IINGRES NASIONAl PERTEMUAN llMIAH NASIONAL PGI-PEGI-PP'I ...staff.ui.ac.id/system/files/users/irsan.hasan/... · 2• 7 Kongres Nasional & Pertemuan llmlah Nasional PGl•-Pf.GI-PPHI,

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

Naskah Lengkap Simposium

Tenofovir Alafenamide Fumarate Has Come: Benefits for the Treatment of

HBV Infections

lrsan Hasan, Monica Raharjo

Division of Hepatobiliary, Department of Internal Medicine Cipto Mangunkusumo Hospital,

Faculty of Medicine Universitas Indonesia, Jakarta

Prevalence and Treatment of Hepatitis B Virus (HBV) Infections in Indonesia

Infection of Hepatitis B virus (HBV) is a health burden globally and

particularly in Indonesia. It is estimated that 240 million individuals are

chronic HBV surface antigen (HBsAg) carriers. 1 In Indonesia, it is estimated

that 4.0-20.3% of the population have chronic HBV infection.2 The 2013

National Health Survey done by Indonesia's Ministry of Health found that

7 .1 % of the population are HBsAg carriers. 3 Furthermore, the 2018 National

Health Survey done by Indonesia's Ministry of Health reported that the overall

prevalence of hepatitis in Indonesia, including HBV infection, experienced

an increase of 0.2% from overall prevalence of hepatitis in 2013.4 Long­

term goals of chronic HBV treatment are 1) to increase quality of life and

survival of infected patients by preventing disease progression to cirrhosis,

liver decompensation, hepatocellular carcinoma (HCC), and death and 2)

to prevent HBV transmission. Current first-line treatments of chronic HBV

infection in Indonesia are pegylated interferon, entecavir, and tenofovir.2

Tenofovir Treatment of HBV Infections in Indonesia

Nucleoside analogues (lamivudine, telbivudine, and entecavir) and

nucleotide analogues (adefovir and tenofovir) are available in Indonesia

46 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019

Naskah Lengkap Simposium ·--·---··---·- ·-·····------ ------

for treatment of chronic HBV infections.5 There are two kinds of tenofovir:

tenofovir disoproxil fumarate {TDF) and tenofovir alafenamide fumarate {TAF),

as shown in Figure 1. In 2012, Indonesia issued a compulsory license on

TDF and its combination.6 As of 2017, TAF is not yet available in lndonesia.2

Hence, tenofovir treatment in Indonesia refers to the use of TDF. In the United

States (US), TDF has been approved for use in human immunodeficiency

virus (HIV) infection in 2001 and later for use in chronic HBV infection in

2008 by the Food and Drug Administration (FDA).7

~

c6 HO'~) N

6H- I

Tenofovir (parent nucleotic»)

TDF (Dl~ESTER p,odrug)

TAF (GS-7340) (MONO--AMIDA TE prodrug)

Figure 1. Chemical structure of tenofovtr, TDF, and TAF

TDF has been shown to be effective in suppressing HBV deoxyribonucleic

acid (DNA) levels, normalizing alanine aminotransferase (Ali) levels, and

achieving seroconversion of hepatitis B envelope antigen (HBeAg). No

resistance to TDF has been detected with up to 7 years of treatment. 8 TDF

is associated with significant renal and bone toxicity in patients with HIV

infection; however, it is tolerated weft in chronic HBV patients. Reported

renal impairment during long-term treatment of TDF in chronic HBV patients

were mild and improved with dose adjustment of TDF. Meanwhile, bone

mineral density (BMD) loss was not significant nor progressive in chronic

HBV patients as in HIV patients. Common adverse events (AEs) associated

with TDF treatment are headache, nasopharyngttis, back pain, and nausea.1,e

The typical dosage of TDF for chronic HBV infection is one 300 mg tablet

taken orally per day. 2• 7

Kongres Nasional & Pertemuan llmlah Nasional PGl•-Pf.GI-PPHI, Palembang 2019 47

Naskah Lengkap Simposium

Introduction to Tenofovir Alafenamide Fumarate

After the emergence of safety concerns with TDF treatment, efforts

were made to introduce a safer drug. On November 10, 2016, the US FDA

approved TAF for the treatment of chronic HBV infection at a dose of 25 mg

per day.9 TAF, formerly known as GS-7340, is a new phosphonate prodrug

of tenofovir specifically synthesized to optimize tenofovir antiviral potency

and clinical safety. Both TAF and TDF are metabolized to tenofovir in the

plasma. HBV-infected hepatocytes express carboxylesterase 1 (CES 1)

which hydrolyze TAF to tenofovir. Levels of circulating plasma tenofovir are

associated with renal and bone toxicity. Tenofovir undergoes phosphorylation

to form tenofovir diphosphate in target viral-infected cells. Tenofovir

diphosphate is the active form of tenofovir. Inhibition of HBV replication

occurs when HBV reverse transcriptase incorporates tenofovir diphosphate

into HBV DNA resulting in HBV DNA chain termination. Metabolism of TAF

is pictured in Figure 2.

Plasma NH,

<?°£J A N N O ~ I O

~.,,o 'y -~

:: NH

,, .. ~oy 0

TAF

Pa ive Perm ability

NH,

t£;

Hepatocyte

CES1•

TAF •

"'£:: <: N N_J O O 0 Renal +- .J. N N o TFV ,-- - I II O"

elimination "-..,O..._....P-

'

Nucleotlde klnases

-....;)• . I 11,..0 ,11..,..0,11 '-..._.,O....,_,P P P-0'

. I I I - 0- :. O' 0- 0-

TFV TFV-DP

• The ester hydrolysis step Is primarily catalyzed by CES1. CatA makes a contribution.

Figure 2. Metabolism of tenofovir alafenamide fumarate

48 Kongres Nasional & Pertemuan llmiah Nasional PGI- PEGI-PPHI, Palembang 2019

Naskah Lengkap Simposium

Compared to TDF, TAF has greater plasma stability and remains mostly

intact when penetrating HBV-infected hepatocytes as depicted in Figure 3.

This enables more efficient delivery of tenofovir diphosphate intracellularly.

Thus, TAF can achieve higher levels of tenofovir diphosphate within

hepatocytes compared to TDF even when given in substantially lower dose

than TDF. An in vitro study showed that after 24 hours incubations in primary

human hepatocytes, intracellular tenofovir diphosphate levels were 20-fold

higher with TAF compared to TDF. Lower systemic exposure to tenofovir

with TAF administration leads to the hypothesis that TAF is safer than TDF.

Circulating plasma tenofovir concentration is 90% lower with 25 mg of TAF

administration compared to 300 mg of TDF.10·11

Compound Stability T 1n. (min)

Human plasma T-cell extract

Tenofovir stable stable

TDF 0.4 71

TAF (GS-7340) 90 28

Figure 3. Plasma stability of TAF compared to TDF

Efficacy of TAF Treatment in HBV Infections

Two randomized, double-blind, phase 3, non-inferiority trial studied

efficacy of TAF compared to TDF in HBeAg positive and negative patients.

1,473 HBeAg-positive patients and 426 HBeAg-negative patients were

randomly assigned to receive either once-daily oral doses of TAF 25 mg or

TDF 300 mg.12•13

In HBeAg-positive patients, inclusion criteria were patients aged at least

18 years old, HBV DNA levels of at least 20,000 IU/ml, ALT levels greater

than 60 U/L in men or 38 U/L in women and at most ten times the upper

limit of normal (ULN). Patients with decompensated cirrhosis and HCC were

excluded. 581/1473 patients received TAF while 292/14 73 patients received

TOF for a median duration of 57 weeks. 371 of 581 patients (64%) receiving

TAF had HBV DNA less than 29 Ul/ml at week 48. 195 of 292 patients (67%)

receiving TDF had HBV DNA less than 29 IU/ml at week 48. 183 of 581

patients (31 %) receiving TAF had treatment failure; meanwhile, 88 of 292

Kongres Nasional & Pertemuan llmlah Nasional PGI-PEGI-PPHI, Palembang 2019 49

Naskah L.engkap Simposium

patients {30%) receiving TDF had treatment failure. Patients receiving TAF

had a significantly greater decrease in FibroTest scores at week 48 than

patients receiving TDF (-0.07 vs -0.04). 10% of patients receiving TAF had

loss of HBeAg at week 48 compared with 8% of patients receiving TDF. Rates

of HBsAg loss and seroconversion were low in both groups. 45 % of patients

receiving TAF achieve normalized ALT levels (s30 U/L for men and s19 U/L

for women) compared with 36% of patients receiving TDF. In HBeAg-positive

chronic HBV patients, TAF was non-inferior to TDF in antiviral efficacy.12

In HBeAg-negative patients, inclusion criteria include patients aged

at least 18 years old, HBV DNA levels of at least 20.000 IU/mL, ALT levels

greater than 60 U/L in men or 38 U/L in women and at most ten times the

ULN. Patients with co-infection, decompensated cirrhosis, and HCC were

excluded. 265/426 patients received TAF while 141/426 patients received

TDF for a mean duration of 56 weeks. 268 of 285 patients (94%) receiving

TAF had HBV DNA less than 29 Ul/ml at week 48. 130 of 140 patients

(93%) receiving TDF had HBV DNA less than 29 IU/mL at week 48. 7 of

285 patients (2%) receiving TAF had treatment failure; meanwhile, 4 of 141

patients (3%) receiving TDF had treatment failure. No patient in both groups

were reported with loss of HBsAg at week 48. 50% of patients receiving TAF

achieve normalized ALT levels (::.30 U/L for men and s19 U/L for women)

compared with 32% of patients receiving TDF. In HBeAg-negative chronic

HBV patients, TAF was also non-inferior to TDF in antiviral efficacy.13

Safety of TAF Treatment in HBV Infections

TAF was well tolerated in patients with chronic HBV infections with

most AEs being mild to moderate in severity. Most common AEs were

upper respiratory tract infection, nasopharyngitis, and headache. Incidence

of common AEs were similar in patients receiving TAF and TDF. Patients

receiving TAF had significantly smaller reductions in BMD compared to

patients receiving TDF, at both hip and spine. Reductions of BMD were

more significant in longer duration of treatment. TAF and TDF were given to

patients with estimated creatinine clearance of ~ 50 ml/min measured by the

Cockcroft-Gault method. At 48 weeks and 96 weeks, decrease in eGFR was

significantly smaller in patients receiving TAF compared to patients receiving

TDF. Independent predictors of eGFR reduction include diabetes mellitus,

50 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGl~PPHI, Palembang 2019

Naskah Lengkap Simposium

treatment with TDF, vitamin D level below the lower limit of normal range, and

baseline ALT value more than five times ULN. Patients who switched from

TDF to TAF at week 96 experienced significant improvement in creatinine

clearance at week 120. Patients receiving long-term TAF maintained stable

creatinine clearance.12-14

TAF Resistance in HBV Infections

Like TDF, TAF has a high barrier to resistance. Results from extensive

sequence analysis and phenotypic assays in patients with virologic

breakthrough demonstrate that no TAF-associated resistance substitutions

were identified through 96 weeks of treatment. 14 of 38 (36.8%} patients

receiving TAF or TDF who experience virologic breakthrough had

breakthrough associated with undetectable levels of tenofovir in the plasma,

suggestive of nonadherence to treatment. Phenotypic assays of patients

with virologic breakthrough in the absence of nonadherence showed that

patients have no changes in sensitivity to tenofovir in vitro. Only one patient

in the TAF group had emergence of rtA181T substitution associated with

resistance mutation. This patient has been treated with long-term lamivudine

at baseline. rtA 181 T is thought to have emerge from lamivudine treatment.

In vitro phenotypic assays demonstrate no changes in sensitivity to TAF

with rtA181T substitution. No resistance to TAF developed in patients with

chronic HBV over 96 weeks of treatment.15

Conclusions

TAF, a novel nucleotide analogue, is a promising drug for the treatment

of chronic HBV infections. Compared to TDF, TAF has shown equivalent

antiviral efficacy and improved safety profiles with regards to BMD loss and

renal impairment for patients with chronic HBV infection. TAF also has a

high barrier to resistance. To date, no studies have been done to determine

efficacy, safety, and tolerability of TAF in the Indonesian population.

Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHl, Palembang 2019 51

Naskah Lengkap Simposium

References

1. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis 8 virus infection. J Hepatot 2017;67:370-98.

2. Perhimpunan Peneliti Hati Indonesia. Konsensus Nasional Penatalaksanaan Hepatitis B di Indonesia. In: Lesmana CRA, editor. Jakarta: Perhimpunan Peneliti Hati Indonesia. 2017.

3. Badan Penelitian dan Pengembangan Kesehatan. Riset Kesehatan Dasar 2013. Jakarta: Kementerian Kesehatan RI. 2013.

4. Sadan Penelitian dan Pengembangan Kesehatan. Hasil Utama Riset Kesehatan Dasar 2018. Jakarta: Kementerian Kesehatan RI. 2018.

5. Gani RA. Comparison of renal safety of tenofovir and telbivudine in chronic hepatitis B patients: A real world study in Indonesia. Jurnal Penyakit Dalam Indonesia. 2018;5(3): 129-34.

6. UNITAID. Patient and licences on antiretrovirals: A snapshot. Geneva: World Health Organization. 2014.

7. Kayaaslan B, Guner R. Adverse effects of oral antiviral therapy in chronic hepatitis B. World J Hepatol 2017; 9(5): 227-41.

8. Buti M, Tsai N, Petersen J, Flisiak R. Gurel S, Krastev Z, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection. Dig Dis Sci 2015;60:1457-64.

9. Tavakolpour S, Oarvishi M, Sali S. Tenofovir Alafenamide: A new drug with various ambiguous aspects in treatment of chronic hepatitis 8 infection, Arch Clin Infect Dis. 2019;14(1 ):e65343.

10. Murakami E, Wang T, Park Y, Hao J, Lepist El, Babusis D, et al. Implications of efficient hepatic delivery by tenofovir alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother 2015;59(6):3563-9.

11. Agarwal K, Fung SK, Nguyen TT, Cheng W, Sicard E, Ryder SD, et ai. Twenty-eight day safety, antiviral activity, and pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. J Hepatol 2015;62:533-40.

12. Chan HLY, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovlr alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg­positive chronic hepatitis B virus infection: a randomized, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1 :185-95.

13. Buti M, Gane E, Seto WK, Chan HLY, Chuang WL, Stepanova T. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomized, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1 :196-206.

52 Kongres Nasional & Pertemuan llmiah Nasional PGI-PEGI-PPHI, Palembang 2019

\ Naskah Lengkap Simposium

~. 14. Byrne A, Carey I, Agarwal K. Tenofovir atafenamide in the treatment of \ chronic hepatitis B virus infection: rationale and clinical trial evidence. Ther

Adv Gastroenterol 2018;11:1-12.

: ,

15. Cathcart AL, Chan HLY, Bhardwaj N, Liu Y, Marcellin P. Pan CO, et al. No resistance to tenofovir alafenamide detected through 96 weeks of treatment in patients with chronic hepatitis B infect.on. Antirnicrob Agents Chemother. 2018;62:1-11.

Kongres Nasional & Pertemuan flmiah NaSfonaJ PGI-PEGI-PPHI, Palembang 2019 53