Challenging Cases in HIV Management.2014

Eric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical CenterProfessor of MedicineDavid Geffen School of Medicine at UCLALos Angeles, California

Challenging Cases in HIV Management

Supported by educational grants from multiple commercial supporters.

clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium

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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


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.


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


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


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


Individualizing First-line Therapy: Specific CircumstancesCircumstance 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


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


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


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 # Total54

28

11

42

12

8

8

30

39

15

282

181

41

194

52

41

18

148

196

86


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, nDelayed

Early

Time to Death (Days)

2628

114

114

103

63

41

Delayed ARTEarly ART

Su

rviv

al P

rob

abili

ty


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

Su

rviv

al P

rob

abil

ity

0 1 2 4 6 8 10 12

Mos From Randomization

Deferred ARTEarly ART

70%

55%

P = .03

DeferredEarly

8988

7154

6551

6047

6047

5845

5744

Pts at Risk, n


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.



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


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




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


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.


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.


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.


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


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



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


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/noCumulative exposure: per yr

Rel

ati

ve

Ris

k o

f M

I (9

5%

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

138,109523

74,407331

29,676148

95,320405

152,009554

53,300221

39,157139


FDA Meta-Analysis of Randomized Controlled Trials

Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.

Study

ACTG 368COL30305ACTG 372AACTG A5202ABCDEFIRSTACTG 5095ACTG A5110STEALNEFACNAF3007CNA30017ESS40003CNAA3006NZTA4002CNA109586CNAB3014ESS40002BIOCOMBOCNAB3002EPZ104057CNA30024CNAC3005ESS100327CNAC3003CNAB3001

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 5Risk Difference (%)

*Exact 95% CIs of risk difference.†CI-based on MH-RD methodology.


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

Th

os

e W

ith

Giv

en

CV

D

Ris

k R

ec

eiv

ing

AB

C (

%)

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

10

20

11

20

09

20

12

35

30

25

20

15

10

5

0

Low CVD riskMod CVD riskHigh CVD riskCVD risk U/KTotal cohort

543

2

10.7

Overall Pre-March2008

Post-March2008

Not Currently on ABC

Events/PYsRate (95% CI)/ 100 PYs

600/2956420.20 (0.19-0.22)

425/1694170.25 (0.23-0.28)

175/1262250.14 (0.12-0.16)

Currently on ABC

Events/PYsRate (95% CI)/ 100 PYs

341/719170.47 (0.42-0.52)

247/408330.61 (0.53-0.68)

94/310840.30 (0.24-0.36)


NRTI-Sparing OptionsRegimen Strengths Weaknesses

LPV/RTV + EFV (A5142)[1] Good efficacyHigh pill countLarge study

Poor tolerabilityLipid elevation

LPV/RTV monotherapy[2-5] SimplicityTolerability

Concerns regarding efficacy

DRV/RTV monotherapy[6,7] SimplicityTolerability

Mixed results for efficacy

LPV/RTV + 3TC[8] Decrease toxicityEfficacy

No data with preferred PI/RTVs

DRV/RTV + RAL[9,10] Good tolerability Twice dailyConcerns regarding efficacy in naives

ATV BID + RAL[11] No booster Poor tolerabilityPoor efficacy

DRV/RTV + MVC (R5-only pts)[12] INSTI sparing Concerns regarding efficacyStudy 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.


1. Boyd M, et al. Lancet. 2013;381:2091-2099. 2. Paton N, et al. IAS 2013. Abstract WELBB06.

Pat

ient

s at

96

Wks

(%

)[2]

6064

56

73*74*

44

Good HIVDisease 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

00 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)RTIr/LPV + RAL

Par

tici

pa

nts

(%

)

Wks

Health & Medicine

Challenging Cases in HIV Management.2014