Slide 1 of 41 IAS–USA Eric S. Daar, MD Michael S. Saag, MD Antiretroviral Therapy: A Case-Based...

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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.

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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

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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

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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

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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

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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

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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)

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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

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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

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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.

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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

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IAS–USA

Michael S. Saag, MDProfessor of Medicine

Director, Center for AIDS ResearchUniversity of Alabama at Birmingham

When to Use New ARV Drugs?


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Assume dolutegravir is now available or approved by FDA

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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

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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

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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


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Cobicistat

Gallant IAS 2012

ATV + Cobi plus TFV/FTC vs ATV + Ritonavir plus TFV/FTC :Study DesignStudy 114

Cobicistat


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From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012

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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.

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From MS Saag, MD and ES Daar, MD at San Francisco, CA: March 29,2013, IAS-USA. Gallant IAS 2012

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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


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Difference in Proportion (95% CI)

(DTG - EFZ/TDF/FTC)

EFZ/TDF/FTC QD (N=419)

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EFZ/TDF/FTC QD

EFZ/TDF/FTC208 cells/mm3


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EFZ/TDF/FTC QD(N=419)

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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).

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EFZ/TDF/FTC QD

EFZ/TDF/FTC QD

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IAS–USA

Eric S. Daar, MDProfessor of Medicine

David Geffen School of Medicineat UCLA

Treatment as Prevention


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• 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%

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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

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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

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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)

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• 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

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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

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• 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

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• 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

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August 1, 2012

Slide 1 of 41 IAS–USA Eric S. Daar, MD Michael S. Saag, MD Antiretroviral Therapy: A Case-Based...

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