Infectivology Xagena

Vfend may be better than Fungizone for invasive aspergillosis survival

The retrospective analysis, published in the Clinical Infectious Diseases, showed that patients who initially received antifungal agent Vfend ( Voriconazole ) were more likely to survive than patients who initially received Amphotericin B deoxycholate ( Fungizone ). The analysis also showed that patients who started on Vfend were less likely to need salvage therapy than those on Amphotericin B.

Salvage therapy is treatment given after the infection has not responded to the initial treatment or if the patient cannot tolerate the initial medicine.

Invasive aspergillosis is a severe pulmonary infection that can occur in patients with weakened immune systems. The fatality rate for invasive aspergillosis is estimated to be 58 percent, but approaches 90 to 100 percent in patients whose infection has spread beyond the primary site.

"These high mortality rates for invasive aspergillosis underscore the importance of initial treatment for this often fatal infection," said Thomas F. Patterson, lead author of the analysis and at the University of Texas Health Science Center at San Antonio. " Our analysis demonstrates that Voriconazole's efficacy and tolerability make it an important choice for first-line therapy."

The Global Comparative Aspergillosis Study ( GCAS ) led to Vfend's 2002 approval for the first-line treatment of invasive aspergillosis and was the basis for this newly published analysis.
In that study, 144 patients with confirmed or probable invasive aspergillosis were started on Vfend and 133 were started on Amphotericin B. If the disease progressed or the patient was unable to tolerate initial therapy, treatment could be changed to salvage therapy, which was referred to in the trial as "other licensed antifungal therapy," or OLAT.

Treatment was considered successful if the infection improved or was cured after 12 weeks of total therapy. Therapies that were used as salvage therapy included lipid formulations of Amphotericin B, Itraconazole, a dose reduction in Amphotericin B, and other systemic antifungal therapy.

Patterson et al retrospectively analyzed the data from the GCAS to assess the effect of salvage therapy on patient outcomes. Their analysis showed that just over a third ( 36 percent ) of patients in the Vfend group required subsequent salvage therapy, while more than three-quarters ( 80 percent ) of patients in the Amphotericin B group required salvage therapy.

In addition, it found that of those patients in either group who had to switch to salvage therapy, patients who started on Vfend had better outcomes.

Patients in the Vfend group, who were switched to OLAT, were more likely to survive than those in the Amphotericin B group who took OLAT ( 48 percent versus 38 percent, respectively ).
Overall survival in the GCAS was 71 percent in the Vfend group versus 58 percent in the Amphotericin B group.

Of patients who had to switch to OLAT due to drug intolerance, those treated initially with Vfend had a higher success rate than those in the Amphotericin B group ( 50 percent versus 38 percent, respectively ) .

Of those who had to switch to OLAT due to their initial treatment not working for them, patients initially treated with Vfend had a higher success rate than those treated with Amphotericin B group ( 26 percent versus 19 percent, respectively ).

In addition, 55 percent of patients treated with Vfend alone had a successful outcome, compared to four percent of those on Amphotericin B alone.
The overall efficacy rate was 53 percent for patients initially treated with Vfend, versus 32 percent for patients initially treated with Amphotericin B, regardless of whether OLAT was used.

It should be noted that lipid formulations of Amphotericin B are often used due to their perceived reduction in toxicity. In the GCAS, the lipid formulations were the most commonly used OLAT ( 38 percent of patients who received OLAT ).

However, the subsequent analysis of that study demonstrated that this salvage therapy was effective in only 30 percent of patients in the Amphotericin B group and 36 percent of patients in the Vfend group.
This success rate decreased to 12 percent when lipid formulations of Amphotericin B were used in patients following an initial insufficient clinical response to Amphotericin B deoxycholate.

" Our analysis concluded that in order to reduce mortality rates associated with invasive aspergillosis, we need to rethink the practice of relying on salvage therapy, including lipid formulations of Amphotericin B, and focus more on making the right initial treatment decision," said Patterson.

Vfend is currently approved in the United States for the treatment of invasive aspergillosis, esophageal candidiasis, candidemia in nonneutropenic patients and certain Candida infections. Vfend is also approved as salvage therapy for fungal infections caused by pathogens Scedosporium apiospermum and Fusarium species.

Vfend is the only IV/oral antifungal specifically indicated for the first-line treatment of mould and yeast infections.

Most frequently reported adverse events in therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain and respiratory disorder.
Treatment-related adverse events that most often led to discontinuation in clinical trials were elevated liver function tests ( LFTs ), rash and visual disturbances.
Vfend treatment-related visual disturbances are common. The effect of Vfend on visual function is not known if treatment continues beyond 28 days.

Vfend is contraindicated with Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine ( since increased plasma concentrations for these drugs can lead to QT prolongation and rare occurrences of torsades de pointes ), Sirolimus, Rifampin, Rifabutin, Carbamazepine, long-acting barbiturates, ergot alkaloids, Efavirenz and Ritonavir ( 400 mg q12h ).

There have been uncommon cases of serious hepatic reactions during treatment with Vfend ( clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities ). LFTs should be evaluated at the start of and during the course of therapy. Patients have rarely developed serious cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with Vfend.

Source: Clinical Infectious Diseases, 2005