Treatment of Chronic Hepatitis B Virus

Infection with Nucleic Acid Polymers

April 6, 2020
Atif Zaman, MD, MPH reviewing Bazinet M et al. Gastroenterology 2020 Mar 5
NAP-based combination therapy with REP 2139 or REP 2165 was shown to be safe and associated with
high rates of functional cure in a phase II study.
Although we have effective treatment to suppress hepatitis B virus (HBV) infection, clearance of
infection is rare. Nucleic acid polymers (NAPs), such as REP 2139 and REP 2165, inhibit assembly and
secretion of HBV subviral particles. To evaluate the use of NAP-based treatment for HBV infection,
international investigators conducted an industry-supported, open-label, randomized, controlled, phase
II study of 40 treatment-naive patients with HBeAg-negative chronic HBV infection.
Patients initially received 24 weeks of tenofovir disoproxil (TDF) and were then randomized to receive
either 48 weeks of NAP-based treatment (TDF) plus peginterferon plus REP 2139 or REP 2165 or 24
weeks of control treatment (TDF plus peginterferon) followed by 48 weeks of NAP-based treatment.
Thereafter, all patients were followed off treatment for 48 weeks. The primary outcome was safety,
and secondary outcomes included virologic control (HBsAg positive, HBV DNA<2000 IU/mL, normal
ALT) and functional cure (HBsAg level <0.05 IU/mL, HBV DNA undetectable, normal ALT) after
completion of therapy.
Regarding safety, no differences between NAP-based treatment versus control treatment were noted,
except that NAP-based treatment was associated with higher rates and degrees of transaminases
elevations (P<0.001 and P=0.002, respectively); however, these elevations were asymptomatic and
eventually normalized. Virologic control was achieved in 33% of patients, and 35% had functional cure
and persistent HBsAg seroconversion.

COMMENT
Previous studies that evaluated NAP monotherapy did not demonstrate long-term functional cure of
HBV infection. In this study, with the addition of a nucleos(t)ide and peginterferon, durable cure was
seen in a third of patients. Safety of this combination therapy was no different than what is seen with
interferon treatment in this population. Larger studies with longer-term follow-up are needed.

Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form
and that subsequent changes might be made.

https://www.jwatch.org/na51234/2020/04/06/treatment-chronic-hepatitis-b-virus-infection-with-
nucleic?query=topic_hepatitis&jwd=000013540748&jspc=GP
May 1, 2020

Plasma Biomarkers May Identify Risk for

Dementia
Jennifer Rose V. Molano, MD reviewing de Wolf F et al. Brain 2020 Apr 1
Plasma amyloid and neurofilament levels were associated with dementia risk in a population-based
cohort.
Assessment of plasma biomarkers is emerging as a potential noninvasive way to determine risk for
dementia. To further evaluate the utility of plasma biomarkers in this setting, researchers analyzed
whether plasma amyloid-β40, amyloid β42, total tau, and neurofilament light chain (NfL) levels were
associated with all-cause dementia and Alzheimer disease (AD) risk in 4444 participants without
dementia in the Rotterdam population-based cohort study. At baseline, the average age of participants
was 72 years, 9% had mild cognitive impairment (MCI), 58% were female, and 26% were
apolipoprotein ℇ4 carriers.
During a median follow-up of ≈7 years, key results were as follows:
 ≈12% of participants developed incident dementia, among whom 68% had AD.
 In adjusted analyses, higher plasma NfL levels were associated with a 54% greater risk for all-
cause dementia and a 49% greater risk for AD dementia.
 Higher amyloid-β42 levels were associated with a 40% decreased risk for all-cause dementia
and AD.
 The associations between plasma NfL and amyloid-β42 levels and dementia risk remained
present after excluding participants with low baseline-screening cognitive test results or MCI.
 Baseline total tau and amyloid-β40 levels were not significantly associated with risk for
dementia.
 A combination of the highest-quartile NfL levels and the lowest-quartile amyloid-β42 levels
conferred a nearly 10-fold increased risk for all-cause dementia and a nearly 16-fold increased
risk for AD compared with a combination of the lowest-quartile NfL levels and the highest-
quartile amyloid-β42 levels.
 Faster rates of change in NfL levels were seen in those who developed AD and had begun to
deviate from a dementia-free cohort approximately 10 years before AD diagnosis.
 Rates of decline in plasma amyloid-β42 levels were not significantly different between those
who developed AD and those who did not.

COMMENT
Assessing plasma biomarker levels continues to show promise as a noninvasive way to identify risk for
dementia. Interestingly, contrary to a prior report (NEJM JW Neurol Jun 2019 and JAMA Neurol 2019;
76:598), plasma total tau levels were not associated with incident dementia. As the researchers
suggest, total tau levels may be more prominent during later stages of the disease. The results of this
study also support following NfL levels in neurodegenerative disease (NEJM JW Neurol Feb 2019 and
JAMA Neurol 2019; 76:318). Higher plasma NfL levels and lower amyloid-β42 levels in combination may
be particularly useful in determining dementia and AD risk. Correlating these results with trajectories
of cognitive performance also may be helpful clinically.

https://www.jwatch.org/na51360/2020/05/01/plasma-biomarkers-may-identify-risk-dementia?
query=etoc_jwneuro&jwd=000013540748&jspc=GP