An open randomized multicentre Phase 2 trial to assess the safety of DAV132 and its efficacy to protect gut microbiota diversity in hospitalized patients treated with fluoroquinolones.

BACKGROUND: DAV132 (colon-targeted adsorbent) has prevented antibiotic-induced effects on microbiota in healthy volunteers. OBJECTIVES: To assess DAV132 safety and biological efficacy in patients. PATIENTS AND METHODS: An open-label, randomized [stratification: fluoroquinolone (FQ) indication] multicentre trial comparing DAV132 (7.5 g, 3 times a day, orally) with No-DAV132 in hospitalized patients requiring 5-21 day treatment with FQs and at risk of Clostridioides difficile infection (CDI). FQ and DAV132 were started simultaneously, DAV132 was administered for 48 h more, and patients were followed up for 51 days. The primary endpoint was the rate of adverse events (AEs) independently adjudicated as related to DAV132 and/or FQ. The planned sample size of 260 patients would provide a 95% CI of ±11.4%, assuming a 33% treatment-related AE rate. Plasma and faecal FQ concentrations, intestinal microbiota diversity, intestinal colonization with C. difficile, MDR bacteria and yeasts, and ex vivo resistance to C. difficile faecal colonization were assessed. RESULTS: Two hundred and forty-three patients (median age 71 years; 96% with chronic comorbidity) were included (No-DAV132, n = 120; DAV132, n = 123). DAV132- and/or FQ-related AEs did not differ significantly: 18 (14.8%) versus 13 (10.8%) in DAV132 versus No-DAV132 patients (difference 3.9%; 95% CI: -4.7 to 12.6). Day 4 FQ plasma levels were unaffected. DAV132 was associated with a >98% reduction in faecal FQ levels (Day 4 to end of treatment; P < 0.001), less impaired microbiota diversity (Shannon index; P = 0.003), increased ex vivo resistance to C. difficile colonization (P = 0.0003) and less frequent FQ-induced VRE acquisition (P = 0.01). CONCLUSIONS: In FQ-treated hospitalized patients, DAV132 was well tolerated, and FQ plasma concentrations unaffected. DAV132 preserved intestinal microbiota diversity and C. difficile colonization resistance.

A Colon-Targeted Adsorbent (DAV132) Does Not Affect the Pharmacokinetics of Warfarin or Clonazepam in Healthy Subjects.

DAV132 is a novel colon-targeted adsorbent that prevents the deleterious impact of antibiotics on gut microbiota without modifying their systemic availability. A randomized, Latin-square crossover, open-label trial with 2 substudies in 18 and 24 healthy volunteers evaluated the pharmacokinetic (PK) bioequivalence of warfarin, a drug with a narrow therapeutic index (NTI), and clonazepam, both widely used for the treatment of chronic conditions, with or without coadministration of DAV132 7.5 g. PK parameters observed with single doses of 5 mg warfarin and 1 mg clonazepam when administered alone did not differ with the PK parameters when administered concomitantly with or 1 hour before DAV132. Geometric mean ratios (GMRs) for S-warfarin, R-warfarin, and clonazepam Cmax were 102.0, 102.8, and 91.9, respectively, after concomitant administration and 106.5, 107.5, and 95.0, respectively, when administered 1 hour before DAV132. After concomitant administration, GMRs for S-warfarin, R-warfarin, and clonazepam AUClast were 100.5, 100.2, and 94.9, respectively, and 101.9, 101.8, and 101.3, respectively, when administered 1 hour before DAV132. All GMR 90% confidence intervals fell within the prespecified 80% to 125% limit for bioequivalence, indicating a lack of drug-drug interaction. In conclusion, DAV132 did not affect the systemic exposure of 2 NTI drugs absorbed in the proximal intestine.

Protection of the Human Gut Microbiome From Antibiotics.

Background: Antibiotics are life-saving drugs but severely affect the gut microbiome with short-term consequences including diarrhea and selection of antibiotic-resistant bacteria. Long-term links to allergy and obesity are also suggested. We devised a product, DAV132, and previously showed its ability to deliver a powerful adsorbent, activated charcoal, in the late ileum of human volunteers. Methods: We performed a randomized controlled trial in 28 human volunteers treated with a 5-day clinical regimen of the fluoroquinolone antibiotic moxifloxacin in 2 parallel groups, with or without DAV132 coadministration. Two control goups of 8 volunteers each receiving DAV132 alone, or a nonactive substitute, were added. Results: The coadministration of DAV132 decreased free moxifloxacin fecal concentrations by 99%, while plasmatic levels were unaffected. Shotgun quantitative metagenomics showed that the richness and composition of the intestinal microbiota were largely preserved in subjects co-treated with DAV132 in addition to moxifloxacin. No adverse effect was observed. In addition, DAV132 efficiently adsorbed a wide range of clinically relevant antibiotics ex vivo. Conclusions: DAV132 was highly effective to protect the gut microbiome of moxifloxacin-treated healthy volunteers and may constitute a clinical breakthrough by preventing adverse health consequences of a wide range of antibiotic treatments. Clinical Trials Registration: NCT02176005.

Adherence to treatment and quality of life during hepatitis C therapy: a prospective, real-life, observational study.

BACKGROUND: Adherence is important for therapy of chronic diseases, but has still not been well studied in real life in chronic hepatitis C. AIMS: To assess adherence to hepatitis C combination therapy in routine clinical practice and to identify factors associated with imperfect adherence. METHODS: This cohort study included unselected chronic hepatitis C patients initiating peginterferon α-2b plus ribavirin. 100% adherence was defined by taking all the prescribed doses of both drugs for the full initially intended duration, as declared by the patient or believed by the physician. Quality of life was assessed using the short-form health survey (SF-36) questionnaire. RESULTS: 1860 patients were analysed, including 72% treatment-naive, 36% genotype 2/3, 23% psychiatric, 44% drug addicts and 3% human immunodeficiency virus (HIV)-positive patients. Early treatment discontinuation occurred in 30% of patients. Overall, 38% of patients reported 100% adherence. Patient- and physician-reported adherences were discordant, with a 20-30% overestimation by physicians. HIV co-infection [odds ratio (OR) 2.52, 95% confidence interval (CI) 1.36-4.67], no drug use during follow-up (2.37, 1.30-4.31), genotype 3 (1.55, 1.20-2.00) and treatment-naive (1.32, 1.03-1.69) were associated with 100% adherence. Quality of life worsened during treatment but returned to baseline after the end of treatment. CONCLUSIONS: Imperfect adherence to combination therapy is common in routine patients. Adherence is markedly overestimated by physicians and is associated with some patient's baseline characteristics. Knowledge of these factors might help identify patients who are most in need of intervention and plan more frequent and accurate follow-up.

Maintenance therapy and 3-year outcome of opioid-dependent prisoners: a prospective study in France (2003-06).

AIMS: To describe the profile of imprisoned opioid-dependent patients, prescriptions of maintenance therapy at imprisonment and 3-year outcome in terms of re-incarceration and mortality. DESIGN: Prospective, observational study (France, 2003-06). SETTING: Health units of 47 remand prisons. PARTICIPANTS: A total of 507 opioid-dependent patients included within the first week of imprisonment between June 2003 and September 2004, inclusive. MEASUREMENTS: Physicians collected socio-demographic data, penal history, history of addiction, maintenance therapy and psychoactive agent use, general health status and comorbidities. Prescriptions at imprisonment were recorded by the prison pharmacist. Re-incarceration data were retrieved from the National Register of Inmates, survival data and causes of death from the National Registers of vital status and death causes. FINDINGS: Prison maintenance therapy was delivered at imprisonment to 394/507 (77.7%) patients. These patients had poorer health status, heavier opioid use and prison history and were less socially integrated than the remaining 113 patients. Over 3 years, 238/478 patients were re-incarcerated [51.3 re-incarcerations per 100 patient-years, 95% confidence interval (CI) 46.4-56.2]. Factors associated independently with re-incarceration were prior imprisonment and benzodiazepine use. After adjustment for confounders, maintenance therapy was not associated with a reduced rate of re-incarceration (adjusted relative risk 1.28, 95% CI 0.89-1.85). The all-cause mortality rate was eight per 1000 patient-years (n = 10, 95% CI 4-13). CONCLUSIONS: Prescription of maintenance therapy has increased sharply in French prisons since its introduction in the mid-1990s. However, the risk of re-imprisonment or death remains high among opioid-dependent prisoners. Substantial efforts are needed to implement more effective preventive policies.

Patient education improves adherence to peg-interferon and ribavirin in chronic genotype 2 or 3 hepatitis C virus infection: a prospective, real-life, observational study.

AIM: To evaluate the impact of therapeutic education on adherence to antiviral treatment and sustained virological response (SVR) in a real-life setting in genotype 2/3 hepatitis C, as there are few adherence data in genotype 2/3 infection, even from randomized trials. METHODS: This prospective survey included genotype 2/3 patients who received peg-interferon alfa-2b and ribavirin. There was no intervention. Adherence was self-reported over the past 4 wk (peg-interferon) or 7 d (ribavirin). Adherence to bitherapy was defined as adherence to the two drugs for >or= 20 wk. SVR was defined as undetectable RNA >or= 12 wk after the end of treatment. RESULTS: 370/674 patients received education during the first 3 mo of treatment. After 6 mo, adherence to bitherapy was higher in educated patients (61% vs 47%, P = 0.01). Adherence to peg-interferon was 78% vs 69% (P = 0.06). Adherence to ribavirin was 70% vs 56% (P = 0.006). The SVR (77% vs 70%, P = 0.05) and relapse (10% vs 16%, P = 0.09) rates tended to be improved. After adjustment for baseline differences, education improved adherence [Odds ratio (OR) 1.58, P = 0.04] but not the SVR (OR 1.54, P = 0.06). CONCLUSION: In genotype 2/3 patients, therapeutic education helped maintain real-life adherence to bitherapy.

Hepatitis B virus genotypes and extrahepatic manifestations.

BACKGROUND/AIMS: This study aimed at correlating the presence of extrahepatic manifestations with hepatitis B virus (HBV) genotypes in patients with chronic HBV infection. METHODS: This was a national (France), multicenter, retrospective, cross-sectional study. HBV genotypes were determined in 190 patients HBsAg-positive for at least 6 months and documented before any treatment. RESULTS: Patients were aged 42+/-15 years and mainly male (77%). Alcohol intake was high in 6% of them, ALT elevated in 73%; 27% were cirrhotic. All HBV genotypes were found, mainly A (24%), D (29%), C (11%), and E (10%). Thirty (16%) patients had clinical extrahepatic manifestations, mainly sensory-motor deficiency, sicca syndrome, myalgia, glomerulonephritis, and arthralgia-arthritis. Their presence was not related to any epidemiologic, viral (including genotypes) or hepatic factor, but to a higher platelet count (P=0.004). Twenty-nine (15%) patients had biological extrahepatic manifestations, mainly anti-smooth muscle, antinuclear, and anti-nucleosome antibodies. Their presence was related only to anti-HBe antibodies positivity (P=0.007) or elevated platelet count (P=0.003). Carrying precore mutant HBV increased by 2.8 folds the risk to have at least one extrahepatic biological manifestation. CONCLUSIONS: No relationships between HBV genotypes and the presence of extrahepatic manifestations were evidenced in patients with chronic HBV infection.