Showing posts with label resistance to protease inhibitors. Show all posts
Showing posts with label resistance to protease inhibitors. Show all posts

Sunday, June 19, 2011

Perspective: Recognizing resistance;The new protease inhibitors can elicit resistance

Perspective: Recognizing resistance


The hepatitis C virus is endemic among injection drug users, who could harbour treatment-resistant viruses. We need to adapt to this reality, says Diana Sylvestre

The first antiviral agents that act directly on the hepatitis C virus (HCV) are about to hit the market. Healthcare workers have been awaiting the release of these new medications for some time, in the hope that treatment response rates would improve, even in populations of patients who are challenging to treat. But underneath the glow of anticipation lies a concern about poorly characterized risks, including the emergence of drug-resistant viral strains. The real-world impact of this risk is unclear as most of those who contract the virus do so through injection drug use and are disregarded from clinical trails.

The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. But when corners are cut, risk rises. Shortening treatment, as new regimens promise to do, might reduce the burden of side effects. But the day-to-day misery will be worse with triple regimens than with the standard dual treatment, and it is important to appreciate the human tendency to reduce or skip doses of medications that make us feel ill.

Injection drug users are more complex patients: many have an unstable housing situation, unreliable transport or subject to prescription refill delays owing to insurance company bungling, which they are poorly equipped to deal with. They might be arrested and jailed during treatment. So, even though studies have shown that injection drug users have similar medication compliance rates to non-drug users4, 5, 6, external circumstances may prevent the medication fidelity that is expected and needed.

So far, modestly reduced adherence to the interferon-α and ribavirin therapy has not led to viral resistance. Taking only 80% of the prescribed interferon and ribavirin dosages for 80% of the projected duration of treatment is sufficient to achieve optimal response rates. This allows those who treat injection drug users (including me) enough latitude to be successful. We have been able to reduce the burden of HCV in those who are most at risk of transmitting it.

Unfortunately, there is no such information on new treatment regimens. It is unclear at what point reduced adherence may become a problem. The virus rapidly mutates, so the antiviral 'pressure' exerted by the medication needs to be maintained so mutant viruses are constantly destroyed. Such protease-inhibitor-resistant strains can persist for at least three years after the withdrawal of medication1, 2, 3. And the conformational changes that underpin resistance to one protease inhibitor may also confer resistance to other inhibitors of that protease — a phenomenon called class resistance. And worse: if active injection drug users become reservoirs of protease inhibitor resistance, these viral strains could predominate, requiring the kind of therapeutic arms race that we see in other infections such as HIV and Staphylococcus aureus.
Regulators should require that clinical trials consider current or former injection drug users. This is not currently being done. The US Food and Drug Administration (FDA) Guidance for Industry document encourages trial sponsors to initiate trials early in drug development for “special populations” with unmet needs: transplant patients, people co-infected with HIV and HCV, and those with decompensated, or severe, cirrhosis. The document fails to mention injection drug users. It is as though they don't exist. If diabetics or out-of-care asthmatics were at risk, the approach would be different. Instead, the FDA has turned its back on the majority population with HCV and is approving new drugs despite having almost no understanding of their potential to cause long-term harm.

Because HCV affects those on the fringes of society, large-scale treatment studies have not been representative of the face of the disease. Their doctors are not invited to enroll them in trials. Therefore, little is known about which patients are good candidates for treatment, the importance of adherence to the treatment regimen and the outcomes in the real world — this ignorance leaves addicted HCV patients subject to the vagaries of a medical system that might not welcome them. This is unacceptable from both a humanist and a public-health standpoint.

It is time that regulators, pharmaceutical companies and healthcare workers come to terms with the fact that many patients with HCV are injection drug users. These patients must be included in safety, tolerability and efficacy trials; regulatory studies should include clinics where HCV-infected drug users are seen. And study investigators should be more representative of the kinds of doctors that usually care for these patients.
The new therapies raise the possibility of eradicating hepatitis C. But that won't happen unless the key parties in this medical drama develop a more realistic approach to understanding and treating this disease.

http://www.nature.com/nature/journal/v474/n7350_supp/full/474S11a.html

References

References
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Saturday, April 2, 2011

Drug-resistant variants emerge in most patients who fail to achieve SVR with telaprevir-based regimen

Drug Resistance

Over 40 posters were presented at the EASL with data highlighting resistance in patients who fail to achieve SVR when treating with the new protease inhibitors, you can view them here .

Yesterday, we received a heads up with this EASL press release " New data suggests liver experts should exercise caution when prescribing novel antiviral HCV drugs".


Data presented at the International Liver CongressTM highlight the fact that new novel antiviral compounds for the treatment of hepatitis C virus (HCV) must be prescribed and monitored by experts and specialists to ensure resistance is minimised.

Several studies observed the rapid onset of HCV resistance in patients treated with NS3-protease, NS5b-polymerase and NS5a inhibitors. Although these direct anti-virals are effective in both treatment-naive HCV patients and those who've been previously unresponsive to current treatment options, the development of resistant viral variants may cause problems in the future. In fact, two studies found HCV strains resistant to novel antiviral compounds pre-existed in patients who had never previously been exposed to the new antiviral compounds. In these patients, the variants were selected out by treatment.

Professor Heiner Wedemeyer, EASL's Secretary General, said: "While the regulatory approval of these new treatments is a highly anticipated milestone in HCV therapy, these studies show that care must be taken in the prescription and use of the new compounds. What we want to avoid is a rapid spread of HCV resistance within the patient population, which could drastically lower the effectiveness of the new drugs."

Because we're on the topic of drug resistance, CCO who provides an expert analysis on data presented at the EASL, today, just published this;
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Telaprevir-Resistant HCV Variants Present at Time of Treatment Failure Replaced by Wild-Type Virus Over Time in Majority of Patients
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*Drug-resistant variants emerge in most patients who fail to achieve SVR with telaprevir-based regimen
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Excerpt;

Summary of Key Conclusions

Telaprevir-resistant HCV NS3 protease variants present at time of telaprevir-based treatment failure replaced by wild-type virus over time in most treatment-naive and treatment-experienced patients with genotype 1 HCV infection

  *Within 1 year after treatment discontinuation, 71% of patients had only wild-type  virus detected with population sequencing

Resistant variants become undetectable more rapidly in patients infected with genotype 1b vs genotype 1a HCV

  *Median time to wild-type virus: 0.8 vs 10.0 months, respectively

Different predominant mutations observed in patients with genotype 1a vs 1b


Further research in patients with resistance at treatment failure and subsequent loss of resistant variants over time to evaluate response to future therapy with same drug class

Click here for complete data

*To view the site free registration is required.

Also Ready To View At CCO;




Main Page;

Thursday, March 31, 2011

HCV Resistance:Liver Experts Should Exercise Caution When Prescribing Novel Antiviral HCV Drugs

New Data Suggests Liver Experts Should Exercise Caution When Prescribing Novel Antiviral HCV Drugs

Mar 31
Data presented at the International Liver CongressTM highlight the fact that new novel antiviral compounds for the treatment of hepatitis C virus (HCV) must be prescribed and monitored by experts and specialists to ensure resistance is minimised.1,2,3,4,5,6

Several studies observed the rapid onset of HCV resistance in patients treated with NS3-protease, NS5b-polymerase and NS5a inhibitors. Although these direct anti-virals are effective in both treatment-naive HCV patients and those who've been previously unresponsive to current treatment options, the development of resistant viral variants may cause problems in the future. In fact, two studies found HCV strains resistant to novel antiviral compounds pre-existed in patients who had never previously been exposed to the new antiviral compounds. In these patients, the variants were selected out by treatment.

Professor Heiner Wedemeyer, EASL's Secretary General, said: "While the regulatory approval of these new treatments is a highly anticipated milestone in HCV therapy, these studies show that care must be taken in the prescription and use of the new compounds. What we want to avoid is a rapid spread of HCV resistance within the patient population, which could drastically lower the effectiveness of the new drugs."

The current standard of care for chronic HCV is the combination of pegylated interferon-alfa and ribavirin, but only 40-54% of patients infected with HCV genotype 1 achieve a sustained virological response (SVR).7,8 Novel antiviral therapeutics are much sought after to treat patients who don't respond to the current standard of care. As such, a large number of new drugs for HCV are at various stages of preclinical and clinical development.9

However, as each new copy of the HCV genome exhibits - on average - one nucleotide change per replication cycle, HCV's replication machinery allows the virus to quickly come up with mutations that render it resistant to antiviral drugs. This is a major concern for successful anti-HCV therapy. 10

NS3 protease inhibitors block the function of the HCV NS3 protease, an enzyme essential for HCV's replication. NS5A replication complex inhibitors block the function of HCV nonstructural protein 5A, a multifunctional protein essential for HCV replication.10

References

1 McPhee F et al. Charactarizaion of virologic escape in HCV gentotype 1 null responders receiving a combination of the NS3 protease inhibitor BMS-650032 and NS5A inhibitor BMS-790052. Abstract presented at The International Liver CongressTM 2011

2 Chevaliez S et a. Molecular characterization of HCV resistance to telaprevir by means of ultra-deep pyrosequencing: pre-existing resistant variants and dynamics of resistant populations. Abstract presented at The International Liver CongressTM 2011

3 Hebner C et al. Emergence and persistence of ns5b mutations following combination treatment with tegobuvir (gs-9190) plus standard of care--long-term follow-up from the phase iib study gs-us-196-0103. Abstract presented at The International Liver CongressTM 2011

4 Zeuzem S et al. Boceprevir Resistance-Associated Variants (RAVs) are observed more frequently in HCV (gt1)-infected Patients with poor response to peginterferon alfa- 2B/ribavirin. Abstract presented at The International Liver CongressTM 2011 (1621)

5 Svarovskaia E et al. Abundant minority drug-resistant ns3 mutants detected by deep sequencing in hcv patients as early as 24 hours after initiating antiviral treatment. Abstract presented at the international liver congresstm 2011 (1773)

6 Sullivan J et al. Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials. (1783)

7 Fried M.W et al. "Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection." New England Journal of Medicine 347.13 (2002): 975-82

8 Hadziyannis S J et al. "Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C - A randomized study of treatment duration and ribavirin dose." Annals of Internal Medicine 140.5 (2004): 346-55.

9 Shiffman M L. "Treatment of hepatits C in 2011:what can we expect?" Curr.Gastroenterol.Rep. 12 (2010): 70-75

10 Raffaele De Francesco and Giovanni Migliaccio (2005). Challenges and successes in developing new therapies for hepatitis C. Nature, 436, 953-960

Source

The International Liver Congress

Saturday, February 5, 2011

Hepatitis C; resistance to protease inhibitors


Only people who have experienced a chronic illness understand the fear and apprehension felt with each step up the ladder, climbing closer to either medical treatment or a possible cure. These millions of people who are living with chronic hepatitis C or just newly diagnosed are often left out in the cold, alone, with many unanswered questions. Enter the sleepless nights, anxiety, waking each day wondering if treatment will work/or is it working, what about the side effects/I can't take these side effects, whats the availability/should I have waited for the new drugs, do I have the right specialist/I hate my doctor; what the hell am I doing?

I understand.

According to the CDC each year in the U.S. approximately 8,000 - 10,000 people die from hepatitis C-related liver disease. The estimate is that 3.2 million persons in the United States have chronic hepatitis C . The estimate does not included those people who have yet to be diagnosed. Quoted from the article;" Prevalence and Challenges of Liver Diseases in Patients with Chronic Hepatitis C Virus Infection" published in Clinical Gastroenterology and Hepatology were these facts; "A recent report commissioned by the Institute of Medicine (IOM) of the National Academies highlighted shortcomings in care for viral hepatitis, including the estimate that up to 75% of HCV-infected persons have not even been diagnosed."

In 2010 an article was published at (Bloomberg) which reported on a hepatitis C clinic located in Los Angeles, where patients are waiting for new drugs before embarking on treatment. You can view the article here.... 'Warehoused' Hepatitis C Patients

As the HCV community waits with anticipation for these new drugs to enter the market they slowly sift through the information available hoping to better understand these new agents.

This sure isn't easy, abstracts are difficult to understand, articles in the media leave out important facts, this leaves us with relevant data undiscovered.

The information we miss, overlook, is found in pages and pages of data. Hidden among abstracts only deciphered easily by a professional. With hunger we read and digest the information at our "reader friendly" HCV websites, HCV Advocate, HIV and Hepatitis
and Natap.

Today this blog will highlight information from the must read entry entitled "New Future Hepatitis C Treatments: Interferon-sparing combinations"

The information points out that "Genotype 1 patients who do not respond to this new triple therapy (telaprevir or boceprevir/PEG-IFN plus ribavirin) will have developed resistance to protease inhibitors"

The Facts;
"In the 30–40% of Genotype 1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors, which will limit future treatment options. Therefore, although the addition of a single DAA=(Direct-acting antivirals) to PEG-IFN and ribavirin may improve cure and shorten the treatment duration of SOC=( PEG-IFN/ribavirin), this approach will not meet the needs of many difficult-to-treat patient groups."

Once again the good news; The SVR for persons treating for the first time (geno 1) with telaprevir-PEG-IFN/ribavirin is at 75%.

The SVR rates treating with telaprevir in genotype 1 for patients who "failed to respond to prior therapy" are a little more complex. However, 65% of people overall achieved a sustained viral response.

In the Phase III REALIZE trial you can view the breakdown between relapsers, partial responders, and null responders here, also included are the SVR rates treating with boceprevir.

With these SVR rates so high, the majority of patients will likely take a chance and go on to treat with either telaprevir or boceprevir.

Another worthy mention in the highlighted blog entry is the drug RG7128, which is a nucleoside polymerase inhibitor, by adding this drug to RG7227 a protease inhibitor, it provides additive viral suppression of the HCV virus and completely prevented the development of phenotypic resistance to the protease inhibitor.

A little back story on the drug; Danoprevir

Danoprevir = (RG7227 formerly R7227 also known as ITMN-191) is an investigational protease inhibitor, which targets the hepatitis C virus, used in combination with the standard of care for HCV infection; peg-interferon alpha-2a and ribavirin. It has demonstrated rapid and profound reductions in HCV RNA, data has shown Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon.

The first study of combination of DAAs=(Direct-acting antivirals) in patients was the proof-of-concept INFORM-1 study completed last year .

In this randomised, placebo-controlled double-blind trial, 87 patients with HCV Genotype 1 infection were randomised to receive up to 13 days of either oral combination therapy with RG7128, a nucleoside polymerase inhibitor, and RG7227/danoprevir, an NS3/4A protease inhibitor or with matched placebos.

Both agents had already been administered to patients for 12 weeks in combination with SOC.

Direct drug interactions between RG7128 and danoprevir were considered very unlikely, because of the different mechanisms of action and routes of elimination and the lack of overlapping toxicities identified in any of the preclinical or human clinical studies.

This combination achieved profound antiviral suppression, greater than the additive effects of either treatment alone.

The median reduction in HCV RNA from baseline was 5 logs, falling below the level of detection in 88% in the cohort who received the highest dose of both RG7128 (1000 mg b.i.d.) and danoprevir (900 mmg b.i.d.).

No evidence of the emergence of resistance to either compound was observed during this study. This combination was well tolerated, with no serious adverse events, treatment-related dose modifications, discontinuations or study withdrawals.
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More information can be found here.

Recently medscape published a guide for physicians ;"Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines" which is highlighted here on the blog.

A quick summary;
Owing to the side-effect cost of DAAs and the risk of development of drug-resistant viral strains, it will be necessary to guide treating physicians through a growing maze of confounding factors. These will likely not only include new drugs but also important predictive tests and relevant mutation analysis.

One such predictive test is the IL28B genetic polymorphism, which has recently been reported to be associated withSVR by three separate groups [Ge et al. 2009; Suppiah et al. 2009; Tanaka et al. 2009].

The IL28B genotype will become a commercially available polymerase chain reaction assay in 2010 and may be helpful for decisions using SOC treatment. It is unknown if the C/C, C/T, and T/T alleles of IL28B will be associated with response rates to DAAs and this information will need to be carefully collected in ongoing trials.

In this proposed system;

Class I
patients would be those with a very high chance of SVR with SOC therapy for 24 weeks, that is, treatment naïve, interferon-tolerant patients with genotype 2/3, or genotype 1 infection with low viral loads or the C/C IL28B allele [Thompson et al. 2009].

As these patients would have an 80–90% probability of cure without the risk of additional side effects or the additional cost of DAAs, they might be well served to be treated with current SOC alone. These patients represent approximately 20–25% of the US population with HCV [Ghany et al. 2009].

Class II
Patients might be those who are treatment naïve, interferon-tolerant with genotype 1 who have high viral loads and/or have C/T or T/T IL28B alleles. These patients would be less likely to have an SVR with current SOC but would have approximately a 75–80% chance of an SVR with the addition of an NS3/4 protease inhibitor followed by consolidation therapy for a total of 24 weeks (if an RVR is attained). The added cost of DAA therapy and the risk of side effects would need to be considered in these patients, who represent the majority of the US HCV population (40–50%) [Ghany et al. 2009].

Class III
Patients would be those requiring 48 weeks of total therapy in order to attain an SVR with SOC and protease inhibitor therapy, such as relapsers and nonresponders of all genotypes, and those in Class I who do not attain an RVR. It would be important to establish a limit on exposure to protease inhibitor therapy in this group as many who are interferon refractory would not clear virus permitting the emergence of resistance. Although this period will require refinement in the future it appears to be 12 weeks based on the data we have presented herein. These patients are prevalent in practices but actually do not represent a majority of the infected population, certainly no more than 20%. It would be anticipated that half of these patients would not attain an SVR based on the data seen in treatment-failure patients Table 2.

Class IV
Patients would include Class IIIs who do not become undetectable by week 12, interferon-intolerant patients and all treatment failures fromtreated Classes I and II. This could be up to 30% of the US population infected with HCV based on the SVR rates proposed above. These patients would probably be best served by waiting for the availability of combination therapy with an NS3/4 protease and either an NS5B polymerase, an NS5A inhibitor, a cyclophilin inhibitor, or another interferon-free combination regimen.

The goal of therapy in these patients would be viral eradication but this is not likely to be an attainable outcome for most. Instead, viral suppression with cessation of histological injury will likely be the new goal in these patients. As such, the risks for resistance and the cost of long-term therapies will need to be major considerations in this population Table 3.

A summary from "New Future Hepatitis C Treatments: Interferon-sparing combinations"

The addition of a protease inhibitor to PEG-IFN plus ribavirin will increase the cure rate in both treatment-naïve and treatment-experienced patients and is likely to become the new SOC. However, there will still be a large ‘unmet need’, including patients unable to or unwilling to receive IFN or ribavirin therapy and previous non-responders to SOC
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The rationale for combining different DAAs is to increase viral suppression and prevent or delay the emergence of antiviral resistance.
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The ultimate goal is to develop a short-duration, IFN-free oral combination, with excellent tolerability and efficacy in both treatment-naïve and treatment-experienced patients.

With boceprevir or telaprevir in some cases resulting in a 67% to 75 % cure; it appears the time is right to consider treatment. Thousands and thousands of people now have a better chance of clearing HCV. It may not be one hundred percent yet folks, but its getting there.

Latest Updates
Feb 3
Protease Inhibitor–Resistant Hepatitis C Virus Mutants With Reduced Fitness From Impaired Production of Infectious Virus

Hepatitis C virus Resistance to Protease Inhibitors;
Halfon P, Locarnini S; Journal of Hepatology (Jan 2011)