ABO-adjusted cPRA metric for kidney allocation in an Asian-predominant population.

Recent studies showed that ABO-adjusted calculated panel reactive antibody (ABO-cPRA) may better reflect the histocompatibility level in a multi-ethnic population, but such data in Asians is not available. We developed an ABO-adjusted cPRA metric on a cohort of waitlist kidney transplant patients (n = 647, 99% Chinese) in Hong Kong, based on HLA alleles and ABO frequencies of local donors. The concordance between the web-based ABO-cPRA calculator and the impact on kidney allocation were evaluated. The blood group distribution for A, B, O and AB among waitlist kidney candidates were 26.2%, 27.5%, 40.1%, and 6.1%, and their chances of encountering incompatible blood group donors were 32.6%, 32.4%, 57.6%, and 0%, respectively. There is poor agreement between web-based ABO-cPRA calculator and our locally developed metrics. Over 90% of patients showed an increase in cPRA after ABO adjustment, most notably in those with cPRA between 70% and 79%. Blood group O patients had a much greater increase in cPRA scores after adjustment while patients of blood group A and B had similar increment. 10.6% of non-AB blood group waitlist patients had ABO-cPRA elevated to ≥80%. A local ABO-adjusted cPRA metric is required for Asian populations and may improve equity in kidney distribution for patients with disadvantageous blood groups. The result from the current study potentially helps other countries/localities in establishing their own unified ABO-cPRA metrics and predict the impact on kidney allocation.

Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression.

BACKGROUND & AIMS: Selgantolimod (GS-9688) is a Toll-like receptor 8 (TLR8) agonist that suppresses HBV in vitro. In a phase II study, we evaluated the safety and efficacy of weekly selgantolimod treatment in virally suppressed individuals with chronic HBV taking oral antiviral treatment. METHODS: Forty-eight patients were randomized into two cohorts (hepatitis B e antigen [HBeAg]-positive and -negative [n = 24 each]) to receive oral selgantolimod 3 mg, 1.5 mg, or placebo (2:2:1) once weekly for 24 weeks while maintaining oral antivirals. The primary efficacy endpoint was the percentage of patients with a ≥1 log10 IU/ml decline in hepatitis B surface antigen (HBsAg) from baseline to week 24. Post-treatment, patients continued on oral antivirals for 24 weeks. RESULTS: The primary endpoint was reached by one participant, who was HBeAg-negative and received selgantolimod 1.5 mg. In contrast with placebo-treated patients (n = 9), only selgantolimod-treated patients (n = 39 total) had HBsAg declines greater than 0.1 log10 IU/ml at weeks 24 (18%, 7/39) and 48 (26%, 10/39), HBsAg loss (5%, 2/39 through 48 weeks), or HBeAg loss (16%, 3/19 through 48 weeks). The most common adverse events in selgantolimod-treated groups were nausea (46%), upper respiratory tract infection (23%), and vomiting (23%). Gastrointestinal disorders were mostly mild and transient. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40, IFN-γ, and IL-1RA, as well as rapid redistribution of some circulating immune cell subsets. CONCLUSION: Oral selgantolimod up to 3 mg once weekly for 24 weeks was generally safe and well tolerated and led to serologic changes associated with progression to durable cure in two individuals by week 48. GOV IDENTIFIER: NCT03491553. IMPACT AND IMPLICATIONS: The only robust criterion for stopping treatment in chronic hepatitis B is loss of hepatitis B surface antigen (known as functional cure), which is rare during nucleos(t)ide analogue therapy. It is likely that novel antiviral and immunomodulatory therapies will be needed to achieve finite functional cure. Selgantolimod is an oral Toll-like receptor 8 agonist that has shown antiviral activity in vitro as well as safety in a phase I clinical trial with weekly dosing. In this phase II study, selgantolimod therapy was associated with transient increases in serum cytokines, rapid redistribution of circulating immune cell subsets, modest reductions in HBsAg and HBeAg levels, and occasional loss of HBsAg (5%) and HBeAg (16%) among participants with chronic hepatitis B on nucleos(t)ide analogue therapy with viral suppression. Our results support continued development of selgantolimod as a component of a future hepatitis B cure regimen.

Programmed death 1 expressing CD8+ CXCR5+ follicular T cells constitute effector rather than exhaustive phenotype in patients with chronic hepatitis B.

BACKGROUND AND AIMS: Classical CD8 T cells are implicated for protective and pathogenic roles in chronic hepatitis B (CHB) infection. Recently, a subset of CD8 T cells expressing C-X-C chemokine receptor type 5 (CXCR5) and exhibiting features of TFH cells has been identified during chronic viral infections. However, in CHB, knowledge of their roles is limited. APPROACH AND RESULTS: We characterized circulating CD8+ CXCR5+/- cells and investigated their association with clinical and viral factors. We found that CHB infection did not influence the overall frequencies of CD8+ CXCR5+ cells whereas CD8+ CXCR5- cells were increased. However, among CHB, CD8+ CXCR5+ cells were higher in patients with low HBsAg and HBV-DNA levels, patients who were HBeAg negative and had high fibrosis scores, and these cells exhibited a significant association with HBsAg and HBV-DNA reduction. Contrarily, CD8+ CXCR5- cells were expanded and positively correlated with patients having high HBsAg, HBV-DNA, and alanine aminotransferase levels. CD8+ CXCR5+ cells express costimulatory molecules ICOS, OX40, CD40 ligand, inhibitory molecule programmed death 1, transcription factors B-cell lymphoma (BCL)-2, BCL-6, and signal transducer and activator of transcription 3, and are enriched in effector and central memory phenotype. Moreover, these cells are heterogeneous in nature given that they constitute different subsets of cytotoxic follicular T cells (TCF), including TCF1, TCF2, TCF17, and TCF22. Despite expressing high PD-1, CD8+ CXCR5+ cells are activated, proliferating, secreting more IFN-γ, IL-21, and IL-22, and have better cytolytic potential than CD8+ CXCR5- cells, which were inhibited after PD-1/PD-L1 blockade. CD8+ CXCR5+ cells are efficient in helping B cells in terms of plasmablasts and plasma cell generation. CONCLUSIONS: In conclusion, CD8+ CXCR5+ cells are enriched in effector phenotypes, produce HBV-specific cytokines despite increased PD-1, and are associated with HBsAg and HBV-DNA reduction. These cells competently support B-cell function, required for viral clearance, which may serve as potential therapeutic targets for CHB.

CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV/HCV-Coinfected Patients.

Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis.

Follicular Helper T (TFH) Cell Targeting by TLR8 Signaling For Improving HBsAg-Specific B Cell Response In Chronic Hepatitis B Patients.

Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (TFH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and TFH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote TFH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced TFH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by TFH cells with enhanced IL-21+BCL-6+ and ICOS+BCL-6+ co-expression. Mechanistically, incubation of isolated naïve CD4+ T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21+ICOS+BCL-6+ TFH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing TFH with autologous naïve B cells led to enhanced memory (CD19+CD27+) and plasma B cell generation (CD19+CD27++CD38+) and IgG production. Importantly, in TFH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated TFH function and may play a role in achieving HBV functional cure.

Publisher Correction: Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients.

Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates. However, little is known about pre-treatment HBsAg levels as an indicator of HBV immune potential. Here, we compared the phenotypes and HBV-specific response of lymphocytes in CHB patients stratified by serum HBsAg levels <500 (HBslo) or >50,000 IU/ml (HBshi) using immunological assays (flow cytometry, ICS, ELISPOT). HBshi patients had significantly higher expression of inhibitory PD-1 on CD4+ T cells, particularly among TEMRA subset, and higher FcRL5 expression on B cells. Upon HBcAg(core) or HBsAg(env)-stimulation, 85% and 60% of HBslo patients had IFNγ+TNFα+ and IFNγ+ IL2+ CD4+ T cell responses respectively, in comparison to 33% and 13% of HBshi patients. Checkpoint blockade with αPD-1 improved HBV-specific CD4+ T cell function only in HBslo patients. HBsAg-specific antibody-secreting cells (ASCs) response was not different between these groups, yet αPD-1 treatment resulted in significantly higher fold change in ASCs among patients with HBsAg <100 IU/ml compared to patients with HBsAg >5,000 IU/ml. Thus, serum HBsAg correlates with inhibitory receptor expression, HBV-specific CD4+ T cell responses, and augmentation by checkpoint blockade.

IL-21-Deficient T Follicular Helper Cells Support B Cell Responses Through IL-27 in Patients With Chronic Hepatitis B.

Chronic Hepatitis B (CHB) affects over 350 million people worldwide. Current treatment does result in reduced complications; however, a cure (development of antibodies to the S antigen) is not achieved, requiring life-long therapy. Humoral responses contribute to viral elimination by secreting neutralizing antibodies; though, effective induction of humoral immunity require CD4T cell differentiation into T follicular helper (TFH) cells that support B cell response through interleukin-21 (IL-21). In CHB, mechanism of TFH-B interactions is seldom described. During CHB, TFH cells are defective in producing IL-21 in response to hepatitis B surface antigen (HBsAg). However, regardless of low IL-21, TFH cells efficiently support B cell responses by producing interleukin-27 (IL-27), which directs the formation of plasmablasts and plasma cells from memory and naïve B cells by enhancing B lymphocyte-induced maturation protein-1. IL-27 not only improved total antibody production but HBsAg-specific IgG and IgM secretion that are essential for viral clearance. Importantly, IL-27+TFH cells were significantly associated with HBV DNA reduction. Therefore, these findings imply a novel mechanism of TFH mediated B cell help in CHB and suggest that IL-27 effectively compensate the function of IL-21 by supporting TFH-B cell function, required for protective antibody response and may contribute to viral clearance by providing potential target for achieving a functional cure.

A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY).

BACKGROUND & AIMS: Cure rates in response to retreatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are high, but this regimen has not been studied in patients with a history of poor adherence or treatment interruption, nor in patients with HIV/HCV coinfection. Herein, we aimed to assess the safety and efficacy of this combination in patients with genotype 1 HCV infection who had relapsed following combination direct-acting antiviral (DAA) therapy, regardless of HIV infection or previous treatment course. METHODS: The RESOLVE study was a multicenter, open-label, phase IIb study investigating the safety, tolerability and efficacy of SOF/VEL/VOX in 77 patients with virologic rebound following combination DAA therapy. Efficacy was defined as HCV RNA below the lower limit of detection 12 weeks after the end of treatment (SVR12), while safety endpoints included the incidence of grade 3 and 4 adverse events (AEs) following treatment, and the proportion of patients who stopped treatment prematurely due to AEs. RESULTS: In an intent-to-treat analysis, 70/77 (90.9%, 95% CI 82.1-95.8%) patients achieved SVR12, including 14/17 (82.4%) HIV coinfected participants and 18/22 (81.8%) of those with previous non-completion of DAA therapy. In an analysis of all patients who completed 12 weeks of study medication, 70/71 patients (99%) achieved SVR12. One patient experienced a grade 3 AE, and 4 experienced a grade 4 AE, all unrelated to study participation. Reported AEs were similar in HIV-coinfected patients, and patients receiving dolutegravir-based antiretroviral treatment experienced no clinically significant increases in aminotransferases. CONCLUSION: Retreatment with 12 weeks of SOF/VEL/VOX was safe and effective in patients with relapsed HCV following initial combination DAA-based treatment. Treatment response was not affected by HIV coinfection or previous treatment course. LAY SUMMARY: Twelve weeks of the combination of direct-acting antivirals (SOF/VEL/VOX) was safe and effective in patients with relapsed hepatitis C virus infection who had previously received combination therapy with direct-acting antivirals. Treatment response was not diminished by HIV coinfection, or non-completion of previous direct-acting antiviral-based therapy.

Chronic Hepatitis B Infection: A Review.

IMPORTANCE: More than 240 million individuals worldwide are infected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who are untreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer. OBSERVATIONS: Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovir disoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation and fibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk of hepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss with undetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and 1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48 weeks and is not associated with the development of resistance; however, its use is limited by poor tolerability and adverse effects such as bone marrow suppression and exacerbation of existing neuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, and tenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance compared with older agents (lamivudine and adefovir) and should be considered as the first-line treatment. CONCLUSIONS AND RELEVANCE: Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates are low, most patients will require therapy indefinitely.

Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis.

BACKGROUND: Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection might pose a risk for hepatitis B virus (HBV) reactivation in patients coinfected with chronic or resolved HBV infection. The need for HBV antiviral prophylaxis during DAA treatment remains controversial. We aimed to analyse the absolute risk of HBV reactivation in patients with active or resolved HBV infection treated with DAAs for HCV infection. METHODS: For this systematic review and meta-analysis, we searched PubMed, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science from Oct 1, 2010, to Sept 30, 2017, to identify studies of patients with chronic or resolved HBV infection at baseline treated with DAAs for chronic HCV infection. Conference proceedings, abstract books, and references from relevant reviews were also examined for potential studies. Two independent researchers extracted data and assessed quality and risk of bias. Data were pooled by use of random-effects models. The primary outcome was HBV reactivation defined by standardised nomenclature. This study is registered with PROSPERO, number CRD42017065882. FINDINGS: We identified 17 observational studies involving 1621 patients with chronic (n=242) or resolved (n=1379) HBV infection treated with different DAAs. The pooled proportion of patients who had HBV reactivation was 24% (95% CI 19-30) in patients with chronic HBV infection and 1·4% (0·8-2·4) in those with resolved HBV infection. In patients with chronic HBV infection, the pooled proportion of patients with HBV-reactivation-related hepatitis was 9% (95% CI 5-16) and the relative risk (RR) of HBV-reactivation-related hepatitis was significantly lower in patients with HBV DNA below the lower limit of quantification at baseline than in those with quantifiable HBV DNA (RR 0·17, 95% CI 0·06-0·50; p=0·0011). Three major clinical events related to HBV reactivation in patients with chronic HBV infection were reported (one patient had liver decompensation and two had liver failure, one of whom required liver transplantation). In patients with resolved HBV infection, no HBV-reactivation-related hepatitis was reported. INTERPRETATION: HBV reactivation occurs frequently in patients with chronic HBV and HCV coinfection receiving DAA therapy but is rare among patients with resolved HBV infection. Use of antiviral prophylaxis might be warranted in patients who test positive for hepatitis B surface antigen (HBsAg), particularly those with quantifiable HBV DNA. FUNDING: None.

A simplified method of calculating cPRA for kidney allocation application in Hong Kong: a retrospective study.

Calculated panel reactive antibody (cPRA) represents possibility of encountering an incompatible donor for organ transplant candidates and has gradually replaced traditional PRA as a measurement of sensitization level. We tested two cPRA calculation methods on a cohort of renal candidate (n = 613). HLA typing of 563 Chinese deceased renal donors was used to estimate allele and haplotype frequencies of Hong Kong donor pool. The OPTN formula was adopted to generate cPRA (cPRA (freq)). We also incorporated a computer script to compare unacceptable antigens of patients against HLA phenotype of donors. The cPRA based on historical donor filtering was the percentage of filter out count over total number of donors (cPRA (filter)). Values of cPRA (freq) and cPRA (filter) showed almost perfect agreement with Lin's correlation coefficient equal to 1.000. SD of bias was 0.6 cPRA point. Limit of agreement was 0.9 to -1.5 points difference. Furthermore, the poor agreement between our in-house cPRA and values from other online calculators indicated the necessity to use local population data for accurate cPRA calculation. Built-in donor filtering method was more practicable for Hong Kong due to factors such as cost and flexibility. An on-going donor pool can reflect population allele frequencies and permits efficient periodic update of cPRA.

Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers: A Nonrandomized Clinical Trial.

Background: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection has resulted in high rates of disease cure; however, not enough specialists currently are available to provide care. Objective: To determine the efficacy of HCV treatment independently provided by nurse practitioners (NPs), primary care physicians (PCPs), or specialist physicians using DAA therapy. Design: Nonrandomized, open-label clinical trial initiated in 2015. (ClinicalTrials.gov: NCT02339038). Setting: 13 urban, federally qualified health centers (FQHCs) in the District of Columbia. Patients: A referred sample of 600 patients, of whom 96% were black, 69% were male, 82% were treatment naive, and 20% had cirrhosis. Seventy-two percent of the patients had HCV genotype 1a infection. The baseline characteristics of patients seen by each provider type were similar. Intervention: Patients were assigned in a nonrandomized but specified manner to receive treatment from 1 of 5 NPs, 5 PCPs, or 6 specialists. All providers underwent an identical 3-hour training session based on guidelines. Patients received treatment with ledipasvir-sofosbuvir, which was provided on site, according to U.S. Food and Drug Administration labeling requirements. Measurements: Sustained virologic response (SVR). Results: 516 patients achieved SVR, a response rate of 86% (95% CI, 83.0% to 88.7%), with no major safety signals. Response rates were consistent across the 3 provider types: NPs, 89.3% (CI, 83.3% to 93.8%); PCPs, 86.9% (CI, 80.6% to 91.7%); and specialists, 83.8% (CI, 79.0% to 87.8%). Patient loss to follow-up was the major cause of non-SVR. Limitation: Nonrandomized patient distribution; possible referral bias. Conclusion: In a real-world cohort of patients at urban FQHCs, HCV treatment administered by nonspecialist providers was as safe and effective as that provided by specialists. Nurse practitioners and PCPs with compact didactic training could substantially expand the availability of community-based providers to escalate HCV therapy, bridging existing gaps in the continuum of care for patients with HCV infection. Primary Funding Source: National Institutes of Health and Gilead Sciences.

Clinical Laboratory Testing in the Era of Directly Acting Antiviral Therapies for Hepatitis C.

Directly acting antiviral (DAA) combination therapies for chronic hepatitis C virus (HCV) infection are highly effective, but treatment decisions remain complex. Laboratory testing is important to evaluate a range of viral, host, and pharmacological factors when considering HCV treatment, and patients must be monitored during and after therapy for safety and to assess the viral response. In this review, we discuss the laboratory tests relevant for the treatment of HCV infection in the era of DAA therapy, grouped according to viral and host factors.

Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment.

AIM: To study impact of baseline mental health disease on hepatitis C virus (HCV) treatment; and Beck's Depression Inventory (BDI) changes with sofosbuvir- and interferon-based therapy. METHODS: This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and naïve to HCV therapy. Two of the studies included HCV mono-infected participants only (SPARE, SYNERGY-A), and 3 included human immunodeficiency virus (HIV)/HCV co-infected participants only (ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon (IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease (MHD) were identified (defined as either a DSM IV diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response (SVR) and adherence (pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher's Exact, and t-test with significance defined as a P value less than 0.05. RESULTS: Baseline characteristics did not differ significantly between all participants with and without MHD groups treated with sofosbuvir-based therapy. Among patients treated with sofosbuvir-based therapy, the percentage of patients with MHD who achieved SVR was the same as those without (SPARE: 60.9% of those MHD compared to 67.6% in those without, P = 0.78; SYNERGY-A: 100% of both groups; ERADICATE: 100% compared to 97.1%). There was no statistically significant difference in pill counts, adherence to study visits between groups, nor mean serum concentrations of GS-331007 for each group at week 2 of treatment (P = 0.72). Among patients with HIV co-infection, pre-treatment BDI scores were similar among patients treated with sofosbuvir, and those treated with interferon (sofosbuvir-based 5.24, IFN-based 6.96; P = 0.14); however, a dichotomous effect on was observed during treatment. Among participants treated with directly acting antiviral (DAA)-based therapy, mean BDI scores decreased from 5.24 (pre-treatment) to 3.28 during treatment (1.96 decrease, P = 0.0034) and 2.82 post-treatment. The decrease in mean score from pre- to post-treatment was statistically significant (-2.42, P = 0.0012). Among participants treated with IFN-based therapy, mean BDI score increased from 6.96 at pre-treatment to 9.19 during treatment (an increase of 2.46 points, P = 0.1), and then decreased back to baseline post-treatment (mean BDI score 6.3, P = 0.54). Overall change in mean BDI scores from pre-treatment to during treatment among participants treated with DAA-based and IFN-therapy was statistically significant (-1.96 and +2.23, respectively; P = 0.0032). This change remained statistically significant when analysis was restricted to participants who achieved SVR (-2.0 and +4.36, respectively; P = 0.0004). CONCLUSION: Sofosbuvir-based therapy is safe and well tolerated in patients with MHD. A decline in BDI associated with sofosbuvir-based HCV treatment suggests additional MHD benefits, although the duration of these effects is unknown.

Treatment of hepatitis B virus: an update.

Chronic hepatitis B virus infection is a global health concern as it affects over 240 million people worldwide and an estimated 686,000 people die annually as a result of complications of the disease. With the development of newer antiviral drugs, viral suppression of HBV is achievable, however elimination of HBV from infected individuals (functional cure) remains an issue. Due to persistence of HBV DNA (cccDNA) in infected cells, chronically infected patients who discontinue therapy prior to HBsAg loss or seroconversion are likely to relapse. Several novel therapeutic strategies are being researched and studied in clinical trials. Here we review these novel strategies to achieve sustained cure or elimination of HBV. These strategies include the targeting of the host or viral factors required for viral persistence as well as therapeutic vaccines.

On-Treatment Elevation in Hepatic Transaminases during HCV Treatment with Ombitasvir, Paritaprevir, Dasabuvir, Ritonavir, and Ribavirin: A Case Series.

Eradication of chronic hepatitis C virus (HCV) infection is now possible with all oral antiviral medications, including the combination of ombitasvir, paritaprevir, dasabuvir, and ritonavir (PrOD) with or without ribavirin. While high rates of sustained virologic response (SVR) can be achieved, a small subset of patients experience on-treatment liver enzyme elevations, in particular women using concurrent estradiol-containing oral contraceptive medications (OCPs). Herein, we describe four cases of liver enzyme elevations within 2-3 weeks of PrOD initiation in African-American men infected with HCV genotype 1a or 1b. Three patients with varying degrees of hepatic fibrosis received a full treatment course without medication modification, achieved SVR, and experienced resolution of liver enzyme abnormalities. One patient with cirrhosis was switched mid-treatment to an alternate HCV regimen, experienced subsequent resolution of liver enzyme abnormalities, and achieved SVR. In summary, these cases suggest that all HCV patients treated with PrOD, independent of gender or concurrent medications, should have laboratory monitoring for liver enzyme elevations, with a particular emphasis on early monitoring in cirrhotic patients.

Hepatitis C genotype 3 disease.

Hepatitis C genotype 3 (GT-3) infection comprises up to 30 % of all HCV infections worldwide, with roughly 54.3 million cases concentrated in South and Southeast Asia. Longitudinal studies have demonstrated significantly increased rates of steatosis, fibrosis, and hepatocellular carcinoma in GT-3 disease, thus distinguishing this genotype as both the most difficult and urgent to treat. However, novel direct-acting antiviral agents currently approved have not demonstrated the uniform potency seen in GT-1 disease for GT-3. This review outlines (1) the epidemiology and natural history, (2) phase II and III clinical trials demonstrating effective treatment options, and (3) current and future therapeutic issues in the quest to eradicate hepatitis C genotype 3 disease.

Systemic manifestations of hepatitis C infection.

Chronic hepatitis C (HCV) is a common infection affecting 185 million people worldwide. The most common manifestation of chronic HCV is progressive liver fibrosis, cirrhosis, liver failure and hepatocellular carcinoma. However, several systemic manifestations of HCV have been recognized and reported in the literature. The purpose of this review is to assimilate published literature based on evidence to categorize these extrahepatic manifestations with the likelihood of a causal association with HCV. Exciting recent developments have resulted in simple all oral interferon-free highly effective therapy for HCV. However, this treatment is also expensive and less accessible to most affected individuals as treatment recommendations are based on stage of liver fibrosis. Expanding the scope of HCV therapy to those with extrahepatic manifestations beyond what is currently recommended will significantly reduce the morbidity and mortality in this aging population.