Methods: This cohort study included patients (n=1552) with virally-suppressed chronic hepatitis B (CHB) who were hepatitis B e antigen (HBeAg)–negative (and without advanced liver disease) and stopped nucleos(t)ide analogue (NA) therapy
Cumulative probability of HBsAg loss was 3.2% at 12 months and 13.0% at 48 months of follow-up
HBsAg loss was higher among Whites (vs Asians: subdistribution hazard ratio, 6.8; P < .001) and among patients with HBsAg levels <100 IU/mL at end of therapy (vs ≥100 IU/mL: subdistribution hazard ratio, 22.5; P < .001)
My take: This study identifies subsets with HBeAg-negative CHB who may benefit from NA therapy cessation.
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).
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.
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.
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!
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.
JE Squires et al. JPGN 2020; 70: 79-86. Using a prospective, longitudinal database, this study from ChiLDReN network with 93 children with biliary atresia and native liver found that NO increased prevalence of neurodevelopmental delays. Markers of advanced liver disease (high bilirubin/GGT for those ≤5 yrs, and portal hypertension for those >5 years) did negatively affect neurodevelopmental measures.
C Jaramillo et al. JPGN 2020; 70: 87-92. This pilot study with 21 patients found that degree of fibrosis, quantified by collagen hybridizing peptide, at time of Kasai, was associated with the risk of requiring a liver transplantation by age 4 years. Total bilirubin >2 mg/dL and Albumin ❤ g/dL at 3 months post-Kasai were also associated significantly with need for liver transplantation.
H-S Chen et al. Hepatology 2019; 70: 1903-12. In this study from Taiwan with 182 children (median age of 10.6 at enrollment) with hepatitis B and a normal ALT, a baseline anti-HBc titer of >500 IU/mL was associated with spontaneous HBeAg seroconversion with hazard ratio of 2.81. Over the median follow-up of 19.8 years, 85 subjects (46.7%) had HBeAg seroconversion. Thus, anit-HBc reflects anti-HBV immune response in the HBeAg-positive patients with normal ALT.
Although I was unable to attend this year’s liver symposium at NASPGHAN19, I reviewed the lecture notes. There is some terrific content. Here are some of the slides (borrowed with permission from NASPGHAN).
P Rosenthal et al. Hepatology 2019; 69: 2326-37. This study examined the efficacy and safety of combined entecavir and Peginterferon for immune-tolerant chronic hepatitis B-infected children (n=60). 48 weeks after completing treatment (week 96), 2 children (3%) achieved the primary outcome of undetectable HBeAg with HBV DNA levels <1000 IU/mL. These two children were also HBsAg negative/anti-HBs positive. In the other children (55 completed study), the ALT and HBV DNA levels were similar to baseline. 37 children experienced adverse events. My take: Entecavir/peginterferon is not very effective in immune-tolerant children infected with chronic HBV.
DL Thomas. NEJM 2019; 380: 2041-50. This article reviews the pathway to the global elimination of chronic hepatitis. Currently, it is estimated that hepatitis C virus (HCV) and hepatitis B virus (HBV) kill more than 1 million persons each year. “In fact, by 2040, deaths from chronic hepatitis are projected to exceed the combined mortality associated with HIV infection, tuberculosis, and malaria.”
JR Dillman et al. J Pediatr 2019; 212: 60-5. This study with 41 patients and 13 patients with biliary atresia prospectively assessed ultrasound shear wave elastography (SWE). The authors found that SWE with a cut-off value of >1.84 m/s had 92% sensitivity and 79% specificity. Also, in their cohort, GGT >320 had a sensitivity of 100% and specificity of 78%.
Z Younossi et al. Hepatology 2019; 69: 2672-82. This review provides a global perspective of NAFLD. 25% of the world’s population is currently thought to have NAFLD with highest prevalence in South America at 30.45% and lowest in Africa at 13.5%. This article usggest North America to have 24.1% prevalence rate.
YH Yeo et al. Hepatology 2019; 69: 1385-97. The prevalence of high risk individuals in the U.S. who are susceptible (not immune) to hepatitis B has decreased from 83% to 69% from 2003 to 2014. That still leaves 64 million who would benefit from HBV vaccination.
M Sharma et al.Hepatology 2019; 69: 1657-75. This meta-analysis compared therapies for primary prevention of esophageal varices and concluded that nonselective beta-blocker (NSBB) monotherapy may decrease all-cause mortality and carried a lower risk of serious complications than variceal band ligation (VBL). However, the commentary (1382-84 by L Laine) reaches a different conclusion. “Current recommendations for primary prevention with VBL or NSBB or carvediolo still appear to be acceptable…using a shared decision-making approach” to weigh issue such as daily medication or periodic endoscopy.
J Nguyen et al. J Pediatr 2019; 207: 90-6. This study modeled the cost-effectiveness of early treatment with direct-acting antiviral therapy in adolescents with hepatitis C infection. With pangenotypic agenst, the cost would be $10000 to $21000 per QALY gained.
S Trinh et al. Clin Gastroenterol Hepatol 2019; 17: 948-56. This retrospective hepatitis B study examined the changes in renal function between 239 tenofovir disoproxil fumarte (TDF) treated patients and 171 entecavir treated patients. Key finding: TDF was not associated with higher risk of worsening renal function in this cohort with a mean followup of 43-46 months in patients with baseline normal renal function. In patients with renal impairment, deterioration of renal function was noted in TDF-treated patients. Thus, TDF should be avoided in patients with impaired renal function.
A recent study (WJ Jeng et al. Hepatology 2018; 68: 425-34) indicates that many patients with Hepatitis B e Antigen-Negative Chronic Hepatitis B benefit from a finite treatment with oral antivirals.
These findings are discussed by P Lampertico and T Berg (editorial 397-400). In the Jeng study, the investigators prospectively followed the effect of antiviral cessation in 691 individuals after patients had undetectable HBV DNA and met Asian Pacific Association for the Study of Liver guidelines for stopping. HBsAg clearance occurred in 13% who discontinued therapy compared to 3% during nucleos(t)ide treatment. The authors note that virologic relapse occurred in 79% and that the immune system activation driven by clinical relapse can be beneficial in yielding a cure. Clinical decompensation was infrequent and most could be retreated; three patients with cirrhosis and decompensation died
My take: These studies show that in carefully-selected and carefully-monitored patients with HBeAg-negative chronic hepatitis B infection, it is feasible to successfully stop oral antiviral therapy.
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
A recent prospective study (C-J Liu et al. Gastroenterol 2018; 154: 989-97) provided some reassurance about the likelihood of hepatitis B virus (HBV) reactivation during hepatitis C virus (HCV) treatment with direct-acting antivirals (DAA).
In this study with 111 patients with both HCV and HBV treated with ledpasvir/sofusbuvir, all (100%) of the patients had a sustained virologic response for their HCV infection. Other key findings:
Of the 37 patients with baseline HBV DNA < 20 IU.mL, 31 (84%) developed detectable HBV DNA levels through posttreatment week 12.
Of the 74 patients with baseline HBV DNA >20 IU/mL, 39 (53%) developed increases in HBV DNA >1 log10 IU/mL through posttreatment week 12.
5 patients developed ALT >2 times ULN and 3 patients were started on HBV therapy.
The associated editorial (pgs 795-8) made the following recommendations:
“HBsAg-negative/HBcAb-positive patients should be monitored with ALT alone until SVR12 and should be tested with HBsAg +/- HBV DNA only if ALT increases or fails to normalize on therapy.”
“HBsAg-positive patients with undetectable baseline HBV DNA should be considered for preemptive anti-HBV treatment, or monitored with ALT and HBV DNA until SVR12”
“HBsAg-positive patients with positive baseline HBV DNA should be started on preemptive anti-HBV treatment until SVR12.”
Using the above management strategy will limit the number of HBV-infected patients who need to be treated.
My take: This study and the associated editorial provide useful information regarding DAA in coinfected HBV/HCV patients; this is important for patients and practitioners, especially given the black box warning on DAA medications.
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.