2/26/2009

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BHIVA ‘Best of CROI’ Feedback MeetingsOpportunistic infections

Hepatitis Co-infectionsMalignancies

February 2009, Manchester, Birmingham, London

Opportunistic infection/hepatitis co-infection & malignancies

�Opportunistic infection:� Primary prophylaxis for cryptococcal infection

� Prednisolone for TB-IRIS

� Early vs. late HAART in cryptococcal meningitis

� Early vs. late HAART in TB (SAPIT)

� Once daily NVP vs. EFV in TB

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Opportunistic infection/hepatitis co-infection & malignancies

�Malignancies� KS-IRIS in SSA

� Infection and non-infection related NADC

�Hepatitis co-infection� Hyaluronic acid

Primary prophylaxis of cryptococcal disease using fluconazole prophylaxis� Aim:

� To determine if routine fluconazole prophylaxis in HIV

infected Ugandan adults can reduce invasive cryptococcal

disease and all cause mortality

� Design:

� Double blind randomised placebo controlled trial

� Fluconazole 200mg 3x week compared with identical placebo

� Enrolment Sept 2004-Jan 2008: follow up till May 2008

� Primary outcomes:

� Incidence of invasive cryptococcal disease

� All cause mortalityRosalind Parkes-Ratanshi #32

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Trial profile

Assessed for eligibility

(n=5337)

Not enrolled

CD4>200=3299

Abnormal LFT = 69

CrAg positive =59

Refractory candida=48

Pregnant/breast feeding=6

Medically unfit=53

Refused or unable to consent=68

Did not attend for enrolment =131

Moved out of area=11

Other =74

Enrolled

(n=1519)

Fluconazole

(n=760)

Placebo

(n=759)

Inclusion criteria:•Adult >15y•ART naïve•CD4 <200 cells/mm3

Exclusion criteria:•LFTs >3x ULN•Previous/active cryptococcal disease•Positive serum CRAG•Moribund/bed bound

Matched:•Age/sex (60% F)

•CD4 count (Median 111)•WHO stage

Rosalind Parkes-Ratanshi #32Median time to starting ART 11 weeks

Follow-up at 4 weeks and then 8 weekly

Results summary

Fluconazole Placebo Adjusted HR P value

Cryptococcal

event

Pre-ARV 1

Post-ARV 0

11

7

18.74 95% CI

(2.50; 140.67)P=0.004

All cause

mortality100 98

0.98 95% CI

(0.74; 1.30)

P=0.89

Oesophageal

candida8 55

7.1, 95% CI

(3.38;14.92)P<0.0001

Oral and

vaginal candida28 163

6.83, 95% CI

(4.54; 10.27), P<0.001

Adverse events

stopping trial

drug

58 581.06 95% CI

(0.74; 1.53)P=0.74

CD4 Cryptococcal

events

(% of CD4 group)

< 50 13 (3.3%)

50-99 4 (1.3%)

100-149 2 (0.6%)

150-199 0

Rosalind Parkes-Ratanshi #32Main AE abnormal LFTs: = between arms/no association with NVP use

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Conclusions� Significant reduction in cryptococcal disease, oesophageal

candidiasis, and oral/vaginal candidiasis� Rate of cryptococcal infection was low because of:

� Exclusion of CrAg positive at screening � Early ART� Only 50% had CD4 count less than 100 cells/mm3

� No difference in all-cause mortality � Only 7 deaths attributed to cryptococcal disease

� Implications for clinical practice � In African clinical practice unlikely to have CrAg screening

and limited access to ART and effective cryptococcal treatment

� Fluconazole prophylaxis may have potentially even greater impact in this setting

Rosalind Parkes-Ratanshi #32

Prednisolone for TB-IRIS

� Background: occurs in 8-43%, anecdotal reports steroids beneficial but concerns may worsen KS/CMV

� Hypothesis: 4w prednisolone would reduce need for medical interventions, be safe and not ↑ infections

� Design:� Prednisolone or placebo, randomised double blind

� 1.5mg/kg for 2 weeks then 0.75mg/kg for 2 weeks

� Follow-up assessments: 1, 2, 4, 8, and 12 weeks

� Open-label at physicians’ discretion if clinical deterioration/relapse

� Primary endpoint:� Cumulative number of days and OPD therapeutic procedures

(arbitrarily counted as 1 additional day), ITT analysisMeintges #35

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Case definition & enrolment

287 screened (June

2005-Dec 2007)

Alternative diagnosis = 44

Did not fulfil case definition = 65

Exclusion criterion = 55

Unwilling/unable to consent = 13

Enrolled = 110

Placebo = 55

Died (2), defaulted (6),

rifampicin resistance (6),

discontinued study drug (3)

Prednisolone = 55

Died (3), defaulted (0),

rifampicin resistance (4),

discontinued study drug (1)

Case definition:Prior to ART•Evidence of TB•Initial improvement with TB treatment•Still on TB treatment•RIF-sensitive strainWithin 3m of starting ART•New/recurrent TB symptoms•Presence of >1 of: ↑LN, cold abscess, serous effusions, lung infiltrates

Exclusion criteria:KSPrior ARTLife-threatening IRIS

Time to initiation of open label prednisone

50

40

30

20

0

10

% initia

ting o

pen label pre

dnis

one

200 40 60 80

Placebo arm

Prednisone arm

P= 0.03

4 Week Visit

Days Meintjes G, et al

Oral Abstract 34

Matched groups at BL apart from length of time from starting TB treatment to starting ART: longer in prednisolone arm

35 patients initiated OL prednisolone;

20 in placebo arm and 15 in prednisolone arm

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Symptom score

Week 4

Week 2

p = 0.001

p = 0.03

n = 55 n = 55

n = 48 n = 54

% P

atie

nts

% P

atie

nts

Meintjes G, et al

Oral Abstract 34

In relation to week 0

Chest Radiograph score

Week 4

Week 2

p = 0.002

p = 0.02

n = 30 n = 39

n = 31 n = 39

% P

atie

nts

% P

atie

nts

Ultrasound score demonstrated no differences at week 2 or 4 Meintjes G, et al

Oral Abstract 34

In relation to week 0

Independent CXR and USS LN

evaluation

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Primary endpoint/AE

Placebo arm

(n=55)

Prednisolone

arm (n=55)P-value

Total days hospitalised 463 282

Total OPD procedures 31 27

Cumulative 1o endpoint

(median, IQR)3 (0-9) 1 (0-3) 0.046

Cumulative number of days and OPD therapeutic procedures

(counted as 1 additional day), ITT analysis

Meintges #35

Placebo Arm Prednisone Arm P-value

Death on Study 2 (4%) 3 (5%) 0.65

Corticosteroid side effects* 18 (33%) 12 (22%) 0.20

Corticosteroid side effectswhile

on study drug

3 (5%) 8 (15%) 0.11

Infections 30 (55%) 36 (65%) 0.24

Severe Infections** 4 (7%) 2 (4%) 0.40

Conclusions

� Prednisolone reduced need for medical interventions (days hospitalised and outpatients procedures combined)

� Consistent benefit maximal in 1st 4 weeks:

� Symptom score, CRP, radiology score, Karnofsky score

� Benefits shown despite crossovers to OL prednisolone

� No excess of steroid complications

� 4 weeks may have been too short and tapering dose probably better

Meintges #35

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Early vs. deferred HAART in cryptococcal meningitis� Primary aim: to determine if immediate ART vs.

delayed ART improves survival and decreases risk of relapse in CM, a leading cause of death in SSA

� Study design:� 2 groups: (AMP B/5-FLU generally unavailable)

� Fluconazole 800mg od orally for 10w starting NVP/D4T/3TC <72h

� Fluconazole 800mg od orally for 10w starting NVP/D4T/3TC at end of 10w

� After 10 weeks all patients maintained on fluconazole 200mg daily and HAART

� All patients received NVP/D4T/3TC Makadzange #36cLB

Early vs. deferred HAART in cryptococcal meningitis

� Study design (cont’d)� Inclusion criteria:

� +ve CRAG or Indian Ink stain in CSF

� Exclusion criteria:� Previous diagnosis/treatment CM� Current ARV� Medications interacting with FLU (e.g., RIF-based regimens)� Major co-morbidities

� LP’s at 0, 2, 4, 10 and more frequently if required

� Patients:� N=26 early treatment group –23 completed till endpoint

reached� N=28 late treatment group – 27 completed till endpoint

reached

Makadzange #36cLB

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Mortality was primarily early

0 200 400 600Days to death

Delayed Early

0 200 400 600

0

5

10

Fre

qu

en

cy

Makadzange T, et al

Oral Abstract 72LB

Treatment Group Univariate Model

Hazard Ratio (95%

CI)

Age, sex, and CD4

Count-adjusted

Model HR(95% CI)

Delayed Treatment

Group

Early Treatment

Group

Reference

2.2 (1.06 – 4.58)

Reference

2.36 (1.12 – 4.97)

Early vs. late

treatment group

Mortality rate 87%

vs. 37% (p=0.002)

Median survival 35d

vs. 274 days (log

rank p-value 0.028)

Survival Estimates Stratified by Treatment Group

0.00

0.25

0.50

0.75

1.00

0 200 400 600 800

Time to death (in days)

Delayed Early

Comparison of Kaplan-Meir survival estimatesby Treatment Group

P = 0.028

Treatment Group Time Days

0 200 400 600 700

Delayed ART No of patients Dead

No of patients at risk

0

23

10

13

0

13

0

13

1

12

Early ART No of patients Dead

No of patients at risk

0

27

21

6

0

6

1

5

0

5

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Conclusions

� Cause of death presumed to be CM

� Early initiation of therapy resulted in increased mortality rates

� Most mortality occurs in the first 4 weeks

� Completely opposite to ACTG 5164

� Is excess mortality related to IRIS or progression of severe disease?

� Suboptimal therapy (higher doses of FLU or AMP B/5-FLU might be more effective)

� Is it related to interaction with NVP and FLU metabolism?

Makadzange #36cLB

SAPIT: Starting ARV therapy at three Points in TB� Primary objective:

� To determine the optimal time to initiate ARVs in TB patients (TB major entry into ARV programmes)

� Inclusion criteria:

� Smear +ve & on standard TB treatment

� HIV +ve with CD4 count <500cells/mm3

� Women using contraception (EFV being used)

� Endpoints:

� Primary – All-cause mortality

� Secondary - Tolerability, toxicity, VL, CD4, TB outcomes & IRIS rate Karim #36a

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Study design and intervention

� Open-label randomised controlled trial

� 3-arm randomisation:

� ART initiated ASAP after diagnosis during intensive phase of TB treatment

� ART initiated after intensive phase

� ART initiated after TB treatment completed

� TB treatment standard regimen

� Co-trimoxazole prophylaxis given to all patients

� ART was ddI/3TC/EFV given OD with TB-DOT

Integrated arm

Karim #36a

Status of trial at DSMB review in Sept 2008

Screened n=1331

Enrolled n=642

Integrated arm n=429 Sequential arm n=213

Initiated ARVs n=358 Initiated ARVs n=132

Completed trial n=94

(22%): Rest continuing

follow-up

Completed trial n=38

(18%): Rest continuing

follow-up

DSMB stopped

Sequential arm

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Mortality rates per CD4 count

CD4 count

<200 cells/mm3 >200 cells/mm3

Integrated arm•# dead/ py (n)•Mortality rate

23/281 (273)8.2 (5.2-12.3)

2/185 (156)1.1 (0.1-3.9)

Sequential arm•# dead/ py (n)•Mortality rate

21/137 (138)15.3 (9.57-23.5)

6/86 (75)7.0 (2.6-15.3)

Hazard ratio•Cox regression

0.54 (0.34-0.98)P=0.04

0.16 (0.03-0.79)P=0.02

Reduction in mortality rates is present in patients with

CD4 counts above and below 200 cells/mm3

ART adherence and TB and HIV outcomes

Integrated arm Sequential arm

ART adherence >95% pill count

90.4% (311/344) 87.1% (115/132)

VL <1000c/ml at 12 months * (same <400)

91.0% (201/221) 80.0% (72/90)

TB treatment successful

78.4% (258/331) 73.3% (121/165)

Incidence of IRIS * 12.1% (52/249) 3.8% (8/213)

Mortality in MDR-TB patients

20% (3/15) 71% (5/7

63% vs. 62% initiated ART in integrated and sequential arm at time of analysis.

*P<0.05

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Conclusions

� Outcome at halt of sequential arm:

� Deaths: integrated arm (25/429), sequential arm (27/213): HR 0.44 (95% CI 0.25-0.79) P=0.003

� Reduced mortality with integrated treatment (56%)

� TB outcomes similar in both arms

� IRIS rate higher in the integrated treatment arm

� VL suppression higher in the integrated treatment arm

� 2 integrated treatment arms of SAPIT continuing (ASAP vs. after initiation phase)

Karim #36a

Once daily NVP vs. EFV in the treatment of HIV/TB� Aim:

� To compare efficacy and safety of two NNRTI regimens given once daily in patients with TB receiving standard TB treatment (EFV preferred but NVP more available)

� Design:

� Randomised non-inferiority open-label CT

� Randomised to EFV or NVP OD after 8w of TB treatment with ddI/3TC

� NVP given with 2w lead in dose of 200mg

� Standard TB treatment given for 6m

� Patients received DOT for TBSwaminathan #35

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Once daily NVP vs. EFV in the treatment of HIV/TB� Inclusion criteria:

� Age <18y

� Pulmonary or extrapulmonary TB

� No previous anti-TB or HIV treatment

� CD4 <250 cells/mm3

� No major co-morbidity/pregnancy

� Outcomes:

� Favourable TB outcome: -ve cultures last 2m of TB treatment

� Favourable HIV outcome: <400 c/ml at 24w

� Median BL CD4 84 VL 300,000 c/mlSwaminathan #35

ITT analysis at 24w

Response EFV regimen

N=59

NVP regimen

N=57

Favourable HIV

response (<400c/ml)50 (85%)* 38 (67%)

Unfavourable

responses9 19

• Failure 6 11

• Death 0 5

• Lost to F/U 3 3

Favourable TB

response95% 84%

RR of failure with NVP 1.28 (1.03-1.6)*P=0.038 Swaminathan #35

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Conclusions

� 3TC/ddI/EFV good virological outcome (85%) and safety with dosing advantages of ddI over d4T:

� Caveats pregnancy and cost

� OD NVP inferior to EFV when given with RIF containing TB treatment

� 90% of patients had a favourable response to TB treatment

� PCK interactions may partly explain:

� RIF induction with NVP lead-in

� Low trough levels with once daily dosing

Swaminathan #35

Opportunistic infection/hepatitis co-infection & malignancies

�Malignancies� KS-IRS in SSA

� Infection and non-infection related NADC

�Hepatitis co-infection� Hyaluronic acid

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KS-IRIS in Africa

� KS-IRIS more common and more severe in SSA� >HHV-8 antigenic burden with later presentaiton

� Lower CD4 at presentation

� Aim:� Prospectively define incidence/ clinical characteristics and

outcomes of KS-IRIS

� Inclusion criteria:� Bx-confirmed

� No indication for chemotherapy

� No prior HAART/chemotherapy

� All participating in ART comparative trial for initial AIDS-KS treatment

Martin #31

KS-IRISDefinition of KS-IRIS:Any of the following <12w of ART

•Signs and symptoms of inflammation within pre-existing lesions (swelling, tenderness, warmth, paraesthesia, or erythema) •New or worse oedema (facial, genital or limb)•New or worse pulmonary disease (symptom, CXR, or pleural effusion)

N=55Age 34

40% femaleVL Log 5.4

CD4 116 (26-251)No. of skin lesions >50

Baseline At 4 weeks

At 4 weeksBaseline

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KS-IRIS

� Prognosis where no oedema or pulmonary involvement good

� 40% mortality where oedema or pulmonary involvement

Mortality

FINDINGS AT 12 WEEKS

22%

61%

Baseline 2 weeks 12 weeks

8 weeks 48 weeks

40%

Oedema/lung

Localised

Pre

-exi

stin

g le

sio

ns

Conclusions

� KS-IRIS more common and severe in SSA

� Determinants such as CD4 not evaluated yet

� May be difficult to distinguish from KS progression

� Wide spectrum of clinical manifestations

� Mucocutaneous lesions get better with HAART alone but may take time

� Lymphnode manifested by oedema or pulmonary disease:

� Often severe and early chemotherapy required

� May contribute to mortalityMartin #31

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Non-ADC in HIV: infection related vs. unrelated

� Review of NADC over 3 time periods:� Infection related

� Infection unrelated

� Comparison of trends in incidence ratios between HIV +ve/-ve

� Findings:� 7x rate of IRC in HIV+ve:

significant reduction over time period

� Mild increase in HIV –ve but no change over time

Silverberg #30

80x19.4x7.4x

Conclusions

� 46% of all NADC in HIV +ve were infection related; 13% in HIV –ve

� HIV +ve have 7.4 fold higher risk of infection-related NADC

� This is driven by anal cancer and Hodgkin's disease

� Smaller differences in more recent years

� Only 20% increased risk for infection unrelated NADC

� Higher for lung, melanoma, kidney and possibly colorectal; lower for prostate

� CD4 count and stage/prognosis

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Hyaluronic acid as a marker of liver fibrosis progression in SMART� Aims:

� Evaluate impact of treatment interruptions on liver fibrosis progression in both HCV/HBV co-infected and HIV monoinfected using an indirect marker of liver fibrosis – hyaluronic acid (HA)

� Determine if baseline level and change in HA levels were associated with risk of opportunistic disease, non-AIDS death or major liver events

� HCV RNA (>615 IU/mL; denoted HCV+) and/or HBsAg (denoted HBV+)

� Control group of HIV monoinfected participants matched 1:1 on randomization date (+/- 6 months), gender, age (+/- 5 years), treatment group (DC vs. VS), history of alcohol abuse

� HA measured in stored plasma samples at BL and at month 6, 12 (co-infected only) and 24

Mocroft #821

Hyaluronic acid as marker of liver fibrosis progression in SMART� Results:

� 110 (16.3%) were HBV+, 553 (81.9%) were HCV+ and 12 (1.8%) were both HBV+ and HCV+

� Median follow-up 33m for co-infected and 35m for HIV monoinfected controls

� Among co-infected participants:

� 52 (31 in DC, 21 in VS) died from non-AIDS causes

� 29 developed an OI

� 21 developed a major liver event (17 cirrhosis, 4 liver-related deaths)

Similar trends, were seen for liver-related outcomes

ART interruption associated with significant

increase in HA levels in DC arm in co-infected

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Conclusions� Hepatitis co-infected patients had higher median

plasma levels of HA at BL and during follow-up than HIV monoinfected

� Interruption of ART was associated with a significant increase in HA levels at month 6 among co-infected patients randomized to the DC arm but not sustained at months 12 and 24

� Baseline HA was an independent predictor of time to development of non-AIDS death, but not OI disease

� Co-infected patients randomized to the DC arm with a baseline HA level > 75 ng/mL had a 37.5% risk of non-AIDS death after 48 months, whereas the risk was only 5% for those with a baseline HA ≤ 75 ng/mL

Mocroft #821

Hyaluronic Acid as a Prognostic Marker of Hepatic Encephalopathy and Liver-related Death in the EUROSIDA study

� Aim:

� To investigate plasma hyaluronic acid (HA) as a prognostic marker for LRE in HIV/viral hepatitis coinfected patients within the EuroSIDA study

� Design:

� 1377 HIV-1 infected patients were included. Of them were 1309 positive for HBsAg (denoted HBV) and/or anti-HCV (denoted HCV). Control group of 68 HIV-monoinfected patients

Peters #821

2/26/2009

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Conclusions

� Baseline HA level was a very strong predictor of later development hepatic encephalopathy or liver-related death in HIV-1 patients coinfected with HBV +/- HCV

� Patients, who during follow-up experienced a liver-related event, had higher annual increase in HA compared to patients without an event

� High CD4 cell count reduced the risk of increasing HA

� Plasma HA may be useful, either alone or in combination with other non-invasive methods to monitor

� Progression of liver disease in patients with chronic viral hepatitis

Peters #821

Background trials� Powderley 1995 NEJM

� Fluconazole vs. clotrimoxazole alone

� 428 participants, hazard ratio placebo vs. fluconazole 8.5 � 17 cryptococcal events; 2 fluconazole group, 15 control group

� All cause mortality equivalent

� Chetchotisakd 2004 HIV Medicine� Fluconazole vs. placebo

� 90 participants

� 10 cryptococcal events; 3 fluconazole group, 7 control group

� Fluconazole increased survival (HR 4.3 95% CI: 0.9–19.8; p=0.065)

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Baseline characteristicsVariable Fluconazole

(n=760)Placebo (n=759)

Overall (n=1519)

Sex Male n (%)Female n (%)

286 (37.6%)474 (62.4%)

251 (33.1%)508 (66.9%)

537 (35.4%)982 (64.6%)

Age (years) Mean (s.d.) 35.9 (9.1) 35.8 (8.8) 35.8 (9.0)

Age (grouped) <25

25-34

35-4445 +

58 (7.6%)

306 (40.3%)

269 (35.4%)127 (16.7%)

47 (6.2%)

323 (42.6%)

270 (35.6%)119 (15.7%)

105 (6.9%)

629 (41.4%)

539 (35.5%)246 (16.2%)

CD4 count median (IQR) 110 ( 45 – 160) 112 (48 – 157) 111 (46 – 159)

CD4 count (grouped)

1 - 4950 – 99

100 – 149

150 – 199

203 (26.7%)

152 (20.0%)

168 (22.1%)237 (31.2%)

193 (25.4%)

150 (19.8%)

185 (24.4%)231 (30.4%)

396 (26.1%)

302 (19.9%)

353 (23.2%)468 (30.8%)

WHO stage 1

2

34

18 (2.4%)

175 (23.0%)

506 (66.6%)61 (8.0%)

20 (2.6%)

164 (21.6%)

524 (69.0%)51 (6.7%)

38 (2.5%)

339 (22.3%)

1030 (67.8%)112 (7.4%)

Time to initiation of open label prednisolone

35 patients initiated OL prednisolone;

20 in placebo arm and 15 in prednisolone arm

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Peters et al

Peters et al

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Peters et al

Peters et al

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Liver Transplantation in 88 HIV-infected Patients Teicher #834