Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial

Background: Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. Methods: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. Findings: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Interpretation: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. Funding: US National Institutes of Health (NIH) and Operation Warp Speed

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection

BACKGROUND Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. RESULTS In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, −10.1 percentage points; 95% confidence interval [CI], −15.9 to −4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, −9.9 percentage points; 95% CI, −15.5 to −4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, −11.6 percentage points; 95% CI, −17.4 to −5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, −10.7 percentage points; 95% CI, −16.4 to −5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. CONCLUSIONS Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239.

A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-1

Background: Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs). Methods: REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5–14 days. The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population. Results: ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, −0.13%; 95% confidence interval, −6.42%–6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild. Conclusions: Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens. Clinical Trials Registration: NCT02600611

Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1–6 without cirrhosis

Background & Aims Hepatitis C virus (HCV) therapy that is highly efficacious, pangenotypic, with a high barrier to resistance and short treatment duration is desirable. The efficacy and safety of 8- and 12-week treatments with glecaprevir (ABT-493; NS3/4 A protease inhibitor) and pibrentasvir (ABT-530; NS5A inhibitor) were evaluated in non-cirrhotic patients with chronic HCV genotype 1–6 infection. Methods SURVEYOR-I and SURVEYOR-II were phase II, open-label, multicenter, dose-ranging trials including patients with chronic HCV genotype 1–6 infection who were either previously untreated or treated with pegylated interferon plus ribavirin. Patients received once-daily glecaprevir plus pibrentasvir at varying doses with or without ribavirin for 8 or 12 weeks. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at post-treatment week 12 (SVR12). Results Of the 449 patients who received varying doses of glecaprevir plus pibrentasvir, 25%, 29%, 39%, and 8% had HCV genotype 1, 2, 3, and 4–6 infection, respectively. Twelve-week treatment achieved SVR12 in 97–100%, 96–100%, 83–94%, and 100% in genotypes 1, 2, 3, and 4–6, respectively. Eight-week treatment with 300 mg glecaprevir plus 120 mg pibrentasvir in genotype 1-, 2-, or 3-infected patients yielded 97–98% SVR12 with no virologic failures. Three (0.7%) patients discontinued treatment due to adverse events; most events were mild (grade 1) in severity. No post-nadir alanine aminotransferase elevations were observed. Conclusions Glecaprevir plus pibrentasvir was well tolerated and achieved high sustained virologic response rates in HCV genotypes 1–6-infected patients without cirrhosis following 8- or 12-week treatment durations. Lay summary The combination of direct-acting antivirals glecaprevir and pibrentasvir comprise a once-daily, all-oral, pangenotypic treatment for HCV genotype 1–6 infection. This article describes results from two phase II trials investigating a range of doses at treatment durations of 8 or 12 weeks in 449 patients without cirrhosis. Efficacy of the optimal dose, as determined by rates of sustained virologic response at post-treatment week 12, ranged from 92%-100%; treatment was well tolerated and significant laboratory abnormalities were rare. Clinical trial registration: clinicaltrials.gov Identifiers: NCT02243280 and NCT02243293. http://www.clinicaltrials.gov/show/NCT02243280, http://www.clinicaltrials.gov/show/NCT01939197

Couple experiences of provider-initiated couple HIV testing in an antenatal clinic in Lusaka, Zambia: lessons for policy and practice.

BACKGROUND: Couple HIV testing has been recognized as critical to increase uptake of HIV testing, facilitate disclosure of HIV status to marital partner, improve access to treatment, care and support, and promote safe sex. The Zambia national protocol on integrated prevention of mother-to-child transmission of HIV (PMTCT) allows for the provision of couple testing in antenatal clinics. This paper examines couple experiences of provider-initiated couple HIV testing at a public antenatal clinic and discusses policy and practical lessons. METHODS: Using a narrative approach, open-ended in-depth interviews were held with couples (n = 10) who underwent couple HIV testing; women (n = 5) and men (n = 2) who had undergone couple HIV testing but were later abandoned by their spouses; and key informant interviews with lay counsellors (n = 5) and nurses (n = 2). On-site observations were also conducted at the antenatal clinic and HIV support group meetings. Data collection was conducted between March 2010 and September 2011. Data was organised and managed using Atlas ti, and analysed and interpreted thematically using content analysis approach. RESULTS: Health workers sometimes used coercive and subtle strategies to enlist women's spouses for couple HIV testing resulting in some men feeling 'trapped' or 'forced' to test as part of their paternal responsibility. Couple testing had some positive outcomes, notably disclosure of HIV status to marital partner, renewed commitment to marital relationship, uptake of and adherence to treatment and formation of new social networks. However, there were also negative repercussions including abandonment, verbal abuse and cessation of sexual relations. Its promotion also did not always lead to safe sex as this was undermined by gendered power relationships and the desires for procreation and sexual intimacy. CONCLUSIONS: Couple HIV testing provides enormous bio-medical and social benefits and should be encouraged. However, testing strategies need to be non-coercive. Providers of couple HIV testing also need to be mindful of the intimate context of partner relationships including couples' childbearing aspirations and lived experiences. There is also need to make antenatal clinics more male-friendly and responsive to men's health needs, as well as being attentive and responsive to gender inequality during couselling sessions