TREATMENT OUTCOMES OF AIDS

ASSOCIATED CRYPTOCOCCAL MENINGITIS

AT MTRH, ELDORET

DR. CONSTANTINE AKWANALOConsultant 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

o Sub-Saharan Africa; 25-30% (hospital based, lab or PM)o KNH: 5.2% (based on Indian ink)14

o KNH: 5.3% (PM)12

o 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 dosefluconazole (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 ofstatistical 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 INTREATMENT 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 WITHAIDS ASSOCIATED CRYPTOCOCCUS MENINGITIS TREATED WITHAMPHOTERICIN B AND FLUCONAZOLE.

Characteristics Amphotericin B (42) Fluconazole (49) P valueAge (yrs): Median (Range) 38 (28 – 65) 34 (20 – 67) 0.5775

Males; no. (%) 23 (54%) 27 (55%) 0.1850Weight : 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%) 0.2483CD4+ 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%)

0.69660.3922

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%)

0.05200.59630.37690.4472

*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%)

0.2520.7391.000.0115

Combined clinical and mycological response 31/42 (73.8%) 22/49 (45%) 0.0101Glasgow Coma Scalei. Unchanged/ improved

ii. Worse13/14 (~93%)1/14 (~7%)

11/13(~85%)2/13(~15%)

0.2790.279

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 TONEGATIVE, 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 PATIENTSPRESENTING 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

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