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

Marucco, D. Aguilar; Requena, Daniel González de; Bonora, Stefano; Tettoni, Cristina; Bonasso, M.; Blasi, T. De; D’Avolio, Antonio; Sciandra, Mauro; Siccardi, Marco; Baietto, Lorena; Trentini, Laura; Sinicco, Alessandro; Castaldo, Giuseppe; Perri, Giovanni Di

doi:10.1093/jac/dkn013

Cited by 41 publications

(41 citation statements)

References 21 publications

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“…In this perspective, RBV TDM might maintain a role in the management of the prevailing proportion of patients with WT ITPA genotype, in whom RBV concentration may be fruitfully modified by RBV dose adjustment. Because RBV Pk exposure is also associated with the rate of SVR, 6,11,13,27,36,37 the same might also apply to carriers of ITPA variants with suboptimal RBV concentration, in whom RBV dose may be increased with a smaller risk of anemia. In conclusion, this retrospective study confirms the high impact of ITPA SNPs on hemolytic anemia and seems to suggest a cut-off value for trough plasma RBV concentration.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5] Repeatedly, individual RBV dose and pharmacokinetic (Pk) exposure have been found to be consistent determinants of treatment-associated anemia, and recommendations on dose reduction have been released in order to mitigate the impact of RBV on the severity of anemia. [6][7][8][9][10] Some other studies have not observed an association between Hb decline and plasma RBV concentrations, when multivariate analyses were performed. [11][12][13] Among the nonmodifiable individual factors also contributing to anemia development in recipients of anti-HCV therapy, single nucleotide polymorphisms (SNPs) in the human DNA region coding for inosine triphosphatase (ITPA) were identified recently as the most significant variables influencing the risk of anemia.…”

Section: Introductionmentioning

confidence: 94%

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Inosine Triphosphatase Polymorphisms and Ribavirin Pharmacokinetics as Determinants of Ribavirin-Associate Anemia in Patients Receiving Standard Anti-HCV Treatment

D’Avolio

Ciancio

Siccardi

et al. 2012

Therapeutic Drug Monitoring

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Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Inosine Triphosphatase Polymorphisms and Ribavirin Pharmacokinetics as Determinants of Ribavirin-Associate Anemia in Patients Receiving Standard Anti-HCV Treatment

D’Avolio

Ciancio

Siccardi

et al. 2012

Therapeutic Drug Monitoring

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“…In summary, high baseline HCV RNA, HCV genotype 1 or 4, and C trough of Ͻ2.5 g/ml RBV were found to be indepen- (1,3). These differences may be explained by distinct characteristics of patients that may affect ribavirin pharmacokinetics (age, gender, renal function, body weight, race, and drug and food interactions) and technical aspects regarding the quantification of RBV C trough (day after therapy initiation at which RBV C trough was quantified, time between blood extraction and plasma separation, and methodology for RBV C trough quantification).…”

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confidence: 86%

Plasma Ribavirin Trough Concentrations at Week 4 Predict Hepatitis C Virus (HCV) Relapse in HIV-HCV-Coinfected Patients Treated for Chronic Hepatitis C

Morello

Soriano²,

Barreiro³

et al. 2010

Antimicrob Agents Chemother

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The standard treatment for chronic hepatitis C virus (HCV) infection is the combination of pegylated alpha interferon (pegIFN) and ribavirin (RBV), which allows cure of HCV in around 50 to 60% of HCV-monoinfected patients (8, 12) and 30 to 40% of HIV-HCV-coinfected individuals (4, 21). Although new drugs for treating HCV infection, such as HCV protease inhibitors, are currently being developed, preliminary evidence (9, 10) suggests that the use of RBV seems unavoidable for maximizing the chances of sustained virological response (SVR).RBV is a synthetic guanosine analogue. Several mechanisms of action have been proposed to explain its anti-HCV effect, including direct inhibition of the viral RNA polymerase, IMP dehydrogenase inhibition, hypermutagenesis, and immunomodulation (7). Pharmacokinetic-pharmacodynamic studies conducted in HCV-monoinfected and HIV-HCV-coinfected patients have found an association between RBV concentrations and achievement of early and sustained virological responses (reviewed in references 5 and 15 and a recent paper [3]), indirectly supporting a role for therapeutic drug monitoring of RBV concentrations to tailor RBV dosage early in treatment and in this way to try to enhance the chances of SVR.In addition to a lower initial response to hepatitis C therapy, a higher rate of HCV relapse (range, 15% to 37%) (4,6,16,20,21,23) could contribute to the lower rate of SVR seen in HIV-HCV-coinfected patients than in HCV-monoinfected patients. Several factors such as high baseline HCV RNA and lack of rapid virological response (RVR) have been associated with HCV relapse (16). However, the impact of RBV concentrations on the risk of HCV relapse is unknown. If a significant association exists, adjustment of RBV dosages based on early RBV concentrations could be very useful to minimize the risk of HCV relapse.A retrospective study was performed in HIV-HCV-coinfected patients who achieved end-of-treatment (EOT) response with pegIFN-␣ 2a or 2b (180 g/week or 1.5 g/kg of body weight/week) plus weight-based RBV (1,000 or 1,200 mg/day for patients weighting Ͻ75 or Ͼ75 kg, respectively) since 2004 at our clinic. The duration of treatment was based on HCV genotype and the achievement of undetectable HCV RNA at week 4 (RVR), ranging from 6 to 18 months (11,17).Demographics and other clinical characteristics were recorded in a case report form specially designed for this study. Serum HCV RNA was measured at baseline, every 4 to 12 weeks of therapy, and 24 weeks after completion of treatment by TaqMan (Roche), with a limit of detection of 10 IU/ml. HCV genotyping was examined using a hybridization assay (InnoLipa-HCV; Bayer). RBV plasma trough concentrations (RBV C trough ) were measured before the intake of the first daily dose of RBV at week 4 of therapy by high-performance liquid chromatography with ultraviolet detector (HPLC-UV) (14).EOT response was defined as undetectable HCV RNA at the end of therapy. HCV relapse was defined as detectable HCV RNA within the next 24 weeks after achieving EOT response.S...

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“…There has therefore been some interest in the utility of therapeutic drug monitoring in plasma or serum to optimize doses and predict SVRs. Some small studies, mainly retrospective, in co-infected patients have suggested a relationship between week 4 serum or plasma concentrations predicted EVR, SVR, haematological toxicity and relapse [53][54][55][56]. Furthermore, once steady state has been achieved, there is a suggestion that concentrations at 3 and 6 months do not vary greatly in co-infected patients and that these concentrations may influence treatment outcomes [57].…”

Section: Ribavirin Dose Monitoring and Interactionsmentioning

confidence: 99%

Current treatment for chronic hepatitis C virus/HIV-infected individuals

Bhagani

2011

Current Opinion in HIV and AIDS

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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

Abstract: Our study confirmed a relationship between ribavirin exposure and both efficacy and toxicity. Moreover, we found ribavirin C(trough) cut-offs for both SVR in genotypes 1 and 4 and overall haematological toxicity. These findings deserve further clinical evaluation.

Cited by 41 publications

References 21 publications

Inosine Triphosphatase Polymorphisms and Ribavirin Pharmacokinetics as Determinants of Ribavirin-Associate Anemia in Patients Receiving Standard Anti-HCV Treatment

Inosine Triphosphatase Polymorphisms and Ribavirin Pharmacokinetics as Determinants of Ribavirin-Associate Anemia in Patients Receiving Standard Anti-HCV Treatment

Plasma Ribavirin Trough Concentrations at Week 4 Predict Hepatitis C Virus (HCV) Relapse in HIV-HCV-Coinfected Patients Treated for Chronic Hepatitis C

Current treatment for chronic hepatitis C virus/HIV-infected individuals

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