The document discusses the evolution of hepatitis C virus (HCV) therapy from interferon-based regimens to all-oral, interferon-free direct-acting antiviral (DAA) combinations. Clinical trials demonstrated that combinations of NS5A inhibitors like ledipasvir or daclatasvir with NS5B inhibitors like sofosbuvir achieved high sustained virologic response rates of over 90%, including in difficult-to-treat groups. New DAA combinations including two or three-drug regimens from AbbVie, Gilead, and BMS were shown to cure HCV in the majority of patients with 8-12 weeks of therapy. While these new therapies represent significant advances, challenges remain
3. The Standard of Care Therapy for HCV
Depends upon giving PegIFN / Ribavirin for
24-48 Wks depending upon the Genotype
4. Both drugs depends mainly in their effect upon
Boosting the Host immune response to control
and eradicate the HCV Infection
5. 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
.
6. 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 .
7. 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 >>>>>)
8. The advent of direct-acting antivirals- DAAs
Has revolutionized hepatitis C treatment .
9. 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 )
10. The Real start of DAAa was Nov. 2011
FDA : PROTEASE INHIBITORS (NS-3 , 4A)
1st
generation
Telaprevir ( Incivek )
Boceprevir ( Vectrelis )
11. ADVANTAGES OF 1ST
GEN. P. I
-INCREASED SVR RATE
( FROM 45 % TO 74% IN G 1A, 1B)
- DECREASED RELAPSE RATE
( FROM 12% TO 4% )
12. 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
14. DURING THE 62ND ANNUAL MEETING
OF AASLD, 2011
NEW HCV DRUG ACHIEVES 100% CURE RATE
WITHOUT INTERFERON
15. 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.
19. 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 .
20. IN Nov. 22ND
2013 ::: FDA APPROVAL FOR
- POLYMERASE INHIBITOR
* SOFOSBUVIR ( SOFALDI – GILEAD )
- PROTEASE INHIBITOR
* SIMEPREVIR ( OLYSIO- JANSSEN )
21. 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 %
22. On the way for FDA Approval, two PIs :
Faldaprivir(Bin) …. Asunaprivir (BMS)
23. IN 2014 … NEW HCV
DAAs COMBINATION –
INTERFERON-FREE THERAPY
24. New hepatitis C therapies -
A medical pick And mix
A plethora of direct-acting anti-virals
27. (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?
29. 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:
30. 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).
31. 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.
32. 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).
33. The second set of three trials
( AbbVie )
Examined the use of
a three-in-one pill
36. 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.
37. 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.
38. 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
39.
40.
41.
42.
43.
44.
45.
46. 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 )
47. 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.
48. 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 .
49. “We can say that we now have a cure
for hepatitis C, which is particularly
true for treatment-naive patients
without advanced cirrhosis.
” Michael Manns, EASL 2014 ”
50. However, as hepatitis C treatment
rapidly evolves, Manns acknowledges that :
Clinicians are currently working with a
“moving target” when it comes to how best
to treat their patients as new drugs and new
drug combinations emerge.
It is not just a question of which drug to use,
but which combination of drugs to choose !!
51. 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 ,
52. 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).
53. 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” .
54. 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 ? )
55. NHS ENGLAND AGREES FUNDING
FOR LIFE-SAVING HEPATITIS C DRUG
( SOFOBUVIR- SOFALDI )
16 APRIL 2014 - 17:37
56. THE RECOMMENDATION OF
NHS ENGLAND’S CLINICAL PRIORITIES ADVISORY GRO
(CPAG)
MEANS THAT WHILST NOT YET NICE-APPROVED,
SOFOSBUVIR WILL BE FUNDED FOR :
THOSE PATIENTS AT SIGNIFICANT RISK OF
MORTALITY OR WHO REQUIRE TRANSPLANTATION.
57. EASL HCV GUIDELINES 2014: GENOTYPE 1
Genotype Options for Therapy
Genotype 1*
PegIFN/ribavirin + sofosbuvir: 12 wks (A1)
PegIFN/ribavirin + simeprevirâ€
: 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.
â€
Not recommended in pts with genotype 1a and detectable Q80K polymorphism.
58. 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.
59. 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.
60. 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 >>>>>)
62. 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.
.
63. 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.
.
64. 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?
65. So , what do we need in Egypt ?
And we have to wait for What ?
* The most effective combinations .
* The least side effects.
* The least resistance, break through and relapse .
•The most economic preparations .
( So , Pick and Mix Policy – Manns, 2014 )
66. 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
BID, twice daily; QD, once daily.
Paul Y. Kwo, MD:
Our discussion covers a number of investigational DAAs representing a variety of drug classes, as outlined in this slide.
BOC, boceprevir; HCV, hepatitis C virus; pegIFN, peginterferon; TVR, telaprevir.
Stefan Zeuzem, MD:
Formal clinical guidelines are challenging to generate and take, on average, 6-12 months to complete. Because of the rapid developments in HCV therapy, currently the field has chosen to switch to reliance on guidelines based on expert opinion. In 2013, EASL established formal guidelines, which proved to be outdated by the time they were published. For the 2014 annual meeting, EASL presented a revised guidance document based on expert opinion,[1] an approach that would not fulfill strict methodological criteria for practice guidelines but functions better in the rapidly evolving field. EASL has summarized treatment options for patients with genotype 1-6 HCV according to the availability of HCV therapies in European countries.
Â
The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA, were effective in publishing updated guidelines almost immediately after the US Food and Drug Administration (FDA) approvals of simeprevir and sofosbuvir in late 2013.[2] EASL has gone a step further by including drugs that are not yet available but whose approval is anticipated, such as the NS5A inhibitor daclatasvir, whose approval is anticipated this fall in Europe. The EASL guideline does not include any recommendation on additional combination therapies that are anticipated to be approved in Europe in late 2014 or early 2015, including sofosbuvir/ledipasvir and ABT-450/ritonavir/ombitasvir and dasabuvir.
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Jordan J. Feld, MD, MPH:
The EASL guidelines, in contrast to the AASLD/IDSA guidelines, acknowledge that not every country gets approval and access to new drugs at the same time. Specifically, EASL has included the option of using telaprevir and boceprevir, and dual therapy with peginterferon and ribavirin alone, in settings where newer agents are not yet available. I applaud EASL for taking treatment access into account because the AASLD/IDSA guidelines are much stricter in that regard.
Â
Stefan Zeuzem, MD:
The difference, of course, is that the AASLD/IDSA guidelines are written with one country in mind. The European guidelines need to cover approximately 30 countries.
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Jordan J. Feld, MD, MPH:
Absolutely. I think EASL was right to include the older regimens because it makes for a more universal guideline. Even though the AASLD/IDSA guidelines are written for the United States, it is certainly the case that many non-Americans read them and rely on them, and so it is useful to have some guidance on other options.
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Paul Y. Kwo, MD:
As new HCV therapies continue to be introduced, it will be helpful for the AASLD/IDSA and EASL guidelines to evolve into living documents that will be revised online periodically rather than waiting for the period of time it usually takes for guidelines to be developed. This is an approach that AASLD/IDSA have already adopted and will ensure that practicing clinicians can access expert treatment advice for their patients.
HCV, hepatitis C virus; pegIFN, peginterferon.
Stefan Zeuzem, MD:
In addition to the 6 options recommended for genotype 1 HCV infection, EASL has recommended a range of treatment options for patients with genotypes 2-6 HCV. These include varying durations of sofosbuvir plus ribavirin with or without peginterferon (depending on genotype). Daclatasvir is included as an option for genotypes 3 and 4, and sofosbuvir plus simeprevir is a further option for genotype 4.
BOC, boceprevir; GT, genotype; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; TVR, telaprevir; WHO, World Health Organization.
Paul Y. Kwo, MD:
WHO also took the opportunity to present revised guidelines on HCV management at the EASL annual meeting.[3] Significantly, by publishing recommendations on HCV treatment, WHO has demonstrated that it recognizes the importance of treating those with hepatitis C around the world and that all people who are infected should be assessed for candidacy for antiviral therapy.
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Jordan J. Feld, MD, MPH:
The WHO guidelines have put hepatitis C on the radar screen at an international level, which was not previously true. The specific therapy recommendations contained in the EASL and AASLD/IDSA guidelines are more detailed than the WHO guidelines. However, the fact that WHO is taking hepatitis seriously is very important.
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Stefan Zeuzem, MD:
I agree, although now that these different guidelines have reinforced the importance of therapy, it also becomes important to find ways to identify patients with HCV. Therefore, EASL and WHO should now consider making further recommendations on how to implement screening strategies across different countries.