Effects of Food Insecurity on Hepatic Steatosis and Fibrosis in People With HIV.

BACKGROUND & AIMS: Food insecurity (FI) is a risk factor for nonalcoholic fatty liver disease (NAFLD) and advanced fibrosis in the general population, but its impact on liver disease in people with HIV (PWH) is unknown. METHODS: We examined the association of FI with prevalence of NAFLD and fibrosis in a diverse cohort of PWH. PWH aged ≥ 18 years on antiretroviral therapy, HIV RNA <200 copies/mL, and without other known liver diseases were screened for NAFLD (controlled attenuated parameter ≥263 decibels/meter) and advanced fibrosis (liver stiffness measurement ≥11 kilopascals) by vibration controlled transient elastography at 8 U.S. CENTERS: Participants were categorized as food insecure using the Six-Item Short Form Household Food Security Survey. We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD and advanced fibrosis by FI status. RESULTS: Among 654 PWH, NAFLD was present in 348 (53%) and advanced fibrosis in 41 (6%). FI was present in 203 of participants (31%), including 97/348 with NAFLD (28%) and 18/41 with advanced fibrosis (44%). In multivariable analysis, FI was associated with lower odds of NAFLD (OR, 0.57; 95% CI, 0.37-0.88) and a greater, but nonsignificant, odds of advanced fibrosis (OR, 1.38; 95% CI, 0.65-2.90). We identified a significant interaction between FI and diabetes (P = .02) on fibrosis risk, with greater odds of fibrosis among food insecure PWH and diabetes (OR, 3.83; 95% CI, 1.15-12.73) but not among food insecure nondiabetics (OR, 1.12; 95% CI, 0.47-2.98). CONCLUSIONS: FI is highly prevalent among PWH and associated with lower odds of NAFLD, and among PWH with diabetes, there is greater odds of advanced fibrosis. FI may contribute to hepatic fibrosis through mechanisms other than steatosis in PWH.

Imaging-based non-invasive liver disease assessment for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Transient elastography (TE), shear-wave elastography (SWE), and/or magnetic resonance elastography (MRE), each providing liver stiffness measurement (LSM), are the most studied imaging-based noninvasive liver disease assessment (NILDA) techniques. To support the American Association for the Study of Liver Diseases guidelines on NILDA, we summarized the evidence on the accuracy of these LSM methods to stage liver fibrosis (F). APPROACH AND RESULTS: A comprehensive search for studies assessing LSM by TE, SWE, or MRE for the identification of significant fibrosis (F2-4), advanced fibrosis (F3-4), or cirrhosis (F4), utilizing histopathology as standard of reference by liver disease etiology in adults or children from inception to April 2022 was performed. We excluded studies with <50 patients with a single disease entity and mixed liver disease etiologies (with the exception of HCV/HIV co-infection). Out of 9447 studies, 240 with 61,193 patients were included in this systematic review. In adults, sensitivities for the identification of F2-4 ranged from 51% to 95%, for F3-4 from 70% to 100%, and for F4 from 60% to 100% across all techniques/diseases, whereas specificities ranged from 36% to 100%, 74% to 100%, and 67% to 99%, respectively. The largest body of evidence available was for TE; MRE appeared to be the most accurate method. Imaging-based NILDA outperformed blood-based NILDA in most comparisons, particularly for the identification of F3-4/F4. In the pediatric population, imaging-based NILDA is likely as accurate as in adults. CONCLUSION: LSM from TE, SWE, and MRE show acceptable to outstanding accuracy for the detection of liver fibrosis across various liver disease etiologies. Accuracy increased from F2-4 to F3-4 and was the highest for F4. Further research is needed to better standardize the use of imaging-based NILDA, particularly in pediatric liver diseases.

Accuracy of blood-based biomarkers for staging liver fibrosis in chronic liver disease: A systematic review supporting the AASLD Practice Guideline.

BACKGROUND AND AIMS: Blood-based biomarkers have been proposed as an alternative to liver biopsy for non-invasive liver disease assessment (NILDA) in chronic liver disease (CLD). Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4) and cirrhosis (F4), as compared to biopsy in CLD. APPROACH AND RESULTS: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aminotransferase-to-platelet ratio index (APRI) and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in hepatitis B virus (HBV) and C virus (HCV), HIV-HCV/HBV co-infection, and nonalcoholic fatty liver disease (NAFLD). Positive (LR+) and negative (LR) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66-6.25 and 0.23-0.80, 1.89-5.24 and 0.12-0.64, and 1.32-7.15 and 0.15-0.86 respectively; LR+ and LR for NAFLD F2-4, F3-4 and F4 were 2-65-3.37 and 0.37-0.39, 2.25-6.76 and 0.07-0.87, and 3.90 and 0.15 respectively. Overall, proportional odds ratio indicated FIB-4 <1.45 was better than APRI <0.5 for F2-4. FIB-4 >3.25 was also better than APRI >1.5 for F3-4 and F4. There was limited data for combined tests. CONCLUSIONS: Blood-based biomarkers are associated with small-to-moderate change in pre-test probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV co-infection, and NAFLD, with limited comparative or combination studies for other CLD.

Non-invasive liver disease assessment to identify portal hypertension: A systematic review supporting the AASLD Practice Guideline.

INTRODUCTION: Portal hypertension is a serious complication of cirrhosis, which leads to life-threatening complications. Hepatic venous pressure gradient (HVPG), a surrogate of portal pressure, is the reference standard test to assess the severity of portal hypertension. However, since HVPG is limited by its invasiveness and by its availability, non-invasive liver disease assessments (NILDAs) to assess portal pressure, especially clinically significant portal hypertension (CSPH), are needed. METHODS: We conducted a systematic review of Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from each database's inception to April 22 nd , 2022. We included only studies in English that examined ≥50 patients in single liver disease etiologies which compared non-invasive tests (blood, and/or imaging) to HVPG for predicting clinically significant portal hypertension (CSPH; defined as HVPG ≥10 mm Hg) in patients with chronic liver disease (this therefore limited the number of studies that could be included). Outcomes reported included measures of diagnostic test accuracy. Additionally, a narrative review of studies not eligible for the systematic review is also provided. RESULTS: Nine studies with 2,492 patients met the inclusion criteria. There was substantial heterogeneity with regard to liver disease studied and cutoff values used to detect CSPH. Blood based tests, including aspartate to platelet ratio index (APRI) (56% sensitivity and 68% specificity) and fibrosis-4 (FIB-4) (54% sensitivity and 73% specificity) had low accuracy measures. Imaging based tests (transient elastography (TE) and shear wave elastography detection of liver stiffness (LSM)) had better accuracy, but also had substantial variation; at 15 kPa, TE sensitivity was 90%-96% and specificity was 48%-50% while at 25 kPa, its sensitivity and specificity were 57%-85% and 82%-93%, respectively. The narrative review suggested that imaging based tests are the best available NILDA to detect CSPH, CSPH is highly unlikely to be present at an LSM ≤15 kPa and likely to be present at an LSM ≥25 kPa. CONCLUSION: While imaging-based NILDA appeared to have higher accuracy than blood-based tests to detect CSPH, only 9 studies fit the a priori established inclusion criteria for the SR. In addition, there was substantial study heterogeneity and variation in cutoffs for LSM to detect CSPH, limiting the ability to establish definitive cutoffs to detect CSPH.

Diagnostic Ability of Simple Noninvasive Blood Tests to Predict Increased Liver Stiffness in People Living With HIV and Steatotic Liver Disease.

INTRODUCTION: Steatotic liver disease is common in people with HIV (PWH). Identifying those with advanced fibrosis (AF, bridging fibrosis or cirrhosis), F3-4, is important. We aimed to examine the performance of FIB-4 and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) in PWH to identify those with AF assessed by liver stiffness measurement (LSM). METHODS: We prospectively collected data on adults participating in 2 National Institute of Health-sponsored HIV NAFLD networks. All had HIV on antiretroviral therapy (ART) ≥6 months with HIV RNA <200 copies/mL. Those with viral hepatitis, other liver disease, excessive alcohol use, or hepatic decompensation were excluded. Vibration-controlled transient elastrography for LSM was performed, and AF defined as ≥11 kPa was compared with FIB-4 and NFS at predefined thresholds (<1.3 and >2.67 for FIB-4 and <-1.455 and >0.675 for NFS). RESULTS: A total of 1,065 participants were analyzed: mean age 51.6 years, 74% male, 28% White, 46% Black, 22% Hispanic, with 34% overweight (body mass index 25-29 kg/m 2 ) and 43% obese (body mass index ≥30 kg/m 2 ). Features of the metabolic syndrome were common: hyperlipidemia 35%, type 2 diabetes 17%, and hypertension 48%. The median CD4 + T-cell count was 666 cells/mm 3 , 74% had undetectable HIV RNA, and duration of HIV-1 was 17 years with most taking a nucleoside reverse transcriptase inhibitor (92%) and an integrase inhibitor (83%). The mean LSM was 6.3 kPa, and 6.3% had AF. The area under the receiver characteristic curve for FIB-4 and NFS to identify AF were 0.70 and 0.75, respectively. While both had high negative predictive values (97%-98%), the sensitivity at low thresholds and specificity at high thresholds were 64% and 97% for FIB-4 and 80% and 96% for NFS, respectively. Neither FIB-4 nor NFS at either threshold had good positive predictive value to detect AF. DISCUSSION: FIB-4 and NFS have excellent specificity and negative predictive value for detecting AF, and thus can be used as screening tools in PWH to exclude those with AF who do not need further testing (LSM) or referral to hepatologist.

Test characteristics for combining non-invasive liver fibrosis staging modalities in individuals with Hepatitis C virus.

Non-invasive methods have largely replaced biopsy to identify advanced fibrosis in hepatitis C virus (HCV). Guidelines vary regarding testing strategy to balance accuracy, costs and loss to follow-up. Although individual test characteristics are well-described, data comparing the accuracy of using two tests together are limited. We calculated combined test characteristics to determine the utility of combined strategies. This study synthesizes empirical data from fibrosis staging trials and the literature to estimate test characteristics for Fibrosis-4 (FIB4), APRI or a commercial serum panel (FibroSure®), followed by transient elastography (TE) or FibroSure®. We simulated two testing strategies: (1) second test only for those with intermediate first test results (staged approach), and (2) second test for all. We summarized empiric data with multinomial distributions and used this to estimate test characteristics of each strategy on a simulated population of 10,000 individuals with 4.2% cirrhosis prevalence. Negative predictive value (NPV) for cirrhosis from a single test ranged from 98.2% (95% CB 97.6-98.8%) for FIB-4 to 99.4% (95% CB 99.0-99.8%) for TE. Using a staged approach with TE second, sensitivity for cirrhosis rose to 93.3-96.9%, NPV to 99.7-99.8%, while PPV dropped to <32%. Using TE as a second test for all minimally changed estimated test characteristics compared with the staged approach. Combining two non-invasive fibrosis tests barely improves NPV and decreases or does not change PPV compared with a single test, challenging the utility of serial testing modalities. These calculated combined test characteristics can inform best methods to identify advanced fibrosis in various populations.

Outcomes of early vs late treatment initiation in solid organ transplantation from hepatitis C virus nucleic acid test-positive donors to hepatitis C virus-uninfected recipients: Results from the HCV-TARGET study.

Curative hepatitis C virus (HCV) therapy has increased transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients (D+/R-). We evaluated outcomes of early and late HCV treatment among D+/R- nonliver organ transplants. Patients received HCV regimens per local standard (n = 10 sites). Outcomes were compared between early and late treatments. Early treatment regimens (ETR) (n = 56) were initiated pretransplantation to day 7 posttransplant. Late treatment regimens (LTRs) (n = 102) began median 31 (range, 8-114) days posttransplant. There were 79 kidney, 50 lung, 23 heart, and 6 mixed transplants, similar between groups. HCV RNA was quantifiable in 98% of LTR versus 44.6% of ETR recipients (P < .001). Mean (range) days on treatment were 28 (7-93) ETR and 81 (51-111) LTR (P < .0001). There were no virological failures with ETR, but relapse (n = 3) and nonresponse (n = 2) in LTR (P = .16), including fibrosing cholestatic hepatitis postrelapse (n = 1). Sustained virological response was 100% (95% confidence interval, 93.4-100.0) in ETR (n = 54) and 94.9% (95% confidence interval, 88.5-98.3) in LTR (n = 98). Acute rejection occurred in 11 (19.6%) ETR and 25 (24.5%) LTR. In total, 11 HCV-unrelated deaths occurred: 8 ETR and 3 LTR. Organ transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients was safe. ETR led to fewer virological failures with shorter treatment duration, supporting recommendations to initiate treatment promptly posttransplant.

Prevalence of steatotic liver disease, MASLD, MetALD and significant fibrosis in people with HIV in the United States.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been proposed as a replacement term for NAFLD. AIMS: To assess the effects of this new nomenclature on the prevalence and distribution of different SLD categories in people with HIV (PWH) and identified factors associated with MASLD and clinically significant fibrosis (CSF). METHODS: PWH were prospectively enrolled from 9 US centres and underwent clinical evaluation and vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). SLD was defined as CAP ≥ 263 dB/m, CSF as LSM of ≥8 kPa, and advanced fibrosis (AF) as LSM ≥ 12 kPa. The prevalence of SLD, MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), ALD, cryptogenic (cSLD), CSF and AF were determined. Uni- and multivariate logistic regression models were used to assess factors associated with MASLD and CSF risk. RESULTS: Of 1065 participants, 74% were male, mean (SD) age 51.6 ± 11.9 years, 46% non-Hispanic Black and 74% with undetectable HIV RNA. The prevalence of SLD was 52%, MASLD 39%, MetALD 10%, ALD 3%, CSF 15% and AF 4%. Only 0.6% had cSLD. Black race was protective whereas obesity, ALT and AST levels were associated with increased risk of MASLD and CSF in MASLD. HIV or antiretroviral therapy did not affect MASLD risk. CONCLUSIONS: MASLD and MetALD are the dominant causes of SLD in PWH, affecting almost half. Application of the new nomenclature resulted in minimal change in the proportion of patients with MASLD who would have been diagnosed previously with NAFLD.

Fibrosis-4 (FIB-4) index as a predictor for mechanical ventilation and 30-day mortality across COVID-19 variants.

Background: The Fibrosis-4 (FIB-4) index, a simple index that includes age, liver enzymes, and platelet count has been studied as a tool to identify patients at a risk of requiring mechanical ventilation due to its high negative predictive value. It is unknown if FIB-4 remains useful to predict the severity of respiratory disease requiring mechanical ventilation amongst new Coronavirus disease 2019 (COVID-19) variants and whether a relationship also exists between FIB-4 and 30-day mortality. The main objective was to determine if FIB-4 can predict mechanical ventilation requirements and 30-day mortality from COVID-19 across variants including Alpha, Delta, and Omicron. Methods: This was a population-based, retrospective cohort analysis of 232,364 hospitalized patients in the National COVID-19 Cohort Collaborative between the age of 18-90 who tested positive for COVID-19 between April 27, 2020 and June 25, 2022. The primary outcome was association between FIB-4 and need for mechanical ventilation. Secondary measures included the association of FIB-4 with 30-day mortality. Results: A FIB-4 > 2.67 had 1.8 times higher odds of requiring mechanical ventilation across all variants of COVID-19 (OR 1.81; 95% CI: [1.76, 1.86]). The area under the ROC curve showed high diagnostic accuracy with values ranging between 0.79 (Omicron wave) and 0.97 (delta wave). Increased FIB-4 was associated with 30-day mortality across the variates. Conclusion: The FIB-4 was consistently associated with both increased utilization of mechanical ventilation and 30-day mortality among COVID-19 patients across all waves in both adjusted and unadjusted models. This provides a simple tool for risk-stratification for front-line health care professionals.

Alterations in gut virome are associated with cognitive function and minimal hepatic encephalopathy cross-sectionally and longitudinally in cirrhosis.

Cognitive dysfunction due to minimal hepatic encephalopathy (MHE) adversely impacts patients with cirrhosis and more precise therapies are needed. Gut-brain axis changes are therapeutic targets, but prior studies have largely focused on bacterial changes. Our aim was to determine linkages between individual cognitive testing results and bacteria with the virome using a cross-sectional and longitudinal approach. We included cross-sectional (n = 138) and longitudinal analyses (n = 36) of patients with cirrhosis tested using three cognitive modalities, which were psychometric hepatic encephalopathy score (PHES), inhibitory control test (ICT), Stroop, and all three. Stool metagenomics with virome and bacteriome were analyzed studied cross-sectionally and in a subset followed for development/reversal of MHE repeated at 6 months (longitudinally only using PHES). Cross-sectional: We found no significant changes in α/ß diversity in viruses or bacteria regardless of cognitive testing. Cognitively impaired patients were more likely to have higher relative abundance of bacteriophages linked with Streptococcus, Faecalibacterium, and Lactobacillus, which were distinct based on modality. These were also linked with cognition on correlation networks. Longitudinally, 27 patients remained stable while 9 changed their MHE status. Similar changes in phages that are linked with Streptococcus, Faecalibacterium, and Lactobacillus were seen. These phages can influence ammonia, lactate, and short-chain fatty acid generation, which are neuro-active. In conclusion, we found linkages between bacteriophages and cognitive function likely due to impact on bacteria that produce neuroactive metabolites cross-sectionally and longitudinally. These findings could help explore bacteriophages as options to influence treatment for MHE in cirrhosis.

A narrative review of supportive and end of life care considerations in advanced hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths, and case numbers continue to rise in the United States. HCC carries a poor prognosis, and management requires a multidisciplinary approach. This narrative review aims to identify opportunities for further integration of palliative care (PC) in HCC care. Given the high symptom burden faced by patients with HCC, early PC consultation can be beneficial for patients. METHODS: A search of PubMed was conducted from inception of the database to March 1, 2023. The search was composed of keywords and controlled vocabulary terms for concepts related to palliative medicine and symptom management in the setting of HCC. KEY CONTENT AND FINDINGS: This narrative review finds that although PC has been integrated into HCC guidelines, partnerships between PC and hepatology are still nascent in clinical practice. Treatment-related barriers pose a challenge to timely integration of PC in the care of HCC patients; evaluation or listing for transplantation can be perceived as a barrier to PC consultation, and unpredictable clinical courses make prognostication challenging. Providers may hesitate to pursue PC referral due to a lack of consensus around the role of PC, and for those that are referred, timing of consultation remains an issue, especially for those who are potential liver transplant candidates. There are few studies of PC in HCC, limiting evidence-based recommendations that can be made regarding PC involvement in this patient population. CONCLUSIONS: While PC is not routinely integrated into HCC care, recent guideline recommendations and a growing number of studies may change this over time. Although further evidence is needed, PC and hepatology teams partnering together can explore ways to improve the care of this patient population. PC consultation early in HCC care could assist in management of symptom relief, psychosocial and spiritual support, and caregiver support. Effective communication will be required to set parameters for referral and clarify potential outcomes of consultation. Teams should be prepared for the challenges involved in a culture change and paradigm shift in clinical practice.

Cost minimization analysis of short-duration antiviral prophylaxis for hepatitis C positive donor kidney transplants.

BACKGROUND: Trials describing 4-12 week courses of direct-acting antiviral drugs (DAAs) to treat hepatitis C virus (HCV) transmission from infected donors to uninfected kidney transplant recipients (D+/R-transplants), may be limited in application by costs and delayed access to expensive DAAs. A short prophylactic strategy may be safer and cost-effective. Here, we report a cost minimization analysis using the health system perspective to determine the least expensive DAA regimen, using available published strategies. OBJECTIVES: To conduct cost-minimization analyses (CMAs) from the health system perspective of four DAA regimens to prevent and/or treat HCV transmission from D+/R-kidney transplants. METHODS: CMAs comparing 4 strategies: 1) 7-day prophylaxis with generic sofosbuvir/velpatasvir (SOF/VEL), with 12-week branded glecaprevir/pibrentasvir (G/P) for those with transmission; 2) 8-day branded G/P prophylaxis, with 12-week branded SOF/VEL/voxilaprevir for those with transmission; 3) 4-week perioperative generic SOF/VEL prophylaxis, with 12-week branded G/P for those with transmission; and 4) 8-week branded G/P "transmit-and-treat." We included data from published literature to estimate the probability of viral transmission in patients who received DAA prophylaxis, and assumed a 100% transmission rate for those who received the "transmit-and-treat" approach. RESULTS: In base-case analyses, strategies 1 (expected cost [EC]: $2326) and 2 (expected cost: $2646) were less expensive than strategies 3 (EC: $4859) and 4 (EC: $18,525). Threshold analyses for 7-day SOF/VEL versus 8-day G/P suggested that there were reasonable input levels at which the 8-day strategy may be least costly. The threshold values for the SOF/VEL prophylaxis strategies (7-day vs. 4- week) indicated that the 4-week strategy is unlikely to be less costly under any reasonable value of the input variables. CONCLUSIONS: Short duration DAA prophylaxis using 7 days of SOF/VEL or 8 days of G/P has the potential to yield significant cost savings for D+/R- kidney transplants.

Human immunodeficiency virus coinfection differentially impacts hepatitis B virus viral markers based on hepatitis Be antigen status in patients with suppressed viremia.

Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), reflecting transcriptional activity of covalently closed circular DNA, are gaining traction as important markers to assess viral activity. Whether their expression differs under viral suppression by HIV co-infection status is unknown. Among adults with chronic HBV on antiviral therapy, we sought to determine if the expression of HBV markers (specialized and well-established) differs between HBV-HIV co-infection vs. HBV mono-infection. We compared HBV marker levels among 105 participants in the Hepatitis B Research Network (HBRN) HBV-HIV Ancillary Study and 105 participants in the HBRN mono-infected Cohort Study, matched for HBeAg status and HBV DNA suppression on therapy. Among HBeAg+ participants (N = 58 per group), after adjusting for age, sex, race, ALT and HBV DNA, viral markers were higher (p < .05) in the HBV-HIV versus the HBV-only sample (HBeAg: 1.05 vs. 0.51 log10 IU/mL; HBsAg: 3.85 vs. 3.17 log10 IU/mL; HBV RNA: 5.60 vs. 3.70 log10 U/mL; HBcrAg: 6.59 vs. 5.51 log10 U/mL). Conversely, among HBeAg(-) participants (N = 47 per group), HBsAg (2.00 vs. 3.04 log10 IU/mL) and HBV RNA (1.87 vs. 2.66 log10 U/mL) were lower (p < .05) in HBV-HIV vs. HBV-only; HBcrAg levels were similar (4.14 vs. 3.64 log10 U/mL; p = .27). Among adults with chronic HBV with suppressed viremia on antiviral therapy, viral markers tracked with HIV co-infection status and associations differed inversely by HBeAg status. The greater sensitivity and specificity of HBV RNA compared to HBcrAg allows for better discrimination of transcriptional activity regardless of HBeAg status.

Hepatitis B e Antigen-Negative Single Hepatocyte Analysis Shows Transcriptional Silencing and Slow Decay of Infected Cells With Treatment.

BACKGROUND: Nucleos(t)ide analogues (NUCs) rarely cure chronic hepatitis B (CHB) because they do not eliminate covalently closed circular deoxyribonucleic acid, the stable replication template. In hepatitis B e antigen (HBeAg)-positive CHB during NUCs, HBV-infected cells decline slowly and are transcriptionally silenced. Whether these occur in HBeAg-negative CHB is unknown. METHODS: Using paired liver biopsies separated by 2.7-3.7 years in 4 males with HIV and HBeAg-negative CHB at both biopsies and 1 male with HIV who underwent HBeAg seroconversion between biopsies, we quantified amounts of viral nucleic acids in hundreds of individual hepatocytes. RESULTS: In the 4 persistently HBeAg-negative participants, HBV-infected hepatocytes ranged from 6.2% to 17.7% (biopsy 1) and significantly declined in 3 of 4 by biopsy 2. In the HBeAg seroconverter, the proportion was 97.4% (biopsy 1) and declined to 81.9% at biopsy 2 (P < .05). We extrapolated that HBV eradication with NUCs would take >100 years. At biopsy 1 in the persistently HBeAg-negative participants, 23%-56.8% of infected hepatocytes were transcriptionally inactive-higher than we observed in HBeAg-positive CHB-and significantly declined in 1 of 4 at biopsy 2. CONCLUSIONS: In HBeAg-negative CHB on NUCs, the negligible decline in infected hepatocytes is similar to HBeAg-positive CHB, supporting the need for more potent therapeutics to achieve functional cure.

Racial Disparities in Treatment Initiation and Outcomes of Chronic Hepatitis B Virus Infection in North America.

Importance: Disparities in treatment initiation may affect outcomes, but data on racially diverse populations with chronic hepatitis B virus (HBV) infection are limited. Objective: To examine whether HBV treatment initiation and outcomes differ among racial groups. Design, Setting, and Participants: From January 14, 2011, to January 28, 2018, hepatitis B surface antigen-positive adults (age ≥18 years) not receiving anti-HBV therapy were enrolled and followed up at weeks 12, 24, and every 24 weeks thereafter in a multicenter longitudinal cohort study (Hepatitis B Research Network [HBRN] adult cohort study) conducted in North America. The last study visit and data collection were completed January 28, 2019. Data were analyzed from August 27, 2021, to August 25, 2022. All HBRN participants were included unless they had acute HBV, HIV, hepatitis C or D, less than 24-weeks of follow-up after enrollment, initiated treatment at or immediately after enrollment, or had unknown race. Exposures: Participants had clinical and laboratory assessments and could receive anti-HBV treatment after enrollment. Main Outcomes and Measures: Hepatitis B virus treatment initiation and major adverse liver outcomes (hepatic decompensation, hepatocellular carcinoma, liver transplant, and death). Results: Of 1550 participants, 193 (12%) were African American or Black, 1157 (75%) were Asian, 157 (10%) were White, and 43 (3%) were other races; 789 (51%) were women, and the median age was 41.2 (IQR, 32.9-51.6) years. Sociodemographic and virologic parameters differed between groups. During 5727 person-years of follow-up, 504 participants initiated treatment, with incidences of 4.8 per 100 person-years in African American or Black individuals, 9.9 per 100 person-years in Asian individuals, 6.6 per 100 person-years in White individuals, and 7.9 per 100 person-years in those of other races (P < .001). A lower proportion (14%) of African American or Black participants met treatment criteria compared with Asian (22%) and White (27%) individuals (P = .01). The cumulative probabilities of treatment initiation after meeting the criteria were not significantly different among racial groups (African American or Black, 0.45; Asian, 0.38; White, 0.40 at 48 weeks and African American or Black, 0.45; Asian, 0.51; White, 0.51 at 72 weeks; P = .68). The incidence of major adverse liver outcomes was 0.1 per 100 person-years and did not differ by race. Conclusions and Relevance: In this observational study of chronic HBV, African American or Black participants were less likely than individuals of other races to meet treatment criteria, but among those who did, HBV treatment receipt did not differ significantly by race or socioeconomic factors. Not all eligible participants initiated treatment, but adverse liver outcomes were rare. These findings may not be generalizable to patients with chronic HBV receiving care in other settings.

Use of HBV RNA and to predict change in serological status and disease activity in CHB.

BACKGROUND AND AIMS: Predicting changes in disease activity and serological endpoints is necessary for the management of patients with chronic hepatitis B (CHB). We examined whether HBV RNA and hepatitis B core-related antigen (HBcrAg), two specialized virological markers proposed to reflect the activity of covalently closed circular DNA, may improve the ability to predict not sustained inactive carrier phase, spontaneous alanine aminotransferase (ALT) flare, HBeAg loss, and HBsAg loss. APPROACH AND RESULTS: Among eligible participants enrolled in the North American Hepatitis B Research Network Adult Cohort Study, we evaluated demographic, clinical, and virologic characteristics, including HBV RNA and HBcrAg, to predict not sustained inactive carrier phase, ALT flare, HBeAg loss, and HBsAg loss through a series of Cox proportional hazard or logistic regression models, controlling for antiviral therapy use. Among the study population, 54/103 participants experienced not sustained inactive carrier phase, 41/1006 had a spontaneous ALT flare, 83/250 lost HBeAg, and 54/1127 lost HBsAg. HBV RNA or HBcrAg were predictive of all 4 events. However, their addition to models of the readily available host (age, sex, race/ethnicity), clinical (ALT, use of antiviral therapy), and viral factors (HBV DNA), which had acceptable-excellent accuracy (e.g., AUC = 0.72 for ALT flare, 0.92 for HBeAg loss, and 0.91 for HBsAg loss), provided only small improvements in predictive ability. CONCLUSION: Given the high predictive ability of readily available markers, HBcrAg and HBV RNA have a limited role in improving the prediction of key serologic and clinical events in patients with CHB.