chronic hepatitis c virus ( hcv ) infection is a major worldwide cause of liver - related deaths , including those caused by cirrhosis and hepatocellular carcinoma .
the eradication of hcv using interferon - based treatment improves liver - related mortality and reduces the risk of hepatocellular carcinoma development .
recently , interferon - free direct - acting antiviral therapy was used , which showed an excellent rate of hcv eradication among patients with chronic hcv genotype 1b , including those with prior interferon - based treatment failure .
however , interferon - based therapy is still a treatment option , and negativity for hcv rna at the end of antiviral treatment ( end - of - treatment response ; etr ) is essential to achieve the viral clearance of chronic infection .
although delayed viral clearance after the completion of 2448 weeks of interferon - based therapy is rarely reported , such a situation has not been observed among patients with the early discontinuation of therapy .
here , we report a case of hcv clearance at 7 months after a 6-week treatment with peginterferon ( pegifn ) plus ribavirin ( rbv ) .
a 76-year - old japanese male ( height , 161 cm ; weight , 63 kg ) with chronic hcv genotype 1b infection had initiated treatment with pegifn -2b plus rbv .
previously , he had been followed up for inactive chronic hepatitis for 15 years , with alanine aminotransferase ( alt ) levels < 40 iu / l , which had fluctuated from 40 to 140 iu / l for a year before the initiation of the latest treatment regimen .
his medical history included hypertension , hyperuricemia , and resistant gastroesophageal reflux disease , which were being treated with nifedipine , candesartan cilexetil , allopurinol , and lansoprazole for more than 5 years .
laboratory examinations ( table 1 ) revealed the following biochemical levels : alt , 129 iu / l ; albumin , 4.3 g / dl ; -glutamyl transpeptidase , 72 iu / l ; platelet count , 23.6  10/l , and -fetoprotein , 4.9 ng / ml . hepatitis c viral load was 5.3 log iu / ml .
genetic studies revealed tt of il28b ( rs8099917 ) and human leukocyte antigen ( hla)-drb1 * 01 : 01/08 : 03 . after the initiation of therapy , he reported a loss of appetite at week 2 and complained of anxiety , irritability , insomnia , and poor concentration at week 3 . although daily etizolam before sleep was started , he experienced poor appetite , taste disorder , and weight loss of 2 kg from the initiation of therapy . therefore , sulpiride was added , and the rbv dose was reduced from 800 to 600 mg per day because of anemia .
however , symptoms did not subside with a further weight loss of 1 kg and the progression of anemia ; thus , the rbv dose was reduced to 400 mg / day . nonetheless , the symptoms persisted , and he reported depression at week 6 , which prompted treatment discontinuation . following this , the symptoms slowly but gradually subsided , and he recovered after 5 weeks .
meanwhile , the hcv rna load decreased to weakly positive , with measured values of less than 1.2 log iu / ml at week 4 , which persisted at this level until 12 days after the discontinuation of treatment ( fig .
1 ) . then , the load gradually increased to 2.6 log iu / ml and 4.3 log iu / ml at 710 and 19 weeks after discontinuation , respectively . concurrently , serum alt levels , which had persisted at levels of less than 34
a posttreatment ultrasound exam revealed a 1.0-cm bladder tumor , which was diagnosed by urinary cytology as class v , and the patient was treated by transurethral resection of the bladder tumor ( tur - bt ) at week 26 of discontinuation .
iu / l ) at 1 week before tur - bt , and hcv rna was found to be negative at 11 days after surgery ( 28 weeks after the discontinuation of antiviral therapy ) , which has been maintained along with low levels ( < 25
this patient showed an unusual and unique clinical course of delayed viral clearance despite only 6 weeks of pegifn plus rbv therapy , without the achievement of hcv rna negativity .
there are relatively few reports of delayed viral clearance among patients with non - etr and those with relapse after pegifn plus rbv therapy ; all these patients had completed 2448 weeks of therapy , and almost all had genotype 2 or 3 and were aged < 60 years [ 4 , 5 , 6 ] . compared with those cases ,
our patient was unique in terms of being infected with hcv genotype 1b , older , and treated for only 6 weeks without achieving etr .
although the mechanism underlying delayed viral clearance remains unknown , we speculate two possibilities for this patient .
one is an immunological modification due to surgical stress caused by tur - bt , and the other is a delayed effect of pegifn plus rbv therapy .
it has been reported that surgical stress or invasive treatment can sometimes induce the clearance of hcv rna [ 7 , 8 ] , but this is not applicable to this case because it is quite unlikely that hcv rna with 4.3 log copies / ml was eliminated within 11 days after tur - bt .
furthermore , although hcv rna was not examined , the normalization of serum alt had already occurred before tur - bt .
chronic infection with hcv is characterized by hcv - specific t cell dysfunction , and t cell function is considered to play an essential role in the elimination of the virus . although it is controversial whether pegifn plus rbv therapy restores t cell function , the marked restoration of hcv - specific cd8 t cells was observed from 1 month after treatment in patients with a sustained viral response , and a correlation between the restoration of hcv - specific cd8 + t - cell function and early / sustained viral response   has been reported . in this case ,
hcv rna rapidly decreased after treatment , although the levels remained positive at < 1.2 log iu / ml at week 4 , and the low levels of viral load persisted for at least 10 weeks after the discontinuation of therapy , suggesting immunological recovery from hcv infection .
furthermore , the mild elevation of alt at 19 weeks could be considered as the t cell response against increased hcv rna .
this phenomenon is well known in patients with chronic hepatitis b virus ( hbv ) infection , in whom alt flare occurs with a preceding increase in hbv dna , often resulting in continuous virus suppression .
the immunological response observed in this phenomenon is also well understood . in our patient , although the elevation of alt was mild , a similar mechanism was presumed .
this patient had a genetic background of hla - b1 * 01 : 01 and tt of il28b rs8099917 .
the cellular immune responses coordinated by cd4 and cd8 t cells are genetically predetermined by the hosts hla molecules .
recently , several studies have revealed that the class ii drb1 * 01 : 01 hla allele and the c and t alleles of il28b ( rs12979860 and rs8099917 , respectively ) are associated with the spontaneous clearance of hcv [ 13 , 14 , 15 ] .
furthermore , hla - drb1 * 01 is suspected to be associated with delayed viral clearance after pegifn plus rbv therapy .
therefore , the genetic background of this patient may be related to the viral clearance after treatment discontinuation . in conclusion ,
interferon - based therapy remains a viable treatment option for chronic hcv infection , and virological follow - up is necessary even for patients with non - etr , particularly for those with persistent low viral loads after treatment .
 following interferon - based therapy for chronic hepatitis c , the negativity of hepatitis c virus rna is essential to achieve viral clearance at the end of treatment . 
 we report a case of clearance of chronic hepatitis c virus infection following early discontinuation ( at 6 weeks ) of peginterferon plus ribavirin therapy , without negativity for hepatitis c virus rna during the treatment period . 
 the patient was a 76-year - old japanese male infected with hepatitis c virus genotype 1b and tt of il28b rs8099917 . 
 hepatitis c virus rna remained positive at persistently low levels for more than 2 months after the cessation of therapy and became negative at 7 months after the discontinuation of therapy . 
 spontaneous clearance of hepatitis c virus rna can occur following antiviral failure in patients with persistently low viral loads , and virological follow - up is therefore necessary in chronic hepatitis c virus infection , even after antiviral failure . 
Introduction
Case Report
Discussion
Statement of Ethics
Disclosure Statement