Interferons And Pegylated Interferons
The two most frequently used recombinant interferon preparations in clinical trials have been IFN alfa-2b and IFN alfa-2a , which differ from each other by only a single amino acid residue. IFN alfacon-1 , or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs. Roferon-A was discontinued from the market in 2007 and Infergen was discontinued from the market in 2013.
The addition of propylene glycol molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.
Two PEG-IFN preparations are available for the treatment of chronic hepatitis C. PEG-IFN alfa-2b consists of IFN alfa-2b attached to a single 12-kd PEG chain it is excreted by the kidneys. PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG molecule it is metabolized predominantly by the liver.
The Origin And Epidemiology Of Hcv
The origin, evolution, and dynamics of HCV-4 are difficult to determine given the limited population-based epidemiological studies and phylogenetic analysis of this genotype in the geographic regions in which it is endemic, such as Egypt and Central and West Africa. The information available from small-scale field surveys from Central African countries and Cameroon in addition to sequence analysis studies applying the Bayesian coalescent approach indicate that HCV-4 strains circulating in Central Africa and Cameroon are extremely heterogeneous and that the estimated date of the most recent common ancestors for HCV-4 was 1500 , suggesting that it probably has been endemic for a long time., , – An exponential spread of genotype between 1920 and 1960 was detected in Cameroon, which coincided with the mass campaign against trypanosomiasis and mass vaccinations., This great genetic diversity in sub-Saharan Africa might lead to the hypothesis that HCV-4 originated and propagated in Central and West Africa before spreading to other regions., However, it is not clear how HCV infection was maintained for long periods among these populations prior to the known parenteral routes of transmission such as blood transfusion and injection. It is likely that other routes of transmission such as scarification, circumcision practices, or sexual transmission might have contributed to persistence and propagation of HCV transmission in tropical and subtropical settings.
Hepatitis C Virus Genotypes
An important variable for all patients with chronic hepatitis C virus is the”genotype” of HCV with which they are infected. This is the strain of the virus towhich they were exposed when they were infected, often many years prior to theirevaluation, and it is determined by a simple blood test. Genotypes of HCV aregenetically distinct groups of the virus that have arisen during its evolution. Approximately 75% of Americans with HCV have genotype 1 of the virus, and 20-25% have genotypes 2 or 3, with small numbers ofpatients infected with genotypes 4, 5, or 6. Most patients with HCVare found to have only one principal genotype, rather than multiple genotypes. Genotype 4 is much more common in Africathan in many other parts of the world, genotype 6 is common in Southeast Asia, andeach area of the world has its own distribution of genotypes.
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Retreatment Of Persons With Prior Peginterferon And Ribavirin Failure
The latest version of the AASLD-IDSA HCV Guidance no longer provides specific recommendations for retreatment of persons with a history of peginterferon plus ribavirin therapy, with or without an earlier generation direct-acting antiviral agent . The AASLD-IDSA HCV Guidance notes that these individuals respond to retreatment similar to treatment-naÃ¯ve persons, thus implying the treatment approach should be the same as with treatment-naÃ¯ve individuals. Although the pool of persons with a history of failure with a peginterferon-based regimen who need retreatment is small and diminishing, there are some individuals with this treatment history who need retreatment and may require special consideration that differs from that of treatment-naÃ¯ve individuals. The following outlines a few of these key considerations based on available data and previous guidance that should be noted when retreating an individual with a history of prior treatment failure with peginterferon plus ribavirin, with or without an earlier generation DAA . Note that except for the 8-week option of glecaprevir-pibrentasvir , when retreating these individuals with first-line DAA combinations that have pangenotypic activity , the treatment will be the same as their treatment-naÃ¯ve counterparts.
Studies Of Retreatment Of Adults With Hcv Genotype 4
The following key studies were used to support the recommendations for treatment of adults with HCV genotype 4 infection who have previously received treatment. Unless noted otherwise, treatment experience in these studies refers to a history of virologic relapse or nonresponse with a regimen that included peginterferon and ribavirin.
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Development Of Future Treatments: Daas
Currently, research is orientated to the development and approval of DAA agents regulated within the Center for Drug Evaluation and Research at the FDA for the treatment of chronic HCV. DAA agents inhibit specific stages in the HCV replication cycle through targeting the HCV polyprotein and its cleavage products.
The HCV life cycle: The HCV genome is composed of approximately 9600 nucleotides and generates structural and non structural proteins. The structural proteins are used to assemble new viral particles and the NS proteins support viral RNA replication. The NS3/4A, a serine protease and cofactor catalyze the post-translational processing of NS proteins from the polyprotein. The products released go on to form a replicative complex responsible for producing viral RNA using the RNA dependent/RNA polymerase . Finally, virions are assembled, packaged, and released.
Study Design And Population
This nationwide cohort study included patients infected with a nonepidemic HCV genotype treated with an interferon-free DAA regimen. Nonepidemic HCV genotypes were defined as genotypes and subtypes other than 1a/1b/2a/2b/3a/4a/4d. All laboratories performing HCV genotyping in the Netherlands were approached. All but 1 participated in the study: the Amsterdam University Medical Centers Sanquin Diagnostics, Amsterdam UMC Groningen, Groningen LUMC, Leiden Erasmus Medical Center, Rotterdam and Maastricht UMC, Maastricht.
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Treatments For Different Genotypes
DAAs are the most common treatment that directly targets the hepatitis C virus. A person may also need to take other medications, depending on the genotype of the virus and any complications of the infection.
The best treatment option tends to depend on whether or not the person has cirrhosis. The options below apply to people who have not previously received treatment for hepatitis C.
The following medications are recommended for genotypes 1a and 1b:
- elbasvir and grazoprevir
- ledipasvir and sofosbuvir
- glecaprevir and pibrentasvir
- sofosbuvir and velpatasvir
If a person has genotype 2 or 3, a healthcare provider may choose to prescribe glecaprevir and pibrentasvir or sofosbuvir and velpatasvir.
For people with genotypes 5 or 6, they may describe a combination of these medications. As one study paper concludes, developing more effective treatments and a better understanding of the prevalence of the condition will require more research.
The right treatment varies from person to person. When recommending a course of action, a healthcare provider will take into consideration previous treatments, medical history, overall health, and any complications of hepatitis C.
Genotype Table: Recommended Treatments For Hepatitis C Genotypes 1 2 3456
|Generic Brand Name|
|Hepatitis c Genotype 1, 4, 5, 6 treatment. It is mainly used to treat Hep C||A combination pill taken once a day. Its usually taken for 12-24 weeks, and sometimes only 8 weeks.||Major side effects are rare.||Natco, Hetero, Mylan, Zydus Cadila, Dr. Reddy|
|Hepcinat, Sofovir, Myhep, Sovihep, Resof||400 mg Sofosbuvir||2, 3, 4, 5, 6||1 Sofosbuvir pill and 1 Daclatasvir pill once a day for 12 weeks. Sometimes used with Ribavirin.||Major side effects are rare.||Natco, Hetero, Mylan, Zydus Cadila, Dr. Reddy|
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Background In Hcv Treatment
At the start of the millennium, two major advances in the management of HCV took place: one, the approval by the FDA of PEG-IFN for the treatment of HCV infection, which allowed weekly subcutaneous injections instead of the previous daily or thrice weekly injections with standard IFN and the use of weight-based RBV. By the mid-2000s, it was established that PEG-IFN-2a or PEG-IFN-2b could be combined with weight-based RBV for GT-1 infected patients, or with flat-dosed RBV for GT-2 or GT-3 infected patients, and that combination was better than treatment with standard IFN and RBV. HCV-GT-4 response to treatment with PEG-IFN/RBV has been considered better than GT-1, and worse than GT-2 and GT-3.
With the introduction of the HCV-GT-1 effective protease inhibitors boceprevir and telaprevir in 2011, HCV-GT-4 became the most difficult to treat, as both protease inhibitors are not indicated for treatment of GT-4. Many studies used 48 wk duration of combined therapy to treat HCV-GT-4, and a few of them compared responses between 24-wk treatment and 48-wk treatment response rates. Figures and summarize the results of those studies after using standard-dose PEG-IFN and RBV. The results show sustained virologic response rates with 24 wk of therapy to be far less than rates with 48-wk, making the longer duration the standard of care.
Liver Biopsy And Hepatic Venous Pressure Gradient
Significant histological improvements have been documented in studies of paired liver biopsies from patients with CHC who achieved sustained viral response . Liver biopsy might be necessary for patients infected with HCV genotype 1 or 4 or if there is TE and biomarker assay discordance. In addition, advanced fibrosis or cirrhosis on initial liver biopsy was associated with a modestly decreased likelihood of SVR to treatment .
Current evidence supports the validity of HVPG endpoints to monitor drug therapy efficacy for variceal bleeding prophylaxis. HVPG reduction to 12 mmHg or by 20% significantly reduced bleeding risk and a reduction of 20% significantly reduced mortality . As such, these hemodynamic targets should be considered for clinical practice .
Sanaa M. Kamal, in, 2018
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Sofosbuvir Plus Daclatasvir In Treatment Of Chronic Hepatitis C Genotype 4 Infection In A Cohort Of Egyptian Patients: An Experiment The Size Of Egyptian Village
1Internal Medicine Department, Gastroenterology and Hepatology Unit, Ain Shams University, Cairo, Egypt
2Tropical Medicine Department, Ain Shams University, Cairo, Egypt
3Tropical Medicine & Infectious Diseases Department, Tanta University, Tanta, Egypt
Several recent studies discussed the epidemiology of HCV infection worldwide. It is estimated that 10.4 million patients are infected with HCV genotype 4 which accounts for 13% of all HCV infections worldwide. HCV genotype 4 infection is common in the Middle East, Northern Africa, and Sub-Saharan Africa. In Egypt, 15% of an estimated population of 80 million is HCV positive, of which 93% are infected with genotype 4 .
During the past few years, there have been enormous efforts to understand the structure and life cycle of hepatitis C virus and to develop specific medications targeting different viral proteins such as NS3/4A protease, NS5B polymerase, and NS5A replication complex. The discovery of direct acting antiviral agents represented a revolution in the management of chronic hepatitis C virus infection .
The pipeline of treatment regimens included combining interferon with DAAs with or without Ribavirin. Later on, interferon-free regimens were introduced through combining different classes of DAAs together. A need has arisen for a DAA based regimen that is pangenotypic, is well tolerated with minimal adverse effects, has low pill burden, and shows minimal drug interactions .
Why Do People Have Different Genotypes
A person of any racial or ethnic group can carry any genotype or subtype. However, some may be more prevalent in some racial or ethnic groups than others. In the United States, over 90% of African Americans, compared to 67% of Caucasians, carry genotype 1.
People who travel between regions where different genotypes are more common can be exposed to different HCV genotypes, leading to a mixed infection. HCV is transmitted through contact with blood, such as through contaminated blood products or medical equipment, blood transfusions, kidney dialysis, or the sharing of drug injection equipment, such as syringes, or non-injection equipment, such as pipes, spoons, cotton balls, or straws for snorting drugs.
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Does Genotype Predict Response To Daa Therapy Like It Did For Interferon Therapy
Maybe maybe not.
Each of HCVs essential proteins work the same, regardless of genotype. These essential proteins may be structurally different due to small mutations.
Because theyre essential for the HCV life cycle, the structure of their active sites is least likely to change due to random mutation.
Because a proteins active site is relatively consistent between different genotypes, how well a particular DAA agent works is affected by where it binds on the target protein.
The effectiveness of those agents that bind most directly to the proteins active site is least likely to be affected by virus genotype.
All DAA drugs suppress ongoing HCV replication, but they dont eject the virus from its host cell. They also dont remove infected cells. This job is left to the persons immune system.
The variable effectiveness of interferon treatment indicates that the immune system is able to clear cells infected with some genotypes better than those infected by others.
Aside from genotype, there are many variables that can affect the likelihood of treatment success. Some of the more significant ones include:
- amount of HCV virus in your blood
- severity of liver damage before treatment
- the condition of your immune system
- ongoing alcohol misuse
- response to prior therapies
Certain human genes can also predict how well treatment may work. The human gene known as IL28B is one of the strongest predictors of response to PEG/ribavirin treatment in people with HCV genotype 1.
Do Genotypes Change Over Time
Typically, the viruss genotype stays the same. However, the hepatitis C virus can mutate. The mutation may have no effect, or it may allow the virus to become resistant to treatments.
Hepatitis C treatment typically involves more than one type of medication. This helps prevent the virus from developing drug resistance.
A person with hepatitis C carries the genotype of the virus that caused the infection. People of all races, ethnicities, and backgrounds can carry any genotype.
However, certain genotypes are more common in certain parts of the world.
According to a
- 46.2% of people with hepatitis C carry genotype 1
- 30.1% carry genotype 3
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Understanding Mutations Of Hepatitis C Genotypes
In addition to the different hepatitis C genotypes and subtypes, there are also quasispecies of the virus. After HCV infects the liver, the virus is constantly reproducing or making copies of itself. This happens on an almost unimaginable scale, with trillions of individual viruses replicating every day. As viruses replicate, some of the copies they make contain errors or mutations in their genetic code. Sometimes, a mutation results in a quasispecies of HCV that is successful at evading the bodys immune system. The immune system is constantly trying to catch up with the HCV virus as it produces slightly different versions of itself. Once the body has successfully eradicated an HCV quasispecies, another takes its place. Experts believe that this process of mutation and quasispecies development is the reason why so many people who are infected with HCV develop chronic disease and why infection is so difficult to cure. This also may be why it is so difficult to develop a vaccine against HCV.3
Hepatitis C Has Different Genotypes What Does This Mean
HCV is a single-stranded RNA virus. That means the genetic code of each virus particle is contained within one continuous piece of the nucleic acid RNA.
Every strand of a nucleic acid is made up of a chain of building blocks. The sequence of these blocks determines the proteins that an organism requires, whether its a virus, plant, or animal.
Unlike HCV, the human genetic code is carried by double-stranded DNA. The human genetic code goes through strict proofreading during the process of DNA replication.
Random changes to the human genetic code occur at a low rate. Thats because most mistakes of DNA replication are recognized and corrected.
In contrast, HCVs genetic code isnt proofread when its replicated. Random mutations occur and stay in the code.
HCV reproduces very quickly up to 1 trillion new copies per day. So, certain parts of HCV genetic code are highly varied and change frequently, even within a single person with an infection.
Genotypes are used to identify particular strains of HCV. Theyre based on differences in particular regions of the viral genome. There are additional branching subcategories within a genotype. They include subtype and quasispecies.
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Treatment For Hepatitis C Genotype : No Longer Scary
Worldwide, approximately 13 percent of patients with chronic hepatitis C infection have genotype 4. In the Middle East and Sub-Saharan African roughly half of the hep C cases are genotype 4. This figure jumps to 90 percent in Egypt, where roughly 11 percent of the population tests positive for hepatitis C-antibody.
Genotype 4 has been difficult to treat. A small study published in the October 2016 issue of Hepatology, showed good results using Harvoni for 12 weeks. The phase 2 study enrolled 44 subjects with varying subtypes 10 had cirrhosis half had no prior treatment. All subjects completed treatment and 3 relapsed within 4 weeks of completing treatment. Interestingly, none of those who relapsed had cirrhosis. Treatment was well-tolerated with mild side effects of weakness, headache, and fatigue.
Although this is fairly new research, note that the AASLD/IDSAs HCV Guidelines have been recommending this and the newer Epclusa for the treatment of Genotype 4 hepatitis C. Here are their recommendations, listed in descending order by the strength of evidence:
- Technivie plus ribavirin for 12 weeks
- Epclusa for 12 weeks