Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings

Abstract

Background: Cryptococcal meningitis (CM) remains a common AIDS-defining illness in Africa and Asia. Subclinical cryptococcal antigenemia is frequently unmasked with antiretroviral therapy (ART). We sought to define the cost-effectiveness of serum cryptococcal antigen (CRAG) screening to identify persons with subclinical cryptococcosis and the efficacy of preemptive fluconazole therapy.

Methods: There were 609 ART-naive adults with AIDS who started ART in Kampala, Uganda, and who had a serum CRAG prospectively measured during 2004-2006. The number needed to test and treat with a positive CRAG was assessed for > or = 30-month outcomes.

Results: In the overall cohort, 50 persons (8.2%) were serum CRAG positive when starting ART. Of 295 people with a CD4(+) cell count < or = 100 cells/microL and without prior CM, 26 (8.8%; 95% confidence interval [CI], 5.8%-12.6%) were CRAG positive, of whom 21 were promptly treated with fluconazole (200-400 mg) for 2-4 weeks. Clinical CM developed in 3 fluconazole-treated persons, and 30-month survival was 71% (95% CI, 48%-89%). In the 5 CRAG-positive persons with a CD4(+) cell count < or = 100 cells/microL treated with ART but not fluconazole, all died within 2 months of ART initiation. The number needed to test and treat with CRAG screening and fluconazole to prevent 1 CM case is 11.3 (95% CI, 7.9-17.1) at costs of $190 (95% CI, $132-$287). The number needed to test and treat to save 1 life is 15.9 (95% CI, 11.1-24.0) at costs of $266 (95% CI, $185-$402). The cost per disability-adjusted life year saved is $21 (95% CI, $15-$32).

Conclusions: Integrating CRAG screening into HIV care, specifically targeting people with severe immunosuppression (CD4(+) cell count < or = 100 cells/microL) should be implemented in treatment programs in resource-limited settings. ART alone is insufficient treatment for CRAG-positive persons.

Figure 1. Study Profile

Of 295 people with CD4⁺≤ 100 cells/μL without CM, 26 (8.8%; 95% CI: 5.8–12.6%) were serum CRAG positive prior to initiating ART.

Figure 2. Survival of People with Asymptomatic Cryptococcal Antigenemia starting HIV Therapy

Kaplan-Meier curve displays the 2 year survival with and without preemptive fluconazole use in 33 asymptomatic people starting HIV antiretroviral therapy (ART) who have a positive serum cryptococcal antigen (CRAG) test. Survival curves are adjusted for pre-ART CD4 as a covariate by Cox-regression. Without CD4 adjustment, the survival in ‘No Fluconazole’ is 25% in all people and 0% in persons with CD4+<100 cells/μL. No mortality occurred after 2 years through a median follow up of 3.9 years on ART. Follow up was complete, and no persons were right-hand censored.

Figure 3. Cost of Serum Cryptococcal Antigen Screening based on Asymptomatic Prevalence

The figure displays the relative cost-effectiveness of cryptococcal antigen (CRAG) screening and preemptive fluconazole therapy based on the prevalence of antigenemia within a given population and outcomes from Kampala, Uganda. The cost to prevent one case of clinical cryptococcal meningitis (black line) and to prevent one death from CM (gray line) are presented with survivors living for >2.5 years on ART. Below the x-axis, displays the reported cross-sectional prevalence rates of asymptomatic antigenemia in various outpatient clinic populations in HIV-infected people without a prior history of cryptococcal meningitis. [, , , , –19] Above a prevalence of approximately 3%, the cost of amphotericin deoxycholate for treatment of people unmasking ART-associated cryptococcal meningitis ($245 per person) is greater than the costs of screening and treating with preemptive fluconazole, not including the additional hospitalization costs. CRAG screening costs are based on $16.75 per test, and different implementation costs would affect the cost-benefit curves proportionally.