Protease Inhibitors

Protease Inhibitor ( Telaprevir ) works by blocking an enzyme that the hepatitis C virus needs in order to replicate itself.  

Why can't someone take a protease inhibitor after failing with them one time?

Patients can repeat SOC (Peginterferon & Ribavirn) multiple times, but why not SOC with a PI?

[spectda]

If you don't succeed with the PI, it is often because resistant mutations can't be eliminated. I am not sure, but I believe they occur with Soc also, but they return to the original (wild type) virus quickly.

In any event, with telaprevir and boceprevir the mutations can last a long time, some as long as 2 years or more, maybe even longer. boce and tela both create several of the same mutants. They have studied them and how long the specific mutations last. Using the same drug will be ineffective against those mutants.

This same kind of problem with mutants occurred with HIV. That is why they created drug cocktails (I believe they are a combination of protease and polymerase inhibitors). The  combination of these drugs were created to attack the wild type virus and the mutations that can occur.

Polymerase inhibitors along with protease inhibitors are being tested for treatment of HCV as we speak. From what I have read the polymerase inhibitors don't create mutants, or at least not as easily and quickly as the current pi's. Eventually they will have these type of cocktails available for tx of HCV.

I don't know that much about HIV, but I wonder why they can't destroy but only contain the virus although with great success for many years. It makes me wonder how long it will be before they will be able to eradicate HCV without adding interferon and riba to the mix.

[Cory255]

Good Answer.....Why are there resitant mutations?  How much do we know about that?  Is there anything that can be done about that?

I've never been in a trial, so I wouldn't know how that works.....From what I've seen it appears as if they control how much Interferon/Ribavirin/Boceprevir is taken at certain times during tx.

How do they know or control this?

[Cory255]

Resistant Mutations....That can't be good.....Might be out of luck for a while if that happens......

I'm wondering what the chances are of this happening?

Is everyone who fails with a Protease Inhibitor in this group with a resistant mutation?  

[spectda]

I am not sure why there are resistant mutations. I think they were there to begin with, but that they become dominant in the virus" fight to survive the very specific and intense attack by the PI's. I am not sure if that is correct, but perhaps someone more scientific then I will give you some input. Resistant mutations are only one of the reasons that the FDA is not jumping on the approval of these drugs as quickly as we might like. I think Magnum mentioned that he was told that by someone from the FDA a few days ago.

Every trial is different. My trial uses the current weight based guidelines for tx of hcv in regards to the amount interferon and riba to use. They are trying foremost to prove that boceprevir works, and how to handle side effects.

The purpose of the trial is not to cure us no matter what they have to do. A private dr has a lot more discretion in tx and you may be allowed a lot more input. The trial has to be consistent and controlled to scientifically prove what the boceprevir does that soc is not able to do on it's own.

When you are in the last phase of trials for a drug likely to be approved somewhat soon, the chance of successful eradication of the virus is much greater and the chance of serious adverse events are much less then with drugs that are in earlier phases and have not been proven effective and safe yet.

They want me to study their drug, I want them because I know my chance of SVR is doubled with the boce. I knew the risks and potential for mutations when I started, but I knew this would likely be my best chance in the next few years. I beleive and hope it's going to work for me, but well just have to wait and see.

[spectda]

I am certainly no expert about mutations although I've read a fair amount about them before I jumped into the trial. I asked member Willing about the possibility of mutations, he told me that they are there to begin with. he also provided me with this information if you want to read about it.     http://www.natap.org/2009/HCV/resistance.pdf

From what I understand when you are not successful with the PI's not because you had to stop because of adverse events, or you didn't comply with the treatment properly, that it is likely because of mutations. As I mentioned before some of them become the dominant virus.

The fear is that they could create a new more resistant strain of HCV permanently and could be potentially passed on through contact. From what I have read the for the most part the mutations revert back to the original wild type virus, but some mutants can take years.

I don't know if they have become permanent for anyone yet but the companies producing the new drugs are certainly studying the sequencing of the mutants (when they occur in treatment and how long they last afterward)

I hope this helps, and I hope someone with more knowledge then I can clarify things for you.

[spectda]

An excerpt from the study above. Willing also mentioned this to me Also. The hope is that interferon and riba will destroy the straggling mutants and they often do, therefore there is a very high success rate. I don't know how many of the people who did not achieve svr were resistant as apposed to unable to complete treatment or did not comply. I guess that number is somewhere between 0 and 25 percent according to the success rates posted from the studies of these PIs


"The resistant mutations at 4 locations in
the HCV protease catalytic domain identified in the first
14-day telaprevir clinical trial were also observed in the
present study (low-level resistance, single mutations at
positions V36A/M, T54A, and R155K/T; high-level resistance,
single mutation at position A156V/T and double
mutations at positions 36/155 and 36/156). No
consistent secondary mutations were detected; however,
this study is limited to observations in the HCV NS3
protease catalytic domain, and further analysis of the
NS4A region and protease cleavage sites and longer exposure
to telaprevir may reveal compensatory mutations.
All patients who received telaprevir alone had an initial
rapid and profound antiviral response to telaprevir, re-
Fig. 5. Plasma HCV RNA levels and frequency of viral variants for patients receiving the combination of telaprevir  PEG-IFN–alpha-2a. Plasma
HCV RNA levels are plotted as a function of days after initial dosing where the end of the 14-day telaprevir dosing period is indicated by the dark
vertical line and followed by up to 12 weeks of PEG-IFN–alpha-2a and RBV treatment. The horizontal dotted line represents the limit of detection for
the sequencing assay of 100 IU/mL, and the lower limit of HCV RNA detection (10 IU/mL) is indicated by the darker gray area. The total plasma
viral titer is depicted by the blue line. Filled white boxes represent samples below the limit of detection of the sequencing assay where no sequence
data are available. For samples with higher viral titer where sequencing was successful, the bars beneath each time point represent the percent of
each variant observed at that time point. Wild-type virus is shown in purple, and resistant variants are ordered from least resistant in green to most
resistant in red.
HEPATOLOGY, Vol. 46, No. 3, 2007 KIEFFER, SARRAZIN, ET AL. 637
flected by a sharp decline in wild-type virus. This initial
decline in HCV RNA was followed by viral persistence in
half of the patients given telaprevir alone (n
4). In these
4 patients, as wild-type virus was cleared, single mutation
variants were uncovered and became dominant by day 8.
Although a mixture of variants was observed at day 4, the
R155K/T or A156V/T variants became predominant at
day 8, likely because they confer higher levels of resistance
than the V36A/M or T54A variants. An increase in HCV
RNA levels occurred by day 12 to 15, which was associated
with the selection of higher-level resistant variants
containing a double mutation at positions 36/155. The
36/155 double mutant confers high-level resistance to
telaprevir, and its predominance by the end of dosing
indicates that this variant likely has an improved fitness
compared with other high-level resistant variants
(A156V/T or 36/156). The dynamic changes in HCV
variants in patients with a rebound response to telaprevir
monotherapy suggest that when resistance is present initially
as a single mutation, upon continued replication,
other resistant mutations may accumulate. However,
treatment with PEG-IFN–alpha-2a and RBV inhibited
growth of all the variants and all patients had a continued
antiviral response pattern through week 24, suggesting
these variants are sensitive to IFN and RBV.
The other 4 patients who received telaprevir alone all
experienced a continuous decline in plasma HCV RNA
titer throughout the dosing period. The high-level resistant
A156V/T variant was detected in 2 of these patients,
butHCVRNA levels continued to decline with telaprevir
alone and were undetectable in all 4 patients at 12 and 24
weeks, suggesting that PEG-IFN–alpha-2a and RBV follow-
on therapy and/or the immune system continued to
inhibit growth of the remaining virus.
All 8 patients given telaprevir alone had an initial rapid
and profound antiviral response. Subsequently, the 4 patients
with genotype 1a infection experienced a viral rebound,
while the other 4 patients with genotype 1b
infection had a continuous decline in viral load. The
V36M and R155K/T variants are observed only in patients
with genotype 1a due to a lower genetic barrier;
these mutations require only 1 nucleotide change in the
triplet codon compared with 2 changes required in genotype
1b. Unlike the A156V/T variants predominantly selected
in genotype 1b patients, the V36M and R155K/T
variants are more fit, and their selection underlies the
rebound response observed in genotype 1a patients. Thus,
the continued decline observed in genotype 1b patients
may be due to the slower growth rate (impaired fitness) of
the A156V/T variant, and perhaps the immune system is
more likely to inhibit growth of the virus. However, in all
7 patients who began follow-on treatment with PEGIFN–
alpha-2a and RBV, HCV RNA levels were reduced
below the limit of detection.
All patients receiving telaprevir PEG-IFN–alpha-2a
had a rapid initial HCV RNA decline followed by continued
slower decline. Resistant variants were detected in
only 2 patients, each at a single sampling time. One patient
had the A156T variant at day 8, but HCV RNA
levels were undetectable (10 IU/mL) at the next sampling
time (day 12), indicating that the combination of
telaprevir  PEG-IFN–alpha-2a was able to inhibit
growth of this variant. The second patient had the V36A
variant 1 week after the end of telaprevir dosing, butHCV
RNA levels were undetectable (10 IU/mL) 12 and 24
weeks after dosing while on PEG-IFN–alpha-2a and RBV
therapy. This suggests that treatment with PEG-IFN–
alpha-2a and RBV and/or the immune system was able to
inhibit growth of the V36A variant. All 8 patients in this
group achieved undetectable levels of HCV by week 12
and through week 24 on PEG-IFN–alpha-2a and RBV.
In conclusion, telaprevir dosing produced a rapid and
dramatic reduction in viral load in all patients when given
alone and in combination with PEG-IFN–alpha-2a. In a
subset of patients given telaprevir alone, clinical breakthrough
associated with resistant variants was observed.
The kinetics of selection of different resistant variants
suggest that these variants are present before dosing at
different levels, depending on their fitness compared with
wild-type. A recent analysis by McPhee et al.30 determined
the baseline prevalence ofHCVprotease inhibitorresistant
variants using a highly sensitive single-nucleotide
polymorphism assay (limit of detection 0.1%). For example,
the A156T variant was detected in 3 of 8 patients
at a frequency of 0.36%-0.75%. However, in this study,
variants were inhibited in all patients after they began
PEG-IFN–alpha-2a and RBV follow-on treatment. Most
importantly, when patients were initiated on the combination
of telaprevir and PEG-IFN–alpha-2a, no clinical
breakthrough was observed in any patient, even though
resistant variants were detected in some samples by our
sensitive methods. In every patient who received telaprevir,
including those in whom resistant variants were detected,
HCV RNA remained undetectable through 24
weeks with PEG-IFN–alpha-2a and RBV follow-on therapy.
These results suggest that the combination of telaprevir
 PEG-IFN–alpha-2a, with or without RBV, can
inhibit growth of both wild-type and resistant variants.
The results of this study provide further support for the
clinical development of telaprevir coadministered with
PEG-IFN–alpha-2a as a promising new strategy to treat
HCV infection."

[Magnum]

Although its means of transmission is fairly well documented, the hepatitis C virus itself largely remains a mystery. Hepatitis C is extremely small, even for a virus - it is only about 50 nanometers in diameter. A nanometer is one billionth of a meter - if you placed 200,000 hepatitis C viruses end to end, they would be only a single centimeter long. (They are so small that they have no color - they are in fact smaller than the wavelength of visible light.) However, what is known about hepatitis C underscores the type of threat that it poses.

Hepatitis C is an RNA virus - which means that it mutates frequently. Once an infection has begun, hepatitis C creates different genetic variations of itself within the body of the host. The mutated forms are frequently different enough from their ancestors that the immune system cannot recognize them. Thus, even if the immune system begins to succeed against one variation, the mutant strains quickly take over and become new, predominant strains. As a result, the development of antibodies against HCV does not produce an immunity against the disease like it does with most other viruses. More than 80% of the individuals infected with HCV will progress to a chronic form of the disease.

As a result of this, hepatitis C is usually not self-limited as a disease. In more than 85% of all cases, whether they progress to chronic liver disease or not, the infected individual carries the virus for life. This means that they also remain contagious for a lifetime, able to transmit the virus to others. And because of the long progression of the illness, even patients who will eventually die as a result of hepatitis C carry the virus for decades before it takes their lives. Most epidemics are self-limiting - they spread rapidly, but over a short period of time the affected population either dies or develops an immunity to the disease, and it stops spreading. Not so with hepatitis C. Much like HIV and AIDS, it lasts a lifetime, and kills slowly - giving the virus plenty of time to spread.

There are six basic genotypes of HCV, with 15 recorded subtypes, which vary in prevalence in different regions of the world. Each of these major genotypes can differ significantly in their biological effects - in terms of replication, mutation rates, type and severity of liver damage, and detection and treatment options. However, these differences are not yet clearly understood.

The 21 current variations in genotype, complicated by the constant mutation of the virus within infected individuals, represents a major challenge for the development of treatments and vaccines against HCV - and even for reliable detection of the virus. There is no guarantee that a treatment, test, or vaccine against one strain will be effective against all of them. Moreover, individuals cured of one strain will be prone to reinfection by any of the other strains.

Magnum

[banarep]

"will be prone to reinfection by any of the other strains"

please explain??

[spectda]

It means that because you have treated and become SVR, you still have the same risk for reinfection with the same genotype you had or any other genotype just like anyone who does not have hepatitis c.

[Cory255]

Couldn't have said it better myself.  

[Cory255]

Initially, telaprevir and boceprevir would be used in combination with interferon and ribavirin, but experts hope that new drugs will ultimately remove the need for interferon. However, it is unlikely that a protease inhibitor will be used alone because of problems with resistance. "The first monotherapy studies with telaprevir have shown that resistance develops within the first 2 weeks. The data have also shown that the [viral] mutants exist before treatment," says Michael Manns, Head of the Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. "As resistance is a problem, the FDA has restricted the use of monotherapy to 3 days in early studies, and then interferon plus ribavirin has to be added because the mutants for the protease are sensitive to interferon."

To combat resistance, researchers are looking at using combinations of direct-acting antivirals. "This approach has been very successful at preventing resistance in HIV treatment," says Robert Kauffman, Vertex's Chief Medical Officer. "If you have two drugs against two different viral targets for which there is no cross-resistance, to get a resistant variant, resistance needs to develop to both drugs, which is obviously much less likely than with just one drug." Still, whether interferon-free regimens are possible, and, if they are, what will be the best combinations of direct-acting antivirals are "open questions," says Manns.

[Cory255]

Telaprevir "generally" does produce a rapid and dramatic reduction in viral load in combination PegIFN Riba which is a good thing.  The combination of Tele w/ PegIFN can also inhibit growth of both wild-type and resistant variants.  HCV mutates rapidly making it more resistant to interferon.  Telaprevir is a specifically targeted antiviral therapy that reduces plasma HCV RNA in genotype 1 patients, and blocks an enzyme that the virus needs to replicate.  You initially can get a sharp reduction in the wild-type virus, which unveils pre-existing VX-950 resistant variants.  Tele PegIFN can inhibit both wild-type and resistant variants, and tela resistant variants are sensitive to Pegifn/riba.