In conversation with Dr Jörg Janne Vehreschild: the implications of the ECIL-6 recommendation of isavuconazole as first-line therapy for invasive aspergillosis
During the 2017 12th Annual Fungal Update, held in the Great Hall at St Bartholomew’s Hospital, London, on February 4th, experts reviewed new evidence on the growing threat of antifungal resistance and latest strategies to optimise treatment.
The recently published sixth update of the European Conference on Infections in Leukemia (ECIL-6) guideline1 for the treatment of invasive fungal infections took into account the results of the SECURE study2.
This randomized controlled clinical trial showed that isavuconazole is non-inferior to voriconazole for efficacy in patients with invasive aspergillosis and better tolerated. Based on this evidence, ECIL-6 has given Isavuconazole a good evidence for use in therapy of invasive aspergillosis (strength A1 – good evidence to support a recommendation for use) [Table 2].1
While ECIL-6 also strongly recommends voriconazole as a first-line therapy, it adds that its use should be supported by therapeutic drug monitoring (TDM). In his presentation Dr Jörg Janne Vehreschild, Research Group Leader at the German Centre for Infection Research, University Hospital of Cologne, presented current management guidelines. In a subsequent interview he commented on the implications of ECIL-6 for clinicians.
Dr. Jörg Janne Vehreschild. Attending Physician, Department I for Internal Medicine, University Hospital of Cologne German Centre for Infection Research, Site Bonn-Cologne, University Hospital of Cologne, Department I for Internal Medicine, Mycoses
What are the most important amendments in ECIL-6?
The A1 recommendation for isavuconazole and TDM for voriconazole.
What is the issue with TDM and voriconazole?
Physicians are very familiar with its adverse effects and drug interactions but it’s accepted that its pharmacokinetics are erratic – patients may get high or low blood levels, and these may change even within patients. Therefore a fixed dose results in variable levels. Low levels may cause treatment failure and high levels are associated with some adverse effects such as CNS toxicity. In the SECURE trial, isavuconazole was non-inferior to fixed-dose voriconazole for efficacy and there was the observation that it was better tolerated.
Is TDM a practical burden for clinicians?
Principally, yes. You need to send blood samples to the lab – these are not cheap tests and this removes some of the financial benefit of using a generic drug. Then you have to wait for the result and adjust the dose. It’s more work for physicians and more to think about. Clearly, there would be a strong preference for physicians towards using a drug where they don’t have to use TDM. I think it is a big issue for ECIL-6 to recommend TDM with voriconazole. If you were to translate this directly into practice, I would say everyone who can afford isavuconazole will now prefer isavuconazole. However, it is not entirely clear to me why ECIL made that recommendation. All land-mark trials with voriconazole used fixed dosing, including the SECURE trial. Even without TDM, the efficacy of voriconazole was comparable to isavuconazole. While voriconazole tolerability and efficacy may in some cases be improved by TDM, I think the guideline overrates the existing evidence by making TDM a prerequisite for treatment with voriconazole.
What does ECIL-6 mean for patients with invasive aspergillosis?
This is the first guideline to fully acknowledge isavuconazole as an option for first-line treatment for invasive aspergillosis. For us in Cologne, isavuconazole is fully reimbursable and we have made it our first choice for three reasons: most importantly, as an academic centre specialising in treatment of invasive fungal diseases, it is important for us to know and evaluate the most current treatment options. In addition, it is less toxic than voriconazole and it has a broader spectrum of activity. Usually, we haven’t identified the pathogen when we treat invasive aspergillosis and we’re relying on surrogate indicators like serology or a CT scan; we don’t know if it might be mucormycosis or other rare fungus. Therefore we’re more comfortable using an antifungal with a slightly broader spectrum of action that’s still very active against aspergillus. However, if reimbursement is an issue, voriconazole is equally effective and toxicity is manageable for the majority of patients.
Which patients would merit treatment with isavuconazole rather than voriconazole?
The adverse effects of vorico- nazole are key to decision-making. It is well tolerated compared with other azoles and it lacks the gastrointestinal toxicity of itraconazole but the issues are that drug interactions, liver toxicity and vision and psychiatric adverse effects are more frequent than with isavuconazole. Isavuconazole would be preferred for patients receiving multiple treatments and with comorbidities including psychiatric disorder, vision disturbance, any kind of liver disease, or a heart condition, including risk of QT prolongation.
So isavuconazole is easier to use because you don’t need to check all these risk factors?
Clearly, isavuconazole is easier to handle, which is an advantage over voriconazole. There is less need to check for interactions and comorbidities or calculate the dose by bodyweight. After the loading dose, you only have to give it once daily and it seems to have reliable pharmacokinetics. Still, voriconazole is not a very toxic drug, and it is well tolerated and highly effective for most patients. But but it’s nice to have a better option now.
How do you see the management of invasive aspergillosis evolving?
The future for the management of invasive aspergillosis will be really interesting. Until today, the SECURE trial was the largest trial in this indication. It’s been difficult to improve major clinical endpoints with changes to treatment and this is partly because of difficulties in diagnosing and defining outcomes. We currently select treatment on the basis of surrogate markers. This leaves uncertainty about the identity of the pathogen – even whether it’s fungal or bacterial – and its susceptibility to antifungal agents. A further problem is that patients with invasive aspergillosis are often very ill with a deteriorating immune system: they might not be dying from a fungal infection but from other causes. There is a real need for improved diagnostics so that we can target treatment better.
Do you think the latest evidence will influence the management of patients undergoing solid organ transplantation?
I’m not sure. It will be interesting to see whether other guidelines will take the SECURE trial into account. Even without guidelines, everyone will be aware of the new evidence for isavuconazole.
What is your clinical experience with isavuconazole?
The department at Cologne has a strong track record of evaluating new antifungal agents and it was an early adopter of isavuconazole. We’ve treated a number of patients and the experiences are good, which was to be expected. Isavuconazole is now our standard treatment for probable and proven aspergillosis. For mucormycosis, it’s usually an alternative – we still prefer liposomal amphotericin B in that group but we use isavuconazole for patients who wouldn’t tolerate amphotericin B, or as an oral step-down treatment when we want to discharge a patient and continue treatment with isavuconazole tablets. Voriconazole and liposomal amphotericin B remain our treatments of choice for infections of the central nervous system until we learn more about how isavuconazole penetrates the bloodbrain barrier.
- Tissot F et al. Haematologica 2017;102(3):433-444
- Maertens J et al. The Lancet 2016;387(10020):760-769