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Pharmacokinetics, pharmacodynamics, efficacy and drug resistance selection of injectable long-acting lenacapavir pre-exposure prophylaxis (PrEP) against HIV

This study utilizes an integrated pharmacokinetic-pharmacodynamic model to demonstrate that twice-yearly injectable lenacapavir achieves sustained protective concentrations against wild-type HIV and specific drug-resistant mutants, while also highlighting the risk of de novo resistance emergence upon discontinuation and the need for strategies to manage PrEP cessation.

Original authors: Kim, H.-y., Liebenberg, A., Zhang, L., Von Kleist, M.

Published 2026-02-06

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Kim, H.-y., Liebenberg, A., Zhang, L., Von Kleist, M.

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

The Big Picture: A Long-Lasting Shield Against HIV

Imagine HIV prevention like wearing a raincoat. For years, the only option was a daily pill (the "oral raincoat"). While it works great, many people struggle to remember to take it every single day, especially women who face higher risks globally.

Enter Lenacapavir (LEN). Think of this as a "super-raincoat" that you only need to put on twice a year. It's a long-acting injection that stays in your body for a very long time, protecting you from HIV infection without the daily hassle.

This paper by Hee-yeong Kim and colleagues acts like a weather forecast and safety inspector for this new super-raincoat. They built a complex computer model to answer two big questions:

How strong is the shield? Does it actually stop the virus?
What happens when you take the coat off? If you stop using the injection, does it leave you vulnerable in a dangerous way?

1. How the Shield Works (The "Magic" of the Injection)

The researchers created a mathematical model to track how the drug moves through the body.

The Injection: When you get the shot (either under the skin or into a muscle), the drug doesn't just vanish. It's like a slow-release candy. A small part dissolves immediately, but most of it forms a "depot" (a little reservoir) at the injection site that slowly leaks the drug into your bloodstream over months.
The Protection Level: The model calculated exactly how much drug needs to be in your blood to stop the virus.
- They found a "magic number": 4.7 nanograms per milliliter. If your blood has this much drug, you are 95% protected.
- If you have 5 nanograms or more, you are fully protected against the standard (wild-type) virus.
- Good News: For an "average" person, this protective level is reached just 23 hours after the first shot and stays high for 50 weeks after the last shot.

2. The Enemy: Drug-Resistant Viruses

Viruses are tricky; they mutate. Imagine the virus as a lock, and the drug as a key. Sometimes, the virus changes the shape of the lock (mutation) so the key no longer fits.

The researchers looked at specific "lock changes" (mutations like Q67H, N74D, etc.) that make the virus resistant to Lenacapavir.

The "Danger Zone" (Mutant Selection Window): This is a specific range of drug levels.
- Too High: The drug kills everything (both normal and mutant viruses).
- Too Low: The drug does nothing; the virus grows freely.
- Just Right (The Danger Zone): The drug is strong enough to kill the normal virus, but too weak to kill the mutant virus. In this zone, the mutant virus wins and takes over.
The Finding: The study found that for some complex mutant viruses (like double or triple mutations), the drug levels in an average person's body actually sit right inside this "Danger Zone." This means if a person is exposed to a resistant virus, the drug might not stop it, and could even help the resistant version spread.

3. The "Long Tail" Problem: What Happens When You Stop?

This is the most critical part of the paper. Because the drug stays in the body for so long (like a slow-dripping faucet), stopping the injections doesn't mean the protection stops immediately.

The Scenario: Imagine a person stops their injections because they can't afford them, lose insurance, or just decide to quit.
The Risk: For about 6 to 8 months (and up to a year for some people) after the last shot, the drug level in their blood slowly drops.
The Trap: During this drop, the drug level might fall into that "Danger Zone" mentioned above.
- If this person gets infected with the normal virus during this time, the drug isn't strong enough to kill it completely.
- However, it is strong enough to kill the normal virus's competition, allowing the virus to mutate and become drug-resistant right inside that person's body.
The Timeline: The model predicts that for an average person, this risk of creating a new, resistant virus starts about 11 months after the last shot and can last for several months.

4. Who is Most at Risk?

The paper highlights a difference between two types of threats:

Transmitted Resistance: If you catch a virus that is already resistant from someone else, the drug might not stop it. The model shows that for some complex mutant viruses, the drug offers very little protection.
De Novo Resistance (Newly Created): This is the risk of creating a resistant virus yourself after stopping the drug. The model suggests that the Q67H mutation is the most likely to appear first because it's "easy" for the virus to make and doesn't hurt the virus much. However, if the virus keeps mutating, it could eventually become a "super-resistant" triple mutant.

Summary: The Takeaway

The paper concludes that while the twice-yearly Lenacapavir injection is a breakthrough that solves the problem of daily pill-taking, it comes with a unique safety challenge.

Because the drug lingers in the body for so long, stopping the treatment is not a clean break. There is a "grace period" where the drug levels are too low to prevent infection but high enough to encourage the virus to mutate and become resistant.

The authors' main message: We need strategies for how to safely stop taking this long-acting drug. People need to know that even after their last shot, they are not immediately "drug-free," and there is a window where they could accidentally create a drug-resistant version of HIV if they get infected.

Note: The paper emphasizes that these findings are based on mathematical models and lab data, serving as a warning to plan for safe discontinuation strategies, rather than a report of widespread current failures.

Technical Summary: Pharmacokinetics, Pharmacodynamics, Efficacy, and Drug Resistance Selection of Injectable Long-Acting Lenacapavir PrEP

Problem Statement
Oral pre-exposure prophylaxis (PrEP) using daily tenofovir disoproxil fumerate/emtricitabine (TDF/FTC) is highly effective but faces significant adherence challenges, particularly among heterosexual cis-women. Long-acting (LA) formulations, such as twice-yearly subcutaneous (SC) injections of the HIV capsid inhibitor lenacapavir (LEN), offer a promising alternative. However, clinical trials have limitations in precisely quantifying prophylactic efficacy benchmarks and assessing the risk of drug resistance emergence. A critical concern is that LA-PrEP agents persist in the body for extended periods (half-lives of 56–84 days for LEN). If a user discontinues PrEP due to side effects, financial constraints, or lack of insurance, drug concentrations may remain in a "mutant selection window" (MSW) for months or years. This creates a risk where a subsequent HIV infection with a wild-type (WT) virus could lead to the de novo selection of drug-resistant variants, a scenario difficult to evaluate in standard clinical trials. Currently, no mathematical framework exists to quantify LEN's prophylactic efficacy across different administration routes or to model the specific risks of resistance emergence upon discontinuation.

Methodology
The authors developed an integrated pharmacokinetic-pharmacodynamic (PK-PD) model coupled with HIV-1 viral dynamics and evolutionary models.

PK Modeling: A one-compartment PK model was fitted to 15 single-dose regimens across three routes (oral, SC, and intramuscular [IM]). The model accounts for:
- Oral: First-order absorption and elimination.
- Parenteral (SC/IM): A dual-release mechanism where a fraction of the dose enters systemic circulation directly ( $k_{direct}$ ), while the remainder forms a solid depot released indirectly ( $k_{indirect}$ ) via an Erlang distribution to capture lag times.
- Variability: Inter-individual variability (IIV) was incorporated using data from the PURPOSE 2 trial, establishing concentration ranges from 0.15 to 4.0 times the median.
PD and Viral Dynamics:
- LEN's mechanism of action was modeled as interfering with the late phase of the viral replication cycle (maturation), producing non-infectious particles.
- Antiviral potency ( $IC_{50}$ ) was estimated by linking the PK model to viral load decay data from a Phase Ib monotherapy study, yielding an $IC_{50}$ of 1.6 ng/mL.
- The model calculates the instantaneous reproduction number ( $R_t$ ) for specific viral strains (WT and mutants) based on drug concentration and strain-specific fold-change (FC) in susceptibility.
Efficacy and Resistance Metrics:
- Prophylactic Efficacy: Calculated as the relative risk reduction of infection compared to a WT challenge without PrEP.
- Mutant Selection Window (MSW): Defined as the concentration range where $1 < R_t(WT) \leq R_t(mutant)$ , allowing resistant strains to replicate while WT is suppressed.
- De Novo Resistance: A multi-strain ODE system was used to compute the probability of infection establishment and subsequent resistance selection after a WT infection, specifically modeling the scenario where a user stops PrEP and the drug concentration declines slowly.

Key Results

Pharmacokinetics: The model accurately captured concentration-time profiles for oral, SC, and IM routes. For SC injections (927 mg), approximately 88–98% of the dose is released via a slow depot mechanism, ensuring sustained levels.
Protective Concentrations:
- The 95% preventive plasma concentration ( $EC_{95}$ ) for WT virus is 4.7 ng/mL.
- Full protection (>99%) requires concentrations >5 ng/mL.
- In an "average" individual, the 927 mg SC injection reaches >5 ng/mL within 23 hours and maintains this level for up to 50.5 weeks after the last dose.
Efficacy Against Transmitted Resistance:
- While population-average steady-state concentrations (32–62 ng/mL) provide full protection against WT and the single mutant Q67H, inter-individual variability (4.8–240 ng/mL) creates gaps.
- Infection with the single mutant N74D is not fully prevented in all individuals; median efficacy drops to as low as 11% in some cases due to intrinsic fitness disadvantages rather than drug failure.
- Double and Triple Mutants: Infection risks for double mutants (e.g., Q67H+N74D, Q67H+T107N) and the triple mutant (Q67H+K70R+T107N) remain high (median infection risks of 24–63% for double mutants and 2–6% for the triple mutant), indicating that transmitted drug resistance poses a significant threat to PrEP efficacy.
De Novo Resistance Emergence:
- Upon stopping LEN-PrEP, drug concentrations remain in the MSW for a prolonged period.
- For an average individual, the window for de novo resistance emergence (where WT infection can occur and select resistance) lasts approximately 206 to 235 days after the last injection for various mutations.
- The single mutant Q67H is the most likely to emerge de novo due to its high intrinsic fitness, followed by N74D.
- Conversely, highly resistant strains (like the triple mutant) are more likely to be transmitted to PrEP users than to emerge de novo in stopping users, as the latter requires sequential accumulation of mutations.
- For once-yearly IM dosing, this risk window extends to approximately two years.

Significance and Claims
The authors claim this study provides the first quantitative framework to assess the benefits and risks of LEN-PrEP regarding drug resistance selection. Key contributions include:

Quantification of Benchmarks: Establishing specific plasma concentration thresholds (4.7 ng/mL for 95% efficacy, >5 ng/mL for full protection) that are difficult to derive solely from clinical trial data.
Risk Stratification: Demonstrating that while LA-LEN PrEP is highly effective against WT virus, it offers limited protection against certain transmitted drug-resistant variants, particularly double and triple mutants.
Discontinuation Warning: Highlighting a critical public health gap: the long pharmacokinetic tail of LEN creates a "silent" risk period where individuals who have stopped PrEP may still harbor drug concentrations sufficient to select resistance if they acquire HIV.
Strategic Implications: The findings underscore the necessity for specific strategies to manage LEN-PrEP discontinuation to prevent de novo resistance, a challenge less pronounced with oral PrEP due to shorter half-lives and higher genetic barriers to resistance.

The paper concludes that while twice-yearly LEN represents a breakthrough, its long persistence necessitates careful management of discontinuation to mitigate the risk of selecting drug-resistant HIV strains.