Comparative effectiveness of induction therapy for human immunodeficiency virus-associated cryptococcal meningitis: a network meta-analysis

Abstract

Background. Multiple international treatment guidelines recommend amphotericin-based combination regimens for induction therapy of cryptococcal meningitis. Yet, only 1 trial has reported a mortality benefit for combination amphotericin-flucytosine, and none have reported a mortality benefit for combination amphotericin-fluconazole. Methods. We conducted a Bayesian network meta-analysis to estimate the comparative effectiveness of recommended induction therapies for HIV-associated cryptococcal meningitis. We searched PubMed and Cochrane CENTRAL for clinical reports of induction therapy for HIV-associated cryptococcal meningitis. We extracted or calculated early (two-week) and late (six to 12-week) mortality by treatment arm for the following induction regimens: amphotericin B alone, amphotericin B + flucytosine, amphotericin B + triazoles, amphotericin B + flucytosine +triazoles, triazoles alone, triazoles + flucytosine, liposomal amphotericin B, and amphotericin B + other medicines. Results. In the overall sample (35 studies, n = 2483), we found no evidence of decreased mortality from addition of flucytosine or triazoles to amphotericin B, compared with amphotericin B alone. Although we did find a nonsignificant benefit for addition of flucytosine to amphotericin B in studies including participants with altered levels of consciousness, we did not identify a benefit for combination therapy in restricted analyses in either resource-rich or resource-limited settings, studies conducted before or after 2004, and studies restricted to a high dose of amphotericin B and fluconazole. Conclusions. Given considerations of drug availability and toxicity, there is an important need for additional data to clarify which populations are most likely to benefit from combination therapies for human immunodeficiency virus-associated cryptococcal meningitis.

Keywords: HIV/AIDS; cryptococcal meningitis; induction therapy; network meta-analysis; therapeutics.

Figure 1.

Schema of inclusion of studies for systematic review and meta-analysis for clinical trials of induction therapy for cryptococcal meningitis. Abbreviations: AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus.

Figure 2.

(A and B) Network diagrams for clinical studies of induction therapy for human immunodeficiency virus-associated cryptococcal meningitis. Blue nodes represent each antifungal therapy. The number in brackets next to each node indicates the number of monotherapy studies of that drug (including comparison trials of different doses or durations). The numbers on lines joining 2 nodes correspond to the number of comparative studies between those 2 drugs. (A) Network diagram for early (2-week) mortality. (B) Network diagram for late (6- to 12-week) mortality. Abbreviation: 5FC, flucytosine; azole, triazole.

Figure 3.

(A and B) Mortality rates by regimen for clinical studies of induction therapy for human immunodeficiency virus-associated cryptococcal meningitis. Estimates were obtained using DerSimonian–Laird random effects. In cases in which no events were observed, 0.5 was added to the numerator and 1 was added to the denominator. All results include 95% confidence intervals (CIs). (A) By arm forest plot of early (2-week) mortality rates. (B) By arm forest plot of late (6- to 12-week) mortality rates. Abbreviations: 5FC, flucytosine; AmB, amphotericin B; ART, antiretroviral therapy; azole, triazole; IFNg, interferon-gamma; Lip, liposomal.

Figure 3.

(A and B) Mortality rates by regimen for clinical studies of induction therapy for human immunodeficiency virus-associated cryptococcal meningitis. Estimates were obtained using DerSimonian–Laird random effects. In cases in which no events were observed, 0.5 was added to the numerator and 1 was added to the denominator. All results include 95% confidence intervals (CIs). (A) By arm forest plot of early (2-week) mortality rates. (B) By arm forest plot of late (6- to 12-week) mortality rates. Abbreviations: 5FC, flucytosine; AmB, amphotericin B; ART, antiretroviral therapy; azole, triazole; IFNg, interferon-gamma; Lip, liposomal.

Figure 4.

Forest plot comparing mortality in a network analysis of human immunodeficiency virus-associated cryptococcal meningitis by treatment regimen at early (2-week) and late (6- to 12-week) time points. Legend: Comparative groups are not consistent. Odds ratios on the left favor the first listed treatment group in each comparison. Abbreviations: 5FC, flucytosine; AmB, amphotericin B; azole, triazole; Lip, liposomal.