Background Lenacapavir is a first-in-class inhibitor of HIV-1 capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. Methods CAPELLA enrolled viremic HTE PWH with resistance to ≥ 3 of 4 of the main antiretroviral classes and resistance to ≥ 2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, RT, integrase genotypic/phenotypic tests). Post-baseline resistance was evaluated in participants experiencing virologic failure. Results At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one third of participants having exhausted all drugs from ≥ 3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Post-baseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. Conclusions LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

Background Lenacapavir in vitro resistance selections identified seven mutations in HIV-1 capsid protein (CA) associated with reduced susceptibility. Objectives To analyse lenacapavir activity against lenacapavir-associated resistance mutations in multiple assays. We also report Day 10 resistance analyses conducted in a Phase 1b study of lenacapavir (Study 4072) in people with HIV (PWH). Methods Mutations were inserted in a proviral DNA clone by site-directed mutagenesis, and viruses (n = 12) were generated by transfection. Sequences were used to generate single-cycle (SC) test vectors that were evaluated in a Gag-Pro assay, and replicative viruses were tested in a multicycle (MC) MT-2 assay to determine lenacapavir susceptibility. Study 4072 was a Phase 1b, double-blinded, placebo-controlled, dose-ranging, randomized study of lenacapavir in untreated PWH. Participants received a single dose of lenacapavir (up to 750 mg) or placebo (10 day monotherapy). CA resistance was characterized using genotypic and/or phenotypic assays. Results Lenacapavir susceptibility in the SC assay showed an inverse relationship between replication capacity and resistance. In Study 4072, all 29 participants receiving lenacapavir showed a robust virological response with no rebound. At baseline, no participant had resistance mutations to lenacapavir, and all had WT susceptibility to lenacapavir. Post-monotherapy analyses revealed the emergence of CA mutation Q67H at Day 10 in two participants. Conclusions In vitro assays confirmed that increased resistance to lenacapavir was associated with decreased replication capacity of mutant viruses. In the clinical study no pre-existing lenacapavir resistance was detected. Emergence of Q67H occurred at exposures below the dose used in current Phase 2/3 studies. These results support development of lenacapavir as an antiretroviral agent.

An eight-year-old boy presented with rhythmic myoclonic jerks that stretched back to the age of four years. He was diagnosed as having subacute sclerosing panencephalitis (SSPE). This is a progressive and almost uniformly fatal disease. His condition gradually deteriorated till he was unable to speak or walk. He also experienced incontinence and severe cognitive decline (stage 3a in the Risk and Haddad scale). An electroencephalogram (EEG) showed myoclonic jerks with periodic, generalised, high-amplitude and slow-wave complexes. Cerebrospinal fluid (CSF) findings also were supportive of the diagnosis of SSPE. The ketogenic diet (KD) therapy was started on the patient. His myoclonic jerks stopped after 11 months. After 36 months, his cognition and physical abilities vastly improved. His EEG showed no slow-wave complexes and background activity was almost normal. SSPE is secondary to measles and causes inflammatory and neurodegenerative changes. KD has an anti-inflammatory effect and can halt and reverse neurodegenerative changes. Its neuroprotective effects could be due to the reduced oxidative stress, enhanced mitochondrial activity, and the suppression of pro-apoptotic factors. Thus, KD could control the myoclonic jerks and also reverse the cognitive and physical decline arising from SSPE.

A 60-year-old man presented with a history of an acute episode of mono-ocular involvement and several acute spinal cord episodes from 1988 to 1991. Multiple MRIs of the spinal cord and brain and cerebrospinal fluid analysis were consistent with a clinical diagnosis of multiple sclerosis (MS). Following this, there was a quiescent period of four to five years, after which he reported progressive weakness and spasticity of lower limbs with urgency and precipitancy of urine. He was put on a ketogenic diet (KD) as a monotherapy in 2016. Within one month of starting the KD, his balance and weakness improved, and there was good bladder control. He continued KD for 18 months, after which he followed it inconsistently and eventually stopped KD, going back to his original diet. His weakness increased gradually until he was wheelchair-bound, and his precipitancy greatly worsened. He was put back on KD and has improved again to the extent that his stamina has increased, he can walk with the help of a cane, and his continence is good. Dietary therapy has a large role in the management of secondary progressive multiple sclerosis (SPMS) and, as in this case, may be effective even as a single-mode therapy. This is probably the first reported case of improvement in SPMS using KD as a monotherapy.

Background Lenacapavir (LEN) is a first-in-class HIV-1 capsid (CA) inhibitor in clinical development for treatment and prevention of HIV-1 infection. CALIBRATE is an ongoing, phase 2 clinical study evaluating subcutaneous (SC) or oral LEN, in combination with other antiretrovirals, in treatment-naïve people with HIV-1. High rates of virologic success (HIV-1 RNA < 50 copies/mL) were achieved with LEN-based regimens by FDA Snapshot analysis at Week 28. Here, we present interim resistance analyses through Week 28. Methods Participants were randomized (2:2:2:1) to treatment groups (TG) (Figure): SC LEN + oral daily emtricitabine/tenofovir alafenamide (F/TAF); at Week 28, participants switch F/TAF to oral TAF (TG-A) or bictegravir (B, BIC) (TG-B); oral daily LEN + F/TAF (TG-C), or oral daily B/F/TAF (TG-D). Genotypic analyses (population sequencing) of HIV-1 reverse transcriptase and integrase, and genotypic (deep sequencing)/phenotypic analyses for CA were performed at screening; genotypic and phenotypic analyses were conducted at confirmed virologic failure. Figure CALIBRATE Study Design Results 182 participants were randomized and dosed in TG-A to D (n=52, 53, 52, 25). Most participants had subtype B HIV-1 (92.9%). Sequence analysis of baseline samples found 65% of amino acid residues were conserved with < 1% variation across CA overall, and 55% of residues were fully conserved. No mutations were detected at 6 positions in CA associated with reduced susceptibility to LEN in vitro; residues were fully conserved at 5 positions (L56, M66, Q67, K70, N74), and < 2% variation was observed at 1 position (T107). Three participants met the criteria for resistance analysis: 2 participants resuppressed to < 50 copies/mL while continuing treatment. One participant on SC LEN + F/TAF developed emergent resistance to LEN (Q67H+K70R) and emtricitabine (M184M/I), followed by resuppression after starting dolutegravir, zidovudine + lamivudine, tenofovir disoproxil fumarate. Conclusion Emergent resistance to LEN was uncommon in treatment-naïve participants receiving SC or oral LEN (0.6%, 1/157). These interim resistance findings support the ongoing evaluation of LEN for treatment and prevention of HIV. Disclosures Laurie VanderVeen, PhD, Gilead Sciences (Employee, Shareholder) Nicolas Margot, MA, Gilead Sciences (Employee, Shareholder) Vidula Naik, MSc, Gilead Sciences (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences, Inc (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences, Inc (Employee, Shareholder) Hadas Dvory-Sobol, PhD, Gilead Sciences (Employee, Shareholder) Martin Rhee, MD, Gilead Sciences (Employee, Shareholder) Christian Callebaut, PhD, Gilead Sciences (Employee, Shareholder)