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In this international trial involving 371 patients with highly drug-resistant HIV-1 infection, fostemsavir reduced the HIV-1 RNA level by 0.79 log 10 copies per milliliter during the first 8 days of treatment. At week 48, more than half the patients treated with fostemsavir and an optimized background regimen had a virologic response.

Weight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied. We conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being). A total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was -13.7% with semaglutide and -3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was -41.7 points with semaglutide and -27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation. Among participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.).

Introduction BMS‐663068 is a prodrug of BMS‐626529, an attachment inhibitor that binds directly to HIV‐1 gp120, preventing initial viral attachment and entry into the host CD4+ T‐cell. AI438011 is an ongoing, Phase IIb, randomized, active‐controlled trial investigating the safety, efficacy and dose–response of BMS‐663068 vs. atazanavir/ritonavir (ATV/r) in treatment‐experienced (TE), HIV‐1‐positive subjects. At Week 24, response rates across the BMS‐663068 arms were consistent with ATV/r. Materials and Methods Antiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (including BMS‐626529 IC50 100 nM) were randomized equally to four BMS‐663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control arm (ATV/r 300/100 mg QD), with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). The complete safety profile through Week 24 is reported. Results In total, 251 subjects were treated (BMS‐663068, 200; ATV/r, 51). No BMS‐663068‐related adverse events (AEs) led to discontinuation. Grade 2–4 drug‐related AEs occurred in 17/200 (8.5%) subjects across the BMS‐633068 arms; however, these events were mostly single instances and no dose‐relationship was seen. Similarly, no noticeable trend for Grade 3–4 laboratory abnormalities was seen and Grade 3–4 hematologic changes and liver chemistry elevations were uncommon (neutropenia, 2.5%; AST/ALT elevations, 1% (n=196)). In the ATV/r arm, Grade 2–4 drug‐related AEs occurred in 14/51 (27.5%) subjects and were mostly secondary to gastrointestinal and/or hepatobiliary disorders. Serious adverse events (SAEs) occurred in 13/200 (6.5%) and 5/51 (9.8%) subjects receiving BMS‐663068 and ATV/r, respectively; most were secondary to infections and none were related to study drugs. The most common AE reported for BMS‐663068 was headache (28/200, 14%), occurring in 5/51 (10%) subjects in the ATV/r arm; in the BMS‐663068 arms, this was not dose‐related. There were no deaths. Conclusions BMS‐663068 was generally well tolerated across all arms, with no related SAEs or AEs leading to discontinuation and no dose‐related safety signals. There were no trends for Grade 2–4 AEs or clinical laboratory abnormalities. These results support continued development of BMS‐663068. Note Previously submitted at IDWeek, Philadelphia, PA, 8 October 2014.

Introduction BMS‐663068 is a prodrug of BMS‐626529, an attachment inhibitor that binds directly to HIV‐1 gp120, preventing initial viral attachment and entry into the host CD4+ T‐cell. AI438011 is a Phase IIb, randomized, active‐controlled trial investigating the safety, efficacy and dose–response of BMS‐663068 versus atazanavir/ritonavir (ATV/r) in treatment‐experienced (TE), HIV‐1‐positive subjects. Materials and Methods Antiretroviral TE subjects (exposure to ≥1 antiretroviral for ≥1 week) with susceptibility to all study drugs (BMS‐626529 IC50 100 nM), were randomized equally to four BMS‐663068 arms (400 or 800 mg, BID; 600 or 1200 mg, QD) and a control group (ATV/r 300/100 mg QD) with tenofovir disoproxil fumarate (TDF) + raltegravir (RAL). A sub‐group analysis of viral efficacy and immunologic reconstitution is presented. Results A total of 251 subjects were treated. Median age was 39 years, 60% were male and 38% were white. Median baseline (BL) viral load (VL) was 4.85 log10 c/mL (43%; 100,000 c/mL) and median CD4+ T‐cell count was 230 cells/mm3 (38%; 200 CD4 cells/mm3). Through Week 24, response rates (HIV‐1 RNA 50 c/mL) were comparable across all BMS‐663068 arms and the ATV/r arm regardless of gender, age and race. Response rates for subjects with BL VL 100,000 c/mL (BMS‐663068, 82‐96%; ATV/r, 93%) were higher than those for subjects with BL VL ≥100,000 c/mL (BMS‐663068, 70‐87%; ATV/r, 73%); however, there were no substantial differences in response across the BMS‐663068 and ATV/r arms in either sub‐group. Response rates for subjects with BL CD4+ cell counts ≥200 cells/mm3 (87‐96%) were higher than those for subjects with BL CD4+ cell counts 200 cells/mm3 (62–82%); however, no substantial differences in response were seen across the BMS‐663068 and ATV/r arms in either sub‐group. Mean changes in CD4+ T‐cell counts from BL were similar across all arms regardless of gender, age and BL CD4+ T‐cell count. Conclusion Virologic response rates were similar across the BMS‐663068 and ATV/r arms in TE subjects, regardless of BL demographic characteristics (gender, race, age), BL HIV‐1 RNA, or BL CD4+ T‐cell count. Mean increases in CD4+ T‐cell counts across the BMS‐663068 arms were consistent with ATV/r, regardless of gender, age and BL CD4+ T‐cell count. These results support continued development of BMS‐663068. Note Previously submitted at IDWeek, Philadelphia, PA, 8 October 2014.