Hepatitis C virus (HCV) infection affects millions of people world-wide, and chronic infection can result in end-stage liver disease and hepatocellular carcinoma. Conventional therapy to date has ...involved combination antiviral therapy including alpha-interferon and ribavirin; response rates with these drugs are variable based on both viral and host factors, such as HCV viral load, HCV genotype, HIV co-infection, host genetic polymorphisms (such as those in the IL28B region), and other factors. Recent advances in HCV treatment have included pegylated forms of alpha-interferon and, more recently, the development of specifically targeted antiviral therapy for HCV (STAT-C) with novel HCV protease inhibitors (PIs) for genotype 1 HCV. Although unlikely to be administered as monotherapy due to the potential for development of HCV PI drug resistance mutations, results of phase II trials of two PIs in development have recently been reported, demonstrating promising therapeutic efficacy of HCV PIs in combination with established conventional treatment. This review outlines the advances and the challenges in the development of these HCV PIs as effective HCV antiviral agents and their role in clinical practice.
Immune biomarkers are implicated in HCV treatment response, fibrosis, and accelerated pathogenesis of comorbidities, though only D-dimer and C-reactive protein have been consistently studied. Few ...studies have evaluated HIV/HCV co-infection, and little longitudinal data exists describing a broader antiviral cytokine response.
Fifty immune biomarkers were analyzed at baseline (BL) and HCV end of treatment follow-up(FU) time point using the Luminex 50-plex assay in plasma samples from 15 HCV-cleared, 24 HCV mono- and 49 HIV/HCV co-infected patients receiving antiretroviral treatment, who either did or did not receive pegylated-interferon/ribavirin HCV treatment. Biomarker levels were compared among spontaneous clearance patients, mono- and co-infected, untreated and HCV-treated, and sustained virologic responders (SVR) and non-responders (NR) at BL and FU using nonparametric analyses. A Bonferroni correction, adjusting for tests of 50 biomarkers, was used to reduce Type I error.
Compared to HCV patients at BL, HIV/HCV patients had 22 significantly higher and 4 significantly lower biomarker levels, following correction for multiple testing. There were no significantly different BL levels when comparing SVR and NR in mono- or co-infected patients; however, FU levels changed considerably in co-infected patients, with seven becoming significantly higher and eight becoming significantly lower in SVR patients. Longitudinally between BL and FU, 13 markers significantly changed in co-infected SVR patients, while none significantly changed in co-infected NR patients. There were also no significant changes in longitudinal analyses of mono-infected patients achieving SVR or mono-infected and co-infected groups deferring treatment.
Clear differences exist in pattern and quantity of plasma immune biomarkers among HCV mono-infected, HIV/HCV co-infected, and HCV-cleared patients; and with SVR in co-infected patients treated for HCV. Though >90% of patients were male and co-infected had a larger percentage of African American patients, our findings may have implications for better understanding HCV pathogenesis, treatment outcomes, and future therapeutic targets.
Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well ...understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 ( p = 1.76 ⁎ 10 - 5 ) and IL-6 ( p = 0.0007 ) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance ( p = 0.17 ). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.
Background. Despite the increasing use of outpatient parenteral antimicrobial therapy (OPAT), little is known about the role of infectious diseases consultants in the process or their perceptions of ...OPAT. Methods. In May 2004, the Infectious Diseases Society of America Emerging Infections Network (EIN) surveyed its members to characterize their involvement and experiences with OPAT. Results. Of the 454 respondents (54%) who completed the questionnaire, 426 (94%) indicated that patients in their primary inpatient facility were “frequently” discharged while receiving OPAT, estimating that, on average, 19 patients are discharged from their hospitals while receiving OPAT each month. Although 86% of EIN members stated that they personally order OPAT for some patients, 18% indicated that they have no involvement, and 37% stated they only rarely or occasionally oversee OPAT. EIN members involved in OPAT estimated that ∼90% of their patients who take OPAT received therapy at home, and the members described variable monitoring and oversight methods. Of the respondents, 68% of providers collectively estimated that they encountered 1951 infectious and serious noninfectious complications of OPAT in the past year. The most frequently used antibiotics included vancomycin, ceftriaxone, and cefazolin, most commonly used for bone and joint infections. Conclusions. These results testify to the pervasive use of OPAT in today's health care system, the variable role of infectious diseases consultants, and the heterogeneity in oversight and management practices. The widespread use of OPAT and its frequent complications indicate the need for additional studies to establish optimal methods of delivery and management to insure the quality and safety of the process.
Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon ...beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19.
We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475.
Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 95% CI 0·87-1·13; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 95% CI 0·69-2·55; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 7% of 442 patients) than in the placebo plus remdesivir group (15 3% of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group.
Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo.
The National Institute of Allergy and Infectious Diseases (USA).
Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone ...plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.
In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.
Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% 95% CI 83·7 to 89·6 in the baricitinib plus remdesivir plus placebo group and 87·6% 84·2 to 90·3 in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 95% CI -3·6 to 4·8; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% 1·6 to 13·3; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% 2·8 to 9·3; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% 1·8 to 13·4; p=0·012).
In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.
National Institute of Allergy and Infectious Diseases.
Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their ...contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo.
Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.
Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.
Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.
The number of older HIV-infected people is growing due to increasing life expectancies resulting from the use of antiretroviral therapy (ART). Both HIV and aging increase the risk of other ...comorbidities, such as cardiovascular disease, osteoporosis, and some malignancies, leading to greater challenges in managing HIV with other conditions. This results in complex medication regimens with the potential for significant drug-drug interactions and increased morbidity and mortality. Area covered: We review the metabolic pathways of ART and other medications used to treat medical co-morbidities, highlight potential areas of concern for drug-drug interactions, and where feasible, suggest alternative approaches for treating these conditions as suggested from national guidelines or articles published in the English language. Expert commentary: There is limited evidence-based data on ART drug interactions, pharmacokinetics and pharmacodynamics in the older HIV-infected population. Choosing and maintaining effective ART regimens for older adults requires consideration of side effect profile, individual comorbidities, interactions with concurrent prescriptions and non-prescription medications and supplements, dietary patterns with respect to dosing, pill burden and ease of dosing, cost and affordability, patient preferences, social situation, and ART resistance history. Practitioners must remain vigilant for potential drug interactions and intervene when there is a potential for harm.
Abstract
Background
MRSA and C. diff are important causes of hospital-onset (HO) or healthcare-associated infections (HAI). Molecular sequencing of bacterial pathogens is often used retrospectively ...during outbreak investigations to determine phylogenetic linkage. We evaluated the utility of on-demand multilocus sequence typing (MLST) in characterizing hospital transmission events.
Methods
Using VA or NHSN criteria, inpatients with MRSA-HAI or HO-C. difficile infection (HO-CDI) were identified by infection preventionists (IPs) for MLST (by time and location) during active hospital surveillance starting October 2016 or September 2017 (for C. difficile and MRSA, respectively) through March 2019. Vitek 2 identified MRSA from blood or other sources, and stool samples positive for C. difficile by Cepheid Xpert® C. difficile or FilmArray® Gastrointestinal (GI) Panel were collected and C. diff isolated on CCFA plates. Sequence types (STs) were generated by Sanger sequencing and MLST using standard protocols (pubmlst.org). C. difficile genes included adk, atpA, dxr, glyA, recA, sodA, tpi. MRSA genes included arc, aro, glp, gmk, pta, tpi, yqil. Staphylococcal protein A gene (spa) type was determined by spa gene sequencing.
Results
MLST assay (C. diff 33, MRSA 26) intervals ranged from 1–4 weeks based on IP request. 109 C. diff isolates from 105 patients representing 44 STs (10 unique) were found. ST1 and ST2 (27, 20) were most common. 5 patients had 2–3 identical ST isolates over 21–180 days. Of 72 HO-CDI identified, 9 possible person-to-person transmissions events (33 cases) were ruled out; 3 events (9 cases) were ruled in; 14 events (21 cases) were not resolved due to missing samples or no growth. 100 MRSA isolates from 96 patients representing 26 STs (9 unique) were found. ST8/spa t008 (USA300) and ST5/spa t002 (USA100) (44, 29) were most common. 11 patients had 2–3 identical ST isolates over 2–367 days. Of 16 MRSA-HAI identified, 1 transmission event (4 cases) was ruled out, 1 event (2 cases) lacked one strain and was unresolvable.
Conclusion
Common MRSA and C. diff STs predominated among hospital isolates, yet significant heterogeneity was seen over a 2-year period and few true transmission events were documented. On-demand MLST-augmented IP surveillance was useful to rule-out hospital transmission.
Disclosures
All authors: No reported disclosures.
IFN-α has been the cornerstone of chronic hepatitis C virus (HCV) treatment for over a decade. Yet, rates of sustained virologic response of HCV infection to interferon-based therapy, particularly in ...difficult-to-treat populations, have been disappointingly low. This is particularly true in HIV/HCV coinfection, in which less than a third of patients typically respond to therapy. New HCV protease inhibitors, most of which will need to be administered with pegylated interferon, are in development, but comprehensive, long-term data for their use in coinfected patients is not yet available. Understanding the basis of this population's poor response to interferon-based therapy is crucial to future exploration of new therapeutic options, immunotherapy and prognosis in HIV/HCV-coinfected population.
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