The document discusses the rapidly evolving landscape of direct-acting antiviral (DAA) treatments for hepatitis C virus (HCV) infection. Three key studies demonstrated that all-oral, interferon-free combinations of DAAs achieved high sustained virologic response rates (SVR) of over 90% for various genotypes and patient populations. These include a combination of sofosbuvir and ledipasvir, a triple therapy of ABT-450/r, ABT-267 and ABT-333, and a combination of daclatasvir and asunaprevir. Several DAAs are now approved or in late-stage trials. These new interferon-free regimens have the potential

1. Changing Concepts in HCV Therapy
Lancet 2015; 385: 1124–35
EASL GUIDELINE :2014
WHO GUIDELINE : 2014
Dr.S.M.Amanat Ullah
Department of Medicine
Chittagong Medical College Hospital

16. ARE WE APPROACHING THE ERA OF
INTERFERON- FREE REGEMINS

17. The Standard of Care Therapy for HCV
Depends upon giving PegIFN / Ribavirin for
24-48 Wks depending upon the Genotype

18. Both drugs depends mainly in their effect upon
Boosting the Host immune response to control
and eradicate the HCV Infection

19. The newly developed Directly Acting Antivirals –
DAAs - acts only at the virus Level with no effect
on the host immune system i.e the host immunity
is passive during these new lines of therapy
.

20. So, we are shifting from the host immune system
manipulation Towards virus body manipulation.
NB : The virus is a living organism and has to
defend its life through
? Resistance? Mutation ? etc
Like Antibiotics with Bacteria .

21. So , do we need to Combine both modalities
in the future Therapy ?
i. e. To have a Whiff of Interferon at the
beginning of therapy with DAAs to boost the host
immune system and this may Decrease the relapse
rate, break-though and resistance
( <<<<< We need more studies >>>>>)

22. The advent of direct-acting antivirals- DAAs
Has revolutionized hepatitis C treatment .

23. The First Protease Inhibitor that was tried in
2004 and was known as PILN 2061 and gave
100% eradication rate after 4 weeks only .
At that time it was considered
a real revolution…..
However at 16 weeks all patients got
cardiac toxicity and the trial was aborted
( Nature 2004 )

24. The Real start of DAAa was Nov. 2011
FDA : PROTEASE INHIBITORS (NS-3 , 4A)
1st
generation
Telaprevir ( Incivek )
Boceprevir ( Vectrelis )

25. ADVANTAGES OF 1ST
GEN. P. I
-INCREASED SVR RATE
( FROM 45 % TO 74% IN G 1A, 1B)
- DECREASED RELAPSE RATE
( FROM 12% TO 4% )

26. DRAWBACKS OF 1ST
GEN. P. I
* HIGHER COST
* FREQUENT SIDE EFFECTS
* HIGH DRUG DOSES ( 12-16 TABLs/D)
* FREQUENT DRUG DISCONTINUTY
( 12% IN SOC # 49% IN TRIPLE TTT)
* INTERFERON DEPENDANT
* GENOTYPE SPECIFIC..G1 ONLY

27. PROTEASE AND POLYMERASE
INHIBITORS : 2ND
GENERATION
<< INTERFERON FREE REGIMENS >>

28. DURING THE 62ND ANNUAL MEETING
OF AASLD, 2011
NEW HCV DRUG ACHIEVES 100% CURE RATE
WITHOUT INTERFERON

29. IN ELECTRON — 1 OF 2 PHASE 2 STUDIES
OF THE INVESTIGATIONAL COMPOUND
PSI-7977 (PHARMASSET) REPORTED HERE
— AN INTERFERON-FREE REGIMEN OF PSI-
7977 PLUS RIBAVIRIN ACHIEVED A 100%
SUSTAINED VIRAL RESPONSE (SVR) AT 12
WEEKS IN ALL STUDY SUBJECTS.

30. IN 2012 : Innovative Trial ::::
* SOFOSBUVIR ( NS5B INH.- GILEAD )
+
* DACLATASVIR (NS5A INH. BMS )
95% SVR

31. GILEAD .. 2013
* SOFOSBUVIR ( NS5B INH. GILEAD )
* LEDIPASVIR ( NS5A INH. GILEAD )
(COMBO)
95% SVR INCREASED TO 100% WITH RIBAVIRIN

32. BMS : 2013
* DACLATASVIR ( NS5A- BMS )
+
* ASUNAPREVIR ( PI. BMS )

33. BMS : A COMBINATION THERAPY INCLUDING TWO
DIRECT-ACTING ANTIVIRAL AGENTS (DAAS)
ASUNAPREVIR AND DACLATASVIR
SUPPRESSED HEPATITIS C VIRUS (HCV) GENOTYPE 1
INFECTION IN A 93% OF PATIENTS WHO HAD
PREVIOUSLY NOT RESPONDED TO TREATMENT .

34. IN Nov. 22ND
2013 ::: FDA APPROVAL FOR
- POLYMERASE INHIBITOR
* SOFOSBUVIR ( SOFALDI – GILEAD )
- PROTEASE INHIBITOR
* SIMEPREVIR ( OLYSIO- JANSSEN )

35. NEW REVOLUTION :
IN FEB. 8TH
, 2014 … GILEAD COMPANY
APPLIED FOR FDA APPROVAL OF
ONE PREPARATION CONTAINING BOTH
- SOFOSBUVIR + LEDIPASVIR ( COMBO )
TO BE GIVEN IN ONE CAPSULE DAILY
FOR 8 WEEKS WITH RESPONSE RATE 95%
-AND IF ADDED RIBA. , RESPONSE RATE 100 %

36. On the way for FDA Approval, two PIs :
Faldaprivir(Bin) …. Asunaprivir (BMS)

37. IN 2014 … NEW HCV
DAAs COMBINATION –
INTERFERON-FREE THERAPY

38. New hepatitis C therapies -
A medical pick And mix
A plethora of direct-acting anti-virals

40. SUMMARY OF DIRECT-ACTING ANTIVIRALS
Class Drug Dosing
NS3/4A protease inhibitor ABT-450/RTV 150/100 mg
NS3 protease inhibitor Asunaprevir 100 mg BID
NS3/4A protease inhibitor MK-5172 100 mg QD
NS3/4A protease inhibitor Simeprevir 150 mg QD
NS5B nonnucleoside polymerase inhibitor Dasabuvir 250 mg BID
NS5B nucleotide polymerase inhibitor Sofosbuvir 400 mg QD
NS5A inhibitor Daclatasvir 60 mg QD
NS5A inhibitor GS-5816 25 or 100 mg QD
NS5A inhibitor Ledipasvir 90 mg QD
NS5A inhibitor MK-8742 20 or 50 mg QD
NS5A inhibitor Ombitasvir 25 mg QD

41. (DAAs) for the treatment of hepatitis C are now
available and new agents are continually being
added to this list.
To coincide with EASL 2014 in London, UK, the N. E.
J. M. has published a series of new HCV therapy
phase III trial results, demonstrating that
We are now truly in the era of interferon- free,
All-oral combination therapies for HCV infection.
These DAAs could potentially revolutionize
Treatment for HCV , but can we call them
a cure yet?

42. NEW POLICY IN HCV TREATMENT
ALL IN ONE PILL

43. The first set of three open-label trials
( All in one Pill )
Examined the use of the HCV NS5A
inhibitor Ledipasvir in combination with
Sofosbuvir
(an HCV NS5B polymerase inhibitor).
( COMBO )
A number of different patient
populations infected with HCV
genotype 1 were studied:

44. 1. HCV-infected patients who were treatment-
naive (16% had cirrhosis; 12-week versus 24-
week regimen, with or without ribavirin);
2. Patients with chronic HCV infection
without cirrhosis (8-week versus 12-week
treatment regimen, with or without ribavirin);
3. HCV-infected patients who had failed to
achieve a sustained virologic response (SVR)
despite treatment with interferon- based
therapies (20% had cirrhosis; 12-week versus
24-week regimen, with or without ribavirin).

45. Patients typically received 90 mg Ledipasvir
and 400 mg Sofosbuvir in a combination
tablet orally each day; Ribavirin, when
required, was administered at 1,000 mg or
1,200 Mg According to bodyweight.
The studies showed that once-daily
ledipasvir– sofosbuvir (with or without
ribavirin) was highly effective (SVRs >90%,
with some rates as high as 99%) in HCV-
infected patients irrespective of whether
they had received HCV treatment before.

46. Importantly, the studies found that there
was No additional benefit of including
ribavirin within the combination therapy,
Kowdley et al. found no benefit of
extension of the treatment period to
12 weeks
(8 weeks were sufficient).

47. The second set of three trials
( AbbVie )
Examined the use of
a three-in-one pill

48. TRIPLE - INTERFERON FREE -
THERAPY FOR HCV INFECTION

50. THE COMBINATION OF THREE DIFFERENT
MECHANISMS OF ACTION OF THIS 3D COMBINATION
INTERRUPTS THE HCV REPLICATION PROCESS
AND OPTIMIZES A SUSTAINED VIROLOGIC
RESPONSE DURING THE 12-WEEK REGIMEN
(SVR12) IN HCV PATIENTS.

51. ABBVIE'S PHASE 2 AVIATOR STUDY COMPARED VARIOUS
INTERFERON-FREE THREE- AND FOUR-DRUG COMBINATIONS
CONTAINING:
* THE HCV PROTEASE INHIBITOR ABT-450 BOOSTED
WITH RITONAVIR,
* THE HCV NS5A INHIBITOR ABT-267 (OMBITASVIR),
* HCV NON-NUCLEOSIDE POLYMERASE INHIBITOR ABT-333
( DASABUVIR )
* AND RIBAVIRIN, FOR DURATIONS OF 8, 12 OR 24 WEEKS.

52. ABBVIE'S PHASE 2 AVIATOR STUDY COMPARED VARIOUS
GROUPS AS REPORTED AT EASL 2013, 96% OF TREATMENT-
NAIVE PATIENTS AND 93% OF PRIOR NULL-RESPONDERS
WHO RECEIVED ALL FOUR DRUGS FOR 12 WEEKS ACHIEVED
SUSTAINED VIROLOGICAL RESPONSE,
OR CONTINUED UNDETECTABLE HCV RNA, AT 24 WEEKS
POST-TREATMENT (SVR24).
THE SUSTAINED RESPONSE RATE WAS LOWER – 87% – FOR
PEOPLE TAKING THE THREE DIRECT-ACTING ANTIVIRALS
WITHOUT RIBAVIRIN FOR 12 WEEKS

59. THIRD STUDY : A COMBINATION OF
TWO DAAA DACLATASVIR & ASUNAPREVIR
DEVELOPED BY BMS CURED 90% OF PREVIOUSLY
UNTREATED PEOPLE WITH G 1B IN 24 WEEKS, WITHOUT
THE NEED FOR PEGYLATED INTERFERON OR RIBAVIRIN.
( MANNS, 49TH ANNUAL MEETING OF EASL IN UK, 2014)
THE INTERFERON- AND RIBAVIRIN-FREE REGIMEN COMBINED THE NS5A
INHIBITOR DACLATASVIR AND THE PROTEASE INHIBITOR
ASUNAPREVIR.
THE TWO DRUGS ARE ALSO BEING TESTED ALONGSIDE A THIRD
AGENT, THE NON-NUCLEOSIDE NS5B POLYMERASE INHIBITOR BMS-
791325, IN TWO PHASE III STUDIES ( TRIPLE THERAPY )

60. IN EUROPE, BMS IS PURSUING AN EARLY
APPROVAL FOR DACLATASVIR AS AN
INDIVIDUAL AGENT, SO THAT IT MAY BE USED
IN COMBINATION WITH SOFOSBUVIR FOR
TREATMENT OF GENOTYPES 1, 3 AND 4 OR IN
COMBINATION WITH PEGYLATED INTERFERON
AND RIBAVIRIN FOR TREATMENT OF
GENOTYPES 1B AND 4, AS RECOMMENDED IN
NEW EASL GUIDELINES, 2014.

61. QUADRUPLE THERAPIES
(THERAPY WITH FOUR DRUGS)
PEOPLE WITH VIRUS WHICH HAS PREVIOUSLY PROVED VERY
DIFFICULT TO TREAT (E.G. NON-RESPONDERS AND NULL-
RESPONDERS), COULD BENEFIT FROM THE COMBINATION OF
:
PEGINTERFERON AND RIBAVIRIN WITH
TWO ANTIVIRAL ACTIVE SUBSTANCES.
IT MAY ALSO BE POSSIBLE TO SHORTEN THE OVERALL
THERAPY PERIOD, ALTHOUGH EVEN MORE SERIOUS SIDE-
EFFECTS MAY HAVE TO BE TAKEN INTO ACCOUNT .

62. Despite their success, a major issue of
concern with these new DAAs has been
their expense, as well as regulatory issues
across different countries.
Hopefully, over the coming years, these
therapies will follow the lead of the HIV
field and substantially reduce in cost ,

63. Several major challenges do remain
before we can truly move towards the
global eradication of HCV infection,
Particularly access to new DAAs in low-
income and middle-income countries and
effective HCV screening programmes .
(Too often diagnosis still comes at a late stage).

64. Moreover, more attention needs to
be focused on special patient
populations.
“We still have yet to explore treatments
in patients with
Decompensated Cirrhosis,
” Manns explains, “which is a major task” .

65. SOFOSBUVIR + RIBAVIRIN IS SAFE AND EFFECTIVE FOR
(LIZ HIGHLEYMAN / 17 APRIL 2014 )
SOFOSBUVIR PLUS RIBAVIRIN IS A SAFE OPTION
THAT CAN LEAD TO SUSTAINED RESPONSE IN
PEOPLE WITH ADVANCED LIVER DISEASE INCLUDING
THOSE WITH DECOMPENSATED CIRRHOSIS AND
PORTAL HYPERTENSION, AND PEOPLE WHO
EXPERIENCE SEVERE HEPATITIS
Q : ( GENOTYPE IV - NON-RESPONDERS, BREAK-
THROUGH- RELAPSERS ? )

66. EASL HCV GUIDELINES 2014: GENOTYPE 1
Genotype Options for Therapy
Genotype 1*
PegIFN/ribavirin + sofosbuvir: 12 wks (A1)
PegIFN/ribavirin + simeprevir†
: 12 wks, followed by 12 wks of pegIFN/ribavirin in
previously untreated pts and prior relapsers (A1), or 36 wks of pegIFN/ribavirin in
previous partial responders and null responders (B1)
PegIFN/ribavirin + daclatasvir (genotype 1b only; B1): 12 wks followed by 12 wks of
pegIFN/ribavirin alone or a further 12 wks of pegIFN/ribavirin + daclatasvir
(response-guided therapy) (B2)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant pts only, where no other
interferon-free option available (B2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added for previous
nonresponders & cirrhotics) (B1)
Sofosbuvir + daclatasvir: 12 wks in previously untreated pts; 24 wks in treatment-
experienced patients (including TVR/BOC-experienced patients) (ribavirin may be
added in previous nonresponders and cirrhotics) (B1)
EASL. J Hepatology. 2014;60:392-420.
*In settings where recommended options are not available, treatment with pegIFN/ribavirin + TVR
or BOC remains acceptable.
†
Not recommended in pts with genotype 1a and detectable Q80K polymorphism.

67. EASL HCV GUIDELINES 2014: GENOTYPE 2-6
Genotype Options for Therapy
Genotype 2*
Sofosbuvir + ribavirin: 12 wks (16-20 weeks in cirrhotic patients, especially treatment
experienced) (A1)
PegIFN/ribavirin + sofosbuvir: 12 wks for cirrhotic and/or treatment-experienced patients (B1)
Genotype 3*
Sofosbuvir + ribavirin: 24 wks (unsuitable for treatment-experienced cirrhotics, no specific
alternative proposed) (A2)
PegIFN/ribavirin + sofosbuvir: 12 wks (A2)
Sofosbuvir + daclatasvir: 12 wks (24 wks for treatment-experienced patients) (B1)
Genotype 4*
PegIFN/ribavirin + sofosbuvir 12 weeks (B1)
PegIFN/ribavirin + simeprevir: 12 wks, followed by 12 wks of pegIFN/ribavirin in previously untreated
patients & prior relapsers (B1), or 36 wks of pegIFN/ribavirin in previous partial responders & null
responders (B1)
PegIFN/ribavirin + daclatasvir: 12 wks followed by 12 wks of pegIFN/ribavirin alone or a further 12 wks of
pegIFN/ribavirin + daclatasvir (response-guided therapy) (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
Sofosbuvir + simeprevir: 12 wks (ribavirin may be added in previous nonresponders and cirrhotics) (B2)
Sofosbuvir + daclatasvir: 12 wks in previously untreated patients; 24 wks in treatment-experienced patients
(ribavirin may be added in previous nonresponders and cirrhotics) (B2)
Genotype
5/6*
PegIFN/ribavirin + sofosbuvir 12 wks (B1)
Sofosbuvir + ribavirin: 24 wks for interferon-intolerant patients (C2)
EASL. J Hepatology. 2014;60:392-420.
*In settings where recommended options are not available, treatment with pegIFN/ribavirin remains acceptable.

68. WHO HCV GUIDELINES 2014: RECOMMENDATIONS ON HCV TREATMENT
• All adults and children with chronic HCV infection, including people who inject drugs, should be
assessed for antiviral treatment (strong recommendation; moderate quality of evidence)
• PegIFN + RBV recommended rather than standard nonpegylated IFN with RBV (strong
recommendation; moderate quality of evidence)
• TVR or BOC, in combination with pegIFN/RBV, suggested for GT1 chronic HCV infection rather
than pegIFN/RBV alone (conditional recommendation; moderate quality of evidence)
• Sofosbuvir, in combination with RBV with or without pegIFN (depending on HCV genotype),
recommended for GT1-4 HCV infection rather than pegIFN/RBV alone (and rather than no
treatment for persons who cannot tolerate IFN) (strong recommendation; high quality of
evidence)
• Simeprevir, in combination with pegIFN/RBV, recommended for GT1b HCV infection and
genotype 1a HCV infection without the Q80K polymorphism, rather than pegIFN/RBV alone
(strong recommendation; high quality of evidence)
WHO 2014. Guidelines for the screening, care and treatment of persons with hepatitis C infection.

69. So , do we still need to have a Whiff of Interferon at
the beginning of therapy with DAAs to boost the
host immune system and this may Decrease the
relapse rate, break-though and resistance
( <<<<< We need more studies >>>>>)

70. PROS AND CONS OF
NEW DAAS

71. HCV variants that are resistant to DAAs
emerge in patients who experience
virologic failure.
Multiclass resistance emerges in patients
on interferon alfa- free regimens that
contain DAAs, with the possible exception
of resistance to nucleoside pol. inhibitors.
.

72. The long-term impact of emergence of
resistant variants is not known at this point.
It is known that such variants decay over
time, but it remains unclear whether re-
exposure to the same drug classes will
result in rapid re-emergence of resistance.
.

73. Progress in devising interferon alfa-free
regimens is rapid and can be expected to
continue in this manner for the next
several years.
Hope remains that interferon- free regimens
can be crafted for the vast majority of HCV
patients within the near future….THEN WHAT?

74. We have to keep also in mind that ::
Eradication of HCV infection in one person
Eradicating a source of infection
The best way of HCV Prevention
And approaching the end of HCV Epidemic

75. THANK YOU