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Background The gastrointestinal microbiota is an important line of defense against colonization with antimicrobial resistant (AR) bacteria. In this post hoc analysis of the phase 3 ECOSPOR III trial, we assessed impact of a microbiota-based oral therapeutic (fecal microbiota spores, live; VOWST Oral Spores [VOS], formerly SER-109]; Seres Therapeutics) compared with placebo, on AR gene (ARG) abundance in patients with recurrent Clostridioides difficile infection (rCDI). Methods Adults with rCDI were randomized to receive VOS or placebo orally for 3 days following standard-of-care antibiotics. ARG and taxonomic profiles were generated using whole metagenomic sequencing of stool at baseline and weeks 1, 2, 8, and 24 posttreatment. Results Baseline (n = 151) and serial posttreatment stool samples collected through 24 weeks (total N = 472) from 182 patients (59.9% female; mean age: 65.5 years) in ECOSPOR III as well as 68 stool samples obtained at a single time point from a healthy cohort were analyzed. Baseline ARG abundance was similar between arms and significantly elevated versus the healthy cohort. By week 1, there was a greater decline in ARG abundance in VOS versus placebo (P =.003) in association with marked decline of Proteobacteria and repletion of spore-forming Firmicutes, as compared with baseline. We observed abundance of Proteobacteria and non–spore-forming Firmicutes were associated with ARG abundance, while spore-forming Firmicutes abundance was negatively associated. Conclusions This proof-of-concept analysis suggests that microbiome remodeling with Firmicutes spores may be a potential novel approach to reduce ARG colonization in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease.

Background and objectivesHepatitis C virus (HCV) RNA level in acute HCV infection is predictive of spontaneous clearance. This study assessed factors associated with HCV RNA levels during early acute infection among people who inject drugs with well-defined acute HCV infection.Study designData were from International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study, an international collaboration of nine prospective cohorts studying acute HCV infection. Individuals with available HCV RNA levels during early acute infection (first two months following infection) were included. The distribution of HCV RNA levels during early acute infection were compared by selected host and virological factors.ResultsA total of 195 individuals were included. Median HCV RNA levels were significantly higher among individuals with interferon lambda 3 (IFNL3, formerly called IL28B) CC genotype compared to those with TT/CT genotype (6.28 vs. 5.39logIU/mL, respectively; P=0.01). IFNL3 CC genotype was also associated with top tertile HCV RNA levels (≥6.3log IU/mL; vs. TT/CT genotype; adjusted Odds Ratio: 4.28; 95%CI: 2.01, 9.10; P

Background Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. Methods Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1–2, 3–4, ≥5); (ii) baseline creatinine clearance (<30, 30–50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. Results Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. Conclusions In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities. [ABSTRACT FROM AUTHOR]

Several challenging issues faced by the clinician treating the patients with hepatitis C virus (HCV)/HIV coinfection is addressed. It is indicated that HIV/HCV-coinfected patients should be evaluated for possible underlying liver disease and be considered for peginterferon/ribavirin therapy.

Background Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. Methods In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. Results 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P <.05) and increased secondary bile acid concentrations (P <.0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. Conclusions Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. Clinical Trials Registration NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4. [ABSTRACT FROM AUTHOR]

A small number of patients discontinued the study early for reasons other than recurrent I C difficile i infection (9.0% in the SER-109 group and 10.8% in the placebo group). Patients who discontinued for reasons other than recurrent I C difficile i infection were imputed as having recurrence through week 24 in analyses of SER-109/placebo I C difficile i infection recurrence risk ratio and time to recurrent I C difficile i infection. Comment & Response B In Reply b Dr Hamilton and colleagues question why taper/pulse regimens of vancomycin were not used in the ECOSPOR III trial for patients with recurrent I C difficile i infection.[1] Vancomycin has excellent bactericidal activity against I C difficile i bacteria with no detectable toxin concentrations by day 4, but has no activity against I C difficile i spores, which germinate in a disrupted microbiome, leading to I C difficile i infection.[2] The rationale for taper/pulse regimens is to allow microbiome diversification with decreasing antibiotic exposure.[3] The IDSA guidelines qualify the strength of the recommendation to use taper/pulse regimens as "weak" and quality of evidence as "low", based on the lack of placebo-controlled trials and small uncontrolled studies of heterogeneous quality.[3] Use of taper/pulse regimens has increased in the absence of approved microbiome therapeutics. [Extracted from the article]

Background: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection. Methods: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels≤120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression. Results: Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P=0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83). Conclusions: Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance. [ABSTRACT FROM AUTHOR]

The author discusses patients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections. He informs that HIV/HCV coinfected patients had significantly lower treatment response ratesthan patients with HCV alone. Also investigated is the risk of developing decompensated cirrhosis in HIV/HCV patients including esophagealbleeding, ascites, hepatic encephalopathy and hepatocellular carcinoma.

Background. Studies of the progression liver fibrosis in human immunodeficiency virus (HIV) and hepatitis C virus-coinfected patients suggest that cirrhosis is associated with immunosuppression, as measured by low absolute CD4+ T cell counts. However, we hypothesized that, in patients with advanced liver disease, low CD4+ T cell counts may occur secondary to portal hypertension and splenic sequestration, regardless of the presence or absence of HIV infection. Methods. Sixty HIV-seronegative outpatients with cirrhosis were enrolled during the period 2001-2003 in a prospective, cross-sectional study of the association between liver disease and CD4+ T cell counts and percentages. Demographic characteristics, liver disease-related characteristics, and laboratory results-including CD4+ T cell parameters-were collected. Results. A total of 39 patients (65%) had a low CD4+ T cell count; 26 patients (43%) and 4 patients (7%) had CD4+ T cell counts <350 and <200 cells/mm³, respectively. Abnormal CD4+ T cell counts were associated with splenomegaly (P = .03 ), thrombocytopenia (P = .002), and leukopenia (P < .001 ). The percentage of CD4+ T cells was normal in 95% of patients who had a low absolute CD4+ T cell count. CD4+ T cell counts were significantly lower among cirrhotic patients than among 7638 HIV-seronegative historic control subjects without liver disease. Conclusions. Cirrhosis is associated with low CD4+ T cell counts in the absence of HIV infection. Discordance between low absolute CD4+ T cell counts and normal CD4+ T cell percentages may be attributable to portal hypertension and splenic sequestration. Our findings have significant implications for the use and interpretation of absolute CD4+ T cell counts in HIV-infected patients with advanced liver disease. [ABSTRACT FROM AUTHOR]

Background: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection. Methods: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study). Participants with well-characterized acute HCV infection (detected within three months post-infection and interval between the peak and subsequent HCV RNA levels≤120 days) were categorised by a priori-defined patterns of HCV RNA levels: i) spontaneous clearance, ii) partial viral control with persistence (≥1 log IU/mL decline in HCV RNA levels following peak) and iii) viral plateau with persistence (increase or <1 log IU/mL decline in HCV RNA levels following peak). Factors associated with HCV RNA patterns were assessed using multinomial logistic regression. Results: Among 643 individuals with acute HCV, 162 with well-characterized acute HCV were identified: spontaneous clearance (32%), partial viral control with persistence (27%), and viral plateau with persistence (41%). HCV RNA levels reached a high viraemic phase within two months following infection, with higher levels in the spontaneous clearance and partial viral control groups, compared to the viral plateau group (median: 6.0, 6.2, 5.3 log IU/mL, respectively; P=0.018). In the two groups with persistence, Interferon lambda 3 (IFNL3) CC genotype was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95%CI: 1.08, 7.02). In the two groups with viral control, female sex was independently associated with spontaneous clearance compared to partial viral control (AOR: 2.86; 95%CI: 1.04, 7.83). Conclusions: Among individuals with acute HCV, a spectrum of HCV RNA patterns is evident. IFNL3 CC genotype is associated with initial viral control, while female sex is associated with ultimate spontaneous clearance.