SARS-CoV-2 mRNA VACCINATION EXPOSES LATENT HIV to Nef-SPECIFIC CD8+ T CELLS

Background: The kinetics and functional profiles (granzyme-B production) of HIV-specific T-cell responses support that those targeting the early viral gene product Nef disproportionately recognize residual antigen expression during long-term antiretroviral therapy (ART). Here, we leveraged this insight to test whether SARS-CoV2 mRNA vaccines-which activate TLR and inflammatory signaling pathways-would reactivate latent HIV, stimulating T-cell responses with these characteristics. Methods: T-cell responses to individual HIV gene products were measured by IFN-g or granzyme B ELISPOT, and by activation induced marker (AIM) assays at baseline and ∼2 weeks after SARS-CoV-2 mRNA vaccine prime and boost, in 13 long-term ART treated adults. Total and unspliced HIV mRNA, as well as intact and defective (IPDA) HIV DNA were measured in parallel by digital droplet PCR (ddPCR). Results: We observed transient increases Nef-specific T-cell responses following vaccine prime by granzyme B ELISPOT (3.1-fold increase, p=0.002) and a trend by AIM assay (1.5-fold increase, p=0.06). Such increases were not observed in granzyme B responses to late gene products nor in any IFN-g responses. Both unspliced and total HIV mRNA decreased significantly across the study, unspliced-1.6-fold decrease p = 0.03;total-1.5-fold decrease p = 0.05. Changes in total HIV mRNA correlated inversely with Nef-specific granzyme B-producing (spearman's ρ =-0.73, p = 0.006) and Nef-specific CD8+ AIM T-cell responses (ρ =-0.76, p = 0.006) following vaccine prime. These reductions in HIV RNA were not accompanied by significant changes in total or intact HIV DNA. Conclusion: Consistent with our hypothesis, a restricted profile of HIV-specific T-cell responses showed significant increases following SARS-CoV-2 vaccine prime, each of which were then correlated with reductions in HIV RNA. This supports that vaccination promoted productive interactions between Nef-specific CTL and HIV-infected cells in vivo. We propose three scenarios for why this was not reflected in reductions in intact or total HIV DNA: i) meaningful depletions in inducible proviruses occurred but were lost against the background of non-inducible proviruses ii) interactions with CTL involved only a fraction of inducible proviruses, or iii) substantive proviral depletions occurred, but were counterbalanced by clonal expansion of HIV-infected cells.

Efficacy and safety of s201086/GLPG1972, an ADAMTS-5 inhibitor, in patients with knee osteoarthritis: roccella, a 52-week, randomized, double-blind, dose-ranging phase 2 study

Purpose: To date, no disease-modifying osteoarthritis drugs (DMOADs) have been approved for the treatment of knee osteoarthritis (OA). S201086/GLPG1972 is a potent and selective inhibitor of ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motif-5) in development as a DMOAD, hypothesized to reduce cartilage loss via inhibition of the enzymatic cleavage of aggrecan (a key component of cartilage). S201086/GLPG1972 has been shown to reduce cartilage degradation in preclinical models of OA. Therefore, we aimed to evaluate the efficacy and safety of S201086/GLPG1972 in patients with knee OA. Methods: ROCCELLA was a randomized, placebo-controlled, dose-ranging, phase 2 study comprising a 5-week screening period, a 52-week double-blind treatment period and a 2-week safety follow-up period (ClinicalTrials.gov ID: ). Patients aged 40-75 years with knee OA and pain severity in the target knee of 40-90 mm on a visual analog scale at screening and baseline were included. Target knees had predominant medial compartment disease, with Kellgren-Lawrence (KL) grade 2 or 3 and OARSI medial joint space narrowing (JSN) grade 1 or 2. Patients were randomized 1:1:1:1 to placebo or 75 mg, 150 mg or 300 mg S201086/GLPG1972 administered orally once daily. Concomitant analgesics (non-steroidal anti-inflammatory drugs and acetaminophen) were permitted. The primary endpoint was change from baseline to week 52 in cartilage thickness of the central medial femorotibial compartment (cMFTC) of the target knee, as measured by quantitative magnetic resonance imaging (qMRI) and analyzed by a central reading facility. Secondary efficacy endpoints included: change from baseline to week 52 in radiographic joint space width of the target knee (JSW;X-ray with central readout);patient-reported outcomes (including WOMAC scores, patient global assessment [PGA] score and pain score, both measured by visual analog scales);and safety outcomes. A mixed-effects model for repeated measures (using all longitudinal observations at each post-baseline visit) was used for the primary analysis. Results: Across 12 countries, 3319 patients were screened and 932 were included in the study. Patients had a mean age of 62.9 years and the majority (69.3%) were women. Baseline characteristics were similar across study groups (Table 1). Overall, 88.8% of knees were KL grade 3 and 67.3% were OARSI medial JSN grade 2. Patients experienced substantial cartilage loss;the mean (SD) change in cMFTC cartilage thickness was −0.12 (0.27) mm from baseline to week 52 in the placebo group. However, no statistically significant differences between treatment groups and placebo were observed for the primary endpoint of cMFTC cartilage thickness loss (placebo vs 75 mg, p = 0.165;vs 150 mg, p = 0.939;vs 300 mg, p = 0.682;Figure 1). These results were confirmed by sensitivity analyses assessing the management of missing data and delayed week 52 qMRI owing to the COVID-19 pandemic. No significant differences between treatment groups and the placebo group were observed at any time point in any of the secondary endpoints, including changes in WOMAC total score and subscores (Figure 2), radiographic JSW, PGA score or pain score. Treatment-emergent adverse events (TEAEs) and serious adverse events were experienced by similar proportions of patients in the placebo and S201086/GLPG1972 groups (Table 2). The most common TEAEs across all S201086/GLPG1972 treatment groups were arthralgia, nasopharyngitis and fall (Table 2). Tolerability was similar across the three S201086/GLPG1972 dose groups, with 6.8% (75 mg) to 8.6% (300 mg) of patients withdrawing from treatment owing to TEAEs, compared with 3.8% in the placebo group. Conclusions: The study successfully selected patients who experienced a substantial decrease in cartilage thickness over 52 weeks;a decrease that would be large enough to demonstrate a sizeable structural benefit of a DMOAD candidate. However, the study failed to meet its primary endpoint (change from baseline to week 52 in cartilage thickness of the cMFTC) and secondary endpoints, and there was no dose-response relationship. S201086/GLPG1972 had a good safety profile and was generally well tolerated. [Formula presented] [Formula presented] [Formula presented] [Formula presented]

The Use of Chisels in the Extraction of Mandibular Third Molars: A Technique That May Prevent the Aerosolization of Severe Acute Respiratory Syndrome Coronavirus 2.

An aerosolizing reducing technique for the extraction of impacted mandibular third molars with the use of a bibevel chisel and mallet will be presented. Every oral and maxillofacial surgeon should have this technique in their armamentarium, especially with the current global pandemic with the severe acute respiratory syndrome coronavirus 2, the cause of coronavirus disease 2019. In this era, we must all consider ways to reduce the number of aerosols produced during the extraction of third molars. Prioritizing hand instrumentation with the use of chisels and mallets will reduce aerosolization as compared with the more traditional technique of using a surgical handpiece.