2016 Sessions: 3 recent advances in oi management

Education

Clinical Care

Research

Recent advances in the management of HIV-related opportunistic infectionsSophia Archuleta, MDSenior Consultant & HIV Program DirectorNational University Hospital, Singapore15 October 2016

Objectives

At the end of this session, participants will be able to:

•Review new evidence and best practices in the management of major HIV-related opportunistic infections (OIs)

•Describe current antiretroviral treatment recommendations in the setting of acute OIs

#AIDS2016 | @AIDS_conference

High-dose rifampicin TB treatment regimen to reduce 12-month mortality of TB/HIV co-infected patients:

The RAFA trial results

Multicenter, open-label, randomized phase III trial

– Patients in Benin, Guinea, and Senegal

– Primary outcome: mortality at 12 months post-randomization

Slide credit: clinicaloptions.com

RAFA: ART With Standard- vs High-Dose Rifampicin in HIV/TB-Coinfected Pts

Merle CS, et al. AIDS 2016. Abstract WEAB0205LB. Pactr.org. PACTR201105000291300. EDCTP Project Portfolio.

Standard-Dose Rifampicin,† Start ART at Wk 8(n = 258)

Standard-Dose Rifampicin,† Start ART at Wk 2(n = 262)

ART-naive HIV/TB-coinfected adults with CD4+

cell count ≥ 50 cells/mm3

(N = 778)

High-Dose Rifampicin,* Start ART at Wk 8(n = 258)

*Rifampicin 15 mg/kg plus ethambutol, isoniazid, pyrazinamide. †Rifampicin 10 mg/kg plus ethambutol, isoniazid, pyrazinamide.ART regimen: EFV 600 mg + 2 NRTIs.

All pts received rifampicin 10 mg/kg

+ isoniazid

Intensive Phase Continuation PhaseWk 8

http://www.clinicaloptions.com/oncology


RAFA: Survival Outcomes With High- vs Standard-Dose Rifampicin Overall survival not improved, but high-dose rifampicin may benefit severely

immunocompromised pts with no evidence of increased hepatotoxicity

Merle CS, et al. AIDS 2016. Abstract WEAB0205LB.Reproduced with permission.

Overall Survival, % HD RIF, ART Wk 8(n = 249)

SD RIF, ART Wk 8(n = 247)

SD RIF, ART Wk 2(n = 251)

12 mos 90 86 89

18 mos 90 85 88

Mortality for Pts With CD4+ Cell Count < 100 cells/mm3 (n = 159)

SD RIF, ART Wk 8 (n = 47)SD RIF, ART Wk 2 (n = 60)HD RIF, ART Wk 8 (n = 52)

HD RIF vs SD RIF, ART Wk 2: HR: 0.20 (95% CI: 0.04-0.90)

HD RIF vs SD RIF, ART Wk 8: HR: 0.12 (95% CI: 0.03-0.55)

1.00

0.75

0.50

0.25

00 2 4 6 8 10 12 14 16 18

Mos Since Randomization

Surv

ival


Daily is better than thrice-weekly ATT in HIV patients with culture confirmed pulmonary TB –

a RCT from South India (CTRI-476/09, NCT00933790 )

NIRTNIRT

First RCT with a head to head comparison globally of a daily vs intermittent regimen among a pure group of newly diagnosed sputum culture positive rifampicin sensitive TB patients with HIV

Abstract no. WEAB0201

Durban

Study RegimensNIRTNIRT ICMRICMR

Primary objective Primary objective Reduction in Incidence of failures and emergence of acquired Reduction in Incidence of failures and emergence of acquired rifampicin resistance rifampicin resistance (ARR)(ARR)

SecondarySecondary objectives objectives Clinical failures, TEADR, sputum conversion Clinical failures, TEADR, sputum conversion

Objectives Along with ART, Cotrimaxozole and high dose pyridoxine

NIRTNIRT ICMRICMR

Design • Open label, prospective, active comparator parallel armOpen label, prospective, active comparator parallel arm• Stratification: Sputum smear grading ( 0 ,1+ and 2+ and 3+) Stratification: Sputum smear grading ( 0 ,1+ and 2+ and 3+)

CD4 at baseline (< 150 or > CD4 at baseline (< 150 or > 150 cells/mm3).150 cells/mm3).

• Age group : > 18 years • HIV-infected with newly

diagnosed sputum smear + or Xpert-MTB Rif + PTB

• Living within 30 -50 kms radius,

• Willing for house visits, surprise checks and give informed consent.

Study population

• Known hypersensitivity to Rifampicin,

• RR/MDR-TB, culture neg, NTM at Baseline or ATT> 1month

• Pregnancy and lactation at initial presentation, Patients on second line ART.

• Moribund, or seriously Ill patients or uncontrolled co-morbid conditions

INCLUSION EXCLUSION

Sputum smear and culture negativity – by month

Modified ITT

Daily (n=111)

Part Daily (n=111)

Intermittent

(n=109)

Outcomes Available 98 95 95

Favourable 88 (90%)

74(78%)

73 (76%)

Unfavourable 10 21 22

ARR among failures 0 0 4

ICMRICMRNIRTNIRT

*p=0.0156 comparing daily vs intermittent , Chi square value calculated is 6.11 (II interim chi square -5.11) , Daily vs part daily – p=0.02

Efficacy Analysis

TB outcome at end of 6 months

Daily (n=111)

Part Daily (n=111)

Intermittent

(n=109)

Outcomes Available 89 84 83

Favourable 85* 72 71*

Unfavourable 4 12 12

DSMB stopped enrollment as study goals have been achieved with the p value crossed the Obrien Fleming’s boundaries at the second interim anlaysis and ARR being limited to the intermittent regimen

RR of unfavorable response in intermittent regimen =2.53 (95% CI 1.24-5.16)

p=0.04

Prospective, randomized trial conducted in Zimbabwe, Malawi, Uganda, and Kenya

– Primary endpoint: mortality at 24 wks


REALITY: Enhanced OI Prophylaxis at ART Initiation in Immunocompromised Pts

Hakim J, et al. AIDS 2016. Abstract FRAB0101LB.

Enhanced Prophylaxis initiated at time of ART†

(n = 906)

Standard Prophylaxis initiated at time of ART‡

(n = 899)

ART-naive HIV-infected adults and children older than 5 yrs of age with CD4+ cell counts

< 100 cells/mm3

(N = 1805)

Additional randomizations conducted in factorial fashion*

*Raltegravir added to ART for 12 wks; food supplementation for 12 wks.†Cotrimoxazole, isoniazid/vitamin B6 300/25 mg/day for 12 wks (IPT), fluconazole 100 mg/day for 12 wks, azithromycin 500 mg/day for 5 days, albendazole 400 mg (single dose).‡Cotrimoxazole, IPT added after 12 wks (except in Malawi). In both prophylaxis regimens, cotrimoxazole and IPT given at half doses if younger than 12 yrs of age.



REALITY: Mortality Benefit With Enhanced OI Prophylaxis for Pts Initiating ART

1. Hakim J, et al. AIDS 2016. Abstract FRAB0101LB.2. Kityo C, et al. AIDS 2016. Abstract FRAB0102LB.

3.3 lives saved for every 100 treated with enhanced prophylaxis[1]

Additional REALITY factorial randomization assessed mortality for ART initiation with 2 NRTIs + NNRTI + RAL vs 2 NRTIs + NNRTI[2]

– Addition of RAL to standard 3-drug ART did not affect all-cause mortality at 24 or 48 wks

Deaths, %[1]Enhanced

Prophylaxis (n = 906)

Standard Prophylaxis

(n = 899)

HR (95% CI) P Value

Wk 24* 8.9 12.2 0.73 (0.54-0.97) .03

Wk 48 11.0 14.4 0.75(0.58-0.98) .04

*Primary endpoint.



REALITY: Additional Secondary Outcomes Favor Enhanced OI Prophylaxis

Hakim J, et al. AIDS 2016. Abstract FRAB0101LB.Reproduced with permission.

WHO stage 4 disease or deathWHO stage 3/4 disease or deathNew TB disease

AE causing OI drug modification

Hospitalizations

New cryptococcal disease

New candida diseasePresumptive severe bacterial infection

Grade 4 AE

Serious AE

Grade 3/4 AE

Grade 4 AE definitely/probably related to prophylaxisGrade 4 AE definitely/probably/possibly related to prophylaxis

Favors Enhanced Prophylaxis Favors Standard Prophylaxis

.006

.007

.01

.01

.02

.04

.06

.07

.35

.21

.60

.21

.97

0.3 0.5 0.7 1.0 1.5 2.0

HR (Enhanced Prophylaxis:Standard Prophylaxis)

P Value


Original Article Adjunctive Dexamethasone in HIV-Associated

Cryptococcal Meningitis

Justin Beardsley, M.B., Ch.B., Marcel Wolbers, Ph.D., Freddie M. Kibengo, M.Med., Abu-Baker M. Ggayi, M.Sc., Anatoli Kamali, Ph.D., Ngo Thi Kim Cuc, M.D., Tran Quang Binh, M.D., Ph.D.,

Nguyen Van Vinh Chau, M.D., Ph.D., Jeremy Farrar, D.Phil., Laura Merson, B.Sc., Lan Phuong, M.D., Ph.D., Guy Thwaites, Ph.D., Nguyen Van Kinh, M.D., Ph.D., Pham Thanh

Thuy, M.D., Ph.D., Wirongrong Chierakul, M.D., Ph.D., Suwatthiya Siriboon, M.D., Ekkachai Thiansukhon, M.D., Satrirat Onsanit, M.D., Watthanapong Supphamongkholchaikul, M.D.,

Adrienne K. Chan, M.D., Robert Heyderman, Ph.D., Edson Mwinjiwa, C.O., Joep J. van Oosterhout, M.D., Ph.D., Darma Imran, M.D., Hasan Basri, M.D., Mayfong Mayxay, M.D., David

Dance, F.R.C.Path., Prasith Phimmasone, M.D., Sayaphet Rattanavong, M.D., David G. Lalloo, M.D., Jeremy N. Day, Ph.D., for the CryptoDex Investigators

N Engl J MedVolume 374(6):542-554

February 11, 2016

• Kaplan–Meier survival estimates for all patients (Panel A) and for those in Africa (Panel B) and Asia (Panel C) during the 6 months of follow-up.

• By 10 weeks (the cutoff for the primary outcome), 106 of 224 patients (47%) in the dexamethasone group and 93 of 226 (41%) in the placebo group had died.

• At 6 months, the estimated risks of death were 57% and 49%, respectively.

Quantitative CSF Fungal Counts

The decrease in CSF fungal counts, as measured in colony-forming units (CFU) per milliliter, during the first 14 days was significantly slower among patients in the dexamethasone group than among those in the placebo group.

Conclusions• Dexamethasone did not reduce mortality

among patients with HIV-associated cryptococcal meningitis

• Associated with slower rates of CSF clearance, more adverse events and disability than was placebo

• Trial stopped early by DSMB

When to Start Therapy

Drug toxicity Preservation of limited

Rx options Risk of resistance (and

transmission of resistant virus)

↑ potency, durability, simplicity, safety of current regimens

↓ emergence of resistance ↓ toxicity with earlier therapy ↑ subsequent treatment options Risk of uncontrolled viremia Near normal survival if CD4+ > 500 ↓ transmission

Early ARTDelayed ART

Slide from Joel E. Gallant, MD, MPH

START: Immediate vs Deferred Therapy for Asymptomatic, ART-Naive Pts

Immediate ARTART initiated immediately

following randomization(n = 2326)

INSIGHT START Study Group. N Engl J Med. 2015;373:795-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.

Deferred ARTDeferred until CD4+ cell count ≤ 350 cells/mm3,

AIDS, or event requiring ART(n = 2359)

HIV-positive, ART-naive adults with CD4+ cell

count > 500 cells/mm3 (N = 4685)

Study closed by DSMBfollowing interim analysis



START: Primary Outcome

Primary Endpoint Immediate ART Deferred ARTNo. with event (%) 42 (1.8) 96 (4.1)

Rate/100 PY 0.60 1.38

HR (immediate/deferred) 0.43 (95% CI: 0.30-0.62; P < .001)

57% reduced risk of serious events or death with immediate ART

68% of primary endpoints occurred in pts with CD4+ cell counts > 500 cells/mm3

10

8

6

4

2

0

Cum

ulat

ive

Perc

ent

With

Eve

nt

0 6 12 18 24 30 36 42 48 54 60Mos

INSIGHT START Group. N Engl J Med. 2015;373:795-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.

2.5

5.3

Immediate ARTDeferred ART



START: Serious AIDS Events 72% reduced risk of serious AIDS events with immediate ART

TB one of 3 most common events, 14% in iART vs 20% in dART

INSIGHT START Study Group. N Engl J Med. 2015;373:795-807. Lundgren J, et al. IAS 2015. Abstract MOSY0302.

Serious AIDS Events Immediate ART Deferred ARTNo. with event (%) 14 50

Rate/100 PY 0.20 0.72

HR (immediate/deferred) 0.28 (95% CI: 0.15-0.50; P < .001)

0 6 12 18 24 30 36 42 48 54 60Mos

10

8

6

4

2

0

Cum

ulat

ive

Perc

ent

With

an

Even

t

Immediate ARTDeferred ART



0

TEMPRANO: Immediate vs Deferred ART Initiation and IPT Delivery for African Pts

TEMPRANO ANRS 12136 Study Group. N Engl J Med. 2015;373:808-822.

Mos From Randomization

Cum

ulat

ive

Prob

abili

ty

of D

eath

or S

ever

e H

IV-R

elat

ed Il

lnes

s (%

) 25

20

15

10

5

06 12 18 24 30

Deferred ARTDeferred ART + IPTImmediate ARTImmediate ART + IPT

30-Mo Probability, %14.18.87.45.7



Favors Deferred ART

Zolopa AR, et al. PLoS ONE. 2009;4:e5575.

ACTG 5164: Immediate vs Deferred ART in Patients With Acute Opportunistic Infections

Risk of AIDS Progression/Death by Entry Diagnoses, Log OR (95% CI)

TotalPCP

Bacterial infectionOther OI*

FungalCrypto

Mycobacterial> 1 OI

CD4+ < 50CD4+ ≥ 50

Events, n/N54/28228/18111/41

42/19412/528/418/18

30/14839/19615/86

0 0.25 0.5 1.0 8.0 202.5

Favors Early ART

*Includes 13 pts with toxoplasmosis

Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response

ART in HIV/TB Co-infection Trials SAPIT - ART initiated within 2 weeks was beneficial in

reducing mortality among all patients with TB whose baseline CD4 counts were < 200

ACTG5221 and CAMELIA did not show a reduction in AIDS or death, except among patients with baseline CD4 counts below < 50

Earlier initiation of ART appears to be beneficial in patients with TB in advanced HIV

Increase in the risks of IRIS and of adverse events that lead to the switching of ART drugs

In patients with higher CD4 counts, the benefit of early initiation of ART is less clear

• Early ART in HIV-infected adults with newly diagnosed TB improves survival in those with CD4 < 50

• Although this is associated with a 2-fold higher frequency of TB-IRIS

• In patients with CD4 > 50, evidence is insufficient to support or refute a survival benefit conferred by early versus delayed ART initiation

Uthman et al 2015

RCT earlier ART initiation (1- 2 weeks after diagnosis, median 8 days) or deferred ART initiation (5 weeks after diagnosis, median 36 days)

The 26-week mortality with earlier ART initiation vs deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients], P = 0.03)

This increase was most pronounced during the first 8 to 30 days of study (P = 0.007)

Recommendations for ART in Patients With Selected Opportunistic InfectionsOpportunistic Infection DHHS Recommendation for ART

Pneumocystis pneumonia Start ART within 2 wks of PCP diagnosis

Toxoplasma gondii encephalitis Many clinicians start ART within 2-3 wks Based on A5164 study, in which the 282 pts

with OIs included 13 pts (5%) with toxoplasmosis

Mycobacterium tuberculosis Start ART within 2 wks if CD4+ < 50 cells/mm3, by 8-12 wks for all others

Consider DDIs, adherence support

Cryptosporidiosis Start ART as part of OI management

Cryptococcal meningitis Consider delaying ART until after antifungal induction (2 wks) or induction/consolidation (10 wks)

DHHS Guidelines. November 2015 Slide credit: clinicaloptions.com


Summary

• ART initiation in the setting of acute OIs is dependent on the level of immunosuppression and type of OI

• Treatment is prevention with early ART being the most effective way to prevent OIs

Education

Clinical Care

Research

Thank you!

Email: [email protected]

2016 Sessions: 3 recent advances in oi management

Health & Medicine

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