Gema González-Pardo

Genetic factors influencing atazanavir plasma concentrations and the risk of severe hyperbilirubinemia.

Background:Hyperbilirubinemia is frequently seen in patients treated with atazanavir (ATV). Polymorphisms at the uridin-glucoronosyl-transferase 1A1 (UGT1A1) and multidrug resistance 1 (MDR1) genes may influence, respectively, bilirubin and ATV plasma concentrations. Patients and methods:HIV-infected individuals receiving ATV 300 mg daily plus ritonavir 100 mg daily at one clinic were examined. ATV plasma concentrations were measured at steady state. MDR1-3435C>T and UGT1A1 polymorphisms were examined in DNA extracted from blood mononuclear cells. Results:A total of 118 patients (all Caucasian) were analysed. The median ATV plasma concentration was 465 ng/ml [interquartile range (IQR), 233–958]. MDR1-3435 genotypes were as follows: CC (32%), CT (47%) and TT (21%). CC patients showed higher ATV minimum concentration than those with CT/TT genotypes: 939 ng/ml (IQR, 492–1266) versus 376 ng/ml (IQR, 221–722) (P = 0.001). In multivariate analyses, having at least one T allele at MDR1-3435 was independently associated with lower ATV plasma concentrations (β: –427 [95% confidence interval (CI), −633 to −223]; P < 0.001). The proportion of patients with grade 3-4 hyperbilirubinemia varied with distinct UGT1A1 genotypes: 80% for 7/7, 29% for 6/7 and 18% for 6/6 (P = 0.012). In the multivariate analysis, having at least one 7 allele at UGT1A1 was independently associated with severe hyperbilirubinemia (odds ratio, 2.96; 95% CI, 1.29–6.78; P = 0.01). Conclusions:Polymorphisms at MDR1-3435 significantly influence ATV plasma concentrations, as does being Caucasian patients with CT/TT genotypes, having lower ATV levels, even using ritonavir boosting. On the other hand, although ATV plasma concentrations directly correlate with bilirubin levels, the risk of severe hyperbilirubinemia is further increased in the presence of the UGT1A1-TA7 allele.

Switch from Ritonavir-Boosted to Unboosted Atazanavir Guided by Therapeutic Drug Monitoring

Plasma concentration of atazanavir (ATV) may be reduced when coadministered with tenofovir (TDF) or proton pump inhibitors. Boosting ATV exposure with ritonavir (r) may make it possible to overcome these drug interactions. However, jaundice and loss of the metabolic advantages of ATV are more frequent using ATV/r than ATV alone. Herein, we assessed whether therapeutic drug monitoring (TDM) could make it possible to identify the subset of patients in whom removal of ritonavir could be attempted without risk of suboptimal plasma ATV exposure and subsequent virological failure. A total of 56 patients with undetectable plasma HIV-RNA under a stable triple regimen containing ATV 300/100 mg qd were switched to ATV 400 mg qd. Plasma ATV concentrations were measured using a reliable high-performance liquid chromatography method. Median plasma ATV C(min) fell from 880 to 283 ng/ml (p = 0.03) after removal of ritonavir. While all patients on ATV/r showed ATV plasma concentrations within therapeutic values (IC(min) above 150 ng/ml) before switching, four patients (7%) fell below this threshold after switching to ATV 400 mg qd. However, only one of this group experienced virological failure at week 24 of follow-up. TDF was part of the antiretroviral regimen in all four cases. From a total of 29 (52%) patients on ATV/r showing grade 3-4 hyperbilirubinemia, only 7 (12%) remained on it upon switching to ATV 400 mg qd (p < 0.001). Patients with complete viral suppression under ATV/r 300/100 mg qd may benefit from switching to ATV 400 mg qd guided by TDM, which may make it possible to minimize adverse events without compromising antiviral efficacy in most cases.

Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin.

Atazanavir use is associated with increases in serum bilirubin. Ribavirin, used to treat hepatitis-C infection, cause hemolysis and may worsen hyperbilirubinemia. We studied HIV/hepatitis-C virus-coinfected patients who initiated hepatitis-C therapy. Hyperbilirubinemia grade 3–4 increased from 9% to 45% after the start of hepatitis-C treatment in patients who used atazanavir concomitantly. Atazanavir use and hemoglobin (Hb) drops were predictors of increases in bilirubin. A substantial proportion of patients under atazanavir-therapy experienced significant hyperbilirubinemia and jaundice following initiation of hepatitis-C therapy.

Value of the HLA-B*5701 Allele to Predict Abacavir Hypersensitivity in Spaniards

The use of abacavir (ABC) may be associated with a hypersensitivity reaction (HSR) that requires discontinuation of the drug. The HLA-B*5701 allele has been linked to this HSR. Information on the strength of this association across distinct geographic regions and ethnicities is scarce. We tested HLA-B*5701 in 53 Spaniards infected with HIV who received ABC treatment. The presence of HLA-B5701 had strong positive and negative predictive values for ABC HSR, 92% and 63%, respectively.

Measurement of Ribavirin Plasma Concentrations by High-performance Liquid Chromatography Using a Novel Solid-phase Extraction Method in Patients Treated for Chronic Hepatitis C

Ribavirin (RBV) in combination with pegylated interferon is the current standard treatment for chronic hepatitis C. Exposure to RBV seems crucial for achieving the best virologic response. However, RBV may cause anemia in a dose-dependent manner. Therefore, monitoring RBV plasma levels could be useful for individual tailoring of RBV dosing. A rapid assay was developed to quantify RBV using high-performance liquid chromatography and ultraviolet detection. Extraction of RBV from plasma was performed using a novel method based on ultrafiltration in one step that allows direct injection into the high-performance liquid chromatography without any prior steps of dryness or reconstitution. The method was validated over the range of 0.05 to 5.0 μg/mL following the EMEA Validation of Analytical Procedures (CPMP/ICH/281/95) recommendations. The clinical interest of this assay was evaluated in a subset of patients under RBV therapy. Mean RBV plasma concentrations at steady state were higher in responders compared with nonresponders (3-3.2 μg/mL versus 2.2-2.3 μg/mL).

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

ABSTRACT The influence of ribavirin trough concentrations (RBV Ctrough) on the risk of hepatitis C virus (HCV) relapse was retrospectively analyzed in 99 HIV-HCV-coinfected patients who achieved end-of-treatment response with pegylated alpha interferon plus weight-based RBV. The independent predictors (odds ratio [OR] [95% confidence interval (CI)]) of HCV relapse were RBV plasma Ctrough of <2.5 μg/ml (4.5 [1.3 to 15.5]), baseline serum HCV RNA (2.5 [1.2 to 5.1]), and HCV genotype 1 or 4 (13.3 [2.6 to 66.7]). Monitoring of RBV Ctrough may permit early adjustment of RBV dosage to avoid HCV relapse.

Use of Different Inhibitory Quotients To Predict Early Virological Response to Tipranavir in Antiretroviral-Experienced Human Immunodeficiency Virus-Infected Patients

ABSTRACT Information about the relationship between pharmacological parameters and an early virological response to tipranavir (TPV) is scarce. Human immunodeficiency virus (HIV)-infected patients who had received TPV as part of a salvage regimen were analyzed retrospectively. A virological response was defined as a decline in the HIV RNA level of ≥1 log unit or to <50 copies/ml between weeks 4 and 12 of therapy. The virtual inhibitory quotient (vIQ) was calculated as the ratio of the TPV plasma trough concentration (Ctrough)/virtual change in the 50% inhibitory concentration. Three genotypic inhibitory quotients (gIQs) were calculated by using different TPV resistance mutation scores (from the International AIDS Society—USA [IAS-USA], Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir [RESIST], and Agence Nationale de Recherches sur le Sida et les Hépatites Virales [ANRS] trials). The sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and likelihood ratios for a positive result (LHR+) and a negative result (LHR−) [LHR+ = sensitivity/(1 − specificity); LHR− = (1 − sensitivity)/specificity] were calculated. A total of 57 HIV-infected patients were analyzed. A virological response was achieved by 77% of the patients. TPV resistance mutations, TPV Ctrough, vIQs, and gIQs were all significantly associated with a virological response. The vIQ had the best PPV and NPV (97% and 78%, respectively). The values of the LHR+ were 7.8 for vIQ, 3.4 for the RESIST gIQ, 3.3 for the IAS-USA gIQ, 3.1 for the ANRS gIQ, 2.2 for TPV Ctrough, and 1.3 for the IAS-USA and RESIST scores. The values of LHR− were 0 for the RESIST score, 0.07 for vIQ, 0.09 for the IAS-USA score, 0.27 for the RESIST gIQ, 0.32 for the IAS-USA gIQ, 0.37 for the ANRS gIQ, and 0.48 for TPV Ctrough. HIV-infected patients who initiate a salvage regimen based on TPV may benefit from baseline drug resistance testing and TPV plasma concentration determination, as vIQ is the best predictor of a virological response.

Short Communication: Association between Tipranavir Plasma Levels and Virological Response in HIV-Infected Patients

The impact of tipranavir plasma levels (TPV C(min)) on virological response was examined in 36 antiretroviral-experienced HIV-infected individuals. Although TPV C(min) did not predict outcome in patients with less than five or more than eight baseline TPV-associated resistance mutations, TPV C(min) values were greater in responders than in nonresponders with five to seven baseline TPV-associated resistance mutations (38.8 vs. 13.8 g/ml, p = 0.017). Thus, therapeutic drug monitoring might be helpful in ensuring a viral response in this subset of patients.

The benefit of simplification from tipranavir/ritonavir 500/200 bid to 500/100 bid guided by therapeutic drug monitoring.

Despite being among the most potent protease inhibitors, the use of tipranavir (TPV) is hampered by a high pill burden and frequent side effects compared with other boosted protease inhibitors. A total of 10 patients receiving TPV/ritonavir (TPV/RTV) 500/200 for longer than 6 months were randomized to stay on the same dosing schedule or switch to TPV/RTV 500/100. Although all patients on TVP/RTV 500/200 remained stable for the next 12 weeks, 3 out of 5 patients who switched doses experienced benefits in terms of reducing aminotransferases and total cholesterol. Fasting triglycerides were also reduced in 2 of them. Plasma HIV-RNA remained undetectable in all patients, despite the observed decline in TPV trough concentrations.