment.

Strategies to Prevent Viral Replication

Our understanding of how HIV infects CD4 T cells helps us come up with methods of preventing infection. Some of the mechanisms that are targeted using existing drugs are described below:

1) Binding/Infection - HIV can be blocked from binding to CD4 receptors by using inhibitors of gp120. Chemokine receptors like CCR5 and CXCR4 function as coreceptors of HIV binding. Inhibitors of these coreceptors also help prevent viral binding.

2) Reverse Transcription - Inhibitors targeting RTs prevent reverse transcription of viral RNA into DNA and thereby inhibit viral replication.

3) Integration: Viral DNA uses an enzyme called Integrase to integrate into the host DNA. Targeting the function of this enzyme inhibits the replication cycle. A specific type of integrase inhibitors that block the viral strand transfer step is called integrase strand transfer inhibitors (INSTIs).

4) Replication and Reinfection: Multiple mechanisms can be targeted to prevent viral replication.

a) Protease inhibition: HIV needs an enzyme called HIV proteases to cleave precursor proteins into smaller fragments required to assemble new viral particles. Therefore, drugs binding to the active site of HIV protease prevent effective viral replication.

b) Capsid inhibition: Capsids are protein shells that protect the viral genetic material. Capsid inhibitors are effective in preventing viral replication and subsequent infection of other healthy cells.

Current Treatment Options

The most common treatment for HIV is antiretroviral therapy (ART). ART uses a combination of drugs targeting different stages of viral infection and replication. This combination approach ensures effective control of viral levels while minimizing drug resistance. With fewer viruses in the body and an increased count of CD4+ T cells, patients can effectively fight the disease and live long and healthier lives.

Limitations of ART

ART has been very effective at controlling the disease. However, it must be taken daily for life. Stopping therapy can cause viral rebound and disease progression. Additionally, ART is associated with side effects like nausea, diarrhea, and mood changes. The ongoing social stigma also contributes to poor adherence, making this approach less ideal.

LENACAPAVIR - A NEW APPROACH

Lenacapavir was formerly approved as Sunlenca by Gilead in 2022. Lenacapavir is a capsid inhibitor that prevents HIV from forming mature virus particles. It was initially indicated for use with other ARTs in individuals with multidrug-resistant HIV. The remarkable six-month half-life means less frequent dosing, making it easier to ensure patient compliance!

YEZTUGO

Yeztugo also contains lenacapavir as its active ingredient. It was approved in June 2025 for pre-exposure prophylaxis (PrEP) in HIV-negative individuals at high risk of infection. As a PrEP medication, Yeztugo reduces HIV acquisition in high-risk adults and adolescents. What makes this drug more remarkable than existing drugs is its long-lasting effects. Yeztugo only needs to be administered biannually or twice-yearly to achieve a significant improvement in disease prevention.

Comparison to Existing PrEPs

PrEP medications significantly reduce the risk of contracting HIV in high-risk adults by 99% when taken as prescribed.

Current PrEP options include daily oral tablets such as Truvada® and Descovy®, both of which inhibit reverse transcriptase-mediated viral replication. Apretude®, a once-monthly injectable Integrase Strand Transfer Inhibitor (INSTI), offers a long-acting alternative. Even more durable, Yeztugo offers the advantage of only two injections per year. However, it requires administration by a healthcare provider, unlike oral PrEP medications that can be self-administered.

Clinical Trial Outcomes

Yeztugo was evaluated in two randomized, double-blind, active-controlled clinical trials. The first trial enrolled a predominantly young cisgender Black female population. This trial demonstrated a 100% efficacy using Yeztugo. The second trial included a broader and more diverse cohort, including cisgender men, transgender women, transgender men, and gender nonbinary individuals. In this study, Yeztugo reduced the risk of HIV infection by 89% in participants compared to those who received daily doses of Truvada.

Side Effects

63% of participants reported an injection site nodule. However, this is based only on the clinical trials that led to the FDA approval.

Cost

Yeztugo costs $14,109 per injection or $28,218 per year in the United States. The annual cost of taking Yeztugo is comparable to existing PrEP options. However, the convenience of a twice-yearly injection may increase compliance.

PrEP	Frequency of Dosing	Mode of Delivery	Side Effects	Cost per year
Truvada®	Daily	Oral	nausea, diarrhea, headache, and fatigue	$24,000
Descovy®	Daily	Oral	nausea, diarrhea, headache, and fatigue	$26,400
Apretude®	Monthly	Injectable intramuscular	nausea, diarrhea, headache, fatigue, injection site reactions	$22,200/year
Yeztugo	Bi-Annual	Injectable subcutaneous	Injection site nodule	$28,218/year

CONCLUSION

Yeztugo marks a significant advance in HIV prevention with its long-lasting formulation and high effectiveness. Its approval signifies a move toward simpler, high-adherence PrEP options that could help high-risk groups. Increased efforts to ensure equitable access across all communities will further improve effectiveness.