During Hepatitis C Virus (HCV) Infection and HCV-HIV Coinfection, an Elevated Plasma Level of Autotaxin Is Associated With Lysophosphatidic Acid and Markers of Immune Activation That Normalize During Interferon-Free HCV Therapy.

BACKGROUND: Immune activation predicts morbidity during hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection, although mechanisms underlying immune activation are unclear. Plasma levels of autotaxin and its enzymatic product, lysophosphatidic acid (LPA), are elevated during HCV infection, and LPA activates immunocytes, but whether this contributes to immune activation is unknown. METHODS: We evaluated plasma levels of autotaxin, interleukin 6 (IL-6), soluble CD14 (sCD14), soluble CD163 (sCD163), and Mac2 binding protein (Mac2BP) during HCV infection, HIV infection, and HCV-HIV coinfection, as well as in uninfected controls, before and after HIV antiretroviral therapy (ART) initiation and during interferon-free HCV therapy. RESULTS: We observed greater plasma autotaxin levels in HCV-infected and HCV-HIV-coinfected participants, compared with uninfected participants, primarily those with a higher ratio of aspartate aminotransferase level to platelet count. Autotaxin levels correlated with IL-6, sCD14, sCD163, Mac2BP, and LPA levels in HCV-infected participants and with Mac2BP levels in HCV-HIV-coinfected participants, while in HIV-infected individuals, sCD14 levels correlated with Mac2BP levels. Autotaxin, LPA, and sCD14 levels normalized, while sCD163 and Mac2BP levels partially normalized within 6 months of starting interferon-free HCV therapy. sCD163 and IL-6 levels normalized within 6 months of starting ART for HIV infection. In vitro, LPA activated monocytes. CONCLUSIONS: These data indicate that elevated levels of autotaxin and soluble markers of immune activation during HCV infection are partially reversible within 6 months of initiating interferon-free HCV treatment and that autotaxin may be causally linked to immune activation during HCV infection and HCV-HIV coinfection.

Implementation and evaluation of a multicomponent quality improvement intervention to improve efficiency of hepatitis C screening and diagnosis.

BACKGROUND: Given recent advances in hepatitis C virus (HCV) treatment, health systems must ensure that patients with a positive HCV antibody receive timely determination of their HCV status through viral testing. At the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, viral testing was completed within six months of the first instance of a positive HCV antibody test for only 45% of patients. Beginning in 2008, three sequential improvements were implemented to close this care gap. METHODS: The three sequential improvements phases were as follows: (1) improving patient-centeredness of screening process in ambulatory patients, (2) local implementation of the Department of Veterans Affairs national HCV reflex testing policy, and (3) local evaluation of the efficiency and effectiveness of local implementation of reflex testing. RESULTS: From 2005 through 2013, 40 to 150 unique patients/quarter required viral testing following a positive antibody test. The firsts and second-phase improvements resulted in a 68% and 96% completion rate for timely viral testing during respective improvement phases. In the third improvement phase, remaining process problems related to the reflex testing process were identified using a locally developed electronic HCV population management application, resulting in a sustained rate of 100% completion of timely viral testing. Interrupted time series analysis revealed that the implementation of HCV reflex testing had the largest impact on the ability to complete timely viral testing. CONCLUSIONS: A continuous quality improvement approach, supported by an HCV population management application, achieved the complete closure of an important HCV care gap. Reflex testing should be initiated at facilities that have yet to adopt this approach.

Genetically associated CD16(+)56(-) natural killer cell interferon (IFN)-αR expression regulates signaling and is implicated in IFN-α-induced hepatitis C virus decline.

BACKGROUND: Natural killer (NK) cells likely contribute to outcome of acute hepatitis C virus (HCV) infection and interferon (IFN)-induced control of chronic HCV infection. We previously observed IFN-αR and NKp30 expression associated with IFN-α-dependent NK cell activity. METHODS: Here, we examined CD16(+)56(-), CD16(+)56(+), and CD16(-)56(+) NK cell subset IFN-αR and NKp30 expression in relation to magnitude of HCV genotype 1 decrease during pegylated IFN-α plus ribavirin therapy. RESULTS: We observed greater baseline IFN-αR and NKp30 expression on CD16(+)56(+) and CD16(-)56(+) NK subsets in HCV-infected patients than in healthy control subjects. Baseline CD16(+)56(-) NK IFN-αR expression was associated with IFN-α-induced pSTAT1, and both were associated with magnitude of HCV decrease during pegylated IFN-α plus ribavirin therapy. Baseline CD16(+)56(-) NK IFN-αR expression was associated with race and interleukin 28B genotype, negatively associated with aspartate aminotransferase-to platelet ratio index, and positively associated with increase in NKp30 expression after in vivo IFN-α exposure. Finally, in vitro IFN-α2a-activated NK cytolysis of HCV-infected target cells was in part dependent on NKp30, and CD16(+)56(-) NK cell IFN-αR expression correlated with cytolytic activity. CONCLUSIONS: IFN-αR expression on CD16(+)56(-) NK cells during chronic HCV infection may in part be genetically determined, and level of expression regulates IFN-α signaling, which in turn may contribute to control of HCV infection.

Treating Hepatitis C Virus Reinfection With 8 Weeks of Ledipasvir/Sofosbuvir Achieves Sustained Virologic Response.

Three patients reinfected with hepatitis C virus after a sustained virologic response were considered treatment naïve and treated with a short-course direct acting antiviral regimen.

Management of Severe Bleeding in Patients Treated With Oral Anticoagulants: Proceedings Monograph From the Emergency Medicine Cardiac Research and Education Group-International Multidisciplinary Severe Bleeding Consensus Panel October 20, 2018.

In this Emergency Medicine Cardiac Research and Education Group (EMCREG)-International Proceedings Monograph from the October 20, 2018, EMCREG-International Multidisciplinary Consensus Panel on Management of Severe Bleeding in Patients Treated With Oral Anticoagulants held in Orlando, FL, you will find a detailed discussion regarding the treatment of patients requiring anticoagulation and the reversal of anticoagulation for patients with severe bleeding. For emergency physicians, critical care physicians, hospitalists, cardiologists, internists, surgeons, and family physicians, the current approach and disease indications for treatment with anticoagulants such as coumadin, factor IIa, and factor Xa inhibitors are particularly relevant. When a patient treated with anticoagulants presents to the emergency department, intensive care unit, or operating room with severe, uncontrollable bleeding, achieving rapid, controlled hemostasis is critically important to save the patient's life. This EMCREG-International Proceedings Monograph contains multiple sections reflecting critical input from experts in Emergency Cardiovascular Care, Prehospital Emergency Medical Services, Emergency Medicine Operations, Hematology, Hospital Medicine, Neurocritical Care, Cardiovascular Critical Care, Cardiac Electrophysiology, Cardiology, Trauma and Acute Care Surgery, and Pharmacy. The first section provides a description of the current indications for the treatment of patients using oral anticoagulants including coumadin, the factor IIa (thrombin) inhibitor dabigatran, and factor Xa inhibitors such as apixaban and rivaroxaban. In the remaining sections, the treatment of patients presenting to the hospital with major bleeding becomes the focus. The replacement of blood components including red blood cells, platelets, and clotting factors is the critically important initial treatment for these individuals. Reversing the anticoagulated state is also necessary. For patients treated with coumadin, infusion of vitamin K helps to initiate the process of protein synthesis for the vitamin K-dependent coagulation proteins II, VII, IX, and X and the antithrombotic protein C and protein S. Repletion of clotting factors for the patient with 4-factor prothrombin complex concentrate, which includes factors II (prothrombin), VII, IX, and X and therapeutically effective concentrations of the regulatory proteins (protein C and S), provides real-time ability to slow bleeding. For patients treated with the thrombin inhibitor dabigatran, treatment using the highly specific, antibody-derived idarucizumab has been demonstrated to reverse the hypocoagulable state of the patient to allow blood clotting. In May 2018, andexanet alfa was approved by the US Food and Drug Administration to reverse the factor Xa anticoagulants apixaban and rivaroxaban in patients with major bleeding. Before the availability of this highly specific agent, therapy for patients treated with factor Xa inhibitors presenting with severe bleeding usually included replacement of lost blood components including red blood cells, platelets, and clotting factors and 4-factor prothrombin complex concentrate, or if not available, fresh frozen plasma. The evaluation and treatment of the patient with severe bleeding as a complication of oral anticoagulant therapy are discussed from the viewpoint of the emergency physician, neurocritical and cardiovascular critical care intensivist, hematologist, trauma and acute care surgeon, hospitalist, cardiologist, electrophysiologist, and pharmacist in an approach we hope that the reader will find extremely practical and clinically useful. The clinician learner will also find the discussion of the resumption of oral anticoagulation for the patient with severe bleeding after effective treatment important because returning the patient to an anticoagulated state as soon as feasible and safe prevents thrombotic complications. Finally, an EMCREG-International Severe Bleeding Consensus Panel algorithm for the approach to management of patients with life-threatening oral anticoagulant-associated bleeding is provided for the clinician and can be expanded in size for use in a treatment area such as the emergency department or critical care unit.

Soluble Markers of Immune Activation Differentially Normalize and Selectively Associate with Improvement in AST, ALT, Albumin, and Transient Elastography During IFN-Free HCV Therapy.

BACKGROUND: During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evaluation of liver damage stage. While a portion of the TE score is attributable to liver fibrosis and relatively irreversible damage, another component of the TE score is attributable to liver inflammation or edema. Markers of inflammation during chronic HCV infection include soluble markers of immune activation, which are also associated with morbid outcome (including cardiovascular disease and liver-disease progression). Whether soluble markers of immune activation or changes in their level during HCV therapy relate to normalization of AST, ALT, Albumin, or TE score, is not clear. METHODS: We evaluated soluble markers of immune activation (plasma sCD14, IL-6, sCD163, autotaxin [ATX], and Mac2BP) and TE score, and their relationship in 20 HCV-infected patients before, during, and after HCV-directed IFN-free direct-acting antiviral (DAA) therapy. We evaluated normalization of parameters and the relationship between each over a 6-month window. RESULTS: Before therapy, serum AST levels positively correlated with plasma levels of sCD14, sCD163, and Mac2BP, while ALT levels positively correlated with Mac2BP. Serum albumin level negatively correlated with plasma IL-6 and ATX levels. IFN-free therapy uniformly resulted in sustained virological response at 12 and 24 weeks after therapy completion. After initiation of therapy AST and ALT normalized, while levels of ATX, Mac2BP, sCD163, and TE score partially normalized over 6 months. Additionally, change in AST level and APRI score correlated with change in sCD163, IL-6, and Mac2BP levels, and change in ALT correlated with change in IL-6 and Mac2BP levels. Improvement in TE score correlated with a decrease in the level of sCD14 at week 4, and almost statistically significant with decrease in sCD14 at weeks 20-24 after initiation of IFN-free HCV therapy. CONCLUSIONS: Soluble markers of immune activation normalize or partially normalize at different rates after initiation of curative HCV DAA therapy, and TE scores improve, with wide variability in the degree of absolute improvement in liver stiffness from patient to patient. Decline magnitude of sCD14 was associated with improvement in TE score, while magnitude of improvement in AST correlated with reduction in sCD163 levels. These data provide support for a model where monocyte/Kupffer cell activation may account for a portion of the liver inflammation and edema, which is at least partially reversible following initiation of HCV DAA therapy.

Treatment Selection Choices Should Not Be Based on Benefits or Costs Alone: A Head-to-Head Randomized Controlled Trial of Antiviral Drugs for Hepatitis C.

BACKGROUND: Clinicians often face dilemmas with decisions related to formulary choices when two similar drugs are simultaneously available in the market. We studied the comparative safety, effectiveness, and treatment costs of the two first generation direct-acting antiviral agents (DAA), boceprevir and telaprevir as uncertainty existed regarding the drug of choice between these two seemingly equally Hepatitis-C treatment options. METHODS: We randomly assigned 50 patients in an open-label, pragmatic randomized controlled trial (RCT) at a VA Medical Center to either boceprevir or telaprevir in combination with peginterferon and ribavirin, stratified by the presence of cirrhosis and prior treatment experience. Tolerability was assessed at each visit and reasons for discontinuation of treatment and severity of adverse events due to PI treatment were adjudicated using a blinded adjudication committee. The primary outcome was difference in tolerability between boceprevir vs. telaprevir. Secondary outcomes included viral response rates and cost-per cure achieved. RESULTS: Higher rates of treatment discontinuations and/or severe DAA associated adverse events were seen in 10/25 (40%) patients randomized to telaprevir compared to 2/25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20; p<0.01). Cure rates did not appear to be significantly different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99; p = 0.39). On an intention-to-treat basis, total cost per cure was $44,329 for boceprevir vs. $57,115 for telaprevir. The significant side effect profile of telaprevir combined with the availability of highly efficacious second generation DAAs led to the early discontinuation of the trial. CONCLUSION: Telaprevir is associated with a significantly higher rate of severe adverse events leading to treatment discontinuations, hospitalizations or severe anemia and a substantially higher cost per SVR when compared to boceprevir. Real-time, point of care, pragmatic randomized controlled trials are necessary for guidance beyond just acquisition costs and to make evidence-based formulary selections when multiple effective treatments are available. (Clinicaltrials.gov registration: NCT02113631).

Evaluating a hepatitis c quality gap: missed opportunities for HCV-related cares.

OBJECTIVES: Diagnosis of chronic hepatitis C virus (HCV) is a 2-step process involving hepatitis C antibody (HCVab) testing followed by viral ribonucleic acid (RNA) testing. The HCV status of those with a positive HCVab without viral testing cannot be determined. This study sought to describe the HCV-related care provided to patients in this care gap. STUDY DESIGN: Retrospective cohort study of active patients with a positive HCVab test who did not complete viral testing. METHODS: Electronic medical records (EMRs) were reviewed to determine if each subject's first positive HCVab result was acknowledged by a provider. For results acknowledged, we described provider actions in response to the result. When providers performed specific clinical actions within 1 year of the positive HCVab test, we captured the type of action taken. When the unsubstantiated diagnosis was documented in the EMR, we determined if the diagnosis was mentioned by subsequent providers. RESULTS: Positive HCVab results were not acknowledged in 31% of subjects. In 35%, providers added chronic HCV to the problem list in the EMR, resulting in a higher likelihood of subsequent providers mentioning the diagnosis in their EMR documentation. In 143 subjects whose providers recommended HCV-related clinical actions within 1 year of the positive result, 45% were educated about HCV and 42% had their liver enzymes monitored. CONCLUSIONS: With more widespread testing anticipated and more effective treatments available, health systems should ensure the HCV diagnostic process results in the delivery of an accurate and timely HCV diagnosis, to reduce the risk of harm to patients.

Pilot study to assess subjective and objective reporting of potential adverse drug reactions in older versus younger HIV-infected patients using antiretroviral therapy.

Limited data exist on tolerability of antiretroviral therapy (ART) in older HIV-infected patients compared to their younger counterparts. There is also concern for overlap of ART toxicities with concomitant conditions potentially leading to an increased burden of ART-related adverse drug reactions (ADRs). A prospective, descriptive-comparative study was conducted to compare incidence and severity of ADRs secondary to ART in older (≥ 50 years) versus younger (<50 years) HIV-infected patients. No differences were found in the presence or severity of subjective or objective ADRs between groups. The burden of intolerance appeared to be high for certain ADRs in both age groups. Regardless of age, subjects with certain concomitant illnesses had higher rates of potential ADRs. Providers need to be aware of patient characteristics that lead to increased rates of ART intolerance; for patients with an increased comorbidity burden, providers need to be attentive to the potential impact on ART tolerability.

Effective antimicrobial stewardship in a long-term care facility through an infectious disease consultation service: keeping a LID on antibiotic use.

DESIGN: We introduced a long-term care facility (LTCF) infectious disease (ID) consultation service (LID service) that provides on-site consultations to residents of a Veterans Affairs (VA) LTCF. We determined the impact of the LID service on antimicrobial use and Clostridium difficile infections at the LTCF. SETTING: A 160-bed VA LTCF. METHODS: Systemic antimicrobial use and positive C. difficile tests at the LTCF were compared for the 36 months before and the 18 months after the initiation of the ID consultation service through segmented regression analysis of an interrupted time series. RESULTS: Relative to that in the preintervention period, total systemic antibiotic administration decreased by 30% (P<.001), with significant reductions in both oral (32%; P<.001) and intravenous (25%; P=.008) agents. The greatest reductions were seen for tetracyclines (64%; P<.001), clindamycin (61%; P<.001), sulfamethoxazole/trimethoprim (38%; P<.001), fluoroquinolones (38%; P<.001), and ß-lactam/ß-lactamase inhibitor combinations (28%; P<.001). The rate of positive C. difficile tests at the LTCF declined in the postintervention period relative to preintervention rates (P=.04). CONCLUSIONS: Implementation of an LTCF ID service led to a significant reduction in total antimicrobial use. Bringing providers with ID expertise to the LTCF represents a new and effective means to achieve antimicrobial stewardship.