Slide 1 of 41 IAS–USA Eric S. Daar, MD Michael S. Saag, MD Antiretroviral Therapy: A Case-Based...
Transcript of Slide 1 of 41 IAS–USA Eric S. Daar, MD Michael S. Saag, MD Antiretroviral Therapy: A Case-Based...
Slide 1 of 41
IAS–USA
Eric S. Daar, MD Michael S. Saag, MD
Antiretroviral Therapy:A Case-Based Panel Discussion
(Part II)
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 2 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. IAS–USA
Eric S. Daar, MDProfessor of Medicine
David Geffen School of Medicineat UCLA
Switch for Toxicity
Slide 3 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
A 45 year old African American woman presents to your clinic having been diagnosed with HIV and severe thrush/onychomycosis• Clinically stable on fluconazole• History mild depression, diabetes, HTN and
dyslipidemia on ACE, metformin, atorvastatin• Laboratories
– HBsAg and HCV antibody negative– AST/ALT- 75/82 IU/mL, CrCl~70 mL/min (relatively stable),
HgbA1C=7.1%, UA- 3+ proteinuria– CD4= 78 cells/uL, HIV-RNA= 219,000 copies/mL– HIV genotype- WT
• Ready to start antiretrovirals if recommended with no specific concerns regarding various adverse events but would prefer simple regimen
Slide 4 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Patient starts TDF/FTC/EFV, TMP/SMX and continues other meds. At 2 months CD4 190 cells/uL, HIV RNA 220 copies/mL, but patient has increasing depression and persistent neurologic symptoms thought to be associated with EFV. CrCl is repeatedly ~50-41 mL/min. She is seeing psych and on antidepressants.
A 45 year old African American woman• H/O depression, DM, HTN, dyslipidemia, CKD• CrCl- 70mL/min with proteinuria• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL
Slide 5 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Switch TDF/FTC + EFV to RPV (N=49)
Mills A, et al. 51st ICAAC; Chicago, IL; September 17-20, 2011. Abst. H2-794c.
RPV mean Ctrough in ECHO/THRIVE
Slide 6 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Patient switched to TDF/FTC + ATV/r and continued other meds. After 4 months neurologic symptoms resolved, CD4 250 cells/uL, HIV RNA <40 copies/mL but patient CrCl has gradually declined (now off TMP/SMX) to 40-45 mL/min with no change in other labs or UA (glucosuria and proteinuria).
A 45 year old African American woman• H/O depression, DM, HTN, dyslipidemia, CKD• CrCl- 40-45 mL/min with proteinuria (HLA-B5701-negative)• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL
Slide 7 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
D:A:D Study: NRTIs and Risk of MI
Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 44LB. Sabin C, et al. Lancet 2008;371:1417-26.
ZDV ddI ddC d4T 3TC ABC TDF#PYFU: 138,109 74,407 29,676 95,320 141,009 41,300 39,157#MI: 413 331 148 405 554 221 139
1.9
1.5
1.2
1
0.8
0.6Recent Exposure*: yes/noCumulative Exposure: per year
**
Rela
tive
Risk
of M
I (95
% C
I)
Adjusting for eGFR does not change ABC MI finding:Adjusted RR 1.89; 95% CI (1.46 – 2.44; P=0.0001)
* Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddC)
Slide 8 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MI
Bedimo R, et al. 2011 Jul 1;41(1):84-91.
Unadjusted HR of AMI for each PY of exposure to each one of the categoriesAdjusted for estimated GFR prior to regimen onset (by MDRD method)
ABC TDF Both ABC and TDF
Haz
ard
ratio
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
NRTI in last regimen during obs. period
Slide 9 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Cumulative Exposure to ARVs and Risk of CKD
Cockcroft-Gault (n=225)MDRD (n=277)CKD-EPI (n=258)INSIGHT def (n=129)Censoring ATVCensoring TDFCensoring boosted PI
Tenofovir
Indinavir
Atazanavir
Lopinavir/r
0.9 1.4Mocroft A, et al. AIDS. 2010; 41:1667-78
Slide 10 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
A4102: ABC/3TC vs. TDF/FTCMedian Change in Creatinine Clearance
ABC/3TC
ATV/r
ABC/3TC
TDF/FTC
TDF/FTC
EFVN= 191 173 217 191 186 157 200 178
Wk 48, p<0.001Wk 96, p<0.001
Wk 48, p=0.83Wk 96, p=0.14
Week 96
Week 48
p-values: ABC/3TC vs. TDF/FTC
Ch
ang
e in
Cal
cula
ted
C
reat
inin
e C
lear
ance
, (m
L/m
in)
>25% decr(%): 3 2 7 6 2 3 1 3Daar ES, et al. Ann Intern Med 2011; 154:445-456.
Slide 11 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Patient switched to ABC + 3TC + DRV/r with good tolerance, sustained viral suppression and improvement in CrCl to consistently between 50 and 41 mL/min.
A 45 year old African American woman• H/O depression, DM, HTN, dyslipidemia, CKD• CrCl- 50-41mL/min with proteinuria (HLA-B5701-negative)• CD4 nadir= 78 cells/uL and BL HIV RNA 212,000 copies/mL
Slide 12 of 41
IAS–USA
Michael S. Saag, MDProfessor of Medicine
Director, Center for AIDS ResearchUniversity of Alabama at Birmingham
When to Use New ARV Drugs?
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 13 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Assume dolutegravir is now available or approved by FDA
Slide 14 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Case 1¨ 34 yo woman diagnosed with HIV 4 weeks ago¨ Initial Lab values
— CD4 82 cells/uL— VL 76,000 c/mL
¨ No other significant medical condition¨ Genotype reveals wild type virus
Slide 15 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
GS-7340: US-120-0104: TFV Levels
0 6 12 18 41
1
10
100
1000
GS-7340 8 mgGS-7340 25 mgGS-7340 40 mgTDF 300 mg
79%86%
96%
AUC
TDF 300 mg
89%94%
98%
Cmax
Time (hr)
TF
V p
lasm
a co
nce
ntr
atio
n (
ng/
ml)
Ruane CROI 2012 #103
Slide 16 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Treatment Group N
Median DAVG11
[log10 c/mL]P value vs.
TDF 300 mg
Placebo 7 -0.01 0.038
TDF 300 mg 6 -0.48 -
GS-7340 8 mg 9 -0.76 0.216
GS-7340 25 mg 8 -0.94 0.017
GS-7340 40 mg 8 -1.08 0.01
GS-7340: US-120-0104 Primary Efficacy Endpoint
Ruane CROI 2012 #103
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TDF GS-7340 GS-7340 GS-73400
50
100
X ~1X~7X
>20X
300 mg 40 mg25 mg8 mgIntr
acel
lula
r T
FV
-DP
(µ
M*h
)
GS-7340: Intracellular (PBMC) TFV-DP
Ruane CROI 2012 #103From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Tenofovir and COBI Interact with Distinct Renal Transport Pathways
• The active tubular secretion of tenofovir and the effect of COBI on creatinine are mediated by distinct transport pathways in renal proximal tubules
Anion Transport Pathway
OAT3
MRP4
Blood(Basolateral)
Urine(Apical)
Active Tubular Secretion
ATPOAT1N
NN
N
NH2
OPO
O--O
Cation Transport Pathway
Blood(Basolateral)
Urine(Apical)
Active Tubular Secretion
OCT2H+MATE1
COBI
N
N
NH2O
CreatinineTenofovir
Ray A, et al. Antimicro Agents Chemo 2006;3297-3304Lepist E, et al. ICAAC 2011; Chicago. #A1-1741
Slide 18 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 19 of 41
Cobicistat
Gallant IAS 2012
ATV + Cobi plus TFV/FTC vs ATV + Ritonavir plus TFV/FTC :Study DesignStudy 114
Cobicistat
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 20 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012
Slide 21 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012
Slide 22 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012
Slide 23 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012 From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 24 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012
Slide 25 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
QUAD vs TFV/FTC/EFV vs ATV plus TFV/FTC:
EFZ/TDF/FTC QD + DTG plus ABC/3TC FDC Placebo
DTG 50mg plus ABC/3TC FDC QD+ EFZ/TDF/FTC Placebo
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EFZ/TDF/FTC: 81%
EFZ/TDF/FTC QD
• DTG 50mg +ABC/3TC QD was statistically superior to EFZ/TDF/FTC at Week 48 (primary endpoint)• Subjects receiving DTG +ABC/3TC achieved virologic suppression faster than EFZ/TDF/FTC, median
time to HIV-1 RNA <50c/mL of 28 days (DTG +ABC/3TC) vs 84 days (EFZ/TDF/FTC), P<0.0001
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 27 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Difference in Proportion (95% CI)
(DTG - EFZ/TDF/FTC)
EFZ/TDF/FTC QD (N=419)
Slide 28 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
EFZ/TDF/FTC QD
EFZ/TDF/FTC208 cells/mm3
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 29 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
EFZ/TDF/FTC QD(N=419)
Slide 30 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
EFZ/TDF/FTC QD(N=419) (%)
*EFZ/TDF/FTC: Most commonly reported events were CNS, gastrointestinal and rash
**DTG+ABC/3TC: 1 drug hypersensitivity^ EFZ/TDF/FTC: 4 psychiatric, 2 drug hypersensitivity, 1 cerebral vascular accident, 1 renal failure
¥ Deaths: n=1 primary cause of death judged unrelated to study drug but complicated by renal failure judged possibly related to EFZ/TDF/FTC, n=1 not related to EFZ/TDF/FTC (pneumonia).
Slide 31 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
EFZ/TDF/FTC QD
EFZ/TDF/FTC QD
Slide 32 of 41
IAS–USA
Eric S. Daar, MDProfessor of Medicine
David Geffen School of Medicineat UCLA
Treatment as Prevention
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 33 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
• Key questions for you– How to minimize risk of HIV transmission?– Can they safely have a biologic child in the
future?
• A 36 year AA male was recently diagnosed with asymptomatic HIV infection– CD4 720 cells/uL, VL 21,000 copies/mL– No other medical problems or medications– Insists that he does not want to start ARVs
• Patient presents with girlfriend who is repeatedly HIV antibody negative– Regular condom use, but not 100%
Slide 34 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
HPTN 041: Immediate vs Delayed ART in Serodiscordant Couples
Cohen MS, et al. IAS 2011. Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]
Immediate ART Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ARTInitiate ART at CD4+ cell count ≤ 250 cells/mm3*(n = 877 couples)
HIV-infected, sexually active serodiscordantcouples; CD4+ cell count of the infected partner: 350-550 cells/mm3
(N = 1763 couples) *Based on 2 consecutive values ≤ 250 cells/mm3.
• Primary efficacy endpoint: virologically linked HIV transmission• Primary clinical endpoints: WHO stage 4 events, pulmonary TB,
severe bacterial infection and/or death• Couples received intensive counseling on risk reduction and
use of condoms
Slide 35 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Cohen M, et al. NEJM July 18, 2011.
n=1; incidence rate0.1 per 100 p-y (95% CI 0.0, 0.4)
n=27; incidence rate1.7 per 100 p-y (95% CI 1.1, 2.5)
HPTN 041: Linked HIV Transmission Events
Slide 36 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Efficacy Rates of Prevention Trials
Adapted from: Abdool Karim SS and Karim QA. Lancet 2011; 378(9809):e23-5 and Celum C and Baeten JM. Curr Opinion Infect Dis 2012; 25:51-57
Efficacy (Percent)
HIV vaccine;RV144, Thailand
Microbicide;CAPRISA 004, South Africa
Sexually transmitted diseases treatment; Mwanza, Tanzania
PrEP for MSMs; iPrEX, Americas, Thailand, South Africa
1000 20 40 41 80
Study
ART for prevention; HPTN 041, Africa, Asia, AmericasPrEP for discordant couples;Partners PrEP, Uganda, KenyaPrEP for heterosexual men and women; TDF2, BotswanaMedical male circumcision; Orange Farm, Rakai, Kisumu
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-41)
31 (1-51)
Effect Size, Percent (95% CI)
PrEP for women; FEM-PrEP, Kenya,SA, Tanzania 0 (-69-41)
Slide 37 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
• Indication (added to MSM recommendations):– Women and men at very high risk for acquiring HIV from
heterosexual sex– One of several options to protect negative partner during
attempts to conceive
MMWR , Aug 2012; 61: 586-589.
Slide 37 of 41
Slide 38 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
MMWR , Aug 2012; 61: 586-589.
• Before PrEP– Exclude HIV (and acute if symptoms or exposure last month)– Exclude pregnancy– Confirm at ongoing, very high risk for acquiring HIV– If partner positive, assist with linkage to care– Confirm CrCl ≥41 mL/min– Screen for HBsAg, STIs
• Prescribe TDF/FTC for 90 days, renew after f/u testing– Risk reduction counseling/condoms– R/O pregnancy in women– HIV antibody, q2-3 months– STI testing q6 months or for symptoms– At 3 months then q6 months check creatinine
Slide 38 of 41
Slide 39 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
• After much discussion partner decides to not use PrEP while partner is on ARVs
• Patient’s viral load is now undetectable and they are more adherent with condoms
• They now want to discuss options for safe conception
• After detailed discussion the following is noted
– They do not want to consider sperm donor
– Sperm washing with or without ICSI is not available or affordable for the couple
Slide 40 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
• Indication (added to MSM recommendations):– Women and men at very high risk for acquiring HIV
from heterosexual sex– One of several options to protect negative
partner during attempts to conceive
MMWR , Aug 2012; 61: 586-589.
Slide 40 of 41
Slide 41 of 41
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
August 1, 2012