View
361
Download
1
Category
Preview:
DESCRIPTION
Challenging Cases in HIV Management,including poorly adherent patients,individuals with cryptococcal meningitis,HBV coinfection, and diabetes and hypertension.2014
Citation preview
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
About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com)
DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th 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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th 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
clinicaloptions.com24th 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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th 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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
clinicaloptions.com24th 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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th 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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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)
clinicaloptions.com24th Annual CCO HIV and Hepatitis C Symposium
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.
clinicaloptions.com24th 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.
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
Recommended