Sensitivity And Heterogeneity Analysis
The summary estimate for SVR rate in patients treated with IFN alone was 9.6% , 32.8% in patients treated with IFN-RIB, and 40.6% in patients receiving PEG-RIB. The summary estimate for SVR rate in studies from Asian countries was 31.7% within the subgroup of cohort trials, the summary estimate for SVR rate was 26.3% .
The summary estimate for drop-out rate in patients treated with IFN alone was 25.4% , 24.4% in patients treated with IFN-RIB, and 20.1% in patients receiving PEG-RIB. In Asian countries, the summary estimate for drop-out rate was 16% within the subgroup of cohort studies, the summary estimate for drop-out rate was 20.5% .
Graft dysfunction occurred in approximately one-fifth of RT recipients who received IFN-based therapy for HCV infection. Although 13 patients who reported graft dysfunction were able to complete their treatment. A total of 31 patients discontinued treatment as a result of side-effects, including 14 patients cessation from treatment because of graft dysfunction. Thus, graft dysfunction was the most frequent side-effect of requiring discontinuation from treatment .Of the 12 reports included in our meta-analysis, only 3 used PEG-based therapies, and no studies included a control group. Thus, we were unable to conduct a subgroup analysis of IFN and PEG to calculate pooled odds ratios or mean differences in comparison.
How Does It Work
While the interferon used for hepatitis treatment is slightly different from the kind made in the body, it helps defeat the virus in three ways:
Interferon helps the body distinguish between cells infected by the virus and non-infected cells, targeting infected cells for destruction. For unknown reasons, a virus in the liver often becomes invisible to the immune system. If your body cant see the virus, it cant destroy it. This invisibility permits the virus to multiply within the liver, fostering a more chronic and severe infection. Scientists have learned that if they gave synthetic interferon to a person with chronic viral hepatitis, they could increase the immune systems ability to detect, or see, the infection. Imagine liver cells blending in with invaders, both a clear transparent color. The addition of interferon is like staining the infection deep red, highlighting them so they can be targeted for the immune systems fighter cells. Interferon also helps patients with viral hepatitis by directly suppressing the formation of new virus particles within the liver.
Treatment Of Hcv Genotype 2
The FISSION study compared SOF/RBV for 12 weeks versus peg-IFN/RBV for 24 weeks in treatment-naïve patients and showed an overall SVR rate of 97% for SOF/RBV, whereas peg-IFN/RBV showed only an SVR of 78% in GT2 patients . The POSITRON study showed an SVR > 90% in cirrhotic and non-cirrhotic patients with GT2 who were treated with SOF/RBV for peg-INF intolerance, contraindication, or due to the patients decision . Based on these studies, most guidelines consider 12 weeks of SOF plus RBV as the standard of care. Treatment may be extended to 16 weeks in patients with liver cirrhosis.
The combination of the NS5A inhibitor DCV in combination with SOF and RBV for 24 weeks showed an SVR of 92% in GT2 without cirrhosis . This combination can be recommended as a second-line therapy for SOF/RBV relapse patients.
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Potential Clinical Use Of The Il28b Snp Genotypes
The Human Genome Project promised to introduce an era of personalized medicine in which genetic testing would improve medical practice by predicting the likelihood of response to drugs . That promise may be fulfilled for the treatment of chronic hepatitis C. There is now a commercially available laboratory test for IL28B rs12979860 genotype however, the optimal use for this test remains to be determined. Clinical decision making for treatment of HCV-infected patients requires a prediction of the likelihood of achieving SVR that considers not only IL28B genotype, but also other factors that influence treatment response such as racial ancestry, viral genotype, pre-treatment HCV RNA levels and fibrosis stage among others. A prototype model was developed for prediction of SVR among the subjects enrolled in the HALT-C Trial of patients with advanced fibrosis or cirrhosis who had failed prior treatment with IFN- . This model, which is based on IL28B genotype and four clinical variables, appears to have much better discrimination and predictive ability than can be obtained by using IL28B genotype alone. Efforts are underway to extend this approach to a wider range of patients with chronic hepatitis C in hopes that it can be used clinically.
What Kinds Are There
Scientists have determined that the body makes three distinct types of interferon alpha, beta and gamma interferon, each containing several members. Alpha interferon has been approved for therapeutic use against a specific type of leukemia, hepatitis B and C, genital warts, AIDS- related Kaposis sarcoma and some rare cancers of blood and bone marrow. Nasal sprays containing alpha interferon provide some protection against colds caused by rhinoviruses.
There are two primary types of interferon currently available. To date, interferon-alpha 2a or 2b is the compound that has been extensively used and tested. Though the dose varies, patients with chronic hepatitis C usually receive 3 million units, three times per week. Individuals with chronic hepatitis B receive a higher dose of 10 million units, three times per week. Although it can widely vary, the typical duration of therapy is 48 weeks for hepatitis C, and 16 weeks for hepatitis B.
Interferon used for hepatitis treatment alpha and pegylated forms have been known to cause severe side effects, including:
- worsening of psoriasis
- elevated liver enzymes
- difficulty concentrating and impaired memory
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Functional Impact Of The Il28b Polymorphisms
The identity of the functional variant underlying this association is unknown. Ge et al. identified two polymorphisms in high linkage disequilibrium with rs12979860 as potential functional variants. As shown in Figure 1, rs28416813 is located 37 bp upstream of the transcription start site for IL28B, and, therefore, might potentially regulate gene transcription. SNP rs8103142 is located in the coding region of exon 2 of IL28B, and results in a single amino acid change from lysine to arginine at position 70 . However, there were no differences in the relative potencies of IFN-3-Arg70 versus IFN-3-Lys70 when these variants were evaluated in two different bioassays .
Viral Kinetics In Response To Interferon
The typical response to IFN therapy is a biphasic decline in HCV RNA levels after a short time period , which is believed to reflect the sum of IFN pharmacokinetics/pharmacodynamics and the features of the HCV life cycle.32,38–40 The first phase decline in viral loads is rapid, dose-dependent, and usually occurs within the first 24 or 48 hours after treatment initiation. The slope of the first phase is not correlated with baseline viral load or alanine aminotransferase level,32 a surrogate marker of liver cell necrosis. The first phase is followed by a second, slower phase, which seems not to be correlated with drug dose. However, the slope of the second phase decline demonstrates considerable inter-patient variability.32 Why does HCV RNA decline undergo a rapid first phase and then a significantly slower second phase? Why does the first phase decline depend on drug dose? Why does the second phase decline vary significantly in patients? Mathematical models have been developed and provided insights into these questions .
Biphasic HCV RNA decline after IFN treatment of chronic hepatitis C. Before initiation of therapy, the viral load is at the set-point level. The first phase decline lowers HCV RNA levels 1-2 logs during the first 1-2 days of treatment. It is followed by a slower second phase viral decline during the subsequent weeks of therapy.
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Antiviral Medication For Hepatitis B
Doctors may recommend antiviral medication for people with chronic hepatitis B, which occurs when the virus stays in your body for more than six months.
Antiviral medication prevents the virus from replicating, or creating copies of itself, and may prevent progressive liver damage. Currently available medications can treat hepatitis B with a low risk of serious side effects.
NYU Langone hepatologists and infectious disease specialists prescribe medication when they have determined that without treatment, the hepatitis B virus is very likely to damage the liver over time. People with chronic hepatitis B may need to take antiviral medication for the rest of their lives to prevent liver damage.
There are many different types of antiviral medications available, and your doctor recommends the right type for you based on your symptoms, your overall health, and the results of diagnostic tests. A doctor may take a wait-and-see approach with a person who has a healthy liver and whose blood tests indicate a low viral load, the number of copies of the hepatitis B virus in your bloodstream.
Someone with HIV infection or AIDS may have a weakened immune system and is therefore more likely to develop liver damage. The U.S. Centers for Disease Control and Prevention strongly recommends that people with HIV infection who are diagnosed with hepatitis B immediately begin treatment with antiviral medication.
Drug Resistance To Direct Hcv Antivirals
Although direct acting small-molecule HCV enzyme inhibitors have shown promising antiviral effects in early clinical trials, emergence of drug resistant variants may complicate the treatment of HCV patients with these STAT-C agents.18 Because of high-level viral replication32 and the error-prone nature of HCV RNA polymerase,111 amino acid mutations in the NS3 and NS5B proteins can be generated before therapy. Indeed, the viral population exists as a complex mixture of genetically distinct, but closely related, variants, referred to as a quasispecies.112,113 Normally, these mutations are associated with a fitness cost. Thus, they are present at low concentrations compared with the dominant wild-type virus before therapy. After treatment initiation, these minor viral populations with reduced sensitivity to the administered drug may gain a fitness advantage and begin to grow. A few factors may influence the selection and evolution of drug resistant variants, e.g., the number of mutations needed to confer resistance, the level of resistance conferred by mutation, the prevalence of viral variants before therapy, intrinsic replication capacity of variants, and replication space .
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Expression Of Fusion Genes In Pichia Pastoris
The positive colonies were cultured and induced with 1.0% methanol to express recombinant fusion proteins for 120hours at 20°C in BMMY pH 5.0 medium with shaking at 300rpm. The total secretory protein from induced culture supernatant were precipitated and analyzed by SDS-PAGE under both reducing and non-reducing conditions. Under non-reducing conditions, a band of ~93.2kDa showed the formation of homodimer of each fusion protein while this size reduced to ~46.6kDa in gel under reducing conditions. The ~46.6kDa band corresponds to the estimated size of monomeric fusion protein .
Expression analysis of fusion genes under reducing and non-reducing SDS-PAGE. SDS-PAGE analysis of expression under reducing conditions and under non-reducing conditions. Lane M: protein size marker, Lane 1: Total secretory proteins of GS115 transformed with pPICZA plasmid, Lane 2: total secretory proteins of GS115 expressing IFN2b-NS3-LAP fusion protein, Lane 3: total secretory proteins of GS115 showing expression of LAP-NS3-IFN2b fusion protein. The bands of size 46.6kDa indicate monomeric form of fusion proteins and 93.2kDa bands indicate homodimeric form of fusion proteins.
Association Of Type Iii Ifn Polymorphisms With Hcv Spontaneous Clearance And Response To Ifn Therapy
Table 2. Type III IFN gene polymorphisms.
In 2013, a new dinucleotide polymorphism rs368234815 located near the IFNL3 gene was identified, and the variants TT or G were associated with a frame shift resulting in either production of a new protein, IFN-4, or absence of the protein due to the introduction of a frameshift creating an early stop codon . This new polymorphism was in high linkage disequilibrium with the IFN-3 rs12979860 polymorphism and was found to be a stronger predictor of HCV spontaneous resolution and treatment outcome of chronic HCV . Another group reported association of the TT/G polymorphism with HCV treatment outcome in a large European cohort . Given that the IFN-3 rs12979860 was located within the newly discovered IFN-4 region, it was suggested to change its nomenclature to IFN-4 rs12979860 .
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Serious Depression And Other Mood Disorders
Interferons can cause or worsen serious depression or other mental illness. The risk for each condition is higher if youve had that condition before. Its not known why interferons can cause mood disorders.
Symptoms may include:
- flu-like symptoms
- skin changes such as bruising, flaking, and redness
Construction And Cloning Of Lap
LAP-NS3-IFN gene was constructed in the same manner as described for IFN-NS3-LAP gene. Briefly, LAP gene was amplified from LAP plasmid without its stop codon using primer RP1 and FP1 . The IFN-2b gene was amplified from pIFN plasmid using primers FP2 and RP2 . The full length gene LAP-NS3-IFN was amplified by SOE-PCR using FP1 and RP2 primers. The tag peptide sequence was introduced by OPW-PCR using FP3 and FP4 primer along with RP2 primer. The primers FP4 and RP2 introduced xbaI and xhoI sites at 5 and 3 end of gene. The fusion gene was cloned in pPICZA plasmid digested with xbaI and xhoI restriction enzymes. The recombinant plasmid was designated as pPICZA-LAP-NS3-IFN.
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Organization And Transcriptional Regulation Of The Ifn
IFNs are part of a larger family of structurally related class-2 proteins that also includes six IL-10-related cytokines: IL-10, IL-19, IL-20, IL-22, IL-24 and IL-26 . This subset of cytokines can be grouped in the same family because they all signal via receptors that share certain common motifs in their extracellular domains . These receptors comprise the class 2 cytokine receptor family. The IFN- proteins share common structural features with the IL-10-related cytokines, particularly IL-22 however, unlike IFN-, IL-22 does not induce antiviral activity in IL-22 receptor-positive target cells. This supports the functional classification of the IFN- proteins as a unique group of IFNs instead of as a novel group of interleukins. Phylogenetically, IL28A, IL28B and IL29 reside somewhere between the type-I IFN and IL-10 gene families . Amino acid sequence comparisons have shown that the type-III IFNs share only weak sequence similarity with either type-I IFNs or the IL-10-related cytokines.
In Vitro Cleavage Assay Of Fusion Proteins
The fusion proteins were incubated overnight with recombinant HCV NS3 protease of genotype 3a in 1: 10 molar ratio at 37°C in total volume of 100µl using 1x reaction buffer . In order to check the chances of fusion protein activation in blood during systemic delivery, the in vitro cleavage assay was also performed using serum and PBMCs isolated from HCV infected patients instead of recombinant NS3 protease in assay. The cleavage of fusion proteins was analyzed by 12% SDS-PAGE, western blot and by sandwich ELISA. For sandwich ELISA, 100µl of cleavage reaction mixture was added to wells of 96 well microtitre plate pre-coated with mouse anti-human LAP antibody and incubated for 4hours at room temperature. The wells were washed thrice with 1x PBS and incubated with 100µl of mouse anti-human IFN2 antibody for 4hours at room temperature. The immunocomplex was detected using 100µl of alkaline phosphatase conjugated goat anti-mouse IgG . After washing with 1x PBS, the color reaction was developed using 100µl of p-nitrophenyl phosphate by incubation of 10minutes at 37°C. The absorbance was recorded at 405nm. The cleavage was monitored using standard curve developed with different concentrations of intact fusion protein by aforementioned sandwich ELISA. The negative control reaction without NS3 protease was also performed.
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Summary Of The Role Of Type Iii Ifns On Hematopoietic Cells
Within the hematopoietic compartment, DCs are the main producers of IFN-, and they can travel between the liver and peripheral blood. The production of IFN- by DCs can inhibit HCV RNA replication in hepatocytes. However, HCV proteins E2 and NS3 can also inhibit IFN- production by DCs. Hematopoietic cells express variable levels and splice variants of IFN-R1, and conflicting results were obtained about the effect of IFN- treatment on these cells. HCV exposed DCs or DCs treated with IFN- display reduced stimulation of T cells by upregulating expression of PDL1 and enhanced proliferation of Tregs. Monocytes are responsive to IFN- treatment resulting in IL-12 and IL-18 production. In turn, these cytokines can influence NK cell functions, and thus, IFN- is an important component of the innate immune response to HCV. The role of IFN- on CD4 and CD8 T cells as well as on B cells in the context of HCV remains understudied, but studies suggest that IFN- could modulate the CD4 Th1/Th2 balance and can also have a positive or negative impact on IgG production by B cells .
Are There Any Differences Among The Different Types Of Interferons
Although interferons are very similar they affect the body differently. Therefore, different interferons are used for different conditions.
- Interferon alphas are used for treating cancers and viral infections
- interferon betas are used for treatingmultiple sclerosis and
- interferon gamma is used for treating chronic granulomatous disease.
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Using Pegylated Interferon And Ribavirin To Treat Patients With Chronic Hepatitis C
RAYMOND P. WARD, M.D., PH.D., St. Marys Family Practice Residency, Grand Junction, Colorado
Am Fam Physician. 2005 Aug 15 72:655-662.
Hepatitis C virus infection is the most common chronic blood-borne infection in the United States, with en estimated 3.8 million persons exposed and 2.7 million persons chronically infected.1 The incidence of new infections was greatest from the 1960s through the 1980s, peaking at around 250,000 new cases annually, and has now dropped to 30,000 to 40,000 new cases annually.2 The most common routes of infection are injection drug use and previous contact with tainted blood products. This disease usually runs an asymptomatic course for many years, and some patients never develop any symptoms. If symptoms do develop, they often are nonspecific . About 10 to 20 percent of chronically infected persons progress to cirrhosis over an average of 20 years.24 Faster rates of progression are seen in persons who are infected at an older age, or who have modifying risk factors such as moderate or heavy alcohol consumption, human immunodeficiency virus , or other coexistent liver diseases.3,4
A = consistent, good-quality patient-oriented evidence B = inconsistent or limited-quality patient-oriented evidence C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 555 orwww.aafp.org/afpsort.xml.