CROI 2021: First results using capsid inhibitor lenacapavir against MDR HIV: potential for six-monthly ART and PrEP

Simon Collins, HIV i-Base

Several studies at CROI 2021 expanded on the profile of the experimental long-acting capsid inhibitor lenacapavir which has an oral formulation for weekly dosing and a subcutaneous injection for 6-monthly dosing. This included the first clinical results in people with multidrug resistant HIV.

Thomas Cihlar presented an overview of capsid inhibition and the potential benefits as a drug target, covering the mechanism of action, pharmacokinetics (PK) and drug resistance. [1]

This included the history of this class and the 15-year development, with discovery of lenacapavir (previously GS-6207) from more than 3000 potential compounds, and with –2.3 log reductions in viral load in treatment-naïve participants in a phase 2b study presented at CROI last year.

Lenacapavir is active at multiple stages of the viral life cycle, including early uncoating (where it is most potent) but also later during core assembly and maturation phases. It has higher potency than other small molecule HIV drugs with activity in a picomolar range (mean EC50 0.05 nM: range 0.02 to 0.15) and in many cell types. As a drug in a new class, it remains sensitive to drug resistant HIV from all other classes. The binding site is conserved across all HIV-1 sub-types and slow metabolic clearance with single subcutaneous injection at doses of 30 mg to 450 mg produces systemic exposure for >6 months.

Significant drug resistant mutations during in vitro passaging include M66I, N74D (after 20 days) with Q67H mutation after 80 days. Further details on the drug resistant profile were presented in two other presentations at the meeting. [2, 3]

Importantly, CROI 2021 included clinical results were from a phase 2/3 study (CAPELLA) in 36 participants with multidrug resistant (to at least three classes) who had detectable viral load (>400 copies/mL) on their current ART. [4]

Participants were randomised (2:1) to add lenacapavir or placebo to current ART for 14 days before switching to an optimised background regimen (OBR) for a further 52 weeks. Entry criteria included having two or fewer sensitive drugs for the OBR.

A second cohort of 36 participants were enrolled in a non-randomised arm using open-label lenacapavir with OBR from day 1.

Baseline characteristics included median age 52 years (range 23 to 78), 25% were female at birth, and race included 38% black. Median CD4 was 150 cells/mm3 (range 3 to 1300) with 64% <200 cells/mm3. Median baseline viral load was 4.5 copies/mL (range 1.3 to 5.7) with 28% >75,000 copies/mL. Participants had considerable drug experience with median of 11 previous ARVs and median 24 years since HIV diagnosis.

At day 15, the primary endpoint of >0.5 log reduction in viral load was reported in 88% vs 17% of the active vs placebo groups respectively (difference: 71%, 95% CI 35 to 90%, p<0.0001). The median (range) change in viral load was –2.0 log copies/mL (range: –3.29 to –0.29) vs –0.08 (–1.93 to +0.31) in the active vs placebo groups. At week 4 (2 weeks after OBR), 58% (21/36) were undetectable (<50 copies/mL).

During median duration of follow up on lenacapavir of 26 weeks (range: 7 to 46), capsid mutations were detected in 2/72 participants. One reported M66I and N74D at week 10 when viral load was approximately 3000 copies/mL. This person had no fully active drugs in the OBR (maraviroc, T-20, DTG twice daily, DRV/COBI and 3TC) but resuppressed after changing the OBR. A second case detected M66I at 26 weeks when viral load was around 500 copies/mL. In this case viral load resuppressed without change to the OBR (F/TAF; with DRV/COBI and DTG twice daily).

There were no serious adverse events related to study drug, related discontinuations, or deaths. The most frequent side effects (any grade) were injection site swelling (28%) and nodule (25%). Injection site reactions (50%) were all mild or moderate.

These are impressive preliminary results and further follow-up will be reported later.

Several other studies looked at drug interactions and dosing.

Jordan Lutz et al. reported results from a PK drug interaction study on potential interaction between lenacapavir and strong inducers/inhibitors of P-gp, CYP3A and UGT1A1 or on sensitive P-gp, BCRP, OATP and CYP3A substrates. [5]

Consistent with in vitro studies, significant interactions were reported with strong UGT1A1 inhibitors and potent inducers of P-gp/UGT which should be avoided. Lenacapavir is a moderate inhibitor of CYP3A, and a weak inhibitor of P-gp and BCRP.

Results from a PK study in 10 participants with moderate hepatic impairment reported lenacapavir AUC and Cmax that were 1.5 and 2.6 fold higher than HIV negative controls. This was not judged clinically significant or needing a dose adjustment. [6]

Finally, results from a macaque study using lenacpavir as PrEP were also presented in at CROI 2021. Following a single long-acting injection and escalating weekly rectal challenge, breakthrough infections were detected in 3/8 animals after week 15, when all placebo animals had become infected (p=0.0002).  Although drug levels at this timepoint dropped below the EC95 these were 6-fold lower than seen with equivalent human formulation, suggesting that in vivo protection could be higher and for longer. [7]

Two large international phase 3 PrEP studies are planned to enroll later in 2021, using six-monthly lenacapavir injections and using either TDF/FTC or TAF/FTC as active controls.

As part of the treatment programme, a phase 2 study in HIV naïve participants (CALIBRATE) is fully enrolled with results expected later this year. [8]


These results highlight a remarkable drug profile and shortly after CROI 2021. Gilead announced in a joint statement with Merck/MSD that lenacapavir will be developed in combination with islatravir. [9]

Reducing ART to a six-monthly treatment without needing daily pills but maintaining undetectable viral load might for many people “feel” like a significant step to a cure.

Also, of interest for the role of capsid in the viral life cycle, a plenary lecture at CROI 2021 included electromicroscopy videos showing that rather than early uncoating early after entry into the CD4 cell, the capsid instead enters the cell nucleus intact and that reverse transcriptase converts viral RNA to DNA as a late stage in the nucleus. [10]


  1. Cihlar T et al. Lenacapavir (GS-6207): first clinically active long-acting inhibitor of HIV capsid. CROI 2021. Oral abstract 22. (abstract) (natap)
  2. Callebaut C et al. Activity and resistance characterization  of the HIV capsid inhibitor lenacapavir. CROI 2021. Oral abstract 128. (abstract) (webcast) (natap)
  3. Bester SM et al. Structural basis for viral resistance to long-acting HIV-1 capsid inhibitor GS-6207. CROI 2021. Poster abstract 420. (abstract) (webcast)
  4. Segal-Maure S et al. Potent antiviral activity of lenacapavir in phase 2/3 in heavily art-experienced PWH. CROI 2021. Oral abstract 127. (abstract) (webcast) (natap)
  5. Lutz J et al. Clinical evaluation of drug interactions with oral lenacapavir and probe drugs. CROI 2021. Oral abstract 89. (abstract) (webcast)
  6. Jogiraju V et al. Pharmacokinetics of lenacapavir, an HIV-1 capsid inhibitor, in hepatic impairment. CROI 2021. Poster abstract 375. (abstract) (poster webcast)
  7. Beckerman E et al. Long-acting HIV capsid inhibitor effective as prep in a shiv rhesus macaque model.
  8. Study to evaluate the safety and efficacy of lenacapavir in combination with other antiretroviral agents in people living with HIV (CALIBRATE).
  9. Gilead and Merck/MSD to collaborate on long-acting HIV combination of lenacapavir and islatravir. HTB (15 March 2021).
  10. HIV capsid uncoats in the CD4 nucleus rather than the cytoplasm – viral lifecycle updated… HTB (12 March 2021).

This report was first published on 16 March 2021.


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