1. COST-BENEFIT OF INTEGRATING CRYPTOCOCCAL ANTIGEN SCREENING AND PREEMPTIVE TREATMENT INTO ROUTINE HIV CARE Radha Rajasingham, David Meya, Melissa Rolfes, Kate Birkenkamp, David R Boulware Presented by: Radha Rajasingham, MD July 23, 2012

2. Background Cryptococcal Meningitis causes ~20-25% of AIDS- related attributable mortality in sub-Saharan Africa Cryptococcal Antigen (CrAg) can be detected >3 weeks before onset of symptoms Asymptomatic CrAg+ persons have a high risk of subsequent CM and death, despite ART. A new CrAg point of care lateral flow assay (LFA) is available with excellent sensitivity and specificity

3. Methods We assessed the cost-benefit of targeted CRAG screening for patients with CD4<100 using the LFA ($2.50/screen) coupled with preemptive fluconazole therapy for CRAG+ persons entering HIV care in sub-Saharan Africa CRAG LFA Cost Components CRAG LFA Assay $2.00 www.Immy.com Lab Supplies $0.05 One pipette tip, one Eppendorf tube Labor $0.25 Overhead $0.20 LFA can be shipped/stored at room temperature

4. Performed CRAG screening at the Infectious Disease Institute in Kampala Uganda between 2004 and 2007 CRAG latex agglutination was $16.75 per test Among HIV+ with a CD4<100, 8.8% (26/295) had asymptomatic/subclinical cryptococcal antigenemia 21 were treated with fluconazole (200-400mg x 2-4 weeks), 30- month survival was 71% 5 were not treated with fluconazole, and all died within 2 months of starting ART Clinical Infectious Diseases 2010; 51:448-55.

5. Cost-Effectiveness Analysis Among CD4<100, the number needed to screen in order to detect one CRAG+ was 11.3 (95% CI: 7.9-17.1) NNS = 1 / prevalence NNS = 1 / 0.088 The number needed to be screened and treated to prevent one death was 15.9 people NNT life-saved = 1 / (prevalence * survival) NNT life-saved = 1 / (0.088 * 0.71)

6. Based on $16.75 CRAG, this translates to: $190 (95% CI: $132-$286) to detect one asymptomatic person with cryptococcal antigenemia $266 (95% CI: $185 to $402) to save one person’s life with preemptive fluconazole Assuming an average increase in life expectancy of 18 years for a 30yo Ugandan initiating ART with a CD4<100,* this is $14.77 per DALY saved * Mills EJ, Bakanda C, Birungi J, et al. Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med 2011; 155: 209-216

8. CRAG Lateral Flow Assay (LFA) Immunochromatographic LFA test FDA approved July 2011

9. Using the same assumptions Among HIV+ with CD4<100 cells/µL with CRAG+ prevalence of 8.8%: To detect one CRAG+, the number need to screen was 11.3 (95% CI: 7.9-17.1) To prevent one death, 15.9 people would need to be screened and treated

10. Based on CRAG LFA cost of $2.50: The cost of detecting one person with subclinical antigenemia with the LFA is $28.37 (95% CI: $20 to $43) The cost of saving one life is $39.73 (95% CI: $28 to $60) Assuming an average increase in life expectancy of 18 years for a 30yo Ugandan initiating ART with a CD4<100,* this is $2.21 per DALY saved * Mills EJ, Bakanda C, Birungi J, et al. Life expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann Intern Med 2011; 155: 209-216

11. Prevalence of asymptomatic antigenemia with corresponding cost per life saved based on LFA cost of $2.50 per test

12. CrAg Latex Agglutination CrAg Lateral Flow Assay No CrAg Screening

13. Conversely, the cost of hospitalization and 14 days of amphotericin for treatment of cryptococcal meningitis is: $425 per episode in Uganda $2883 per episode in South Africa Thus for the treatment costs of 1 cryptococcal meningitis episode, one could perform CRAG LFA screening on: 170 persons in Uganda 1153 persons in South Africa Above a CRAG+ prevalence of 1%, pre-ART CRAG screening is C OST S AVING compared to the cost of amphotericin and CM treatment CRAG Screening is Cost Saving

14. Conclusions Targeted CRAG screening and preemptive fluconazole therapy is cost-saving to health care systems and should be integrated into routine HIV care for persons with CD4<100. Better understanding of the implementation science is needed to determine how best to scale up CRAG screening and define optimal treatment.