CROI 2026: Long-Acting PrEP, Limits of Resistance, and Implementation
At the Conference on Retroviruses and Opportunistic Infections (CROI 2026), held in Denver (USA), an oral abstract session was dedicated to HIV pre-exposure prophylaxis (PrEP). There were no revolutionary discoveries in this session, but something more important happened: experts gave a technically mature assessment of the state of prevention science in 2026.
The session, which included five interconnected presentations, highlighted two major points: the exceptional biological effectiveness of prevention drugs and emerging structural problems in their use.
1. Islatravir and M184V: An Important Condition for Single-Agent PrEP
One of the most important presentations at the session was the preclinical study of the islatravir (MK-8591) implant.
At plasma concentrations considered clinically relevant (~1–4 nM), biodegradable islatravir implants provided full protection against repeated rectal exposure to wild-type SHIV (simian-human immunodeficiency virus). However, protection was significantly weakened when the animals were challenged with SHIV carrying the M184V mutation.
Key results:
- In vitro, there was a 10–20 fold reduction in drug susceptibility with M184V.
- Most animals became infected with the resistant SHIV strain.
- The difference compared to wild-type protection was statistically significant.
- Plasma and peripheral blood mononuclear cell drug levels were similar in both challenge groups.
Importantly, the failure to protect was not due to insufficient drug concentration. The same concentrations that protected against wild-type virus were ineffective against the virus with M184V — indicating that the issue is not dosage adequacy but a shift in pharmacodynamic targets.
QUESTIONS
During the discussion, one participant asked directly:
“If drug levels fall to the lower end of the protective range, will protection against virus with the M184V mutation be lost first?”
The presenter replied:
“The preventive threshold we use is based on wild-type virus. We do not yet know what that threshold will be for resistant variants.”
Another participant questioned the real-world relevance:
“In real transmission, viruses with M184V have reduced fitness. How does this challenge model reflect that ecological balance?”
Researchers acknowledged that differences in fitness make interpretation difficult but noted that resistant variants still transmit and circulate among treated populations.
Key conclusion:
Single-agent long-acting strategies with NRTTIs should consider pharmacodynamic thresholds adjusted for resistance, not only suppression of wild-type virus.
2. MK-8527: Monthly Oral PrEP and Quantitative Evaluation
The presentation on MK-8527 showed a different type of progress — less striking biologically but strategically important.
Using integrated population pharmacokinetic modeling based on multiple Phase 1 and Phase 2 studies, scientists selected a dose of 11 mg once a month for Phase 3 trials.
The choice was based on maintaining intracellular MK-8527 triphosphate (MK-8527-TP) above 0.03 pmol/10^6 PBMC, a preventive efficacy threshold derived from preclinical modeling and early human dose–response relationships.
Investigators emphasized the depth of the modeling:
- A five-compartment pharmacokinetic model
- Body weight included as a covariate
- No significant effects of sex or age
- Protective concentrations predicted at Day 31
- Protective exposures maintained through Day 38
- Adequate exposure predicted in pregnancy
QUESTIONS
One audience member focused on onset kinetics:
“If intracellular levels rise so quickly, could lower doses sustain efficacy in an event-driven approach?”
Answer:
“Current development focuses on maintaining stable monthly concentrations. Alternative strategies will require further evaluation.”
In light of the earlier islatravir discussion, resistance was also raised:
“How confident can we be that the preventive threshold holds in the presence of resistance mutations?”
Investigators acknowledged that resistance-adjusted modeling has not yet been fully developed.
Thus, MK-8527 occupies an intermediate position:
- Less invasive than injectable PrEP
- More stable adherence than daily oral regimens
- Potentially scalable in resource-limited settings
- Success dependent on how robust the pharmacokinetic threshold is across real-world viral diversity
3. ANRS Prévenir: Proof of PrEP Efficacy and Its Limits
The Prévenir cohort provided one of the most compelling long-term PrEP datasets shown at CROI in recent years.
Key findings:
- Over 13,000 person-years of follow-up
- Overall HIV incidence: 0.11 per 100 person-years
- No difference between daily and event-driven dosing
- Equivalence of event-driven PrEP over a median of nearly four years is now beyond doubt
But the most significant moment came from the epidemiological analysis comparing regional diagnoses in 2015–2016 versus 2023–2024:
- –33% among MSM born in France
- +73% among MSM born abroad
- +95% among transgender women
QUESTIONS
An epidemiologist in the audience asked:
“Can the regional decline be explained by the study itself, or are we observing broader long-term trends?”
Professor Molina responded:
“The study was not designed solely to assess efficacy, but also to promote PrEP uptake. We believe it contributed — but obviously not in all population groups.”
Another question addressed structural inequality:
“Are we protecting only those who already have access to care?”
The conclusion was clear. Biologically, PrEP worked. However, it did not transform the system everywhere.
Behavioral data further confirmed biological effectiveness: unprotected anal sex increased during follow-up, yet HIV incidence remained very low. Still, hepatitis C incidence (0.46 per 100 person-years) and high STI rates indicate persistent syndemic risk patterns.
4. PURPOSE 1: Lenacapavir in Cisgender Women — Near-Complete Protection
PURPOSE 1 remains one of the most important PrEP studies globally.
In the updated analysis of the randomized, blinded phase:
- 2 HIV cases among 2,134 participants receiving lenacapavir
- Incidence: 0.07 per 100 person-years
- Much higher incidence in oral comparator arms
Detailed analysis of breakthrough cases was presented:
Participant C:
- Received injections on schedule
- Diagnosis at Week 65
- Lenacapavir level at diagnosis: 44.6 ng/mL
- Inhibitory quotient (IQ4) above the target
This raised a critical question:
“How can infection occur at therapeutic drug levels?”
Researchers noted that the explanation remains under investigation, with potential hypotheses:
- Infection closer to the end of the dosing interval
- Viral load exceeding pharmacologic limits
- Local tissue variability not reflected in plasma levels
Participant D:
- Missed injection at Week 52
- Diagnosis about 487 days after last injection
- Lenacapavir level at diagnosis: 0.65 ng/mL (below threshold)
QUESTIONS
One listener asked:
“Are there demographic or biological predictors of breakthrough infections?”
Answer:
“At this stage, no consistent distinguishing features have been identified.”
There was also discussion of community perceptions:
“How do participants react to rare breakthrough infections?”
Response:
“Acceptability remains high. The efficacy profile is still exceptional.”
5. PURPOSE 2: Lenacapavir in MSM and Gender-Diverse Individuals
Updated data showed:
- 2 HIV cases in the lenacapavir arm during primary analysis
- Additional cases during extended follow-up
- 12 cases in the daily oral TDF/FTC arm
Conclusions remained unchanged: lenacapavir provides substantially greater protection than daily oral PrEP. Breakthrough analyses again focused on pharmacokinetics and adherence. No clear new resistance profiles have yet emerged, but monitoring continues.
Unified Scientific Message
Across all five presentations, a clear hierarchy of prevention strategies emerged:
- Twice-yearly injectable lenacapavir: highest efficacy
- Monthly oral MK-8527: promising flexible alternative
- Daily and event-driven TDF/FTC: proven, sustainable, scalable
- Single-agent NRTTI strategies: sensitive to resistance
CROI 2026 demonstrated that pharmacologic prevention is no longer the limiting factor in the fight against HIV. Instead, the key limiting factors are:
- Resistance ecology
- Adherence to dosing intervals
- Structural inequality in drug access
- Population coverage
As one leading prevention researcher noted after the session:
“The biological problem is nearly solved. What remains is the problem of distribution — of medicines, of access, and of trust.”