Update on Hepatitis B and C in CEE

Miłosz Parczewski

Dept. of Infectious Tropical Diseases and Immune Deficiency,

Pomeranian Medical University in Szczecin, Poland

4th CEE Meeting on Viral Hepatitis and HIV

Biology is a science on the self-replicating machines

Freitas, Merkle, Kinematic Self-Replicating Machines, 2004

Thus: A virus maybe considered a self replicatingmachine in the

cellularenvironment.

Janos von Neumnn, https://pl.wikipedia.org/wiki/John_von_Neumann

General principles of Von Neumann machines as viruses

Concept of self-replicating machines

A „construction element”

B „replicating element”

C „controlling elements”

F(ABC) „instruction”

Freitas, Merkle, Kinematic Self-Replicating Machines, 2004

Rybosom (human), proteases, structural

proteins

transcriptases, DNA polimerases (human)

NS5A? Tat, rev, nef…

Viral RNA/DNA, copyDNA, genomicDNA, mRNA

3

Von Neumann Machine vs. viruses

Infecting vironBudding

infectiousviron

Infected host cell

Integrated viral RNA/DNA

Messenger viral RNA/DNA, viral proteins, host

ribosome , host restictionfactors

(inhibition of self-replication)

HBV/HCV - global perspective

Global hepatitis report, WHO, 2017

WHO 2030 targets to stop two key self-replicating viral machines: HBV and HCV

HBV/HCV in the European Region

• 18.5 mln estimated to live with chronic HBV

• 15 mln with chronic HCV

• Annual deaths >170 000 cases

• Expected increase in mortality in the near future

• Target in context: If 7% of HCV the epidemic in 2016 is cured each year (net), >90% of people infected in 2016 should be cured by 2030.

PWID

Viral resistance

Drug and vaccination roll-

out and pricecompetition

Issues to be addressed for HBV/HCV elimination in CEE.

Diagnostics including the

point-of –caretesting

Surveillance overtransmissionnetworks and reinfections

Treatment of HCV complications

(cirrhosis, HCC, OLTx)

HBV in the European context

Global hepatitis report, WHO, 2017

Global hepatitis report, WHO, 2017

HBV in the European context: success of early vaccination programs – HBs

prevalence among children <5 years

HBV seroprevalence across CEE

Global hepatitis report, WHO, 2017

Outcome of vaccination programmes: Acute HBV infections across CEE countries

Distribution of HBV genotypes in Europe

Kmet Lunaček N, Poljak M, Matičič MActa Dermatovenerol Alp Pannonica Adriat. 2018 Sep;27(3):141-146.

HCV in European context

Impact of migration on chronic HCV cases

% contribution to the total number of HCV cases in Europe

Mulitifaceted issue of injecting drugs

• Large array of behaviour form chemsex/rectreational, homemade or verycheap drugs e.g. „kompot (Polish heroine)”, orpseudoephedrine/manganate concotions

• Marginalisation, criminalisation stigma

• Insurance issues,

• HCV reinfection risk (data gap for CEE, to be addressed in the setting of expanding DAAtreatment programms)

Top countries with PWIDHBV among PWIDHCV among PWID

Grebely at al., Additionan, 2018, https://doi.org/10.1111/add.14393

Beyond hepatitis in PWID: Commentary on CNS manganosis

Pseudoephedrine is oxidated withhipermanganate (mix until cherry smell isobtained) and injected.

➢Cheap, short term drug

➢Manganate deposited in the periventriculararea of the brain

➢ Occasionally visualised by MRI

Elimination of HIV/HBV/HCV among PWID: Harm reduction programms in CEE

• Opioid substitution widely available except in Russian Federation, Turkmenistan and Uzbekistan.

• Coverage was low - 5.3% in Belarus, 4.9% in Kyrgyzstan, 3.5% in Ukraine and 0.2% in Kazakhstan.

• Sterile injecting equipment distribution: needle–syringe programmes often insufficient except Kyrgyzstan, where 241 needles were provided per client per year (target is 200).

2016 prevention gap report, UNAIDS

Next level: test and treat: testingavailibility across Euorpean Countries

DAA treatment uptake across Eurosida cohorts (HIV/HCV coinfected)

AIDS 2018

Restrictions to DAA use in EEA (1.4.2018)

Marshall AD et al. The removal of DAA restrictions in Europe… ( J. Hepatol 2018)

Reported restriction to DAA careacross Europe

HCV treatment disparities – net cures

5:1 (5x more people reach SVR than are new infections)1:1 – the same number of SVR ads new infections1:5 5x less people acheive SVR than get infected

Transmission networks as the issuewhich may negatively affect hepatitis

elimination targets

Acute HCV infections and shift in G1 patterns

Acute HCV; n (%) Chronic HCV; n (%) P value

Gender

Male 66 (100) 45 (71.4) <0.001

Female 0 18 (28.6)

Reported HCV infection route

Intravenous drug use (IDU) 0 53 (84.1) <0.001

Heterosexual partners of IDUs 0 4 (6.4)

Men-who-have-sex-with-men 66 (100) 9 (9.5)

HCV genotype 1a vs. 1b

Genotype 1a 24 (36.4) 19 (30.2) n.s

Genotype 1b 42 (63.6) 44 (69.8)

History of syphilis during follow-up

Yes 27 (77.2) 4 (8.0) <0.001

No 8 (22.8) 46 (92.0)

History of HBV coinfection

HBs antigen positive 1 (1.9) 1 (2.9) n.s

HBs antigen negative 52 (98.1) 54 (97.1)

G1A tended to be more prevalent compared to G1B among men-having-sex-with-men (MSM)

[34/52(65.38%) vs. 48/96(50.0%), p=0.07] and patients with a history of syphilis [18/34 (52.94%)

vs. 15/56(26.79%),p=0.01].

Parczewski et al., EACS 2017, Milan, PS3/3

HCV intercity transmission clusters aredriven by MSM

Parczewski et al., JAIDS, 2018

Genotype 1a acute HCV clustersCLADE I

CLADE II

Q80K RAS transmission was observed among six

G1A individuals.

Parczewski et al., EACS 2017, Milan, PS3/3

Gentotype 1b acute HCV clustersPart of the Genotype 1b tree

37 sequence G1B cluster containing sequences from 5 cities (mean

intercity distance 370 km).(sampling timeline 2012-2017)

Parczewski et al., EACS 2017, Milan, PS3/3

HCV re-infections are expected to be more commonly revealed in CEE

Chemsex

HCV resitance which may potentiallyaffect DAA treatment response

G1a 0 0 1 1 15 0 0 1 0 0G1b 1 2 0 0 0 1 1 0 1 1Total 1 2 1 1 15 1 1 0 1 1

1,9% 1,9%

27,8%

1,9%0,3% 0,7% 0,3% 0,3% 0,3% 0,3%

0,0%

5,0%

10,0%

15,0%

20,0%

25,0%

30,0%

36L 54S 55A 55A,80K

80K 80L 80R 156T 168E 170A

1a

1b

Baseline NS3 RAVs prevalence (n=384)

Parczewski at al., CMI, 2018

3,7%

1,9%0,3% 0,6%

3,3%5,1%

0,0%

5,0%

10,0%

15,0%

20,0%

25,0%

30,0%

28T 30R 31F 31I 31M 93H

G1A

G1B

G1a 2 1 0 0 0 0G1b 0 0 1 2 11 17Total 2 2 1 2 11 17

Parczewski at wl., CMI, 2018

Baseline NS5A RAVs prevalence (n=384)

7,07% 6,56%

12,50%

20,34%

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

F0/1 F2 F3 F4

p=0.019

p=0.003

p=0.003

p=0.004

Present 13 4 5 12

Absent 171 57 35 47

Total 184 61 40 59Parczewski at al., CMI, 2018

NS5A RAVs atbaseline

Fibrosis stage

p=0.009

p=0.007

p=0.008

p=0.04

Present 5 1 4 7

Absent 179 60 36 52

Total 184 61 40 59

2,72%1,64%

10,00%11,86%

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

F0/1 F2 F3 F4

Y93HNS5A

RAVs atbaseline

Fibrosis stage

Parczewski at al., CMI, 2018

8,00%9,43%

3,03%5,36%

0,00%

5,00%

10,00%

15,00%

20,00%

25,00%

F0/1 F2 F3 F4

Present 14 5 1 3Absent 161 48 32 53Total 175 53 33 56

p=ns

p=ns

p=ns

p=ns

NS3A RAVs atbaseline

Fibrosis stage

Parczewski at al., CMI, 2018

No clustering of NS5A RAVs neither in G1 nor in G1b which suggest de novo selection of NS5A variants in the course of long-term

chronic HCV

Real life: DAA resistance amongexperienced patients (unpublished)

0,00%

20,00%

40,00%

60,00%

80,00%

100,00%

NS5A RAS Y93H

NS5A failure and RAS

NS5A RAS

Y93H

0,00%

20,00%

40,00%

60,00%

80,00%

100,00%

NS3 RAS

NS3 falure and RAS

N=41 N=52

NS3 variant decay ater treatment termination NS5A decay ater treatment termination

Insignificant trendsignificant trend (p=0.01)

If you want to get somewhere else, you must run atleast twice as fast as that! ) - Lewis Carroll(Comment: viruses run faster, anyway)

Thank you