A recent open-label randomized controlled study (M Bazinet et al. Gastroenterol 2020; 158: 2180-94. https://doi.org/10.1053/j.gastro.2020.02.058) showed that the addition of nucleic acid polymers (NAPs) which inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles significantly improved outcomes in a phase 2 HBV trial (n=40).
Full text: Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy
NAP therapy was administered intravenously once a week.
- During the first 24 weeks of tenofovir (TDF) and peg-Interferon (pegIFN) administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P < .001 vs control) and HBsAg seroconversion (P = .046 vs control).
- At the time patients completed the TDF + pegIFN + NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants
- During 48 weeks of treatment-free follow-up, virologic control persisted in 13 of 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion
The associated editorial (pg 2051-4 by D Durantel, T Asselah) makes the following points:
- The authors call for larger multicenter studies with longer followup. They note that more evaluation is needed to determine if seroconversion is sustained.
- It remains unclear whether PEG-IFN is needed. TDF/NAP therapy without PEG-IFN was not studied.
- They state that more information about flares during treatment are needed. In this study, flares were safe and associated with beneficial outcomes. It is not clear if therapy flares would be detrimental in those with advanced fibrosis.
- Optimistically, they state that there are multiple competing therapies being studied (eg. small interfering RNA, and small molecule HBs-RNA destabilizer) which could be more easily administered.
My take (borrowed from authors): In a phase 2 randomized trial, “we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy.”
A related commentary (Gastroenterol 2020; 158: 2028-32) calls for investment/study of treatment for immune-tolerant patients along with curative therapy when it becomes available. The authors also argue for a study of long-term viral suppression with either entecavir or tenofovir alafenamide.
Plus one: N Rodriguez-Baez et al. JPGN 2020; 71: 99-105. This study examined liver histology from 134 liver biopsies from treatment-naive children with chronic hepatitis B infection. 60% acquired infection vertically, 69% were HBeAg-positive. Interface hepatitis was mild in 31%, moderate in 61% and severe in 6%; lobular inflammation was mild in 54%, moderate in 29% and severe in 7%. Fibrosis: 18% had no fibrosis, 59% had portal fibrosis without bridging, 19% had bridging fibrosis and 4% had cirrhosis. Alanine amnotransferase was a fairly good indicator of the severity of hepatic inflammation and extent of fibrosis.
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For PDF copy of slides: NAFLD and NASH
Dr. Zobair Younassi gave a recent virtual grand rounds –here are some of the slides:
- Progression of disease is not linear
- Fatty liver disease is a multisystem disorder. Cardiovascular disease is leading cause of death in patients with fatty liver disease
- Fatigue (~50%) is common with fatty liver disease
- Weight loss -Mediterranean diet may be helpful
- No FDA-approved treatments, though pioglitizone supported by AASLD for biopsy-proven NASH
- Public health interventions are needed
I was keenly interested in a recent study: BP Lee, NA. Terrault. Liver Transplantation in Unauthorized Immigrants in the United States. Hepatology 2020; 71: 1802-12. Given the potential for causing a political firestorm, I was surprised it was published.
Definitions: “Unauthorized immigrants, also termed illegal aliens in US federal statures are…all foreign-born non-citizens who are not legal residents.” Since March 2012, UNOS has required transplant centers to record citizenship…”primarily to better understand transplant tourism.” The authors excluded international transplant tourists in their cohort.
- 116 of 43,192 (0.4%) liver transplant (LT) recipients were unauthorized immigrants
- The majority were from Mexico (52%). Others came from Guatemala (7%), China (6%), El Salvador (5%) and India (5%).
- Unauthorized immigrant recipients had a similar risk of graft failure (sHR 0.74) and death (sHR 0.68), though at time of LT, there was higher disease severity (higher MELD scores and increased need for renal replacement therapy).
- Most LTs for unauthorized immigrants took place in California (47%) and New York (18%). Texas (3%) and Florida (4%) had a lower proportion of LTs for unauthorized immigrants based on population distribution.
- The authors note that unauthorized immigrants are different that transplant tourists –they pay social security tax/other taxes and contribute to organ donation (~3% of donated organs) whereas transplant tourists do not.
- The authors note that unauthorized immigrant LTs were less than half the number of transplant tourist LTs; the later LT recipients are commonly individuals from Persian Gulf countries.
- Current federal law mandates that LT be distributed based on “established medical criteria” which does not suggest a “tiered allocation system by citizenship.” Almost half of the unauthorized immigrant LTs were covered by Medicaid.
My take: Unauthorized immigrants are underrepresented as LT recipients compared to their total population distribution in the U.S. This likely is due to a number of barriers. Interestingly, this population is not underrepresented when it comes to organ donation.
NY Times: C.D.C. Recommends Sweeping Changes to American Offices
FDA Approves Hepatitis C Pangenomic Treatment for Children (Mar 19, 2020):
The U.S. Food and Drug Administration today approved a supplemental application for Epclusa (sofosbuvir and velpatasvir) to treat hepatitis C virus (HCV) in children ages 6 years and older or weighing at least 37 pounds (17 kilograms) with any of the six HCV genotypes—or strains—without cirrhosis (liver disease) or with mild cirrhosis.
Review: NAFLD in China 1999-2018 J Zhou et al. Hepatology 2020; 71: 1851-4.
- NALFD increased by 8-9% in prevalence, to 29.1%. This means there are more than 230 million individuals with NAFLD in China.
Use of HCV-positive donors for liver transplantation to HCV-negative recipients. N Anwar et al. Liver Transplantation 2020; 26: 673-80. Key finding: HCV-positive organs had similar outcomes regarding graft function, patient survival and post-LT complications.
Recent Decline in Hepatocellular Carcinoma Rates in U.S. MS Shiels, TR O’Brien. Gastroenterol 2020; 158: 1503-5. Using SEER-21 population based cancer registries covering 37% of U.S. population, the authors found a recent decline in rates of HCC:
- 2000-2016: 119,078 cases of HCC in SEER-21 registries, 5.84/100,000
- Rates increased b 5.6% per year from 2000-2007, then by 2.7% per year from 2007 to 2013, subsequent rate reached a plateau and declined with drop of 1.4% per year (P=.12)
- Improvement could have been due in part to improvement in viral hepatitis treatment; a less favorable explanation could be that the drop occured due to a death from another cause (eg. non-HCC death due to cirrhosis, opioid-related death
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Potential Treatment for Nonalcoholic Steatohepatitis N Chalasani et al. Gastroenterol 2020; 158: 1334-45. The study explored the use of Belapectin, an inhibitor of Galectin-3, in patients with nonalcoholic steatohepatitis and cirrhosis. n=162, phase 2 randomized, double-blind study. Key finding: 1 year of every 2 week infusions were safe but not associated with significant reductions in hepatic venous pressure gradient (HVPG) or fibrosis. However, in a subgroup without varices, there was lowered HVPG and lowered risk of new varices.
Treatment Options for Minimal Hepatic Encephalopathy: RK Dhiman et al. Clin Gastroenterol Hepato 2020; 18: 800-12. This meta-analysis which included 25 trials (n=1563) found the following:
- For reversing minimal hepatic encephalopathy (MHE), rifaximin (OR 7.53) and lactulose (OR 5.39) were effective with moderate quality evidence. Probiotics had OR 3.89 and L-ornithine L-aspartate had OR 4.45 —both with low quality evidence.
- For prevention of HE, L-ornithine L-aspartate had OR 0.19 (‘high moderate’ quality), and lactulose had OR 0.22 (moderate quality) were effective. Probiotics had OR 0.27 with low quality evidence.
- The authors conlude that lactulose is the most effective agent for prevention and reversal of MHE.
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A recent commentary (KS Liem et al. Gastroenterol 2020; 158: 1185-90) reviews the challenge of stopping nucleos(t)ide (NUC) treatment for chronic hepatitis B viral (HBV) infection.
- NUC therapy “prevents liver failure, decreases the risk of hepatocellular carcinoma, and has excellent safety”
- Yet, there are “low rates of on-therapy functional cure” which is indicated by loss of HBV surface antigen [HBsAg]
- Divergent recommendations: Guidelines “recommend NCU therapy in noncirrhoitic patients can be stopped after >3 years of virologic suppression (EASL), after ≥1 year of undetectable HBV DNA and 2 years of treatment (APASL), or only after achieving HBsAg loss (AASLD)
- “Relapse is highly variable, but is especially dangerous in patients with stage 3 fibrosis or cirrhosis”
- “Hepatic decompensation is relatively rare but is best prevented by continuing NUC therapy in all cirrhotics or those with advanced fibrosis.”
- In a randomized controlled trial in Canada, 72 weeks after NUC discontinuation, “only 33% of pretreatment HBeAg-negative patients had a sustained off-treatment response.”
- “The major guidelines suggest that noncirrhotic pretreatment HBeAg-positive patients can stop NUC therapy after reaching HBeAg seroconversion with undetectable HBV DNA and completing 1-3 years of consolidation therapy…these recommendations are of poor quality.”
- Three issues need to be studied: retreatment criteria in those who stop NUC therapy, biomarkers to distinguish beneficial from detrimental flares, and better criteria for identifying those who are likely to decompensate.
My take: It is hard to argue with the author’s conclusion that “without the tools for proper patient selection, potential benefits of NUC discontinuation do not outweigh limitations of long-term NUC therapy for most patients in clinical practice.” This is due to the safety of NUC therapy and the frequency of relapse when NUC is stopped.
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From NPR: New Evidence Suggests COVID-19 Patients On Ventilators Usually Survive
A study of some New York hospitals seemed to show a mortality rate of 88%. But Cooke and others say the New York figure was misleading because the analysis included only patients who had either died or been discharged. “So folks who were actually in the midst of fighting their illness were not being included in the statistic of patients who were still alive,” he says….
The mortality rate among 165 COVID-19 patients placed on a ventilator at Emory was just under 30%. And unlike the New York study, only a few patients were still on a ventilator when the data were collected.
Also: What do you get from a pampered cow? Spoiled milk!
A recent terrific review on Alpha-1-Antitrypsin (A1AT) Deficiency: P Strnad et al. NEJM 2020; 382: 1443-55
- 95% of A1AT deficiency is due to homozygosity for the Z allele; prevalence of 1 in 2000 in those of European descent.
- A1AT protects the lung tissue against attack by the enzyme neutrophil elastase.
- The presence of A1AT genetic variants suggests that these mutations may confer a selective advantage, perhaps by amplifying the inflammatory response to invasive respiratory/gastrointestinal infections.
- Table 1 lists the key alleles/mutations associated with A1AT deficiency -17 deficiency/null listed including: F, I, Iners, King’s, M-malton, M-procida, Pittsburgh, Queen’s, S, S-iyama, Z, QO-bellingham, QO-granitefalls, QO-hongkong
- S allele deficiency often results in disease (emphysema, cirrhosis) in the setting of SZ heterozygotes. The disease is typically less severe than in ZZ disease. This allele is the most common deficiency variant (1 in 5 in Southern Europe, 1 in 30 in U.S.)
- Z allele deficiency is the most common severe deficiency variant. Carrier frequency: 1 in 27 persons in Northern Europe, 1 in 83 in the U.S. It is NOT seen in China, Japan, Korea, Malaysia, or Northern and Western Africa.
PI ZZ Genotype:
- 73% of infants with PI ZZ genotype had elevated ALT level in the 1st 12 months of life
- Cholestatic jaundice noted in 10% of infant; 15% of these infants progress to juvenile cirrhosis
- Only 15% with abnormal ALT values by 12 years of age
- 35% of adults with ZZ genotype show clinically-significant liver fibrosis. Risk factors for advanced fibrosis: male gender, metabolic syndrome/obesity, and alcohol consumption.
Lung Disease Due to A1AT Deficiency:
- The clinical features of lung disease due to A1AT deficiency are “mainly indistinguishable from those of nonhereditary emphysema…this is partly why severe A1AT deficiency remains undiagnosed in approximately 90% of case, with an interval of 5 to 7 years from the onset of symptoms to diagnosis.” When the diagnosis is late, lung disease has become irreversible.
- Early diagnosis allows lifestyle changes (eg. smoking cessation), reduction in occupational risks, and access to therapies.
PI MZ genotype is more susceptible to multiple disorders, including a predisposition to COPD (at least among smokers) with odds ratio of 1.4. Other conditions with increased risk: NAFLD-related cirrhosis (OR 3-7), Alcoholic cirrhosis, and CF-associated liver disease
- Smoking cessation
- Plasma-purified A1AT infusions. “Randomized, controlled trials have focused on decreased loss of lung density as the primary efficacy outcome;” however, augmentation therapy has not been to shown to effect other measures, “such as FEV1, quality of life, or exacerbation of COPD.”
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Also, this study was previously alluded to by this blog, but now is in print:
Briefly noted: X Lu et al. SARS-CoV-2 Infection in Children (NEJM 2020; 382: 1663-5). In 171 Chinese children with confirmed SARS-CoV-2 infection, 41.5% had fever during illness; 27 (15.8%) had no symptoms of infection or radiographic findings. Three required ICU/ventilator support; all had coexisting conditions. One 10 month old child with intussusception died.
Today’s post on Hepatitis C follows a few screenshots from twitter regarding the coronavirus epidemic.
Pediatric report of coronavirus in children: NEJM Full link: SARS-CoV-2 Infection in Children A recent review of 72,314 cases by the Chinese Center for Disease Control and Prevention showed that less than 1% of the cases were in children younger than 10 years of age (n=171)…3 patients required intensive care support and invasive mechanical ventilation; all had coexisting conditions. There was one death in a 10-month-old child with intussusception had multiorgan failure and died 4 weeks after admission.
As noted yesterday, this post will review a recent practice guidance for hepatitis C
Some specific recommendations for children:
- “All children born to HCV-infected women should be tested for HCV infection. Testing is recommended using an antibody-based test at or after 18 months of age.”
- “Testing with an HCV-RNA assay can be considered in the first year of life, but the optimal timing of such testing is unknown” (but can be done as early as 2 months of life).
- “The siblings of children with vertically-acquired chronic HCV should be tested for HCV infection, if born from the same mother.”
Counseling for parents:
- “Parents should be informed that hepatitis C is not transmitted by casual contact and, as such, children with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions.”
- “Parents should be informed that universal precautions should be followed at school and in the home of children with HCV infection. Educate families and children about the risk and routes of HCV transmission, and the techniques for avoiding blood exposure, such as avoiding the sharing of toothbrushes, razors, and nail clippers, and the use of gloves and dilute bleach to clean up blood.”
- “Direct-acting antiviral (DAA) treatment with an approved regimen is recommended for all children and adolescents with HCV infection aged ≥3 years as they will benefit from antiviral therapy, regardless of disease severity.”
- Early treatment in childhood is expected to be cost-effective compared to treatment at later ages based on previous studies
This chart provides recommendations for pediatric patients who have not received prior direct-acting antivirals. More information at HCVguidelines.org
A recent study (EB Tapper et al. Hepatology 2020; 71: 225-34, editorial 11-13) shows that advanced practice providers (APPs) provide care that translates into better outcomes for adults with cirrhosis. APPs include physician assistants and nurse practitioners.
In a retrospective analysis (2001-15) of the Optum Clinformatics database (private insurance) with 389,257 adult patients, the authors show that patients who had an APP involved in their care had better outcomes.
Key findings among patients with APP care (with and without specialist involvement):
- Reduced risk of death, aHR 0.43
- Improved metrics: higher HCC screening aOR 1.23, higher variceal screening OR 1.20, increased use of rifaximin after discharge for HE OR 2.09, and reduced risk of hospital 30-day readmission OR 0.68.
- Overall, AAP care alone was inferior to specialist care alone for all metrics except 30-day readmissions; however, shared care (APP and specialist care) was more successful than specialist care alone (eg. 30-day readmissions OR 0.91 with shared care)
- APP involvement was associated with an almost 2-fold increase in costs per person per year (~$9600 compared to $4500) and increased procedures
- Due to the retrospective nature, it is unclear how many of the APPs had specialty training; as such, it is not clear whether primary care APP involvement is equivalent to specialty care APP involvement
My take: Based on my experience, this study likely could be replicated in most medical fields. APPS improve patient outcomes.
Island Ford National Recreational Area, Sandy Springs
Two recent studies have suggested that tenofovir may be more effective for hepatitis B virus (HBV) infections.
- T C-F Yip et al. Gastroenterol 2020; 158: 215-25.
- J Choi et al. JAMA Oncol 2019; 5: 30-6. (Reviewed in a commentary by P Lampertico, M Colombo. Gastroenterol 2019; 157: 1682-88)
In the first retrospective study from Hong Kong, the authors analyzed 29,350 consecutive treated-patients (mean age 52.9 years). 1309 were treated with tenofovir disoproxil fumarate (TDV) and 28,041 were treated with entecavir. Key findings:
- TDF-treated patients were younger (mean age 43.2 years vs. 53.4 years) and had less cirrhosis at baseline (2.9% vs. 13.6%).
- After a median follow-up of 3.6 years, 8 TDF-treated patients (0.6%) and 1386 (4.9%) of entecavir-treated patients developed hepatocellular carcinoma (HCC). The authors note that TDF maintained a lower rate of HCC after propensity score weighting (hazard ratio of 0.36)
The second study was a nationwide population cohort database with >24,000 patients –all with ALT >80. Key finding:
- HCC was significantly lower in TDF group than in the entecavir group, the percent person-years being 0.64 compared to 1.06; though, there was not a lower mortality rate or a lower liver transplantation rate.
The commentary associated with the latter study makes the following points:
- Both TDF and entecavir could prevent “the incidence and mortality of HCC …in >85% of patients who received [them] for years.”
- Studies comparing TDF and entecavir have come up with conflicting results. “Three studies in Korea, the U.S, and Europe reported no differences between NAs even after patient matching by a propensity score.”
- “Cumulatively, all these studies deliver the reassuring message of a robust risk reduction of liver cancer taking place in patients with chronic hepatitis B who experience prolonged virus suppression after NA therapy, but currently they fail to provide convincing evidence that one NA is superior to the other one in determining such clinical benefit.”
My take: Tenofovir may be better but the answer is not definitive; due to lack of randomization, there may still be confounding variables in which sicker patients are receiving entecavir and this could be contributing to the difference in outcomes. Also, in patients with bone disease and renal impairment, tenofovir alafenamide (TAF) or entecavir is recommended.
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From P’tit Train Du Nord Linear Park
A recent study (AJ Sanyal et al. Hepatology 2019; 70: 1913-27) used prospectively collected data from two large randomized, placebo-controlled phase 2b studies of simtuzumab in patients with either bridging fibrosis (n=217) or compensated cirrhosis (n=258) due to nonalcoholic fatty liver disease (NAFLD). The age range of participants were 48-61 years with median ages of 55 years and 57 years for the two cohorts. All patients had liver biopsies at screening and at weeks 48 and 96.
- Progression to cirrhosis occurred in 22% (48/217) of patients with bridging fibrosis (F3) over a median of 29 months
- Liver-related adverse clinical events (eg. ascites, variceal bleeding, encephalopathy, MELD score ≥15, liver transplantation or death) occurred in 19% (50/258) with compensated cirrhosis over a median of 29 months. Only 1 patient in this cohort died.
- Higher baseline hepatic fibrosis or serum markers of fibrosis were associated with disease progression in patients with F3 disease
My take: Among those with advanced liver disease, this study indicates that disease progression/deterioration is rather rapid in about 20%.
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P’tit Train du Nord Linear Park (near Montreal) -124 Miles
NY Times: Easy Slopes, Please: Biking the Mountains of Quebec