Sophia Archuleta, MD Senior Consultant & HIV Program Director National University Hospital, Singapore

1. Education
Clinical Care
Research
Recent advances in the management of
HIV-related opportunistic infections
Sophia Archuleta, MD
Senior Consultant & HIV Program Director
National University Hospital, Singapore
15 October 2016

2. 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

3. #AIDS2016 | @AIDS_conference
High-dose rifampicin TB treatment regimen to
reduce 12-month mortality of
TB/HIV co-infected patients:
The RAFA trial results

4.  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

5. 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
0
0 2 4 6 8 10 12 14 16 18
Mos Since Randomization
Survival

6. 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

7. Study Regimens
NIRTNIRT ICMRICMR
Primary objectivePrimary objective
Reduction in Incidence of failures and emergence of acquiredReduction in Incidence of failures and emergence of acquired
rifampicin resistancerifampicin resistance (ARR)(ARR)
SecondarySecondary objectivesobjectives
Clinical failures, TEADR, sputum conversionClinical failures, TEADR, sputum conversion
Objectives
Along with ART, Cotrimaxozole and high dose pyridoxine

8. 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 > 150CD4 at baseline (< 150 or > 150
cells/mm3).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

9. Sputum smear and culture negativity – by month

10. Modified ITT
Daily
(n=111)
Part Daily
(n=111)
Intermitte
nt
(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)
Intermit
tent
(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

11.  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.

12. 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.

13. 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 death
WHO stage 3/4 disease or death
New TB disease
AE causing OI drug modification
Hospitalizations
New cryptococcal disease
New candida disease
Presumptive severe bacterial infection
Grade 4 AE
Serious AE
Grade 3/4 AE
Grade 4 AE definitely/probably related to prophylaxis
Grade 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

14. 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 Med
Volume 374(6):542-554
February 11, 2016

16. • 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.

17. 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.

18. 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

19. 2015-

20. 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

21. START: Immediate vs Deferred Therapy for
Asymptomatic, ART-Naive Pts
Immediate ART
ART 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 ART
Deferred 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 DSMB
following interim analysis
Slide credit: clinicaloptions.com

22. START: Primary Outcome
Primary Endpoint Immediate ART Deferred ART
No. 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
CumulativePercent
WithEvent
0 6 12 18 24 30 36 42 48 54 60
Mos
INSIGHT START Group. N Engl J Med. 2015;373:795-807.
Lundgren J, et al. IAS 2015. Abstract MOSY0302.
2.5
5.3
Immediate ART
Deferred ART
Slide credit: clinicaloptions.com

23. 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 ART
No. 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 60
Mos
10
8
6
4
2
0
CumulativePercent
WithanEvent
Immediate ART
Deferred ART
Slide credit: clinicaloptions.com

24. 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
CumulativeProbability
ofDeathorSevere
HIV-RelatedIllness(%)
25
20
15
10
5
0
6 12 18 24 30
Deferred ART
Deferred ART + IPT
Immediate ART
Immediate ART + IPT
30-Mo Probability, %
14.1
8.8
7.4
5.7
Slide credit: clinicaloptions.com

25. 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)
Total
PCP
Bacterial infection
Other OI*
Fungal
Crypto
Mycobacterial
> 1 OI
CD4+ < 50
CD4+ ≥ 50
Events, n/N
54/282
28/181
11/41
42/194
12/52
8/41
8/18
30/148
39/196
15/86
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

27. 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

28. • 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

29. 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)

30. Recommendations for ART in Patients
With Selected Opportunistic Infections
Opportunistic 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

31. 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

32. 33 | 1.1 Topic goes here | Project number | 14.12.08 Copyright © 2008 National University Health System

33. Education
Clinical Care
Research
Thank you!
Email: sophia@nus.edu.sg