Assessment and Simplification of Treatment Eligibility Among Patients With Chronic Hepatitis B Infection in Vietnam
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Clinical Infectious Diseases
MAJOR ARTICLE
Assessment and Simplification of Treatment Eligibility
Among Patients With Chronic Hepatitis B Infection
in Vietnam
Vinh Vu Hai,1,a Yusuke Shimakawa,2,a, Jin Kim,3 Hai Do Ngoc,4 Quang Le Minh,5 Didier Laureillard,6,7 and Maud Lemoine3
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1
Infectious and Tropical Diseases Department, Viet Tiep Hospital, Hai Phong, Vietnam, 2Unité d’Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France, 3Department of Metabolism,
Digestion and Reproduction, Division of Digestive Diseases Section of Hepatology, Imperial College London, London, United Kingdom, 4Point of Care Laboratory, Viet Tiep Hospital, Hai Phong,
Vietnam, 5Hospital Management Department, Viet Tiep Hospital, Hai Phong, Vietnam, 6Pathogenesis and Control of Chronic Infections, Inserm U1058, Etablissement Français du Sang, University of
Montpellier, Montpellier, France, and 7Infectious and Tropical Diseases Department, Caremeau University Hospital, Nîmes, France
Background. Treatment eligibility and the accuracy of its simplified criteria have been poorly documented in patients with
chronic hepatitis B virus (HBV) infection worldwide, especially in low- and middle-income countries.
Methods. From a cohort of HBV-infected patients in Vietnam, we assessed the proportion of patients eligible for treatment using the
national guidelines based on reference tests (HBV DNA quantification and FibroScan); and the accuracy of simplified treatment criteria
free from HBV DNA and FibroScan (Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score and simplified World
Health Organization [WHO] criteria) to select patients for antiviral therapy using the national guidelines as a reference.
Results. We analyzed 400 consecutive treatment-naïve HBV-monoinfected patients: 49% males, median age 38 years (range,
18–86), 32% hepatitis B e antigen-positive, median HBV DNA 4.8 log10 IU/mL (undetectable −8.4), median FibroScan 5.3 kPa
(3.0–67.8), and 25% having significant liver fibrosis including 12% with cirrhosis. Of these, 167 (42%) fulfilled treatment criteria ac-
cording to national guidelines. Using the national criteria as a reference, the performance of TREAT-B to select patients for treatment
was high (area under the receiver operating characteristic [AUROC], 0.89 [95% confidence interval 0.87-0.92]) with a sensitivity
of 74.3% and a specificity of 88.4%. In a subset of patients with 2 alanine aminotransferase measurements over a 6-month period
(n = 89), the AUROC of TREAT-B was significantly higher than that of the simplified WHO criteria (P < .001).
Conclusions. Our study suggests that a large proportion of patients with chronic HBV infection require antiviral therapy in
Vietnam. Compared with the simplified WHO criteria free from HBV DNA quantification, TREAT-B is a better alternative to easily
indicate treatment eligibility and might help scale up treatment intervention in Vietnam.
Keywords. hepatitis B; treatment; simplification; Vietnam.
Chronic infection with hepatitis B virus (HBV) affects 292 mil- to assess these conditions (ie, nucleic acid test to measure HBV
lion people worldwide and is responsible for 887 000 deaths DNA levels and liver biopsy or liver elastography [FibroScan])
annually, mainly from cirrhosis and hepatocellular carcinoma to evaluate fibrosis stage are expensive and hardly accessible in
(HCC) [1]. most low- and middle-income countries (LMICs) [7, 8].
In 2016, the World Health Organization (WHO) set up an To address this issue and improve treatment coverage in
ambitious strategy to eliminate viral hepatitis as a public threat LMICs, in its 2015 guidelines, the WHO added a conditional
by 2030 [2, 3]. In patients with chronic HBV infection, antiviral recommendation to consider treatment based on persistently
treatment initiation is generally recommended if moderate or abnormal alanine transaminase (ALT) levels alone, if HBV DNA
severe liver inflammation and/or fibrosis coexist with an on- testing is not available [6]. Without undertaking expensive tests
going viral replication [4–6]. However, the recommended tools (HBV DNA quantification and FibroScan), antiviral treatment
can be initiated in (1) case of cirrhosis defined clinically or bi-
ologically using aspartate aminotransferase-to-platelet ratio
Received 14 July 2020; editorial decision 11 November 2020; published online 17 December index > 2.0 or (2) case of persistently elevated ALT on 3 ALT
2020.
a
V. V. H. and Y. S. contributed equally to this work.
measurements over a period of 6 to 12 months [6].
Correspondence: M. Lemoine, Division of Digestive Disease, Department of Metabolism, Recently, we developed a simple score named Treatment
Digestion and Reproduction, Liver Section, 10th Floor QEQM Building, St Mary’s Hospital,
Imperial College London, South Wharf Road, London, W2 1NY, UK (m.lemoine@imperial.ac.uk).
Eligibility in Africa for the Hepatitis B Virus (TREAT-B), free
Clinical Infectious Diseases® 2021;XX(XX):1–6
from HBV DNA quantification and liver fibrosis measure-
© Crown copyright 2020. This article contains public sector information licensed under the Open ments, based on only serum hepatitis B e antigen (HBeAg)
Government Licence v3.0 (http://www.nationalarchives.gov.uk/doc/open-government-licence/
serostatus and ALT levels [9], and found higher accuracy of
version/3/).
DOI: 10.1093/cid/ciaa1814 TREAT-B compared with the simplified WHO treatment
Simplified Hepatitis B Virus Treatment Criteria in Vietnam • cid 2021:XX (XX XXXX) • 1criteria to identify HBV-infected African patients who require FibroScan (FibroScan 402, Echosens, France) was unreliable,
antiviral therapy [9]. The performance of TREAT-B score for defined as a ratio of interquartile range divided by the median
the identification of patients with chronic HBV infection in LSM exceeding 0.3, when the LSM was ≥7.1 kPa. FibroScan
need of antiviral therapy has been also assessed in subsequent was performed in a fasting state in all patients. Liver transamin-
African, European, and Australian studies [10–15]; however, ases (ALT, aspartate transaminase) levels were measured locally
this has never been assessed in an Asian country. at the biochemistry laboratory, HBeAg was detected using a
The HBV burden is of particular importance in Asia, where rapid point-of-care test (SD Bioline, South Korea), and HBV
>75% of people chronically infected with HBV worldwide re- DNA was measured using an in-house reverse transcriptase-
side and from where >70% of new HCC cases diagnosed world- polymerase chain reaction (Viet-A Corp., Vietnam) approved
wide arise [16]. The current HBV treatment coverage is below by the Vietnamese Ministry of Health, with a lower limit of de-
5% in most Asian LMICs [1, 17], making unrealistic the in- tection of 50 IU/mL. The study was approved by the local ethics
Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1814/6040789 by guest on 11 May 2021
crease of treatment coverage to 80% by 2030 as recommended committee (ref 03/QĐ-BVVT-HĐKH).
by WHO [1, 2].
Vietnam is highly endemic for HBV infection with an es- National Hepatitis B Treatment Guidelines
timated prevalence >8% in the general adult population [18] The treatment criteria recommended by the Vietnamese na-
and up to 15% in subgroups such as people who inject drugs tional guidelines largely depend on HBV viral load measure-
or female sex workers [17]. In 2017, Vietnam accounted 15 868 ment, ALT level, and fibrosis staging using liver histopathology
deaths attributable to HBV; between 2007 and 2017, the number or LSM. These criteria are summarized in Supplementary Table
of deaths from cirrhosis increased by 26.5%, with HBV being 1. In case of compensated/decompensated cirrhosis, antivirals
the main cause. are indicated if HBV DNA is detectable, regardless of ALT
In 2015, the Vietnamese Ministry of Health developed a na- levels and HBeAg status. In case of noncirrhosis, antivirals are
tional strategic plan for viral hepatitis and released guidelines indicated if patients fulfilling both of these criteria: (1) liver
for the diagnosis and treatment of chronic hepatitis B. These disease, defined as ALT >2× upper limit of normal (ULN)
guidelines based on complex and expensive tests are difficult to or liver fibrosis ≥F2; and (2) high viral replication, defined
implement in remote and rural areas. Moreover, the proportion as HBV DNA ≥20 000 IU/mL for HBeAg-positive patients
of HBV-infected subjects in need of antiviral therapy according and HBV DNA ≥2000 IU/mL for HBeAg-negative patients.
to these national guidelines or international criteria has never For those not meeting either of these 2 criteria, antivirals are
been documented in Vietnam. indicated for the following conditions: (1) >30 years of age,
We aimed to fill this gap by assessing, in a cohort of with persistently abnormal ALT >ULN (at least 3 times over
treatment-naïve HBV monoinfected patients in Hai Phong, a period of 24–48 weeks) and HBV >20 000 IU/mL, regard-
Northern Vietnam: (1) the proportion of patients with signif- less HBeAg status; (2) family history of HCC or cirrhosis; (3)
icant liver disease in need of antiviral therapy and (2) the accu- presenting extrahepatic manifestations such as glomerulone-
racy of simplified criteria free from HBV DNA quantification phritis, polyarthritis, cryoglobulinemia, polyarteritis nodosa,
and FibroScan (TREAT-B score and the simplified WHO treat- etc.; and (4) relapse after stopping HBV antivirals. In this
ment criteria) to select patients for antiviral therapy using the analysis, we defined significant fibrosis and cirrhosis for the
national treatment criteria as a reference. national treatment eligibility criteria as Metavir ≥F2 and F4
using LSM cut-offs of >7.0 and >11.0 kPa, respectively [19].
In the national guidelines, the ULN for ALT were defined as
METHODS
25 IU/L for women and 35 IU/L for men; these are similar
Study Population thresholds as the American Association for the Study of Liver
We conducted a retrospective analysis using an electronic re- Diseases [20].
cord system of all adult patients who attended the outpatient
liver clinic at Viet Tiep hospital, Northern Vietnam, from the Simplified Criteria
1 January 2017 to 31 December 2018. This hospital is the re- In the WHO guidelines, there are 2 types of treatment criteria:
ferral hospital for HBV infection in the region. We excluded those with or without HBV DNA quantification [6]. Because
from the analysis patients with prior or current HBV antiviral our aim was to evaluate treatment eligibility criteria free from
treatment, co-infection with hepatitis C virus (HCV) or human HBV DNA measurement, we only considered the latter for
immunodeficiency virus, pregnancy, HCC, and intrahepatic this analysis (Supplementary Table 1). In these criteria without
mass, or missing clinical or virological data. Coinfection with HBV DNA, treatment is indicated for: (1) decompensated cir-
hepatitis D virus (HDV) was however not excluded because rhosis diagnosed by physical examination or cirrhosis using
HDV serology is not done routinely in Vietnam. We also ex- aminotransferase-to-platelet ratio index >2.0 or (2) persistently
cluded patients whose liver stiffness measurement (LSM) using elevated ALT alone. The ULN for ALT recommended by the
2 • cid 2021:XX (XX XXXX) • Vu Hai et alWHO were applied for these criteria: 19 IU/L for women and in accordance with the Standards for Reporting of Diagnostic
30 IU/L for men [6]. Accuracy.
TREAT-B score is obtained by adding the HBeAg score (negative
[0 point] or positive [1 point]), and ALT score (200 000 IU/mL, and the simplified WHO criteria indicated to
ALT level more than 6 months apart. Within this subgroup, 39
treat those having “persistently abnormal ALT” irrespective of
were men (39.8%), the median age was 40 years (range, 18–79),
age or HBV DNA levels. Because the WHO treatment criteria
29 (32.6%) were HBeAg positive, with a median viral load of
require longitudinal data, we restricted the analysis of the per-
5.4 log10 IU/mL (range, undetectable −7.9), and 37 (41.5%) had
formance of the simplified WHO treatment criteria in the sub-
clinically significant liver fibrosis including 23 (25.8%) with cir-
group of patients with repeated ALT measurement.
rhosis (Table 1).
The performances of the simplified criteria (TREAT-B and
WHO) were assessed using the national guidelines as the “gold HBV Treatment Eligibility and Performance of TREAT-B Score and the WHO
standard,” and the area under the receiver operating character- Simplified Criteria
istic (AUROC), sensitivity, and specificity were calculated. In the entire study population, the number of patients eligible
Statistical analysis was performed using STATA, version for treatment was 167 (41.8%) according to the Vietnamese
14.2 (StataCorp, College Station, TX). Results were reported guidelines. Using the TREAT-B score (cutoff ≥ 2), a larger
Figure 1. Study flow chart. Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular cancer; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HBsAg, hepatitis
B s antigen.
Simplified Hepatitis B Virus Treatment Criteria in Vietnam • cid 2021:XX (XX XXXX) • 3Table 1. Characteristics of the Study Population (n = 400) by the Number of ALT Measurements
Entire Cohort With 2 ALT Measure- With 1 ALT Measure- P
Variables (N = 400) ments (n = 89) ment (n = 311) Value
Median age (y) … 38 (18–86) 40 (18–79) 37 (18–86) .25
Male, n (%) … 195 (48.8) 39 (43.8) 156 (50.2) .29
Median HBV viral load (log10 IU/mL) … 4.8 (undetect- 5.4 (undetectable −7.9) 4.4 (undetectable −8.4) .04
able −8.4)
Positive HBeAg, n (%) … 128 (32.0) 29 (32.6) 99 (31.8) .89
Median first ALT (IU/L) … 44 (10–456) 69 (10–456) 40 (12–356)Table 3. Performance of the Simplified Criteria to Select Patients Eligible for Antiviral Therapy in Reference to the Vietnamese National Guidelines in a
Subgroup of Patients With 2 ALT Measurements Over 6 Months (n = 89)
TREAT-B Simplified WHO Criteria Without HBV DNA
AUROC 0.87 (0.80–0.94) 0.63 (0.55–0.71)
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