CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS Dr. Andrew D. Kambugu Infectious Diseases Institute Makerere University College of Health Sciences Uganda

CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS

Dr. Andrew D. Kambugu

Infectious Diseases InstituteMakerere University College of Health SciencesUganda

Discussion outline

• Why co-infections in this era?

• Challenges of managing co-infections in RLS

• ART initiation in TB studies

• ART initiation in Cryptococcal meningitis

• Conclusions

Patients starting ART at higher CD4+ cell counts overall, but disparities remain

• CD4+ cell count at start of ART (cells/mm3), 20091

• In San Francisco study, overall trends of starting ART at higher CD4+ counts, but pts initiating ART at CD4+ counts >350 cells/mm3 significantly more likely to be white, older, MSM, non-poor, and diagnosed by private provider2

1. Mugglin C, et al. CROI 2012. Abstract 100; 2. Truong HH, et al. CROI 2012. Abstract 139.

307246

225

262252

150 286

118

89145-176

137 140234Low incomeMiddle incomeHigh income

200

185

The HIV care cascade

• Data for adherence to ART for the US represent the proportion of persons withviral suppression

• For Mozambique, the data represent the proportion of persons with adherence to ART, according to responses on questionnaires and pill counts among persons who were retained in care for >1 year (as viral levels were not obtained)

Piot P. and Quinn TC. N Engl J Med 2013;368:2210–8

The challenge of retention is a reality for both developed and developing world settings

0

20

40

60

80

100

Perc

ent o

f per

sons

Diagnosis ofHIV infection

Linkageto care

Retentionin care or eligibilityfor ART

Receiptof ART

Adherenceto ART

United StatesMozambique

Factors involved in the diagnosis, access to care, retention andtreatment of HIV infection in the United States and Mozambique

Forest plot of estimates of mortality at 12 months by individual studies and pooled by region

Gupta A, et al. PLoS ONE 2011;6:e2869

Sub-SaharanAfrica

Asia

Americas

Multi- regional

Sub-Saharan Africa

Asia

Americas

Multi-regional

Combined

0.0 0.1 0.2 0.3 0.4Proportion (95% confidence interval)

0.17 (0.11, 0.24)

0.11 (0.10, 0.13)

0.07 (0.007, 0.20)

0.08 (0.06, 0.10)

0.14 (0.10, 0.20)

0.0 0.1 0.2 0.3 0.4Proportion (95% confidence interval)

Impact of ART on mortality:Ugandan cohort study

• The impact of ART treatment on mortality trends of HIV-positive adults in rural Uganda: a longitudinal population-based study, 1999–2009

Kasamba I, et al. Trop Med Int Health 2012;17:e66–73

All cause mortality in adults aged 15–59 years, pre- and post-ART roll-outAdults 15–99, 1999–2009, entire population

Deaths/pyrs (rate/1000 pyr) Unadjusted RR (95% CI) Adjusted RR (95% CI)All individuals 0–5 years pre ART ART period 1 ART period 2

390/35,626 (10.9)71/7713 (9.2)

225/33,650 (6.7)

P<0.0011

0.84 (0.65–1.08)0.61 (0.52–0.72)

P<0.0011

0.82 (0.64–1.06)0.58 (0.50–0.68)

Stratified by sex Male 0–5 years pre ART ART period 1 ART period 2

Female 0–5 years pre ART ART period 1 ART period 2

185/17,145 (10.8)34/3671 (9.3)

109/15,907 (6.9)

205/18,481 (11.1)37/4042 (9.2)

116/17,743 (6.5)

P<0.0011

0.86 (0.60–1.24)0.64 (0.50–0.80)

P<0.0011

0.83 (0.58–1.17)0.59 (0.47–0.74)

P<0.0011

0.84 (0.58–1.20)0.60 (0.47–0.76)

P<0.0011

0.81 (0.57–1.15)0.57 (0.45–0.71)

Current realities in RLS

• Leaky HIV care cascade: Low ART coverage

• Low CD4 at ART initiation

• Substantial (early) mortality with ART

• Early mortality in ART cohorts driven largely by opportunistic infections (OIs) (co-infection)

The ART eligibility pendulum

Early HIVinfection

Moderate immune

suppressionAdvance immune

suppression

Early ART Start Delayed ART Start

12

3

ART initiation dilemmawith co-infections

IRIS EVENTS

Early ART Start Delayed ART Start

DRUG –DRUG INTERACTIONS

PILL BURDEN

OI RISK

LOSS TO FOLLOW-UP

Baseline 8 weeks 12 weeks

16 weeks 20 weeks 24 weeks

IRIS: A case report summary

Patient attending clinic at IDI - with kind permission of patients and study team

When to start ART in TB:Building on previous studies

A5221/STRIDE CAMELIA1 SAPIT2

N 806 660 429

Sites Africa, Asia, S. America,N. America Cambodia S. Africa

Arms Imm vs. 8–12 weeks Imm vs. 8 weeks Early vs. 24 weeks

Endpoint ↓ Death/AIDS <50 CD4 ↓ Death ↓ Death

Median CD4 (IQR) 77 (36, 145) 25 (11, 56) 150 (77, 254)

1. Blanc IAC, 2010; 2. Abdool Karim SS, et al. N Engl J Med 2010;362:697–706

Effect of ART timing on TB death (CAMELIA) or death/AIDS progression (STRIDE, SAPIT)

0

2

4

6

8

10

12

14

16

18

CAMELIA STRIDE SAPIT

34% ↓ P=0.004

19% ↓ P=0.45

11% ↓ P=0.73

Blanc FX, et al. N Engl J Med 2011;365:1471–81; Havlir DV, et al. N Engl J Med 2011;365:1482–91; Abdool Karim SS, et al. N Engl J Med 2011;365:1492–501

Earlier: 2–4 weeks after TB treatment started

Later: 8–12 weeks after TB treatment started

Significant reduction in death/AIDS amongthose with TB and CD4 <50 cells/mm3


0

5

10

15

20

25

30


34% ↓ P=0.004

42% ↓ P=0.02

68% ↓ P=0.06

Earlier: 2–4 weeks after TB treatment started

Later: 8–12 weeks after TB treatment started

Greater reduction in mortality at lower CD4


0

20

40

60

80

100

120

140

160

0

5

10

15

20

25

30

35

40


Med

ian

base

line

CD4

cell

coun

t

% d

ecre

ase

in d

eath

/AID

S w

ith e

arlie

r ART

P=0.004

P=0.45

P=0.73

ART in TB/HIV co-infection

• Suggested timing of ART initiation in TB/HIV co-infection according to CD4/mm3:

EACS treatment guidelines, Version 6.1, Nov 2012. Available at: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed June 2013

CD4 count, cells/mm3 When to start ART

<100 As soon as possible and ideally within 2 weeks

100–350 As soon as practical, but can wait until after completing2 months TB treatment especially when there are difficulties with drug interactions, adherence and toxicities

>350 At physician discretion

ART initiation within the first2 weeks of Cryptococcal Meningitis is

associated with higher mortality:A Multisite Randomized Trial

David R Boulware, David B Meya, Conrad Muzoora, Melissa A Rolfes, Kathy Huppler Hullsiek, Abdu Musubire, Kabanda Taseera, Henry W Nabeta, Charlotte Schutz, Darlisha Williams, Radha Rajasingham, Joshua Rhein,

Melanie W Lo, Friedrich Thienemann, Andrew Kambugu, Yukari Manabe, Edward N. Janoff, Paul R Bohjanen, Graeme Meintjes, and the COAT Team

Cryptococcal Optimal ART Timing (COAT) TrialClinicaltrials.gov NCT01075152

Possible Benefits of Early ART Possible Risks of Early ART

Possible increased survival

Mortality continues post hospitalization

Mortality decreases after ART initiation following CM (observational)

Incidence of IRIS may be increased

CM IRIS has mortality (20-40%) Unclear if timing of ART is risk for IRIS

Decreased time with low CD4 count

Earlier immune recovery Less time at risk of new OIs & AIDS-

defining events

ART compliance

Altering ART counseling procedures Comprehension of more ill persons More reliance on caregivers Acceptance of need for ART

Improved microbiologic clearance of cryptococcus, decreased CM relapse

Tolerability of ART during CM illness

Earlier improvement of functional status

Shorter reliance on caregivers for activities of daily living

Psychological benefit of starting early therapy in remaining engaged in medical care

Unforeseen drug-drug interactions

Amphotericin does not have any known interactions with ART

Transient renal insufficiency is common

Equipoise:

Existing conflicting dataACTG a5164, median 12 days vs. 42 days after OIs: CROI 20081

– Fewer deaths and new AIDS events, P=0.035 • 14% early ART vs. 24% deferred ART, overall

– N=41 cryptococcal meningitis enrolled– Trend favoring early ART (OR: ~0.2, 95% CI: 0.05 to 1.5)

Zimbabwe RCT, n=54 CROI 20092

– ART at <72 hours (median <24 Hr) (n=26) vs. 10 weeks after CM (n=28)– Fluconazole 800 mg for induction Rx with d4T/3TC/NVP– 88% vs. 54% mortality in immediate vs. delayed ART arms– Per Protocol Analysis, censoring of persons w/delayed ART lost early

Botswana RCT, n=27 no difference 20133

– Early ART more IRIS

1. Zolopa A, et al. PLoS One 2009;4:e5575; 2. Makadzange AT, et al. Clin Infect Dis 2010;50:1532–8;3. Bisson G, et al. Clin Infect Dis 2013;56:1165–73

Randomized strategy trialCryptococcal Optimal ART Timing (COAT) trial

Clinicaltrials.gov NCT01075152

Randomization stratified by site and by altered mental status

COAT trial endpointsPrimary: 1) Survival at 26-weeks Intention to Treat

Secondary:1. Cryptococcal-IRIS incidence through 46 weeks2. Survival through 46 weeks, by time-to-event3. Functional Status (Karnofsky) through 46 weeks4. Microbiologic clearance

a. Quantitative clearance (log10 CFU/mL CSF/day)

b. Sterile CSF culture at 14-days of amphotericinc. Cryptococcal relapse incidence

5. Virologic suppression at 26 weeks6. Tolerability (ART discontinuation ≥3 days)7. Safety (DAIDS Grade ≥3 events)

Enrollment criteria

Inclusion:• HIV-infection• ART naïve• Age >14 years• Cryptococcal meningitis by :

– CSF culture – CSF cryptococcal antigen

• Receiving amphotericin-based therapy

• Informed consent

Exclusion:• Prior cryptococcal meningitis• Pregnancy or breastfeeding• Cannot attend regular visits• Chemotherapy • Inability to take enteral meds• Serious co-morbidities, co-

infections, or laboratory values who should not receive ART immediately or have ART delayed

• Females must use >2 methods of contraception– (fluconazole is teratogenic in 1st

trimester)

Medication and dose 2 weeks ~ 3 weeks 8 weeks 46 weeks

Amphotericin (0.7–1.0 mg/kg/day)

Fluconazole 800 mg daily Continue until CSF is sterile1

Fluconazole 400 mg daily 1

Fluconazole 200 mg daily

Continue for ≥12 months AND until CD4 > 200 cells/mL for ≥ 6 months

Treatment phase Induction Consolidation Secondary Prophylaxis

1Longer duration of consolidation therapy if CSF culture positive at 2-weeks

Therapeutic LPs at diagnosis, Day 7, Day 14, and additional LPs as needed for pressure control

COAT trial treatment for cryptococcal meningitis

CONSORT diagramScreened

N=389

Positive for Cryptococcal meningitis

N=237

RandomizedN=177

147 alternate concomitant diagnosis4 death1 left hospital

33 died15 not eligible6 left hospital against medical advice4 declined2 received HIV care elsewhere

KampalaN=115

MbararaN=35

Cape TownN=27

N=152

N=60

Randomized groupGCS <15 GCS=15 Early ART Deferred ART

13 6 7102 51 51

9 5 426 12 14

2 1 125 13 12

Overall 24 153 88 89

Baseline characteristics by armEarly ART

(n=88)Deferred ART

(n=89)

Age, median (IQR) 35 (28,40) 35 (30,40)

Male gender, n (%) 46 (52%) 47 (53%)

No prior AIDS or TB, n (%) 57 (65%) 59 (66%)

Prior/current TB 22 (25%) 19 (21%)

Prior AIDS illness and TB 9 (10%) 11 (12%)

Altered mental status, n (%) Glasgow Coma Scale <15 at study entry

12 (13.6%) 12 (13.5%)

CD4 cells/mL, median (IQR) 19 (9, 69) 28 (11, 76)

CSF opening pressure, mm H2O 283 (±128) 287 (±148)CSF Quant. culture log10 CFU/mL 5.2 (4.0, 5.6) 4.8 (3.7, 5.5)

CSF WBC <5 cells/mm3 45% 32%

P=0.03

70%

55%

0 1 2 4 6 8 10 12

0.4

0.6

0.8

1.0

Months from randomization

Cum

ulati

ve p

roba

bilit

y of

sur

viva

l

1. Early ART2. Deferred ART

Number at risk1: 88 54 51 47 47 45 442: 89 71 65 60 60 58 57

Overall survival

Number at risk1: 12 3 2 2 2 2 22: 12 8 7 7 7 7 7

Overall survival for those with baseline GCS <15

P=0.05

0 1 2 4 6 8 10 12

0.4

0.6

1.0

0.2

0.8

Cum

ulati

ve p

roba

bilit

y of

sur

viva

l


1. Early ART2. Deferred ART

Number at risk1: 31 17 16 14 14 14 132: 28 26 25 25 25 25 23

Overall survival for those with CSF WBC <5at randomization

P=0.01

0 1 2 4 6 8 10 12

0.2

0.4

0.6

1.0


Cum

ulati

ve p

roba

bilit

y of

sur

viva

l

0.8 1. Early ART2. Deferred ART

Number at risk1: 40 29 27 25 25 24 202: 39 28 24 21 21 21 20

Overall survival for those with CSF WBC ≥5at randomization

P=0.73HR=0.80

0 1 2 4 6 8 10 12

0.2

0.4

0.6

1.0


Cum

ulati

ve p

roba

bilit

y of

sur

viva

l

0.8 1. Early ART2. Deferred ART

IRIS incidenceSubjects with IRIS Events - by treatment group (Adjudicated)

Early ART Deferred ART P-value1

Subjects with at least one event

Definite/Probable CM-IRIS 5 (5.7%) 5 (5.6%) 0.999

Possible CM-IRIS 9 (10.2%) 2 (2.2%)

No CM-IRIS 74 (81.8%) 62 (69.6%)

Died before ART 2 (2.3%) 20 (22.4%)

Overall 88 (100.0%) 89 (100.0%)

Definite/Probable/Possible CM-IRIS of those receiving ART

14 (16.2%) 7 (10.1%) 0.347

1Fisher's exact p-value

Odds Ratio: 1.7 (95% CI: 0.65–4.54) for IRIS with early ART

Causes of death

• Early vs. Deferred:– Cryptococcosis (21 vs. 10)– Septicemia (8 vs. 5)– TB (2 vs. 2) – IRIS-related (1 vs. 2)

Adjudication still ongoing

Time to grade 4 or 5 adverse event (grade 5 events not related to CM)

1. Early ART2. Deferred ARTLog rank P=0.19

0 1 2 4 6 8 10 12

0

0.4

0.6

1.0


Even

t pro

babi

lity

0.2

0.8

Conclusions

• There’s no one-size-fits all model for optimal timing of ART in setting of co-infections as disease-specific studies indicate opposing recommendations

• Earlier ART initiation before onset of OIs may alleviate the complexity of optimal timing

• Disease-specific approaches to ART timing will still inform practice in RLS due to health systems (and resource) constraints

Acknowledgements• The Infectious Diseases Institute

(IDI), Makerere University College of Health Sciences

David MeyaAbdu MusubireHenry Nabetta

• Mbarara University of Science and Technology (MUST)

Conrad MuzooraKabanda Tessera

• University of Minnesota (UMN)David BoulwarePaul BohjanenJoshua Rhein

• University of Cape Town (UCT)Graham Meintjes

Documents

CRYPTOCOCCAL MENINGITIS AND TUBERCULOSIS Dr. Andrew D. Kambugu Infectious Diseases Institute Makerere University College of Health Sciences Uganda