Effect of oral fluconazole 1200 mg/day on QT interval in African adults with HIV-associated cryptococcal meningitis.

We assessed the effect of fluconazole 1200 mg/day on the QT interval in cryptococcal meningitis patients. Mean corrected QT (QTc) change from baseline to day 7 was 10.1 ms (IQR: -28 to 46 ms) in the fluconazole treatment group and -12.6 ms (IQR: -39 to 13.5 ms) in those not taking fluconazole (P = 0.04). No significant increase in QTc measurements over 500 ms was observed with fluconazole. Nevertheless, it remains important to correct any electrolyte imbalance and avoid concomitant drugs that may increase QTc

Ophthalmic features of HIV associated cryptococcal meningitis in Malawian Adults: an observational study [version 1; peer review: awaiting peer review]

BACKGROUND: Cryptococcal meningitis (CM) is the commonest neurological complication in patients with advanced HIV. Visual disturbance is a frequent presenting symptom. Papilloedema is commonly reported but other ophthalmic findings are not well described. METHODS: We performed an observational study comparing severely immunocompromised HIV-infected patients with and without CM to determine the nature and prevalence of retinal pathology attributable to CM. 70 adult patients were enrolled in Blantyre Malawi, 35 with CM and 35 HIV-infected patients without CM. RESULTS: 79% (19/24) of CM patients examined on day one had evidence of retinal abnormalities compared to 17% (6/35) of HIV-infected controls (p <0.001). In the CM group, retinal whitening was the commonest abnormality (50%), followed by optic disc swelling (29%), haemorrhage (25%) and vascular abnormalities (7%). Retinal whitening was the only abnormality observed in the comparator group (17%). In CM, there was no significant difference between those with and without retinal abnormalities in fungal burden (13,550 cfu/ml vs. 9,150 cfu/ml; p = 0.65), CD4 count (28 cells/µl vs. 76 cells/µl; p = 0.79) or CSF opening pressure (21cm H20 vs. 27cm H20; p = 0.5). There was no association between presence/absence of retinal abnormalities and death (40% 10-week mortality vs. 26%; p = 0.6). CONCLUSIONS: Whether the presence of CM retinopathy could be used as a marker of disease severity warrants further investigation. The observed ophthalmic findings provide a descriptive framework for CM retinopathy to be utilised in future CM studies. TRIAL REGISTRATION: ISRCTN (ISRCTN45035509) 19/06/2012

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

Background Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)–related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. Methods We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. Results A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. Conclusions One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509.