interferon

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Interferon:

Interferon Dr. D.Babu Vinish M.D.,

Introduction&Classification :

Introduction&Classification Cytokines with anti- viral, immunomodulatory , anti proliferative activities Synthesized by host cells in response to inducers leading to an anti viral state a , β , ɣ -IFN’S IFN a & β -produced by all cells –infection IFN ɣ restricted to T-lymphocytes & NK cells responding to antigenic stimuli

Anti-viral activity:

Anti-viral activity IFN a & β exhibit anti- viral& anti proliferative activities stimulate cytotoxic activity of lymphocytes, NK cells & macrophages - up regulate MHC antigen surface markers IFN ɣ less antiviral activity potent immunomodulatory expression of MHC II antigens mediation of local inflammatory response

Anti-viral activity:

Anti-viral activity IFN down regulate production of cellular proteins-----important mediator for pharmacological benefits DNA viruses relatively insensitive to IFN Activity of IFN is measured- antiviral effects in cell culture expressed in IU

Mechanism of Action:

Mechanism of Action Activate JAK-STAT signal transduction pathway Nuclear translocation of cellular complex Bind to genes of IFN specific response element

IFN effects :

IFN effects I nhibition of transcription- activates Mx protein-protein with anti viral activity blocks m- rna synthesis Inhibition of translation- A ctivates 2’5’oligoadenylate synthetase - Inhibits m rna splicing by activating RNaseL -cleaves mRNA(cellular &viral RNA) Protein kinase 1-blocks eIL-2( eukaryatoic factor) inhibits initiation of mRNA translation Phosphodiesterase -cleaves portion of t-RNA preventing elongation

IFN effects :

IFN effects Viruses counter the effects of IFN- blocking production or activity of IFN inducible proteins IFN resistance in Hep –C inhibition of IFN induced protein kinase Ifn ameliorate viral fn by direct antiviral effects or by modifying immune response to infection Ifn expression on MHC enhances the lytic activity of cytotoxic T- lymhocytes May also mediate the systemic symptoms as with viral infns & contribute to immunological mediated tissue damage

Absorption :

Absorption O ral administration – does not result in detectable IFN levels IM/SC IFN a >80% absorbed Plasma levels dose related peak4-8 hrs , base line 18-36 hrs Levels of 2-5A increase in 6 hrs lasts for 4 days Antiviral state mononuclear cells peaks 24 hrs , base line in 6 days IFN β negligible plasma levels, Levels of 2-5A increase may occur Low levels seen in respiratory secretions ,eye , brain

Distribution :

Distribution U npredictable pharmacokinetics bcoz of the long lasting cellular effects s c / im -t½ IFN a 3 -8 hrs Elimination depends on cellular uptake & tissue distribution Catabolism in liver & kidney Negligible amounts excreted in urine ˜80%IFN 2 β clearance reduced when on HD

Polyethylene glycol IFN:

P olyethylene glycol IFN Adding PEG -slows absorption ,decreases clearance provides higher &prolonged serum concentrations The result is increase in the t1/2 of the pegylated protein. PegIFN a -2a ,40KDa , t½ ~ 80-90 hrs , stable dispensed in solution, peak concentration 120 hrs after dosing , steady state 5-8 wks after initiation of weekly dosing PegIFN a - 2b ,12KDa, t½ ~ 30-54 hrs Increasing PEG size associated with longer t ½, less renal clearance 30% PegIFN a -2b cleared by kidneys,2a -liver. Dose reductions in ESRD required for both

Contraindications or cautions for pegIFN preparations:

C ontraindications or cautions for pegIFN preparations A utoimmune diseases can be exacerbated by the immunomodulatory actions of pegIFN H emoglobinopathies such as sickle cell anemia or major thalassemia

Adverse effects:

Adverse effects I nfluenza-like illness most common side effect. Doses>1 MU –flu like symptoms Fever resolves in 12 hrs , Tolerance usually develops, Reduced by pre treatment Mild injection site reactions may occur with pegIFN preparations Depression-more seen in Hep C thanB Neurotoxicity- somnolence , confusion, rarely seizures, neuroasthenia

Adverse effects:

Adverse effects Elevations in triglycerides Alopecia Hepatotoxicity-elevation of hepatic enzymes, worsening of liver disease - exacerbation of an underlying autoimmune hepatitis. May impair fertility, safety in pregnancy not established Increases hematological toxicity of zidovudine ribavarin

IFN-Myelosuppression:

IFN- Myelosuppression Neutropenia(750 cells/cm3) & thrombocytopenia -Dose reduction recommended RCT have not identified an association between neutropenia & increased risk for infections. R eduction criterion ( < 500 absolute neutrophils /dl) has been adopted prospectively in some studies without an increase in adverse events . G-CSF should be reserved only for the most severe neutropenia not responsive to dose reduction of pegIFN .

Hematologic abnormalities:

Hematologic abnormalities incidence of significant thrombocytopenia is low & responds to dose reduction to maintain platelet counts above 50,000 /dl. 3% of patients discontinue treatment due to thrombocytopenia . dose reduction or premature termination are uncommon except in patients who have decreased cell counts prior to treatment. trials of peg IFN- -2a & peg IFN- -2b, combined with ribavirin, 10–14% of patients prematurely discontinued the therapy due to adverse events - anemia & thrombocytopenia are the most frequent indications for dose reduction which occurs in up to 25% of patients.

Interferon-associated depression:

Interferon-associated depression emotional lability -troublesome side effect of IFN can occur in the absence of a prior history of emotional problems. Prior to starting interferon-based therapy at a tertiary referral center , 47 % reported a past history of depression & 14% reported anxiety . The frequency of preexisting psychiatric disease & the incidence of interferon-associated neuropsychiatric adverse events is variable Evon DM, Verma A, Simpson K, Galanko JA, Dougherty KA, Fried MW. Psychiatric symptoms during interferon treatment for hepatitis C: experiences from a tertiary care hepatology centre. AlimentPharmacol Ther 2008;27:1071–80 .

VIRAHEP-C cohort:

VIRAHEP-C cohort African-American patients treated with pegIFN -- 2a & ribavirin ,depression was present at baseline in 12% of patients -were more likely to have psychiatric adverse events, to begin antidepressants during treatment , or to have earlier treatment discontinuation, although SVR rate was not significantly different others. New-onset depression developed in 26% of patients, esp during the first 12 wks of therapy. 1/3 of patients started antidepressants during the course of the study . patients with new-onset depression were less likely to discontinue treatment ( 6% vs 15%) & had similar SVR rates compared with those who did not develop depression (47% vs 38 %). There was no difference in the rates of depression before or during treatment between the African-American & the Caucasian-American participants

Interferon-associated depression:

Interferon-associated depression P sychiatric co-morbidities in chronic hepatitis C pts complicate antiviral therapy I nterferon-associated depression - the most common reason for withdrawal of therapy , by self reporting 20–30% of patients Psychiatric co-morbidities may be a contraindication to interferon-based therapies. Patients with stable depression, on therapy , may be treated with interferon-based therapies albeit with close monitoring for exacerbation.

Interferon-associated depression:

Interferon-associated depression Prophylactic SSRI - no benefit in reducing the rate of major depression, but the severity of depressive symptoms has reduced in those with elevated depressive symptoms at baseline Lower depression scores during retreatment when preemptively started on an SSRI for those who experienced major depression initially Selective pre treatment warranted in those at highest risk for interferon associated depression. In others, symptom-directed management is the best strategy. Kraus MR, Schafer A, Al- Taie O, Scheurlen M. Prophylactic SSRIduring interferon alpha re-therapy in patients with chronic hepatitis C & a history of interferon-induced depression. J Viral Hepat 2005;12:96–100 .

IFN depression-Treatment:

IFN depression-Treatment Antidepressants started early reduce symptoms & allow for completion of antiviral therapy Selecting the best agent for an individual basis, close monitoring, & regular follow-up with mental health providers maximizes the chances of successful antiviral treatment.

side effects -IFN/THYROID:

side effects -IFN/THYROID I nduce autoantibodies. Thyroid dysfunction- 10 % of patients treated with interferon Risk factors - female gender & the presence of pretreatment thyroid autoantibodies Monitor TSH every 12 weeks during therapy & during 6 months of post-treatment Hypothyroidism managed with thyroid hormone replacement, continuing pegIFN . Mild hyperthyroidism managed symptomatically while still on therapy Severe hyperthyroidism - discontinuation of therapy Thyroid abnormalities resolve once pegIFN is discontinued.

Ocular abnormalities:

Ocular abnormalities Diabetic or hypertensive patients need baseline fundoscopic examination Cotton wool spots are frequently evanescent & rarely prompt discontinuation of therapy. Retinal haemorrhage with or without visual symptoms - may also resolve with continued treatment. Visual loss from retinal vein thrombosis & retinal detachment prompt discontinuation of treatment Patients with visual disturbances during pegIFN therapy require close ophthalmologic follow-up.

Interstitial pneumonitis:

Interstitial pneumonitis rare complication of interferon-based therapies interstitial pneumonitis may progress to respiratory failure differentiated from other pulmonary causes such as bacterial/viral pneumonia interferon-induced sarcoidosis , or the benign, dry cough seen with ribavirin . Pneumonitis is usually characterized by fever, dyspnea , & characteristic findings on chest X-ray or CT Prompt recognition & immediate discontinuation of pegIFN may prevent progression, although severe cases may require steroid therapy

Quality of life:

Quality of life Quality of life, in all its dimensions, is diminished during treatment with pegIFN & ribavirin as measured by standardized instruments such as SF-36 Health-Related Quality of Life Questionnaire Hepatitis Quality of Life Questionnaire & the Sexual Health, & Work Productivity & Impairment Index

PegIFN Vs conventional :

PegIFN Vs conventional PegIFN better tolerated than conventional Discontinuation rates 2-11% Frequency of fever, nausea & injection site inflammation, neutropenia higher than conventional Severe neutropenia dose modifications are higher in HIV co- infected persons Clinical trials suggest that efficacy of pegIFN similar to or slightly better than standard IFN PegIFN - advantage of more convenient administration more sustained virus suppression largely replaced standard IFN

Role of prednisone priming:

Role of prednisone priming Steroid withdrawal has been observed to be frequently accompanied by a flare in serum ALT levels & HBeAg seroconversion . Prednisone priming followed by IFN- treatment has very little additional beneficial effect compared with IFN- alone risk of fatal exacerbation in patients with underlying cirrhosis .

Hepatitis B:

Hepatitis B G oal of treatment of chronic hepatitis B - prevent cirrhosis , hepatic decompensation , & HCC . B est achieved by eradicating HBV before there is irreversible liver damage . Eradication of HBV difficult- extrahepatic reservoirs of HBV integration of HBV DNA into the host genome presence of an intracellular conversion pathway ( cccDNA ) in the hepatocyte nucleus without the need for reinfection .

Hepatitis B:

Hepatitis B Parameters used to assess response -normalization of serum ALT decrease in serum HBV DNA level loss of HBeAg with or without detection of anti- HBe (for HBeAg -positive patients ) loss of HBsAg improvement in liver histology

IFN:

IFN A dministered for predefined durations NUCs -until a specific endpoint is achieved. HBeAg seroconversion occurs a few months after cessation of IFN treatment, because of the lag between immune priming & decrease in expression of viral protein viral relapse is inevitable if NUCs are withdrawn prior to achieving the therapeutic endpoint.

Standard IFN-α:

Standard IFN- α Efficacy HBeAg -positive chronic hepatitis . meta-analyses confirmed a beneficial effect of IFN therapy in HBV DNA suppression , ALT normalization , & HBeAg loss. HBeAg -negative chronic hepatitis . treated patients were more likely than controls to have viral suppression but most relapsed when treatment was stopped . H igher rate (30%) of sustained response with 24 months of IFN- therapy compared with 15–20% IFN- for 12 months. Longer duration of treatment may increase the rate of sustained response . Lampertico P, Del Ninno E, Manzin A, et al. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 1997;26:1621–5.

Standard IFN-α:

Standard IFN- α HBV DNA-positive clinical cirrhosis . Patients with histologic cirrhosis but no evidence of hepatic decompensation appeared to tolerate IFN- treatment . IFN- even when administered in very low doses is associated with a risk of infections & severe exacerbations leading to hepatic failure in patients with clinically evident cirrhosis

Long-term outcome of IFN therapy:

Long-term outcome of IFN therapy Hepatitis B e antigen Most HBeAg -positive patients who responded to IFN-therapy maintain their response . Relapses usually occur within 1 year of treatment, but delayed reactivation can occur. sustained responders , increasing proportion cleared HBsAg during the course of follow-up. The percent of sustained responders who cleared HBsAg within 5 years of HBeAg clearance varied geographically 65 % in US study to 19–24 % in European studies to 0–9% in two studies from Asia despite similar durations of follow-up.

Long-term outcome of IFN therapy:

Long-term outcome of IFN therapy In those who clear both HBeAg & HBsAg , is accompanied by normalization of ALT levels & a decrease in necroinflammation ,but residual liver damage may be present. IFN- treated pts in Taiwanese study for 8 years found that treated patients had a lower incidence of HCC (1.5% vs 12%, P = 0.04) a higher survival rate (98% vs 57 %, P = 0.02) BUT compared to controls but there was no difference in the rate of new onset of cirrhosis Lin SM, Sheen IS, Chien RN, et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 1999;29:971–5.

Long-term outcome of IFN therapy:

Long-term outcome of IFN therapy B enefits were not observed in a studies from Hong Kong ,European or North American patients, probably because of the low rate of HCC in untreated patients. Studies comparing responders vs non responders found that patients who cleared HBeAg had better overall survival & survival free of hepatic decompensation clinical benefit was most evident among patients with cirrhosis

Hepatitis B e Ag-negative patients:

Hepatitis B e Ag-negative patients Relapse after cessation of IFN- treatment is frequent, with sustained response only in 15–30 % Among the long-term responders, approximately 20% cleared HBsAg after 5 years of follow-up . IFN- therapy did not have any overall effect on survival, complication-free survival, or HCC but patients with sustained response had significantly lower rates of hepatic decompensation

Dose regimen:

Dose regimen IFN- is administered as subcutaneous injections. The recommended dose for adults is 5MU daily or 10MU thrice weekly C hildren - 6MU/m2 thrice weekly to a max of 10 MU. Recommended duration of treatment for patients with HBeAg -positive chronic hepatitis B - 16–24 weeks . HBeAg negative chronic hepatitis B should be treated for at least 12 months; O ne study suggested that higher rates of sustained response can be achieved with 24 months of treatment

PegIFN-2a Vs standard IFN-2a :

P egIFN-2a Vs standard IFN-2a In one phase II trial, 194 patients were randomized to receive 90, 180,or 270 g pegIFN-2a weekly or 4.5MU standard IFN-2a thrice weekly for 24 weeks. A higher percent of patients who received pegIFN - had HBeAg seroconversion : 32% vs 25% of those who received standard IFN Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa ): an advance in the treatment of hepatitis B e antigenpositive chronic hepatitis B. J Viral Hepat 2003;10:298–305.

Efficacy -HBeAg-positive chronic hepatitis.:

Efficacy - HBeAg -positive chronic hepatitis. phase III trial, 814 patients were randomized to receive pegIFN-2a pegIFN-2a + lamivudine or lamivudine 100mg daily for 48 weeks. At the end of treatment, virus suppression was most marked in the group that received the combination therapy HBeAg seroconversion was similar in the three groups at the end of treatment , but significantly higher in the two roups that received pegIFN - when response was assessed 24 weeks after treatment was stopped Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, & the combination for HBeAg -positive chronic hepatitis B. N Engl J Med 2005;352:2682–95. pegIFN-2a 180g weekly, 48weeks pegIFN-2a 180g weekly + lamivudine 100mg daily lamivudine 100mg daily HBV DNA reduction 4.5 copies/ml 7.2 5.8 HBeAg seroconversin 27% 24% 20% 24 wks after treatment 27% 32% 19%

PegIFN-2b:

P egIFN-2b Data indicate that pegIFN-2a was superior to lamivudine monotherapy in inducing HBeAg seroconversion ,& comparable to the combination therapy of pegIFN-2a & lamivudine. Similar results in pegIFN-2b was administered in tapering doses (100 → 50 g) for 52 weeks or 1.5g/kg for 32 weeks. /24 weeks after treatment was stopped one study reported identical rates (29%) of HBeAg seroconversion in patients who received pegIFN-2b monotherapy with & without lamivudine whereas the other study reported a significantly higher rate of HBeAg seroconversion in those who received a combination vs lamivudine only, 36% vs 14% Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg -positive chronic hepatitis B: a r&omised trial. Lancet 2005;365:123–9. Chan HL, Leung NW, Hui AY, et al, Ann Intern Med 2005;142:240–50 .

PowerPoint Presentation:

Follow-up of patients of pegIFN-2b for a mean of 3.5 years after completion of pegIFN ±lamivudine found that 37% had lost HBeAg & 11%had lost HBsAg The rate of HBsAg loss was higher in patients with genotype A infection: 28% compared to 3% in those with non-A genotypes. Among the initial responders, 81% had durable HBeAg loss & 30% had HBsAg loss.

PowerPoint Presentation:

552 patients were randomized to receive 48 weeks of pegIFN-2a 180g weekly, a combination of pegIFN-2a 180g weekly + lamivudine 100mg daily, or lamivudine100mg daily. Virus suppression was most marked in the group that received combination therapy: the mean HBV DNA reduction at week 48 in the three groups was 4.1, 5.0, & 4.2 log10 copies/mL, respectively[276].

HBeAg-negative chronic hepatitis.:

HBeAg -negative chronic hepatitis. In a phase III trial of pegIFN - in HBeAg -negative patients 3 yrs after treatment , a HBV DNA of < 10,000 copies/mL was maintained in 22.6% vs 9.4%, ALT normalization in 31.3% vs 18.9%, & HBsAg loss in 8.7% vs 0% of patients who received pegIFN ± lamivudine vs lamivudine alone, respectively Marcellin P, Bonino F, Lau GK, et al. Sustained response of hepatitis B e antigen-negative patients 3 years after treatment with peginterferon alpha-2a . Gastroenterology 2009;136:2169–79, e1–4 552 patients 48 weeks of pegIFN-2a 180g weekly pegIFN-2a 180g weekly + lamivudine 100mg daily Lamivudine 100mg daily HBV DNA reduction 48 4.1, 5.0, 4.2 log10 copies/mL HBV DNA reduction 72 15 16 6

Dose regimen:

Dose regimen The recommended dose of pegIFN-2a for both HBeAgpositive & HBeAg -negative hepatitis is 180 micro gm weekly for 48 weeks . The optimal dose & duration of pegIFN - 2b for hepatitis B is unclear.

Predictors of response to standard & pegylated interferon-α:

Predictors of response to standard & pegylated interferon- α Predictors of response to standard & pegIFN - are similar. HBeAg -positive patients for HBeAg seroconversion strongest predictor pretreatment ALT level high histologic activity index , low HBV DNA level HBV genotypes A & B vs C & D a greater decline in HBeAg or HBsAg titer during treatment were more likely to undergo HBeAg seroconversion Fried MW, Piratvisuth T, Lau GK, et al. HBeAg & hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg -positive chronic hepatitis B. Hepatology 2008;47:428–34 .

Predictors of response:

Predictors of response HBeAg -negative patients low pretreatment HBV DNA level, undetectable HBV DNA at the end of 48 weeks of treatment, HBV genotype B or C vs D patients with greater decline in HBsAg titer during treatment had a lower HBsAg titer at the end of treatment were more likely to have sustained virologic response during post-treatment follow-up Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop : a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg -negative patients. Hepatology 2009;49:1151–7 .

Combination therapies:

Combination therapies advantages are additive or synergistic antiviral effects , diminished or delayed resistance . disadvantages costs increased toxicity drug interactions. To date, none of the combination therapies evaluated have been proven to be superior to monotherapy in inducing a higher rate of sustained response . combination therapies have been shown to reduce the rate of lamivudine resistance compared with lamivudine monotherapy , as yet no data to support the suggestion that combination therapies will reduce the rate of resistance to antiviral agents that have a high genetic barrier to resistance such as entecavir or tenofovir .

Standard or peg IFN & lamivudine:

S tandard or peg IFN & lamivudine IFN- & lamivudine have different mechanisms of action-logical comb. Treatment-naive patients ( combination therapy ) Five large trials (1-standard IFN- & 4-pegIFN- , four in HBeAgpositive patients & one in HBeAg -negative patients) compared a combination of IFN- & lamivudine to lamivudine alone &/ or IFN- alone C ombination therapy had greater on-treatment virus suppression but there was no difference in the sustained off-treatment virologic response compared to IFN- alone. resulted in higher rates of sustained off-treatment response compared to lamivudine alone . associated with lower rates of lamivudine resistance compared with lamivudine monotherapy , a low rate of lamivudine resistance was encountered compared to none in patients who received IFN- alone .

Interferon- nonresponders:

Interferon- nonresponders . Combination therapy of standard IFN- & lamivudine is not more effective than lamivudine alone in the retreatment of IFN- nonresponders Schiff ER, Dienstag JL, Karayalcin S, et al. Lamivudine & 24 weeks lamivudine/interferon combination therapy for hepatitisB e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol 2003;38:818–26.

Hepatitis C:

Hepatitis C Sustained virologic response rates ( SVRs)have increased from 5–10% with standard interferon therapy to over 40% when standard interferon is combined with ribavirin. Peg IFN further increases rates of SVR C ombining these agents with direct-acting antiviral agents increases SVR rates to over 70% for patients with genotype 1 infection.

Antiviral therapy of chronic hepatitis C:

A ntiviral therapy of chronic hepatitis C G oal SVR defined as undetectable HCV RNA in the serum when measured 6 months after the end of treatment. Why achieve a SVR SVR pts the relapse rate evaluated up to 7 years after treatment is less than 1 % P ersistent inability to detect HCV RNA in serum or hepatic tissue implies permanent viral eradication & that SVR is analogous to “cure” Evidence exists whereby HCV viral sequences have been detected in peripheral blood mononuclear cells even in patients with SVR, although no clinical sequelae

Patients who achieve SVR:

P atients who achieve SVR Serum ALT activity decreases into the low normal range H epatic histology shows marked decrease in necro inflammatory activity . Improvement in hepatic fibrosis may also occur L ower rates of hepatic decompensation & HCC compared with treatment failures US Veterans study suggested that SVRs after antiviral therapy were associated with a significant decrease in all-cause mortality compared with non acheivers Backus L, Boothroyd DB, Phillips BR, Mole LA. Impact of sustained virological response to pegylated interferon/ribavirin on all-cause mortality by HCV genotype in a large real-world cohort: the US Department of Veterans Affairs’ experience [Abstract]. Hepatology 2010;52:428A .

Definition of nonresponse & relapse:

Definition of nonresponse & relapse Patients who remain with detectable HCV RNA throughout a course of therapy are considered to be nonresponders . Within the nonresponder category , null responders achieve the least reduction in HCV RNA, usually less than a 1 log decrease in HCV levels by 12 weeks of treatment, & are considered the most refractory to pegIFN & ribavirin therapy. Partial responders may have multiple log-fold decreases in HCV RNA in serum but always have detectable viremia during treatment Relapsers are those who do achieve undetectable HCV RNA during treatment, as measured by a assay , but then recur with HCVRNA measurable in the serum after the end of a prescribed treatment regimen .

Relapsers:

Relapsers Relapsers can be further categorized based upon the time point at which they cleared virus for the first time Rapid virologic responders - undetectable viremia by week 4 of treatment U ndetectable viremia for the first time at week 12 had a complete early virologic response ( cEVR ) HCV RNA decreased by at least 2 logs at this point but remained detectable are considered to have only a partial early virologic response ( pEVR ). Patients with a pEVR who then become undetectable by week 24 are considered to have a slow virologic response Accurate characterization of virologic response during treatment influences decisions regarding retreatment of patients with new new triple therapy combinations

IFN a treatment for chronic hepatitis C Initial study:

IFN a treatment for chronic hepatitis C Initial study In 1986, before the discovery HCV, the first report of successful treatment for NANB hepatitis was published by Hoofnagle from the NIH Ten patients received recombinant human –interferon at doses between 0.5 million & 5 million IU for 4–12 months. Serum aminotransferases rapidly decreased during therapy in most patients & remained normal in those with prolonged therapy. Hepatic histology also demonstrated improvement in some patients. This uncontrolled series suggested that interferon could achieve clinical improvement in patients with NANB hepatitis & provided a rationale for more comprehensive studies of interferon for chronic hepatitis

IFN a treatment for chronic hepatitis C dosage study:

IFN a treatment for chronic hepatitis C dosage study Davis & colleagues randomized patients to 6 months of IFN- -2b at either 1 or 3 MIU thrice weekly or placebo. Normalization of ALT was achieved in 46% -3 million IU, compared with only 28% treated with the lower dose . Significant reduction in periportal & lobular inflammation 51 % of patients with an initial biochemical response relapsed once treatment was discontinued. This landmark study confirmed that patients with chronic hepatitis C could benefit from treatment with interferon T rial by Di Bisceglie demonstrated nearly identical results .

IFN a treatment for chronic hepatitis C duration :

IFN a treatment for chronic hepatitis C duration Another early controlled trial of IFN--2b for NANB hepatitis included 252 patients with anti-HCV antibody treated for 6 months with IFN--2b at 3 million IU & then randomized to either stop therapy, continue for an additional 12 months, or continue a lower dose for an additional 12 months. In those treated for a total of 18 months with the higher dose of interferon, 22% maintained normalization of serum ALT after discontinuation of therapy, compared with only about10% in those with shorter treatment duration group or receiving lower doses of interferon. The protocol prior to the availability HCV RNA testing & this was not a prospective end-point.

Higher initial doses:

H igher initial doses Lindsay & colleagues treated patients with 3, 5, or 10 million IU thrice daily for the first 12 weeks of therapy to determine if higher initial doses improved biochemical response rates. Higher doses of interferon did not increase the likelihood of sustained biochemical response, which overall was quite low & ranged between 8% & 17 %. dose escalation in patients who had not had a biochemical response by week 12 did not improve the rate of sustained normalization of serum ALT activity once treatment was discontinued . This study also demonstrated that patients with genotype 1 were less likely to be responsive to treatment than those with genotypes 2 & 3

Meta analysis -IFN:

Meta analysis -IFN By 1999, 76 randomized controlled trials of interferon for hepatitis C -meta-analysis Trials indicated that 17% of patients treated with interferon remained HCV RNA-negative for at least 6 months after therapy was discontinued, indicating sustained virologic response . This meta-analysis also suggested that longer duration of therapy & higher doses of interferon were associated with a better rate of sustained virologic response

trials of pegIFN--2b & -2a:

trials of pegIFN --2b & -2a . Manns et al. [569] randomized over 1,500 patients to treatment for 48 weeks with either: ( i ) pegIFN --2b 1.5g/ kg/week; (ii) pegIFN --2b 1.5g/kg/week for 4 weeks then decreased to 0.5g/kg/week; (iii) or IFN--2b 3MU subcutaneously three times per week. All patients received ribavirin 1,000–1,200 mg/day. Overall, SVR rates (54%, 47%, & 47%, respectively) demonstrated that the higher dose pegIFN was significantly more effective. Among genotype 1 patients, rates of SVR were 42% for the higher dose pegIFN compared with 34% for the lower dose pegIFN & 33% for the standard interferon arm. Genotype 2 or 3 patients, as expected, fared better with SVR rates as high as 82% with higher dose pegIFN .

Combining ribavirin with interferon improves antiviral response :

Combining ribavirin with interferon improves antiviral response pretreatment characteristics associated with SVR - non-1 genotype, lower baseline viral load, lighter weight, younger age, & the absence of cirrhosis. Logistic regression analysis indicated that the dose of ribavirin on a mg/kg basis was an important factor in determining treatment outcome. Thus, patients who received more than 10.6 mg/kg/day of ribavirin had higher rates of SVR for all dose groups & genotypes 1500 pts Peg 2b-1.5mg/kg/ wk + ribavirin 1-1.2 gm /d Peg 2b-1.5mg/kg/ wk,dec 0.5 mg/kg/ wk + ribavirin 1-1.2 gm /d IFN--2b 3MU Sc thrice a week+ ribavirin 1-1.2 gm /d SVR 54% 47% 47% Genotype 1 42% 34% 33% Genotype 2/3 82%

PegIFN vs interferon & ribavirin. :

PegIFN vs interferon & ribavirin. Fried & colleagues compared the efficacy : pegIFN --2a 180g/week alone or in combination with ribavirin 1,000–1,200mg/ day , or standard interferon & ribavirin. The best rate of overall SVR, 56%, was achieved in those treated with pegIFN - -2a & ribavirin compared with 44% of those treated with standard interferon & ribavirin & only 29 % with pegIFN alone. Genotype 1 patients had SVR rates of 46%, 36%, & 21%, respectively, while patients with genotype 2 or 3 achieved a SVR in 76% of those treated with pegIFN --2a & ribavirin . Three factors, non-1 genotype, age less than 40 years, & body weight of 75 kg or less were independently associated with virologic response

Refining treatment regimens to optimize response:

Refining treatment regimens to optimize response Hadziyannis et al. randomized ~ 1,300 patients to four arms of treatment with pegIFN --2a 180g/week plus ribavirin at doses of either 1,000–1,200 mg/day or 800 mg/day for either 24 or 48 weeks’ duration. Including patients with genotypes 1, 2, & 3 allowed for several comparisons between ribavirin dosing & treatment duration across genotypes. The results confirmed that genotype 1 patients required higher doses of ribavirin (1,000–1,200mg/day) for 48 weeks. Those treated for 24 weeks or with only 800 mg/day of ribavirin had a higher chance of relapse once therapy was discontinued. In contrast, patients with genotypes 2 or 3 did equally well regardless of duration or ribavirin dosing suggesting that 24 weeks of treatment with only 800 mg/day of ribavirin was sufficient

Rationale for FDA approval:

R ationale for FDA approval PegIFN - -2b is administered sc once weekly as a weight-based dose (1.5g/kg/week ) PegIFN - -2a is administered as a fixed weekly dose of 180 g/week. Both drugs must be combined with ribavirin for maximal efficacy A 48-week course of treatment is recommended for patients with genotype 1 or 4 utilizing higher doses of ribavirin. Failure to achieve undetectable viremia by week 24-treatment termination is recommended for genotype 1 G enotypes 2 or 3 - treated for 24 weeks with only 800mg of ribavirin. Recommendations for other genotypes are based on sparse data but follow similar recommendations as for genotype 1.

Viral kinetics & virologic response:

Viral kinetics & virologic response The rapidity of HCV RNA clearance during therapy has implications for subsequent treatment & outcome Absence of an EVR has the best negative predictive value for treatment outcome P atients who failed to achieve an EVR (either complete or partial) have a small chance of ultimately achieving SVR , & stopping futile therapy at week 12 of treatment was considered Patients who achieve a RVR have the highest chance of achieving a SVR (over 90%) In a retrospective analysis of patients with genotypes 1–4 treated with pegIFN -- 2a & ribavirin, RVR was attained in only 16% of individuals with genotype 1 & in 60–71% of those with genotype 2 or 3. However, among those with RVR, the rate of SVR was high across all genotypes ranging from 88% to 100% (Fig. 25.13).

Baseline factors predictive of RVR :

Baseline factors predictive of RVR genotype non-1 lower initial viral load higher ALT levels absence of advanced fibrosis, & younger age . the presence of RVR most predictive of SVR when compared with baseline characteristics regardless of HCV genotype although the IL28B genotype was not included in this analysis

RVR to shorten treatment in genotype 1:

RVR to shorten treatment in genotype 1 48 weeks treatment -better SVR than 24-week due to a lower relapse rate RVR-present in about 15% of patients -highest chance of SVR led to studies to determine whether a treatment duration shorter than the recommended 48 weeks would be effective for this subgroup. Databases that included patients with genotype 1 treated for only 24 weeks with pegIFN & ribavirin demonstrated that the rates of SVR among those who had first achieved RVR were comparable to those treated for 48 weeks. Baseline viral loads of less than 6,00,000 IU/mL were most highly associated with this response.

Genotype 1 & RVR:

Genotype 1 & RVR In a single arm study of patients with a pretreatment viral load of < 600,000 IU/mL , Zeuzem & colleagues treated those who had achieved an RVR with pegIFN --2b & ribavirin for a total of 24 weeks & found an SVR rate of 89% The PREDICT study utilized a response guided algorithm to treat RVR patients with genotype 1 & a low viral load for 24 weeks . This study yielded an SVR of 88% for the short treatment duration, adding support to the assertion for 24 weeks. Other studies also found similar results – that patients with RVR with low baseline viral loads received maximal benefit from only 24 weeks of treatment with pegIFN & ribavirin Common to all these studies was the diminished rate of relapse when RVR was attained, which was only approximately 10 %.

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These data led to the recommendation into European practice to truncate therapy to 24 weeks for patients with genotype 1 & a low baseline viral load who had achieved RVR.

Utilizing RVR to shorten treatment in genotype 2 or 3:

Utilizing RVR to shorten treatment in genotype 2 or 3 genotype 2 or 3 have the highest rates of SVR compared with other genotypes. recommended treatment duration is already shorter than that of genotype 1 (24 weeks vs 48 weeks ), Shorten to 12 weeks without compromising SVR Mangia & colleagues randomized genotype 2 or 3 patients to treatment with a standard 24-week regimen of pegIFN --2b & weight-based ribavirin (1,000–1,200 mg/day) or to a response-guided treatment whereby patients achieving RVR received only 12 weeks of treatment & non-RVR participants completed 24 weeks of therapy. Similar overall rates of SVR were achieved in both the fixed 24-week duration & the RVR guided regimen (76% & 77%, respectively). SVR among those who achieved RVR ( 91% vs 85%) were not statistically significant, suggesting that the shorter treatment regimen was not inferior to the fixed 24-week regimen. However , the end-of-treatment relapse rate was noted to be higher in the short duration treatment arm despite a RVR.

Truncated therapy in genotypes 2 & 3:

Truncated therapy in genotypes 2 & 3 The largest study to investigate truncated therapy in genotypes 2 & 3 was performed by Shiffman et al . 1,500 patients were randomized to either 16 weeks or 24 weeks of treatment with pegIFN - - 2a plus ribavirin 800 mg/day. The overall SVR rate was significantly lower in the 16- week treatment arm compared with the standard 24-week ( 62% vs 70%, respectively). An increase in relapse treated for 16 weeks (31% vs 18%). Multivariate analysis seatment response was positively associated viral genotype 2 vs genotype 3 , low viral load at baseline (< 400,000 IU/mL ), age <45 years, weight <80 kg, higher serum ALT activity the absence of advanced fibrosis , & longer treatment duration

truncated therapy in genotypes 2 & 3:

truncated therapy in genotypes 2 & 3 lower pretreatment HCV RNA had similar rates of SVR with either treatment duration (∼80 %). among patients who achieved RVR, the rate of SVR was lower in those treated for a shorter duration (79% vs 85%). among non-RVR patients the SVR rate was low regardless of duration of therapy: 26% (16 weeks) & 45% (24 weeks) . lower response rates & higher relapse rates for patients treated with 12–16 weeks of therapy appear to be a consistent data suggest that 24 weeks remains the optimal treatment duration for most patients with genotypes 2 or 3, although an ideal patient with a low viral level <400,000 IU/mL who achieves RVR may be considered for shortened duration of treatment. the impact of negative prognostic factors such as African-American race, HIV, cirrhosis, & obesity has been incompletely characterized & thus shortened therapy should only be selectively considered

Slow virologic response:

Slow virologic response 15 % of patients treated with pegIFN & ribavirin exhibit a slow virologic response defined as undetectable HCV RNA between weeks 12 & 24 of therapy . These patients have lower rates of SVR compared with patients who clear HCV RNA earlier in their treatment . Modeling of viral kinetics with slow virologic response suggested that a standard 48-week course of therapy would be insufficient It was postulated that a longer duration of undetectable viremia of at least 36 weeks would minimize relapse & maximize the chances of SVR .

Slow viral response=extended Rx:

Slow viral response=extended Rx Berg & colleagues evaluated whether extended therapy with pegIFN & ribavirin would enhance rates of SVR. Patients with genotype 1 were randomized to treatment with pegIFN --2a & ribavirin 800 mg/day for either 48 or 72 weeks. SVR rates for both groups were almost identical. post hoc analysis demonstrated that slow virologic responders had a significantly higher rate of SVR (29% vs 17%) & a lower relapse rate (40% vs 64 %) when treated for 72 weeks. The TeraVic-4 study focused on patients who failed to achieve a RVR prospectively randomized them to 48 weeks or 72 weeks of therapy with pegIFN --2a & ribavirin 800 mg/day. significant improvement was seen in SVR with prolonged treatment (44% vs 28%) along with diminished relapse rates

Slow viral response=extended Rx:

Slow viral response=extended Rx Pearlman & colleagues Single- center study of genotype 1 patients with numerous treatment resistant characteristics such as African-American race, high baseline levels of HCV RNA, & advanced fibrosis. Slow virologic responders treated with pegIFN -- 2b & ribavirin 800–1,400 mg/day for 72 weeks had a significantly higher rate of SVR compared with those who received a standard 48-week regimen (38% vs 18%). Relapse rates were also lower with the extended treatment duration . M ulticenter study performed in Europe did not support the concept that prolonged therapy was beneficial in patients with slow virologic response .

SUCCESS trial:

SUCCESS trial Randomized slow virologic responders to pegIFN --2b & weight-based ribavirin for either 48 weeks or 72 weeks In the intention-to-treat analysis SVR rates were similar for the extended duration treatment (48%) to those treated for only 48 weeks (43%). However , the study did show that relapse rates were ∼14% lower with prolonged therapy, although this was not statistically significant A numeric but statistically insignificant advantage for prolonged therapy was also evident A meta-analysis examined all RCT’s evaluated extended duration of therapy for patients with a non-RVR .- prolonged therapy slow virologic responders provided about a 15% higher chance to achieve SVR along with a similar decline in the chance for relapse, which likely was the contributing factor to improved SVR

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