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PAPot CA.a.ANG SUM~I.L
-
IINGRES NASIONAl & PERTEMUAN llMIAH NASIONAL PGI-PEGI-PP'I , ,3
PALEMBANG 2019
Hotel Novotel Palembang 11-14 September 2019
P,PHI dalam Meningkatkan Kompetensi ng Gastroenterohepatologi dan Endoskopi rna pada Era Teknologi 4.0
Dr. ... lumiawan, SpPO-KGEH IUJIZ.J0.1/11n.ot/·1.779.J/201S
Kumpulan Naskah Lengkap & Abstrak
Kongres Nasional & Pertemuan llmiah Nasional
PGI-PEGI-PPHI 2019
Editor:
A. Fuad Bakry Imam Suprianto Achmad Fauzi Kaka Renaldi
Juferdy Kurniawan
Perkumpulan Gastroenterologi Indonesia (P.G.I)
' \
I.
Daftar lsi
Kata Sambutam Ketua Panitia Kata Sambutan Ketua PB Gabungan PGI-PEGI-PPHI Kontributor Daftar lsi
NASKAH LENGKAP SIMPOSIUM
iii V
vii ix
Understanding the Anatomy & Diagnosis of Hemorrhoidal Disease 1 Neneng Ratnasari
Long Term Nucleos(t)ides Analogues Treatment in Chronic Liver Disease: A Comprehensive Review 10
lrsan Hasan, Steven Zulkifly, Monica Raharjo
The Natural Course of Chronic Liver Disease 21 lrsan Hasan, $tetanus lmanuel Setiawan, Monica Raharjo
General Concept of Gut Dysbiosis 25 Chyntia Olivia Maurine Jasirwan
Probiotic Treatment in Liver Cirrhosis 34 Juferdy Kurniawan
Treatment Options in the Management of Post-ERCP Pancreatitis 40 Kaka Renaldi
Tenofovir Alafenamide Fumarate Has Come: Benefits for the Treatment of HBV Infections 46
lrsan Hasan, Monica Raharjo
lntrahepatic Cholestasis and the Role of Liver Biopsy Neneng Ratnasari
The Role of Albumin in Decompensated Cirrhosis A Fuad Bakry
Cedera Ginjal Akut pada Sirosis Hati Nurul Akbar
Test Diagnosis Invasive dan Non Invasive pada lnfeksi Helicobacter pylori
Imam Suprianto
ix
54
60
64
76
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N.askah Lengka~) Simposiwr, ---·.-,,... .. ... ~-, ......... .... _. ___ .. ,,- .... ~ ... ~ ·---........ --~--.. ~ ... -.... . ._ _ __ -..-..-.--.. ..---4--- ------
Long Term Nucleos(t)ides Analogues Treatment in Chronic Liver Disease:
A Comprehensive Review
lrsan Hasan, Steven Zulkifty, Monica Raharjo
Division of Hepatobiliary, Department of Internal Medicine Cipto Mangunkusumo Hospital,
F acuity of ~,,1edicine Universitas Indonesia, Jakarta
Introduction
The World Health OrgMization {VVHO) reported in 2017 that hepatitis
8 vh·us {HBV) mf~cti{)ns have become a globaJ health issue. Approximately
3.5% ot the wor1d's popuiaUon or 257 million individuals have chronic HBV
infection, 68% of them in Africa and the West Pacific., In Indonesia, the
prevalanc-e of chronic HBV infe.ctions based on positive hepatitis B surface
.antigen {HBsAg} tests is 7.1% in 20·,3_2 The prevalence of chronic HBV
in chHdrer1 aged < 5 years old had substantially decreased following the
introducHcn of hepatitis B vaccination in newborns {4.7% in 1980 to 1.3%
in ·2000). '
PatfentS with chrontc HBV who do not receive appropriate treatment
can oev~iop t-iver fibres~ s and furt~~er progress into liver cirrhosis and
nepatoceUuJar carcinorr1a {HCC) . 8-20% of patients with chronic HBV
tnfections receiving no trootfnent will progress into liver cirrhosis in 5 years
arid 20% among them wiit progress into decompensated liver cirrhosis in 1 o years. 21 % of cirrni::>tic patients due to chronic HBV infection will progress
into HCC in 6 years. :s
tnctications for Chrontc HBV Tre-atment
Not aH chronlc HSV pati&nts are given antiviral therapy. Several
10 KQl)Qf'4 NaSJorlal & ?ertemuM Hmlah NasioNtl PGi-PEGt-PPHt, Palembang 2019
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Naskah Lengkap Simposium
parameters should be taken into consideration including: 1) alanine
aminotransferase (ALT) levels, 2) HBV deoxyribonucleic acid (DNA) serum
levels, 3) hepatitis B envelope antigen (HBeAg} status, 4) liver histology, and
5) specific considerations (age, health status, family history of liver cirrhosis
or HCC, and extrahepatic manifestations).3
Antiviral therapy should be given immediately to patients with
decompensated liver cirrhosis and patients with severe chronic HBV
reactivation. Patients have severe chronic HBV reactivation if there is
coagulopathy (prolonged prothrombin time/PT more than 3 seconds or
elevated international normalized ratio/lNR more that 1.5). Compensated
liver cirrhosis patients are given antiviral therapy if: 1) HBV DNA levels are
above 2,000 IU/ml with normal ALT levels or 2) HBV DNA levels are detected
with elevated ALT levels. 3·"
Sirosis kompensata
• HBV DNA >2000 IU/ml dengan ALT normal
• HBV DNA terdeteksi denganALT meningkat
Terapi antivirus
Pasien sirosis hati
Sirosis Dekompensata
Terapi segera
----I ~ - -,
I Reaktivasi berat I I hepatitis B kronik !
--·---i L Terapi segera j
Figure 1. Chronic HBV treatment indications in patient with liver cirrhosis
In patients without liver cirrhosis, HBeAg status, HBV DNA levels, and
ALT levels determine if the patient is indicated to receive treatment or not.
Chronic HBV patients with positive HBeAg should receive treatment when
HBV DNA levels are above 20,000 IU/mL and ALT levels are elevated more
than 2 times the upper limit of normal (ULN).3
Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019 11
Naskah Lengkap Simposium
HBVONA < 2x103 IU/ml
HBVDNA 2xl03-2x104 tU/mL
HBVDNA > 2xl04 tu/ml
ALT ALT ALT ALT
1-lx bilti'IS -;n nilai >2:xbatas atas berapapun berapapun norm;i,t atao normal ni!ai normal
1 l . EIGtdU'Si penyebab lt!m . Elcstdusi perr;ebab lain . Ob5ervasi tiap 3 - obsffvasi &lam 3 hula ll jik I tidiilc
jika ditemukan jll(a ditemukan bulan. adaunda
penin&lcatanAlT. peningkatan ALT. . Penilaian fibrosis dekornpensaJi. . Omeniasi tiap 3 bu!ao. . Observasi tiap 3 bulan. non i.nvasif. '!Milpi bil;i . Penilalao fibrosis. non . Penilaian fibrosis non . Biopsi hati bila kYlaikanALT
illlll!sif. irwasif. ada indikasi. • menet.iip ;,; 3 ·bilan . Biopsi hati bila ada . Biopsi hati bila ada . Tera pi dim ulaf at.iiu twd.iJYt
indikasi.• indlkasi.• jilca ditemukan nsilco . Terapi dimul111 jilca . Terapi dimulaijika inflamasi sedan( . da;~. -riJ:sa¥t
ditemubn inflama.si <litemukan inftamasi - beratatau .histologi atau sedang- berat a tau sedang - berat atau fibrosis dg ,1jat fb-osis fibrosis signifilcan # fibrosis signifikan • signifil<an.# noo invasitl!
Figure 2. Chronic HBV treatment indications in patients with positive HBeAg
HSVONA < 2xl011U/ml
AH febth dan normaJ
• ~:h;si pen·,,.bllb u,i r,j,udibrnu~ ,,.~,,,~ Nol.
• ClaMrvlli t •IO J
• Penillitn ftotatis non hwalt
• l iopsi t,IRI b'l11de i nd1k11Si. •
• T4trioi dimufai JI~ dlttmubtl inff.lffla.i ,..dan1-tt..,• ttw 6b,ros,1 s.ip>ifil<.ln.t
AlT persist@ n norma4
• Mc>nitc,r iacf.- ..._T t i IC) 3-o bulan dlltl liEIV DNA t i• i-12 b\lfll'l,
• l"enilli-, flbtw1 fton invasi(
• &ioplli l'•ICHMlallA i,ui1qa:;,•
• Ter,pi dirnul Iii jib diumu~ int,_,.,.,.
wdq- bu.c•..., 6bro1tni1nif.qn,lt
HBVONA > 2xl0' IU/ml
Al.T 1-2'.ll'NWltas "llei norm.4 ateu normal
j • P~nllafen fibrosis
non lnvlrSif. • Slopsl hatl bil&
Ida it1dikast • • Ter epi dlmu~ jib
di~!'NJQI\
rnflamasi sedana -berat6tau ftbrOSis 5i&nifibn.•
ALT >2x bew-,tas nita,normal
• 011 .. ,.,.... dll.tltn 3 lh1l 111jilc.ltidalt ~
tltlda d•kQ~r,,:esJ.
• Te-rapi bi'la uitaiUt! /!LT 11"1•fletlt/ ? 3 b"l ltl ~IK, t'l!•d•tt ritiko dtkDmP4ns;ail.
• Ptl'r'ltriluMin hiflolo,i MI\I
der~•flt1rosi1fl0Ct ttwnlt#
Figure 3. Chronic HBV treatment indications in patients with negative HBeAg
12 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019
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Naskah Lengkap Simposium
Chronic HBV patients with negative HBeAg should be treated when \ HBV DNA levels are above 2,000 IU/rnl and ALT level are elevated more
than 2 times the ULN.3
\
\ \ 'lo \
....
Liver biopsy should be done in patients with these conditions: 1) noninvasive tests showing no significant fibrosis, 2} persistent elevations of ALT levels, 3} age more than 30 years old, or 4) age less than 30 years old with family history of liver cirrhosis or HCC. Patients with significant fibrosis or moderate to severe liver inflammation on liver biopsy should be given antiviral therapy.3
Targets of Chronic HBV Treatment
Long-term goal of chronic HBV treatment is to increase survival rates of patients by preventing progression to liver cirrhosis, decompensated liver cirrhosis, HCC, or death. Treatment of patients with chronic HBV also strives to prevent transmission of virus and reduce the incidence of chronic HBV infection.3.4
The ideal target of chronic HBV treatment is loss of HBsAg with or without seroconversion of hepatitis B surface antibody (anti-HBs). However, because this ideal target is difficult to achieve, satisfactory target and expected target are also formulated. Satisfactory target of chronic HBV treatment is no clinical relapse after discontinuation of antiviral therapy or seroconversion of hepatitis B envelope antibody (anti-HBe} for patients with positive HBeAg, Expected target of chronic HBV treatment is supression of HBV DNA throughout long-term antiviral therapy for patients with negative HBeAg or patients with positive HBeAg wi1hout seroconversion of anti-HBe.3.4
Treatment Modalities for Chronic HBV
Pegylated interferon (Peg-lFN) and nucteos(t)ides analogues (NAs) are antivirals widely used in the treatment of chronic HBV. Differences in characteristics of each drug are presented in Table 1. The NAs include lamivudine, adefovir, tefbivudine, tenofovir, and entecavir. a
Kongres Nasional & Pertemuan llmiah Nasional PGl··PEGt-PPHI, Palembang 2019 13
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Naskah Lengkap Simposium
Tabel 1. Differences in characteristics of interferon and nucleos(t)ide
~~~logue:..:·s~------------------------
Duration of treatment
Method of administration
Can be used in dee om pen sated cirrhosis
Side effects
Efficacy in supressing HBV DNA within one year
Efficacy in seroconversion of HBeAg (in HBeAg positive patients) within one year
Efficacy in seroconversion of HBsAg within one year
Biochemical response
Histopathologic response
Drug resistance
Long-term response
Interferon Limited (maximum 48 weeks)
Subcutaneous injection
No
Many
Lower efficacy compared to NAs
Lower efficacy compared to NAs
Higher efficacy compared to NAs
Balanced
Balanced
Not observed
Tends to improve when the therapeutic target is reached
Nucleos(t)ide Analogues
Nucleos(t)ide Analogues
Long-term (lifetime)
Orally once daily
Yes
Minimal
Higher efficacy compared to interferon (increased efficacy after one year)
Higher efficacy compared to interferon (increased efficacy after one year)
Lower efficacy compared to interferon (after one year efficacy comparable to interferon)
Balanced
Balanced
High in a few drug types
High relapse if treatment is not continued long term
The first-line NA treatment for chronic HBV patients is tenofovir
and entecavir. Recommended dose for tenofovir is 300 mg; whereas
recommended dose for entecavir is 0.5 mg. Both drugs are recommended
for all chronic HBV patients, both treatment narve patients and also cirrhotic
patients. Tenofovir is not recommended for chronic HBV patients with
14 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019
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impaired liver function. Entecavir is not recommended for chronic HBV
patients with history of drug resistance to entecavir. 3
Lamivudine, adefovir, and telbivudine are second-line NA treatment.
Second-line NA treatment is considered in conditions where first-line NA
treament Is not available whereas patients need immediate treatment and
have no known history of drug resistance. Lamivudine can be considered
in treatment na'ive chronic HBV patients with HBV DNA levels less than 2 x
108 IU/mL and elevated ALT levels more than 2 times ULN. Lamivudine can
be continued if HBV DNA levels are less than 2 x 103 IU/ml in week-4 and
less than 2 x 102 IU/rnl in week-24. Patients with history of drug resistance
to lamivudine, telbivudine, or entecavir are not recommended to receive lamivudine.3
Considerations for the administration of adefovir in chronic HBV are 1)
low HBV DNA levels and high serum ALT levels and 2) history of failure to
respond to NA treatment. Patients with impaired kidney function or history
of drug. resistance to adefovir are not recommended to receive adefovir. 3
Considerations for the administration of telbivudine are similar to
lamivudine, which are: 1) HBV DNA levels below 2 x 108 IU/ml, 2) increase
in ALT levels more than 2 times ULN, and 3) positive HBeAg. Telbivudine is
continued if HBV DNA level is undetected at week-24. Telbivudine cannot be
given to patients with history of drug resistance to lamivudine, telbivudine,
and entecavir. 3
Monitoring of NA Treatment
Duration of NA treatment varies according to HBeAg status and the
presence of liver cirrhosis. Chronic HBV patients with Jiver cirrhosis, positive
or negative HBeAg, should not discontinue NA treatment. Chronic HBV
patients without liver cirrhosis and positive HBeAg are recommended to
receive NA treatment for a minimum of 1 year after seroconversion of anti
H Be with undetected HBV DNA level. Chronic HBV patients without liver
cirrhosis and negative HBeAg are recommended to continue NA treatment,
unless Joss of HBsAg Is achieved.3
For the first three months of NA treatment, ALT level, HBV DNA level,
and HBeAg status should he monitored every month followed by every three
months during the first year of treatrnent. lf relapse dtd not occur during NA
Kongres Nasional & Pertemuan llrniah Naslonet PGI--PEGI-PPHJ, Pa,ernbang 2019 15
Naskah Lengkap Simposium ------------------treatment, monitoring can be done every six months for patients without
cirrhosis and every three months for patients with cirrhosis.
Long-Term Effect of NA Treatment on HBV DNA Suppression and Normalization of ALT
A study by Zountendjik reported the virological response (HBV DNA
< 80 IU/ml) of 333 patients with chronic HBV receiving entecavir, 243
patients treatment na'ive and 90 patients with history of NA treatment prior
to entecavir. In treatment na·ive patients with positive HBeAg, virological
response was found in 48%, 76%, and 90% of patients at week-46, 96,
and 144 respectively. In treatment na'ive patients with negative HBeAg,
virological response was found in 89%, 98%, and 99% of patients at week-
46, 96, and 144 respectively. Furthermore, this study also reported partial
virological response in 36 treatment naive patients. 29 patients among them
achieve virological response after prolonged entecavir treatment and none
of them experienced drug resistance to entecavir. Entecavir monotherapy
can be continued in cases with partial virological response especially with
low viral loads. 5
In another study following 183 patients receiving entecavir treatment
for five years, 94% of these patients had HBV DNA levels of less than 300
copies/ml and normal ALT levels at the end of study. Only one case of drug
resistance was reported.6 A similar study was done by Seto, et al, which
reported that cummulative cases with undetected HBV DNA(< 20 IU/ml)
after 5 years of treatment was 97.1%. Two cases of drug resistance were
reported.7 A more recent study conducted by Suzuki, et al, in 2018 reported
results of entecavir treatment after 10 years. Ninety six percent of patients
were reported with undetected HBV DNA and 79% of patients had normal
ALT levels after 10 years of treatment.8 These studies show that long-term
entecavir treatment can suppress HBV DNA levels and normalize serum
ALT levels.
Long-Term Effect of NA Treatment on HBeAg Seroconversion
A meta-analysis done in 2017 evaluated incidence of HBeAg
seroconversion in patients with chronic HBV and positive HBeAg receiving
16 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019
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long-term NA treatment. Monitoring one year after treatment found that telbivudine had statistically higher probability of seroconversion (OR 3.99; Cl 95% 0.68-23.6) followed by tenofovir (OR 3.36; Cl 95% 0.70-16.75). Monitoring two years after treatment found that telbivudine still had the highest probability of seroconversion (OR 1.38; Cl 95% 0.92-2.22) followed by entecavir (OR 1.14; Cl 95% 0.72-1.72).9
A study evaluating 1 O years of entecavir treatment showed that seroconversion rates of HBeAg increased during the first six years of treatment (16% after one year of treatment to 38% after six years of treatment) but remained constant in the following years of evaluation. Multivariate analysis showed that genotype A, higher serum ALT levels, and higher HBV DNA levels were associated with seroconversion of HBeAg.8
A multicentre study reported that drug adherence, increased serum ALT levels, and non-vertical transmission of HBV were predictors of HBeAg seroconversion in chronic HBV patients receiving NA treatment.10
Long-Term Effect of NA Treatment on Histological Improvement liver cirrhosis is an irreversible end-stage liver damage characterized
by formation of fibrosis due to various etiologies, including chronic HBV infection. Histological improvement Is defined as a reduction in Knodell score of~ 2 without a reduction in Ishak fibrosis score. Histological improvement was found in 96% of patients receiving entecavir treatment for a minimum of 3 years. Improvement of th$ Ishak fibrosis score:;?, 1 was reported in 88% of patients, including patients with advanced liver fibrosis or liver cirrhosis. 11
A study conducted by Marceltin, et at, evaluated regression of cirrhosis in chronic HBV patients receiving tenofovir. 96 patients had an tshak score of 5 or 6 (cirrhosis) at the beginning of treatment. 71 patients of these patients no longer had cirrhosis after treatment.1
i Jwa, et al, rePorted a case of complete regression of esophageal varices after long-term entecavir treatment. This regression is believed to be associated with histological improvement of the cirrhotic liver. 13
Long-Term Effect of NA Treatment on HBsAg Seroconversion
A study which evaluated entercavfr treatment after 1 0 years reported
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that HBsAg seroconversion was observed in 28 patients (2.6%); 19 patients
had negative HBeAg and 8 patients had positive HBeAg. Average time
needed to achieve seroconversion is 3.03 years. Multivariate analysis found
that HBV genotype A and high HBsAg levels were associated with HBsAg
seroconversion. 8
Long-Term Effect of NA Treatment on Survival Rate
A multicentre cohort study in 372 chronic HBV patients receiving
entecavir treatment reported that virological response was associated with
lower risk of disease progression to decompensated cirrhosis, HCC, and
death {HR 0.29; Cl 95% 0.08-1.00; p = 0.05). Health benefits associated with
virological response were greater in patients with liver cirrhosis.14
Hosaka, et al, compared incidence of HCC in chronic HBV patients
receiving entecavir treatment with controls receiving no treatment.
Cummulative incidence of HCC in five years is 3.7% in patients receiving
entecavir treatment and 13.7% in patients receiving no treatment {p <
0.001). Despite this finding, long-term entecavir treatment did not affect
HCC incidence in patients without liver cirrhosis.15 Watanabe, et al, reported
that long-term entecavir treatment improved liver function and decreased
HCC incidence after three years. Incidence of HCC decreased with time up
to 1.8% after 5 years of entecavir treatment.16
Entecavir treatment in chronic HBV patients with cirrhosis decreased
overall mortality rate (HR 0.34; Cl 95% 0.18-0.62; p < 0.01) and liver
related mortality (HR 0.26; Cl 95% 0.13-0.55; p < 0.01 ). Cirrhotic patients
receiving entecavir treatment that do not achieve virological response had
the same probability of decompensation and mortality as patients receiving
no treatment. 17
Conclusions
Indications to start treatment in chronic HBV patients have to be
observed to achieve an optimal therapeutic response. NAs are among
the treatment modalities available for chronic HBV which are increasingly
being used as a long-term antiviral therapy. Clinical and laboratory
evaluation during treatment are necessary to determine optimal duration
18 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019
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Naskah Lengkap Simposium
of NA treatment Increasing risk of drug resistance to several types of NAs
associated with longer duration of treatment warrants the use of NAs with
low barrier resistance, such as tenofovir and entecavir, as first-line NA
treatment. Long-term use of NA has been associated with improvements
in serology, liver histology, and survival rate.
References
1. World Heallonth Organization. Global hepatitis report, 2017. France: World Health Organization. 2017.
2. Handayani S. Uji Serologi Penyakit yang Dapat Dicegah dengan lmunisasi dan Penyakit lnfeksi pada Spesimen Biomedis Riskesdas 2013. Jakarta: Sadan Litbang Kesehatan Kementerian Kesehatan Pusat Biomedis dan Teknologi Dasar Kesehatan. 2014.
3. Perhimpunan Peneliti Hati Indonesia. Konsensus Nasional Penatalaksanaan Hepatitis 8. Jakarta. 2017.
4. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, et al. AsianPacific clinical practice guidelines on the management of hepatitis 8: A 2015 update. Hepatol Int. 2016;10:1-98.
5. Zoutendjik R, Reijnders JGP, Brown A, Zoulim F, Mutimer D, Deterding K, et al. Entecavir treatment for chronic hepatitis B: adaptation is not needed for the majority of na'ive patients with a partial virological response. Hepatology. 2011 ;54:443-51.
6. Chang TT, Lai CL, Yoon SK, Lee SS, Coelho HSM, Carrilho FJ, et al. Entecavir treatment for up to 5 years in patients with hepatitis 8 e antigen-positive chronic hepatitis 8. Hepatology. 2010;51 :422-30.
7. Seto WK, Lam YF, Fung J, Wong DKH, Huang FY, Hung IFN, et al. Changes of HBsAg and HBV DNA levels in Chinese chronic hepatitis B patients after 5 years of entecavir treatment. J Gastroenterol Hepatol. 2014;29(5}: 1028-34.
8. Suzuki F, Hosaka T, Suzuki Y, Sezaki H, Akuta N, Fujiyama S, et al. Longterm outcome of entecavir treatment of nucleos(t)ide analogue-na"ive chronic hepatitis B patients in Japan. J Gastroenterol. 2019;54(2):182-93.
9. Xing T, Xu H, Cao L, Ye M. HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving long-term nucleos(t)ide analog treatment: a systematic review and netweok meta-analysis. PLoS One. 2017; 12(1 ):1-18.
1 O. Yu W, Wang Y, Shen C, Ji R, Zhang L, Zhao X, et al. Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting. Braz J Infect Dis. 2017;21 (3):213-8.
11 . Chang TT, Liaw VF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term
Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019 19
Naskah Lengkap Simposium
entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52:886-93.
12. Marcellin P, Gane E. Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow up study. Lancet. ~ 2013;381 :468-75.
13. Jwa HY, Cho YK, Choi EK, Kim HU, Song HJ, Na SY, et al. Regression of esophageal varices during entecavir treatment in patients with hepatitis-8-virus-related liver cirrhosis. Clin Mol Hepatol. 2016;22:183-7.
14. Zoutendjik R. Reijnders G, Zoulim F, Brown A, Mutimer OJ, Deterding K, et al. Virological response to entecavir is associated with a better clinical outcome in chronic hepatitis B patients with cirrhosis. Gut. 2013;62(5):760-5.
15. Hosaka T. Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58:98-107.
16. Watanabe T, Tokumoto Y, Joko K, Michitaka K, Mashiba T, Hiraoka A, et al. Effects of long-term entecavir treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients. Hepatol Int. 2015; 10(2):320-7.
17. Wong GL, Chan HL, Mak CW, Lee SK, Ip ZM, Lam AT, et al. Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis. Hepatology. 2013;58(5): 1537-4 7.
18. Papatheodoridis GV, Sypsa V, Dalekos G, Yurdaydin C, Boemmel F, Butt M, et al. Eight-year survival in chronic hepatitis B patients under long-term entecavir or tenofovir therapy is similar to the general population. J Hepatol. 2018;68(6):1129-36.
20 •• , Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang ,_
