ITPA Deficiency and Ribavirin Level are Still Predictive of Anaemia in HCV–HIV-Coinfected Patients Receiving Ribavirin Combined with a First-Generation DAA (ANRS HC27 Study)
Free accessResearch articleFirst published online August, 2017
ITPA Deficiency and Ribavirin Level are Still Predictive of Anaemia in HCV–HIV-Coinfected Patients Receiving Ribavirin Combined with a First-Generation DAA (ANRS HC27 Study)
We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV–HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC).
Methods
Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctrough on anaemia was also studied.
Results
Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0–W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctrough was associated with Hb decrease both at W4 and W8 and an RBV Ctrough cutoff value of 2 μg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough (P=0.012). ITPA deficiency, W4 RBV Ctrough and gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response.
Conclusions
ITPA deficiency and RBV Ctrough are still predictive of RBV-induced anaemia in HIV–HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.
References
1.
KohliA., ShafferA., ShermanA., KottililS.Treatment of hepatitis C: a systematic review.JAMA2014; 312: 631–640.
2.
FriedM.W., ShiffmanM.L., ReddyK.R.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med2002; 347: 975–982.
3.
MorelloJ., Rodriguez-NovoaS., Jiménez-NacherI., SorianoV.Usefulness of monitoring ribavirin plasma concentrations to improve treatment response in patients with chronic hepatitis C.J Antimicrob Chemother2008; 62: 1174–1180.
4.
Stanke-LabesqueF., Loustaud-RattiV., BabanyG., GagnieuM.C., MarquetP. French Ribavirin Group OPTIRIB. Ribavirin therapeutic drug monitoring: why, when and how?Fundam Clin Pharmacol2010; 24: 401–406.
5.
SolasC., ParéM., QuarantaS., Stanke-LabesqueF. Groupe Suivi Therapeutique Pharmacologique de la Societe Francaise de Pharmacologie et de Therapeutique. Evidence-based therapeutic drug monitoring for ribavirine.Therapie2011; 66: 221–230.
6.
FellayJ., ThompsonA.J., GeD.ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C.Nature2010; 464: 405–408.
7.
ThompsonA.J., FellayJ., PatelK.Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction.Gastroenterology2010; 139: 1181–1189.
8.
HitomiY., CirulliE.T., FellayJ.Inosine triphosphate protects against ribavirin-induced adenosine triphosphate loss by adenylosuccinate synthase function.Gastroenterology2011; 140: 1314–1321.
9.
SakamotoN., TanakaY., NakagawaM.ITPA gene variant protects against anemia induced by pegylated interferon-α and ribavirin therapy for Japanese patients with chronic hepatitis C.Hepatol Res2010; 40: 1063–1071.
10.
AzakamiT., HayesC.N., SezakiH.Common genetic polymorphism of ITPA gene affects ribavirin-induced anemia and effect of peg-interferon plus ribavirin therapy.J Med Virol2011; 83: 1048–1057.
11.
KurosakiM., TanakaY., TanakaK.Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirine.Antivir Ther2011; 16: 685–694.
12.
D'AvolioA., CiancioA., SiccardiM.Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.Ther Drug Monit2012; 34: 165–170.
13.
RauM., StickelF., RussmannS.Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection.J Hepatol2013; 58: 669–675.
14.
HolmesJ.A., RobertsS.K., AliR.J.ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.Hepatology2014; 59: 2152–2160.
15.
RallónN.I., MorelloJ., LabargaP.Impact of inosine triphosphatase gene variants on the risk of anemia in HIV/ hepatitis C virus-coinfected patients treated for chronic hepatitis C.Clin Infect Dis2011; 53: 1291–1295.
16.
DomingoP., GuardiolaJ.M., SalazarJ.Association of ITPA gene polymorphisms and the risk of ribavirin-induced anemia in HIV/hepatitis C virus (HCV)-coinfected patients receiving HCV combination therapy.Antimicrob Agents Chemother2012; 56: 2987–2993.
17.
NaggieS., RallonN.I., BenitoJ.M.Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.J Infect Dis2012; 205: 376–383.
18.
OsinusiA., NaggieS., PooniaS.ITPA gene polymorphisms significantly affect hemoglobin decline and treatment outcomes in patients coinfected with HIV and HCV.J Med Virol2012; 84: 1106–1114.
19.
ChayamaK., HayesC.N., AbeH.IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C.J Infect Dis2011; 204: 84–93.
20.
SuzukiF., SuzukiY., AkutaN.Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir.Hepatology2011; 53: 415–421.
21.
BoglioneL., De NicolòA., CusatoJ., CaritiG., Di PerriG., D'AvolioA.Significant early higher ribavirin plasma concentrations in patients receiving a triple therapy with pegylated interferon, ribavirin and telaprevir.J Viral Hepat2014; 21: 260–263.
22.
OgawaE., FurusyoN., NakamutaM.Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy.J Hepatol2013; 59: 667–674.
23.
IshidaH., SakaneS., ToyamaT.Administration of low-dose epoetin-alpha facilitates adherence to ribavirin in triple therapy with pegylated interferon-alpha-2b and telaprevir.Hepatol Res2014; 44: E84–E91.
24.
Poizot-MartinI., BellissantE., GarraffoR.Addition of boceprevir to PEG-interferon/ribavirin in HIV-HCV coinfected, treatment-experienced patients: efficacy, safety and pharmacokinetics data from the ANRS HC27 study.HIV Clin Trials2016; 17: 63–71.
SulkowskiM.S.Anemia in the treatment of hepatitis C virus infection.Clin Infect Dis2003; 37Suppl 4: S315–S322.
28.
AmpueroJ., Del CampoJ.A., RojasL.Role of ITPA and SLC28A2 genes in the prediction of anaemia associated with protease inhibitor plus ribavirine and peginterferon in hepatitis C treatment.J Clin Virol2015; 68: 56–60.
29.
NarayananS., TownsendK., MachariaT.Favorable adverse event profile of sofosbuvir/ribavirin compared to boceprevir/interferon/ribavirin for treatment of hepatitis C.Hepatol Int2014; 8: 560–566.
30.
ClarkP.J., AghemoA., DegasperiE.Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy.J Viral Hepat2013; 20: 858–866.
31.
AghemoA., GrassiE., RumiM.G.Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving telaprevir.PLoS ONE2014; 9: e95881.
32.
KobayashiT., HigeS., TerashitaK.Anemia and thrombocytosis induced by ribavirin monotherapy in patients with chronic hepatitis C.J Gastroenterol2012; 47: 1228–1237.
33.
HaiH., TamoriA., EnomotoM.Relationship between inosine triphosphate genotype and outcome of extended therapy in hepatitis C virus patients with a late viral response to pegylated-interferon and ribavirin.J Gastroenterol Hepatol2014; 29: 201–207.
34.
MorelloJ., CuencaL., SorianoV.Influence of a single nucleotide polymorphism at the main ribavirin transporter gene on the rapid virological response to pegylated interferon-ribavirin therapy in patients with chronic hepatitis C virus infection.J Infect Dis2010; 202: 1185–1191.
35.
CotteL., Barrail-TranA., VincentC.Telaprevir enhances ribavirin-induced anaemia through renal function impairment.Antivir Ther2015; 20: 479–486.
36.
Gutierrez-ValenciaA., Ruiz-ValderasR., Ben-Marzouk-HidalgoO.J.Telaprevir and ribavirin interaction: higher ribavirin levels are not only due to renal dysfunction during triple therapy.Antimicrob Agents Chemother2015; 59: 3257–3262.
37.
Aguilar MaruccoD., Gonzalez de RequenaD., BonoraS.The use of trough ribavirin concentration to predict sustained virological response and haematological toxicity in HIV/HCV-co-infected patients treated with ribavirin and pegylated interferon.J Antimicrob Chemother2008; 61: 919–924.
