TREATMENT OUTCOMES OF AIDS ASSOCIATED CRYPTOCOCCAL MENINGITIS AT - - PowerPoint PPT Presentation

TREATMENT OUTCOMES OF AIDS ASSOCIATED CRYPTOCOCCAL MENINGITIS AT MTRH, ELDORET

• DR. CONSTANTINE AKWANALO

Consultant Physician. MTRH

INTRODUCTION

 Cryptococcosis: invasive fungal infection caused by cryptococcus

neoformans1,2 .

 Predisposing factor: profound CMI defect 3.  Cryptococcal meningoencephalitis: most frequent manifestation of

cryptococcosis in HIV-infected patients4 .

 Occur when CD4+ count < 100 cells/µl (1st manifestation in up to 1/3)  Reduces life of AIDS patients by 2yrs regardless of the CD4 count6

 High mortality in the1st 2 wks

BACKGROUND

 Pre AIDS era: rare: < 300 /yr in USA6  AIDS era: pre-cART  Annual incidence of 6 to 10% in USA & Europe7

 77 to 89% of meningitis in AIDS pts in N/York

• Sub-Saharan Africa; 25-30% (hospital based, lab or

PM)

• KNH: 5.2% (based on Indian ink)14
• KNH: 5.3% (PM)12
• MTRH: 12% (Reason for admission- 2006)

PROBLEM STATEMENT

 Crypto. Meningitis affects 30% of AIDS pts in

SSA.

 Contributes 11-44% of deaths (Pfaller et al)  Limited resources; 1st line drugs

unavailable, erratic supply of Amphotericin B.

PROBLEM STATEMENT QUESTIONS

 What are the clinical and mycological outcomes of

AIDS associated cryptococcus meningitis at MTRH?

 Is there a difference in these outcomes when

using amphotericin B or fluconazole?

OBJECTIVES



Broad objectives

1.

To determine treatment outcomes of AACM at MTRH

2.

To determine difference in outcomes using amphotericin B or fluconazole during induction

OBJECTIVES

 Specific objectives 1.

To determine clinical and mycological outcomes of AACM at MTRH on day fourteen

2.

To determine the difference in outcomes using amphotericin B and fluconazole

STUDY JUSTIFICATION

 High acute mortality rate  Varying data on outcomes using fluconazole or

Amphotericin B alone during induction.

 No local data evaluating treatment outcome

LITERATURE REVIEW

 Clinical outcomes  Untreated,100% clinical/mycological failure, with acute

mortality rate (AMR) of 80% (Ford et al)

 With optimal treatment; AMR of 15% (range 5 – 30%)  Induction with single agents has varied outcomes too.

LITERATURE REVIEW- COMBINATIONS

 Amphot.B (0.7mg/kg) + 5FC vs. amphot.B alone  Clinical & mycological success of 60% vs. 51% (p=0.06.)

Overall acute MR of 5.5% (Van der Horst, 1997)

 Ampho.B vs. Ampho.B + 5FC vs. Ampho.B +FLC

400mg/d or all the three drugs combined

 Cryptococcus clearance rate faster with Ampho.B/5 FC

combination (Brouwer et al, 2004)

LITERATURE REVIEW- COMBINATIONS

 Mycological success: (Moottsikapun et al, 2004)  Ampho.B/5FC : 84%,  Ampho.B/ITC : 92%  Ampho.B/FLC (400mg): 87% respectively

COMBINATION AGENTS

 Fluconazole (Milefchik, 1997)  800mg 75%  1200 87%  1600mg 69%  2000mg + 5FC 82%

LITERATURE REVIEW- MONOTHERAPY

 Monotherapy: FLC 800mg/day to 11 pts  54.5% mycologic cure  Acute MR of 18.2% (Menichetti)  Fluconazole 800mg, 1200, 1600mg or 2000mg

alone

 clinical/mycological cure rates of 11%, 37%, 62% & 62%

respectively (Milefchik, 1997)

 Fluconazole 600mg in 19 pts: 100% mycological

cure (Moottsikapun, 2003)

RECOMMENDED TREATMENT: HIVMA/IDSA, 2008



Induction: 1st 2 weeks 1- Ampho.B (0.7mg/kg) + 5FC (A1) 2- Ampho.B + FLC 400mg (BII) 3- Ampho.B alone (BII) 4- FLC 400mg to 800mg + 5 FC (CII)

METHODOLOGY

 Study design

• cohort study

STUDY AREA

 MTRH, in Eldoret, serves a population of ~ 13

millions

 Inpatients in the medical wards 1 & 2

STUDY POPULATION

 HIV-infected pts presenting with neurological

signs & symptoms.

 Case definition: laboratory: either +ve Indian ink,

csf culture or CRAG.

 Consecutive sampling of cases  Choice of antifungal: availability, ampho.B

preferred to FLC.

 Study period: June 2007 to February 2008

SAMPLING SPECIFICATION

 Inclusion criteria  Admitted in the medical wards at MTRH  Positive test for HIV-1 antibody  First episode of AIDS associated cryptococcus

meningitis based on either positive Indian ink, CSF culture or positive CRAG.



Age ≥13 yrs

EXCLUSION CRITERIA

1.

Patients on treatment for tuberculosis

2.

Patients / Parents / guardian declined to participate

3.

Receiving both drugs during the 1st 14 days

SAMPLE SIZE

 Successful treatment of AIDS associated

cryptococcus meningitis (survival & mycological) at two weeks varies

• using amphotericin (0.7 -1 mg/d)alone is

estimated at ~ 68% (range 38% to 100%)

• and ~ 47% (range 11% to 87%) for high dose

fluconazole (400mg to 800mg)

[Chen, Larsen, Milefchik, Saag, Van der Horst] 24, 27, 48.

SAMPLE SIZE

 Sample size (n) = [p1 (1 - p1) + p2 (1 - p2)] x Cp, power

(p1 - p2)

 Where (n) is the sample size

• P1 is the response rate of amphotericin B (~ 68%)
• P2 is the response rate of fluconazole (~ 47%)
• Cp, power is a constant defined by the level of

statistical significance (0.05) and Power (80%) values chosen in this study; it equates to 7.9.

• CONT. SAMPLE SIZE



Therefore;

(n) = [0.68(1 - 0.68) + 0.47(1 - 0.47)] / (0.68 - 0.47)2 x 7.9 = 0.2176 + 0.2491 / (0.21)2 x 7.9 = 0.4667 / 0.0441 x 7.9 = ~10.583 x 7.9 = ~ 84 patients

 Thus, each treatment arm should have ~ 42

patients each.

DATA COLLECTION METHODS

 A data collection tool administered  Captured demographic data / contacts / parents /

guardian / drug history

 History & clinical exam: special emphasis on the

central nervous system: signs of meningism

 Laboratory data: CSF fungal studies; day 1 &14

(only if culture positive on day 1)

 Side effects of treatment drugs

FLOW OF PATIENTS

 All patients with neurologic signs/sy admitted to the

medical wards by admitting medical team

 LP done after fundoscopy by researcher. Sample taken

to the laboratory immediately

 HIV positive patients meeting case definition of

cryptococcus meningitis started on treatment by admitting physician

 Cases consecutively recruited by the researcher after

consenting, within 24 hrs.

 Followed daily for fourteen days. Researcher repeated

LP on day fourteen, for fungal cultures if initially positive.

MANEUVERS

 Consent signing  Lumbar puncture: CSF

(a) 3mls: microbiological examination: Gram stain, Ziehl-Neelsen (ZN) stain and India ink stain (b) 2mls: biochemical tests: protein & sugar estimation (c) 4mls: Cultures: blood agar and chocolate agar (in presence of 5-10% CO2), Sabouraud agar (without antibiotics) & MIGIT . (d) 2mls for CRAG

 Done at admission and day fourteen (for culture +ve only)

 Culture on blood agar were incubated at 37°C

and sabouraud agar was incubated at room temperature.

 Observed for a period of 3 week  Adequate humidity within the incubator (Petri

dish with water within.)

 Culture for acid fast bacillus (AFB): MIGIT:

3WKS.

DATA ENTRY AND ANALYSIS

 The data was entered into the computer by the

researcher

 Double data entry for quality control using EpiData

v2.1

 A biostatistician consulted to assist in data analysis.  Analyzed using SPSS version 14 and SAS [Statistical

Analysis System] Institute version 9.1.

 A p-value of < 0.05 was considered significant in all

analyses

DATA ANALYSIS

 Descriptive statistics (frequency listing) used to

analyze categorical variables (sex, negative / positive, normal /altered mental status)

 Mean, median, range & standard deviation used to

analyze continuous variables: (age, temp, CSF glucose / protein)

 Chi square test used to asses association between

categorical variables & predictor variables :

 T-test used to compare means of continuous variables  Fisher’s exact test used in a 2x2 contingency table

when cell counts < 10.

CONT

 Odds ratio to asses characteristics that are

associated with negative CSF at 2 weeks. Analyzed at 95% CL

 Multivariate logistic-regression model was used

to assess association between binary outcomes (mycologic failure/success) and a set of variables during therapy.

ETHICAL CONSIDERATION

 IREC approval  Consent signing  Next best available treatment given  Other recommended practices.  No risk in participating

FIGURE 1: SCREENING AND ENROLLMENT OF PARTICIPANTS IN

TREATMENT OUTCOMES OF AIDS ASSOCIATED CRYPTOCOCCUS MENINGITIS STUDY AT MTRH, ELDORET.

273 HIV-infected patients with signs and symptoms of meningitis 5 patients with 2nd episode of cryptococcal meningitis excluded 91 patients with 1st episode cryptococcal meningitis included 177 patients with negative CSF studies for cryptococcal meningitis excluded 42 patients initiated on Amphotericin B 50mg daily for 14 days 49 patients initiated on fluconazole 800mg daily for 14 days

TABLE 1 SUMMARY OF BASELINE CHARACTERISTICS OF 91 PATIENTS WITH AIDS ASSOCIATED CRYPTOCOCCUS MENINGITIS TREATED WITH

AMPHOTERICIN B AND FLUCONAZOLE.

Characteristics Amphotericin B (42) Fluconazole (49) P value Age (yrs): Median (Range) 38 (28 – 65) 34 (20 – 67) 0.5775 Males; no. (%) 23 (54%) 27 (55%) 0.1850 Weight : mean : range (kg) 45.3 (39 – 82) 51.2 (41 – 78) Known HIV status, presenting with CM for the first time. 16 (39%) 17(35%) 0.2656 Patients on ARVs 12 (28.5%) 11 (22%) 0.2483 CD4+ count (cells/mm3)*1 : Median (Range) 55 (0 – 256) 83 (0 – 188) 0.1783 CSF Indian ink positive: number (%) CSF Culture positive for cryptococcus: no (%) CSF CRAG positive: number (%) 14 (33%) 17 (40.5%) 42 (100%) 19 (38%) 14 (28.6%) 49 (100%) 0.6966 0.3922 CSF Glucose: mean (range) in mmol/L 2.18 (0.3 -3.2) 2.4 (0.4 -5.3) 0.4884 CSF Proteins: mean (range) in mg/dl 73 (24 - 647 ) 61 (20 - 425 ) 0.2584 Mental status: Altered: number (%) 14 (33%) 13 (26%) 0.6966 Symptoms and signs Headache present: number (%) Fever present: number (%) Meningism: number (%) Focal neurologic deficits: number (%) 38 (90.5%) 13 (31%) 22 (52.4%) 7 (16.7%) 41 (83.7%) 16 (33%) 19 (38.8%) 5 (10.2%) 0.0520 0.5963 0.3769 0.4472

*1: CD4+ count was available for 13 patients in the amphotericin group and 11 patients in the fluconazole group.

TWO WEEKS CLINICAL AND MYCOLOGICAL OUTCOME

Outcome Amphotericin B group Fluconazole group P value Mycological: Conversion of Positive CSF culture to Negative 16/17(94%) 9/14(64.3%) 0.019 Clinical: Headache present: no (%) Fever present: no (%) Meningism: no (%) Combined clinical response 5/42 (12%) 0/42 (0%) 1/42 (2.4%) 32/42 (76%) 9/49(18%) 2/49 (4%) 3/49 (2.0%) 25/49 (51%) 0.252 0.739 1.00 0.0115 Combined clinical and mycological response 31/42 (73.8%) 22/49 (45%) 0.0101 Glasgow Coma Scale i. Unchanged/ improved

• ii. Worse

13/14 (~93%) 1/14 (~7%) 11/13(~85%) 2/13(~15%) 0.279 0.279 Deaths within first 14 days 4/42 (9.5%) 10/49 (20.4%) 0.1513

meningitis at MTRH, Eldoret

PREDICTORS OF CONVERSION OF POSITIVE CSF CULTURE TO

NEGATIVE, TWO (2) WEEKS AFTER INITIATING ANTIFUNGAL TREATMENT Characteristic Odds ratio (95% CI ) P value Absence of fever 1.915 (0.142 – 25.847) 0.624 Negative CSF Indian ink 0.414 (0.045 – 3.770) 0.434 Treatment with amphotericin B 6.357 (1.092 – 37.000) 0.019 Initial CD4 count > 50cell/L 0.999 (0.977 - 1.021) 0.924 Normal initial CSF glucose > 2.5mmol/L 0.305 (0.065 - 1.443) 0.134 Normal initial CSF proteins 0.988 (0.970 – 1.007) 0.206

PREDICTORS OF ACUTE MORTALITY IN HIV-INFECTED PATIENTS

PRESENTING WITH 1ST EPISODE CRYPTOCOCCAL MENINGITIS AT

MTRH

Characteristic Odds Ratio (95% CI) P value Initial altered mental status 1.38 (0.56 – 3.41) 0.4788 Initial negative CSF Indian ink 0.79 (0.33 – 1.87) 0.5903 Initial positive CSF culture 1.70 (0.71 - 4.07) 0.2322 Initial treatment with amphotericin B 0.73 (0.4 – 1.32) 0.2994 Initial treatment with Fluconazole 1.03 (0.43- 2.48) 0.9451 Male gender 1.38 (0.58 - 3.25) 0.4620

ADVERSE EVENTS

 In ampho. B only  Chills and rigors – 23/42 (55%)  Increase in creat. 3/42 (7%)  Low potassium. 2/42(4.8%)

DISCUSSION

 Frequency of crypto meningitis; HIV-infected

with neurol. Findings (34%) july 2007 to february 2008.

 No signif. Diff. from SSA estimates  Methodological diff. with the KNH studies; 5.2-

5.3 %

 Higher than 12% initial reported at MTRH

TWO WEEKS TREATMENT OUTCOME

 Clinical; 76% vs. 51% in the ampho / FLC

(p=0.0115)

 Similar to findings from other studies  Mycological success; 94% vs 64.5% (p=0.019).

Higher than what documented; short duration of incubation

 Combined: 73.8% vs 45% (p=0.035)

DISCUSSION

 Acute mortality: overall 15.4. (west 5-15%)  Ampho. Grp- 9.5%, FLC 20.4% (p= 0.109)

PREDICTORS OF OUTCOME

 clinical & mycological success; ampho. B

(p=0.019)

 Acute mortality: none; Had small numbers

CONCLUSION

 Clinical and mycological outcomes better in

patients treated with ampho. B

 Acute mortality lower in ampho. B

RECOMMENDATION

 Hospital to procure & recommend use of

amphotericin B during induction

LIMITATION

 Short incubation period for fungal cultures

REFERENCES

1.

Panther LA, Sande MA: seminar, Respiratory infection.1990 Jun: 5(2):138-45

2.

TI - Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. AU - Lee SC; Dickson DW; Casadevall A. SO - Hum Pathol 1996 Aug;27(8):839-47. )

3.

Steenbergen JN, Casadevall A. AIDS Clin Care. 2005 Feb ;17 (2):13-4 15754451 (P,S,E,B)

4.

Vidal Jose. Epidemiology of HIV CNS Disease in Brazil and South America. Second HIV Infection and the Central Nervous System: Developed and Resource- Limited Settings, Venice, Italy, 2007.

5.

Jow JO, Mativo PM, Musoke SS: East African Medical journal 2007 Feb: 84(2):67-

• 76. Clinical and laboratory characteristics of hospital patients with neurological

manifestations of HIV/AIDS at Nairobi Hospital

• 6. Currie, B. P., and A. Casadevall. 1994. Estimation of the prevalence of

cryptococcal infection among patients infected with the human immunodeficiency virus in New York City. Clin. Infect. Dis. 19:1029-1033

• 7. Hajjeh, R. A., L. A. Conn, D. S. Stephens, W. Baughman, R. Hamill, E.

Graviss, P. G. Pappas, C. Thomas, A. Reingold, G. Rothrock, L. C. Hutwagner, A. Schuchat, M. E. Brandt, and R. W. Pinner. 1999. Cryptococcosis: Population-based multistate active surveillance and risk factors in human immunodeficiency virus-infected persons. Cryptococcal Active Surveillance Group. J Infec Dis. 179:449-454.

• 8. TI - Emergence of cryptococcal disease: epidemiologic perspectives 100 years

after its discovery. AU - Hajjeh RA; Brandt ME; Pinner RW SO - Epidemiol Rev 1995;17(2):303-20.

• 9. Clark, R. A., D. Greer, W. Atkinson, G. T. Valainis, and N. Hyslop. 1990.

Spectrum of Cryptococcus neoformans infection in 68 patients infected with human immunodeficiency virus. Rev Infect Dis. 12:768-77.

• 10. Palella, F. J., Jr., K. M. Delaney, A. C. Moorman, M. O. Loveless, J. Fuhrer,
• G. A. Satten, D. J. Aschman, S. D. Holmberg, and HIV Outpatient Study
• Investigators. 1998. Declining mortality and morbidity among patients with

advanced human immunodeficiency virus infection. N. Engl. J. Med. 338:853-860.

• 11. French, Neil a,b; Gray, Katherine b; Watera, Christine b; Nakiyingi, Jessica b;

Lugada, Eric b; Moore, Michael a,b; Lalloo, David a; Whitworth, James A. G. b; Gilks, Charles F. a. Cryptococcus infection in a cohort of HIV-1 infected Ugandan

• adults. AIDS. 16(7):1031-1038, May 3, 2002.
• 12. P Imwidthaya, N Poungvarin. Cryptococcosis in AIDS. Postgrad Med J 2000;76:85–

88

• 13. F A Odhiambo, E M Murage, W Ngare, J O Ndinya-Achola East Afr Med J. 1997 Sep

;74 (9):576-8 9487434 (P,S,G,E,B) Detection rate of Cryptococcus neoformans in cerebrospinal fluid specimens at Kenyatta National Hospital, Nairobi

• 14. Franc¸ oise Dromer, Simone Mathoulin-Pe´ lissier, Odile Launay, Olivier

Lortholary, the French Cryptococcosis Study Group. Determinants of Disease Presentation and Outcome during Cryptococcosis:The CryptoA/D Study. PLoS Medicine: February 2007 | Volume 4 | Issue 2 | e21

• 15. Mitchell TG, Perfect JR (1995) Cryptococcosis in the era of AIDS—100 yea9rs after

the discovery of Cryptococcus neoformans. Clin Microbiol Rev 8: 515–548. 2.

• 16. j. Clin Microbiol. 1993 Jan ;31 (1):97-101 8417038 (P,S,E,B)

• 17. Mitchell, T. G., and J. R. Perfect. 1995.

Cryptococcosis in the era of AIDS—100 years after the discovery of Cryptococcus neoformans.

• Clin. Microbiol. Rev. 8:515–548.
• 18. Antifungal drug susceptibility of Cryptococcus

neoformans from clinical sources in Nairobi, Kenya. Christine C. Bii , Koichi Makimura , Shigeru Abe , Haruhiko Taguchi , Olga M. Mugasia , Gutura Revathi , Njeri C. Wamae and Shigeru

• Kamiya. Mycosis: Volume 50 (1) Pages 25 - 30
• 19. Hajjeh, R. A., M. E. Brandt, and R. W. Pinner.
• 1995. Emergence of cryptococcal. disease:

epidemiologic perspectives 100 years after its

• discovery. Epidemiol. Rev. 17:303–320

• 20. M. A. PFALLER, J. ZHANG, S. A. MESSER, M.
• E. BRANDT, R. A. HAJJEH, C. J. JESSUP, M. TUMBERLAND, E. K. MBIDDE,AND M. A.
• GHANNOUM. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jan. 1999, p. 169–171
• 21. Saag, M. S., W. G. Powderly, G. A. Cloud, P. Robinson, M. H. Grieco, P. K. Sharkey, S. E. Thompson, A.
• M. Sugar, C. U. Tuazon, J. F. Fisher, H. N, J. M. Jacobson, R. Hafner, and W. E. Dismukes. 1992.

Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal

• meningitis. N. Engl. J. Med. 326:83-89.

22 . clin. Infectiou D’se: 2008 jun 1:46(11): 1694-701 23 Oxford jnl of medicine vol89(7) 499-504. Bergman & Karstaerdt

• 24. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome.

National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials

• Group. AU - van der Horst CM; Saag MS; Cloud GA; Hamill RJ; Graybill JR; Sobel JD; Johnson PC;

Tuazon CU; Kerkering T; Moskovitz BL; Powderly WG; Dismukes WE. SO - N Engl J Med 1997 Jul 3;337(1):15-21

• 25. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal
• meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. AU - Saag MS;

Powderly WG; Cloud GA; Robinson P; Grieco MH; Sharkey PK; Thompson SE; Sugar AM; Tuazon CU; Fisher JF; et al. SO - N Engl J Med 1992 Jan 9;326(2):83-9.

• 26. TI - Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole

monotherapy: the role of fluconazole resistance and immune reconstitution.U - Bicanic T; Harrison T; Niepieklo A; Dyakopu N; Meintjes G. SO - Clin Infect Dis. 2006 Oct 15;43(8):1069-73. Epub 2006 Sep 7.

• 25. Laroche ; B. Dupont ; J.E. Touze ; H. Taelman J.

Bogaerts ; A. Kadio ; P. M'pele ; A. Latif ; P. Aubry J.P. Durbec ; J.F. Sauniere. Cryptococcal meningitis associated with acquired immunodeficiency syndrome (AIDS) in African patients: treatment with fluconazole. Authors: Medical Mycology, Volume 30, Issue 1 1992 , pages 71

• 78
• 26. P Mwaba, J Mwansa, C Chintu, J Pobee,M

Scarborough, S Portsmouth, A Zumla Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J 2001;77:769–773