73. Interim Resistance Analysis of Long-Acting Lenacapavir in Treatment-Naïve People with HIV at 28 Weeks

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)

Disease Severity, Resistance Analysis, and Expression Profiling of Pathogenesis-Related Protein Genes after the Inoculation of Fusarium equiseti in Wheat

Wheat (Triticum aestivum) is an important cereal crop, grown throughout the temperate and in some tropical and sub-tropical zones, at higher elevations. Several biotic and abiotic factors influence the production of wheat. In the present study, two wheat varieties have been subjected to disease severity and resistance analysis against Fusarium equiseti. Disease severity analysis revealed Shafaq-2006 to be more resistant than Sahar-2006. Both varieties were further subjected to the expression analysis of six important defense-related genes by RT-PCR and quantitative real-time PCR. This analysis revealed that PR-1, TLP, Chitinase, and β-1,3-glucanase genes were highly expressed in Shafaq-2006 and possibly play a significant role in its defense mechanism. In addition, biochemical and physiochemical parameters were also studied to further explore the difference between resistant and susceptible varieties. With total proline and protein contents, sugar and chlorophyll contents also increased significantly in resistant variety. Likewise, higher relative water content, total plant length, and the high root–shoot ratio was observed in resistant plants, compared to susceptible wheat plants. These increases in chemical and physiological parameters might be related to the activation of the defense mechanism due to the higher expression of PR genes in the resistant wheat variety. These genes can further be employed for cloning into wheat and other transgenic crops to develop resistance against F. equiseti.