2016 sessions: 3 recent advances in oi management
TRANSCRIPT
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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.
Slide credit: clinicaloptions.com
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.
Slide credit: clinicaloptions.com
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
2015-
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
Slide credit: clinicaloptions.com
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
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