Prognostic implications of baseline anaemia and changes in haemoglobin concentrations with amphotericin B therapy for cryptococcal meningitis

Abstract

Objectives: Anaemia represents a common toxicity with amphotericin B-based induction therapy in HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anaemia on survival.

Methods: We used data from Ugandan and South African trial participants to characterize the variation of haemoglobin concentrations from diagnosis to 12 weeks post-diagnosis. Anaemia severity was classified based on the haemoglobin concentration at cryptococcal meningitis diagnosis, and nadir haemoglobin values during amphotericin induction. Cox proportional hazard models were used to estimate 2- and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir haemoglobin < 8.5 g/dL during amphotericin induction and who survived ≥ 2 weeks post-enrolment.

Results: The median haemoglobin concentration at meningitis diagnosis was 11.5 g/dL [interquartile range (IQR) 9.7-13 g/dL; n = 311] with a mean decline of 4.2 g/dL [95% confidence interval (CI) -4.6 to -3.8; P < 0.001; n = 148] from diagnosis to nadir value among participants with baseline haemoglobin ≥ 8.5 g/dL. The median haemoglobin concentration was 8.1 g/dL (IQR 6.5-9.5 g/dL) at 2 weeks, increasing to 9.4 g/dL (IQR 8.2-10.9 g/dL) by 4 weeks and continuing to increase to 12 weeks. Among participants with haemoglobin < 8.5 g/dL at diagnosis, mortality risk was elevated at 2 weeks [hazard ratio (HR) 2.7; 95% CI 1.5-4.9; P < 0.01] and 10 weeks (HR 1.8; 95% CI 1.1-2.2; P = 0.03), relative to those with haemoglobin ≥ 8.5 g/dL. New-onset anaemia occurring with amphotericin therapy did not have a statistically significant association with 10-week mortality (HR 2.0; 95% CI 0.5-9.1; P = 0.4).

Conclusions: Amphotericin induced significant haemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anaemia at baseline had a higher mortality risk at 2 and 10 weeks post-enrolment.

Keywords: HIV; amphotericin B; anaemia; cryptococcal meningitis.

Figure 1. Median (IQR) hemoglobin concentrations from amphotericin B initiation through 12 weeks post-diagnosis among patients in the COAT trial

among patients with Grade ≤1 anemia vs. those with Grade ≥2 anemia (<8.5g/dL) at diagnosis. Overall median nadir hemoglobin among all COAT participants was 7.4g/dL (IQR 6.2, 8.9). The median percentage change from baseline to nadir was a decrease of 31% (IQR −44%, −22%). Patients with ≤Grade 1 anemia at diagnosis shown as solid line; patients with ≥Grade 2 anemia (hemoglobin <8.5g/dL) at diagnosis shown as long dashed line.

Figure 2

Kaplan-Meier survival curves by anemia status at cryptococcal meningitis diagnosis. HIV-infected persons with cryptococcal meningitis who had hemoglobin ≤8.4g/dL (≥Grade 2 adverse event severity) at diagnosis had higher 2-week mortality (Hazard Ratio =2.3; 95%CI: 1.3-4.1; P<0.01) and 10-week mortality (Hazard Ratio =1.7; 95%CI: 1.0-2.9; P=0.05).

Figure 3

10-week survival based on nadir hemoglobin level during amphotericin induction therapy among persons with hemoglobin ≥8.5 g/dL at diagnosis who survived >14 days post-diagnosis. Participants developing moderate to life-threatening anemia (Grade 2-4 adverse event, i.e. hemoglobin ≤8.4 g/dL) during amphotericin therapy had non-statistically higher 10-week mortality (adjusted Hazard Ratio = 2.58; 95%CI: 0.64-10.48; P=0.19).