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.
,
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
.
The rationale for combining different DAAs is to increase viral suppression and prevent or delay the emergence of antiviral resistance.
.
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)

No comments:

Post a Comment