Hartwig Klinker

The protease inhibitor, GS‐9256, and non‐nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C

Tegobuvir (GS‐9190), a non‐nucleoside nonstructural protein (NS)5B polymerase inhibitor, and GS‐9256, an NS3 serine protease inhibitor, individually have activity against hepatitis C virus (HCV) genotype 1. The antiviral activity of tegobuvir and GS‐9256 as oral combination therapy, or together with ribavirin (RBV) or pegylated interferon (Peg‐IFN) alpha‐2a and RBV, was assessed in a phase II, randomized, open‐label trial. Treatment‐naïve patients with genotype 1 HCV were assigned 28 days of tegobuvir 40 mg twice‐daily (BID) and GS‐9256 75 mg BID (n = 16), tegobuvir and GS‐9256 plus RBV 1,000‐1,200 mg daily (n = 15), or tegobuvir and GS‐9256 plus Peg‐IFN alpha‐2a (180 μg once‐weekly)/RBV (n = 15). The primary efficacy endpoint was rapid virologic response (RVR), with HCV RNA <25 IU/mL at day 28. After 28 days, all patients received Peg‐IFN/RBV. All patients with viral rebound or nonresponse, defined as >0.5‐log10 increase in HCV RNA from nadir or <2‐log decrease at day 5, initiated Peg‐IFN/RBV immediately. Median maximal reductions in HCV RNA were −4.1 log10 IU/mL for tegobuvir/GS‐9256, −5.1 log10 IU/mL for tegobuvir/GS‐9256/RBV, and −5.7 log10 IU/mL for tegobuvir/9256/Peg‐IFN/RBV. RVR was observed in 7% (1 of 15) of patients receiving tegobuvir/GS‐9256, 38% (5 of 13) receiving tegobuvir/GS‐9256/RBV, and 100% (14 of 14) receiving tegobuvir/9256/PEG‐IFN/RBV. The addition of Peg‐IFN/RBV at day 28 or earlier resulted in HCV RNA <25 IU/mL at week 24 in 67% (10 of 15), 100% (13 of 13), and 94% (13 of 14) of patients in the three treatment groups. Transient elevations in serum bilirubin occurred in all treatment groups. Conclusion: In genotype 1 HCV, adding RBV or RBV with Peg‐IFN provides additive antiviral activity to combination therapy with tegobuvir and GS‐9256. (HEPATOLOGY 2012)

Clinical management of drug-drug interactions in HCV therapy: challenges and solutions.

Hepatitis C virus (HCV) infected patients often take multiple co-medications to treat adverse events related to HCV therapy, or to manage other co-morbidities. Drug-drug interactions associated with this polypharmacy are relatively new to the field of HCV pharmacotherapy. With the advent of the direct-acting antivirals telaprevir and boceprevir, which are both substrates and inhibitors of the cytochrome P450 (CYP) 3A iso-enzyme, knowledge and awareness of drug-drug interactions have become a cornerstone in the evaluation of patients starting and continuing HCV combination therapy. In our opinion, an overview of conducted drug-drug interaction studies and a list of contraindicated medications is not enough for the clinical management of these drug-drug interactions. Knowledge of pharmacokinetic profiles and concentration-effect relationships is key for the interpretation of these data, and insight into how to manage these interactions (e.g., dose adjustments, safe alternatives and therapeutic drug monitoring) is of equal importance. This review provides a practical overview of the safe and effective management of these clinical challenges.

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens

OBJECTIVES Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. METHODS Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. RESULTS Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. CONCLUSIONS These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.

Individualized treatment strategy according to early viral kinetics in hepatitis C virus type 1-infected patients.

Individualized treatment on the basis of early viral kinetics has been discussed to optimize antiviral therapy in chronic hepatitis C virus (HCV) infection. Individually tailored reduction in treatment duration in HCV type 1–infected patients represents one possible strategy. Four hundred thirty‐three patients were randomly assigned to receive either 1.5 μg/kg peginterferon alfa‐2b weekly plus 800‐1,400 mg ribavirin daily for 48 weeks (n = 225, group A) or an individually tailored treatment duration (18‐48 weeks; n = 208, group B). In the latter group, treatment duration was calculated using the time required to induce HCV RNA negativity (branched DNA [bDNA] assay; sensitivity limit, 615 IU/mL) multiplied by the factor 6. All bDNA negative samples were retested with the more sensitive transcription‐mediated amplification (TMA) assay (sensitivity limit, 5.3 IU/mL). Sustained virologic response (SVR) rates were significantly lower in group B (34.6% versus 48.0% [P = 0.005]) due to higher relapse rates (32.7% versus 14.2% [P< 0.0005]). Important predictors of response were the levels of baseline viremia as well as the time to TMA negativity on treatment. Taking the simultaneous presence of low baseline viral load (<800,000 IU/mL) and a negative TMA test within the first 4 weeks as predictors for treatment response, SVR rates were comparable between both treatment schedules with an SVR probability of >80% obtained in patients treated for only 18 or 24 weeks. Conclusion: The individualized treatment strategy according to time to bDNA negativity failed to provide comparable efficacy compared with the standard of care. The inferiority of the individualized protocol may be explained by the use of a less sensitive HCV RNA assay, and also by underestimation of the importance of baseline viremia. (HEPATOLOGY 2009.)

Lipid Lowering Therapy with Fluvastatin and Pravastatin in Patients with HIV Infection and Antiretroviral Therapy: Comparison of Efficacy and Interaction with Indinavir

Abstract.Background:Lipoprotein disorders in HIV-positive patients receiving highly active antiretroviral therapy (HAART) are becoming a major concern in HIV treatment, since there is growing evidence for an association between HAART-induced hyperlipidemia and increased cardiovascular risk. Yet relatively few data are available on the possible interactions of HAART and treatment with statins.Patients and Methods:In this prospective study, 25 HIV-positive, treatment-experienced patients (five female, 20 male, all Caucasian) were treated with either fluvastatin or pravastatin. Total cholesterol, low density lipoprotein (LDL) and high density lipoprotein (HDL) levels, and serum triglycerides were determined at regular intervals, as well as therapeutic drug monitoring to assess possible drug interactions.Results:In 13 pravastatin-treated patients, a decrease in total cholesterol levels (from 7.12 mmol/l to 6.29 mmol/l) after 12 weeks of therapy was seen. In 12 patients treated with fluvastatin, a permanent reduction of total cholesterol (from 6.46 mmol/l to 5.31 mmol/l) after 12 weeks was observed. The reduction of LDL levels was 30.2% in the fluvastatin group and 14.4% in the pravastatin group. In eight patients receiving an indinavir-containing HAART, indinavir plasma levels were not significantly influenced. No effect on triglycerides or HDL was observed.Conclusion:Fluvastatin and pravastatin are efficient in lowering total and LDL cholesterol levels in HIV-positive patients receiving HAART. Furthermore, no influence on indinavir plasma levels could be observed. Therefore, both compounds seem to be a viable treatment option in HAART-induced hypercholesterolemia.

[Expert opinion on boceprevir- and telaprevir-based triple therapies of chronic hepatitis C].

With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 - 44 % to 63 - 75 % for treatment-naïve and from 17 - 21 % to 59 - 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naïve patients and relapsers benefit from shorten treatment durations to 24 - 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies.

The role of therapeutic drug monitoring in the management of patients with human immunodeficiency virus infection.

Therapeutic drug monitoring (TDM) is a well-established method to optimize dosing regimens in individual patients for drugs that are characterized by a narrow therapeutic range and large interindividual pharmacokinetic variability. For some antiretroviral drugs, mainly nonnucleoside reverse transcriptase inhibitors and protease inhibitors, TDM has been proposed as a means to improve the response in human immunodeficiency virus-infected patients. In contrast, nucleoside reverse transcriptase inhibitors do not show a predictable plasma concentration-response (toxicity, efficacy) relationship, and intracellular analyses are expensive. Therefore, TDM is generally not recommended for this class of drugs. TDM has been successfully applied in the clinical practice for certain antiretroviral drugs, but there are ongoing research efforts on the use and refinement of TDM for human immunodeficiency virus treatment, and convincing data from randomized trials are still needed. The best pharmacokinetic measures of drug exposure such as trough and peak concentrations or concentration ratios have not been unambiguously established.

Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C.

BACKGROUND & AIMS There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. METHODS Treatment-naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5μg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0μg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5μg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800-1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). RESULTS The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs. B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. CONCLUSIONS For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5μg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment.

Improved Responses to Pegylated Interferon Alfa-2b and Ribavirin by Individualizing Treatment for 24–72 Weeks

BACKGROUND & AIMS Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS We treated 398 treatment-naïve patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P < .0001 for noninferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P < .0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders.

Epidemiology of Candida blood stream infections in patients with hematological malignancies or solid tumors.

Invasive Candida infections are associated with high morbidity and mortality. Due to an increased incidence in patients with hematological or oncological malignancies, fluconazole prophylaxis became a common practice in many centers in the late 1990s. Until recently, there was insufficient data on the effect of the use of azoles on the incidence of Candida blood stream infections and species distribution. Here we present a single center retrospective study of the epidemiology of Candida blood stream infections in hospitalized patients at a German university medical center from 2003-2009. Twenty-one Candida species were isolated in culture from blood specimens of 20 patients. The annual rate of candidemia approached 1.1 per thousand hospitalizations, during the first 5 years of the survey, but showed a significant increase after 2007. Candida albicans, although still the dominant species, was recovered as the responsible pathogen from only 28.6% of the cases. A high rate of fatal outcomes was noted at 30 days (56%) and 100 days (67%) after the first positive finding of Candida in blood culture. These results underline the clinical significance of this infectious complication, and the need for continuous monitoring for Candida blood stream infections in order to improve the clinical and therapeutic management of this specific patient population.