Page 20 - SAHCS HIVMed Journal Vol 20 No 1 2019

Page 7 of 16 Guideline

Recommendation 3: Management efforts to provide greater access to flucytosine through fast-
of a first episode of cryptococcal track SAHPRA registration and development of additional
generic products, particularly in light of the findings of the
meningitis recently published Advancing Cryptococcal Treatment in

Detailed recommendations Africa (ACTA) trial. 8,10,41,42 This trial demonstrated a
substantial mortality reduction among participants
The antifungal treatment of HIV-associated CM is divided randomised to flucytosine-based combination therapies
into three phases: induction, consolidation and maintenance (Table 4). Overall, the best-performing treatment arm in the
(Table 3). ACTA trial was the 1-week combination of amphotericin B
deoxycholate and flucytosine, followed by high-dose oral
Induction phase (2 weeks) fluconazole in the second week. This regimen was also
The WHO recommends that the first choice for induction associated with fewer adverse effects, specifically a
phase treatment is amphotericin B 1 mg/kg/day and reduction in amphotericin B deoxycholate-related
flucytosine 100 mg/kg/day divided into four doses per nephrotoxicity and anaemia, and lower costs. This is the
day. Flucytosine is not currently registered in South Africa preferred regimen recommended by the panel. Both the all-
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or any other African country. 10,41 A flucytosine product oral fluconazole/flucytosine regimen and 1-week
manufactured in Poland was acquired by Mylan in 2016. amphotericin B deoxycholate/flucytosine regimen were
Despite previously lapsed registration in South Africa and non-inferior to the previous gold standard (i.e. 2 weeks of
approval by the WHO Pre-Qualification Program, the South amphotericin B and flucytosine) in terms of 2-week
African Health Products Regulatory Authority (SAHPRA) mortality. The all-oral regimen is useful in cases where a
requires a full dossier to be submitted. The panel and the delay in administration of amphotericin B deoxycholate is
Southern African HIV Clinicians Society support advocacy expected or its use is contraindicated. The panel now also
recommends a higher induction dose of fluconazole (1200
mg daily) based on doses used in the ACTA trial. There is no
TABLE 3: Summary of recommendation 3.
Phase Duration Treatment evidence from fluconazole monotherapy trials to suggest an
Induction 2 weeks Preferred regimen: 1 week of increased toxicity at this higher dose. 43,44 If flucytosine is
amphotericin B deoxycholate unavailable, the preferred treatment option is 2 weeks of
(1 mg/kg/day) and flucytosine
(100 mg/kg/day divided into four amphotericin B and fluconazole (not 1 week of amphotericin
doses per day), followed by 1 week
of fluconazole (1200 mg daily for B and fluconazole) because the 2-week regimen was
adults; 12 mg/kg/day for children associated with lower 2- and 10-week mortality rates than 1
and adolescents up to a maximum
of 800 mg daily) week of this drug combination in the ACTA trial (Table 4). In
Alternative options
• 2 weeks of fluconazole (1200 mg settings with access to liposomal amphotericin B, this
daily for adults; 12 mg/kg/day for
children and adolescents) and antifungal may be used instead of the deoxycholate
flucytosine (100 mg/kg/day divided formulation, especially among patients with renal
into four doses per day)
• Preferred option if flucytosine is impairment. Although there is no evidence of improved
unavailable: 2 weeks of amphotericin
B deoxycholate (1 mg/kg/day) and efficacy compared to amphotericin B deoxycholate,
fluconazole (1200 mg daily for liposomal amphotericin B is associated with fewer adverse
adults, 12 mg/kg/day for children
and adolescents) effects and may be available at a reduced cost for CM in
• If liposomal amphotericin B is
available for patients with renal some countries. 45,46 In countries where amphotericin B is
dysfunction: 1 week of liposomal
amphotericin B (3 mg/kg/day – unavailable, the panel advises clinicians to follow the WHO
4 mg/kg/day) and flucytosine guideline with respect to high-dose fluconazole options. In
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(100 mg/kg/day divided into four
doses per day), followed by 1 week South Africa, all patients with CM should be treated with an
of fluconazole (both fluconazole
and flucytosine doses adjusted amphotericin B-based induction regimen unless there is a
for renal impairment) specific contraindication to this.
Consolidation 8 weeks Fluconazole (800 mg daily for adults;
12 mg/kg/day for children and
adolescents up to a maximum of
800 mg daily) Consolidation phase (further 8 weeks)
Maintenance Continue for at least 12 Fluconazole (200 mg daily for adults; The panel recommends a fluconazole dose of 800 mg
months until a single CD4 6 mg/kg/day for children and
count > 200 cells/µL and a adolescents up to a maximum of daily for 8 weeks. This recommendation is based on expert
suppressed HIV viral load 200 mg daily)
opinion.
TABLE 4: Unadjusted 2- and 10-week mortality outcomes for the five combination treatment regimens in the Advancing Cryptococcal Treatment in Africa trial.
Regimen 2-week mortality 10-week mortality
n/N % 95% CI n/N % 95% CI
One-week amphotericin B and flucytosine (short course) 13/113 11.6 5.7–17.5 27/113 24.2 16.2–32.1
Two-week fluconazole and flucytosine (all-oral regimen) 41/225 18.2 13.2–23.3 79/225 35.1 28.9–41.3
Two-week amphotericin B and flucytosine 24/115 20.9 13.4–28.3 44/115 38.3 29.4–47.2
Two-week amphotericin B and fluconazole 25/114 21.9 14.3–29.5 47/114 41.3 32.3–50.4
One-week amphotericin B and fluconazole 36/111 32.4 23.7–41.1 54/111 48.6 39.4–57.9
CI, confidence interval; n/N, number of deaths divided by number of participants in that trial arm.

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