THE CHB TREATMENT GUIDELINE NAVIGATOR REVIEW AN ONLINE INTERACTIVE GUIDE FOR CLINICIANS FEATURING EXPERT AUDIO COMMENTARY

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1 The Americn Assocition for the Study of Liver Diseses () nd the Europen Assocition for the Study of Liver Disese () provide clinicl prctice guidelines for the mngement nd tretment of chronic heptitis B (CHB). This summry sheet provides quick reference for key recommendtions from both guidelines nd ccompnies the full online progrm, the CHB Tretment Guideline Nvigtor Online Interctive Review. The CHB Tretment Guideline Nvigtor Review discusses the recommendtions provided by the nd guidelines in more detil nd includes expert udio commentry on the prcticl clinicl implictions of the specific recommendtions. CHB SCREENING AND TESTING GUIDELINES SUMMARY SHEET Who to screen Persons born in countries with HBsAg prevlence >2% (intermedite to high HBV endemicity) Unvccinted children of persons from countries with 8% prevlence (high HBV endemicity) Blood, orgn, plsm, semen, tissue donors Hemodilysis ptients All pregnnt women Infnts born to HBsAg-positive women Household contcts, needle-shring or sex prtners of HBV-infected persons Sources of blood or body-fluid exposures tht might wrrnt postexposure prophylxis HIV-infected nd HCV-infected persons Persons with select medicl conditions (eg, elevted ALT or AST levels of unknown etiology) Persons with behviorl exposures (eg, IDUs, MSM) No guidnce provided Which tests to use HBsAg nd nti-hbs No guidnce provided, Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; nti-hbs, ntibody to heptitis B surfce ntigen; AST, sprtte minotrnsferse; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; HCV, heptitis C virus; HIV, humn immunodeficiency virus; IDU, injection drug user; MSM, men who hve sex with men.

2 CHB DIAGNOSIS AND ASSESSMENT OF DISEASE GUIDELINES SUMMARY SHEET Initil evlution Liver biopsy Ptient history (including lcohol use), physicl exmintion, fmily history of HBV infection, liver disese, nd HCC Lb tests to ssess liver disese (heptic pnel, CBC with pltelets, nd prothrombin time) HBV DNA, HBeAg, nd nti-hbe ssys Test for HCV, HIV, nd HDV (in persons from countries where HDV is common or who hve injected drugs), nd for HAV (with vccintion for persons with CHB who re susceptible to HAV) Tests to screen for HCC-AFP; ultrsound in high-risk ptients Recommended for ptients who do not clerly meet criteri for tretment, evlute by: ge, HBV DNA levels, ALT levels (ULN: 30 ml for men, 19 ml for women), HBeAg sttus, nd clinicl fetures suggesting chronic liver disese or portl hypertension Consider for HBeAg-positive ptients with HBV DNA level >20,000 IU/mL And ALT level >2 ULN with compensted liver disese (biopsy before strting tretment) or ALT level 1-2 ULN for 3-6 months Or who re older thn 40 yers Or hve fmily history of HCC Consider for HBeAg-negtive ptients with HBV DNA level >2000 IU/mL nd ALT level 1 to >2 ULN Mesure biochemicl mrkers (AST, ALT, GGT, lkline phosphtse, bilirubin, nd serum lbumin nd globulins), blood counts nd prothrombin time, nd heptic ultrsound HBV DNA detection nd quntifiction ssys HCV, HIV, nd HDV tests; test those dignosed with CHB for nti-hav Assess for other cuses of chronic liver disese (eg, lcoholism, utoimmune, nd metbolic liver disese with stetoheptitis or stetosis) Consider for ptients in the immune-tolernt stge who re older thn 30 yers nd/or with fmily history of HCC or cirrhosis Consider for HBeAg-positive ptients with HBV DNA level >20,000 IU/mL nd ALT level >2 ULN; however, results usully do not chnge the decision to tret Consider for HBeAg-negtive ptients with HBV DNA level >20,000 IU/mL nd ALT level >2 ULN; however, results usully do not chnge the decision to tret Consider using noninvsive method to estimte the extent of fibrosis nd to identify cirrhosis for ptients who hve not hd biopsy but re strting tretment The recommendtions do not discuss dignosis but ssume ptients hve lredy been dignosed s hving HBeAg-positive or HBeAg-negtive CHB., Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; nti-hav, ntibody to heptitis A virus; nti-hbs, ntibody to heptitis B surfce ntigen; AST, sprtte minotrnsferse; CBC, complete blood count; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; GGT, gmm glutmyl trnsferse; HBeAg, heptitis B e ntigen; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; HCC, heptocellulr crcinom; HCC-AFP, heptocellulr crcinom-lph-fetoprotein; HCV, heptitis C virus; HDV, heptitis D virus; HIV, humn immunodeficiency virus; ULN, upper limit of norml.

3 CHB TREATMENT AND MANAGEMENT GUIDELINES SUMMARY SHEET Summry of nd criteri for tretment HBeAg positive HBV DNA level >20,000 IU/mL fter 3-6 month period of ALT level 1-2 ULN HBV DNA level >20,000 IU/mL nd older thn 40 yers with biopsy results showing moderte/severe inflmmtion or significnt fibrosis HBV DNA level >20,000 IU/mL fter 3-6 month period of ALT level >2 ULN HBeAg negtive HBV DNA level ,000 IU/mL nd ALT level 1-2 ULN: tret s needed HBV DNA level 20,000 IU/mL nd ALT level 2 ULN: tret if persistent HBeAg positive HBV DNA level >2000 IU/mL nd/or ALT level norml or >ULN nd liver histology showing moderte to severe liver histology: tret HBV DNA level >2000 IU/mL, in the immune-tolernt phse, nd older thn 30 yers with HCC fmily history or cirrhosis: consider tretment HBV DNA level >20,000 IU/mL nd ALT level >2 ULN: tret HBeAg negtive HBV DNA level >2000 IU/mL nd ALT level norml or >ULN with moderte to severe liver histology: tret HBV DNA level >2000 to <20,000 IU/mL nd no evidence of liver disese: tretment is not generlly recommended HBV DNA level >20,000 IU/mL nd ALT level >2 ULN: tret Cirrhosis (HBeAg-positive or -negtive) Compensted HBV DNA level >2000 IU/mL: tret HBV DNA level <2000 IU/mL nd elevted ALT level: consider tretment Undetectble HBV DNA level: monitor Decompensted Detectble HBV DNA level: coordinte ntivirl tretment with trnsplnt center Undetectble HBV DNA level: refer for trnsplnt Cirrhosis (HBeAg-positive or -negtive) Compensted with detectble HBV DNA level: tret t ny ALT level Decompensted: ll require urgent ntivirl tretment; coordinte with trnsplnt center, Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBeAg, heptitis B e ntigen; HBV, heptitis B virus; HCC, heptocellulr crcinom; ULN, upper limit of norml.

4 CHB TREATMENT AND MANAGEMENT GUIDELINES SUMMARY SHEET Summry of nd tretment-recommended gents First-line options Second-line options Compensted cirrhosis Decompensted cirrhosis ETV TDF PegIFN ADV LAM TVD IFN Tret with NAs; TDF or ETV preferred Tret promptly with NAs; TDF or ETV preferred Coordinte tretment with trnsplnt center Do not use IFN or pegifn ETV TDF PegIFN,b ADV LAM TVD IFN Tret with NAs; TDF or ETV preferred In well-compensted cirrhosis: pegifn cn be used Refer to specilized liver center; ptients my be cndidtes for liver trnsplnttion Use TDF or ETV Do not use IFN or pegifn Not to be used in pregnnt women, chemotherpy prophylxis, decompensted cirrhosis, nd cute infection. b Minly recommended for HBeAg-positive ptients with the best probbility of nti-hbe seroconversion., Americn Assocition for the Study of Liver Diseses; ADV, defovir; nti-hbe, ntibody to heptitis B e ntigen; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; ETV, entecvir; HBeAg, heptitis B e ntigen; IFN, interferon; pegifn, pegylted interferon; LAM, lmivudine; NA, nucleos(t)ide nlog; TDF, tenofovir disoproxil fumrte; TVD, telbivudine.

5 CHB TREATMENT AND MANAGEMENT GUIDELINES SUMMARY SHEET Summry of nd tretment durtion Tretment HBeAg positive HBeAg negtive IFN 4-12 months 48 weeks (pegifn only) NAs Response guided b 12 months c IFN 12 months 48 weeks (pegifn only) NAs Response guided d Long-term Compensted cirrhosis NAs Long-term e Long-term f Decompensted cirrhosis NAs Lifelong Lifelong PegIFN pproved for 12 months. b Tretment until HBeAg seroconversion occurs, HBV DNA is undetectble, nd for t lest 6 months fter nti-hbe develops. c Tretment for t lest 12 months fter nti-hbe seroconversion occurs nd my be continued until HBsAg clernce occurs, with or without development of nti-hbs. d Tretment until HBsAg clernce occurs. e Discontinution my be considered in HBeAg-positive ptients who seroconvert nd hve completed t lest 6 months of consolidtion therpy, nd in HBeAg-negtive ptients with confirmed HBsAg clernce. f Discontinution my be considered in HBeAg-positive ptients who seroconvert or hve confirmed HBsAg clernce with nti-hbs nd in HBeAg-negtive ptients with confirmed HBsAg loss nd nti-hbs seroconversion., Americn Assocition for the Study of Liver Diseses; nti-hbe, ntibody to heptitis B e ntigen; nti-hbs, ntibody to heptitis B surfce ntigen; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBeAg, heptitis B e ntigen; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; IFN, interferon; pegifn, pegylted interferon; LAM, lmivudine; NA, nucleos(t)ide nlog.

6 CHB TREATMENT AND MANAGEMENT GUIDELINES SUMMARY SHEET Summry of nd recommended tests nd timing for monitoring of ptients on IFN Timing Timing Test HBeAg sttus During tretment Post-tretment HBV DNA CBC HBeAg positive or HBeAg negtive Every 3 months until undetectble; then every 3-6 months +Absolute neutrophil nd pltelet count Every 2-4 weeks At Weeks 12 nd 24 for response; then t Week 48 +ALT Every 4 weeks TSH Every 12 weeks Every 12 weeks HBeAg HBeAg positive Every 6 months until HBeAg seronegtive; then initite testing for nti-hbe Following seroconversion to nti-hbe-positive, test for HBsAg every 12 months HBsAg HBeAg negtive Every 12 months fter sustined suppression of HBV DNA +Anti-HBe Weeks 24 nd months fter nti-hbe seroconversion if HBV DNA is undetectble Every 12 weeks for first 24 weeks Every 12 weeks for first 24 weeks Every 6 months fter HBeAg seroconversion if HBV DNA is undetectble; test ptients who become HBsAg negtive for nti-hbs Long-term follow-up is required for HBeAg-negtive ptients who chieve sustined response off-tretment t 1 yer due to the risk of disese rectivtion., Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; nti-hbe, ntibody to heptitis B e ntigen; nti-hbs, ntibody to heptitis B surfce ntigen; CBC, complete blood count; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBeAg, heptitis B e ntigen; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; IFN, interferon; TSH, thyroid-stimulting hormone.

7 CHB TREATMENT AND MANAGEMENT GUIDELINES SUMMARY SHEET Summry of nd recommended tests nd timing for monitoring of ptients on NAs HBV DNA ALT Test HBeAg sttus Timing Timing HBeAg positive or HBeAg Every 3 months until undetectble; then every 3-6 months Every 3 months until normlized; then every 3-6 months HBeAg HBeAg positive Every 6 months until HBeAg seronegtive; then initite nti-hbe testing Following seroconversion to nti-hbepositive, test for HBsAg every 12 months HBsAg HBeAg negtive Every 12 months fter sustined suppression of HBV DNA Renl monitoring At Week 12 to verify response; then every weeks +Anti-HBe Every 6 months Every 3 months for the first yer; if there is no worsening, then every 6 months For ptients t high risk: every month for the first 3 months; then every 3 months for the first yer; if there is no worsening, then every 6 months Less frequent monitoring my be considered in ptients treted with TDF or ETV if tretment efficcy nd dherence re confirmed., Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; nti-hbe, ntibody to heptitis B e ntigen; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; ETV, entecvir; HBeAg, heptitis B e ntigen; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; NA, nucleos(t)ide nlog; TDF, tenofovir disoproxil fumrte.

8 EVALUATING CHB TREATMENT RESPONSE GUIDELINES SUMMARY SHEET Biochemicl response Normliztion of ALT levels Normliztion of ALT levels Serologic response Virologic response Sustined response Primry nonresponse (only for NAs) Virologic relpse Histologic response Complete response Serologic response for HBeAg: HBeAg loss nd seroconversion to nti-hbe Serologic response for HBsAg: HBsAg loss nd development of nti-hbs Undetectble HBV DNA by sensitive PCR ssy Loss of HBeAg in those who were HBeAg positive Reduction in HBV DNA to undetectble levels by sensitive PCR ssy, nd loss of HBeAg in those who were HBeAg-positive for 12 months fter discontinution Reduction in HBV DNA by <2 log 10 IU/mL fter t lest 24 weeks of therpy At lest 2 tests more thn 4 weeks prt showing n increse in HBV DNA of 1 log 10 IU/mL fter discontinution of tretment Reduction in liver histology ctivity index by t lest 2 points nd no worsening of fibrosis score compred with pretretment histologicl findings Fulfill criteri of biochemicl nd virologic response with loss of HBsAg Serologic response for HBeAg: HBeAg loss nd seroconversion to nti-hbe Serologic response for HBsAg: HBsAg loss nd development of nti-hbs NAs: undetectble HBV DNA by sensitive PCR ssy IFN/pegIFN: HBV DNA level <2000 IU/mL Prtil virologic response (NAs only): reduction in HBV DNA level >1 log 10 IU/mL, but HBV DNA remins detectble fter t lest 24 weeks of therpy in dherent ptients HBV DNA level <2000 IU/mL for t lest 12 months fter discontinution <1 log 10 IU/mL reduction in HBV DNA level from bseline t 12 weeks of therpy No definition provided Reduction in necroinflmmtory ctivity by t lest 2 points with no worsening in fibrosis score compred with pretretment histologic finding Sustined off-tretment virologicl response together with loss of HBsAg, Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; nti-hbe, ntibody to heptitis B e ntigen; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBeAg, heptitis B e ntigen; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; IFN, interferon; pegifn, pegylted interferon; NA, nucleos(t)ide nlog; PCR, polymerse chin rection.

9 CHB IN SPECIAL POPULATIONS GUIDELINES SUMMARY SHEET Tretment of CHB ptients with HCV coinfection No guidnce provided Ptients should be treted for HCV Monitor HBV DNA levels Use NAs to tret ny HBV rectivtion tht occurs during or fter HCV tretment, Americn Assocition for the Study of Liver Diseses; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBV, heptitis B virus; HCV, heptitis C virus; NA, nucleos(t)ide nlog.

10 CHB IN SPECIAL POPULATIONS GUIDELINES SUMMARY SHEET Tretment of pregnnt women All children born to HBsAg-positive women must be given HBIg nd HBV vccintion immeditely fter delivery Administrtion of orl therpy to the newborn is not recommended Guidnce from is lcking on tretment of HBsAg-positive women during pregnncy All children born to HBsAg-positive women must be given HBIg nd HBV vccintion immeditely fter delivery For women with high HBV DNA levels (> IU/mL) in the third trimester, tretment with LAM, TVD, or TDF in combintion with HBIg dministrtion nd HBV vccintion of the newborn my be used to reduce the risk of intruterine nd perintl trnsmission If NA therpy ws dministered only to prevent perintl trnsmission, it my be discontinued within the first 3 months following delivery Monitor women for heptic flres if tretment is discontinued following delivery or if the women re untreted For ptients who become pregnnt during ntivirl therpy: Reevlute tretment indictions; ptients with dvnced fibrosis or cirrhosis should definitely continue to be treted, but those on pegifn should be stopped nd switched to NAs; ADV nd ETV should be chnged to ctegory B drug (TDF is preferred), Americn Assocition for the Study of Liver Diseses; ADV, defovir;, Europen Assocition for the Study of the Liver; ETV, entecvir; HBIg, heptitis B immune globulin; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; pegifn, pegylted interferon; LAM, lmivudine; NA, nucleos(t)ide nlog; TDF, tenofovir disoproxil fumrte; TVD, telbivudine.

11 CHB IN SPECIAL POPULATIONS GUIDELINES SUMMARY SHEET Tretment of ptients scheduled for immunosuppressive therpy or chemotherpy Screen ll cndidtes for chemotherpy or immunosuppressive therpy who re t high risk for HBV infection for HBsAg nd nti-hbc HBV crriers: initite prophylctic ntivirl therpy t the onset of chemotherpy or for finite course of immunosuppressive therpy Bseline HBV DNA level <2000 IU/mL: continue tretment for 6 months fter chemotherpy or immunosuppressive therpy completion HBV DNA level >2000 IU/mL: continue tretment for sme durtion s immunocompetent ptients If durtion of chemotherpy or immunosuppressive therpy is 12 months nd HBV DNA is undetectble, LAM or TVD my be used; for longer durtion of therpy, use TDF or ETV Do not use IFN HBsAg-negtive, nti-hbc- nd nti-hbs-positive or only nti-hbc-positive: monitor closely nd initite tretment when HBV DNA becomes detectble; prophylctic tretment is not currently recommended due to lck of informtion Screen ll cndidtes for chemotherpy or immunosuppressive therpy for HBsAg nd nti-hbc; vccinte ll HBV-seronegtive ptients HBsAg-positive or HBsAg-negtive + nti-hbc-positive + detectble HBV DNA: tret with NAs during therpy nd for 12 months fter HBV DNA level <2000 IU/mL: my consider LAM for short nd finite period of immunosuppressive therpy HBV DNA level >2000 IU/mL nd/or scheduled for longer or repeted cycles of immunosuppression: use TDF or ETV HBsAg-negtive, nti-hbc-positive with undetectble HBV DNA: follow closely, test nd HBV DNA nd ALT levels every 1-3 months, nd initite NA tretment on confirm of HBV rectivtion My consider LAM prophylxis for nti-hbs-negtive ptients nd/or if close monitoring of HBV DNA is uncertin, nd rituximb is to be used nd/or combined regimens for hemtologicl mlignncies For the most up-to-dte guidnce on tretment of HIV-positive ptients with CHB, plese consult the DHHS guidelines for the use of ntiretrovirl gents in HIV-1-infected dults nd dolescents, vilble t: Americn Assocition for the Study of Liver Diseses; ALT, lnine minotrnsferse; nti-hbc, ntibody to heptitis B core ntigen; nti-hbs, ntibody to heptitis B surfce ntigen; CHB, chronic heptitis B; DHHS, Deprtment of Helth nd Humn Services;, Europen Assocition for the Study of the Liver; ETV, entecvir; HBIg, heptitis B immune globulin; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus; LAM, lmivudine; NA, nucleos(t)ide nlog; TDF, tenofovir disoproxil fumrte; TVD, telbivudine.

12 CHB PREVENTING AND MANAGING ANTIVIRAL RESISTANCE GUIDELINES SUMMARY SHEET Tretment of ptients scheduled for immunosuppressive therpy or chemotherpy Prevention strtegies LAM resistnce ADV resistnce ETV resistnce TVD resistnce c TDF resistnce Select the most potent gent with the highest genetic brrier to resistnce; void unnecessry tretment Monitor HBV DNA levels every 3-6 months for ntivirl response Check for mediction dherence in ptients with virologic brekthrough Confirm ntivirl resistnce with genotypic testing Add ADV or TDF Stop LAM; switch to TDF + FTC Add LAM b Stop ADV; switch to TDF + FTC Switch to or dd ETV b Switch to TDF or TDF + FTC Add ADV or TDF Stop TVD; switch to TDF + FTC No guidnce provided Mnging resistnce Select the most potent gent with the highest genetic brrier to resistnce Monitor HBV DNA levels for ntivirl response Switch to TDF (dd ADV if TDF is not vilble) If ADV ws the first NA used in the ptient, switch to TDF or ETV; ETV my be preferred in such ptients with high viremi If the ptient hd prior LAM resistnce, switch to TDF nd dd n NA Switch to or dd TDF (dd ADV if TDF is not vilble) Switch to or dd TDF (dd ADV if TDF is not vilble) TDF resistnce hs not been detected to dte nd, therefore, there is no experience If resistnce is confirmed, possibly dd ETV, TVD, LAM, or FTC Switching to ETV be considered for ptients never treted with LAM; dding ETV my be the preferred option for ptients with prior LAM resistnce In HIV-coinfected persons; miniml dt re vilble in non-hiv-infected persons. b Durbility of virl suppression unknown, especilly in ptients with prior LAM resistnce. c Clinicl dt re not vilble., Americn Assocition for the Study of Liver Diseses; ADV, defovir; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; ETV, entecvir; HBV, heptitis B virus; LAM, lmivudine; NA, nucleos(t)ide nlog; TDF, tenofovir disoproxil fumrte; TVD, telbivudine.

13 CHB PREVENTION GUIDELINES SUMMARY SHEET Prevention nd Vccintion Preventive mesures for those who re: HBsAg positive Susceptible to HBV infection Hve sexul contcts vccinted Use brrier protection during sexul intercourse if prtner is not vccinted or nturlly immune Do not shre toothbrushes or rzors Cover open cuts nd scrtches Clen blood spills with detergent or blech Do not donte blood, orgns, or sperm Vccinte ccording to the CDC nd ACIP guidelines For newborns born to HBsAg-positive women: dminister HBIg nd HBV vccine immeditely fter delivery nd complete the vccintion series Persons who remin t risk for HBV infection (infnts of HBsAg-positive women, helth cre workers, dilysis ptients, nd sexul prtners of crriers) should be tested for response to vccintion Chronic hemodilysis ptients who respond to vccintion should undergo nnul follow-up testing Does not discuss preventive mesures for those with CHB Vccinte, Americn Assocition for the Study of Liver Diseses; ACIP, Advisory Committee on Immuniztion Prctices; CDC, Centers for Disese Control nd Prevention; CHB, chronic heptitis B;, Europen Assocition for the Study of the Liver; HBIg, heptitis B immune globulin; HBsAg, heptitis B surfce ntigen; HBV, heptitis B virus.