Cost-effectiveness of screening for cryptococcal antigenemia (CrAg)

Boston University has collaborated with colleagues from South Africa, Botswana, Uganda, Nigeria, and the US to evaluate the costs and cost effectiveness of alternative screening and treatment strategies for HIV-patients with low CD4 counts for cryptococcal antigenemia (CrAg) and cryptococcal meningitis. Cryptococcal meningitis (CM) remains a leading cause of death among HIV-infected patients.

This program of work began in 2015 with an initial analysis of alternative strategies to screen treatment naïve, HIV-positive adults with a CD4 count <100 cells/μl for cryptococcal disease, using a cryptococcal antigen (CrAg) test, before initiating antiretroviral therapy. While the South African government recommended screening HIV-positive adults, two main strategies for screening were under discussion: reflex screening after CD4 testing in laboratories or provider-initiated screening.  We developed a decision analytic model to evaluate the cost-effectiveness for the screening strategies. Results published in 2016 supported a reflex strategy, which have been the approach followed in South Africa.

Following the initial work in South Africa, we expanded the analysis to evaluate the cost-effectiveness of CrAg screening in Uganda and Botswana, which had not yet adopted such a policy.  Results published in 2019 suggested that CrAg screening was cost-effective compared to no CrAg screening in both countries. In addition, the 2019 Botswana analysis show that expanding CrAg screening to treatment experienced patients was cost saving. To support policy discussions of expanding CrAg screening to patients with higher CD4 cell counts (all < 200 /μL), a third study in Botswana published in 2021 considered this policy and showed that CrAg screening for individuals with CD4 101–200 cells/μL was estimated to have a modest impact (e.g. CM cases and deaths avoided) and be less cost-effective than screening populations with CD4 counts ≤100 cells/μL.

In additional to these basic evaluations for CrAg screening policies, additional studies began to evaluate new approaches for preemptive treatment for asymptomatic CrAg-positive persons and hospital-based treatment for CM. A study published in 2022 evaluated the threshold of efficacy necessary for adding a single dose of liposomal amphotericin B (AmpB-L) to the standard fluconazole only approach. And another study also published in 2022 evaluated costs of new induction-phase treatment regimens for CM, the initial two-weeks of treatment after a CM diagnosis, including flucytosine and AmpB-L (as a substitute for amphotericin-B deoxycholate).

As of the end of 2022, BU is continuing to assist with cost-effectiveness analysis for new cluster randomized clinical trials in Uganda evaluating a new package of care for HIV-patients with advanced disease (Dr. Radha Rajasingham PI: NCT05085171, study period 2022-2027) and for a proposed study to evaluate new regimens for preemptive treatment.

Publications and other documents:

Larson BA, Rockers PC, Bonawitz R, Sriruttan C, Glencross DK, Cassim N, et al. Screening HIV-Infected Patients with Low CD4 Counts for Cryptococcal Antigenemia prior to Initiation of Antiretroviral Therapy: Cost Effectiveness of Alternative Screening Strategies in South Africa. PLoS ONE. 2016; 11(7):e0158986. doi: 10.1371/journal.pone.0158986.

Rajasingham R, Meya DB, Greene GS, Jordan A, Nakawuka M, Chiller TM, Boulware DR, Larson BA. Evaluation of a national cryptococcal antigen screening program for HIV-infected patients in Uganda: A cost-effectiveness modeling analysis. PLoS One. 2019; 14(1):e0210105. PMID: 30629619.

Tenforde MW, Muthoga C, Callaghan A, Ponetshego P, Ngidi J, Mine M, Jordan, A, Chiller, T, Larson, BA*, and JN Jarvis* (* joint senior authors). Cost-effectiveness of reflex laboratory-based cryptococcal antigen screening for the prevention and treatment of cryptococcal meningitis in Botswana. Wellcome Open Research. 2019;4:144.

Tenforde MW, Muthoga C, Ponatshego P, Ngidi J, Mine M, Greene G, Jordan J, Chiller T, Larson BA, JN Jarvis. Cost-effectiveness of cryptococcal antigen screening at CD4 counts of 101–200 cells/µL in Botswana [version 2; peer review: 2 approved]. Wellcome Open Res 2021, 6:55 (https://doi.org/10.12688/wellcomeopenres.16624.2 )

Rajasingham R, Nalintya E, Isrealski DM, Meya DB, Larson BA, DR Boulware. Cost-effectiveness of single-dose AmBisome preemptive treatment for the prevention of cryptococcal meningitis in African low and middle-income countries. Medical Mycology 2022 (60)2: myab079. DOI: 10.1093/mmy/myab078

Larson B, Shroufi A, Muthoga C et al. Induction-phase treatment costs for cryptococcal meningitis in high HIV-burden African countries: New opportunities with lower costs [version 3; peer review: 3 approved]. Wellcome Open Res 2022, 6:140 (https://doi.org/10.12688/wellcomeopenres.16776.3 ). Note: Results from this analysis also included in: Ending Cryptococcal Meningitis Deaths by 2030 – Strategic Framework, developed by GAFFI, ITPC, NICD, CDC Foundation, MSF, St. Georges University, DNDi, Univ. of Minnesota, available at: https://msfaccess.org/ending-cryptococcal-meningitis-deaths-2030-strategic-framework.

Presentations:

Rajasingham R, Meya DB, Nalintya E, Larson BA, Boulware DR. The cost-effectiveness of ambisome for asymptomatic cryptococcal infection. Abstract 707, Conference on Retroviruses and Opportunistic Infections (CROI 2019). Seattle, Washington, March 4-7, 2019.

Radha Rajasingham, David Meya, Greg Greene, Alex Jordan, Mina Nakawuka, Tom Chiller, David Boulware, Bruce Larson, oral presentation, WEAB0101, Evaluation of a Ugandan national cryptococcal antigen screening program: a cost-effectiveness analysis, 22^nd International AIDS Conference, July 2018, Amsterdam, The Netherlands.

Larson et al., “Screening HIV-infected patients with low CD4 counts for cryptococcal antigenemia prior to initiation of antiretroviral therapy: cost effectiveness of alternative screening strategies in South Africa”, poster presentation at the 21^th International AIDS Conference, Durban, South Africa, 18-22 July 2016.