Calvin Cohen, MDHarvard Medical School

CRI New EnglandBoston, MA

Reexamining the Concept of Stable Therapy: When Should ART Be Adjusted?

Reexamining the Concept of Stable Therapy: When Should ART Be Adjusted?

Modifying Virologically Suppressive Therapy

• First: do no harm Maintain virologic control Maintain CD4 responses

• Second: address shortcomings of existing regimen Simplification: fewer pills, less frequent dosing Substitutions: address long-term toxicity issues

associated with some antiretrovirals when better alternatives exist

DHHS 2006 Initial Treatment: “Preferred” Components

NNRTI Option

• EFV*

OR

PI Options

• Atazanavir (ATV) + ritonavir (RTV)

• Fosamprenavir (FPV) + RTV (bid)

• Lopinavir/ritonavir (LPV/RTV) (bid)

NRTI Options

• Tenofovir (TDF) + emtricitabine (FTC)†

• ZDV + 3TC†

*Avoid in pregnant women and women with significant pregnancy potential.†Emtricitabine can be used in place of lamivudine and vice versa.

DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 2006.

2006 Initial Antiretroviral (ARV) Regimens:International AIDS Society-USA Treatment Guidelines

Recommended

NRTI NNRTI PI

TDF/FTC or ZDV/3TC or ABC/3TCEFV

(or NVP*)

LPV/r SQV/r

ATV/r FPV/r

Alternative

No specific alternatives listed†

Adapted from Hammer S et al. JAMA. 2006;296:827-843.

*In selected patients; †Triple-NRTI regimens are no longer recommended as initial therapy because of insufficient antiretroviral potency compared with a regimen containing efavirenz. However, for patients requiring treatment with regimens that preclude use of NNRTIs or protease inhibitors, a combination consisting of zidovudine, abacavir, and lamivudine may be considered.

ABC, abacavir; r, boosted with RTV; SQV, saquinavir.ABC, abacavir; r, boosted with RTV; SQV, saquinavir.

Considerations for NRTI Choice Major Toxic Effects and Cautions

• Well tolerated• Efficacy superior to ZDV/3TC, similar to

stavudine (d4T)/3TC• Available as once-daily fixed dose

• Baseline renal function should be evaluated before initiating TDF

• Reduce dose or avoid in patients with renal dysfunction

• Noninferior to TDF/FTC in 1 trial• May have less activity in patients with

HIV RNA >100K • Available as once-daily fixed dose

• Hypersensitivity syndrome in 5%-8% of persons (risk associated with HLA B*5701 genotype)

• Risk reduced with HLA B*5701 screening• May be associated with increased risk of

myocardial infarction (MI)AB

C/3

TC

TD

F/F

TC

2008 Updated Treatment Guidelines: Recommended Initial NRTI Backbones for ARV-Naïve Adults

EFVATV/rFPV/r

+TDF/FTCABC/3TC

orLPV/rSQV/r

DRV/r

JAMA. 2008;300(5):555-570.

ACTG 5142: Lipoatrophy at 96 WeeksLipoatrophy defined as >20% limb fat loss by DEXA scan

Haubrich R et al. 14th CROI; 2007; Los Angeles. Abstract 38.

DEXA, dual energy x-ray absorptiometry.DEXA, dual energy x-ray absorptiometry.

Percent patients with lipoatrophyPercent patients with lipoatrophy

d4T

ZDV

TDF

d4T

ZDV

TDF

(n=41)51

(n=43)33

(n=63)40

(n=73)16

(n=67)12

(n=50)6

0 20 40 60 80 100

LPVLPV

EFVEFV

Moyle G et al. AIDS. 2006; 20:2043-2050.

RAVE: Median Change in Limb FatDEXA Arm Fat + Total Leg Fat in Grams

(ITT M=F Analysis)

P <.01, baseline to week 48P=NS, between arms

SWEET: Study Design

• Undetectable viral load (≤ 50 copies/mL) at screening• Adequate baseline renal function (CrCl ≥ 60 mL/min) and hepatic

(AST/ALT ≤ 5 x ULN) function. HBsAg negative• No known resistance to TDF, FTC, ZDV, 3TC, or EFV

SWEET = Simplification With Easier Emtricitabine and Tenofovir . CrCl, creatinine clearance; ULN, upper limit of normal.

TDF/FTC qd

EFV qd

48weeks

Stable ZDV/3TC + EFV ≥ 6 months

(N = 250)Randomized 1:1

ZDV/3TC bid

EFV qd

Fisher M et al. 11th EACS; 2007; Madrid. Abstract PS5/7.

DEXA substudy (N = 100)

SWEET: Percentage <50 c/mL (ITT) at Week 48

Virological failure*: TDF/FTC 0/116 (0%), ZDV/3TC 1/116 (<1%)*Virological failure = Subjects with 2 consecutive postbaseline value ≥ 400 copies/mL.

Fisher M et al. 11th EACS; 2007; Madrid. Abstract PS5/7.

% P

atie

nts

wit

h H

IV

RN

A <

50

c/m

L

Time

88%

85%

P = .70

SWEET: Effect of Previous ZDV Exposure on Total Limb Fat

Change From Baseline at Week 48 by Years of Previous Exposure to ZDV

DEXA substudy treated analysis set and subset of whole body fat composition*Median baseline limb fat

Med

ian

Ch

ang

e in

Lim

b F

at (

kg)

Years on ZDV<3 Years ≥3 Years

0.4

0.3

0.2

0.1

0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

P = .99

P = .53

P = .014

P = .13

P = .053

5.41*

6.20* 3.68* 4.01*

n=20

n=20

n=18 n=16

TDF/FTC

ZDV/3TC

P = .37

Moyle G et al. 15th CROI; 2008; Boston. Abstract 938.

D:A:D Study: Recent but Not Past Use of ABC or ddI Predicted Risk of MI

NRTIs

Cumul., Recent,* + Past† Use

Rel Rate [5% Cl] P Value

ABC

Any recent* use 1.94 [1.48, 2.55] .0001

Cumulative use (per year) 1.00 [0.92, 1.08] .91

Any past† use 1.29 [0.94, 1.77] .12

Didanosine (ddI)

Any recent* use 1.53 [1.10, 2.13] .01

Cumulative use (per year) 1.00 [0.93, 1.07] .91

Any past† use 1.08 [0.84, 1.39] .54

*Recent = still using or stopped within last 6 months; †Past = last used more than 6 months ago.

Suggests drug effect is reversible upon cessation of drugs

Rates of MI

D:A:D Study Group. Lancet. 2008;371(9622):1417-1426.

D:A:D Study: Increased Risk of MI Associated with Recent ABC or ddI Use Remained After

Additional Adjustment

*Recent = still using or stopped within last 6 months.†All data depicted are also adjusted for demographic factors, calendar year, cohort, CV risk factors that are unlikely to be modified strongly by ART use, and cumulative exposure to other antiretroviral drugs.

No further adjustment†

Adjustment also for:Latest CD4Latest HIV RNALatest LipidsLatest blood pressureDiabetesFat loss/gainLatest glucose

Adjusted Relative Rate (95% CI)

Adjusted Relative Rate (95% CI)

Association With Recent* Didanosine Use

Association With Recent* Abacavir Use

0.5 1 1.5 2 2.5 3

1.49 1.90

0.5 1 1.5 2 2.5 3

D:A:D Study Group. Lancet. 2008;371(9622):1417-1426.

SMART Study: Hazard Ratios for Four Types of CVD While Patient Receiving ABC vs

Using “Other NRTIs” or TDF

ABC compared to “other NRTIs”

ABC compared to TDF

Hazard ratio (95% CI) of CVD

CVD, expanded def.

CVD, minor

Clinical MI

CVD, major

1.8Favors “Other” / TDF ◄ Favors ABC

4.313

2.7

1.9

0.1 1 10

Adapted from: Lundgren J et al. XVII IAC; 2008; Mexico City. Abstract THAB0305.; SMART/INSIGHT, D:A:D Study Groups, AIDS. 2008;22:F17-F24.

1.6

2.2

1.5

8.970.4

GSK: Analysis of ABC Studies From 1995 to 2006

Exposure to ABC

Events/ Patients Frequency

Events/ Person-Years

Rate /1000 Person-Years

Relative Rate (95% CI)

Any Myocardial Infarction or Acute Myocardial Infarction:

No ABC 7/5044 0.139% 11/4653 2.36

ABC 11/9639 0.114% 16/7845 2.040.863

(0.40, 1.86)

Any Ischemic Coronary Artery Disease or Disorder:

No ABC 21/5044 0.416% 27/4642 5.82

ABC 24/9639 0.249% 27/7832 3.450.593

(0.35, 1.01)

Cutrell A et al. XVII IAC; 2008; Mexico City. Abstract WEAB0106.

CV Outcomes With No Exposure to ABC Compared With Exposure to ABC

ACTG 5202: Targeted Events

ABC/3TC

N (%)

TDF/FTC

N (%)

Fractures 7 (2) 10 (3)

Myocardial infarction 0 (0) 0 (0)

Malignancy 3 (1) 3 (1)

Renal failure 2 (1) 2 (1)

Suspected hypersensitivity reaction 27 (7) 27 (7)

Deaths* 7 (2) 5 (1)

*One subject in ABC/3TC arm died, possibly as result of drug hypersensitivity reaction (HSR) after rechallenge

Sax PE,et al. XVII IAC; 2008; Mexico City. Abstract THAB0303.

TDF vs ZDV / d4T: Change in renal labs to wk 144 on TDF: Subset – BL mild renal impairment*

Gallant JE et al. 11tth EACS; 2007; Madrid. Poster P9.7/05.

Renal parametersa TDF Control NRTI P valueb

Serum creatinine (mg/dL) 1.1 (1.0, 1.2) 1.1 (0.8, 1.3) .60

Change from baseline 0 (-0.1, 0.2) -0.1 (-0.2, 0) .03

GFR by CG in mL/min 72 (65, 77) 73 (69, 75) .89

Change from baseline 1 (-3, 7) 8 (1, 12) .07

GFR by MDRD in mL/min/1.73m2

78 (72, 93) 74 (64, 90) .29

Change from baseline -1 (-13, 8) 12 (-1, 20) .01

a. Median (IQR) valuesb. P value is for comparison of the TDF and control distributions (Wilcoxon rank sum test)

*Glomerular filtration rate (GFR) 50-80 mL/min by Cockroft-Gault (CG)

Retrospective Chart Review: Assessment of Nephrotoxicity Risk With TDF

• Retrospective study to assess incidence and risk factors for nephrotoxicity on TDF Definition: Decrease in CrCl by ≥25 mL/min or GFR by >50%

• Nephrotoxicity risk similar between TDF-exposed (4.7%) and TDF-unexposed patients (4.2%)

• Factors associated with nephrotoxicity on TDF:

Odds Ratio 95% CI

P Value

Concurrent nephrotoxic medications 6.36 2.21, 18.4 <.001

Other medical comorbidities 5.43 2.22, 13.25 <.001

Hypertension 4.79 2.00, 11.45 <.001

Chronic pain (marker of NSAID use) 4.58 1.59, 13.21 .003

Concurrent PI 3.79 1.47, 9.75 .004

Previous PI 2.80 1.18, 6.63 .02

History of opportunistic infections 2.40 1.03, 5.60 .04

Concurrent NNRTI 0.36 0.16, 0.83 0.01

Castellano C et al. XVII IAC; 2008; Mexico City. Abstract WEAB0104.Castellano C et al. XVII IAC; 2008; Mexico City. Abstract WEAB0104.

NSAID, nonsteroidal anti-inflammatory drugNSAID, nonsteroidal anti-inflammatory drug