Implementation of free-draft text messaging to enhance care retention and satisfaction for persons living with HIV infection.

Eligible persons with HIV infection can receive client-centered case management to coordinate medical and social services. Novel mobile health interventions could improve effective case management and retention in care, an important goal to help end the HIV epidemic. Using a hybrid type I effectiveness-implementation design, we assessed whether access to bidirectional, free-draft secure text messaging with a case manager and clinic pharmacist could improve client satisfaction and care retention in a Southern academic HIV clinic. Sixty-four clients enrolled between November 2019 and March 2020, had a median age of 39 years, and were mostly male, single, and African-American. Heavy app users texted over 100 times (n = 6) over the course of the 12-month intervention while others never texted (n = 12). App usage peaked during months of clinic closure due to COVID-19. Most participants reported high satisfaction with the app and planned continued usage after study completion. Changes in clinic retention and virologic suppression rates were not observed, a result confounded by practice changes due to COVID-19. High usage and satisfaction of free-draft text messaging in case-managed HIV clients supports inclusion of this communication option in routine HIV clinical care.

Perspectives of HIV specialists and cardiologists on the specialty referral process for people living with HIV: a qualitative descriptive study.

BACKGROUND: Cardiology care may be beneficial for risk factor management in people living with HIV (PLWH), yet limited information is available about the referral process from the perspectives of HIV specialists and cardiologists. METHODS: We conducted 28 qualitative interviews at academic medical centers in the United States from December 2019 to February 2020 using components of the Specialty Referral Process Framework: referral decision, entry into referral care, and care integration. We analyzed the data using applied thematic analysis. RESULTS: Reasons for cardiology referral most commonly included secondary prevention, uncontrolled risk factors, cardiac symptoms, and medication management. Facilitators in the referral process included ease of referral, personal relationships between HIV specialists and cardiologists, and close proximity of the clinic to the patient's home. Barriers included lack of transportation, transportation costs, insurance coverage gaps, stigma, and patient reluctance. CONCLUSIONS: Our results will inform future studies on implementation strategies aimed at improving the specialty referral process for PLWH. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04025125 .

Association of Referral Source and Substance Use with Hepatitis C Virus Outcomes at a Southern Academic Medical Center.

OBJECTIVES: Therapeutic advances make the cure of chronic hepatitis C virus (HCV) infection achievable for individuals aware of their diagnosis who can access care. Identifying barriers to accessing care is critical to achieve population-level HCV elimination and improve the cascade of care from diagnosis to cure. METHODS: To identify barriers to HCV care, we performed a retrospective observational analysis of outcomes for patients with chronic HCV referred to an infectious diseases clinic at an academic medical center in Charleston, South Carolina between January 1, 2015 and January 1, 2020. We categorized outcomes in the cascade of care between "never presenting for evaluation" and "completed treatment with documented cure." Patient demographic factors, referral source, ZIP code of residence, insurance status, clinical characteristics, antiviral regimen, psychiatric and substance use history, and route of infection were assessed for associations with care outcomes. RESULTS: Of 407 referrals, 32% of patients never presented for an initial evaluation, an outcome that was associated with active substance use, mental health disease, and referral from an emergency department or obstetrics-gynecology provider. Of the patients who presented for an initial evaluation, 78% of patients initiated treatment. Active substance use was the only variable associated with lack of therapy initiation after presenting for an initial evaluation (odds ratio 2.5, 95% confidence interval 1.07-5.84). Once treatment had been initiated, no clinical or demographic variables were associated with odds of achieving documented or presumed HCV cure. CONCLUSIONS: Active substance use, mental health disease, and referral from an emergency department or obstetrics-gynecology provider were associated with a lower odds of presenting for evaluation and initiation of HCV treatment. Innovative models to improve access to care and increase outreach to vulnerable populations will be essential to eliminate HCV.

Hepatitis C virus treatment with direct-acting antivirals induces rapid changes in the hepatic proteome.

Treatment of chronic hepatitis C virus with direct-acting antivirals usually eradicates infection, but liver fibrosis does not resolve concurrently. In patients who develop cirrhosis prior to hepatitis C virus treatment, hepatic decompensation and hepatocellular carcinoma can still occur after viral elimination due to residual fibrosis. We hypothesized the liver proteome would exhibit meaningful changes in inflammatory and fibrinogenic pathways change upon hepatitis C virus eradication, which could impact subsequent fibrosis regression. We analysed the liver proteome and phosphoproteome of paired liver biopsies obtained from 8 hepatitis C virus-infected patients before or immediately after treatment with direct-acting antivirals. Proteins in interferon signalling and antiviral pathways decreased concurrent with hepatitis C virus treatment, consistent with prior transcriptomic analyses. Expression of extracellular matrix proteins associated with liver fibrosis did not change with treatment, but the phosphorylation pattern of proteins present within signalling pathways implicated in hepatic fibrinogenesis, including the ERK1/2 pathway, was altered concurrent with hepatitis C virus treatment. Hepatitis C virus treatment leads to reduced expression of hepatic proteins involved in interferon and antiviral signalling. Additionally, changes in fibrosis signalling pathways are detectable before alteration in extracellular matrix proteins, identifying a putative chronology for the dynamic processes involved in fibrosis reversal.

Longitudinal analysis of serum microRNAs as predictors of cirrhosis regression during treatment of hepatitis B virus infection.

BACKGROUND AND AIMS: Most patients with cirrhosis induced by chronic HBV infection experience fibrosis regression after long-term antiviral treatment, while some remain cirrhotic. Fibrosis regression is associated with lower odds of developing hepatic decompensation and hepatocellular carcinoma, but mechanisms impacting differential fibrosis regression between individuals are unclear. We asked whether soluble molecules, including serum microRNAs, could serve as biomarkers of fibrosis regression. METHODS: We analysed cryopreserved sera from clinical trials in which cirrhotic HBV-infected patients (baseline Ishak fibrosis score of 5-6) received 240 weeks of nucleotide analogue treatment. Liver biopsies at week 240 in these trials showed 71/96 patients (74%) had fibrosis regression (Ishak ≤ 4) while 25/96 (26%) remained cirrhotic (Ishak 5-6). We quantified inflammatory markers (CXCL10, soluble CD163) and miRNAs (n = 179) from serum at baseline, week 48 and week 240 of treatment in a sub-cohort of patients with (n = 14) or without (n = 14) fibrosis regression. RESULTS: CXCL10, sCD163 and miRNAs previously associated with HBV replication and inflammation decreased during treatment but did not differ based on fibrosis regression. Two miRNAs (miR-421 and miR-454-3p) had lower baseline expression in patients with subsequent fibrosis regression. In all, 27 miRNAs differed at week 240 and had higher expression in patients with fibrosis regression (eg miR-199a-3p, miR-423-3p, miR-142-3p, miR-let-7d-5p). Several miRNAs (miR-141-3p, let-7d-5p) that correlated with regression have previously been implicated in the pathophysiology of non-alcoholic steatohepatitis. CONCLUSIONS: In cirrhotic patients with chronic HBV infection treated with antiviral therapy, serum miRNAs have differential expression based on fibrosis regression, suggesting potential utility as biomarkers.

Peripheral blood correlates of virologic relapse after Sofosbuvir and Ribavirin treatment of Genotype-1 HCV infection.

BACKGROUND: Treatment of chronic hepatitis C virus infection with direct acting antiviral therapy results in viral elimination in over 90% of cases. The duration of treatment required to achieve cure differs between individuals and relapse can occur. We asked whether cellular and transcriptional profiling of peripheral blood collected during treatment could identify biomarkers predictive of treatment outcome. METHODS: We analyzed peripheral blood collected during treatment of genotype 1 HCV with 24 weeks of sofosbuvir and weight-based or low dose ribavirin in a trial in which 29% of patients relapsed. Changes in host immunity during treatment were assessed by flow cytometry and whole blood gene expression profiling. Differences in expression of immune-relevant transcripts based on treatment outcome were analyzed using the Nanostring Human Immunology V2 panel. RESULTS: Multiple cellular populations changed during treatment, but pre-treatment neutrophil counts were lower and natural post-treatment killer cell counts were higher in patients who relapsed. Pre-treatment expression of genes associated with interferon-signaling, T-cell dysfunction, and T-cell co-stimulation differed by treatment outcome. We identified a pre- and post-treatment gene expression signature with high predictive capacity for distinguishing treatment outcome, but neither signature was sufficiently robust to suggest viability for clinical use. CONCLUSIONS: Patients who relapse after hepatitis C virus therapy differ immunologically from non-relapsers based on expression of transcripts related to interferon signaling and T-cell dysfunction, as well as by peripheral neutrophil and NK-cell concentrations. These data provide insight into the host immunologic basis of relapse after DAA therapy for HCV and suggests mechanisms which may be relevant for understanding outcomes with currently approved regimens.

Characterization of changes in intrahepatic immune cell populations during HCV treatment with sofosbuvir and ribavirin.

Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) results in a sustained virologic response (SVR) in most patients. While highly efficacious, ~3%-5% of patients do not achieve SVR despite having virus that appears susceptible. It is unclear whether host factors contribute to treatment failures, although innate and adaptive immunity may play a role. Previous studies showed that after DAA treatment, the composition of intrahepatic immune cells does not normalize relative to healthy volunteers, even in cases where SVR is achieved. We used paired pre- and post-treatment liver biopsies from 13 patients treated with sofosbuvir and ribavirin, 4 of whom relapsed, to analyse intracellular immune changes during DAA treatment and explore correlations with inflammation and treatment outcome. We performed single marker immunohistochemistry followed by electronic image capture, manual annotation of parenchymal and non-parenchymal regions, and quantitative image analysis. The predominant cellular change during treatment was a decrease in CD8+ cellular density in both parenchymal and non-parenchymal regions. CD68+ Kupffer cell density correlated with hepatic inflammation (AST, ALT) pre-treatment, but did not change during treatment. CD4+ cellular density decreased in non-parenchymal regions and, intriguingly, was lower pre-treatment in subjects who eventually relapsed. Other cellular markers (CD56, CD20), as well as markers of apoptosis (TIA-1) and activated stellate cells, did not change significantly during treatment or differ by treatment outcome. The predominant intrahepatic cellular change during DAA treatment of chronic HCV infection is a reduction in CD8+ cellular density, but this did not correlate with treatment outcome.

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling.

Type III IFNs are important mediators of antiviral immunity. IFN-λ4 is a unique type III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear hepatitis C virus infection. In this study, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on hepatitis C virus clearance. We used fresh primary human hepatocytes (PHHs) treated with recombinant type III IFNs or infected with Sendai virus to model acute viral infection and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-λ4 protein was detectable only in Sendai virus-infected PHHs from individuals with the dG allele, where it was poorly secreted but highly functional, even at concentrations < 50 pg/ml. IFN-λ4 acted faster than other type III IFNs in inducing antiviral genes, as well as negative regulators of the IFN response, such as USP18 and SOCS1 Transient treatment of PHHs with IFN-λ4, but not IFN-λ3, caused a strong and sustained induction of SOCS1 and refractoriness to further stimulation with IFN-λ3. Our results suggest unique functional properties of IFN-λ4 that can be important in viral clearance and other clinical conditions.

Increasing Prevalence of Chronic Hepatitis C Virus Infection in a Southern Academic Obstetrical Clinic.

OBJECTIVES: The opioid epidemic has resulted in rising rates of hepatitis C virus (HCV) infection in women of childbearing age. With this changing epidemiology in mind, the Infectious Diseases Society of America/American Association for the Study of Liver Diseases guidelines were updated in 2018 to recommend screening all pregnant women for HCV infection, irrespective of risk factors. Because HCV infection can affect maternal-fetal health and result in vertical transmission, presentation for pregnancy-related medical care represents an opportunity to diagnose and manage HCV infection, as well as prepare for treatment postpartum. METHODS: We performed a retrospective chart review spanning 2007-2016 to examine the epidemiology of HCV infection and opioid use disorder in a southern academic obstetrical clinic and to explore the impact of new screening guidelines if implemented. Composite data from the electronic health record and individual chart review were used to determine rates of HCV infection and opioid use disorder in obstetrics, explore patient demographics, and examine perinatal outcomes. RESULTS: Rates of both opioid use disorder and chronic HCV infection increased significantly during the 10-year period of analysis. Patients diagnosed as having chronic HCV infection were primarily white (95%) and there was no observed impact of HCV on perinatal outcomes. HCV testing in pregnancy, even when patients had documented opioid use disorder, was infrequent (0.7% of all pregnancies). Documented follow-up for HCV postpartum for both mothers and infants was incomplete, with only one-third of identified HCV-exposed infants referred and only 9% receiving HCV testing at our institution. CONCLUSIONS: HCV prevalence increased between 2007 and 2016, but screening and treatment of HCV in this southern obstetrical cohort was infrequent. The implementation of universal screening in pregnancy will likely identify additional cases, and an improved cascade of care will be necessary to address the HCV epidemic.

Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy.

Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/µL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/µL) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4+ T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4+ T cells relative to memory CD4+ T cells. Consistently, increased frequencies of CD107a+ NK cells and profound decreases of naive CD4+ T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4+ T-cell reconstitution despite effective ART.

Update in HIV-hepatitis C virus coinfection in the direct acting antiviral era.

PURPOSE OF REVIEW: Availability of direct acting antivirals (DAAs) that demonstrate remarkable clinical efficacy and safety has revolutionized the ability to treat chronic infection with hepatitis C virus (HCV). An equal measure of clinical success has now been achieved in persons coinfected with HCV and the HIV, a historically harder to cure cohort with interferon-based therapy. Global goals include identifying all HIV-HCV-infected persons, gaining access to DAA therapy, preventing de novo and reinfection, and managing the sequelae of chronic infection. This review will discuss advances in the field of HIV-HCV coinfection reported during the last 18 months, and will suggest areas for future investigation. RECENT FINDINGS: An expanding body of literature has enhanced our understanding of the clinical and epidemiologic issues surrounding HIV-HCV coinfection. DAA therapy for HCV is highly efficacious in HIV-HCV-coinfected persons if drug-drug interactions are appropriately considered. SUMMARY: Eradicating HCV infection in persons with HIV coinfection can be achieved safely and effectively with available DAAs. Economic and social approaches to enable access and delivery of curative HCV therapy to HIV-infected persons require continued research and resource allocation.

Across state lines: Fulminant Babesia microti infection in a liver transplant recipient.

The potential for transmission of Babesia microti by blood transfusion is well recognized. Physicians may be unaware that products used for transfusion may be collected from geographically diverse regions. We describe a liver transplant recipient in South Carolina who likely acquired B. microti infection from a unit of blood collected in Minnesota.

Cardiovascular Disease, Statins, and HIV.

Human immunodeficiency virus (HIV)-infected patients are at an increased risk of serious, non-AIDS-defining comorbidities, even in the setting of viral suppression with combination antiretroviral therapy. This increased risk is due in part to immune dysfunction and heightened inflammation and immune activation associated with chronic HIV infection. Statins have wide-reaching immunomodulatory effects, and their use in the HIV-infected population may be of particular benefit. In this article, we review the pathogenesis of increased inflammation during HIV infection and how it contributes to the risk of cardiovascular disease among HIV-infected individuals. We then we review the immunomodulatory effects of statins and how they may attenuate the risk of cardiovascular disease and other comorbidities in this unique patient population.

Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study.

BACKGROUND: Direct-acting antiviral drugs have a high cure rate and favourable tolerability for patients with hepatitis C virus (HCV). Shorter courses could improve affordability and adherence. Sofosbuvir and ledipasvir with ribavirin have high efficacy when taken for 8 weeks but not for 6 weeks. We assessed whether the addition of a third direct-acting antiviral drug to sofosbuvir and ledipasvir would allow a shorter treatment duration. METHODS: In this single-centre, open-label, phase 2A trial, we sequentially enrolled treatment-naive patients with HCV genotype 1 infection into three treatment groups: 12 weeks of sofosbuvir and ledipasvir; 6 weeks of sofosbuvir, ledipasvir, and GS-9669; or 6 weeks of sofosbuvir, ledipasvir, and GS-9451. Patients and investigators were not masked to treatment assignment. The primary endpoint was the propotion of patients with sustained viral response at 12 weeks after treatment completion (SVR12), assessed by serum HCV RNA concentrations lower than 43 IU/mL (the lower limit of quantification). We did an intention-to-treat analysis for the primary endpoint and adverse events. This study is registered with ClinicalTrials.gov, number NCT01805882. FINDINGS: Between Jan 11, 2013, and Dec 17, 2013, we enrolled 60 patients, and sequentially assigned them into three groups of 20. We noted an SVR12 in all 20 patients (100%, 95% CI 83-100) allocated to sofosbuvir and ledipasvir for 12 weeks; in 19 (95%, 75-100) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9669 for 6 weeks (one patient relapsed 2 weeks after completion of treatment); and in 19 (95%, 75-100%) of the 20 patients allocated to sofosbuvir, ledipasvir, and GS-9451 for 6 weeks (one patient was lost to follow-up after reaching sustained viral response at 4 weeks). Most adverse events were mild and no patients discontinued treatment. Two serious adverse events occurred (pain after a post-treatment liver biopsy and vertigo), both unrelated to study drugs. INTERPRETATION: In this small proof-of-concept study, two different three-drug regimens that were given for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Addition of a third potent direct-acting antiviral drug can reduce the duration of treatment required to achieve sustained viral response in patients with chronic HCV genotype 1 infection without cirrhosis. FUNDING: National Institute of Allergy and Infectious Diseases (NIAID), National Cancer Institute and Clinical Center Intramural Program, German Research Foundation, National Institutes of Health, Gilead Sciences.

Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients.

UNLABELLED: Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response [SVR]; n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n=17 SVR; n=8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse. CONCLUSION: Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis.

Simtuzumab treatment of advanced liver fibrosis in HIV and HCV-infected adults: results of a 6-month open-label safety trial.

BACKGROUND: Chronic liver injury can result in fibrosis that may progress over years to end-stage liver disease. The most effective anti-fibrotic therapy is treatment of the underlying disease, however when not possible, interventions to reverse or slow fibrosis progression are needed. AIM: The aim of this study was to study the safety and tolerability of simtuzumab, a monoclonal antibody directed against lysyl oxidase-like 2 (LOXL2) enzyme, in subjects with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or HCV-HIV co-infection and advanced liver disease. METHODS: Eighteen subjects with advanced liver fibrosis received simtuzumab 700 mg intravenously every 2 weeks for 22 weeks. Transjugular liver biopsies were performed during screening and at the end of treatment to measure hepatic venous pressure gradient (HVPG) and to stage fibrosis. RESULTS: Treatment was well-tolerated with no discontinuations due to adverse events. No significant changes were seen in HVPG or liver biopsy fibrosis score after treatment. Exploratory transcriptional and protein profiling using paired pre- and post-treatment liver biopsy and serum samples suggested up-regulation of TGF-ß3 and IL-10 pathways with treatment. CONCLUSION: In this open-label, pilot clinical trial, simtuzumab treatment was well-tolerated in HCV- and HIV-infected subjects with advanced liver disease. Putative modulation of TGF-ß3 and IL-10 pathways during simtuzumab treatment merits investigation in future trials.

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial.

BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE: To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN: Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING: Single-center. PATIENTS: 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION: 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS: The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS: Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION: Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION: Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Serum and cellular ribavirin pharmacokinetic and concentration-effect analysis in HCV patients receiving sofosbuvir plus ribavirin.

OBJECTIVES: Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. PATIENTS AND METHODS: Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations. RESULTS: Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (P = 0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range. CONCLUSIONS: RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.

Persistently elevated abnormal B-cell subpopulations and anti-core antibodies in patients co-infected with HIV/HCV who relapse.

Hepatitis C (HCV) treatment for patients coinfected with human immunodeficiency virus (HIV) and HCV is associated with modest rates of sustained virologic response (SVR) and an increased rate of relapse when compared to HCV monoinfected patients. As patients who attain SVR and patients who relapse are clinically indistinguishable during treatment, where both groups have fully suppressed HCV viral load, it has not been possible to identify in advance those who will relapse. Biomarkers that may distinguish patients with differential treatment response may be clinically useful and provide insight into mechanisms of relapse. In this retrospective study, serum and PBMCs were obtained from 41 HIV/HCV co-infected patients and 17 healthy volunteers. Changes in antibody titers to various regions of the HCV proteome during treatment for HCV were determined using a novel luciferase immunoprecipitation assay. Changes in B-cell subtypes in patients with differential treatment response as well as healthy volunteers were compared. This study demonstrates that elevated anti-HCV core antibody titers persisted during HCV treatment in patients who relapsed when compared to those who attained SVR. Furthermore, characterization of B cells in patients who relapsed demonstrated an abnormal B-cell phenotype distribution characterized by elevated frequencies of exhausted B cells among relapsers at baseline, which persisted despite suppression of HCV viremia at 24 weeks, along with increased frequencies of plasmablasts. These data suggest that anti-HCV specific B cells may be responding to ongoing subclinical HCV replication in patients who will relapse.

Re-treatment of chronic hepatitis C virus genotype 1 infection after relapse: an open-label pilot study.

BACKGROUND: The interferon (IFN)-free regimen of sofosbuvir and ribavirin for 24 weeks was recently approved to treat chronic hepatitis C virus (HCV) genotype 1 (GT-1) infection for patients ineligible for IFN. However, sofosbuvir plus ribavirin therapy is associated with relapse in 15% to 30% of patients with HCV GT-1. Neither the mechanism of relapse nor the optimal re-treatment strategy for these patients is defined. OBJECTIVE: To assess the safety and efficacy of sofosbuvir plus ledipasvir in patients with chronic HCV GT-1 that relapsed after sofosbuvir plus ribavirin therapy. DESIGN: Phase 2a, open-label study. (ClinicalTrials.gov: NCT01805882). SETTING: Single U.S site. PATIENTS: 14 patients with HCV GT-1 that relapsed after treatment with sofosbuvir plus ribavirin for 24 weeks were re-treated with sofosbuvir plus ledipasvir for 12 weeks. MEASUREMENTS: HCV RNA concentration and population sequencing to detect NS5B S282T mutations. RESULTS: All 14 patients treated with sofosbuvir plus ledipasvir for 12 weeks achieved a sustained virologic response, including 7 with advanced liver disease (Knodell Histology Activity Index score of 3 or 4) and 1 with a detectable NS5B S282T mutation after sofosbuvir plus ribavirin therapy. Sofosbuvir plus ledipasvir was well-tolerated with few adverse events. Four grade 3 events (elevated serum creatinine in a patient with baseline renal insufficiency, hypercholesterolemia, and hypophosphatemia) occurred. There were no grade 4 events or treatment discontinuations. LIMITATION: Small sample size. CONCLUSION: The fixed-dose combination of sofosbuvir plus ledipasvir was efficacious in a small cohort of patients with HCV GT-1 that relapsed after sofosbuvir plus ribavirin therapy, even in the setting of advanced liver disease. Larger studies are needed to confirm these preliminary efficacy results. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Cancer Institute, and Gilead Sciences.