Cross-resistance to entry inhibitors and lenacapavir resistance through Week 52 in study CAPELLA.

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people with HIV (PWH) harbouring multidrug resistance in combination with an optimized background regimen (OBR). Here, we describe in vitro analysis of the interplay between entry inhibitors (EI; enfuvirtide, fostemsavir, ibalizumab, and maraviroc) susceptibility and LEN susceptibility in samples from 72 participants in the phase 2/3 CAPELLA study, as well as the emergence of resistance in CAPELLA through 52 weeks. METHODS: The phenotypic susceptibility to EIs of screening samples from participants was analysed using entry assays, and susceptibility to LEN was generated. Genotypic and phenotypic resistance to LEN was evaluated for subjects with virological failure through Week 52. RESULTS: Overall, viruses with resistance to EIs showed no cross-resistance to LEN, with a mean fold change from wild type close to 1.0. Of the 22 participants analysed for resistance through Week 52, 9 participants (13%) had emergence of capsid resistance mutation(s) while the remaining 13 participants (18%) had no change in the capsid sequence. CONCLUSION: The gag sequence from EI-resistant isolates did not affect LEN susceptibility. The lack of cross-resistance to LEN across ARV-resistant isolates supports the use of LEN in PWH regardless of their treatment history. During the second half-year period of the CAPELLA Study, development of LEN resistance was rare and was overall associated with functional LEN monotherapy due to either nonadherence or resistance-driven non-susceptibility to OBR.

Rapid HIV-1 genotyping assay for the detection of capsid mutations.

Human immunodeficiency virus (HIV) capsid is one of the most recent viral proteins successfully targeted for the development of antiretrovirals. Lenacapavir is a first in class HIV-1 capsid inhibitor that was recently approved for the treatment of highly treatment-experienced people with HIV in combination with other anti-HIV drugs. Owing to the novelty of the viral target, methods to characterize the potential resistance-associated mutations present in capsid upon treatment failure have not been fully established yet. Here, we describe a rapid and simple method to amplify capsid fragments and to determine their sequence from various clinical samples including diverse HIV-1 subtypes. These methods could easily be implemented in laboratories, including hospital laboratories often caring for this patient population.

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir.

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (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 (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline 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. Postbaseline 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.

Phenotypic resistance to lenacapavir and monotherapy efficacy in a proof-of-concept clinical study.

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.

Substantial Remission in Subacute Sclerosing Panencephalitis by Following the Ketogenic Diet: A Case Report.

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.

Dietary Therapy in Secondary Progressive Multiple Sclerosis: A Case Report.

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.