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

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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.

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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. - PowerPoint PPT Presentation

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

Page 1: 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.

Page 2: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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;

Page 3: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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

Page 4: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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

Page 5: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 6: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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

Page 7: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 8: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 9: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 10: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 11: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 12: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

311 had CD4 ≤100 cells /μL

42 CRAG positive when starting ART

269 CRAG negative when starting ART

16 treated for CM prior to ART

26 presenting with Cryptococcal antigenemia

21 treated with fluconazole

5 received ART only

6 (29%) died within 1 year of starting ART

15 (71%) alive at >2 years on ART

All 5 died within 1 year of diagnosis

Page 13: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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)

Page 14: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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).

Page 15: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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).

Page 16: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

Cost of Serum Cryptococcal Antigen Screening based on Asymptomatic Prevalence

Page 17: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

9 Micol R et al, JAIDS 2007

Page 18: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

DiscussionWhy 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

Page 19: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 20: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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

Page 21: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

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.

Page 22: Meya DB , Castelnuovo B, Kambugu A, Cook B,  Kamya M, Bohjanen P,  Manabe  YC,  Boulware DR.

Acknowledgement

• Our Friends at the IDI

• Co- authors

• Research department - IDI