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A post hoc, descriptive analysis of three prospective, randomised, controlled clinical studies investigating cefiderocol in gram-negative bacterial infections was conducted to assess its efficacy in patients with baseline bacteraemia.Data from APEKS-cUTI (NCT02321800), APEKS-NP (NCT03032380) and CREDIBLE-CR (NCT02714595) studies were assessed individually. Patients received cefiderocol 2g, q8h, for 7-14 days or comparators (imipenem/cilastatin [APEKS-cUTI], meropenem [APEKS-NP] or best available therapy [BAT; CREDIBLE-CR]). Bacteraemia and clinical outcomes were assessed at early assessment (EA), end of treatment (EOT) and test of cure (TOC) for patients in the intention-to-treat populations with baseline blood samples positive for aerobic gram-negative species. Eradication, persistence or recurrence of baseline blood pathogen was confirmed from follow-up blood cultures; in the absence of follow-up blood cultures, clinical response, administration of additional antibiotics and vital status were used to assess bacteraemia outcome.Of 885 patients randomised, 84 had bacteraemia and 89 (cefiderocol: 55, comparators: 34) gram-negative pathogens were isolated, namely Enterobacterales (n = 62) and non-fermenters (n = 27). At EA, on-therapy bacteraemia eradication rates in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 50.0% (4/8) and 72.0% (18/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 100% (10/10) and 69.2% (9/13), respectively. Persistence in blood at EA was seen in six patients overall (cefiderocol: 3, comparators: 3); indeterminate responses were common (cefiderocol: 8, comparators: 3), usually due to lack of blood cultures. Clinical cure/improvement rates at EA in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 62.5% (5/8) and 64.0% (16/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 90.0% (9/10) and 30.8% (4/13), respectively. Bacteraemia eradication rates with cefiderocol in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 89.5%, 37.5% and 60.0% at EOT and 78.9%, 12.5% and 44.0% at TOC.This descriptive analysis suggests that cefiderocol may be a useful treatment option for gram-negative bacteraemia, including pathogens resistant to other antibiotics.

Critically ill patients often present with low serum iron levels or anemia. We evaluated the impact of iron levels and iron homeostasis on the efficacy and safety of cefiderocol, an iron-chelator siderophore cephalosporin, in patients with nosocomial pneumonia in a post hoc analysis of the randomized, double-blind, Phase 3 APEKS-NP study (NCT03032380). Patients with Gram-negative nosocomial pneumonia received cefiderocol 2 g, 3-h infusion, q8h, or high-dose, extended-infusion meropenem 2 g, 3-h infusion, q8h, for 7–14 days. Efficacy and safety parameters, including specific iron homeostasis parameters (i.e., hepcidin, iron, total iron binding capacity, transferrin saturation), were analyzed according to baseline iron levels. In the cefiderocol and meropenem arms, 79.1% (117/148) and 83.3% (125/150) randomized patients, respectively, had low baseline serum iron levels. Rates of 14-day (12.3% [14/114] vs 11.6% [14/121]) and 28-day all-cause mortality (20.5% [23/112] vs 19.0% [23/121]), clinical cure (63.2% [72/114] vs 67.2% [82/122]), and microbiological eradication (43.6% [41/94] vs 48.1% [51/106]) at test of cure were similar in cefiderocol vs meropenem arms, respectively. In the overall safety population, rates of anemia-related adverse events were similar (cefiderocol arm 18.2% [27/148], meropenem arm 18.7% [28/150]). Changes from baseline to test of cure in hepcidin, iron, total iron binding capacity, and transferrin saturation were similar between treatment arms. Cefiderocol treatment did not affect iron homeostasis, and its efficacy and safety were not influenced by baseline serum iron levels. Clinicaltrials.gov registration: NCT03032380. Date of registration: 26 January 2017.

ObjectivesLung penetration of cefiderocol, a novel siderophore cephalosporin approved for treatment of nosocomial pneumonia, has previously been evaluated in healthy subjects. This study assessed the intrapulmonary pharmacokinetic profile of cefiderocol at steady state in hospitalized, mechanically ventilated pneumonia patients.MethodsPatients received cefiderocol 2 g (or ≤1.5 g if renally impaired), administered IV q8h as a 3 h infusion, or 2 g q6h if patients had augmented renal function (estimated CLCR > 120 mL/min). After multiple doses, each patient underwent a single bronchoalveolar lavage (BAL) procedure either at the end of the infusion or at 2 h after the end of infusion. Plasma samples were collected at 1, 3, 5 and 7 h after the start of infusion. After correcting for BAL dilution, cefiderocol concentrations in epithelial lining fluid (ELF) for each patient and the ELF/unbound plasma concentration ratio (RC, E/P) were calculated. Safety was assessed up to 7 days after the last cefiderocol dose.ResultsSeven patients received cefiderocol. Geometric mean ELF concentration of cefiderocol was 7.63 mg/L at the end of infusion and 10.40 mg/L at 2 h after the end of infusion. RC, E/P was 0.212 at the end of infusion and 0.547 at 2 h after the end of infusion, suggesting delayed lung distribution. There were no adverse drug reactions.ConclusionsThe results suggest that cefiderocol penetrates the ELF in critically ill pneumonia patients with concentrations that are sufficient to treat Gram-negative bacteria with an MIC of ≤4 mg/L.

Background Baloxavir marboxil has demonstrated safety and efficacy in treating adult and adolescent outpatients with acute influenza (CAPSTONE-1 trial). Here, we report a subgroup analysis of outcomes in adolescents from the trial. Methods CAPSTONE-1 was a randomized, double-blind, placebo-controlled study. Eligible adolescent outpatients (aged 12-17 years of age) were randomized in a ratio of 2:1 to a single dose of baloxavir 40/80 mg if less than/greater than or equal to 80 kg or placebo. The main outcomes were the time to alleviation of symptoms (TTAS), duration of infectious virus detection, and incidence of adverse events (AEs). Results Among 117 adolescent patients, 90 (77%) comprised the intent-to-treat infected population (63 baloxavir and 27 placebo; 88.9% A(H3N2)). The median TTAS was 38.6 hours shorter (95% confidence interval: −2.6, 68.4) in the baloxavir group compared with placebo (median TTAS, 54.1 hours vs 92.7 hours, P = .0055). The median time to sustained cessation of infectious virus detection was 72.0 hours for baloxavir compared with 120.0 hours for placebo recipients (P < .0001). Treatment-emergent PA/I38X-substituted viruses were detected in 5 of the 51 (9.8%) baloxavir recipients. In the safety population (76 baloxavir and 41 placebo), AEs were less common in baloxavir than placebo recipients (17.1% vs 34.1%; P = .0421). In the baloxavir group, no AEs except for diarrhea were reported in 2 or more patients. Conclusions Baloxavir demonstrated clinical and virologic efficacy in the otherwise healthy adolescents with acute influenza compared with placebo. There were no safety concerns identified. These results were similar to the adult population in CAPSTONE-1 and support baloxavir as a treatment option in adolescents., Single-dose baloxavir marboxil was clinically and virologically effective in otherwise healthy adolescent influenza patients (12-17 years) in CAPSTONE-1 randomized, double-blind, placebo-controlled study. This analysis supports the use of baloxavir marboxil in an adolescent population with uncomplicated influenza.

Background: The APEKS-cUTI study demonstrated the non-inferiority of cefiderocol to imipenem−cilastatin in the primary endpoint of the composite of clinical and microbiological outcome in patients with complicated urinary tract infections (cUTIs). We piloted a structured patient interview (SPI) to evaluate clinical outcomes based on patient-reported symptoms while conducting this pivotal randomized, double-blind, phase-2 study. The objectives were to assess the value of the SPI, using its performance relative to physician assessment, and also to strengthen the value of patient-reported measures in conducting clinical trials for cUTI treatment. Methods: In addition to the protocol-defined clinical and microbiological outcomes, patients randomized in the APEKS-cUTI study were interviewed by the investigator or qualified study personnel at screening/baseline, early assessment (EA), end of treatment (EOT), test of cure (TOC), and follow-up (FUP). The 14-element questionnaire graded cUTI symptoms as absent or present, and if present, as mild, moderate, or severe. Changes in post-baseline symptoms based on patients’ responses were rated by the interviewer. The overall clinical outcome was evaluated based on the responses provided by patients at each time point. Results: Among the 371 patients in the modified intention-to-treat population, the rate of SPI completion in each treatment arm exceeded 90% at each time point. SPI-assessed clinical cure rates were 89.7% in the cefiderocol arm and 84.9% in the imipenem–cilastatin arm. There was substantial agreement between SPI evaluation and investigator global assessment of clinical outcome at TOC and FUP, with lower agreement at EA and EOT. Conclusion: This analysis suggests that patient-reported symptoms can be effectively captured in hospitalized patients with cUTI in a clinical trial setting. Development of a validated patient-reported outcome for use in such a setting is warranted. Registration: NCT02321800 (registered on 22 December 2014).

BackgroundSingle-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.MethodsWe evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.ResultsViruses containing PA/I38X substitutions were identified 3–9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.ConclusionsThe emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.Clinical Trial RegistrationNCT02954354.

Background For new antibiotics developed to treat antibiotic-resistant Gram-negative infections, the US Food and Drug Administration (FDA) regulatory pathway includes complicated urinary tract infection (cUTI) clinical trials in which the clinical isolates are susceptible to the active control. This allows for inferential testing in a noninferiority study design. Although complying with regulatory guidelines, individual clinical trials may differ substantially in design and patient population. To determine variables that impacted patient selection and outcome parameters, 6 recent cUTI trials that were pivotal to an new drug application (NDA) submission were reviewed. Methods This selective descriptive analysis utilized cUTI trial data, obtained from publicly disclosed information including FDA documents and peer-reviewed publications, from 6 new antibiotics developed to treat multidrug-resistant Gram-negative infections: ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol, plazomicin, and fosfomycin. Eravacycline was not approved for cUTI and is not included. Results Microbiologic modified intent-to-treat sample size, age, proportions of female patients, acute pyelonephritis (AP), Escherichia coli and other pathogens at baseline, protocol-specified switch to oral antibiotic, and the noninferiority margin were compared. Outcome data included clinical response, microbiologic eradication, and composite outcomes, including a subset of patients with AP. Conclusions A study design can follow regulatory guidelines but still have variable populations. The proportion of AP within a study varied greatly and influenced population demographics (age, gender) and baseline microbiology. A smaller proportion of AP resulted in an older patient population, fewer females, less E coli, and lower proportions of patients achieving success. Fluoroquinolones and piperacillin/tazobactam should be reconsidered as active comparators given the high rates of resistance to these antibiotics., In cUTI trial data from 6 new antibiotics targeting MDR Gram-negative infections, proportion of acute pyelonephritis (AP) varied; influencing population demographics and baseline microbiology. Smaller proportion of AP resulted in older patient population, fewer females, less E coli, and lower treatment success.

Summary Background New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections. Methods We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7–14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov ( NCT02714595 ) and EudraCT (2015-004703-23). Findings Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8–66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9–75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2–65·5) of 23 patients in the cefiderocol group and six (43%, 17·7–71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8–77·0) of 17 patients in the cefiderocol group and one (20%, 0·5–71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug. Interpretation Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options. Funding Shionogi.

Summary Background Carbapenem-resistant Gram-negative bacteria represent the highest priority for addressing global antibiotic resistance. Cefiderocol (S-649266), a new siderophore cephalosporin, has broad activity against Enterobacteriaceae and non-fermenting bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii , including carbapenem-resistant strains. We assessed the efficacy and safety of cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infection in patients at risk of multidrug-resistant Gram-negative infections. Methods We did a phase 2, multicentre, double-blind, parallel-group non-inferiority trial at 67 hospitals in 15 countries. Adults (≥18 years) admitted to hospital with a clinical diagnosis of complicated urinary tract infection with or without pyelonephritis or those with acute uncomplicated pyelonephritis were randomly assigned (2:1) by an interactive web or voice response system to receive 1 h intravenous infusions of cefiderocol (2 g) or imipenem-cilastatin (1 g each) three times daily, every 8 h for 7–14 days. Patients were excluded if they had a baseline urine culture with more than two uropathogens, a fungal urinary tract infection, or pathogens known to be carbapenem resistant. The primary endpoint was the composite of clinical and microbiological outcomes at test of cure (ie, 7 days after treatment cessation), which was used to establish non-inferiority (15% and 20% margins) of cefiderocol versus imipenem-cilastatin. The primary efficacy analysis was done on a modified intention-to-treat population, which included all randomly assigned individuals who received at least one dose of study drug and had a qualifying Gram-negative uropathogen (≥1 × 10 5 colony-forming units [CFU]/mL). Safety was assessed in all randomly assigned individuals who received at least one dose of study drug, according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02321800. Findings Between Feb 5, 2015, and Aug 16, 2016, 452 patients were randomly assigned to cefiderocol (n=303) or imipenem-cilastatin (n=149), of whom 448 patients (n=300 in the cefiderocol group; n=148 in the imipenem-cilastatin group) received treatment. 371 patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) had qualifying Gram-negative uropathogen (≥1 × 10 5 CFU/mL) and were included in the primary efficacy analysis. At test of cure, the primary efficacy endpoint was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18·58% (95% CI 8·23–28·92; p=0·0004), establishing the non-inferiority of cefiderocol. Cefiderocol was well tolerated. Adverse events occurred in 122 (41%) of 300 patients in the cefiderocol group and 76 (51%) of 148 patients in the imipenem-cilastatin group, with gastrointestinal disorders (ie, diarrhoea, constipation, nausea, vomiting, and abdominal pain) the most common adverse events for both treatment groups (35 [12%] patients in the cefiderocol group and 27 [18%] patients in the imipenem-cilastatin group). Interpretation Intravenous infusion of cefiderocol (2 g) three times daily was non-inferior compared with imipenem-cilastatin (1 g each) for the treatment of complicated urinary tract infection in people with multidrug-resistant Gram-negative infections. The results of this study will provide the basis for submission of a New Drug Application to the US Food and Drug Administration. Clinical trials of hospital-acquired pneumonia and carbapenem-resistant infections are ongoing. Funding Shionogi & Co Ltd, Shionogi Inc.

Background The CREDIBLE-CR study assessed the efficacy and safety of cefiderocol (CFDC), a novel siderophore cephalosporin, in the treatment of serious infections due to carbapenem-resistant (CR) Gram-negative (GN) bacteria. Methods CREDIBLE-CR was an open-label, prospective, randomized 2:1, Phase 3 study (NCT02714595) in patients with nosocomial pneumonia (NP), bloodstream infections/sepsis (BSI/Sepsis), or complicated urinary tract infections (cUTI) with evidence of CR GN pathogens. Adults received intravenous CFDC 2 g, q8h, 3-h infusion or best available therapy (BAT; up to 3 drugs) for 7–14 days (extendable to 21 days). The primary endpoint at test of cure in the CR microbiological intent-to-treat (CR-MITT) population was clinical cure (NP, BSI/Sepsis) or microbiological eradication (cUTI). Secondary endpoints were clinical and microbiological outcomes, all-cause mortality (ACM) and safety. Only descriptive statistics were pre-specified. Results A total of 101 patients received CFDC and 49 received BAT (CR-MITT: CFDC n=80, BAT n=38): 50% had pneumonia, 31.4% BSI/Sepsis, and 18.6% cUTI (Table 1). Most frequent CR pathogens were Acinetobacter baumannii (45.8%), Klebsiella pneumoniae (37.3%), and Pseudomonas aeruginosa (23.7%). CFDC monotherapy was given to 83% of patients, while BAT monotherapy to 29% of patients. Primary outcome in the CFDC and BAT arms was achieved in 50.0% and 52.6% in NP, 43.5% and 42.9% in BSI/Sepsis, and 52.9% and 20.0% in cUTI patients (Figure). CFDC was highly efficacious vs CREs and NDM-producing pathogens. Day 28 ACM was 24.8% (25/101) with CFDC and 18.4% (9/49) with BAT. Rescue therapy was given more frequently in the BAT than CFDC arm. Mortality results by pathogen showed an imbalance in Acinetobacter spp. infections (Table 2) with a higher rate in the CFDC arm than BAT arm. ICU and shock at randomization were more frequent in the CFDC arm than in the BAT arm in Acinetobacter spp. infections (Table 2). No safety concerns related to CFDC emerged. Table 1. Baseline demographics and characteristics (CR-MITT population) Figure. CREDIBLE-CR study primary efficacy endpoints and secondary outcomes at test-of-cure visit in CR-MITT population. Table 2. All-cause mortality by baseline pathogen inpatients with or without Acinetobacter spp. infection (safety population) Conclusion Efficacy of CFDC was demonstrated in this descriptive pathogen-focused study, including CREs, metallo-NDM producers and CR non-fermenters. Baseline imbalances of ICU and shock in the subset of infections with Acinetobacter spp. may have contributed to the mortality difference between CFDC and BAT arms. Disclosures Matteo Bassetti, MD, Shionogi Inc. (Advisor or Review Panel member) Roger Echols, MD, Shionogi Inc. (Consultant) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

Background Cefiderocol (CFDC), a novel siderophore cephalosporin, has demonstrated potent antibacterial activity against a wide range of Gram-negative bacteria including carbapenem-resistant strains. We aimed to evaluate relationships between drug exposure and outcomes in critically ill patients. Methods Sparse pharmacokinetic (PK) samples at steady state from critically ill patients with pneumonia, bloodstream infection/sepsis, or complicated urinary tract infection receiving CFDC in two Phase 3 studies were analyzed. Percent time of dosing interval of free drug concentration exceeding the minimum inhibitory concentration (MIC) in plasma and epithelial lining fluid (ELF) (%fT>MIC and %fT>MIC,ELF, respectively) were determined for 60 (CREDIBLE-CR; NCT02714595) and 97 patients (APEKS-NP; NCT03032380), using a 3-compartment population PK model. The %fT>MIC,ELF was calculated for 125 pneumonia patients based on an intrapulmonary PK model. Relationships between %fT>MIC, %fT>MIC,ELF and clinical and microbiological outcomes at test of cure (TOC), or mortality at Day 28 were assessed. Results The median (90th percentile) MICs of Gram-negative pathogens in the PK/pharmacodynamic (PD) analyses were 0.25 (4) µg/mL (CREDIBLE-CR) and 0.25 (2) µg/mL (APEKS-NP), respectively. Individual plasma %fT>MIC was 100% in ≥95% of patients in each study, and estimated %fT>MIC,ELF was 100% in 89.3% (25/28 pneumonia patients; CREDIBLE-CR) and 97.9% (95/97 pneumonia patients; APEKS-NP). Clinical cure rates and survival rates in patients with 100% fT>MIC or %fT>MIC,ELF were similar between the two studies (Table). No PK/PD relationships between %fT>MIC, %fT>MIC,ELF and clinical cure, microbiological eradication, or survival were identified in either study because high %fT>MIC or %fT>MIC,ELF was achieved in all patients. Table. Clinical cure and survival rates in patients with 100% fT>MIC or %fT>MIC,ELF in CREDIBLE-CR and APEKS-NP studies Conclusion PK/PD relationship was not identified between CFDC plasma or ELF exposure and clinical or microbiological outcomes, or mortality as high %fT>MIC and %fT>MIC,ELF were achieved, suggesting the recommended dosing regimen of 2 g q8h or renally adjusted dosage (including augmented renal clearance), infused over 3 hours, provides sufficient exposure to CFDC in critically ill patients. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee) David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member) Michael J. Satlin, MD, MS, Achaogen (Consultant)Allergan (Grant/Research Support)Merck (Grant/Research Support)Shionogi Inc. (Consultant) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee)

Background Cefiderocol (CFDC), the first siderophore cephalosporin, is approved in the United States (complicated urinary tract infections [cUTI]) and Europe for the treatment of patients with Gram-negative (GN) infections with limited treatment options. Methods This analysis investigated the safety profile of CFDC across three prospective, multicenter, randomized clinical studies: APEKS-cUTI (double-blind, non-inferiority Phase 2 study in patients with cUTI) vs imipenem-cilastatin (1 g/1 g, three-times daily); APEKS-NP (double-blind, non-inferiority Phase 3 study in patients with nosocomial pneumonia [NP]) vs meropenem (2 g, q8h); CREDIBLE-CR (open-label, descriptive Phase 3 study in patients with cUTI, NP, bloodstream infections/sepsis [BSI/sepsis]) caused by carbapenem-resistant GN bacteria; patients in the control arm received best available therapy (BAT; up to 3 agents, dosing based on local label). CFDC was given at 2 g, q8h, infused over 1 (APEKS-cUTI) or 3 (APEKS-NP, CREDIBLE-CR) hours. One adjunctive agent with CFDC was only allowed in CREDIBLE-CR. Results 549 patients were treated with CFDC, 347 control treated (Table 1). More than 50% of patients were aged ≥65 years, except BAT arm in CREDIBLE-CR. The majority of patients were admitted to the ICU in APEKS-NP and CREDIBLE-CR. The median treatment duration with CFDC was similar (9–11 days) across studies. The rates of TEAEs and serious AEs (SAEs) between CDFC and comparators were similar in each study (Table 2). The rates of adverse drug reactions were lower with CFDC than with comparators in each study, with a greater difference in CREDIBLE-CR than in APEKS-cUTI and APEKS-NP. TEAEs leading to death rates are shown in Table 2. Eight CFDC-related Clostridioides difficile infections occurred across studies (APEKS-cUTI: n=1; APEKS-NP: n=4; CREDIBLE-CR: n=3 [ie, C. difficile colitis; pseudomembranous colitis]). In total, eight experienced seizures (APEKS-cUTI: CFDC n=1; APEKS-NP: CFDC n=3, meropenem n=2; CREDIBLE-CR: CFDC n=1, BAT n=1), none of which were related to study drugs. Parameters of iron homeostasis showed no differences between CFDC and comparators. Table 1. Baseline characteristics and treatment duration (safety populations) Table 2. Overall safety parameters (safety populations) Conclusion CFDC demonstrated a comparable safety profile to carbapenems or other cephalosporins and was generally well tolerated in critically ill patients. Disclosures Yuko Matsunaga, MD, Shionogi Inc. (Employee) Takuhiro Sonoyama, MD, Shionogi & Co., Ltd. (Employee) Luis Casanova, PharmD, Shionogi B.V. (Employee) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Fabio De Gregorio, MD, Shionogi B.V. (Employee) Eriko Ogura, MD, Shionogi & Co., Ltd. (Employee) Simon Portsmouth, MD, Shionogi Inc. (Employee)

Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (-7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.Shionogi.

Background Cefiderocol (CFDC), a novel siderophore cephalosporin, has potent in vitro activity against Gram-negative bacteria causing nosocomial pneumonia (NP). The non-inferiority of CFDC to meropenem in Day 14 all-cause mortality in NP was previously demonstrated. In this study, we assessed the intrapulmonary pharmacokinetics of CFDC in hospitalized and ventilated patients with bacterial pneumonia receiving standard of care (SOC) antibiotics. Methods A multicenter, single-arm, open-label study was conducted to assess epithelial lining fluid (ELF) and plasma concentrations of CFDC at steady state in mechanically ventilated patients with bacterial pneumonia receiving SOC antibiotics (NCT03862040). Seven patients received 2 g doses of CFDC (or renally adjusted doses), infused over 3 hours, q8h, or q6h for patients with augmented renal function (creatinine clearance estimated by Cockcroft-Gault equation >120 mL/min). One bronchoalveolar lavage (BAL) sample per patient was collected to determine ELF concentration at 3 or 5 hours after at least 3 CFDC doses (or ≥6 doses in patients with severe renal impairment). Four blood samples were collected per patient for plasma concentrations at 1, 3, 5, and 7 hours after the start of the infusion used for BAL sampling. Urea concentrations in blood and BAL were measured to calculate CFDC concentrations in ELF. Results Geometric mean (minimum, maximum) ELF concentration of CFDC was 7.63 (3.10, 20.7) µg/mL at the end of infusion (3 h after the start of infusion) (N=4) and 10.4 (7.19, 15.9) µg/mL at 2 hours after the end of infusion (5 h after the start of infusion) (N=3). ELF/free plasma concentration ratios were estimated to be 0.212 at the end of infusion and 0.547 at 2 hours after the end of infusion based on the in vitro unbound fraction of 0.422. Conclusion The individual ELF concentrations of CFDC were close to, or higher than, 4 µg/mL in pneumonia patients. Compared with the ELF/free plasma area under the curve ratio in healthy subjects (0.239), the ELF/free plasma concentration ratio at the end of infusion (0.212) was comparable, and at 2 hours after the end of infusion (0.422) was higher in pneumonia patients. These findings suggest delayed distribution and sustained exposure of CFDC in the ELF of pneumonia patients. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Simon Portsmouth, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Keith Rodvold, PharmD, FCCP, FIDSA, Shionogi Inc. (Consultant) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

Background Baloxavir marboxil (baloxavir) is an antiviral drug that inhibits the viral "cap-snatching" step in virus RNA transcription initiation. In Phase 2 study, baloxavir significantly shortend the time to alleviation of symptoms (TTAS) and showed significantly greater reduction in influenza virus titer compared with placebo. This provides additional outcomes including efficacy against virus types/subtypes and pharmacokinetic/pharmacodynamic (PK/PD) analysis. Methods Subgroup analyses by virus types/subtype were conducted for the primary and key secondary endpoints. Blood samples were collected totally at 2 to 5 points including Day 2 after baloxavir dosing. PK/PD analyses were conducted for TTAS and change in virus titer using the liner model and the Emax model, respectively. Results The median TTAS in each baloxavir dose group was significantly shorter than in the placebo group for patients with A/H1N1pdm virus, and was numerically shorter than the placebo group for patients with A/H3N2 and type B virus. Baloxavir significantly reduced virus titer within 1 day after treatment: for A/H1N1pdm, A/H3N2, and B virus, all 3 doses of baloxavir marboxil reduced virus titer on Day 2 to a greater extent than placebo. No clear PK/PD relationships were found for the TTAS, but the larger reduction in virus titer was observed in increasing C24. Conclusion These results support that baloxavir marboxil will be effective against a range of virus types/subtypes.

BACKGROUND Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents. METHODS We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population. RESULTS In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P

To evaluate the efficacy and safety of pegylated interferon-lambda-1a (Lambda)/ribavirin (RBV)/daclatasvir (DCV) for treatment of patients coinfected with chronic hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Treatment-naive patients were assigned to cohort A [HCV genotype (GT)-2 or -3] or cohort B [HCV GT-1(a or b) or -4]. All patients received Lambda/RBV/DCV for the first 12 weeks; cohort A received Lambda/RBV for an additional 12 weeks, followed by 24 weeks of follow-up, and cohort B received response-guided therapy. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post-treatment week 12 (SVR12). In cohort A (n = 104), 84.6% achieved SVR12 (95.0% in GT-2; 83.1% in GT-3). In cohort B (n = 196), 76.0% achieved SVR12 (71.7% in GT-1a; 86.0% in GT-1b; 70.7% in GT-4). Rates of discontinuation due to adverse events (AEs) (3.8% and 6.1%) and serious AEs (5.8% and 6.1%) were low in cohorts A and B, respectively. In addition, treatment with Lambda/RBV/DCV had little impact on CD4 counts. SVR12 rates with Lambda/RBV/DCV in an HCV/HIV-coinfected population ranged from 71.7% to 95.0%. Treatment was generally well tolerated, with a low proportion of patients discontinuing due to AEs. Clinical trial registration NCT01866930.

Background Based on the 2009 US FDA guidance, patient-reported outcome (PRO) measures are recommended in clinical study designs for certain indications to evaluate response to therapy from the patient’s perspective, and a PRO was recommended in the final complicated urinary tract infection (cUTI) guidance in 2014. Several PRO tools have been rigorously validated, but currently, no tool exists for evaluating cUTI. We included a “structured patient interview (SPI)“ while conducting a randomized, double-blind, study (NCT02321800) investigating cefiderocol (CFDC) vs. imipenem–cilastatin (IPM/CS) in cUTI patients to support the physician’s assessment of clinical response. Methods Patients, who were fully alert and oriented, were interviewed at randomization, end of treatment, test of cure (TOC), and follow-up (FUP) by the same interviewer. The questionnaire identified the presence or absence of relevant symptoms pertinent to cUTI. Responses were graded as none, or if present, mild, moderate, or severe. Investigator assessment included objective measures of clinical outcome(s) and was performed independently from the patient-reported symptoms collected in the SPI. Changes in the patient’s responses were compared with the investigator’s assessment at randomization and at each study visit. A kappa correlation coefficient comparing the SPI and physician’s clinical assessment was calculated at each evaluation time point. Results Based on investigator assessment, 89.7% (226 out of 252 patients) in the CFDC arm and 87.4% (104 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 2.39%; 95% CI: –4.66; 9.44) at TOC. Based on the SPI responses, 89.7% (226 out of 252 patients) in the CFDC arm and 84.9% (101 out of 119 patients) in the IPM/CS arm achieved clinical cure (adjusted treatment difference: 4.96%; 95% CI: –2.48; 12.39) in favor of CFDC. The correlation between SPI evaluation and physician’s assessment of clinical outcomes was very high at TOC and FUP visits (Kappa coefficients: 0.820 and 0.766, respectively). Conclusion The strong correlation between patients’ reported symptoms collected in the SPI and investigator assessment showed that SPI responses could be a useful alternative measure of clinical outcomes in cUTI studies. Disclosures All authors: No reported disclosures.

Background Cefiderocol, a novel siderophore cephalosporin with broad activity against Gram-negative bacteria, requires dose adjustment in patients with renal impairment or augmented renal clearance, similarly to other β-lactams. The efficacy and safety of cefiderocol were assessed according to degree of renal impairment as part of a pivotal study vs. imipenem–cilastatin (IPM/CS) in patients with cUTI (NCT02321800). Methods A total of 448 randomized adults with cUTI received cefiderocol (2 g) or IPM/CS (1 g / 1 g), IV, q8h, for 7–14 days (safety population), with 371 patients in the microbiological intent-to-treat (Micro-ITT) population. Dose adjustments were made based on body weight (to enable IPM/CS blinding) and creatinine clearance (CrCL). The composite (clinical and microbiological) outcome at a test of cure (TOC; 7 days after treatment cessation) was analyzed by CrCL subgroup. Adverse events (AEs) according to renal subgroup were monitored throughout the study. Results A treatment difference in the composite outcome at TOC in favor of cefiderocol vs. IPM/CS was observed across renal subgroups (table), with greater differences in moderate and severe groups, consistent with that observed in the overall population (n = 371; 18.0%, 95% confidence interval: 7.5; 28.5). The incidence of AEs in the cefiderocol group was comparable across all renal subgroups. Conversely, AE incidence increased with the degree of impairment in the IPM/CS group (table). Conclusion In contrast to IPM/CS, the efficacy of cefiderocol was maintained across all renal function subgroups with no increase in the rate of AEs. These findings underscore the efficacy and safety of cefiderocol in patients with renal impairment and support the adequacy of the dose adjustment. Disclosures All authors: No reported disclosures.

Changes in HIV tropism from R5 to non-R5 or development of drug resistance is often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials. All patients had R5 HIV by the original Trofile assay before entry. We used population-based sequencing methods and the geno2pheno algorithm to examine changes in tropism and V3 sequences at the time of failure. Using deep sequencing, we assessed whether V3 sequences observed at failure emerged from preexisting subpopulations. From population genotyping data at failure, 90 patients had R5 results, and 91 had non-R5 results. Of the latter group, the geno2pheno false-positive rate (FPR) value fell from a median of 20 at screening to 1.1 at failure. By deep sequencing, the median percentage of non-R5 variants in these patients rose from 1.4% to 99.5% after a median of 4 weeks on maraviroc. In 70% of cases, deep sequencing could detect a pretreatment CXCR4-using subpopulation, which emerged at failure. Overall, there were two distinct patterns of failure of maraviroc. Patients failing with R5 generally had few V3 substitutions and low non-R5 prevalence by deep sequencing. Patients with non-R5 HIV who were failing developed very-high-prevalence non-R5 HIV (median, 99%) and had very low geno2pheno values.

HIV-1 tropism can be predicted using V3 genotypic algorithms. The performance of these prediction algorithms for non-B subtypes is poorly characterized. Here, we use these genotypic algorithms to predict viral tropism of HIV-1 subtype A, B, C, and D to find apparent sensitivity, specificity, and concordance against a recombinant phenotypic assay, the original Trofile assay. This is a substudy of an epidemiological study (Pfizer A4001064). Plasma samples were selected to represent a large number of DM/X4 and R5 viruses. The HIV-1 env gene V3 loop was genotyped by Sanger sequencing (N=260) or 454 "deep" sequencing (N=280). Sequences were scored with g2p[coreceptor], PSSM X4/R5, PSSM SI/NSI, and PSSM subtype C matrices. Overall, non-B subtypes tropism prediction had similar concordance and apparent sensitivity and specificity as subtype B in predicting Trofile's results in both population sequencing (81.3%, 65.6%, and 90.5% versus 84.2%, 78.5%, and 88.2%) and 454 "deep" sequencing (82.3%, 80.0%, and 83.6% versus 86.8%, 92.0%, and 82.6%) using g2p[coreceptor]. By population sequencing, subtype A had lower sensitivity, whereas subtype D had lower specificity for non-R5 predictions, both in comparison to subtype B. 454 "deep" sequencing improved subtype A sensitivity but not subtype D. Subtype C had greater concordance than subtype B regardless of sequencing methods. In conclusion, genotypic tropism prediction algorithms may be applied to non-B HIV-1 subtypes with caution. Collective analysis of non-B subtypes revealed a performance similar to subtype B, whereas a subtype-specific analysis revealed overestimation (subtype D) or underestimation (subtype A).

This study was performed to evaluate a once-daily dual-therapy regimen, maraviroc (MVC) + atazanavir/ritonavir (ATV/r), in treatment-naive patients.A phase 2b, randomized, open-label pilot study.In Study A4001078 (NCT00827112), treatment-naive patients with CCR5-tropic HIV-1 (HIV-1 RNA ≥1000 copies/mL; CD4 cell count ≥100 cells/mm) were randomized to receive either MVC 150 mg once daily (n = 60) or tenofovir/emtricitabine (TDF/FTC) 300/200 mg once daily (n = 61) + ATV/r 300/100 mg once daily. Primary endpoint was proportion of patients with HIV-1 RNA50 copies per milliliter at week 48.At week 48, 44 (74.6%) and 51 (83.6%) patients in the MVC and TDF/FTC treatment groups, respectively, had plasma HIV-1 RNA50 copies per milliliter. Median change from baseline in CD4 cell count at week 48 was +173 and +187 cells per cubic millimeter with MVC and TDF/FTC, respectively. Seven patients discontinued from each arm; there were no deaths. The incidence of serious adverse events (AEs) was similar in each group; however, there were more grade 3/4 AEs in the MVC group (18 vs 11), mostly due to hyperbilirubinemia. Three patients in each arm were evaluable for virological analysis at discontinuation or failure (HIV-1 RNA500 copies/mL); no genotypic resistance, change in tropism, or loss of susceptibility relevant to treatment was observed.The virological activity and immunological benefit of once-daily MVC + ATV/r were confirmed. Indirect hyperbilirubinemia and associated signs were the most commonly reported AEs in both study treatment groups and were not associated with significant transaminase increases. No drug resistance occurred.

Assessment of HIV-1 co-receptor usage is essential to identify patients who are likely to respond to maraviroc (MVC)-containing regimens. Co-receptor usage of plasma virus from all treatment-naive patients screened for a MVC clinical trial was assessed using phenotypic and genotypic methodologies to evaluate concordance between testing methods and to assess the quantity of CXCR4-using (non-R5) virus in samples giving discordant results. Co-receptor usage was prospectively measured using the enhanced sensitivity Trofile assay (Trofile ES) to screen patients for enrollment in Study A4001078. Population and deep sequencing methodologies were utilized retrospectively to analyze all screening samples, with co-receptor usage determined using the geno2pheno algorithm. Concordance between methods was explored using descriptive statistics. The quantity of non-R5 virus in all samples was measured using deep sequencing. Trofile ES and matched genotype results were obtained for 199 screening samples. Concordance of Trofile ES with population genotyping (5.75% false-positive rate [FPR]) and deep sequencing (3.5% FPR; 2% non-R5 threshold) was 91.7% and 89.6%, respectively. Population genotype data were available for all samples with non-reportable Trofile ES results; the distribution of co-receptor usage in this set was consistent with that in the overall population: 75% (12/16) R5 and 25% (4/16) non-R5. The majority of samples contained non-R5 plasma HIV-1 RNA estimated at either 10 (62.0%) or ⩾4 log 10 (30.5%) copies/mL; the absolute amount of detectable non-R5 virus remained stable between screening and baseline visits. Samples originally classified as non-R5 by Trofile ES but R5 by population sequencing had a relatively low absolute amount of non-R5 virus (mean 2.1%, median 0.1%). The determination of co-receptor usage using either Trofile ES or genotyping methodologies showed similar frequencies of R5 and non-R5 virus in this treatment-naive study population. For both concordant and discordant samples, population sequencing appropriately identified R5 samples with low levels of non-R5-using virus.

The study objective was to compare the efficacy and safety of peginterferon lambda-1a combined with ribavirin/daclatasvir (Lambda/RBV/DCV), versus peginterferon alfa-2a combined with ribavirin/telaprevir (Alfa/RBV/TVR), in patients chronically infected with hepatitis C virus (HCV), genotype 1b. This was a prospective, randomized, open-label, phase 3 study (NCT01718158) in adults (aged ≥18 years) who were treatment naïve or prior relapsers to peginterferon alfa/ribavirin therapy. The primary endpoint was sustained virologic response at post-treatment follow-up week 12 (SVR12). Patients were randomized in a 2:1 ratio to receive 24 weeks of Lambda/RBV/DCV or response-guided 24 or 48 weeks of Alfa/RBV/TVR. Overall, 440 patients were treated (294 with Lambda/RBV/DCV; 146 with Alfa/RBV/TVR). The proportion of patients achieving SVR12 was 88.8% in the Lambda/RBV/DCV arm and 70.5% in the Alfa/RBV/TVR arm (difference between arms: 18.3%; 95% confidence interval: 9.9-25.7; P 0.0001). Patients in the Lambda/RBV/DCV group had fewer rash-related adverse events (AEs), cytopenic abnormalities, flu-like symptoms, serious AEs, and discontinuations due to AEs, but more liver abnormalities than those in the Alfa/RBV/TVR group. In conclusion, treatment with Lambda/RBV/DCV led to higher SVR12 rates and a more favorable safety profile than Alfa/RBV/TVR in patients with chronic HCV, genotype 1b infection.

Background and purpose: Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection. Methods: In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12). Results: Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV. Conclusion: The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Baloxavir marboxil (BXM), a selective cap-dependent endonuclease inhibitor, has demonstrated efficacy + safety for influenza in otherwise healthy patients. We present subgroup analyses for (i) United States vs. Japan (J), (ii) time (t) of treatment (early: ≥0 to ≤24 hours, vs. late: >24 to ≤48 hours), and (iii) influenza type B infections from the global Ph 3 trial (16/17 season). Methods A multicenter, randomized, double-blind, placebo (PLC)- and oseltamivir (OV)-controlled study recruited patients in Japan (n = 846) and United States (n = 590). Inclusion criteria: age 12–64 years, fever + flu symptoms, and ≤48 hours from symptom onset. Patients (20–64 years) randomized (2:2:1) to a single oral dose of BXM, PLC, or 75 mg OV BID for 5 days; patients 12–19 years were randomized (2:1) to receive BXM or PLC. BXM dose: 40/80 mg for BW Results BXM reduced the median TTAS by 30.6 hours versus PLC (87.3 versus 117.9 hours, P = 0.1373) in the US pop and t to cessation of viral shedding: 24 versus 72 hours for PLC (P < .0001). Median TTAS in the United States versus J pop was longer, due to imbalances between groups. In both early/late treatments from symptom onset, BXM reduced TTAS versus PLC (Table 1). Regardless of the t to treatment from symptom onset, BXM reduced virus titer significantly from BL versus PLC and OV (Table 2). No significant reduction in TTAS was seen, while BXM reduced virus titer versus PLC and OV in type B virus infection. Conclusion Outcomes for United States were aligned with the Ph 3 Results. Early treatment with BXM leads to a significantly faster TTAS vs. PLC. BXM caused significant viral titer reduction regardless of treatment time versus OV. BXM reduced virus titer vs. PLC and OV in type B virus infection. Disclosures K. Kawaguchi, Shionogi & Co., Ltd.: Employee, Salary. S. Portsmouth, Shionogi Inc: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary.T. Uehara, Shionogi & Co., Ltd.: Employee, Salary. F. Hayden, Shionogi & Co., Ltd.: Scientific Advisor, Consulting fee (donated) and travel support for attending 6th ESWI meeting, 10–13 September 2017, Latvia, to present phase 3 OWH results.

Background For new antibiotics to treat Gram-negative infections, one regulatory pathway includes complicated urinary tract infections (cUTI) clinical trials. Although individual clinical trials comply with regulatory guidelines, they may differ substantially in design and execution. Six recent cUTI trials that supported or are likely to support FDA regulatory review were compared to determine variables that impacted patient selection and outcome parameters. Methods cUTI trials for six new antibiotics developed to treat multi-drug-resistant Gram-negative infections were obtained from publicly disclosed information including FDA documents, publications, or presentations at scientific meetings. Antibiotics included were: ceftolozane-tazobactam (CTL-TAZ), ceftazidime–avibactam (CTZ-AVI), meropenem-vaborbactam (MER-VAB), cefiderocol, plazomicin, and fosfomycin. Comparison variables included: mMITT sample size, age, % female patients, % acute pyelonephritis, % E. coli and other pathogens at baseline, switch to PO antibiotic, and the non-inferiority margin. Other variables as well as the microbiologic eradication, clinical response, and the combined outcomes will be included in the poster. Results CTL-TAZ CTZ-AVI MER-VAB Cefiderocol Plazomicin Fosfomycin mMITT (n) 800 810 374 371 388 362 Non-inferiority margin (%) 10 10 15 15 15 15 Age, years (mean) 48.6 52.4 54.3 62 59.4 Not Reported % female 74 69.8 65.5 55 52.8 63.5 Acute pyelonephritis (%) 82 72 59 27 42 53 E. coli (%) 78.6 73.8 64.7 62.3 69.6 73.4 IV-to-PO no Yes yes no yes no Conclusion Study design and eligibility criteria significantly influences patient characteristics. The proportion of acute pyelonephritis varied greatly and influenced population demographics (age, gender) and baseline microbiology. Studies with a smaller proportion of acute pyelonephritis resulted in an older patient population, fewer females and less E. coli. Larger sample size did not impact outcomes. Disclosures A. Bass, Shionogi Inc.: Employee, Salary. R. Echols, Shionogi Inc.: Consultant, Consulting fee. S. Portsmouth, Shionogi Inc: Employee, Salary. A. Howell, Shionogi Inc.: Employee, Salary.

Objective: We investigated whether previous treatment interruptions are associated with a raised risk of viral rebound in individuals who have attained virological suppression.Methods: All patients achieving an undetectable viral load while on therapy were followed until viral rebound or the time of the last viral load. Poisson regression was used to describe the independent impact of treatment interruptions on rebound rates.Results: A total of 12 977 patients from the United Kingdom Collaborative HIV Cohort (UK CHIC) Study achieved a viral load of less than 50 copies/ml. These patients contributed a total of 37 314 person-years of follow-up. The overall rebound rate was 8.07 (7.78, 8.36) per 100 person-years. In adjusted analyses, rates of viral rebound were up to 64% higher (rate ratio 1.64; 1.43, 1.88) in those who had previously interrupted therapy compared with those who had not. Patients who had interrupted at detectable viral loads had upto a 74% (1.74; 1.42, 2.14) higher chance of rebounding compared with those who had not interrupted with a detectable viral load. We found no evidence to suggest interrupting treatment at an undetectable viral load was associated with viral rebound.Conclusion: Among patients with an undetectable viral load, having previously interrupted therapy while the viral load was detectable is associated with a raised risk of rebound. (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.

We investigated whether the rate of viral rebound decreases with increasing duration of viral suppression and, if so, whether rebound rates in patients previously failing antiretroviral regimens ultimately decline to levels as low as those seen in patients who have never experienced virological failure.All patients from the UK CHIC Study (n = 21 256) who achieved a viral load (VL) ofor = 50 copies/ml while receiving HAART were followed until viral rebound (two consecutive VL400 copies/ml). Patients could re-enter the analysis if they experienced a subsequent VLor = 50 copies/ml. Rebound rates were calculated according to the number of regimens previously failed and duration of viral suppression.Of 12 648 patients on HAART 10 237 (80.9%) achieved a VLor = 50 copies/ml. During 26 494 person-years (PY) of follow-up, 1853 (18.1%) patients experienced at least one viral rebound 'event', with 2460 events in total [rebound rate, 9.3 (range, 8.9-9.7)/100 PY). Within the first year of viral suppression, the rate of viral rebound was 8.3 (7.5-9.1)/100 PY in patients who had not previously failed treatment, increasing to 32.7 (27.6-37.8)/100 PY in patients who had failed more than four regimens. Irrespective of previous treatment failure, rebound rates in those who remained suppressed for4 years were similar to those in patients who had at no time experienced treatment failure.After around 4 years of viral suppression rebound rates in individuals with multiple prior treatment failures approach those of individuals with no prior treatment failure.

Objectives Highly active antiretroviral therapy (HAART) has been advocated for the management of primary HIV-1 infection. We investigated the use of a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen in this setting. Methods Twenty-one antiretroviral-naive individuals with early HIV-1 disease were treated with a combination of efavirenz and Combivir (GlaxoSmithKline, Uxbridge, Middlesex, UK). They were evaluated for immune and lymphocyte function by standard immunological assays. Results The median time to an undetectable HIV-1 viral load was 12 weeks (range 4–36 weeks). CD4 and CD16/56 counts increased during treatment and CD8 counts decreased minimally. The main side-effects observed were transient sleep disturbances (five patients). In addition, we observed a decrease in lymphocyte activation as assessed by CD38 surface expression. Conclusions This study demonstrates that primary HIV-1 infection can be treated with NNRTI-based HAART.

Background Murine data indicate that angiogenesis is central to the aetiopathogenesis of Kaposi’s sarcoma (KS). Therefore, we measured angiogenic cytokines and growth factors in patients with AIDS-related KS during treatment with both antiretrovirals and second-line paclitaxel chemotherapy. Cytokines measured included tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and the interleukins IL-2, -6 and -12. Patients and methods Enzyme-linked immunosorbent assays (ELISAs) were carried out to measure plasma cytokine levels in 17 patients with AIDS-related KS who had progressed within 6 months of receiving liposomal anthracyclines and were treated with paclitaxel 100 mg/m2 every 2 weeks. Measurements were carried out before progression, at commencement and at the completion of paclitaxel. Results The objective response rate to paclitaxel was 71% (95% confidence interval 60% to 81%). In 17 patients with AIDS-related KS, we observed eight partial responses and four complete responses. Patients with AIDS Clinical Trial Group stage T1 disease had higher plasma VEGF (P = 0.05) and lower plasma TNF-α levels (P = 0.05) than patients with earlier stage T0 KS. There were no correlations between plasma cytokines (bFGF, VEGF, TNF-α, and IL-2,-6 and -12) and the CD4 and CD8 cell counts or HIV-1 RNA viral load. Response to paclitaxel was associated with a fall in plasma IL-6 levels (P = 0.04) but no change in other cytokines. There were no significant changes in CD4, CD8, CD16/56, CD19 cell counts and HIV-1 viral loads during chemotherapy. Conclusions Angiogenic cytokines may correlate with KS disease extent but not with cellular immune function or HIV viraemia. Response to paclitaxel therapy correlates with a fall in plasma IL-6 levels and recent data indicate this may be a surrogate marker of KS-associated herpesvirus viral load. Overall, clinical response in KS correlates poorly with known angiogenic cytokines.

The most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ patients with Kaposi sarcoma (KS) were matched for CD4 count and HIV-1 RNA viral load to HIV-1+ patients without Kaposi sarcoma (and negative for Kaposisarcoma–associated herpesvirus). We then investigated the pathways used by tumor lysates, viral lysates, and viral particles in their activation. In particular, we observed immune responses after HSP depletion using antitumor antibiotics and blockade of the common HSP receptor, CD91. Despite the impaired functional capacity of dendritic cells (DCs) derived from patients with KS, DCs retain the ability to prime the adaptive arm of the immune system through the common HSP receptor, leading to phenotypic activation and stimulation of tetramer-positive CD8+ cytotoxic T cells. We also show that interferon-producing plasmacytoid DCs are selectively depleted in KS-positive compared with matched KS-negative HIV-1–infected patients. Functionally impaired DCs can effectively cross-present immune responses through the common HSP receptor. These results have important implications for the etiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.

Objective: To determine the incidence of Kaposi's sarcoma (KS) in a prospective longitudinal cohort of HIV-1-infected individuals before during and after the introduction of highly active antiretroviral therapy (HAART) and to compare the incidence of KS between specific HAART regimens. Design: Univariate and multivariate analysis of 8640 HIV-1-infected individuals. Methods: The protective effect of HAART regimens based on either protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI) on the development of KS was examined in prospectively recorded data to determine whether treatments based on the two types of drug were comparable with regard to a reduction in the incidence of KS. Results: A total of 1204 patients with KS were identified. The incidence of KS decreased from 30/1000 patient-years prior to 1995 to 0.03/1000 patient-years in 2001. Multivariate analysis showed that age, nadir CD4 cell count and antiretroviral class exposure were significant independent predictors of KS. NNRTI-based HAART (adjusted rate ratio, 0.42; 95% confidence interval 0.24-0.37) had a similar protective effect to PI-based HAART (adjusted rate ratio, 0.47; 95% confidence interval 0.38-0.58). Most patients who develop KS on HAART [30/35 (86%)] had evidence of virological treatment failure. Conclusion: PI- and NNRTI-based HAART regimens are equally effective as protection against KS. This is the first study to demonstrate a decreased incidence of an AIDS-defining disease with NNRTI-based therapy.

As highly active antiretroviral therapy (HAART) is available for less than one million individuals worldwide, Kaposi's sarcoma (KS) remains a common complication of infection with the human immunodeficiency virus (HIV). Use of HAART has reduced the incidence of KS and, in affected individuals, HAART alone can lead to KS resolution. Pos- sible mechanisms include general improvements in immune function including the specific generation of anti-KS responses, the inhibition of HIV-1 cofactors that are thought to be important in tumour development and inhibitory effects on angiogenic growth factors and cytokines that promote KS formation. The relative contributions of these mechanisms will be discussed. Infection with HIV-1 is associated with a significant and increased risk of developing KS, a tumour that remains a significant cause of morbidity and mortality. 1-3 Its aetiologic agent is Kaposi's sarcoma-associated herpesvirus (KSHV), 4 a γ-herpesvirus that is widely prevalent in immunosuppressed populations, associated with all the clinico-epidemiological forms of KS and levels of which appear predictive of its devel- opment. 3 The introduction of HAART with combinations of nucleoside analogue reverse transcriptase inhibitors and protease inhibitors (PIs) or non-nucleoside reverse tran- scriptase inhibitors (NNRTIs) has altered survival associated with HIV 5 and there is increasing evidence that the incidence of KS in the HIV-seropositive population is declining; 6 this fall coincides with the increasing use of HAART. 2 The epide- miological evidence is supplemented by observations that individual KS lesions resolve with HAART 7 and KSHV loads decrease during this resolution. 8 The lower incidence and regression of KS observed with HAART may result from a variety of effects. These include one or more of the following: (i) immune reconstitution fol- lowing initiation of HAART; (ii) the inhibition of HIV-1 replication and the resultant decrease in its 'angiogenic' Tat protein; and (iii) the reduction in intracellular cytokine pro- duction, which triggers the production of angiogenic factors and KSHV reactivation, and, related to this, direct anti- angiogenic effects of HAART on KS. The potential role of each of these is discussed below.

Background: Tenofovir is a novel nucleotide analogue recommended for use in HIV-1 infected treatment-experienced patients. Recent data suggest an effect on Hepatitis B virus (HBV) replication. We therefore investigated the use of tenofovir in HIV-1 and HBV co-infected individuals. Methods: Twenty HIV-1/HBV co-infected patients with a median of 108 weeks lamivudine experience (range, 0-270 weeks) received tenofovir 245 mg daily in addition to or as part of their combination antiretroviral therapy. Their immunologic parameters and HIV-1 RNA and HBV DNA viral loads were followed over a period of 52 weeks. In addition, their HBV DNA polymerase was sequenced at baseline to measure the frequency of YMDD mutations that are associated with lamivudine resistance. Findings: A significant decrease in HBV DNA viral load (4 × log 10 ) and alanine aminotransferase levels was observed. There were no significant overall differences between the lamivudine-experienced (n = 15) and -naive (n = 5) individuals and tenofovir was well tolerated. Five patients (25%) underwent HBe antigen seroconversion during the study period. Out of the 15 lamivudine-experienced individuals, 10 had YMDD mutations and one had YIDD mutations in HBV DNA. Interpretation: These results indicate that 52 weeks of tenofovir in addition to antiretroviral therapy is active against HBV, and it appears to overcome lamivudine resistance.

SETTING Inpatient medical wards, Department of Medicine, University Teaching Hospital, Lusaka, Zambia. OBJECTIVE To define the natural history, clinical presentation, and management outcome of microbiologically confirmed cryptococcal meningitis in adult AIDS patients treated under local conditions where antifungal and antiretroviral therapies are not routinely available. Design A descriptive, longitudinal, observational study. METHODS All adult patients admitted to the medical wards of the University Teaching Hospital, Lusaka, Zambia with cerebrospinal fluid culture proved, primary cryptococcal meningitis, during a 12 month period were enrolled into the study. The following details were acquired: clinical features, HIV status, laboratory data, treatment accorded, and survival. Results A total of 230 patients with primary cryptococcal meningitis were studied (median age 32 years; range 15–65 years; 112 males, 118 females). Cryptococcal meningitis was the first AIDS defining illness in 210 (91%) patients. One hundred and thirty of the 230 (56%) patients had received treatment with fluconazole monotherapy and 100 (43%) patients received palliative care only without any antifungal therapy. A 100% case fatality rate was observed in both groups at follow up: by seven weeks in the untreated group and at six months in the fluconazole treated group. The cumulative median survival from time of diagnosis was 19 days (range 1–164 days) for the fluconazole treated group and 10 days (range 0–42 days) for the untreated group. Conclusion Cryptococcal meningitis, under current treatment accorded at the University Teaching Hospital, Lusaka, has a 100% mortality in young Zambian adults with AIDS. The current treatment accorded to Zambian adults with cryptococcal meningitis is inappropriate. An urgent need exists to improve strategies for the clinical management of AIDS patients in poor African countries. The wider ethical and operational issues of making available antifungals to African AIDS patients are discussed.

The objective of this prospective, observational study was to define the natural history of neutropenia in human immunodeficiency virus (HIV) disease. Eighty-seven consecutive patients developing neutropenia (absolute neutrophil count [ANC]

Background: Maraviroc is unique among approved antiretroviral drugs in targeting the host-cell chemokine coreceptor type-5 receptor. With its novel mechanism of action, we sought to describe the 5-year safety profile of maraviroc. Methods: Two large phase 3 studies of maraviroc enrolled HIV-infected treatment-experienced patients and followed them up for 5 or more years. Survival and selected clinical end points were identified and assessed. Results: A total of 938 enrolled patients received maraviroc-containing regimens. Rates of death and selected clinical events (eg, hepatic failure, malignancy, and myocardial infarction) were low during follow-up. Conclusions: Maraviroc was generally safe in treatment-experienced participants for >5 years.

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining40% until week 48. At the end of treatment, 26.7% of patients had a viral load400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/μl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

Pneumocystis carinii pneumonia (PCP) remains a serious opportunistic infection in HIV infected individuals. Seasonal changes in climate are associated with changes within individual susceptibility to infection. The possibility of monthly variability in the incidence of PCP was therefore examined by means of a cohort study of a database of 8640 HIV infected individuals attending the Chelsea and Westminster Hospital. There were 792 cases of PCP diagnosed since 1985. A marked decline was observed in the incidence of PCP in mid-1992 coincident with the introduction of PCP prophylaxis. There was a further decline in 1996 after the introduction of highly active antiretroviral therapy. Despite no significant monthly variation in the mean attendance to clinic and CD4 count, both new and all cases of PCP were higher in January than in other months (15.9% and 14.5% of all cases, respectively). A correlation with low rainfall in January and new cases of PCP was observed. These data are consistent with an influence of climatic conditions on the presentation of PCP. The diagnosis of PCP is more common in winter months suggesting that this is a transmissible infection.

Angiogenesis is thought to play a major role in the development of Kaposi's sarcoma (KS), considered by many to be a hyperplastic disorder caused in part by local production of inflammatory cytokines. The antiangiogenic effects of protease inhibitors, in particular ritonavir, have been suggested in laboratory work to lead to regression of KS, and recent data have shown the importance of ritonavir as a model of pharmaceutical development. As our clinical cohort data has shown that non-nucleoside reverse transcriptase inhibitor-based regimens are not inferior to protease inhibitor-based therapy in the prevention of KS, we investigated the specific contribution of ritonavir to chemoprevention of this AIDS-defining illness. In a logistic regression analysis, we found that ritonavir-based therapy confers no advantages compared to other regimens in the prevention of KS. This is consistent with data suggesting that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals.

HIV-1 subtype A infection predominates in Russia; however, little experience of response to maraviroc in this subtype exists and population genotyping in this setting requires further exploration. One hundred and twenty-one treatment-naive HIV-1-infected individuals from seven centres in Russia were screened using V3 loop population genotyping with a false-positive rate of 10% (geno2pheno); 75% of patients were confirmed to have CCR5 (R5)-tropic HIV-1, 21% of patients had non-R5 HIV-1, and 4% of tests were non-reportable. Seventy-seven patients met the inclusion criteria and were treated with maraviroc 300 mg twice daily (BID) in combination with lamivudine/zidovudine. Virologic and immunologic responses were assessed in this 24-week planned interim analysis. Fifty-one male (66.2%) and 26 (33.8%) female patients were enrolled. In total, 76.3% of patients had subtype A infection, and 28.6% were co-infected with hepatitis C virus. At baseline, the mean (± standard deviation [SD]) CD4 count was 404±122 cells/mm 3 , and the mean viral load was 4.77±0.74 log 10 copies/mL, with 38% of patients having viral loads ≥100,000 copies/mL. At Week 24, 80.5% of patients had viral loads