Changing Concepts in HCV Therapy

( Pros and Cons )

Hosny Salama, MD( Cairo University )

Alex Hept. August, 21st, 2014

ARE WE APPROACHING THE ERA OF

INTERFERON- FREE REGEMINS

The Standard of Care Therapy for HCV

Depends upon giving PegIFN / Ribavirin for

24-48 Wks depending upon the Genotype

Both drugs depends mainly in their effect upon

Boosting the Host immune response to control

and eradicate the HCV Infection

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 .

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 .

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 >>>>>)

The advent of direct-acting antivirals- DAAs

Has revolutionized hepatitis C treatment .

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 )

The Real start of DAAa was Nov. 2011

FDA : PROTEASE INHIBITORS (NS-3 , 4A) 1st generation

Telaprevir ( Incivek )

Boceprevir ( Vectrelis )

ADVANTAGES OF 1ST GEN. P. I

-INCREASED SVR RATE ( FROM 45 % TO 74% IN G 1A, 1B)

- DECREASED RELAPSE RATE ( FROM 12% TO 4% )

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

PROTEASE AND POLYMERASE

INHIBITORS : 2ND GENERATION

<< INTERFERON FREE REGIMENS >>

DURING THE 62ND ANNUAL MEETING

OF AASLD, 2011

NEW HCV DRUG ACHIEVES 100% CURE RATE

WITHOUT INTERFERON

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.

IN 2012 : Innovative Trial ::::

* SOFOSBUVIR ( NS5B INH.- GILEAD ) +

* DACLATASVIR (NS5A INH. BMS )

95% SVR

GILEAD .. 2013

* SOFOSBUVIR ( NS5B INH. GILEAD )

* LEDIPASVIR ( NS5A INH. GILEAD )

(COMBO)

95% SVR INCREASED TO 100% WITH RIBAVIRIN

BMS : 2013

* DACLATASVIR ( NS5A- BMS )+

* ASUNAPREVIR ( PI. BMS )

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 .

IN Nov. 22ND 2013 ::: FDA APPROVAL FOR

- POLYMERASE INHIBITOR* SOFOSBUVIR ( SOFALDI – GILEAD )

- PROTEASE INHIBITOR* SIMEPREVIR ( OLYSIO- JANSSEN )

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 DAILYFOR 8 WEEKS WITH RESPONSE RATE 95%

-AND IF ADDED RIBA. , RESPONSE RATE 100 %

On the way for FDA Approval, two PIs :

Faldaprivir(Bin) …. Asunaprivir (BMS)

IN 2014 … NEW HCV

DAAs COMBINATION –

INTERFERON-FREE THERAPY

New hepatitis C therapies -

A medical pick And mix

A plethora of direct-acting anti-virals

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

(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?

NEW POLICY IN HCV TREATMENT

ALL IN ONE PILL

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:

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).

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.

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).

The second set of three trials

( AbbVie )

Examined the use of

a three-in-one pill

TRIPLE - INTERFERON FREE -

THERAPY FOR HCV INFECTION

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.

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.

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

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 )

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.

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 .

“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 ”

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 !!

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 ,

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).

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” .

SOFOSBUVIR + RIBAVIRIN IS SAFE AND EFFECTIVE FOR PEOPLE WITH HCV WHO HAVE ADVANCED LIVER DISEASE

(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 ? )

NHS ENGLAND AGREES FUNDING

FOR LIFE-SAVING HEPATITIS C DRUG( SOFOBUVIR- SOFALDI )

16 APRIL 2014 - 17:37

THE RECOMMENDATION OF NHS ENGLAND’S CLINICAL PRIORITIES ADVISORY GROUP (CPAG)

MEANS THAT WHILST NOT YET NICE-APPROVED, SOFOSBUVIR WILL BE FUNDED FOR :

THOSE PATIENTS AT SIGNIFICANT RISK OF MORTALITY OR WHO REQUIRE TRANSPLANTATION.

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.

EASL HCV GUIDELINES 2014: GENOTYPE 2-6Genotype 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.

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.

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 >>>>>)

PROS AND CONS OF

NEW DAAS

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.

.

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.

.

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?

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 )

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

THANK YOUTHANK YOU