Immunogenicity and Safety of Hepatitis B Virus (HBV) Vaccine With a Toll-Like Receptor 9 Agonist Adjuvant in HBV Vaccine-Naïve People With Human Immunodeficiency Virus.

In this international, multicenter open-label study (ACTG A5379) of HepB-CpG vaccine in people with human immunodeficiency virus (HIV) without prior hepatitis B virus (HBV) vaccination, all 68 participants achieved HBV seroprotective titers after the 3-dose series in the primary analysis. No unexpected safety issues were observed.

Long-term Follow-up of Hepatitis C Patients Who Achieved Sustained Virologic Response in the Pragmatic PRIORITIZE Study.

Multiple real-world studies have confirmed the safety and efficacy of hepatitis C (HCV) direct-acting antivirals (DAAs); however, few studies have provided data on long-term outcomes of patients without cirrhosis after achieving sustained virologic response (SVR).1-3 The aims of this analysis were to describe, among individuals in the PRIORITIZE Study achieving SVR: (1) the frequency of laboratory testing and imaging during long-term follow-up (LTFU), (2) changes in liver tests, (3) occurrence of hepatic decompensation or hepatocellular carcinoma (HCC) and deaths, and (4) durability of SVR.

Hepatitis E virus: has anything changed?

PURPOSE OF REVIEW: Infection with hepatitis E virus (HEV) is a global health concern, yet a clinically underdiagnosed cause of acute and chronic hepatitis. The WHO estimates that 20 million people are infected with HEV annually, yet the epidemiology, diagnosis and prevention remain elusive in many clinical settings. RECENT FINDINGS: Orthohepevirus A (HEV-A) genotypes 1 and 2 cause acute, self-limited hepatitis through faecal-oral transmission. In 2022, the first-ever vaccine campaign was implemented as a response to an HEV outbreak in an endemic region. HEV-A genotypes 3 and 4 are zoonotic infections that primarily cause chronic HEV infection in immunosuppressed populations. Pregnant women and immunocompromised persons are at high risk for severe illness in some settings. Another recent advance in our knowledge of HEV is the zoonotic transmission of Orthohepevirus C (HEV-C) to humans, presumably from contact with rodents and/or their excrement. Previously, HEV infection in humans was presumed to be limited to HEV-A only. SUMMARY: Clinical recognition and accurate diagnosis are essential to the management of HEV infection and understanding the global burden of the disease. Epidemiology affects clinical presentations. Targeted response strategies in HEV outbreaks are needed for the prevention of disease, and vaccine campaigns may prove to be an effective part of these strategies.

Potential utility of a multi-component coagulation factor panel to calculate MELD scores and assess the risk of portal vein thrombosis in chronic liver disease.

BACKGROUND: Current quantitative approaches to assess chronic liver disease (CLD) severity have limitations. Further, portal vein thrombosis (PVT) pre-liver transplant (LT) is a major contributor to morbidity in CLD; the means of detecting and/or predicting PVT are limited. We sought to explore whether plasma coagulation factor activity levels can serve as a substitute for prothrombin time/international normalized ratio (PT/INR) in the Model for End-stage Liver Disease (MELD), and/or help assess the risk of PVT. METHODS: Plasma activity levels of Factor V (FV), Factor VIII (FVIII), Protein C (PC), and Protein S (PS) and the concentrations of D-dimer, sP-selectin, and asTF were assessed in two cohorts of CLD patients (ambulatory, n = 42; LT, n = 43). RESULTS: FV and PC activity levels strongly correlated with MELD scores, which enabled the development of a novel scoring system based on multiple linear regressions of the correlations of FV and PC activity with MELD-Na that substitutes PT/INR. Six-month and 1-year follow-up revealed that our novel approach was non-inferior to MELD-Na at predicting mortality. A significant inverse correlation between FVIII activity levels and PVT was found in the LT cohort (p = 0.010); FV and PS activity levels were in-trend (p = 0.069, p = 0.064). We developed a logistic regression-based compensation score to identify patients at risk of PVT. CONCLUSIONS: We demonstrate that FV and PC activity levels may be used to replace PT/INR in MELD scoring. We also show the potential of using the combination of FV, FVIII, and PS activity levels to assess the risk of PVT in CLD.

Viral hepatitis in pregnancy.

Viral hepatitis is caused by a heterogenous group of viral agents representing a wide range of phylogenetic groups. Many viruses can involve the liver and cause liver injury but only a subset are delineated as 'hepatitis viruses' based upon their primary site of replication and tropism for hepatocytes which make up the bulk of the liver cell population. Since their discovery, beginning with the agent that caused serum hepatitis in the 1960s, the alphabetic designations have been utilized. To date, we have five hepatitis viruses, A through E, though it is postulated that others may exist. This chapter will focus on those viruses. Note that hepatitis D is included as a subset of hepatitis B, as it cannot exist without concurrent hepatitis B infection. Pregnancy has the potential to affect all aspects of these viral agents due to the unique immunologic and physiologic changes that occur during and after the gestational period. In this review, we will discuss the most common viral hepatitis and their effects during pregnancy.

A Pragmatic, Randomized Controlled Trial of Oral Antivirals for the Treatment of Chronic Hepatitis C: The PRIORITIZE Study.

BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

The synthetic opioid fentanyl increases HIV replication and chemokine co-receptor expression in vitro.

The US is experiencing a major public health crisis that is fueled by the illicit use of synthetic opioids including fentanyl. While several drugs of abuse can enhance viral replication and/or antagonize immune responses, the impact of specific synthetic opioids on HIV pathogenesis is poorly understood. Thus, we evaluated the effects of fentanyl on HIV replication in vitro. HIV-susceptible or HIV-expressing cell lines were incubated with fentanyl. HIV p24 synthesis and chemokine receptor levels were quantified by ELISA in culture supernatants and cell lysates, respectively. Addition of fentanyl resulted in a dose-dependent increase in HIV replication. Fentanyl enhanced expression of the HIV chemokine co-receptors CXCR4 and CCR5 and caused a dose-dependent decrease in cell viability. The opioid antagonist naltrexone blocked the effect of fentanyl on HIV replication and CCR5 receptor levels but not CXCR4 receptor levels. TLR9 expression was induced by HIV; however, fentanyl inhibited TLR9 expression in a dose-dependent manner. These data demonstrate that the synthetic opioid fentanyl can promote HIV replication in vitro. As increased HIV levels are associated with accelerated disease progression and higher likelihood of transmission, additional research is required to enhance the understanding of opioid-virus interactions and to develop new and/or optimized treatment strategies for persons with HIV and opioid use disorder.

A review of alcohol-pathogen interactions: New insights into combined disease pathomechanisms.

Progression of chronic infections to end-stage diseases and poor treatment results are frequently associated with alcohol abuse. Alcohol metabolism suppresses innate and adaptive immunity leading to increased viral load and its spread. In case of hepatotropic infections, viruses accelerate alcohol-induced hepatitis and liver fibrosis, thereby promoting end-stage outcomes, including cirrhosis and hepatocellular carcinoma (HCC). In this review, we concentrate on several unexplored aspects of these phenomena, which illustrate the combined effects of viral/bacterial infections and alcohol in disease development. We review alcohol-induced alterations implicated in immunometabolism as a central mechanism impacting metabolic homeostasis and viral pathogenesis in Simian immunodeficiency virus/human immunodeficiency virus infection. Furthermore, in hepatocytes, both HIV infection and alcohol activate oxidative stress to cause lysosomal dysfunction and leakage and apoptotic cell death, thereby increasing hepatotoxicity. In addition, we discuss the mechanisms of hepatocellular carcinoma and tumor signaling in hepatitis C virus infection. Finally, we analyze studies that review and describe the immune derangements in hepatotropic viral infections focusing on the development of novel targets and strategies to restore effective immunocompetency in alcohol-associated liver disease. In conclusion, alcohol exacerbates the pathogenesis of viral infections, contributing to a chronic course and poor outcomes, but the mechanisms behind these events are virus specific and depend on virus-alcohol interactions, which differ among the various infections.

Immune Activation: A Link Between Food Insecurity and Chronic Disease in People Living With Human Immunodeficiency Virus.

Persistent immune activation is a hallmark of human immunodeficiency virus (HIV) infection and thought to play a role on chronic diseases in people with HIV (PWH). Food insecurity is disproportionately prevalent in PWH and is associated with adverse health outcomes. We determined whether food insecurity was associated with increased plasma levels of soluble CD14, CD27, and CD163 in 323 antiretroviral-treated PWH from the Miami Adult Studies on HIV cohort. Nearly half (42.7%) of participants were food insecure, and 85.5% were virally suppressed (<200 copies/mL). Food insecurity was independently associated with higher levels of soluble CD14 and soluble CD27. Very low food security was associated with increased soluble CD163 levels among those with lower CD4+ cell counts. Food insecurity may promote immune activation in PWH, suggesting a biological link between food insecurity and chronic disease among PWH. Improving financial security and access to high-quality diets could reduce the burden of disease in this highly vulnerable population.

The Enhanced Liver Fibrosis Index Predicts Hepatic Fibrosis Superior to FIB4 and APRI in HIV/HCV Infected Patients.

BACKGROUND: Accurate noninvasive biomarkers of fibrotic progression are important for hepatitis C virus (HCV) management, but commonly used modalities may have decreased efficacy in human immunodeficiency virus (HIV)/HCV-coinfected persons. The enhanced liver fibrosis (ELF) index is a highly sensitive noninvasive marker of hepatic fibrosis that has had limited assessment in the HIV/HCV population. We compared ELF index performance to FIB4 and aspartate to platelet ratio index (APRI) at different stages of liver fibrosis as determined by liver histology, and validated the efficacy of the three noninvasive biomarkers in HIV/HCV-coinfected versus HCV-monoinfected. METHODS: The ELF index was determined in 147 HIV/HCV-coinfected and 98 HCV-monoinfected persons using commercial ELISA assays for the component elements of the index. Area under the receiver-operator curve was used to validate ELF and to compare its performance to liver histology as well as to other noninvasive biomarkers of liver fibrosis, FIB4, and APRI. RESULTS: The ELF index increased with histological stage of liver fibrosis and exhibited a linear relationship with Metavir score in all subjects. ELF performance was comparable between HIV/HCV and HCV with advanced liver fibrosis/cirrhosis. In the HIV/HCV cohort ELF cutoffs of 8.45 and 9.23 predicted mild and moderate fibrosis with 85% sensitivity, whereas the ELF cutoff of 9.8 had the highest specificity for advanced fibrosis and the cutoff of 10.4 was 99% specific for cirrhosis. ELF performance was superior to FIB4 and APRI in all subjects regardless of HIV status. CONCLUSIONS: ELF index demonstrated excellent characteristics toward accurate prediction of liver fibrosis and cirrhosis with superior performance to APRI and FIB4 in HIV/HCV coinfection. Applying this noninvasive biomarker index for diagnosis of liver fibrosis and progression in HIV/HCV is warranted.

Pulmonary Vascular Resistance Predicts Mortality and Graft Failure in Transplantation Patients With Portopulmonary Hypertension.

Portopulmonary hypertension (POPH) is a pulmonary vascular disease associated with significant morbidity and mortality in those with liver disease, conferring a higher mortality in patients awaiting liver transplantation (LT). Although not a transplant indication, patients with POPH can experience significant clinical improvement following LT, and those maintaining a mean pulmonary artery pressure (MPAP) <35mm Hg and a pulmonary vascular resistance (PVR) <5 Woods units (WU) are granted additional listing points to expedite LT. The effect of POPH on posttransplant outcomes such as mortality and graft failure, however, is not well defined. We performed a retrospective cohort study of the US Organ Procurement and Transplantation Network database of all adult patients who underwent LT between January 1, 2006, and December 1, 2020. Using adjusted accelerated failure time models, we examined the relationship between a diagnosis of POPH and outcomes following LT and the relationship between pre-LT hemodynamics and post-LT survival (alive with a functioning graft) in patients with POPH. Compared with those undergoing transplants without exception points, patients with POPH had comparable post-LT survival rates but were significantly more likely to have graft failure. Both pre-LT MPAP and PVR predicted post-LT survival in POPH, with a pre-LT PVR of ≥1.6 WU, more than doubling the hazard for mortality (death or a nonfunctioning graft; coefficient, 2.01; standard error, 0.85; hazard ratio, 2.21; P = 0.02). POPH may confer a significantly higher risk of post-LT graft failure compared with patients with cirrhosis without POPH, and a pre-LT PVR of ≥1.6 WU may predict post-LT survival. Further investigation into the relationship between pre-LT hemodynamics, right ventricular function, and post-LT outcomes of mortality and graft failure in POPH is needed.

Food Insecurity and Cognitive Impairment in the Miami Adult Studies on HIV (MASH) Cohort.

BACKGROUND: Food insecurity is a social determinant of health associated with cognitive impairments in older adults and people living with HIV (PLWH). Few studies have examined this relation longitudinally, and no studies have explored how the frequency of food insecurity over time may impact cognitive impairment. OBJECTIVE: This study aimed to examine the impact of food insecurity on cognitive impairment over a 2-y follow-up period in a cohort of people living with and without HIV. METHODS: This was a 2-y longitudinal analysis of primarily economically disadvantaged, middle-aged, Black, and Hispanic participants from the Miami Adult Studies on HIV (MASH) cohort. Food insecurity was assessed with the USDA Household Food Security Module at baseline and 12- and 24-mo follow-ups. Food insecurity in all 3 assessments was considered persistent food insecurity. Cognitive impairment was assessed with the Mini-Mental State Examination. Statistical analyses consisted of logistic regressions. RESULTS: A total of 394 participants (247 HIV positive) with 2-y follow-up data were included in this analysis. At baseline, 104 (26.4%) were food-insecure and 58 (14.7%) had cognitive impairment. Very low food security was associated with cognitive impairment at baseline (OR: 3.23; 95% CI: 1.08, 9.65). PLWH not virally suppressed had higher risk for cognitive impairment compared with HIV-uninfected participants (OR: 2.87; 95% CI: 1.15, 7.18). Additionally, baseline food insecurity (OR: 2.28; 95% CI: 1.08, 4.81) and the frequency of food insecurity over time (OR: 1.50 per year; 95% CI: 1.08, 2.10), particularly persistent food insecurity (OR: 3.69; 95% CI: 1.15, 11.83), were associated with cognitive impairment at 2-y follow-up; the results were consistent after excluding cognitively impaired participants at baseline. CONCLUSIONS: Food insecurity is a significant risk factor for cognitive impairment, particularly among individuals who experience food insecurity frequently or persistently. Screening for food insecurity and interventions to secure access to sufficient, nutritious foods may help delay cognitive decline among socioeconomically disadvantaged individuals.

Sustained Virologic Response of Patients Hospitalized Compared With Those Not Hospitalized During Treatment for Hepatitis C Virus With Direct-Acting Antivirals.

BACKGROUND: Direct-acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) have resulted in great success through high attainment of sustained virologic response (SVR). Risk factors for DAA treatment failure are important to identify because of worsened outcomes with failure and high treatment cost. OBJECTIVE: We sought to identify whether hospitalization during treatment affects SVR. The primary outcome was the difference in SVR at 12 weeks after treatment. METHODS: This multicenter, single health system retrospective cohort review compared achievement of SVR between patients hospitalized during DAA treatment for HCV with those not hospitalized during treatment. RESULTS: Patients in the hospitalized cohort (n = 94) had more severe disease at baseline than nonhospitalized patients (n = 167) as indicated through higher Model for End-Stage Liver Disease (MELD) scores, Fibrosis-4 scores, and imaging-suggested or biopsy-confirmed cirrhosis. Patients hospitalized during treatment had lower SVR rates compared with those not hospitalized (87.2% vs 95.2%; P = 0.043) but failed to reach significance when inpatient mortality was excluded on secondary analysis (91.1% vs 95.2%; P = 0.195). Patients who were hospitalized and did not achieve SVR had higher MELD scores, were more likely to have intensive care unit stay, and had longer hospital stay compared with those who achieved SVR. Of 94 patients, 93 provided home supply of DAAs during hospitalization. CONCLUSION AND RELEVANCE: Patients hospitalized during DAA treatment for HCV had reduced rates of SVR. This reduced SVR rate may be driven by inpatient mortality and severity of liver disease. Patient education to bring home supply of medication for use during admission is an effective intervention.

Multicenter Study to Transplant Hepatitis C-Infected Kidneys (MYTHIC): An Open-Label Study of Combined Glecaprevir and Pibrentasvir to Treat Recipients of Transplanted Kidneys from Deceased Donors with Hepatitis C Virus Infection.

BACKGROUND: Single-center trials and retrospective case series have reported promising outcomes using kidneys from donors with hepatitis C virus (HCV) infection. However, multicenter trials are needed to determine if those findings are generalizable. METHODS: We conducted a prospective trial at seven centers to transplant 30 kidneys from deceased donors with HCV viremia into HCV-uninfected recipients, followed by 8 weeks of once-daily coformulated glecaprevir and pibrentasvir, targeted to start 3 days posttransplant. Key outcomes included sustained virologic response (undetectable HCV RNA 12 weeks after completing treatment with glecaprevir and pibrentasvir), adverse events, and allograft function. RESULTS: We screened 76 patients and enrolled 63 patients, of whom 30 underwent kidney transplantation from an HCV-viremic deceased donor (median kidney donor profile index, 53%) in May 2019 through October 2019. The median time between consent and transplantation of a kidney from an HCV-viremic donor was 6.3 weeks. All 30 recipients achieved a sustained virologic response. One recipient died of complications of sepsis 4 months after achieving a sustained virologic response. No severe adverse events in any patient were deemed likely related to HCV infection or treatment with glecaprevir and pibrentasvir. Three recipients developed acute cellular rejection, which was borderline in one case. Three recipients developed polyomavirus (BK) viremia near or >10,000 copies/ml that resolved after reduction of immunosuppression. All recipients had good allograft function, with a median creatinine of 1.2 mg/dl and median eGFR of 57 ml/min per 1.73 m2 at 6 months. CONCLUSIONS: Our multicenter trial demonstrated safety and efficacy of transplantation of 30 HCV-viremic kidneys into HCV-negative recipients, followed by early initiation of an 8-week regimen of glecaprevir and pibrentasvir.

Liver Fibrosis Progression and Mortality in Hepatitis B- and C-Coinfected Persons Treated With Directly Acting Antiviral Agents: Results From ERCHIVES.

For persons with baseline Fibrosis-4 1.46-3.25, cirrhosis incidence/1000 patient-years was 49.3 among hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfected and 18.2 among HCV monoinfected (P = .03). Cirrhosis risk was numerically higher but statistically nonsignificant among HBV/HCV coinfected (hazards ratio [HR] 1.51; 95% confidence intervals [CI], .37-6.05) but lower among those who attained sustained virologic response (HR, .52; 95% CI, .42-.63).

Treatment of HCV reduces viral hepatitis-associated liver-related mortality in patients: An ERCHIVES study.

BACKGROUND & AIMS: Treating HCV infection reduces overall mortality and reduces the risk of multiple extrahepatic complications. Whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications is unknown. METHODS: We identified HCV-positive individuals treated for HCV, and propensity score-matched them to HCV-positive/untreated and HCV-uninfected individuals in ERCHIVES between 2002-2016. We extracted cause of death data from the National Center for Health Statistics' National Death Index. Viral hepatitis-associated liver-related mortality rates among treated and untreated HCV-infected persons were calculated by treatment and attainment of sustained virologic response (SVR). RESULTS: Among 50,674 HCV-positive/treated (Group A), 31,749 HCV-positive/untreated (Group B) and 73,526 HCV-uninfected persons (Group C), 8.6% in Group A, 35.0% in Group B, and 14.3% in Group C died. Among those who died, viral hepatitis-associated liver-related mortality rates per 100 patient-years (95% CI) were: 0.28 (0.27-0.30) for Group A; 1.44 (1.38-1.49) for Group B; and 0.06 (0.05-0.06) for Group C; (p <0.0001 for both comparisons). Among HCV-positive/treated persons, rates were 0.06 (0.05-0.06) for those with SVR vs. 0.78 (0.74-0.83) for those without SVR. In competing risks Cox proportional hazards analysis, treatment with all-oral DAA regimens (adjusted hazard ratio 0.11; 95% CI 0.09-0.14) and SVR (adjusted hazard ratio 0.10; 95% CI 0.08-0.11) were associated with reduced hazards of liver-related mortality. CONCLUSIONS: Treatment for HCV is associated with a significant reduction in viral hepatitis-associated liver-related mortality, which is particularly pronounced in those treated with DAA regimens and those who attain SVR. This may account for a significant proportion of the reduction in all-cause mortality reported in previous studies. LAY SUMMARY: Treating hepatitis C virus (HCV) infection is known to reduce overall mortality. However, whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications was previously unknown. Herein, we show that while treating HCV with direct-acting antiviral regimens has numerous extrahepatic benefits, a significant benefit can be attributed specifically to the reduction in liver-related mortality.

Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial.

Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.

Cost-effectiveness of Using Kidneys From HCV-Viremic Donors for Transplantation Into HCV-Uninfected Recipients.

RATIONALE & OBJECTIVE: Less than 4% of patients with kidney failure receive kidney transplants. Although discard rates of hepatitis C virus (HCV)-viremic kidneys are declining, ~39% of HCV-viremic kidneys donated between 2018 and 2019 were discarded. Highly effective antiviral agents are now available to treat chronic HCV infection. Thus, our objective was to examine the cost-effectiveness of transplanting kidneys from HCV-viremic donors into HCV-uninfected recipients. STUDY DESIGN: Markov state transition decision model. Data sources include Medline search results, bibliographies from relevant English language articles, Scientific Registry of Transplant Recipients, and the US Renal Data System. SETTING & POPULATION: US patients receiving maintenance hemodialysis who are on kidney transplant waiting lists. INTERVENTION(S): Transplantation with an HCV-unexposed kidney versus transplantation with an HCV-viremic kidney and HCV treatment. OUTCOMES: Effectiveness measured in quality-adjusted life-years and costs measured in 2018 US dollars. MODEL, PERSPECTIVE, AND TIMEFRAME: We used a health care system perspective with a lifelong time horizon. RESULTS: In the base-case analysis, transplantation with an HCV-viremic kidney was more effective and less costly than transplantation with an HCV-unexposed kidney because of the longer waiting times for HCV-unexposed kidneys, the substantial excess mortality risk while receiving dialysis, and the high efficacy of direct-acting antiviral agents for HCV infection. Transplantation with an HCV-viremic kidney was also preferred in sensitivity analyses of multiple model parameters. The strategy remained cost-effective unless waiting list time for an HCV-viremic kidney exceeded 3.1 years compared with the base-case value of 1.56 year. LIMITATIONS: Estimates of waiting times for patients willing to accept an HCV-viremic kidney were based on data for patients who received HCV-viremic kidney transplants. CONCLUSIONS: Transplanting kidneys from HCV-viremic donors into HCV-uninfected recipients increased quality-adjusted life expectancy and reduced costs compared with a strategy of transplanting kidneys from HCV-unexposed donors.

Validation and Refinement of Noninvasive Methods to Assess Hepatic Fibrosis: Magnetic Resonance Elastography Versus Enhanced Liver Fibrosis Index.

BACKGROUND: Noninvasive fibrosis markers are routinely used in patients with liver disease. Magnetic resonance elastography (MRE) is recognized as a highly accurate methodology, but a reliable blood test for fibrosis would be useful. We examined performance characteristics of the Enhanced Liver Fibrosis (ELF) Index compared to MRE in a cohort including those with HCV, HIV, and HCV/HIV. METHODS: Subjects enrolled in the Miami Adult Studies on HIV (MASH) cohort underwent MRE and blood sampling. The ELF Index was scored and receiver-operator curves constructed to determine optimal cutoff levels relative to performance characteristics. Cytokine testing was performed to identify new markers to enhance noninvasive marker development. RESULTS: The ELF Index was determined in 459 subjects; more than half were male, non-white, and HIV-infected. MRE was obtained on a subset of 283 subjects and the group that had both studies served as the basis of the receiver-operator curve analysis. At an ELF Index of > 10.633, the area under the curve for cirrhosis (Metavir F4, MRE > 4.62 kPa) was 0.986 (95% CI 0.994-0.996; p < 0.001) with a specificity of 100%. For advanced fibrosis (Metavir F3/4), an ELF cutoff of 10 was associated with poor sensitivity but high specificity (98.9%, 95% CI 96.7-99.8%) with an AUC of 0.80 (95% CI 0.749-0.845). ELF Index performance characteristics exceeded FIB-4 performance. HCV and age were associated with increased fibrosis (p < 0.05) in a multivariable model. IP-10 was found to be a promising biomarker for improvement in noninvasive prediction algorithms. CONCLUSIONS: The ELF Index was a highly sensitive and specific marker of cirrhosis, even among HIV-infected individuals, when compared with MRE. IP-10 may be a biomarker that can enhance performance characteristics further, but additional validation is required.

Improvement in Hepatic Fibrosis Biomarkers Associated With Chemokine Receptor Inactivation Through Mutation or Therapeutic Blockade.

BACKGROUND: The C-C chemokine receptor Type 5 (CCR5) is a key receptor for human immunodeficiency virus type 1 (HIV-1) entry into T-cells and a variant allele, CCR5 delta-32, is associated with decreased viral replication and disease progression. Active HIV-1 replication is highly associated with accelerated rates of hepatic fibrosis. We postulated that CCR5 plays a role in the development of hepatic fibrosis and evaluated the longitudinal effect of natural or drug-induced CCR5 mutation and blockade on biomarkers of liver fibrosis in HIV-1 patients. METHODS: To accomplish this goal, we examined 2 distinct cohorts. First, we evaluated fibrosis markers in the Multicenter Hemophilia Cohort Studies (MHCS), which included subjects with HIV and hepatitis C virus (HCV) coinfection with the CCR5 delta-32 allele. We also evaluated an HIV-1 infected cohort that was treated with a dual CCR5/CCR2 antagonist, cenicriviroc. The enhanced liver fibrosis (ELF) index was validated against liver histology obtained from HCV/HIV and HCV patients and demonstrated strong correlation with fibrosis stage. RESULTS: In both the MHCS patients and patients treated with cenicriviroc, CCR5 mutation or blockade was associated with a significant decrease in the ELF index. Among the patients with the delta-32 allele, the ELF index rate significantly decreased in sequential samples as compared to CCR5 wild-type patients (P = .043). This was not observed in control subjects treated with efavirenz nor with a lower dose of 100 mg cenicriviroc. CONCLUSION: These findings suggest that hepatic fibrosis in HIV-1 infected patients can be modulated by the mutation of CCR5 and/or use of CCR5/CCR2 blockade agents. CLINICAL TRIALS REGISTRATION: NCT01338883.