interferon - alfa ( ifn- ) monotherapy has been found with normalization of alanine aminotransferase ( alt ) levels in a few patients diagnosed as non - a , non - b hepatitis even before hepatitis c virus ( hcv ) was identified as the chief etiologic agent in this diagnosis . in 1989 ,
the first cases of successful treatment of documented chronic hepatitis c ( chc ) with ifn- monotherapy were reported , but relapse after the cessation of treatment was common [ 2 , 3 ] .
the introduction of combination therapy with ifn- and ribavirin has markedly improved treatment response . nevertheless , less than one - half of patients with chc were able to experience a favorable response to the combination therapy [ 46 ] . since 2000 , the attachment of inert polyethylene glycol to conventional ifn- , pegylated ifn- ( pegifn- ) , reduced degradation and clearance , prolonging the half - life of ifn and permitting less frequent , weekly dosing while maintaining higher sustained ifn levels ( compared with 3 times weekly for conventional ifn ) .
now , pegifn--ribavirin combination treatment has been recommended for all patients infected with hcv . for patients infected with hcv genotype 1 ( hcv-1 ) ,
the recommended treatment duration is 48 weeks , whereas for patients infected with hcv-2 or hcv-3 , the recommended treatment duration is 24 weeks .
there are two distinct but complementary mechanisms for the antiviral effects of ifn- : ( a ) induction of a non - virus - specific antiviral state in infected cells , resulting in direct inhibition of viral replication , and ( b ) immunomodulatory effects that enhance the host 's specific antiviral immune responses and may accelerate the death of infected cells .
food and drug administration ( fda ) has approved 3 ifn preparations for treatment of hcv : ( a ) 3 million units ( mus ) ifn--2a 3 times weekly ; ( b ) 3 mus of ifn--2b 3 times weekly ; and ( c ) 9  gs of ifn alfacon-1 twice weekly , or 15  g 3 times weekly in nonresponders .   pegifn is a product of pegylation to conventional ifn ( the attachment of inert polyethylene glycol ( peg ) polymers to a therapeutic protein such as ifn ) .
the larger molecular size of the compound results in a longer half - life due to reduced clearance , while retaining biological activity , and allows more convenient once - weekly dosing .
two pegifns [ 11 , 12 ] were studied : ( a ) pegifn--2a , a 40  kda branched molecule with a terminal half - life of 80 hours ( range : 50140 hours ) and a mean clearance of 22  ml / hrkg administered at a fixed 180  g per week and ( b ) pegifn--2b , a 12  kda linear molecule with a mean terminal half - life of 40 hours ( range : 2260 hours ) and a mean clearance of 94  ml / hr  kg , administered on the basis of weight ( 1.5  g / kg / week ) .
maximal serum concentrations ( c 
 max ) occur between 15 and 44 hours post dose and are sustained for up to 4872 hours .
these two pegifns much improved the rates of svr in comparison with their nonpegylated counterparts [ 11 , 12 ] .  
ribavirin ( 1--d - ribofuranosyl-1,2,4-triazole-3-carboxamide ) is an oral purine nucleoside analogue with broad activity against viral pathogens .
the mechanism of action of ribavirin in chc remains controversial . among the suggested , but not proven , roles of ribavirin in the treatment of chc are an immunologic modulation through switching the t - cell phenotype from type 2 to type 1 ; inhibition of host inosine monophosphate dehydrogenase activity ; depletion of intracellular guanosine triphosphate pools ; induction of mutational catastrophe ; or a moderate , transient , early direct antiviral effect .
ribavirin may lead to rapid and lethal mutation of virions or depletion of intracellular guanosine triphosphate , which is necessary for viral rna synthesis . additionally , ribavirin may act synergistically with ifn by upregulating the activity of double - stranded rna - activated protein kinase and enhances the action of interferon - alfa against hepatitis c virus .  
the most interesting clinical observation is that ribavirin monotherapy had a minimal effect on hcv viremia , despite the fact that serum alt levels were reduced significantly in a considerable proportion of patients with chronic hcv infection .
however , the combination of ribavirin and ifn provides a clinically synergistic anti - hcv effect .
hence it was proposed that ribavirin may exert its effect on the host immune response .
several studies on virus - specific t - cell reactivity in association with ifn treatment have found increased numbers of patients with chc with demonstrable hcv - specific th responses either during treatment or after a sustained therapeutic response .
these findings raise the possibility that enhancement of hcv - specific t - cell reactivity may be one mechanism for successful antiviral treatment .
hcv - specific t - cell reactivity was uncommon at baseline but increased markedly during antiviral therapy , peaking around treatment weeks 48 .
the main difference in t - cell reactivity of patients treated with ifn - ribavirin was a significant decrease of the expression of ifn- , whereas inf- expression was similar to that in patients receiving ifn monotherapy .
the greater efficacy of ribavirin may exert an anti - inflammatory effect and may help reducing ifn--driven t - cell activation and liver damage .
  in earlier studies , the primary end point for hcv therapies was a biochemical response , defined as the normalization of alt levels [ 2 , 3 ] .
the introduction of virologic assays to detect hcv rna further allows the assessment of a virologic response , defined as polymerase chain reaction- ( pcr- ) seronegative ( 50  iu / ml , or 100  copies / ml ) for hcv rna .
histological response has been assessed in some clinical studies , but there is little indication for posttreatment biopsy in clinical practice .  
four on - treatment and three patterns of off - treatment virological responses to antiviral therapy for hepatitis c have emerged over the past decade [ 2123 ] .
they include the following : 
 rapid virologic response ( rvr ) : pcr - seronegative of hcv rna at week 4 ; 
 early virologic response ( evr ) : there are two kinds stratifications of evr : 
 complete evr ( cevr ) : pcr - seronegative of hcv rna at week 12;partial evr ( pevr ) : decrease of hcv rna by > 2 log from baseline values at week 12 ; 
  complete evr ( cevr ) : pcr - seronegative of hcv rna at week 12 ; partial evr ( pevr ) : decrease of hcv rna by > 2 log from baseline values at week 12 ;  
  end - of - treatment virologic response ( etvr ) : pcr - seronegative of hcv rna at the end of therapy ;  
  virologic breakthrough : hcv rna reappearance in serum while still on treatment ; 
 sustained virologic response ( svr ) : pcr - seronegative of hcv rna 6 months after completing therapy ; 
 virologic relapse : pcr - seronegative of hcv rna at the end of therapy , with return of circulating virus after completion of therapy ; 
 nonresponders : persistently seropositive for hcv rna throughout treatment .
more than 97% of patients with svr remain nonviremic by pcr for the subsequent 514 years [ 24 , 25 ] .
these patients are regarded as having a high probability of a durable biochemical , virologic , and histological response .
until the 1990s , the only therapy of proven benefit for patients with chc was ifn-. initially , a 6-month course of 3 weekly injections of 3 mus of ifn- was approved for treatment of chc , and a biochemical response , defined as the normalization of alt levels , was assigned as the primary end point [ 2 , 3 ] .
ifn- monotherapy suppresses serum hcv rna to undetectable levels and normalizes the alt level in 25% to 40% of chc patients , usually within the first 2 - 3 months of treatment .
however , these initial responses to ifn- monotherapy are usually transient , and sustained response is documented in only about 8% to 9% of patients . when virologic assays for detection of hcv rna became available ,
the virological response rates were observed to be lower than those reported with biochemical end points . in the meta - analysis of ifn- monotherapy ,
normalization of alt levels at the end of treatment and 6 months after stopping treatment was seen in 47% and 23% of treated patients , respectively .
etvr and svr , however , were observed in only 29% and 8% of treated patients , respectively .
improvement of efficacy on chc could be achieved with higher doses and/or a longer duration of ifn- monotherapy .
a doubling of the duration of therapy to 12 months increased the frequency of svrs to approximately 20% .
the best efficacy / risk ratio was in favor of 3 mus of ifn- 3 times weekly for at least 12 months in treatment - nave patients with chc .  
the introduction of ribavirin in combination with ifn- was a major breakthrough in the treatment of chc . even though ribavirin monotherapy was shown to be ineffective , the rate of svrs was 43% and 6% for the ifn--2a with and without ribavirin combination , respectively , and 36% and 18% for the ifn--2b with and without ribavirin combination .
a meta - analysis in 1995 showed that the svr rate was significantly higher for ifn - ribavirin combination therapy than for ifn or ribavirin monotherapy ( odds ratio [ or ] : ifn - ribavirin versus ifn = 9.8 ; 95% confidence interval [ ci ] = l.950 ) .   
several landmark studies then followed and consistently demonstrated the dramatically improved responses to combination therapy , especially for hcv-2 or hcv-3 patients . in 1998 , two multicenter randomized controlled trials ( rcts ) ( one u.s .
study and one international study ) totaling 1,744 previously untreated patients with compensated chc compared 24- and 48-week drug regimens of ifn--2b monotherapy ( 3 mus 3 times weekly ) with those of ifn--2b and ribavirin ( 1.000  mg / day or 1.200  mg / day for patients weighing < 75  kg or > 75  kg , resp . )
combination therapy followed by 24 weeks of off - therapy followup [ 5 , 6 ] .
the overall svr rates for 24 and 48 weeks of therapy were 33% and 41% , respectively , for patients receiving ifn--2b - ribavirin , compared with svr rates of 6% at 24 weeks and 16% at 48 weeks ifn--2b monotherapy .
in addition to definitively showing the benefit of combination therapy over ifn alone , these studies made several other important clinical points .
second , the likelihood of response to treatment was related to pretreatment virus level and genotype .
svrs to 48 or 24 weeks of combination therapy occurred in 29% and 17% of hcv-1 patients , respectively , and in 65% and 66% of hcv-2 or hcv-3 patients .
the two studies reinforced the importance of longer duration therapy for 48 weeks in patients with hcv-1 infection .
similarly , svrs to 48 or 24 weeks of combination therapy occurred in 38% and 27% of patients with pretreatment hcv rna levels of greater than 2  10  copies / ml , respectively , but the svr rates were no different for those with lower levels ( 45% and 43% , resp . ) .
a systematic review in 2001 included data from 15 trials in which patients received ifn- monotherapy or ifn--ribavirin combination therapy . in comparison with ifn- monotherapy ,
combination therapy reduced the nonresponse rate ( absence of svr ) by 26% in treatment - nave patients ( relative risk = 0.74 ; 95% ci = 0.700.78 ) .
morbidity and mortality showed a nonsignificant trend during treatment in favor of combination therapy .  
in 1998 , the fda approved the combination of ifn- and ribavirin for patients with chronic hcv infection . in 1999 , the easl international consensus conference on hepatitis c recommended that , for patients with chc who have not been previously treated , ( a ) standard therapy should consist of ifn- and ribavirin in combination for 24 weeks and that ( b ) treatment should be extended to 48 weeks in patients with both hcv-1 and hcv rna levels greater than 2  10  copies / ml .   four rcts compared the efficacy and safety of once - weekly pegifn- monotherapy compared with ifn- monotherapy three times per week for the treatment of chronic hcv infection in treatment - nave patients [ 11 , 12 , 32 , 33 ] .
the recommended dose of pegifn--2a monotherapy , administered fixed at 180  g / week for 48 weeks , achieved higher svr rates compared with ifn--2a monotherapy ( 30% to 39% versus 8% to 19% ) [ 12 , 32 , 33 ] ; the pegifn--2b monotherapy , administered according to body weight at 1.5  g / kg / week for 48 weeks , achieved an svr rate of 23% , compared to 12% with ifn--2b monotherapy .   of note ,
conducted the first substantive prospective study confined to patients with compensated cirrhosis or advanced fibrosis .
cirrhosis has been a poor predictor of responsiveness and is associated with a high risk of leucopenia and thrombocytopenia [ 5 , 6 ] . this study
, however , showed that pegifn monotherapy was both well tolerated and effective in cirrhotic chc patients , with an svr rate of 30% .  
pegifn monotherapy has been recommended for patients with contraindications to ribavirin , such as those with renal insufficiency , hemoglobinopathies , and ischemic cardiovascular disease .
some clinical trials have been reported to date in these populations [ 34 , 35 ] . for patients with contraindications to ribavirin but who have indications for antiviral therapy , pegifn represents the best option of treatment .  
the results of pegifn- monotherapy encouraged more clinical trials to go on and anticipation that combination therapy with pegifn- and ribavirin would be even more effective .
the earlier two large rcts were applied with fixed durations of 48 weeks [ 36 , 37 ] . in these trials ,
pegifn--2b was dosed by weight ( 1.5  g / kg was fda approved ) and coupled with 800  mg of ribavirin ; pegifn--2a was given at a fixed dose of 180  g along with a weight - adjusted , higher dose of ribavirin ( 1.000  mg / day or 1.200  mg / day for patients weighing < 75 kg or > 75  kg , resp . ) .
these trials demonstrated that higher svr rates could be achieved with the combination of pegifn- weekly plus oral ribavirin given twice daily than with the combination of ifn- given 3 times weekly plus ribavirin or than with pegifn- monotherapy .   
the issue of influence of ribavirin dose by body weight on the response rate was first addressed . in the pegifn--2b study ,
a post hoc analysis demonstrated that an svr of 61% was achieved in the subgroup whose daily dose of ribavirin exceeded 10.6 mg / kg . logistic regression analyses observed that the response rates generally increased as ribavirin dose increased up to about 13  mg / kg / day .
some studies highlighted the potential importance of higher doses of ribavirin [ 38 , 39 ] .
the first 4 weeks of weight - based ribavirin exposure ( > 13  mg / kg / day ) have been associated with the achievement of an rvr . in non - rvr patients , one post hoc analysis showed that providing and maintaining optimal dose of ribavirin within 12 weeks of treatment was pivotal for the attainment of a cevr .
patients with a cevr in this study received a ribavirin dose of 16.3  mg / kg / day . moreover , a higher weight - based dose of ribavirin ( 15.2  mg / kilogram / day ) was associated with a lower relapse rate and higher svr rate .  
later , the optimal treatment duration and ribavirin dose were investigated in a multicenter rct in which all chc patients received pegifn--2a at a dose of 180  g , while patients in the four arms received either 24 or 48 weeks of ribavirin at a dose of 800 mg or at the higher , weight - based doses of 1.000 or 1.200  mg daily . in the subsequent registration trial ,
a high frequency of svrs occurred in patients with hcv-2 or hcv-3 , regardless of the regimen ( 79% to 84% ) , but optimal frequencies of svrs in hcv-1 ( 52% ) required longer duration and full - dose ribavirin , independent of the level of hcv rna . in patients with hcv-1 with a low viral load ( < 2  10  copies / ml , or 800.000  iu / ml ) , the svr was highest in those who had received the higher ribavirin dose and who were treated for 48 weeks ( 61% ) .
this regimen was also optimal for patients with hcv-1 and a high viral load ( svr rate : 46% ) .
in contrast , in patients with hcv-2 or hcv-3 , regardless of the pretreatment viral load , no differences were detected with the 4 treatment regimens .
another single - arm , open - label , historical - control study of 24 weeks of treatment with pegifn--2b plus ribavirin limited to patients with hcv-2 or hcv-3 demonstrated that 24 weeks of treatment was sufficient in hcv-2- or hcv-3-infected patients , with an overall svr rate of 81% .
this study supports the current recommendations that patients with hcv-1 require 48 weeks of pegifn- therapy with higher doses of ribavirin , while patients with hcv-2 or hcv-3 can be treated for only 24 weeks and with only 800  mg daily of ribavirin [ 7 , 45 ] .
so far , there are 3 rcts to compare the rates of svr of these two pegifns .
one rct showed no significant difference between the two available peginterferon - ribavirin regimens in patients infected with hcv genotype 1 .
two rcts showed that svr rates were significantly greater in hcv patients treated with pegifn--2a than patients treated with pegifn--2b [ 12 , 47 , 48 ] .
one recent meta - analysis showed that peginterferon alpfa-2a significantly increased the number of patients who achieved a sustained virological response ( svr ) versus peginterferon alfa-2b ( 47% versus 41% ; risk ratio : 1.11 ; 95% confidence interval : 1.041.19 ; p = .004 ( eight trials ) ) .   
physicians should look specifically for contraindications to antiviral therapy and assess both therapeutic risk and benefit .
ribavirin is contraindicated in pregnancy , necessitating strict precautions and contraception in women of childbearing age and their sexual partners and in hcv - infected men with female partners of childbearing age .
flu - like side effects of ifn can be managed with acetaminophen or nonsteroidal anti - inflammatory drugs ; antidepressants and hypnotics can be used for depression and insomnia , respectively .
for management of neutropenia , dose reduction suffices ; the addition of granulocyte colony - stimulating factor is generally not recommended , although it may be considered in individual cases of severe neutropenia .
treatment with ribavirin should be avoided in patients with ischemic cardiovascular and cerebrovascular disease and in patients with renal insufficiency .
patients with decompensated cirrhosis are at high risk of adverse events and relatively contraindicated to ifn - ribavirin .   
patients receiving combination therapy had an increased risk for requiring medication dose reduction ( rr = 2.44 ; 95% ci = 1.583.75 ) or discontinuation ( rr = 1.28 ; 95% ci = 1.071.52 ) compared with those receiving ifn monotherapy .
the rates of ifn dose reduction and discontinuation were similar among subjects receiving pegifn and conventional ifn [ 11 , 12 ] .
with the great progress in the management of chc , clinical factors have been identified as predictors for the efficacy of the ifn - based therapy .
they could be divided into two major categories : baseline and on - treatment predictors ( table 2 ) .  
the pretreatment variable most strongly predictive of an svr is the presence of hcv-2 or hcv-3 infection , whether with conventional ifns or pegifns , alone or in combination with ribavirin [ 5 , 6 , 36 , 37 ] . on the basis of variations in the nucleotide sequence of hcv ,
six genotypes ( numbered 16 ) and more than 50 subtypes ( identified by lowercase letters , e.g. , 1a and 1b ) have been identified .
why hcv-1 is harder to treat than other hcv genotypes is not yet fully understood .
several studies demonstrated that there exists a genotype - specific difference of viral kinetics [ 23 , 53 ] .
the turnover of hepatocytes infected with hcv-1 is slower than that of hepatocytes infected with other hcv genotypes after initiation of ifn - based therapy [ 53 , 54 ] , implying that hcv-1 might be more resistant to antiviral therapy . under the current recommendation , svr rates were 42% to 60% for hcv-1 infection with a 48-week pegifn - ribavirin treatment , compared with 76% to 95% for hcv-2 or hcv-3 infections with a 24-week regimen
[ 23 , 36 , 37 , 43 , 44 , 55 , 56 ] .
patients with hcv-4 , which is common in egypt , are intermediate in responsiveness to therapy between those infected with hcv-1 and hcv-2 or hcv-3 , and it is suggested that they should be treated for a full 48 weeks with full - dose ribavirin , like patients with hcv-1 [ 4 , 41 ] . there is insufficient experience to provide recommendations for the treatment of persons with hcv-5 and hcv-6 so far .
experienced providers need to make treatment judgments on a case - by - case basis .
since hcv genotype is the strongest predictor of responses to ifn - based therapy for chc , it should be determined in all hcv - infected persons prior to treatment to determine the duration of therapy and the likelihood of response .   pretreatment hcv rna level , even less important than hcv genotype , is a predictor of sustained response in ifn - based therapy [ 5 , 6 , 11 , 37 , 57 ] .
the impact of hcv rna level on the response to combination therapy was different between patients with different hcv genotype infections .
high viral load ( with a cutoff value of 200.000  copies / ml , or 40.000  iu / ml ) influenced the response rate in patients with hcv-1 ( 41% versus 56% ) but not those in patients with hcv-2 or hcv-3 ( 74% versus 81% ) .
under the circumstances of a determined hcv genotype for chc patients , testing hcv rna levels is beneficial and recommended for hcv-1 patients but seems variable for hcv-2 or hcv-3 patients .  
higher quasispecies complexity at baseline has been observed in nonresponders than in sustained virological responders .
an increasing number of mutations within the carboxyl terminal region of the hcv nonstructural 5a protein , named the ifn - sensitivity - determining region ( isdr ) , were correlated with treatment response in hcv-1-infected patients .
patients infected with the so - called mutant type , defined by four or more amino acid substitutions in the isdr , showed a more favorable response toward ifn - based therapy in japan and taiwan [ 60 , 61 ] .
additionally , a high degree ( 6 ) of sequence variation in the variable region 3 ( v3 ) plus its upstream flanking region of ns5a ( amino acid 23342379 ) , referred to as ifn / rbv resistance - determining region ( irrdr ) , would be a useful marker for predicting svr , whereas a less diverse ( 5 ) irrdr sequence predicts non - svr .  
the presence of bridging fibrosis and cirrhosis has been reported as one of the most unfavorable predictors for ifn - based therapy [ 5 , 6 , 12 , 51 , 64 , 65 ] .
patients with cirrhosis generally respond poorly to standard ifn monotherapy , with svr rates of 5% to 20% [ 6 , 32 ] .
responses are improved when conventional ifns or pegifns are combined with ribavirin , resulting in svr rates of 33% to 44% [ 6 , 36 , 37 ] .   a gender effect on response has been reported .
female sex was a predictor of svr in studies of conventional ifn - based therapy , but not in the studies of pegifn - ribavirin [ 11 , 36 , 43 ] .
younger patients ( < 40 years ) had higher svr rates with pegifn - ribavirin [ 36 , 37 , 43 ] .
several studies have demonstrated that svr rates are lower in patients with coexistent insulin resistance and/or hepatic steatosis or steatohepatitis [ 67 , 68 ] . in hcv-1 patients treated with pegifn - ribavirin , a lower svr rate was observed in patients with insulin resistance ( homeostasis model of assessment , homa - ir > 2 ) compared to those without insulin resistance [ 69 , 70 ] .  
kg / m are more likely to be insulin - resistant , to have more advanced hepatic steatosis or steatohepatitis and fibrosis , and to experience a reduced response to combination therapy [ 71 , 72 ] .
additionally , other possible mechanisms of the impact of obesity on the therapeutic response include the linear correlation of efficacy and body - weight - based doses of ribavirin ( 10.615 
mg / kg / day ) . to encourage weight loss and exercise before treatment , which has been associated with a reduction in steatosis fibrosis scores ,
excessive alcohol use could reduce the likelihood of a response to therapy [ 74 , 75 ] . to increase the efficacy of antiviral therapy
, it has been suggested that abstinence be recommended before and during treatment for chc .  
racial differences in response to efficacy of ifn exist and have been one of the host factors
. a lower response rate to ifn monotherapy was observed among african - american patients compared with white patients [ 17 , 76 ] . a pool analysis of two clinical trials with ifn - ribavirin combination therapy demonstrated that svrs were highest among asians ( 61% ) , followed by whites ( 39% ) , hispanics ( 23% ) , and african - americans ( 14% ) .
hispanics and african - americans were less likely to respond to pegifn--ribavirin compared to whites . in studies of taiwanese chc patients ,
the svr rate was 23.7% , 37.1% , and 63.6% for a 24-week treatment of 3 mus of ifn- 3 times weekly alone , 6 mus of 3 times weekly alone , and 3 mus of 3 times weekly plus ribavirin , respectively [ 65 , 79 ] .
the svr rate of hcv-1b patients to 24-week pegifn--ribavirin was 48.9% to 65.8% and could be as high as 80% with a 48-week regimen in taiwan [ 79 , 80 ] . a relative lower body weight ( 6770  kg ) in asian patients compared to u.s .
patients ( 7881  kg ) may also play an important role .   the different ethnic response rates may reflect the important role of genetics .
host genetic variations are probably involved in the efficacy of ifn - based therapies for chc .
genetic polymorphisms of human leukocyte antigen , cc chemokine receptor 5 , cytotoxic t lymphocyte antigen-4 , interleukin-10 , low molecular mass polypeptide 7 , mxa , and transforming growth factor-1 have been reported to have significant associations with responsiveness [ 8289 ] .
tnf--308 polymorphism was associated with svrs to ifn - ribavirin in patients with hcv-1b infection and a high viral load .
these results reflect the important role of unique genetic predisposition , at least in part , in the response to ifn - based therapy for chc .
recent advances in pharmacogenomics have demonstrated the potential applications of genetic single nucleotide polymorphism and expression patterns in determining treatment responsiveness in chc [ 91 , 92 ] .
a recent candidate gene study showed that genetic variation in the il28b gene , which encodes ifn-3 , is associated with spontaneous hcv clearance .
several genome - wide associated studies observed that il28b single nucleotide polymorphisms played an important role in the treatment outcome of pegifn - rbv for chc [ 9496 ] .
a genome - wide association study in 2010 confirmed that il28b genetic variation was the strongest genetic predictor in both natural and treatment - induced control of hcv .
the increasing evidence for the role of ifn-3 for both spontaneous and treatment - induced control of hcv infection opens new avenues for prognosis and treatment of hcv infection .
individuals with hcv genotype 1 or 4 who carry the risk allele , particularly in homozygosis , will have a very low probability of natural or treatment - induced clearance .
half of the ethnic differences in response to interferon and ribavirin combination therapy can be explained by genetic polymorphism of il28b .   because of the presumably shared routes of transmission , approximately one - fourth to one - third of all persons infected with hiv are coinfected with hcv .
patients with hiv - hcv coinfection have been shown to respond less favorably to antiviral therapy than patients infected with hcv alone [ 98 , 99 ] .
several rcts recommended 48 weeks of pegifn - ribavirin for hcv , regardless of hcv genotype , in hcv - hiv coinfected patients [ 100 , 101 ] .  
dual infections of hcv and hepatitis b virus ( hbv ) are not uncommon and occur in up to 5% of the general population in hcv - endemic areas .
combined chronic hepatitis b and c leads to more severe liver disease and an increased risk of hcv .
although hbv - hcv dual infection was refractory to conventional ifn monotherapy , recent studies in taiwan have demonstrated that conventional ifn - ribavirin combination therapy was effective in hcv clearance among hcv - dominant , hbv / hcv dually infected patients [ 105 , 106 ] .
recently , a large , open - label , comparative , multicenter study confirmed the efficacy of pegifn - ribavirin for patients with chronic hcv - hbv dual infection in taiwan .  
nonresponders are more resistant to retreatment with subsequent ifn - based therapy , compared to relapsers ( or = 3.912 ; 95% ci = 1.45910.49 ) .
retreatment with pegifn - ribavirin could achieve an svr rate of 47% to 60% for relapsers and 18% to 23% for nonresponders
, hcv rna levels generally fall in a biphasic manner . the first rapid phase of viral suppression , from a few hours after the first ifn- injection to the end of the first day , is related to an inhibition of viral replication by a direct , nonspecific action of ifn-. this early initial decline in hcv rna levels correlates poorly with the eventual response to ifn - based therapy [ 74 , 113 ] .
the second , slower phase of viral suppression , beginning on day 2 and gradually leading to seroclearance of hcv rna , is possibly related to the gradual clearance of infected cells by the patient 's immune system , while hcv replication is efficiently inhibited .
this phase , less influenced by the dosage of ifn and hcv genotype , exhibits a good response to pegifn and is an excellent marker of an svr to the treatment [ 36 , 54 , 74 ] .  
an rvr at week 4 could predict an svr to ifn - ribavirin with a high degree of accuracy in both hcv-1 and hcv-2 patients , with positive predictive values of 78% and 92% , respectively .
recent studies have demonstrated that an rvr is the single best predictor of an svr to pegifn - ribavirin for hcv-1 [ 114 , 115 ] and hcv-2 or hcv-3 patients [ 23 , 55 , 56 , 116 ] . for hcv-1 or hcv-4 patients with lower baseline viral loads and an rvr
, an abbreviated 24-week regimen could achieve a comparable svr rate with a standard 48-week regimen [ 115 , 117 , 118 ] .
selected patients with rvr might have their treatment courses abbreviated to 16 weeks if they are infected with hcv-2 or hcv-3 [ 23 , 56 ] .
but , the shortening of therapy duration for genotype 2/3 with rvr is still controversial .
abbreviated regimens may be considered in patients with a low baseline viral load who achieve an rvr [ 120 , 121 ] .   among patients with an evr ,
however , as a negative predictor , non - evr is even an more robust predictor . in cases without an evr ,
the non - evr is a significantly negative predictor in hcv-1 patients , but not in hcv-2 patients .
thus it is recommended that hcv-1 patients who do not achieve an evr at week 12 should discontinue the therapy beyond 12 weeks [ 22 , 78 ] .
recently , stratification of early virological response ( evr ) into complete evr ( cevr ) and partial evr ( pevr ) has been possible to further improve the prediction of an svr and may allow for optimizing treatment duration in non - rvr patients .
studies for hcv-1 non - rvr patients have demonstrated that the current recommended 48 weeks of treatment could achieve high svr rates in patients with a cevr but could lower rates of svr in patients with a pevr [ 124 , 125 ] .
the svr rates would be more than 90% if patients could reach a cevr with a standard regimen ( 48 weeks for hcv-1 or 24 weeks for hcv-2 ) . for non - rvr patients , hcv viral loads < 10  iu / ml at week 4 provided an early and accurate prediction of who would or would not achieve a cevr and following svr . in hcv-1-infected patients with a pevr ,
the svr rates were 10% and 21% only and the relapse rates were up to 83% and 63% in the 24-week and 48-week groups , respectively .
the treatment responses were inadequate , even with a standard 48-week regimen in these patients [ 124 , 125 ] .  
based on these predictors associated with treatment efficacy , response - guided individualized therapy has become a major consideration for clinicians .
it is desirable to expose chc patients to the lowest doses and shortest durations of treatment , to reduce the likelihood of adverse events and to minimize costs , without compromising treatment efficacy .
on the other hand , some difficult - to - treat patients have to receive longer and/or higher dose therapy to achieve responses .
to date , hcv genotype , baseline viral load as well as on - treatment virological responses will provide information for individualized therapy decisionmaking for chc patients in the near future [ 115 , 126 ] .
people who have an rvr may have a chance to abbreviate their treatment courses to avoid unnecessary costs and preventable drug side effects . in patients without an rvr treated with standard of care , the svr rate would be more than 90% if cevr could be accomplished . in patients with only a pevr , it has been suggested to extend the treatment course to 72 weeks [ 124 , 125 , 127 ] or adhere to high - dose peginterferon plus ribavirin combination therapy . in the future ,
additional therapy other than interferon - based treatment , such as protease inhibitors , might be anticipated in those difficult - to - treat patients .
one would like to be able to evaluate whether a treatment response is likely as early as possible so that individualized strategies can be made or altered earlier before or during the treatment course .
< 10  iu / ml at week 4 provided an accurate prediction of cevr and svr in non - rvr patients .
medical adherence is an important factor associated with response to ifn - ribavirin , especially among patients with hcv-1 infection . in a retrospective analysis of data collected in the large registration trials of ifn - ribavirin , svrs
have been reported to be more likely in patients who had taken at least 80% of all projected ifn injections and at least 80% of all projected ribavirin for at least 80% of the anticipated duration of treatment .
recent development of direct - acting antiviral agents , also named  specifically targeted antiviral therapy for hepatitis c  ( stat - c ) compounds , to treat hcv has focused predominantly on inhibitors of the viral enzymes ns3/4a protease and the rna - dependent rna polymerase ns5b [ 129 , 130 ] .
the administration of hcv ns3/4a protease inhibitors to patients with chronic hcv infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti - hcv therapy .
newer data have demonstrated promise for 2 protease inhibitors , sch 503034 ( boceprevir ) and vx-950 ( telaprevir ) , both of which appear to be able to improve sustained response while shortening duration of therapy .
telaprevir ( vx-950 ) , the hcv protease inhibitor , is in the most advanced phase of clinical development .
a first case of sustained virological response ( svr ) achieved in a patient with chronic hepatitis c by monotherapy with telaprevir without interferon therapy was reported .
owing to a low genetic barrier , resistant variants emerge within a few days when used in monotherapy , thereby decreasing its efficacy .
consequently , telaprevir has been combined with pegylated - interferon and ribavirin in clinical trials .
this triple combination is more effective but has a higher rate of adverse events ( notably rash ) than the standard of care , despite the shorter duration of therapy .
results of the milestone studies prove 1 and 2 indicate that 12 weeks of telaprevir - based triple therapy is too short because of the high rate of relapse after treatment completion
. however , 24 to 48 weeks of total therapy including 12 weeks of triple therapy with telaprevir in addition to standard treatment greatly improved svr rates in treatment - nave genotype 1 patients compared with the standard of care .
prove 3 has shown that telaprevir is also highly effective in the treatment of prior nonresponders or relapsers infected with hcv genotype 1 [ 130 , 135 ] .
 since 1986 , interferon - alfa ( ifn- ) monotherapy has been administered for patients with chronic hepatitis c ( chc ) . however , sustained response rate is only about 8% to 9% . 
 subsequent introduction of ribavirin in combination with ifn- was a major breakthrough in the treatment of chc . 
 sustained virological responses ( svrs ) rate is about 30% in hepatitis c virus genotype 1 ( hcv-1 ) patients , and is about 65% in hcv-2 or -3 patients . 
 after 2000 , pegylated interferon ( pegifn ) much improved the rates of svr . 
 presently , pegifn--ribavirin combination therapy has been current standard of care for patients infected with hcv . in patients with hcv-1 , 
 treatment for 48 weeks is optimal , but 24 weeks of treatment is sufficient in hcv-2 or -3 infected patients . 
 clinical factors have been identified as predictors for the efficacy of the ifn - based therapy . 
 the baseline factor most strongly predictive of an svr is the presence of hcv-2 or -3 infections . 
 rapid virological response ( rvr ) is the single best predictor of an svr to pegifn - ribavirin therapy . 
 if patients ca n't achieve a rvr but achieve a complete early virological response ( cevr ) , treatment with current standard of care can provide more than 90% svr rate . 
 hcv-1 patients who do not achieve an evr should discontinue the therapy . 
 recent advances of protease inhibitor may contribute the development of a novel triple combination therapy . 
1. Introduction
2. Approved Agents for Treatment of Hepatitis C
3. Assessment of Treatment Response for Hepatitis C
4. Evolution of IFN-Based Therapy for Chronic Hepatitis C
5. Factors Associated with Treatment Efficacy
6. Protease Inhibitors and IFN-Based Therapy