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Department of Internal Medicine
National Taiwan University Hospital
Chien-Ching Hung, MD, PhD, has disclosed that he has received funds for research support from Gilead Sciences, Merck, and ViiV and has served as a consultant and on speaker bureaus for Gilead Sciences.
Of all the excellent studies presented at the 2021 International AIDS Society (IAS) Conference on HIV Science, I think the AMBITION-cm trial using a single high-dose liposomal amphotericin (LAmB)–based treatment for HIV-associated cryptococcal meningitis (CM) is the most important and most relevant study to Asia, Taiwan, and globally.
Defining the Problem
In 2014, the prevalence of cryptococcal infection among people with HIV who had a CD4+ cell count <100 cells/mm3 was 6%. CM is responsible for 15% to 20% of all AIDS-related deaths globally, with 75% of those deaths occurring in sub-Saharan Africa. In Asia and the Pacific, the annual global disease burden of CM was estimated to be 43,200 cases, a large share of the approximately 223,000 CM cases worldwide.
In the phase III AMBITION-cm trial, patients with HIV and having their first episode of CM were recruited from 6 large referral hospitals across 5 countries in sub-Sahara Africa. Lawrence and colleagues randomized patients to receive either a single high-dose LAmB given along with 14 days of high-dose fluconazole 1200 mg/day plus flucytosine 100 mg/kg/day (a 3-drug LAmB arm) or a 7-day course of amphotericin B (AmB) deoxycholate 1 mg/kg/day plus flucytosine 100 mg/kg/day, followed by fluconazole 1200 mg/day for 7 days (a 2-drug AmB arm). The hypothesis was that the LAmB-containing regimen would be noninferior to the 7-day course of the AmB deoxycholate–containing regimen.
Efficacy and Safety
Antiretroviral therapy was started 4-6 weeks after initiation of antifungal therapy. At 10 weeks, all-cause mortality rate for the single-dose LAmB arm was 24.8% vs 28.7% in the AmB arm. Both regimens showed similar early fungicidal activity (-0.4 for LAmB vs -0.42 log10 for AmB). The LAmB arm had a better safety profile in terms of the mean change of hemoglobin, the percentage of mean change of serum creatinine, and hypokalemia. The LAmB arm also had a significantly lower incidence of thrombophlebitis requiring antibiotics.
The investigators concluded that single high-dose LAmB plus flucytosine plus high-dose fluconazole was superior to the 7-day course of conventional AmB plus flucytosine followed by a 7-day course of fluconazole. The 2-week course of AmB deoxycholate plus flucytosine used to be the standard antifungal treatment for people with or without HIV who presented with CM. However, AmB deoxycholate requires a lengthy IV administration and can cause several adverse events such as phlebitis (which can lead to secondary infections), severe anemia, hypokalemia, hypomagnesemia, and renal function impairment. In my opinion, the results of this study show that LAmB can prevent or reduce the risk of those toxicities and provide similar or better efficacy in CM treatment.
Although this study is highly relevant and will shift the CM treatment paradigm in Taiwan and most Asia-Pacific countries, the study consists of a few limitations. I think we should be concerned about the extremely high all-cause mortality rate of 25% or 29% in both arms. Early diagnosis and appropriate management of HIV-associated CM in medical care facilities in resource-limited settings, such as in sub-Saharan Africa, need to be improved. Although CM may be the major cause of the high mortality rates, mortality may be caused by concomitant infections or complications from administration of the therapeutic agents. We will have to wait for the full study results to see the causes of mortality and if there were any relapses of CM in either arm.
Also, the cost of LAmB is a major concern. A single high-dose of LAmB can cost 10-20 times more than conventional AmB. For this reason, I believe conventional AmB will remain the cornerstone of antifungal therapy for CM in most of the Asian countries in the near future. The investigators do plan to compare the cost of each regimen to see if the single high-dose LAmB regimen will be cost-effective in resource-limited settings. However, data on cost-effectiveness were not shown at IAS.
LAmB in Elevated ICP?
In Taiwan, we usually administer AmB deoxycholate 0.7-1.0 mg/kg/day plus flucytosine 100 mg/kg/day to patients who present with CM, especially people with HIV. Given that patients with HIV and CM often present with very high ICP in Taiwan, the lumbar puncture (LP) procedure is often needed to relieve the elevated ICP. In addition, LP is used for the diagnosis of CM. It is important to note that our general population believes that the LP procedure is hazardous to their health. Thus, it is often the case that healthcare professionals have to explain how LP is performed and its benefit and risk each time before the procedure.
For example, several years ago, I had a patient with HIV who presented with CM and an extremely high ICP (>600 mm H2O) with severe headache and diplopia. He initially declined daily therapeutic LPs, but when we finally did the LP and relieved the pressure, his headache immediately went away. Approximately 8 hours later, the elevated pressure returned with a severe headache. Although we continued to administer AmB and flucytosine, the headache did not resolve within 2 weeks, and management of CM still needed the prolonged hospitalization. Therefore, I think this case raised a very important question: Could single high-dose LAmB provide benefit to individuals with very elevated ICP?
Since many patients with CM in Taiwan present to the healthcare setting very late, most of them have elevated ICP. An elevated ICP significantly contributes to the mortality of patients with CM observed within the first 2 weeks, and many patients will require hospitalization, likely for 2-4 weeks, to manage this elevated ICP. Therefore, both the medicine cost and the cost of continued hospitalization for the management of the elevated ICP must be considered.
The results of the AMBITION-cm study did not shed light on whether single high-dose LAmB will reduce the ICP faster or result in a sustained, reduced ICP. If they confirm that the use of LAmB could lead to the reduced requirement for therapeutic LP, it could shorten hospitalization time and significantly reduce the related cost.
What is your experience with CM in your practice, and how do you see single high-dose LAmB fitting into the treatment landscape in your home country? Join the discussion by posting a comment sharing your experiences.