Daclatasvir plasma level and resistance selection in HIV patients with hepatitis C virus cirrhosis treated with daclatasvir, sofosbuvir, and ribavirin

Parisi, Saverio Giuseppe; Loregian, Arianna; Andreis, Samantha; Nannetti, Giulio; Cavinato, Silvia; Basso, Monica; Scaggiante, Renzo; Bello, Federico Dal; Messa, Lorenzo; Cattelan, Anna María; Palù, Giorgio

doi:10.1016/j.ijid.2016.06.020

Cited by 7 publications

(4 citation statements)

References 6 publications

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“…This plasma was obtained at steady state, just before the morning intake of the drug (Ctrough). This method is currently used as a part of our routine TDM of DCV for both HCV-infected and HCV/HIV-coinfected patients [22]. These data confirm the clinical applicability of the present analytical method.…”

Section: Analysis Of Patient Samplessupporting

confidence: 76%

Development and validation of a simple and robust HPLC method with UV detection for quantification of the hepatitis C virus inhibitor daclatasvir in human plasma

Nannetti

Messa

Celegato

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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Daclatasvir is an inhibitor of hepatitis C virus NS5A protein that is used for the therapy of chronic hepatitis. So far, published methods for analysis of daclatasvir in plasma are exclusively based on mass spectrometry, which is not always available in standard clinical laboratories. Thus, we wished to develop and validate a simple, but still reliable and sensitive high-performance liquid chromatography (HPLC) assay with UV detection for the quantification of daclatasvir, feasible for a wide-spread clinical routine use. The method consisted of solid-phase extraction of daclatasvir using Waters Oasis HLB 1cc cartridges, reversed-phase liquid chromatography with a Waters XTerra RP18 (150mm×4.6mm, 3.5μm) column and a mobile phase of ammonium acetate buffer (pH 5.0, 10mM) and acetonitrile (56:44, v/v), and UV detection at 318nm. This assay proved to be sensitive (lower limit of quantification of 0.05μg/mL), linear (correlation coefficients ≥0.997), specific (no interference with various potentially co-administrated drugs), reproducible (both intra-day and inter-day coefficients of variation ≤8.9%), and accurate (deviations ranged from -2.2 to 8.0% and from -6.5 to 9.2% for intra-day and inter-day assays, respectively). The method was applied to therapeutic monitoring of patients undergoing daclatasvir therapy for hepatitis C and showed to be reliable and robust. Thus, this method provides a simple, sensitive, precise, and reproducible assay for dosing daclatasvir that can be readily adaptable to routine use by clinical laboratories with standard equipment. In addition, the stability of daclatasvir in plasma was evaluated under various conditions, including after the heating procedure required for inactivation of infectious viruses and in different light exposure conditions. These studies evidenced photo-instability of the compound under sunlight exposure over time. Thus, blood sampling and the whole handling procedure have to be performed quickly and with minimal light exposure.

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Section: Analysis Of Patient Samplessupporting

confidence: 76%

Development and validation of a simple and robust HPLC method with UV detection for quantification of the hepatitis C virus inhibitor daclatasvir in human plasma

Nannetti

Messa

Celegato

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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“…In regard to NS5A sequence from HCV GT 3a, substitution A30S has previously been reported by Malta F. et al . (2017) [11] in a viral sequence of a HCV GT 3a/HIV non-responder coinfected patient (baseline prevalence of 6.7%; 1/15) and in an international case report [24]. In the present study, we found RAS A30S in one GT 3a non-responder patient, however, the inexpressive number of GT 3a patients available in our study (n = 4) prevented us to verify whether this substitution is common in HCV strains circulating in Brazil.…”

Section: Discussionmentioning

confidence: 99%

Treatment of chronic HCV infection with DAAs in Rio de Janeiro/Brazil: SVR rates and baseline resistance analyses in NS5A and NS5B genes

et al. 2019

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The selection of viral strains with resistance-associated substitutions at hepatitis C virus (HCV) NS5A and NS5B genes is considered one of the limiting factors for achieving sustained virologic response (SVR) to combination of direct-acting antivirals daclatasvir (DCV) and sofosbuvir (SOF). Since 2015, this interferon-free regimen has been available in Brazilian clinical routine for treating mono- and HCV/HIV-coinfected patients chronically infected with genotypes 1 and 3. Our aim was to assess SVR rate for Brazilian patients chronically infected with genotypes 1 and 3 after DCV/SOF therapy and the frequency of baseline RASs in HCV NS5A and NS5B genes. Serum samples were collected from 107 monoinfected patients and 25 HCV/HIV co-infected patients before antiviral therapy with DCV/SOF. Genetic diversity of NS5A and NS5B genes was assessed by direct nucleotide sequencing. Overall, SVR rate was 95.4% (126/132), and treatment failure occurred in five monoinfected and one HCV/HIV co-infected patient. NS5A RASs frequency was higher for HCV/HIV patients (28%) than monoinfected patients (16.8%). No difference was evidenced between mono- and HCV/HIV-coinfected groups (15% vs. 16%) regarding NS5B gene. Genotype (GT) 1b strains had significantly more baseline substitutions in NS5A (31.6%) than GT 1a and 3a. At least one primary NS5A RAS described in literature at loci 28, 30, 31 or 93 was identified in HCV GTs 1 strains for both groups. As for NS5B, RASs at positions 159 and 316 was observed only in GT 1b strains. This study highlighted that SVR rate in clinical routine in Brazil was similar to randomized clinical trials (89–98%). Our research provided genetic data about the circulation of resistant variants in Brazil. Despite its presence, most of identified baseline mutations did not negatively impact treatment outcome. Genetic diversity of circulating strains suggested that most of the Brazilian HCV chronic carriers are susceptible to new therapeutic regimens including recently approved DAAs.

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“…To our knowledge, this is the first study exploring ribavirin TDM in decompensated cirrhotic individuals treated with new DAAs regimens and showing an overexposure in this group of patients. Indeed, while few data report RBV plasma levels in therapeutic range in patients with Child-Pugh A treated with a fixed dose (800 mg daily) of RBV associated with SOF and DCV[ 19 ], no information about Child-Pugh B or C patients are currently available. These findings might be useful to clinicians, since an overexposure can be modulated by lowering the initial RBV dosage from the weight-based dosage in certain patients with advanced liver disease, avoiding secondary and detrimental effects.…”

Section: Discussionmentioning

confidence: 99%

Liver decompensation predicts ribavirin overexposure in hepatitis C virus patients treated with direct-acting antivirals

Guardigni

Badia

Conti³

et al. 2017

WJH

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AIMTo determine whether ribavirin (RBV) concentrations differ according to cirrhosis stage among cirrhotic patients treated with interferon-free regimens.METHODSWe included patients with hepatitis C virus and cirrhosis [Child-Pugh (CP) A or B], Glomerular Filtration Rate ≥ 60 mL/min, who started therapy with DAAs and weight-based RBV between October 2014 and February 2016. RBV plasma levels were assessed during the treatment. We focused our analysis on the first 8 wk of therapy.RESULTSWe studied 68 patients: 54 with compensated (CP-B) and 14 with decompensated (CP-A) cirrhosis. Patients with decompensated cirrhosis displayed significantly higher RBV concentrations than those with compensated cirrhosis at week 1, 2, 4 and 8 (P < 0.035). RBV levels were positively correlated with Hb loss over the treatment (P < 0.04). Majority (71%) of CP-B patients required a RBV dosage reduction during the treatment. After adjustment for confounders, Child-Pugh class remained significantly associated (95%CI: 35, 348, P = 0.017) to RBV levels, independently from baseline per-Kg RBV dosage.CONCLUSIONLiver decompensation might affect RBV clearance leading to an overexposure and increased related toxicities in decompensated cirrhosis. Our findings underscore the importance of an early ribavirin therapeutic drug monitoring and suggest that an initial lower RBV dose, rather than weight-based, might be considered in those with advanced liver disease (CP-B) treated with direct-acting antivirals.

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Daclatasvir plasma level and resistance selection in HIV patients with hepatitis C virus cirrhosis treated with daclatasvir, sofosbuvir, and ribavirin

Abstract: Sub-optimal DCV drug levels allow the selection of resistance-associated variants and fail to contribute to antiviral activity. No definite reason for the low DCV level was found. Quantifying the drug is suggested in difficult-to-treat patients.

Cited by 7 publications

References 6 publications

Development and validation of a simple and robust HPLC method with UV detection for quantification of the hepatitis C virus inhibitor daclatasvir in human plasma

Development and validation of a simple and robust HPLC method with UV detection for quantification of the hepatitis C virus inhibitor daclatasvir in human plasma

Treatment of chronic HCV infection with DAAs in Rio de Janeiro/Brazil: SVR rates and baseline resistance analyses in NS5A and NS5B genes

Liver decompensation predicts ribavirin overexposure in hepatitis C virus patients treated with direct-acting antivirals

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