Discussion
AIDS, PWH, toxicity, cardiac dysfunction, CM, ill, CM illness
DISEASE, AIDS, CARDIAC ARRHYTHMIAS
This study has shown that weight based FCZ higher than 1200mg and up to 2000mg/day in the induction phase of the first episode of CM in PWH is safe and effective. Amphotericin B was associated with better fungicidal activity than FCZ at any dose tested. Survival was improved but not statistically significantly in the AMB cohort compared with the 1600mg and 2000mg FCZ arms. We demonstrated that doses of FCZ higher than the 1200mg/day as recommended by the WHO and USA Guidelines had better CSF sterilisation at week 10 (2,3). From a study in Malawi, it was also shown FCZ 1600mg/day and 2000mg/day alone in the induction phase was more fungicidal compared to FCZ 1200mg/day combined with flucytosine as reported [Our study was conducted simultaneously across 10 international sites (“This study was conducted in 2 stages and per protocol Stage 1 was a dose determining strategy for stage 2. Based on predetermined criteria the 1200mg FCZ arm was stopped due to higher mortality. It is possible that the lower BMI in this cohort may partly explain the higher mortality. There was no statistical difference in clinical severity and demographic criteria between the 1200mg, and the 1600mg and 2000mg cohorts in Stage 1.The bioavailability of oral FCZ has been studied in humans from 50 to 400mg daily; enteral absorption of FCZ is 90%, not affected by food, and demonstrates linear pharmacokinetics within this dose range. Based on the dose response within the dose range in this study, the linearity is likely to continue at least up to a dose of 2000mg. The CSF penetration of FCZ is presumed to be linear as well explaining the CM dose response effect up to 2000mg/day, although no CSF drug levels were analysed in the present report [Rifampicin may reduce the bioavailability of FCZ and was only permitted in Stage 2 of the protocol in the 1600mg and 2000mg FCZ cohorts. A pharmacokinetic study of 400mg FCZ in the consolidation phase of CM following 2 weeks of AMB, showed a 39% increase in the elimination constant of serum FCZ with concomtitant rifamipicin at 600mg daily [The duration of the present study was almost 7 years and reflected several challenges in the implementation and conduct across multiple resource limited international sites. These included delays in obtaining IRB and country approvals, determination of participation at national level by government agencies, training of laboratory personnel to conduct quantitative cultures with proficiency testing, delays in approval of laboratories to Division of AIDS of the USA National Institutes of Health standards, availability of AMB at sites, widespread implementation of ART programs, introduction of screening for serum cryptococcal antigen, and implementation of FCZ prophylaxis for serum cryptococcal antigen positive persons initiating ART [The mortality in our study was much lower than that reported in a previous study comparing 1200mg FCZ to 1200mg FCZ combined with flucytosine [The WHO recommended dose of FCZ 1200mg daily in the induction phase was shown to be more effective than 800mg in a study in Uganda that enrolled 30 participants in each group sequentially [Fluconazole is known to prolong the ECG QTc interval at high doses (≥1200mg/day). This study recorded a high incidence of QTc prolongation that was not associated with increased mortality or life-threatening cardiac arrhythmias. This was likely due to frequent ECG monitoring and avoiding concomitant medications known to prolong the QTc. It is notable that QTc prolongation across grades of severity from mild to severe was similar in all FCZ cohorts and in the AMB cohort. This suggests that QTc is more likely a reflection of cardiac dysfunction and electrolyte abnormalities in a severely ill patient and warrants further study. None of the earlier studies with FCZ doses ranging from 400 to1200mg reported routine QTc monitoring. Pfizer has issued a precaution regarding QTc prolongation in severely ill patients, and concomitant medication known to prolong QTc should be avoided in doses greater than 400mg daily. Routine ECG monitoring was not done in the 2 published studies that used 1200mg FCZ and there was no report of any QTc abnormality, which could have been overlooked [Fluconazole is a potent inhibitor of cytochrome P450 [The addition of flucytosine to high dose FCZ induction dose may improve the efficacy, but the additional toxicity may mitigate any potential benefit [This study is a phase II study and has several limitations. The long duration of the study may account for some of the observations but we could not identify any specific issues. Only participants who could swallow tablets were enrolled implied that potential participants who were extremely ill and with significantly impaired levels of consciousness were not enrolled. We demonstrated a lower mortality compared to other published studies of CM. This may be attributed to the relatively less severe CM illness. It reinforces the view that early recognition and treatment of CM is important. It also shows that oral treatment is feasible in the majority of patients despite the high pill burden with higher doses FCZ.Whilst flucytosine was permitted this was not available anywhere except in the USA site. This exposes the reality of challenges with optimal treatment access in regions where disease burden is high and reinforces the need for alternative strategies whilst access for optimal treatment is explored. At one point, the study was temporarily halted because of the shortage of study provided FCZ. This highlights the challenges of treating CM in resource limited regions.The 1200mg FCZ cohort enrolled participants with a lower BMI and lower GCS and this may partially explain the higher mortality. This occurred by chance as enrolment into the increasing dose cohorts was sequential and enrolment was halted after each cohort until safety was assessed by the SMC. This was mandatory to ensure safety of participants before escalating enrolment to the next dose of FCZ. The mortality was still lower than that in published studies of 1200mg FCZ. This does not detract from the observation that 1200mg FZC in the induction phase of CM treatment is inadequate. Fluconazole doses in the induction phase was weight and eGFR adjusted as per protocol. This was considered mandatory for safety because of the higher doses of FZC studied, particularly in respect of QTc prolongation. This is the same protocol for standard of care use of AMB.