Transcript Slide 1

Slide 1 of 41
Antiretroviral Therapy:
A Case-Based Panel Discussion
(Part II)
Eric S. Daar, MD
Michael S. Saag, MD
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
IAS–USA
Slide 2 of 41
Switch for Toxicity
Eric S. Daar, MD
Professor of Medicine
David Geffen School of Medicine
at UCLA
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
IAS–USA
Slide 3 of 41
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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 4 of 41
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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 5 of 41
Switch TDF/FTC + EFV to RPV
(N=49)
RPV mean Ctrough
in ECHO/THRIVE
Mills A, et al. 51st ICAAC; Chicago, IL; September 17-20, 2011. Abst. H2-794c.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 6 of 41
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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 7 of 41
Relative Risk of MI (95% CI)
D:A:D Study: NRTIs and Risk of MI
1.9
1.5
1.2
1
**
0.8
Recent Exposure*: yes/no
Cumulative Exposure: per year
0.6
#PYFU:
#MI:
ZDV
138,109
413
ddI
74,407
331
ddC
29,676
148
d4T
95,320
405
3TC
141,009
554
ABC
41,300
221
TDF
39,157
139
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)
Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 44LB. Sabin C, et al. Lancet
2008;371:1417-26.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 8 of 41
VA Case Registry: Use of ABC or
TDF in Last Regimen and Risk of MI
2.2
Unadjusted HR of AMI for each PY of exposure to each one of the categories
Adjusted for estimated GFR prior to regimen onset (by MDRD method)
2.0
Hazard ratio
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
ABC
TDF
NRTI in last regimen
during obs. period
Bedimo R, et al. 2011 Jul 1;41(1):84-91.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Both ABC and TDF
Slide 9 of 41
Cumulative Exposure to ARVs and Risk
of CKD
Tenofovir
Cockcroft-Gault (n=225)
MDRD (n=277)
CKD-EPI (n=258)
INSIGHT def (n=129)
Censoring ATV
Censoring TDF
Censoring boosted PI
Indinavir
Atazanavir
Lopinavir/r
0.9
1.4
Mocroft A, et al. AIDS. 2010; 41:1667-78
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 10 of 41
A4102: ABC/3TC vs. TDF/FTC
Median Change in Creatinine Clearance
p-values: ABC/3TC vs.
TDF/FTC
Change in Calculated
Creatinine Clearance, (mL/min)
Wk 48, p=0.83
Wk 96, p=0.14
Week 48
Wk 48, p<0.001
Wk 96, p<0.001
Week 96
TDF/FTC
ABC/3TC
ATV/r
N= 191
>25% decr(%):
3
173
2
TDF/FTC
ABC/3TC
EFV
217
191
7
6
186 157
2
3
Daar ES, et al. Ann Intern Med 2011; 154:445-456.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
200
178
1
3
Slide 11 of 41
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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 12 of 41
When to Use New ARV Drugs?
Michael S. Saag, MD
Professor of Medicine
Director, Center for AIDS Research
University of Alabama at Birmingham
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
IAS–USA
Slide 13 of 41
Assume dolutegravir is now
available or approved by FDA
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 14 of 41
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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 15 of 41
TFV plasma concentration (ng/ml)
GS-7340: US-120-0104: TFV Levels
TDF 300 mg
GS-7340 40 mg
GS-7340 25 mg
GS-7340 8 mg
1000
100
AUC
Cmax
TDF 300 mg
79% 89%
86% 94%
10
96% 98%
1
0
6
12
18
41
Time (hr)
Ruane CROI 2012 #103
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
GS-7340: US-120-0104
Primary Efficacy Endpoint
Slide 16 of 41
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
Ruane CROI 2012 #103
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 17 of 41
Intracellular TFV-DP (µM*h)
GS-7340: Intracellular (PBMC) TFV-DP
100
>20X
50
~7X
X
~1X
0
TDF
GS-7340 GS-7340
8 mg
25 mg
300 mg
GS-7340
40 mg
Ruane CROI 2012 #103
From 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
Anion Transport Pathway
OAT1
Slide 18 of 41
Cation Transport Pathway
ATP
OCT2
MRP4
MATE1
H+
OAT3
Tenofovir
Creatinine
COBI
Blood
(Basolateral) Active Tubular Secretion
Urine
(Apical)
Blood
(Basolateral) Active Tubular Secretion
Urine
(Apical)
• The active tubular secretion of tenofovir and the effect of COBI
on creatinine are mediated by distinct transport pathways in
renal proximal tubules
Ray A, et al. Antimicro Agents Chemo 2006;3297-3304
Lepist E, et al. ICAAC 2011; Chicago. #A1-1741
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 19 of 41
Cobicistat
ATV + Cobi plus TFV/FTC vs ATV + Ritonavir plus TFV/FTC :
Study Design
Study 114
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Gallant IAS 2012
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
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
QUAD vs TFV/FTC/EFV vs ATV plus TFV/FTC:
DTG 50mg plus ABC/3TC FDC QD
+ EFZ/TDF/FTC Placebo
EFZ/TDF/FTC QD + DTG plus ABC/3TC FDC Placebo
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 26 of 41
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
EFZ/TDF/FTC
QD (N=419)
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)
Slide 28 of 41
EFZ/TDF/FTC
208 cells/mm3
EFZ/TDF/FTC QD
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 29 of 41
EFZ/TDF/FTC QD
(N=419)
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 30 of 41
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).
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 31 of 41
EFZ/TDF/FTC QD
EFZ/TDF/FTC QD
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 32 of 41
Treatment as Prevention
Eric S. Daar, MD
Professor of Medicine
David Geffen School of Medicine
at UCLA
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
IAS–USA
Slide 33 of 41
• 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%
• Key questions for you
– How to minimize risk of HIV transmission?
– Can they safely have a biologic child in the future?
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 34 of 41
HPTN 041: Immediate vs Delayed ART
in Serodiscordant Couples
HIV-infected, sexually
active serodiscordant
couples; CD4+ cell count
of the infected partner:
350-550 cells/mm3
(N = 1763 couples)
Immediate ART
Initiate ART at CD4+ cell count 350-550 cells/mm3
(n = 886 couples)
Delayed ART
Initiate ART at CD4+ cell count ≤ 250 cells/mm3*
(n = 877 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
Cohen MS, et al. IAS 2011. Abstract MOAX0102.
Cohen MS, et al. N Engl J Med. 2011 Jul 18. [Epub ahead of print]
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 35 of 41
HPTN 041: Linked HIV Transmission
Events
n=27; incidence rate
1.7 per 100 p-y (95% CI 1.1, 2.5)
n=1; incidence rate
0.1 per 100 p-y (95% CI 0.0, 0.4)
Cohen M, et al. NEJM July 18, 2011.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 36 of 41
Efficacy Rates of Prevention Trials
Effect Size,
Percent (95% CI)
Study
ART for prevention; HPTN 041, Africa,
Asia, Americas
PrEP for discordant couples;
Partners PrEP, Uganda, Kenya
PrEP for heterosexual men and
women; TDF2, Botswana
Medical male circumcision;
Orange Farm, Rakai, Kisumu
PrEP for MSMs; iPrEX, Americas,
Thailand, South Africa
Sexually transmitted diseases
treatment; Mwanza, Tanzania
Microbicide;
CAPRISA 004, South Africa
HIV vaccine;
RV144, Thailand
PrEP for women; FEM-PrEP, Kenya,
SA, Tanzania
0
20
96 (73-99)
73 (49-85)
63 (21-84)
54 (38-66)
44 (15-63)
42 (21-58)
39 (6-41)
31 (1-51)
0 (-69-41)
40
41
80
100
Efficacy (Percent)
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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 37 of 41
• 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.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 38 of 41
•
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
MMWR , Aug 2012; 61: 586-589.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 39 of 41
• 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
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 40 of 41
• 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.
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.
Slide 41 of 41
August 1, 2012
From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA.