Geno types and Treatment Regimens Paper

During the last 5 years, the availability of direct-acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV). Compared with interferon/ribavirin-the previous standard of care-DAA combination regimens offer improved sustained virological response (SVR) rates, shorter treatment durations of 8-24 weeks, convenient once-daily single-tablet formulations and more favourable tolerability profiles. HCV treatment is complex, and the choice of therapy must consider a complex range of factors, including baseline viral load, fibrosis stage, the HCV genotype and subgenotype, and the presence of resistance-associated substitutions at baseline. Globally, HCV genotype 1 predominates, and there are extensive data and various treatment options available for this phenotype. Geno types 2-6 are prevalent and may even predominate in different geographical regions, reflecting diverse factors including human migration patterns and unsafe use of injection drugs and blood products. Such factors are themselves influenced by sociology-economic factors, and poor regions often have the greatest unmet need for effective HCV therapies. The latest pan-genotypic DAA combination regimens provide the potential to eradicate HCV around the globe, regardless of genotype, hence minimizing the need for virological testing services, which often are unavailable in poorer regions. Economics inevitably remain a barrier to access, and extensive cooperation will be required between clinical organizations and pharmaceutical manufacturers to agree appropriate pricing policies, especially in poorer economic regions. This review considers key data and treatment guidelines for DAA therapies, including pan-phenotype combination regimens, in the context of regional differences in HCV genotype and sociology-economic factors.Geno types and Treatment Regimens Paper

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A number of recent studies demonstrated that, when treated with direct-acting antivirals, there were comparable response rates in patients with hepatitis C virus genotype 4 as those reported for other genotypes. That is, upward of 95%. However, experts remain confounded by a host of obstacles that stand in the way of marginalizing — or eradicating — hepatitis C virus genotype 4.

The first is that genotype 4 disease affects very few North Americans but accounts for the majority of the burden in the Mediterranean and Middle East region, particularly in Egypt, the country with the highest prevalence of HCV. Because U.S.-based pharmaceutical companies have led the way in developing HCV drugs, they have not gathered sufficient numbers of patients to show definitive efficacy rates in this patient group. Moreover, creating intervention strategies in two hemispheres will require a coordinated international public health effort and must account for immigration patterns among those moving west to east and east to west.

Within the Mideast and African regions, wealthy countries like Saudi Arabia and the United Arab Emirates may have the resources to eliminate genotype 4 entirely, whereas more economically challenged states like Egypt or those in West Africa may be left at the mercy of high prices in the current marketplace.Geno types and Treatment Regimens Paper

For Tarek Hassanein, MD, professor of medicine at the School of Medicine at the University of California, San Diego, director of Southern California Liver Centers and director of Southern California Research Center, the current debate hinges on the FDA. He told HCV Next that genotype 4 disease responds to two-drug combinations like sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) and three-drug combinations like ombitasvir/paritaprevir/ritonavir with dasabuvir (Viekira Pak, AbbVie), but that those formulations are mostly left sidelined because they lack FDA approval for genotypes outside genotype 1.

“The FDA runs the show,” Hassanein said. “When they set the rules, the companies follow. Insurance companies tell me they can’t approve the use of these drugs, even though we know they work.”

In short, although many clinicians would consider off-label use of sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir with dasabuvir in genotype 4 patients, this approach is cost-prohibitive for most of the estimated 20 million people worldwide with this disease.

But despite these concerns, preliminary findings indicate that genotype 4 could be manageable with current therapies.

SYNERGY, PEARL-I

In the SYNERGY trial, researchers assessed 21 patients with HCV genotype 4 from Washington, D.C. However, the majority of patients came from Cameroon, Egypt and Ethiopia originally. Patients were treated with 12 weeks of sofosbuvir/ledipasvir.Geno types and Treatment Regimens Paper

The overall sustained virologic response rate at 12 weeks was 95%. Treatment history or fibrosis status did not affect outcomes. The researchers observed normalized alanine aminotransferase in 75% of the cohort after 4 weeks of treatment. The adverse event profile was consistent with what is normally reported for this regimen.

“This is the first report of an interferon and ribavirin free therapy for patients with HCV GT4. Interim data suggests that this single-pill combination therapy may be an effective regimen for this patient population,” the researchers concluded.Geno types and Treatment Regimens Paper

Findings from the open-label phase 2 PEARL-I study of ombitasvir/paritaprevir/ritonavir with ribavirin demonstrated 100% SVR12 rates in 42 treatment-naive patients and 49 previous treatment failures with peginterferon and ribavirin who received the three-drug regimen plus ribavirin.

Among 44 treatment-naive patients who received ombitasvir/paritaprevir/ritonavir, but without ribavirin, 90.9% achieved SVR12.

No patients discontinued treatment due to adverse events, and the regimens were generally well tolerated. No virologic failures were reported.

Sanaa Kamal, MD, professor of medicine in the department of gastroenterology, hepatology and infectious diseases at the Ain Shams Faculty of Medicine in Cairo, put these findings in perspective. “Exciting news,” she said. “However, such results must be interpreted cautiously. Let’s look at the numbers. In SYNERGY and PEARL-1, only 21 and 86 [genotype 4] patients were enrolled. Thus, the conclusions derived from such studies may require careful consideration of the assumptions and inferences, given the small sample size.”Geno types and Treatment Regimens Paper

She added, “Currently, several trials are being conducted in Egypt to investigate the outcome of various DAA combinations on patients with chronic HCV genotype 4 to optimize therapies with high sustained virologic response, reasonable treatment period and minimal adverse events. Cost-effectiveness is an important issue given the huge numbers of patients treated. The results of such trials are important to standardize therapy of HCV genotype 4.”

What does pan-phenotype mean?

Before we can get into the definition of pan-genotypic, let’s back up and talk about genotypes overall. Currently, there are seven known hepatitis C genotypes (called “genotype 1,” “genotype 2,” and so on). However, some field experts think there might be even more genotypes – at least eleven.

Different genotypes impact the genetic makeup of hepatitis C (hep C) in different ways, with up to 1/3 of a difference in each genotype. This means that the viruses are different if one is within genotype 1 and another is within genotype 2. That means that the medications that work for genotype 1 might not work at all or might be less effective in someone with genotype 2. As a result, when it comes to treating people who have hep C as effectively as possible, the genotype matters. The most common genotype is genotype 1. Genotypes 2 and 3 are fairly common, and the other known genotypes (4, 5, 6, 7) are incredibly rare (less than 1% of people combined have these genotypes).Geno types and Treatment Regimens Paper

Based on this information, most medications are targeted toward the genotypes 1, 2, and 3. This makes sense, as this accounts for approximately 99% of all hepatitis C infections. However, what works great for one might not work for another, which means that, in the past, there has been some trial and error when it comes to hep C medication. It also means that some do not have medication-based relief of symptoms during the period of time in which their physician is narrowing down what medication is best, based on which genotype of hepatitis C the particular patient has.

Obviously, this can be a very stressful process for everyone involved, and it can be expensive, since it may mean multiple visits to the doctor (including office fees, commuting costs, missing work, arranging childcare, etc.), as well as spending money on medications that may not work.Geno types and Treatment Regimens Paper

This is where pan-genotypic drugs come in. Pan-genotypic means that the drug treats numerous genotypes, not just one.

How does this research impact Hep C in general?

With information available that has lead to one initial drug that is pan-genotypic (currently being researched by Gilead), it is possible for researchers to begin to measure the impacts of such a drug. This is information that can be incredibly important to drug makers, since it helps them to decide whether it is worth putting more money into finding additional pan-genotypic drugs for those with hepatitis C.

Researchers will measure the frequency of doctors prescribing this new medication compared to the previously existing medications. They will measure how often patients purchase the new medication, and they will begin to ascertain whether pan-genotypic drugs can become profitable for their drug company. If one company believes there is enough profit to be made, other companies will likely take notice and begin their own research.

Thus, if the first pan-genotypic drug is successful among doctors and patients, it could be the beginning of many more pan-genotypic drug options in the future.

How can this new research benefit me and impact my experience with Hep C?

Some researchers believe that an individual with hepatitis C can have multiple genotypes in their viral load, even as much as 25%. For those people, current medications may never have worked as well as one would wish, since they could only truly be targeting one genotype at a time. With the new pan-genotypic drug (right now, being tested by Gilead), treatment options may be better.Geno types and Treatment Regimens Paper

This might mean a greater reduction in your symptoms, this might mean a drop in your viral load, or it might mean that you’ll need to take fewer medications to control your infection. In addition, the treatment method(s) being offered to you in the present or in the future may be much more effective for your specific virus’ genotype (or genotype combination) than you’ve experienced with previous treatment options.

If you have struggled with finding medication that works for you, do not give up hope, see your doctor to discuss the new possible options.

Just remember that research is ongoing, and as initial research is being done for pan-genotypic medication options, it is best to speak with your physician if you have questions about your current medication(s) or whether the new pan-genotypic option is right for you and your individual needs.

As is true with all medication, it is important not to self-diagnose or use a friend’s prescription to test whether something may work for your own infection. Only your doctor will know your own medical history, and they can help you to understand which medications and medical options are best for you.

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In this month’s The Five I will discuss pan-genotypic drugs. I will begin with a brief discussion of hepatitis C (HCV) genotypes, a definition of pan-genotypic drugs, why they have emerged as an important part of treatment, what pan-genotypic drugs are approved and ones in the pipeline to treat HCV.Geno types and Treatment Regimens Paper

1. Genotypes – there are seven genotypes—numbered 1 through 7—although some experts believe there may be as many as 11 genotypes. The difference in the genotypes is due to a 1/3 difference in the genetic makeup of the HCV virus.

The most common genotype worldwide and in the United States is genotype 1. Genotype 3 is the second most common in the U.S. followed by genotype 2. Genotype 4, 5 and 6 accounts for less than 1% of HCV the U.S. population. There have been only four people identified with genotype 7—one person—an immigrant in Canada from the Democratic Republic of the Congo and three other people who live in the Democratic Republic of the Congo.

2. Pan-genotype Drugs – these are drugs that work against every genotype. The drugs may not have the same amount of antiviral activity against every genotype. For instance, one pan-genotypic drug may have a high rate of antiviral activity against genotype 1, but have a low level of antiviral activity against genotype 3. There will need to be clinical trials conducted to find out how well a particular drug works on every genotype. Most likely there will be a combination of different types of HCV inhibitors combined with the pan-genotypic drugs and different treatment durations because of the different levels of antiviral activities of the drugs.Geno types and Treatment Regimens Paper

3. The Future – Pan-genotypic drugs are the next leap forward in the treatment of hepatitis C. This is for many reasons. As stated above they can be combined with other drugs to treat many different genotypes. We know that some people have multiple genotypes. This is an area that needs much more research, but it is believed that about 5% to 25% of people have multiple genotypes. This can happen if people received blood transfusions before the blood products and organ transplants were screened for hepatitis C, and in people who inject drugs who share needles and works, and have multiple exposures. Treating hepatitis C with pan-genotypic drugs will treat these multiple genotypes.

4. Current Pan-genotypic Drugs – Sofosbuvir and daclatsavir are examples of current drugs that are FDA approved that are in fact pan-genotypic drugs. While they are active against all genotypes, they work better against some genotypes more than others. That is the main reason they are combined with other direct acting antiviral drugs.

5. Pan-genotypic Pipeline – There are currently two combinations that are under review by the Food and Drug Administration for marketing approval. The combination of sofosbuvir plus velpatasvir—formerly GS-5816 (with and without ribavirin) has cure rates from 80% to 100% in genotypes 1 to 6 (see the article on page 2). Merck’s combination of grazoprevir plus elbasvir is expected to be approved in January 2016 to treat genotypes 1,4 and 6 – the cure rates from the phase 3 clinical trials were 92% to 99%.Geno types and Treatment Regimens Paper

There are many pan-genotypic drugs in development. Janssen, Achillion, and Johnson and Johnson are collaborating on various drug combinations that include pan-genotypic drugs. AbbVie and Enanta are also developing a combination of two drugs (including a pan-genotypic drug) to treat hepatitis C.

The future of hepatitis C has never been more promising in HCV drug development. The only dark cloud is the price and subsequent access to treatment. Hopefully, as more drugs become available, the prices will come down so that everyone will have access.

HCV treatment can vary based on the genotype of the virus, as well as other treatments attempted or failed. Ultimately, your provider will help you determine the best treatment regimen for your specific situation, but there are many guidelines that exist that provide typical treatment recommendations for each genotype. Your provider will consider guidelines like these as well as other factors including efficacy, adverse effects, drug interactions, past medical history (including kidney or liver problems, as well as HIV and other medical concerns), duration, stage of fibrosis, and insurance coverage. Most treatment regimens range from 12 to 24 weeks; however, some can reach up to 48 weeks. It is important to note that treatment guidelines are continually changing, which is why it is important to always consult your physician for the most recent information. Currently, the three main classes of medications for HCV are interferon, ribavirin, and direct-acting antivirals (DAA’s).Geno types and Treatment Regimens Paper

Interferon

Interferon treatments, like pegylated interferon (peginterferon) mimic proteins in our body that are designed to fight off infections.¹ As your body is fighting off infections it produces interferons. These proteins are largely responsible for the fatigue, nausea, and other symptoms we commonly associate with the flu. Interferons are given via an injection, and used to be the main form of treatment for all individuals with HCV. Interferon can be administered with or without ribavirin. Interferon treatment is slowly being replaced by direct-acting antivirals which have higher rates of sustained virologic response, and a better rate of treatment completion due to their fewer, and more tolerable, side effects. Interferon can be used for many different genotypes, however, it has the lowest success rate for genotype 1. Common side effects of interferon include, but are not limited to:

 

• Flu-like symptoms (chills, fever, headaches, generalized aches and pains, and poor appetite)
• Fatigue
• Drowsiness
• NauseaVomiting

Ribavirin

Ribavirin is not a stand-alone treatment, and is used across genotypes depending on what it is used in conjunction with. Ribavirin can be used alongside both DAA’s and interferon. The decision to add ribavirin to your treatment will be made by your provider, and can be influenced by the main medication your treatment will include, as well as the presence and severity of cirrhosis. The side effects that accompany ribavirin are often the product of other medications taken with it. For example, ribavirin taken with peginterferon still produces flu-like symptoms.Geno types and Treatment Regimens Paper

Direct-Acting Antivirals

Direct-acting antivirals (DAA’s) are a relatively newer class of medication that acts to target specific steps in the HCV viral life cycle.² The goals of DAA’s are to shorten the length of therapy, minimize side effects, target the virus itself, and improve sustained virologic response rate. HCV is an RNA molecule that makes its own structural and non-structural proteins that help it replicate and assemble new virions. Due to their high rates of sustained virologic response and minimal side effects, DAA’s are slowly replacing interferon treatment. Genotype 1 has the most DAA treatment options, however, all other genotypes have at least one DAA option. Deciding which DAA to use depends on the genotype, as well as if the patient is treatment-naïve (meaning never experiencing HCV treatment) or treatment-experienced (meaning tried and failed other treatment options).

Treatment options for HCV Genotype 1

Genotype 1 HCV was previously the hardest to treat, as its response to interferon was the least impressive. Now, there are six DAA-driven treatment options for both genotypes 1a and 1b, with 1b typically having the higher success rate of the two. For individuals with genotype 1 HCV without cirrhosis or with compensated cirrhosis, who are either treatment-naïve or have failed treatment with peginterferon and ribavirin, the treatment options are as follows:Geno types and Treatment Regimens Paper

• Harvoni (Ledipasvir-sofosbuvir)
• Epclusa (Sofosbuvir-velpatasvir)
• Zepatier (Elbasvir-grazoprevir)
• Technivie (Ombitasvir-paritaprevir-ritonavir) plus Exviera (dasabuvir), with or without ribavirin
• Viekira Pak (ombitasvir-paritaprevir-ritonavir tablet with accompanying dasabuvir tablet)
• Viekira XR (dasabuvir-ombitasvir-paritaprevir-ritonavir)
• Daklinza (daclatasvir) plus Sovaldi (sofosbuvir)
• Mavyret (glecaprevir-pibrentasvir)

For individuals with prior protease inhibitor exposure, including telaprevir, simeprevir or boceprevir, this list is the same, with the exception of Technivie and Simeprevir with Sovaldi. With previous exposure to Sovaldi (sofosbuvir), this list shrinks even further to include only Harvoni and Epclusa. For individuals with decompensated cirrhosis, the use of DAA’s is not recommended unless under direct supervision. Potential DAA’s to be used under supervision for genotype 1 with decompensated cirrhosis are Harvoni, Epclusa, and Daklinza with Sovaldi.^3,4

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Treatment options for HCV Genotypes 2 and 3

Genotype 2 HCV shows strong success rates with peginterferon and ribavirin alone. However, there are a few DAA’s indicated for use by those with genotype 2 HCV without cirrhosis or with compensated cirrhosis, regardless of treatment history. These include:

• Epclusa (Sofosbuvir-velpatasvir)
• Mavyret (glecaprevir-pibrentasvir)
• Daklinza (daclatasvir) plus Sovaldi (sofosbuvir)
• Sovaldi (sofosbuvir) plus ribavirin (with or without peginterferon)

Currently, treatment guidelines recommend Epclusa and Mavyret first, followed by Daklinza as an alternative.Geno types and Treatment Regimens Paper

Genotype 3 HCV is similar in treatment options to genotype 2 HCV, with one additional DAA option. Regardless of treatment history, there are several DAA’s indicated for use by those with genotype 3 HCV without cirrhosis or with compensated cirrhosis. These include:⁵

• Mavyret (glecaprevir-pibrentasvir)
• Epclusa (Sofosbuvir-velpatasvir)
• Daklinza (daclatasvir) plus Sovaldi (sofosbuvir)
• Sovaldi (sofosbuvir) plus ribavirin (with or without peginterferon)

Currently, treatment guidelines recommend Mavyret and Epclusa first, followed by Daklinza as an alternative.

For individuals with decompensated cirrhosis, the use of DAA’s is not recommended unless under direct supervision. Potential DAA’s to be used under supervision for genotype 2 or 3 HCV with decompensated cirrhosis are Epclusa plus ribavirin as well as Daklinza plus Sovaldi.

Treatment options for HCV Genotype 4

Genotype 4 HCV has several interferon-free treatment options that have high efficacy rates in comparison to their interferon-only containing counterparts. Genotype 4 treatments for individuals without cirrhosis or with compensated cirrhosis, regardless of treatment history are:

• Harvoni (Ledipasvir-sofosbuvir)
• Epclusa (Sofosbuvir-velpatasvir)
• Zepatier (Elbasvir-grazoprevir)
• Technivie (Ombitasvir-paritaprevir-ritonavir) plus ribavirin
• Sovaldi (sofosbuvir) plus ribavirin
• Mavyret (glecaprevir-pibrentasvir)

Ribavirin may be added in conjunction with several of the above DAA’s if patients are treatment-experienced.^{6Geno types and Treatment Regimens Paper}

For individuals with decompensated cirrhosis, the use of DAA’s is not recommended unless under direct supervision. Potential DAA’s to be used under supervision for genotype 4 HCV with decompensated cirrhosis are Harvoni and Epclusa, both in addition to ribavirin.

Treatment options for HCV Genotype 5 and 6

Genotype 5 and 6 currently have the same treatment options available. Genotype 5 and 6 treatments for individuals without cirrhosis or with compensated cirrhosis, regardless of treatment history are:

• Harvoni (Ledipasvir-sofosbuvir)
• Epclusa (Sofosbuvir-velpatasvir)
• Sovaldi (sofosbuvir) plus ribavirin
• Mavyret (glecaprevir-pibrentasvir)

Like other genotypes, treatment with peginterferon and ribavirin is also a possibility if DAA treatments aren’t effective, however, the efficacy rate of this alternative treatment is substantially lower than the DAA treatment options.⁶

For individuals with decompensated cirrhosis, the use of DAA’s is not recommended unless under direct supervision. Potential DAA’s to be used under supervision for genotype 5 and 6 HCV with decompensated cirrhosis are Harvoni and Epclusa in addition to ribavirin, the same as genotype 4 HCV.Geno types and Treatment Regimens Paper

Genotype 3 (GT3) hepatitis C virus (HCV), the second most common HCV genotype worldwide, has emerged as the most difficult-to-cure genotype. Sustained virological response (SVR) rates with new direct-acting antiviral regimens for GT3 patients who are treatment-naïve and noncirrhotic are now similar to those seen in patients with non-GT3 HCV infection. However, GT3 HCV patients who are treatment-experienced or who have cirrhosis, particularly those with decompensated disease, continue to be a more challenging group to treat due to lower SVR rates. Here, we review the current evidence for the treatment of patients with GT3 HCV including current data for patients with GT3 HCV who are HIV coinfected. Future studies in GT3 HCV treatment will need to focus on direct-acting antiviral combinations that improve cure rates and potentially eliminate the need for ribavirin in GT3 patients who have advanced liver disease. The significance of HCV resistance-associated variants in GT3 HCV patients who have failed prior treatment also needs further assessment to help guide re-treatment strategies.

An international team of scientists, including KAIMRC’s Faisal Sanai, have had encouraging results using a new combination of antivirals on patients with a hepatitis C virus genotype common in the Middle East. Their results suggest that the combination therapy is highly effective, especially if the infection is caught in the early stages.

The development of new antiviral drugs to treat the hepatitis C virus (HCV) has transformed our ability to tackle the disease, but there is scope for improvement. One challenge is to create fast-acting treatments, reducing discomfort for patients and limiting costs.Geno types and Treatment Regimens Paper

HCV is a leading cause of liver disease and, if left untreated, can lead to liver cancer and cirrhosis. The virus is categorised into seven genotypes, each responding to treatment with varying degrees of success. Genotype 4 is most prevalent in the Middle East, where it accounts for 80 per cent of cases. However, it is notoriously difficult to treat, requiring a 48-week treatment regimen using peg-interferon α and ribavirin (known together as PR), with only a moderate success rate.

The development of drugs called ‘direct-acting antivirals’, or DAAs, used in combination with PR, has enabled scientists to target the virus more efficiently than ever before. However, the cost of DAAs limits availability to patients, particularly in resource-poor places.

The research team trialled a combination treatment of a DAA, called simeprevir, and PR on 67 patients with HCV genotype 41 who had never received treatment.Geno types and Treatment Regimens Paper

All patients had mild to moderate fibrosis: thickening and scarring of liver tissues. Those who responded well to the treatment within the first two weeks, and who showed undetectable levels of HCV RNA by week eight, were eligible for cessation of treatment at week 12. All others continued treatment until week 24.

Of the 67 patients treated, 34 received the 12-week treatment, and all of these patients had undetectable HCV RNA at the end of the course. Further, 97 per cent of the group continued to be clear of the virus three months later.

“[Such] regimens may broaden the range of patients able to access effective treatment … [and] decreasing treatment duration is very appealing to patients and physicians,” state the authors in their paper published in PLOS One, which reports only on the results of the 12-week regimen. “The cost-effectiveness of early treatment is well-established, particularly [considering] the risks of transmission and [disease] complications.”Geno types and Treatment Regimens Paper