TREATMENT OUTCOMES OF AIDS ASSOCIATED CRYPTOCOCCAL .... Akwanalo.pdf · Double data entry for...
Transcript of TREATMENT OUTCOMES OF AIDS ASSOCIATED CRYPTOCOCCAL .... Akwanalo.pdf · Double data entry for...
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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