Eric S. Daar , MD Michael S. - PowerPoint Presentation

Slide1

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.

Slide2

Eric S. Daar, MDProfessor of MedicineDavid Geffen School of Medicine

at UCLASwitch for Toxicity

Slide3

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

Slide4

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

Slide5

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 C

trough

in ECHO/THRIVE

Slide6

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

Slide7

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

0.6

Recent Exposure*: yes/no

Cumulative Exposure: per year

**

Relative Risk of MI (95% CI)

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

)

Slide8

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 categories

Adjusted for estimated GFR prior to regimen onset (by MDRD method)

ABC

TDF

Both ABC and TDF

Hazard 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

Slide9

Cumulative Exposure to ARVs and Risk of CKD

Cockcroft-Gault (n=225)

MDRD (n=277)

CKD-EPI (n=258)

INSIGHT def (n=129)

Censoring ATV

Censoring TDF

Censoring boosted PI

Tenofovir

Indinavir

Atazanavir

Lopinavir/r

0.9

1.4

Mocroft

A, et al. AIDS. 2010;

41:1667-78

Slide10

A4102: ABC/3TC vs. TDF/FTC

Median Change in Creatinine Clearance

ABC/3TC

ATV/r

ABC/3TC

TDF/FTC

TDF/FTC

EFV

N=

191

173

217

191

186

157

200

178

Wk 48, p<0.001

Wk 96, p<0.001

Wk 48, p=0.83

Wk 96, p=0.14

Week 96

Week 48

p-values: ABC/3TC vs. TDF/FTC

Change in Calculated

Creatinine Clearance, (mL/min)

>25%

decr

(%):

3 2 7 6 2 3 1 3

Daar ES, et al. Ann Intern Med 2011; 154:445-456.

Slide11

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

Slide12

Michael S. Saag, MDProfessor of MedicineDirector, 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.

Slide13

Assume dolutegravir is now available or approved by FDA

Slide14

Case 134 yo woman diagnosed with HIV 4 weeks ago

Initial Lab valuesCD4 82 cells/uLVL 76,000 c/mLNo other significant medical conditionGenotype reveals wild type virus

Slide15

GS-7340: US-120-0104: TFV Levels

0

6

12

18

41

1

10

100

1000

GS-7340 8 mg

GS-7340 25 mg

GS-7340 40 mg

TDF 300 mg



79%



86%



96%

AUC

TDF 300 mg



89%



94%



98%

Cmax

Time (hr)

TFV plasma concentration (ng/ml)

Ruane

CROI 2012 #103

Slide16

Treatment

Group

N

Median

DAVG

11

[log

10

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

Slide17

TDF

GS-7340

GS-7340

GS-7340

0

50

100

X

~1X

~7X

>20X

300 mg

40 mg

25 mg

8 mg

Intracellular TFV-DP (µM*h)

GS-7340:

Intracellular

(PBMC) TFV-DP

Ruane

CROI 2012 #103

From MS

Saag

, MD and ES

Daar

, MD at San Francisco, CA: March 29,2013, IAS-USA.

Slide18

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

ATP

OAT1

Cation Transport Pathway

Blood

(Basolateral)

Urine

(Apical)

Active Tubular Secretion

OCT2

H

+

MATE1

COBI

Creatinine

Tenofovir

Ray A, et al.

Antimicro

Agents Chemo 2006;3297-3304

Lepist

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.

Slide19

Cobicistat

Gallant IAS 2012

ATV + Cobi plus TFV/FTC vs ATV + Ritonavir plus TFV/FTC :

Study Design

Study 114

Cobicistat

From MS

Saag

, MD and ES

Daar

, MD at San Francisco, CA: March 29,2013, IAS-USA.

Slide20

Gallant IAS 2012

Slide21

Gallant IAS 2012

Slide22

Gallant IAS 2012

Slide23

Gallant IAS 2012

From MS

Saag

, MD and ES

Daar

, MD at San Francisco, CA: March 29,2013, IAS-USA.

Slide24

Gallant IAS 2012

Slide25

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

Slide26

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.

Slide27

Difference in

Proportion (95% CI)

(DTG - EFZ/TDF/FTC)

EFZ/TDF/FTC QD (N=419)

Slide28

EFZ/TDF/FTC QD

EFZ/TDF/FTC

208 cells/mm

3

From MS

Saag

, MD and ES

Daar

, MD at San Francisco, CA: March 29,2013, IAS-USA.

Slide29

EFZ/TDF/FTC QD

(N=419)

Slide30

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).

Slide31

EFZ/TDF/FTC QD

EFZ/TDF/FTC QD

Slide32

Eric S. Daar, MDProfessor of MedicineDavid 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.

Slide33

Key questions for youHow 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%

Slide34

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/mm

3

(n = 886 couples)

Delayed ART

Initiate ART at CD4+ cell count ≤ 250 cells/mm

3*(n = 877 couples)HIV-infected, sexually active serodiscordant

couples; CD4+ cell count of the infected partner:

350-550 cells/mm

3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm

3

.

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

Slide35

Cohen M, et al. NEJM July 18, 2011.

n=1; incidence rate

0.1 per 100 p-y (95% CI 0.0, 0.4)

n=27; incidence rate

1.7 per 100 p-y (95% CI 1.1, 2.5)

HPTN

041:

Linked HIV Transmission Events

Slide36

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

100

0

20

40

41

80

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

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)

Slide37

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.

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37

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41

Slide38

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 monthsSTI testing q6 months or for symptomsAt 3 months then q6 months check creatinineSlide 38

of 41

Slide39

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 condomsThey 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

Slide40

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

Slide41

August 1, 2012