Outpatient Antibiotic Stewardship: A Growing Frontier-Combining Myxovirus Resistance Protein A With Other Biomarkers to Improve Antibiotic Use.

BACKGROUND: The majority of oral antibiotics are prescribed in outpatient primary and urgent care clinics for acute respiratory infections. Effective antibiotic stewardship must include proper prescribing for outpatients as well as for those in a hospital or long-term care facility. METHODS: Major databases, including MEDLINE and the Cochrane Library, were searched for prospective human clinical studies, including children and/or adults published between January 1966 and November 2017 that evaluated Myxovirus resistance protein A (MxA) as a biomarker for diagnosing viral infections as well as both C-reactive protein (CRP) and procalcitonin (PCT) as potential biomarkers for identifying and differentiating true bacterial upper respiratory infection (URI) from colonization. RESULTS: Ten prospective human studies, totaling 1683 patients, were identified that evaluated MxA as a viral biomarker in children and/or adults. Both systematic review articles, meta-analyses, and randomized controlled clinical trials that examined CRP and/or PCT as a biomarker for identifying clinically significant bacterial infections and supporting antibiotic stewardship were identified. CONCLUSIONS: Quick and accurate differentiation between a viral and bacterial respiratory infection is critical to effectively combat antibiotic misuse. MxA expression in peripheral blood is a highly specific marker for viral infection. Combining MxA with other inflammatory biomarkers to test for respiratory infections offers enhanced sensitivity and specificity, forming an excellent tool for antibiotic stewardship in the outpatient setting.

Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2).

UNLABELLED: Hepatitis C virus (HCV)-infected patients with cirrhosis are historically a difficult-to-treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1-infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open-label, single-arm study (OPTIMIST-2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1-infected treatment-naive or treatment-experienced patients with cirrhosis. Patients (aged 18-70 years) with chronic HCV GT1 infection and documented presence of cirrhosis received oral simeprevir 150 mg once daily + sofosbuvir 400 mg once daily for 12 weeks. The primary efficacy endpoint of the study was the proportion of patients achieving SVR12 versus a composite historical control (SVR12 rate of 70%). Safety and patient-reported outcomes were assessed. Overall, 103 patients received treatment. SVR12 with simeprevir + sofosbuvir (83%, 95% confidence interval 76%-91%) met the primary objective of superiority versus the historical control (70%). SVR12 rates for treatment-naive and treatment-experienced patients were 88% (44/50) and 79% (42/53), respectively. Adverse events occurred in 72 (70%) patients, with most (64%) being grade 1 or 2. Serious adverse events (none considered related to study treatment) occurred in five (5%) patients, and three (3%) patients discontinued all study treatment due to adverse events. Patient-reported outcomes improved from baseline to follow-up week 12. CONCLUSION: Simeprevir + sofosbuvir for 12 weeks achieved superiority in SVR12 rates versus the historical control in treatment-naive and treatment-experienced HCV GT1-infected patients with cirrhosis and was generally safe and well tolerated. (Hepatology 2016;64:360-369).

Whole Genome Sequencing of a Methicillin-Resistant Staphylococcus aureus Pseudo-Outbreak in a Professional Football Team.

Two American football players on the same team were diagnosed with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections on the same day. Our investigation, including whole genome sequencing, confirmed that players did not transmit MRSA to one another nor did they acquire the MRSA from a single source within the training facility.

IDX184 in combination with pegylated interferon-α2a and ribavirin for 2 weeks in treatment-naive patients with chronic hepatitis C.

BACKGROUND: IDX184 is a liver-targeted nucleotide prodrug that selectively inhibits HCV NS5B polymerase. METHODS: This randomized, double-blind, placebo-controlled, ascending-dose study investigated the antiviral activity, safety and pharmacokinetics of IDX184 plus pegylated interferon-α2a and ribavirin (P/R) in treatment-naive patients with genotype-1 HCV. A total of 81 patients with baseline HCV RNA≥5 log10 IU/ml, alanine aminotransferase ≤3× upper limit of normal and compensated liver disease were dosed. Sequential cohorts of 20 patients, randomized 16:4 (active:placebo), received IDX184 for 14 days at rising daily doses of 50, 100, 150 or 200 mg in combination with P/R for 14 days. RESULTS: At the end of triple dosing, HCV RNA changes from baseline (mean ±sd log10) and proportion of patients achieving undetectable viral load (<15 IU/ml) based on the efficacy-evaluable population were -2.7 ±1.3 (13%), -4.0 ±1.7 (50%), -4.2 ±1.9 (50%), -4.1 ±1.2 (40%), -4.3 ±1.5 (29%) and -3.7 ±1.2 (25%) for the 50 mg once daily, 50 mg twice daily, 100 mg once daily, 150 mg once daily, 100 mg twice daily and 200 mg once daily IDX184 doses, respectively. P/R alone resulted in a reduction of -1.5 ±1.3 log10 with only 6% of patients with undetectable viral load. Patients with genotypes-1a or -1b responded similarly. No viral breakthrough or resistance associated with IDX184 was observed. Anti-HCV activity of IDX184 correlated with plasma exposure of its nucleoside metabolite 2'-methylguanosine. Most adverse events were mild or moderate in severity and were consistent with those associated with P/R. The most common adverse events were fatigue and headache. CONCLUSIONS: IDX184 in combination with P/R for 14 days was well tolerated and demonstrated greater antiviral activity with more patients achieving undetectable viral load than P/R.

Why should infectious disease physicians care for the hepatitis C-infected patient?

Hepatitis C virus (HCV) has evolved into a true infectious disease that needs the increased involvement of infectious disease (ID) physicians. HCV is a serious public health concern requiring screening, education, reduction of disease transmission, and access to care. Patients coinfected with HCV/human immunodeficiency virus need their ID physicians to be more involved in HCV care and the unique challenges that exist in this patient population. HCV patients overall need more provider resources with expertise. The era of direct-acting antivirals for HCV is creating the need and opportunity for ID physicians to assume an active role in this disease.

Recommendations for standardized nomenclature and definitions of viral response in trials of hepatitis C virus investigational agents.

Outdated virological response terms used at key trial timepoints in clinical trials with first-generation direct-acting antivirals plus pegylated interferon and ribavirin have failed to keep pace with hepatitis C virus (HCV) drug development. A more intuitive and flexible nomenclature capable of adapting to continuing advances in HCV drug development is needed. Assistance in standardization of the field was provided by members of the Hepatitis C Virus Drug Development Advisory Group, a project of the Forum for Collaborative HIV Research with participation from the American Association for the Study of Liver Diseases, European Association for the of the liver, and the Infectious Diseases Society of America. Our proposed descriptive, virological response nomenclature for key decision points in trials (with and without lead-in treatment) is based on an assay-specified lower limit of quantitation cutoff. This allows responses to be categorized as either quantifiable or unquantifiable HCV RNA, with unquantifiable responses further divided based on whether target HCV RNA was detected or not detected. The unified reporting recommendations will facilitate interpretation of results across clinical trials and validation of new response-guided timepoints. As time-critical treatment parameters are shortened in HCV trials, the proposed nomenclature will greatly simplify and facilitate future adaptations of virological response terms. Our proposed nomenclature will also be helpful in developing treatment guidelines for use in clinical practice.

Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy.

BACKGROUND: Cyclophilin inhibitors have shown activity against a variety of viruses, including HCV. NIM811, a novel, non-immunosuppressive cyclophilin inhibitor was studied in ascending doses in a randomized, double-blind, placebo-controlled 14-day trial in genotype 1 HCV patients. Doses of 10 up to 600 mg were given orally once or twice daily as monotherapy (9:3 randomization of NIM811:placebo). 600 mg or placebo bid for 14 days was then co-administered with pegylated interferon alpha (PEG-IFN-α) administered on days 1 and 8 to genotype 1 relapsers. RESULTS: NIM811 was well tolerated at all doses. Although lack of antiviral effect was noted in the monotherapy arms, liver transaminase normalization occurred at doses over 75 mg. Mild, clinically non-significant elevations of bilirubin, and significant declines in platelet numbers were observed in the 400 and 600 mg bid groups. In the combination group, the mean HCV RNA decline was 2.85 log, compared to a 0.56 log in the PEG-IFN alone arm. The mean ALT (alanine transaminase) declined significantly by day 14 in the combination, but was unchanged in the PEG-IFN alone group. In the combination therapy group, the mean platelets were 203×10(9)/L at baseline and fell to 105×10(9)/L by day 14; for patients treated with PEG-IFN the values were 177×10(9)/L and 139×10(9)/L. There was a significant increase in bilirubin, although this did not reach clinically concerning levels. There were no severe or serious adverse events. The pharmacokinetics in both monotherapy and combination arms were dose linear and not affected by PEG-INF. CONCLUSION: NIM811 monotherapy resulted in a normalization of liver transaminases in the absence of significant virological response. The combination of NIM811 and pegylated interferon alpha showed significant antiviral activity compared to interferon alone in genotype 1 HCV relapsers. The use of oral cyclophilin inhibitors as part of a combination regime for treatment of hepatitis C, especially to deter resistance, holds promise.

Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults.

Ibalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log(10)) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4(+) T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4(+) T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.

R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.

UNLABELLED: R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. CONCLUSION: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.

Efficacy and safety of 48 weeks of enfuvirtide 180 mg once-daily dosing versus 90 mg twice-daily dosing in HIV-infected patients.

PURPOSE: To evaluate the safety and antiviral activity of once-daily (qd) enfuvirtide (ENF) compared with twice daily (bid) ENF. METHOD: T20-401 was a phase 2, open-label, randomized, 48-week pilot study comparing ENF 180 mg qd versus ENF 90 mg bid, added to an optimized background (OB) regimen. Patients were randomized 1:1 to receive ENF 180 mg qd given as two 90-mg injections (n = 30) or one 90-mg injection bid (n = 31), plus OB. The primary efficacy endpoint was the proportion of patients achieving a HIV-1 RNA viral load <400 copies/mL. Adherence, pharmacokinetics, safety, and tolerability parameters, including injection site reactions (ISRs), were compared between treatment arms. RESULTS: At Week 48, 23.3% of patients on once daily versus 22.6% on twice daily (p = .969) reached <400 copies/mL and 13.3% and 22.6% (p = .323), respectively, reached <50 copies/mL. The proportion reporting 1 adverse event or ISRs was comparable between arms, despite an increased incidence of grade 4 erythema (13% vs. 0%), induration (33% vs. 12%), and ecchymosis (7% vs. 0%) on twice daily versus once daily. ENF adherence (95% of prescribed doses) was higher on once daily (80.0%) versus twice daily (58.1%). CONCLUSION: The antiviral efficacy, safety, and tolerability of 180 mg ENF qd appeared comparable with that of 90 mg ENF bid at Week 48, although the study was not powered to demonstrate the noninferiority of once daily versus twice daily.

Enfuvirtide does not require dose adjustment in patients with chronic kidney failure: results of a pharmacokinetic study of enfuvirtide in HIV-1-infected patients with impaired kidney function.

OBJECTIVE: The aim of this study was to examine the influence of kidney disease and hemodialysis on the pharmacokinetics ofenfuvirtide. DESIGN: An open-label, multicenter, parallel group study of HIV-1-infected patients with varying degrees of kidney dysfunction. METHODS: A 90-mg dose of enfuvirtide was administered by subcutaneous injection to 3 groups of patients: group A, patients with normal kidney function; group B, patients with chronic kidney disease; and group C, patients with end-stage renal disease (ESRD) requiring dialysis. Patients with ESRD requiring dialysis received the 90-mg dose of enfuvirtide on 2 separate occasions; a dialysis day and a nondialysis day. After each dose, a full 48-hour pharmacokinetic profile was collected and pharmacokinetic parameters were estimated using model-independent techniques. RESULTS: Enfuvirtide area under the curve (AUCinfinity) and maximum observed enfuvirtide plasma concentration (Cmax) for patients with normal kidney function (group A) was 49.6 microg h/mL and 3.79 microg/mL, respectively. Patients with chronic kidney disease (group B) had higher AUCinfinity (80.3 microg h/mL) and Cmax (5.72 microg/mL), which was similar to patients with ESRD (group C) on both nondialysis days (AUCinfinity 71.1 microg h/mL; Cmax 5.34 microg/mL) and dialysis days (AUCinfinity 66.9 microg h/mL; Cmax 6.31 microg/mL). An average of< 13% of enfuvirtide was removed during the dialysis procedure. The incidence of adverse events was comparable for all study groups. CONCLUSION: Enfuvirtide exposure observed in patients with ESRD requiring dialysis or chronic kidney disease was slightly higher than in patients with normal kidney function and similar to historical Cmax and AUC values from studies in patients with normal kidney function. Thus, enfuvirtide does not require dosage adjustment in patients with impaired kidney function.

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial.

UNLABELLED: This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. CONCLUSION: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.

Baseline factors prognostic of sustained virological response in patients with HIV-hepatitis C virus co-infection.

OBJECTIVE: To identify baseline characteristics predictive of a sustained virological response (SVR) in patients with HIV-hepatitis C virus (HCV) co-infection treated with interferon-based therapy. DESIGN/METHODS: A stepwise multiple logistic regression analysis was used to explore the prognostic factors associated with SVR [undetectable HCV-RNA (< 50 IU/ml) at the end of untreated follow-up in week 72]. RESULTS: In all patients (n = 853), in addition to the HCV therapy received, the factors most predictive of SVR were baseline HCV-RNA [< or = versus > 400 000 IU/ml; odds ratio (OR) 4.77; 95% confidence interval (CI) 3.15-7.22; P < 0.0001] and HCV genotype (OR 2.87; 95% CI 2.00-4.12; P < 0.0001). HIV treatment (with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor; P = 0.034), race (P = 0.027), and body mass index (P = 0.039) were also weak predictors of HCV treatment response. CONCLUSIONS: In the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT), the predictors of SVR among HIV-HCV co-infected patients treated with peginterferon alfa-2a plus ribavirin were similar to those in patients with HCV mono-infection. The HCV genotype and pretreatment HCV-RNA level had the greatest influence on SVR.

Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1.

BACKGROUND: We wished to determine the safety and anti-human immunodeficiency virus (HIV) type 1 activity of single doses of TNX-355, a humanized IgG4 anti-CD4 monoclonal antibody with potent activity against HIV-1 in vitro, in HIV-infected subjects. METHODS: Sequential cohorts of 6 HIV-1-infected subjects each received infusions of TNX-355. Data included plasma HIV-1 RNA level, CD4+ T cell count, TNX-355 coating of CD4+ T cells, and serum TNX-355 levels. RESULTS: Dose-related reductions in plasma HIV-1 RNA loads correlated with complete CD4+ T cell coating by TNX-355. Peak median decreases in plasma HIV-1 RNA loads were 0.56, 1.33, and 1.11 log10 copies/mL and occurred on days 4-7, 14, and 21 for the 3.0, 10, and 25 mg/kg doses, respectively. Dose-dependent increases in CD4+ T cell count occurred within 24 h of dosing. CONCLUSIONS: Single doses of TNX-355 reduced plasma HIV-1 RNA loads and increased CD4+ T cell counts in HIV-infected subjects. The further assessment of therapeutic potential awaits data from longer-duration trials.