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Meya DB , Castelnuovo B, Kambugu A, Cook B, Kamya M, Bohjanen P, Manabe YC, Boulware DR.

Serum Cryptococcal antigen (CRAG) screening: Cost-effective Method to Prevent Death in HIV- infected persons with CD4 ≤100/μL in sub-Saharan Africa. Meya DB , Castelnuovo B, Kambugu A, Cook B, Kamya M, Bohjanen P, Manabe YC, Boulware DR. Introduction.

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Meya DB , Castelnuovo B, Kambugu A, Cook B, Kamya M, Bohjanen P, Manabe YC, Boulware DR.

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  1. Serum Cryptococcal antigen (CRAG) screening: Cost-effective Method to Prevent Death in HIV- infected persons with CD4 ≤100/μL in sub-Saharan Africa.. Meya DB, Castelnuovo B, Kambugu A, Cook B, Kamya M, Bohjanen P, Manabe YC, Boulware DR.

  2. Introduction • Globally, an estimated 957,900 cases of cryptococcal meningitis (CM) occur annually, with 624,700 deaths within 3 months of infection1. • Highest burden in Sub-Saharan Africa (SSA) with incidence of 3.2% & 720,000 cases annually with mortality of 20-50%2,3 even with ART availability 4,5 1 Park BJ, et al AIDS 2009; 2 Mayanja-Kizza H, et al CID 2007; 3 Jarvis, et al AIDS 2007; 4 Kambugu et al, CID 2008; 5 Bicanic T et al JAIDS 2009;

  3. Introduction • Studies in Uganda & Tanzania suggest 80-90% of patients with CM had CD4+ counts ≤100 cells/μL 6,7 • Early diagnosis & treatment is paramount in reducing CM-related mortality. 6Kisenge PR et al, BMC Inf Dis 2007; 7 French N et al AIDS 2002

  4. Introduction • Cryptococcal antigenemia known to be predictor of mortality, utility of serum CRAG testing to identify patients with asymptomatic cryptococcal infection & clinical impact of treatment not clearly defined. • High incidence of CM in patients who are cryptococcal antigen (CRAG) +ve but not treated with fluconazole8 8 Castelnuovo B et al CID, 2009

  5. Objective • To analyze the number of HIV patients with a ≤100 CD4+/μL that would have to be tested and treated to prevent one case of CM & one death as function of the prevalence of asymptomatic serum cryptococcal antigenemia.

  6. Methods • Data from a cohort of 609 ART-naïve patients initiating ART prospectively enrolled between 2004 -2007 at the Infectious Diseases Institute (IDI) in Kampala, Uganda. Inclusion criteria: • ART eligible adults (≥18 years) regular attendance in clinic. • Informed consent • Stable residence within a 20 km radius of the clinic

  7. Methods • At enrollment, full medical history & physical examination done. • A qualitative serum CRAG was measured at ART start regardless of presence of symptoms. • During enrollment, 2004-2006, no clinic-wide protocol for clinical intervention for +ve serum CRAG in asymptomatic persons, thus intervention depended on physician discretion.

  8. Methods • 1st line ART regimen was D4T/AZT + 3TC, NVP/EFV. Daily CTX prophylaxis was provided regardless of CD4+ count. • Assessed interventions & patient-outcomes within this prospective cohort using chart review.

  9. Methods • We determined mean incidence with 95% CI of cryptococcal disease, & the number needed to test and treat (NNT) prior to ART initiation to prevent one case of CM or one death. • The cost of CRAG testing & treatment was calculated based on current actual cost in Kampala, Uganda. • Cost of a CRAG test was US$ 16.75 at the Makerere University-Johns Hopkins University laboratory.

  10. Methods • CRAG cost encompasses reagents, personnel, overhead & quality control measures beyond absolute reagent cost of $4.50 to run a sample with positive & negative controls.

  11. Results • Of 609 HIV-infected adults with CD4+<200 cells/μL, 50 (8.2%) were serum CRAG positive when starting HIV therapy. • Females - 418 (69%) & mean cohort CD4 count was 79 cells/μL (95% CI 12-156). • 311 (51%) patients had a CD4+ count ≤100 cells/μL at enrollment.

  12. Results • In all persons with cryptococcal antigenemia, fluconazole use was associated with survival (Odds Ratio=7.7; 95% CI: 1.2 to 48, P=.035). • In a multivariate logistic regression model including CD4+ count, fluconazole remained protective for survival (OR=26.2; 95% CI: 1.5 to 463: P=.026)

  13. Cost-Benefit • Excluding patients with prior history of fluconazole use for cryptococcal infection, cost benefit analysis was done to determine no. of serum CRAG tests needed to prevent CM & CM-related death. • In order to detect 1 person with a +ve serum CRAG, the NN for screening was 11.3 (95% CI: 7.9-17.1).

  14. Cost-Benefit • To prevent 1 death, 15.9 (95% CI: 11.1-24.0) persons would need to be screened & treated. • Based on cost of fluconazole & CRAG screening, this translates to $190 (95% CI: $132 -$286) to detect an asymptomatic person with cryptococcal antigenemia. • To save 1 person’s life by presumptive fluconazole cost is $266 (95% CI: $185 to $402).  

  15. Cost of Serum Cryptococcal Antigen Screening based on Asymptomatic Prevalence

  16. Discussion • With CD4+ ≤100 cells/μL9 ,13.5% prevalence of cryptococcal antigenemia at this urban health facility in Kampala, Uganda, comparable with 21% in Cambodia. • The NNT to save one person’s life with CRAG screening was 16. At $266 approximates the cost of 14 days of amphotericin • Not screening does not necessarily save healthcare resources & results in worse mortality. 9Micol R et al, JAIDS 2007

  17. Discussion Why screen? • Occult cryptococcal antigenemia precedes clinical CM symptoms by a median of 22 days7 • Attributable mortality risk associated with a positive CRAG is 17-18% in rural community cohorts from Uganda 7,10. • Asymptomatic, untreated cryptococcal antigenemia independently predicts death during the first 12 weeks of ART 1,11 • Unmasking of CM after initiating ART is a relatively common occurrence and accounts for 30% of CM diagnosed in two 2006 African cohorts 7,10 10 Liechty CA et al, Trop Med & Int Health, 2007 11 Lawn SD et al, AIDS, 2005

  18. Discussion • A good screening test should have an effective intervention. In our experience, untreated patients had a 75% mortality rate overall & all of those with CD4+ ≤100 died. • With use of fluconazole, 71% survived for >2 years.

  19. Discussion • Fluconazole primary prophylaxis has been shown to be safe & effective in improving survival in persons with CD4+ <200 cells/μL12 • No prospective studies have determined the optimal treatment strategy in asymptomatic patients with cryptococcal antigenemia. 12 Rosalind P et al, Abstract 32, CROI 2009

  20. Conclusion • Overwhelming cost-benefit, is affordable for programs in resource limited settings. • Serum CRAG screening should be integrated as part of HIV care policies, for severely immunosuppressed patients. • Prospective trials of the best therapy in these patients are warranted.

  21. Acknowledgement • Our Friends at the IDI • Co- authors • Research department - IDI

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