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Senior Consultant, Infectious Diseases
Hospital Juan Fernández
Director, Fundación Huesped
Professor of Infectious Diseases
Buenos Aires University Medical School
Buenos Aires, Argentina
Pedro Cahn, MD, PhD, has disclosed that he has received funds for research support and consulting fees from Merck and ViiV and fees for non-CME/CE services from Gilead Sciences, Merck, and ViiV.
Late HIV diagnosis occurs in approximately 30% of patients, many of them having their first contact with the healthcare system with an active opportunistic infection (OI). One of the most frequent OIs seen in people with HIV with a low CD4+ cell count (usually <100 cells/mL) is cryptococcal meningitis (CM) caused by the fungus Cryptococcus neoformans. CM is associated with high mortality rates and can produce severe neurologic sequelae. This infection often leads to meningitis, which is a major cause of AIDS-related deaths.
AMBITION-cm: Single High-Dose Liposomal Amphotericin for HIV-Associated CM
Since CM contributes up to 15% of HIV-related mortality and is the leading cause of HIV-related meningitis in many low-income and middle-income countries, such as some in the Latin American region, finding ways to effectively treat HIV-associated CM in these countries remains an urgent need. In the phase III AMBITION-cm trial presented at IAS 2021, Lawrence and colleagues evaluated the efficacy and safety of using a single dose of liposomal amphotericin B in high-dose form vs the standard therapy for CM. In total, 814 adults with HIV-associated CM were enrolled in 5 low-income and middle-income sub-Saharan African countries.
In this study, patients in the exploratory arm received liposomal amphotericin B (10 mg/kg), with oral flucytosine and fluconazole for 14 days. Those in the control arm received standard of care with a 7-day course of intravenous amphotericin-B deoxycholate 1 mg/kg plus oral flucytosine and then 7 days of high-dose oral fluconazole. Patients in both arms received a maintenance regimen of oral fluconazole.
The primary outcome was all-cause mortality at 10 weeks, with a noninferiority margin of 10%, and this outcome was met. Safety benefits in the high-dose liposomal amphotericin B arm included significantly lower rates of anemia, a statistically significantly smaller increase in creatinine, and a reduced need for blood transfusions. The study also reported that the single high-dose was much easier to administer and had significantly fewer adverse events. A total of 101 (24.8%) deaths occurred in the high-dose liposomal amphotericin B arm (95% CI: 20.7-29.0) vs 117 (28.7%) in the control arm (95% CI: 24.4-33.4).
Implications for Individuals With HIV in Latin America
It is estimated that at the end of 2019, Latin America had 2.1 million individuals with HIV, with 120,000 new infections and 37,000 estimated deaths. Within multiple Latin American countries, the distribution of people with HIV is concentrated in specific urban areas, with approximately 50% of mortality concentrated in less than 10% of the municipalities. In these countries, the prevalence of CM infection remains high despite the availability of highly active antiretroviral therapy. The Latin American region is struggling with many patients showing up to the healthcare system with profound immunodeficiency and active OIs such as CM, tuberculosis, Pneumocystis jirovecii pneumonia, and toxoplasmosis.
The main obstacles in the Latin American region for achieving timely HIV diagnosis are the bureaucratic barriers for HIV testing and the environment of stigma and discrimination still active in many countries. This acts as a discouraging factor to get tested. As a consequence, many people with HIV are late presenters, missing the window of opportunity of being treated early in their disease. Every effort should be made to offer HIV testing at any contact with the healthcare system, particularly for most at-risk populations.
What are the implications of AMBITION-cm for the treatment of HIV-associated CM in Latin America? A common practice in Latin America is to treat CM with amphotericin deoxycholate for at least 7 days (plus 5-fluorocytosine in some countries), followed by oral fluconazole, as recommended by the WHO guidelines. Even though the liposomal amphotericin studied in AMBITION-cm will likely be more expensive than the classical intravenous amphotericin B formulation, the liposomal one might be cost-saving if it shortens the duration of the hospitalization. Of course, to make it affordable in Latin America, the cost of the product needs to be discussed between governments and manufacturers at the country level or, even better, at the regional level.
Will the results of this study influence your practice and how you treat CM in your patients with HIV? Join the discussion by posting a comment.