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Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015 Mar.

Cover of Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection

Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection.

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APPENDIX 1PICO questions

PICO questions

PICO 1a
Vaccination		Among persons at high risk of acquisition of hepatitis B, what are the most effective hepatitis B screening and vaccination strategies?
PHousehold and sexual contacts of HBsAg-positive persons (includes HIV-infected and HIV-negative or unknown HIV status)
IDifferent active screening and hepatitis B vaccination strategies
CNo active screening or HBV vaccination
ONew HBsAg-positive transmissions among contacts; identification of existing HBsAg-positive cases; number of cases referred for care; number of cases referred for vaccination; number completed vaccination course; number hepatitis B immune; potential harms of screening (disclosure, stigmatization); cost; cost-effectiveness
PICO 1b
Vaccination		Among HIV-infected persons, what are the most effective hepatitis B vaccination strategies?
PHIV-positive adults, adolescents and children
IAny hepatitis B vaccination strategy (e.g. double dose, additional booster doses, decreased dose interval)
CAny hepatitis B vaccination strategy (including different time intervals) or no vaccination
OImmunogenicity (sAb titre); HBV DNA positivity; HBeAg seropositivity; HBsAg seropositivity; adverse events of vaccination (any); cost-effectiveness
PICOT 2a
Who to Treat?		Among HBsAg-positive persons, what factors/tests best identify individuals at highest risk of progression, as well as those at very low risk of progression?
PHBsAg-positive persons
IKey permutations of key baseline risk factors from studies of prognosis: clinical factors only (age, cirrhosis/fibrosis); clinical plus ALT: clinical plus ALT and HBV DNA:
Sample stratifications include: age >40 vs <40 years; HBeAg-positive vs -negative; cirrhosis (compensated or decompensated) vs no cirrhosis; fibrosis (METAVIR 1-3) vs no fibrosis; HBV DNA (any positive or unknown, or >2000 or >20 000 IU/mL or >106 copies/mL) vs undetectable; ALT (>2x ULN or >ULN) vs normal
CAbsence of these baseline factors
OLiver-related morbidity (fibrosis, cirrhosis, end-stage liver disease, hepatocellular carcinoma); progression of liver disease; mortality
TAnnual progression and mortality
PICOT 2b
Who to Treat?		Among HBsAg-positive persons, what factors/tests best identify individuals with greatest benefit of treatment, and least benefit from treatment in those with and without access to laboratory tests?
PHBsAg-positive persons stratified according to key baseline prognostic factors and : clinical factors only (age, cirrhosis/fibrosis); clinical plus ALT: clinical plus ALT and HBV DNA:
sample stratifications include:
Age >40 vs <40 years; HBeAg positive vs. negative; cirrhosis (compensated or decompensated) vs no cirrhosis; Fibrosis (METAVIR 1-3) vs no fibrosis; HBV DNA (any positive or unknown, or >2000 or >20 000
IU/mL or >106 copies/mL) vs undetectable; ALT (>2x ULN or >ULN) vs normal
IHBV antiviral treatment
CNo HBV treatment
OHBeAg seroconversion; HBsAg loss; undetectable HBV DNA; liver-related morbidity (fibrosis, cirrhosis, end-stage liver disease); progression of liver disease; reversion of fibrosis stage; mortality; severe adverse effects; antiviral resistance
TAnnual progression and mortality
PICOT 3a
What treatment to use?		What is the most effective regimen for the treatment of chronic hepatitis B infection?
PTreatment-naïve HBsAg-positive persons (stratified by HIV status, and different permutations of baseline risk factors from treatment studies, including HBeAg status, present or absence of cirrhosis, fibrosis stage, HBV DNA level
IHBV treatment with highly active medicines and a high barrier to resistance (tenofovir and entecavir)
CHBV treatment with other medicines with a low barrier to resistance (lamivudine, telbivudine or adefovir)
OHBeAg seroconversion; HBsAg loss; undetectable HBV DNA; liver-related morbidity (fibrosis, cirrhosis, end-stage liver disease); progression of liver disease; reversion of fibrosis stage; mortality; severe adverse effects; antiviral resistance; cost; cost-effectiveness
TAnnual progression and mortality
PICOT 3b
Management of treatment failure		What is the most effective regimen for management of treatment failure?
PHBsAg-positive persons previously treated with HBV regimens with a low barrier to resistance (lamivudine, telbivudine or adefovir)
IHBV treatment with highly active medicines and a high barrier to resistance (tenofovir and entecavir)
CContinuation of HBV treatment regimens with a low barrier to resistance (lamivudine, telbivudine or adefovir)
OLiver-related morbidity (fibrosis, cirrhosis, end-stage liver disease); progression of liver disease; reversion of fibrosis stage; mortality; HBeAg seroconversion; HBsAg loss; undetectable HBV DNA; severe adverse effects; antiviral resistance; cost; cost-effectiveness
TAnnual progression and mortality
PICOT 4
Treatment duration		What criteria should be used to decide when to stop treatment?
PHBsAg-positive persons receiving HBV treatment
IDifferent criteria for discontinuation of HBV treatment (HBeAg seroconversion, HBsAg loss, undetectable HBV DNA)
CContinuation of HBV treatment for 1, 2, 3, 4, 5 years or more
OLiver-related morbidity (fibrosis, cirrhosis, end-stage liver disease); progression of liver disease; mortality; HBeAg reversion and hepatitis flare; severe adverse effects; antiviral resistance
PICOT 5a
Monitoring		What is the optimal frequency of monitoring for disease progression?
PHBsAg-positive persons stratified according to baseline disease stage (cirrhosis, fibrosis stage, eAg status, HIV status)
IAnnual clinical evaluation or symptom-based referral
CSix-monthly comprehensive evaluation with fibrosis assessment, ALT, eAg status and HBV DNA
OLiver-related morbidity (fibrosis, cirrhosis, end-stage liver disease); progression of liver disease; mortality at different time points
PICOT 5b
Monitoring		What is the optimal nature and frequency of monitoring for toxicity in patients receiving tenofovir?
PHBsAg-positive persons receiving tenofovir stratified by age, gender, pregnancy status, HIV status and baseline disease stage (cirrhosis, fibrosis stage)
ISymptom-based referral versus laboratory/other monitoring
CLaboratory/other monitoring
ORenal impairment, bone mineral density decline (osteoporosis, osteopenia)
PICOT 6
Monitoring for HCC		What is the most effective monitoring strategy to identify HCC early in people with chronic HBV?
PPeople with chronic hepatitis B viral infection, defined by the persistence of HBsAg for more than six months
IScreening using the following methods or combinations: liver ultrasound scan (USS); serum alpha-fetoprotein (AFP); liver USS and serum AFP
CThe screening interventions listed above or no intervention
ONew diagnosis of hepatocellular carcinoma; disease-specific mortality; all-cause mortality; lesion or hepatocellular carcinoma size (< 3cm in diameter; ≥ 3cm in diameter); liver cancer stage; cost-effectiveness
PICOT 7
PMTCT		What is the most effective antiviral therapy during the third trimester of pregnancy, to reduce transmission of HBsAg?
PPregnant women in the third trimester of pregnancy (defined as 27–40 weeks gestation) with chronic hepatitis B virus infection (positive for HBsAg persistently for more than 6 months) (stratified by HBeAg status)
IMaternal treatment with the following drugs or drug combinations during third trimester of pregnancy (with or without use of birth dose vaccine): tenofovir; lamivudine; telbivudine; emtricitabine plus tenofovir/tenofovir plus emtricitabine; entecavir; adefovir)
CInterventions listed above versus each other (either as monotherapy or combination therapy), placebo or no intervention
ONewborn (0–9 months) and infant (9–15 first months) HBV DNA positivity; newborn and infant HBeAg seropositivity; newborn and infant HBsAg seropositivity; congenital abnormalities; adverse events (maternal (any); infant (any); infant (serious adverse events); cost-effectiveness
PICOT 8
Non-invasive assessment of liver disease stage		How should staging of liver disease be carried out in persons with HBV infection?
PPersons with chronic hepatitis B infection
INon-invasive assessment of liver fibrosis using FIB-4, APRI (AST-to-platelet index), FibroTest or FibroScan
CLiver biopsy
ODiagnostic accuracy of non-invasive tests for staging fibrosis
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