Continuous versus Episodic Use of Fluconazole for Candidiasis in
HIV Patients on HAART
Fluconazole (Diflucan) prophylaxis is associated with reductions in the
rate of fungal infection in HIV patients. However,
concerns exist with regard to the use of
fluconazole prophylaxis and
the risk of development of fluconazole treatment-resistant
infections.
In the current
study [1], Mitchell Goldman and colleagues of the AIDS
Clinical Trials Group Study
Team 323 and Mycoses
Study Group Study Team
conducted a randomized, open-label trial
that compared oral fluconazole given continuously (200 mg 3 times
weekly; the "continuous fluconazole
arm") with fluconazole that
was provided only for episodes of orophayngeal candidiasis
(OPC) or esophageal
candidiasis (EC)
(the "episodic fluconazole
arm") in HIV-infected persons with CD4+
T cell counts of <150 cells/mm3 and a
history of OPC.
The
primary study end point was the time to
development of fluconazole-resistant
OPC or EC, which was defined as lack of
response to 200 mg fluconazole
given daily for 14 or 21 days, respectively.
The study results appear in the current issue of Clinical Infectious
Diseases (November 15, 2005).
Results
A total of 413 subjects
were randomized to receive continuous fluconazole, and 416 were randomized to receive
episodic fluconazole.
After
42 months, 17 subjects (4.1%) in the continuous
fluconazole arm developed
fluconazole-refractory OPC or EC
infections, compared with 18 subjects (4.3%) in
the episodic fluconazole arm,
with no difference between treatment arms with
regard to the time to development of a fluconazole-refractory
infection within 24 months or before the end
of the study.
Continuous
fluconazole therapy was associated with fewer cases
of OPC or EC (0.29 vs. 1.08 episodes per
patient-year; P < .0001) and fewer invasive
fungal infections (15 vs. 28 episodes; P
= .04), but not with improved survival,
compared with episodic fluconazole
therapy.
The
authors conclude, “Continuous fluconazole
therapy is not associated with significant
risk of fluconazole-refractory
OPC or EC, compared with episodic fluconazole
therapy, in HIV-infected patients with access
to active antiretroviral therapy.”
Discussion
This
study may represent the largest randomized, controlled,
prospective study in HIV patients designed to examine
the risk of fluconazole-refractory mucosal Candida infections
(FRI), according to the authors.
In the authors’
view, their study “does not support the belief
that continuous fluconazole exposure in HIV-infected persons
is associated with a significant risk for FRI:
Continuous fluconazole therapy was associated with a higher
incidence of thrombocytopenia and smaller increase
in CD4+ T cell counts. There was, however,
no increase in bleeding or a significant
increase in non-fungal opportunistic complications
observed in the continuous fluconazole
arm. Fluconazole is rarely
associated with thrombocytopenia,
and lower CD4+ T cell counts
have not been reported for fluconazole.”
The
authors do not recommend routine use of continuous fluconazole
treatment in industrialized nations, however, due to the significant
decline in fungal infections effected by HAART use
and to the lack of a survival benefit
associated with continuous fluconazole.
“However,”
conclude the authors, “continuous fluconazole
therapy could be considered for individuals experiencing
recurrent mucosal infections. In resource-poor
settings, where access to HAART
is limited, mortality
attributed to fungal infections may
be considerable, and fluconazole prophylaxis
in such a setting has been associated with
improved survival rates.”
In
these settings, note the authors, “It is our
opinion that the decision to use azole
prophylaxis should not be based on a concern
for excess risk for FRIs;
rather, it should be based on the frequency
of mucosal candidiasis and invasive fungal infections.”
In
an editorial that accompanies the article [2], Samuel Bozzette
of The RAND Corporation, Santa
Monica, and University of
California, San Diego, endorses the
primary conclusions of this study: “These results,” he writes,
“coupled with the fact that there is no general
risk to microbial ecology from the use of
fluconazole, indicate that concern
about resistance should not be a factor in
the decision to provide [fluconazole]
prophylaxis.” [emphasis added—Ed]
He
continues, “With this new information, and because
generic fluconazole is available
at 
10% of the
price of the branded drug, reassessment
of the use of prophylaxis against mucosal Candida
infection in HIV-infected persons is timely.”
Bozzette also notes, “This study confirms the potency
of fluconazole prophylaxis in
cutting the risk of invasive fungal infection
by one-half and the risk of deep fungal
infection by two-thirds.
Regarding
the use of fluconazole prophylaxis in underdeveloped countries, he states,
“Use of prophylaxis in high-incidence areas is not
unreasonable at this time.”
10/19/05
References
1. M Goldman
and others (AIDS Clinical Trials Group
Study Team 323 and
Mycoses Study Group Study
Team 40). Clinical Infectious Diseases
41(10): 1473-1480. November 15, 2005.
2. S A Bozzette.
Fluconazole Prophylaxis
in HIV Disease, Revisited
(Editorial). Clinical Infectious Diseases 41(10): 1473
80. November 15,
2005.
Articles on Fluconazole (Diflucan)
