Peg-interferon and ribavirin treatment in HIV/HCV co-infected patients in Thailand: efficacy, safety and pharmacokinetics.

OBJECTIVE: In Thailand, 7.2% of HIV patients are co-infected with hepatitis C virus (HCV), and these patients are treated with peg-interferon + ribavirin (PR) for their HCV infection. This study evaluates efficacy and safety of PR treatment and pharmacokinetics of ribavirin in this population. METHODS: HIV/HCV co-infected Thai patients were treated with PR for 24 or 48 weeks. Sustained virological response 24 weeks after the end of treatment (SVR24) was used to describe efficacy. (laboratory) safety parameters and ribavirin plasma concentrations were evaluated during study visits. Ribavirin concentrations were compared with t-tests for patients with and without anaemia (haemoglobin <10 g/dl) and SVR24. RESULTS: A total of 101 HIV/HCV co-infected patients were included; 88% were male (n = 88), and 46% were infected with genotype 3. The median (IQR) start dose was 14.28 mg/kg/day. SVR24 rate was 56%. All patients reported at least one (serious) adverse event, of which 28% of patients developed anaemia. Seven patients discontinued treatment due to toxicity issues. Geometric mean (IQR) ribavirin concentration was 1.81 (1.42-2.32) mg/l at week 8 of treatment. At week 8, patients with and without anaemia and SVR had ribavirin concentrations of 2.29 and 1.63 mg/l and 1.91 and 1.74 mg/l, respectively. CONCLUSIONS: PR treatment has comparable response rates and toxicity profile in Thai HIV/HCV co-infected patients as in Western HIV/HCV patients. However, ribavirin plasma concentrations were comparable with previously published studies in HIV/HCV co-infected patients, but both, just as SVR rate, were lower than in mono-infected patients.

Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C-infected patients treated with direct-acting antivirals.

BACKGROUND: In the era of highly effective direct-acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients. AIM: To assess the association between RBV steady-state plasma levels and sustained virological response (SVR). METHODS: Consecutive HCV-infected patients treated with DAAs plus RBV from four Dutch academic medical centres were enrolled. RBV steady-state plasma levels were prospectively measured at treatment week 8 using validated assays. Logistic regression analyses were performed to assess the influence of RBV steady-state plasma level on SVR, and RBV therapeutic range was explored using area under the ROC curve analyses. RESULTS: A total of 183 patients were included, of whom 85% had one or more difficult-to-cure characteristics (ie treatment experienced, HCV genotype 3, cirrhosis). The majority was treated with a sofosbuvir-based regimen and 163 (89%) patients achieved SVR. Median RBV dose was 12.9 (interquartile range 11.2-14.7) mg/kg/d, and median RBV steady-state plasma level was 2.66 (1.95-3.60) mg/L. In multivariable analyses, higher RBV steady-state plasma level (adjusted odds ratio 1.79 [95% CI 1.09-2.93]) was an independent predictor of SVR. With regard to the optimal RBV therapeutic range, 2.28 mg/L was the optimal lower cut-off for achieving SVR and 3.61 mg/L was the upper cut-off for preventing significant anaemia (Haemoglobin < 10 g/dL). CONCLUSION: In this cohort of mainly difficult-to-cure patients treated with DAAs plus RBV, higher RBV steady-state plasma level was an independent predictor of SVR.

Decreased tacrolimus plasma concentrations during HCV therapy: a drug-drug interaction or is there an alternative explanation?

Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.

Daclatasvir 30 mg/day is the correct dose for patients taking atazanavir/cobicistat.

BACKGROUND: Atazanavir is boosted with the cytochrome P450 (CYP) 3A4 inhibitor ritonavir. When combined with the CYP3A4 substrate daclatasvir, the daclatasvir dosage should be reduced from 60 to 30 mg once daily. Recently, cobicistat was licensed as a CYP3A booster and used with atazanavir. OBJECTIVES: To determine whether the fixed-dose combination of atazanavir/cobicistat has an influence on daclatasvir pharmacokinetics comparable to that of the separate agents atazanavir and ritonavir. METHODS: A prospective, open-label, two-period, randomized, cross-over trial was performed in 16 healthy subjects (NCT02565888). Treatment consisted of 300/100 mg of atazanavir/ritonavir plus 30 mg of daclatasvir once daily (reference) and a second period of 300/150 mg of atazanavir/cobicistat plus 30 mg of daclatasvir once daily (test). A 24 h pharmacokinetic, steady-state curve was recorded for all drugs. Geometric mean ratios (GMRs) with 90% CI were calculated for daclatasvir and atazanavir AUCτ and Cmax to compare the effect of both treatments (test versus reference). Laboratory safety and adverse events were evaluated throughout the trial. RESULTS: All 16 healthy subjects completed the study. Median (range) age and BMI were 48.5 (21-55) years and 24.5 (19.0-29.2) kg/m2, respectively. Pharmacokinetic parameters of ritonavir and cobicistat were comparable to those in the literature. The GMRs (90% CI) of daclatasvir AUCτ and Cmax (test versus reference) were 101% (92%-111%) and 97% (89%-106%), respectively. Atazanavir GMRs (90% CI) of AUCτ and Cmax were 82% (75%-79%) and 74% (68%-81%), respectively. No serious adverse events were reported. CONCLUSIONS: Atazanavir/cobicistat and atazanavir/ritonavir had a similar influence on daclatasvir pharmacokinetics in healthy volunteers. Daclatasvir at 30 mg once daily is the correct dose when combined with atazanavir/cobicistat.

Drug-Drug Interactions Between Direct-Acting Antivirals and Psychoactive Medications.

Treatment options for chronic hepatitis C virus (HCV) infection have drastically changed since the development and licensing of new potent direct-acting antivirals (DAAs). The majority of DAAs are extensively metabolized by liver enzymes and have the ability to influence cytochrome P450 (CYP) enzymes. Additionally, these DAAs are both substrates and inhibitors of drug transporters, which makes the DAAs both possible victims or perpetrators of drug-drug interactions (DDIs). There is a high prevalence of mental illnesses such as depression or psychosis in HCV-infected patients; therefore, psychoactive medications are frequently co-administered with DAAs. The majority of these psychoactive medications are also metabolized by CYP enzymes but remarkably little information is available on DDIs between psychoactive medications and DAAs. Hence, the aim of this review is to provide an overview of the interaction mechanisms between DAAs and psychoactive agents. In addition, we describe evidenced-based interactions between DAAs and psychoactive drugs and identify safe options for the simultaneous treatment of mental illnesses and chronic HCV infection.

Pharmacokinetics of two generic co-formulations of lopinavir/ritonavir for HIV-infected children: a pilot study of paediatric Lopimune versus the branded product in healthy adult volunteers.

OBJECTIVES: To determine the pharmacokinetic profiles of lopinavir and ritonavir in two newly developed generic co-formulations for HIV-infected children (Lopimune paediatric tablets and granules, 100/25 mg of lopinavir/ritonavir, Cipla Pharmaceuticals), and to compare these with the branded product (Kaletra). METHODS: This Phase I, comparative, open-label, three-period, single-dose, crossover study was designed as a pilot study to exclude large (>40%) differences in the exposure to lopinavir. Single doses of medication, normalized to 400 mg of lopinavir, were administered on an empty stomach, 1 week apart. A 32 h pharmacokinetic curve was recorded. In an additional part of the study, in five of the same volunteers, a pharmacokinetic curve was recorded after administration of the Lopimune granules and Kaletra oral solution, both with food. RESULTS: Twelve healthy subjects were enrolled (four females). The median (range) age, height and body weight were 24 (21-55) years, 1.79 (1.63-1.95) m and 72 (51-87) kg, respectively. The median [interquartile range (IQR)] AUC(0-t) of lopinavir was 71.8 (48.8-93.5), 38.7 (28.7-52.2) and 58.7 (42.5-79.4) mg.h/L with Kaletra tablets, Lopimune granules and Lopimune paediatric tablets, all taken on an empty stomach, respectively. The respective C(max) values were 7.2 (5.8-8.3), 4.6 (4.1-5.2) and 6.5 (5.0-7.1) mg/L after intake of the different formulations. When comparing the Lopimune formulations with the reference product Kaletra, for all parameters the differences were statistically significant (P