Challenging Cases in HIV Management.2014

1. Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine at
UCLA
Los Angeles, California
Challenging Cases in HIV
Management
Supported by educational grants from multiple commercial supporters.

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Case 1
 39-yr-old man presents to your clinic having recently been
diagnosed with asymptomatic HIV infection
 He has no past medical history, comorbid conditions
 CD4+ count is 44 cells/mm³ with VL of 135,000 copies/mL
 HIV genotype is wild type
 States he is willing to take whatever you recommend and
has no concerns about dosing frequency or any particular
adverse effects

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DHHS Guidelines May 2014: What to Start
DHHS guidelines. May 2014.
For All Pts, Regardless of BL
VL or CD4+ Count
Only for Pts With Pre-ART
VL < 100,000 c/mL
NNRTI  EFV/TDF/FTC  EFV + ABC/3TC*
 RPV/TDF/FTC
Boosted PI  ATV/RTV + TDF/FTC
 DRV/RTV + TDF/FTC
 ATV/RTV + ABC/3TC*
INSTI  RAL + TDF/FTC
 EVG/COBI/TDF/FTC
 DTG + ABC/3TC*
 DTG + TDF/FTC
*Only for pts who are HLA-B*5701 negative.

Only for those with CD4+ counts > 200 cells/mm3
.

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24th Annual CCO HIV and Hepatitis C Symposium
Case 1: Adherence Concerns
 The patient has been inconsistent with clinic visits
 Although willing to start treatment, he is concerned about
his ability to adhere to therapy

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Expert Panel Discussion
 Deciding between a twice-daily and once-daily regimen is
difficult for a patient at risk of nonadherence
– Twice-daily dosing may be harder to adhere to
– Once-daily dosing may result in greater consequences of
nonadherence
 Dolutegravir offers once-daily dosing with a high barrier to
resistance
– Real-world resistance data are currently lacking
– Experts believe real-world resistance profile of dolutegravir
will resemble that of boosted PI regimens

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Case 1: No Adherence Concerns but
Comorbidity
 Same patient without adherence concerns
 Now has HTN, DM (HbA1c 9.2%), CrCl 70 mL/min,
UA 2+ proteinuria
 Receiving ACE inhibitor and sulfonylurea
 No concerns regarding adherence, dosing, or adverse
effects

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Individualizing First-line Therapy: Specific
Circumstances
Circumstance Agents
No genotype  Use boosted PI
High HIV-1 RNA  Caution with ABC/3TC + ATV/RTV or EFV and with RPV
Renal disease  Caution with TDF, ATV/RTV; monitoring complicated with
COBI and DTG
Dyslipidemia  RAL, DTG, RPV most lipid neutral
CV risk factors  Possible association with ABC, ddI, LPV/RTV
 No data for DRV/RTV, INSTIs, MVC
Pregnancy  Preferred: ZDV/3TC, ABC/3TC, TDF/FTC (3TC) + LPV/RTV
or ATV/RTV
 EFV can be used after first 8 wks
Chronic HBV infection  Preferred TDF + (3TC or FTC)
 Alternative is entecavir
Decreased BMD  Caution with TDF
Psychiatric disease  Caution with EFV

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24th Annual CCO HIV and Hepatitis C Symposium
Case 2: 41-Yr-Old Woman Presents to
Your Emergency Department
 No PMH except 2 wks of increasing fever and headache
 Rapid HIV test: positive
 CD4+ count: 23 cells/mm³; VL: 230,000 copies/mL
 Head CT shows atrophy
 LP with opening pressure 42 mm H2O, 15 cells/μL, glucose
31 mg/dL, protein 98 mg/dL, and positive cryptococcal
antigen and culture
 Pt gradually improves after serial LPs, liposomal
amphotericin B, and 5FC
 Clinically stable at 10 days with plan for discharge on
fluconazole after 2 wks

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24th Annual CCO HIV and Hepatitis C Symposium
Case 2: HIV Treatment
 Willing to come to clinic for follow-up and open to starting
ART whenever recommended
 Resistance genotype: pending
 No other comorbid conditions
 Renal function: normal
 Hepatitis serologies: negative

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Zolopa AR, et al. PLoS One. 2009;4:e5575.
ACTG 5164: Immediate vs Deferred ARVs
During Acute OI
Total
PCP
Bacterial Infection
Other OI
Fungal
Crypto
Mycobacterial
> 1 OI
CD4+ < 50
CD4+ ≥ 50
Death/AIDS Progression (Log OR)
Favors Early
ART
Favors
Deferred ART
0 200.250.5 1.0 2.5 8.0
# Events # Total
54
28
11
42
12
8
8
30
39
15
282
181
41
194
52
41
18
148
196
86

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Makadzange AT, et al. Clin Infect Dis. 2010;50:1532-1538.
Zimbabwe: Early vs Deferred Therapy for
Cryptococcal Meningitis
Primary endpoint: 3-yr mortality:
88% vs 54% (P < .006)
Fluconazole With d4T + 3TC + NVP
Delayed ART (after 10 wks of Rx)
Early ART (within 72 hrs)
1.00
0.75
0.50
0.25
0
0 200 400 600 800 1000
Pts at Risk, n
Delayed
Early
Time to Death (Days)
26
28
11
4
11
4
10
3
6
3
4
1
Delayed ART
Early ART
SurvivalProbability

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Boulware D, et al. CROI 2013. Abstract 144.
COAT: Increased Mortality With Early ART
During CM Induction Therapy
 Significantly lower 6-mo
survival with early vs deferred
ART
– Enrollment halted early by
NIAID Africa DSMB
 Mortality associated with
– Altered mental status at study
entry (Glasgow Coma Scale
score < 15; HR: 3.0; P = .05)
– Patients with CSF WBC
count < 5 cells/mm3
at
randomization (HR: 3.3;
P = .01)
1.0
0.8
0.6
0.4
SurvivalProbability
0 1 2 4 6 8 10 12
Mos From Randomization
Deferred ART
Early ART
70%
55%
P = .03
Deferred
Early
89
88
71
54
65
51
60
47
60
47
58
45
57
44
Pts at Risk, n

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Starting ART in Patients With
Cryptococcal Meningitis
 DHHS guidelines[1]
– In patients with severe cryptococcosis particularly those with
elevated ICP, it may be prudent to delay initiation of ART
until induction (2 wks) or consolidation (10 wks) phase has
been completed
– However, for patient with severe immunosuppression (CD4+
cell count < 50 cells/mm³), earlier initiation may be
necessary (BIII), but one should be prepared to deal with
complications of IRIS, eg, elevated ICP (BIII)
 Southern African HIV Clinicians Society guidelines[2]
– Initiate ART 4-6 wks from diagnosis (not more than 6 wks)
1. DHHS guidelines. February 2013. 2. Southern African HIV Clinicians Society guidelines. 2013.

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24th Annual CCO HIV and Hepatitis C Symposium
Expert Panel Discussion
 ART-naive patients with cryptococcal meningitis present a
unique challenge and a high risk for IRIS
 Current US guidelines do not offer clear-cut recommendations
 Decisions about when to initiate ART must consider both the
risk of IRIS in severely immunocompromised patients and
strategies to ensure the patient can access continuous therapy
after it is started, eg, ADAP enrolment, insurance issues, etc
 In practice, most clinicians begin ART after follow-up in the
clinic
 The choice of ART regimen should account for the potential for
transmitted resistance mutations, the rate of CD4+ recovery,
and assessment of anticipated patient adherence

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Case 2: ART Initiation and Developing
Symptoms
 After approximately 4 wks of cryptococcal therapy, the
patient initiated TDF/FTC + DRV/RTV with good tolerance
and virologic response at 4 and 8 wks (CD4+ cell count:
184 cells/mm³; VL: 132 copies/mL)
 Now complains of 1 wk of increasing frontal headaches
 Laboratories: unremarkable
 Head CT: negative
 LP: opening pressure, 38 mm H2O; 132 cells/mm³ (all
lymphocytes); glucose 48 mg/dL; protein 130 mg/dL; India
Ink positive; CrAg+; culture pending
 Pt states adherence has been very high with all
medications

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24th Annual CCO HIV and Hepatitis C Symposium
Expert Panel Discussion
 Continuing fluconazole with serial LPs or changing to
liposomal amphotericin B ± 5FC with serial LPs are both
good options
 Adding steroids to either treatment is also acceptable
 The decision to continue fluconazole or switch to liposomal
amphotericin B ± 5FC should be based on confidence in
the patient’s adherence to the initial fluconazole regimen

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Cryptococcal IRIS
 Paradoxical and unmasking occur
 15% to 30% of patients (onset 4-10 wks post-ART
initiation)
 Risk factors:
– Higher virus burden
– Lower CD4+ cell count
– Low CSF inflammation
 Dx depends on temporal relationship to ART
– Elevated ICP (> 25 mm H20) in ~ 65%
Bahr N, et al. Curr Infect Dis Rep. 2013;15:583-593.

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DHHS: Managing Cryptococcal Meningitis
IRIS
 DHHS guidelines:
– Appropriate management of IRIS is to continue both ART
and antifungal therapy and reduce elevated ICP, if present
(AII)
– In patients with severe symptoms of IRIS, some specialists
recommend a brief course of glucocorticosteroids (CIII), but
data-based management strategies have not been
developed
DHHS guidelines. February 2013.

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SAHIVCS: Managing Cryptococcal
Meningitis IRIS
 Mild symptoms
– Increase fluconazole dose to 1200 mg and LP
– If culture positive, reinduction; if negative, reduce fluconazole dose
– Serial LPs
 Severe symptoms
– Induction treatment (including amphotericin B + fluconazole)
– If culture positive, continue induction; if negative, return to fluconazole
– Serial LPs
– Prednisone 1 mg/kg/d PO or dexamethasone IV consider if severe or
persistent despite serial LPs (ideally only after cultures confirmed negative
unless life-threatening IRIS)
– (Duration of steroids not specified, but for TB IRIS, it is recommended to titrate
after 2-4 wks based on response; usually requires 2-4 mos of treatment)
Southern African HIV Clinician Society guidelines. 2013.

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Case 3: 49-Yr-Old Asymptomatic Man
Recently Diagnosed With HIV
 Presents to your clinic
 Not currently in a relationship
 History of controlled HTN, DM
– CrCl ~ 60 mL/min; UA 2-3+ proteinuria (on ACE-I); HbA1c
~ 7% (on metformin)
 HBsAg+, HCV antibody negative
 CD4+ cell count: repeatedly ~ 250 cells/mm³
 Plasma HIV-1 RNA: 50,000-75,000 copies/mL
 Genotype: wild type
 HLA-B*5701: negative

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Case 3: HIV Treatment
 Patient started TDF/FTC + ATV/RTV with good tolerance
and viral suppression more than 18 mos
 Although DM and HTN remained controlled, patient
experienced progressive decline in CrCl to 40-50 mL/min
with stable 2-3+ proteinuria
 HBV DNA undetectable

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24th Annual CCO HIV and Hepatitis C Symposium
Expert Panel Discussion
 Changing to a TDF- and ABC-sparing regimen (plus
entecavir) is an optimal strategy for this patient in light of
his renal disease and cardiovascular risk
 Consider switching from ATV/RTV to an INSTI
– Should be aware of potential drug–drug interactions
between dolutegravir and metformin
 ABC should be used with great caution in patients at high
risk for CVD
– Clinical data on the risk of myocardial infarction in patients
on ABC are mixed

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D:A:D Study: NRTIs and Risk of MI
Adjusting for eGFR does not change ABC MI finding:
Adjusted RR 1.89 (95% CI: 1.46-2.44; P = .0001)
Adjusting for eGFR does not change ABC MI finding:
Adjusted RR 1.89 (95% CI: 1.46-2.44; P = .0001)
*Recent use = current or within the last 6 mos.
Recent exposure*: yes/no
Cumulative exposure: per yr

RelativeRiskofMI(95%CI)
Lundgren J, et al. CROI 2009. Abstract 44LB. Sabin C, et al. Lancet. 2008;371:1417-1426.
1.9
1.5
1.2
1.0
0.8
0.6
#PYFU:
#MI:
ZDV ddl ddC d4T 3TC ABC TDF
138,109
523
74,407
331
29,676
148
95,320
405
152,009
554
53,300
221
39,157
139

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FDA Meta-Analysis of Randomized
Controlled Trials
Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.
Study
ACTG 368
COL30305
ACTG 372A
ACTG A5202
ABCDE
FIRST
ACTG 5095
ACTG A5110
STEAL
NEFA
CNAF3007
CNA30017
ESS40003
CNAA3006
NZTA4002
CNA109586
CNAB3014
ESS40002
BIOCOMBO
CNAB3002
EPZ104057
CNA30024
CNAC3005
ESS100327
CNAC3003
CNAB3001
Mantel Haenszel
ABC, n/N (%)
0/140 (0)
0/58 (0)
4/116 (3.45)
2/923 (0.22)
0/115 (0)
0/93 (0)
6/758 (0.79)
0/48 (0)
4/178 (2.25)
1/149 (0.67)
1/96 (1.04)
0/80 (0)
0/51 (0)
0/102 (0)
0/150 (0)
0/192 (0)
0/165 (0)
1/85 (1.18)
1/167 (0.6)
0/91 (0)
1/343 (0.29)
1/324 (0.31)
1/262 (0.38)
0/137 (0)
1/156 (0.64)
0/49 (0)
Non-ABC,
n/N (%)
0/143 (0)
0/29 (0)
3/113 (2.65)
5/925 (0.54)
2/122 (1.64)
0/89 (0)
1/376 (0.27)
0/53 (0)
1/175 (0.57)
0/311 (0)
1/91 (1.1)
2/127 (1.57)
0/44 (0)
0/103 (0)
3/152 (1.97)
1/193 (0.52)
0/164 (0)
0/166 (0)
1/66 (0.6)
0/93 (0)
0/345 (0)
0/325 (0)
0/264 (0)
1/141 (0.71)
0/80 (0)
1/50 (2)
Non-ABC Worse ABC Worse
Risk Difference
(95% CI)*
0 (-2.73 to 2.87)
0 (-13.79 to 6.38)
0.79 (-4.77 to 6.54)
-0.32 (-1.08 to 0.33)
-1.64 (-6.17 to 1.64)
0 (-4.49 to 4.13)
0.53 (-0.75 to 1.5)
0 (-7.01 to 8.34)
1.68 (-1.27 to 5.17)
0.67 (-0.55 to 4.04)
-0.06 (-5.23 to 4.9)
-1.57 (-5.61 to 3.38)
0 (-9.09 to 7.08)
0 (-3.79 to 3.88)
-1.97 (-5.94 to 0.58)
-0.52 (-3.12 to 1.55)
0 (-2.42 to 2.4)
1.18 (-1.14 to 7.08)
0 (-3.15 to 3.11)
0 (-4.35 to 4.19)
0.29 (-0.86 to 1.75)
0.31 (-0.91 to 1.86)
0.38 (-1.13 to 2.29)
-0.71 (-4.27 to 2.21)
0.64 (-4.21 to 3.6)
-2 (-11.05 to 5.37)
0.01 (-0.26 to 0.27)†
-5 -2.5 -1 0 1 2.5 5
Risk Difference (%)
*Exact 95% CIs of risk difference.
†
CI-based on MH-RD methodology.

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D:A:D Revisited: Is Abacavir Associated
With Cardiovascular Events?
Sabin C, et al. CROI 2014. Abstract 747LB.
Use of ABC Over Time,
Overall, and by CVD Risk
Adjusted RR for MI in Those
Currently Receiving ABC,
Overall, and by CVD Risk
Presentation of D:A:D ABC findings
ThoseWithGivenCVD
RiskReceivingABC(%)
2000
2001
2002
2003
2004
2005
2006
2007
2008
2010
2011
2009
2012
35
30
25
20
15
10
5
0
Low CVD risk
Mod CVD risk
High CVD risk
CVD risk U/K
Total cohort
5
4
3
2
1
0.7
Overall Pre-March
2008
Post-March
2008
Not Currently on ABC
Events/PYs
Rate (95% CI)/
100 PYs
600/295642
0.20 (0.19-0.22)
425/169417
0.25 (0.23-0.28)
175/126225
0.14 (0.12-0.16)
Currently on ABC
Events/PYs
Rate (95% CI)/
100 PYs
341/71917
0.47 (0.42-0.52)
247/40833
0.61 (0.53-0.68)
94/31084
0.30 (0.24-0.36)

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24th Annual CCO HIV and Hepatitis C Symposium
NRTI-Sparing Options
Regimen Strengths Weaknesses
LPV/RTV + EFV (A5142)[1]
Good efficacy
High pill count
Large study
Poor tolerability
Lipid elevation
LPV/RTV monotherapy[2-5]
Simplicity
Tolerability
Concerns regarding efficacy
DRV/RTV monotherapy[6,7]
Simplicity
Tolerability
Mixed results for efficacy
LPV/RTV + 3TC[8]
Decrease toxicity
Efficacy
No data with preferred PI/RTVs
DRV/RTV + RAL[9,10]
Good tolerability Twice daily
Concerns regarding efficacy in naives
ATV BID + RAL[11]
No booster Poor tolerability
Poor efficacy
DRV/RTV + MVC (R5-only pts)[12]
INSTI sparing Concerns regarding efficacy
Study recently stopped
1. Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. 2. Delfraissy JF, et al. AIDS. 2008;22:385-393. 3. Cameron DW, et
al. J Infect Dis. 2008;198:234-240. 4. Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40:280-287. 5. Nunes EP, et al.
HIV Clin Trials. 2009;10:368-374. 6. Arribas J, et al. AIDS. 2010;24:223-230. 7. Katlama C, et al. AIDS. 2010;24:2365-2374.
8. Cahn P, et al. EACS 2013. Abstract LBPS7/6. 9. Raffi F, et al. CROI 2014. Abstract 84LB. 10. Taiwo B, et al. AIDS.
2011;25:2113-2122. 11. Kozal MJ, et al. HIV Clin Trials. 2012;13:119-130. 12. http://clinicaltrials.gov/show/NCT01345630.

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24th Annual CCO HIV and Hepatitis C Symposium
1. Boyd M, et al. Lancet. 2013;381:2091-2099. 2. Paton N, et al. IAS 2013. Abstract WELBB06.
Patientsat96Wks(%)[2]
60
64
56
73*74*
44
Good HIV
Disease Control
HIV-1 RNA
< 50 Copies/mL
*P < .0001 vs LPV/RTV monotherapy.
LPV/RTV + 2-3 NRTIs (n = 426)
LPV/RTV + RAL (n = 433)
LPV/RTV monotherapy (n = 418)
SECOND-LINE and ERNEST Studies in
Pts With VF on First-line NNRTI Regimen
100
80
60
40
20
0
100
80
60
40
20
0
0 12 24 36 48
HIV-1 RNA < 200 copies/mL (ITT)[1]
82.6% (78.1-87.1)
80.8% (76.1-85.5)
P = .59
r/LPV + 2-3 N(t)RTI
r/LPV + RAL
Participants(%)
Wks