chronic hepatitis c virus ( hcv ) infection has a detrimental effect on the health of persons with chronic kidney disease .
it leads to higher mortality in maintenance hemodialysis patients compared to noninfected patients and reduces the survival rates of patients undergoing kidney transplantation as well as their grafts .
it renders patients with a higher risk of developing diabetes mellitus , de novo or recurrent membranoproliferative glomerulonephritis , lymphoproliferative disorders , and fibrosing cholestatic hepatitis after kidney transplantation . until recently , in the absence of any efficient treatment for hcv infection after kidney transplantation , treating all anti - hcv - positive rna - positive patients that were candidates for kidney transplantation has been recommended . for several years , standard
reduced interferon- ( ifn- ) alpha or pegylated- ( peg- ) ifn--2a , given as a monotherapy , has been the main treatment given to hemodialysis patients with hcv replication . because ribavirin has been found to be responsible for hemolytic anemia in patients with impaired kidney function   as well as in hemodialysis patients , it was first prohibited and then used at markedly reduced daily doses with careful monitoring for anemia and other adverse effects .
hcv - positive dialysis patients that received standard ifn- or peg - ifn- achieved 50% efficacy .
first - generation direct - acting antiviral agents ( daas ) , such as the protease inhibitors telaprevir and boceprevir , have been developed over the past few years . they have been introduced as an adjunctive therapy for patients with chronic hcv but normal kidney function and have significantly improved the svr .
however , scarce data regarding their use in hemodialysis patients have been published [ 810 ] .
in addition , no data regarding the use of new - generation daas , such as sofosbuvir , daclatasvir , simeprevir , or ledipasvir , have been reported in this setting .
the aim of this study was to assess the efficacy and safety of a combined therapy of peg - ifn , ribavirin , and boceprevir to treat anti - hcv - positive rna - positive hemodialysis patients who were candidates for kidney transplantation .
between february 2013 and september 2014 , six patients who were chronically infected by genotype-1 hcv and were receiving hemodialysis three times weekly , and who were candidates for kidney transplantation , were treated with peg - ifn , ribavirin , and boceprevir as a triple therapy , after having given their written informed consent .
there were three men and three women , ranging in age from 39 to 72 years ( median : 49.5 ) .
five of the six patients had previously received interferon for hcv infection : one had a relapse and the other four patients were partial responders .
ribavirin was given at the dose of 200  mg / d , three times a week , after each dialysis session .
a sustained virological response was defined as negative hcv rna six months after the end of therapy .
a virological breakthrough was defined as hcv replication during therapy and after a period of nonviral replication .
patients were followed up every 15 days during the first month and then at three - month intervals for 6 months after therapy was completed .
hcv rna was assessed using the quantitative cobas amplicor hcv monitor assay ( limit of detection 15  log  iu / ml ) .
at the initiation of antiviral therapy , median viral concentration was 5.68 ( 4.36.55 )  log  iu / ml . the evolution of hcv concentration is presented in figure 1 . a rapid virological response , that is , undetectable hcv rna at week 4 , was observed in four of the six patients ( 66.6% ) .
all patients had at least once undetectable hcv rna during therapy , and hcv rna was undetectable in all patients at week 24 .
however , a breakthrough was observed in two patients ( p3 and p4 ) between weeks 24 and 48 , and a third patient ( p2 ) had to stop antiviral therapy between weeks 24 and 48 because of severe peripheral neuropathy . at week 48 ,
overall , when therapy was scheduled to finish , hcv rna was undetectable in three patients .
however , of these , two patients relapsed within the month after antiviral therapy had finished .
hence , overall , only one patient ( 16.7% ) had a sustained virological response : he had been a previous partial responder .
as is usually observed in hemodialysis patients , liver - enzyme levels were within the normal ranges at the beginning of therapy and also at the end of therapy ( data not shown ) .
because of fatigue and a flu - like syndrome , peg - ifn doses were decreased at week 4 from 135 to 90  g / week in three patients ( p2 , p3 , and p4 ) and then decreased further at week 24 from 90 to 45  g / week in one patient ( p4 ) .
one patient ( p2 ) developed peripheral neuropathy that was attributed to the antiviral therapy , which was stopped at week 28 although the patient was nonviremic .
overall , as expected , the main adverse effect was hematological tolerance , namely , anemia .
median hemoglobin level decreased from 11.5 ( range : 1013 )  g / dl at the initiation of antiviral therapy to 9.75 ( range : 8.511.5 )  g / dl at week 4 and to 9.55 ( range : 8.810.8 ) at week 12 .
it then remained at 9.55 ( range : 8.110.5 )  g / dl until week 24 , but then it decreased again to 8.75 ( range : 8.410.7 )  g / dl by week 48 . at the initiation of ribavirin therapy , three patients
were given recombinant erythropoietin ( repo ) at the median dose of 12,000 ( range : 8,00015,000 ) units / week . from week 4 and until the end of the therapy , repo was given to all patients at the median doses of 12,000 ( 8,00024,000 ) , 12,000 ( 8,00024,000 ) , 16,000 ( 12,00030,000 ) , and 18,000 ( 12,00030,000 ) units / week at weeks 4 , 12 , 24 , and 48 , respectively .
ribavirin dose was reduced at week 24 to 200  mg / week in one patient ( p4 ) because of very severe anemia , despite receiving high doses of recombinant erythropoietin .
boceprevir doses were reduced at week 24 to 1600  mg / d in patient 4 and to 800  mg / d in patient 2 .
within the last few years , the first - generation daa ns3 - 4a protease inhibitors , that is , boceprevir and telaprevir , have been developed and used in combination with peg - interferon and ribavirin to treat patients with chronic hcv infection .
boceprevir- or telaprevir - based anti - hcv therapy was first used in immunocompetent patients that had preserved kidney function .
it significantly improved the sustained virological rate in genotype-1 hcv infected patients , mainly for noncirrhotic patients . in hemodialysis patients ,
the recommended treatment for chronic hcv infection remains standard or pegylated - interferon . as pointed out in a meta - analysis by fabrizi et al .
, the svr response was 39% after standard ifn- therapy and 31% when peg - ifn- was used .
in other studies , although ribavirin accumulates in hemodialysis patients and causes severe hemolytic anemia , low doses of ribavirin , that is , 200  mg / day or 200  mg every other day , when added to interferon , improved the svr .
the svr ranged from 17 to 70% , and the dropout rate was up to 50% .
boceprevir- or telaprevir - based anti - hcv therapy has been used in a small number of hemodialysis patients .
treated four hemodialysis patients with a combined therapy of peg - ifn- , ribavirin , and telaprevir .
three of their four patients achieved viral clearance at week 12 ; however , no further outcomes were reported , and the number of svrs is unknown .
treated seven hemodialysis patients with peg - ifn- , ribavirin , and telaprevir : the duration of treatment ranged from 24 to 47 weeks .
successfully treated a hemodialysis patient with peg - ifn- , ribavirin , and boceprevir for 48 weeks . in the present study ,
six patients were given peg - ifn- , ribavirin , and boceprevir for 48 weeks .
antiviral therapy was stopped in one patient because of severe neuropathy , which was attributed to the interferon therapy .
two breakthrough events were observed in two patients , which required doses of antiviral drugs to be reduced because of adverse events .
however , two of these patients then relapsed one month and six months after treatment was finished .
eight of the 14 hemodialysis patients that received antiviral triple therapy , who had a sufficiently long follow - up , and were included in either a previously published series or in the present study , had a sustained virological response ( 57% ) .
the poor results observed in our study are probably related to poor tolerance to the antiviral therapy , which required dose reductions .
similar to previous studies , the main side effect observed in our study was anemia , which required the introduction of repo , or an increased dose of repo plus blood transfusions .
hence , this triple - therapy strategy did not effectively treat our hemodialysis patients with chronic hcv infection .
very recently , the use of new - generation daas , that is , sofosbuvir combined with daclatasvir , simeprevir , or ledipasvir , has been shown to be highly efficient at treating hcv infection in cirrhotic and noncirrhotic immunocompetent patients [ 1216 ] , in liver - transplant patients [ 1719 ] and in some kidney - transplant patients .
individually , daclatasvir , simeprevir , and ledipasvir can be eliminated by the liver and so can be given to hemodialysis patients .
however , no data regarding the use of sofosbuvir in patients with a glomerular - filtration rate < 30  ml / min exist : hence , a combination of daclatasvir , simeprevir , or ledipasvir is still not recommended in this setting .
a phase - ii multicenter study has assessed the efficacy and safety of the combination of grazoprevir ( mk-5172 ) and elbasvir ( mk-8742 ) given to patients with chronic hepatitis and chronic kidney disease , including hemodialysis patients ( clinicaltrials.gov : nct02092350 ) . in summary ,
a triple antiviral therapy based on peg - ifn- , ribavirin , and either telaprevir or boceprevir did not optimally treat hemodialysis patients with chronic hcv infection .
studies using new - generation drugs are required in this population as well as for kidney - transplant patients .
 
 background . 
 there are few data on the combination of ( pegylated- ) interferon- ( peg - ifn- )  , ribavirin , and first - generation direct - acting antiviral agents ( daas ) . 
 our aim was to describe the efficacy and safety of peg - ifn- , ribavirin , and boceprevir in hemodialysis patients . 
 patients . 
 six hemodialysis patients , chronically infected by genotype-1 hcv , were given peg - ifn- ( 135  g / week ) , ribavirin ( 200  mg / d ) , and boceprevir ( 2400  mg / d ) for 48 weeks 
 . results . at initiation of antiviral therapy , 
 median viral concentration was 5.68 ( 3.786.55 )  log  iu / ml . hcv rna was undetectable in four of the six patients at week 4 and in all patients at week 24 . 
 a breakthrough was observed in two patients between weeks 24 and 48 , and a third patient stopped antiviral therapy between weeks 24 and 48 because of severe peripheral neuropathy . at week 48 , hcv rna was undetectable in three patients . 
 of these , two patients relapsed within a month after antiviral therapy was stopped . 
 hence , only one patient had a sustained virological response ; he was a previous partial responder . 
 overall , anemia was the main side effect . 
 conclusion . 
 a triple antiviral therapy based on peg - ifn- , ribavirin , and boceprevir is not optimal at treating hemodialysis patients with chronic hcv infection . 
 studies using new - generation drugs are required in this setting . 
1. Introduction
2. Patients and Methods
3. Results
4. Discussion