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When to Start When to Stop? What to Start?. Joseph J. Eron, Jr, MD Professor of Medicine Principal Investigator AIDS Clinical Trials Unit School of Medicine University of North Carolina at Chapel Hill Chapel Hill, NC. Benefits and Risks of Deferred ARV Therapy.

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When to start when to stop what to start

When to StartWhen to Stop?What to Start?

Joseph J. Eron, Jr, MD

Professor of Medicine

Principal Investigator

AIDS Clinical Trials Unit

School of Medicine

University of North Carolina at Chapel Hill

Chapel Hill, NC


Benefits and risks of deferred arv therapy

Benefits and Risks of Deferred ARV Therapy

  • Potential risks of deferred therapy

    • Potential for irreversible immune damage

      • Is immune recovery the same as immune preservation

    • Increased possibility of clinical progression

      • HIV related

        • Malignancy and cognitive disorder

        • Non-HIV clinical events.

    • Increased risk for HIV transmission

  • Potential benefits of deferred therapy

    • Avoidance of toxicity, improved quality of life

    • Preservation of future treatment options

    • Delayed development of drug resistance

    • Decreased total time on drug therapy

    • Increased time for patient education

    • More time for development of more potent, less toxic, and better studied combinations

Adapted from DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov. Accessed December 13, 2006.


The case for earlier initiation of therapy

The Case for Earlier Initiation of Therapy

  • Availability of more potent, easier, and less toxic regimens

  • Cohort studies showing benefit with earlier therapy

  • Better response to therapy

  • Decreased transmission

  • Cost-effectiveness


The case for earlier initiation of therapy1

The Case for Earlier Initiation of Therapy

  • Easier, more potent, and less toxic therapy


Collated results of haart studies

Collated Results of HAART Studies

  • Previous analysis emphasized relation b/w pill burden and response

  • Updated analysis: pill burden less important

  • Highlights efficacy of boosted-PI and NNRTI regimens

Unboosted PI

NNRTI

NRTI

Boosted PI

0

10

20

30

40

50

60

70

80

90

100

% With VL < 50 at Week 48

Bartlett JA, Fath MJ, Demasi R, et al.  An updated systematic overview of triple combination therapy in antiretroviral-naive HIV-infected adults. AIDS 2006;20:2051-64.


Treatment responses in 1st year of haart improving over time

150

Median CD4 increase

150

127

135

125

121

120

119

120

105

97

90

Median CD4 Increase

75

60

45

30

15

0

Treatment Responses in 1st Year of HAARTImproving Over Time

  • 4143 subjects from 5 clinic cohorts in Europe and Canada

  • Treatment-naive; started HAART from 1996-2002

  •  risk of virologic failure,  med. CD4 count increase in later years

    • Most “failure” now due to loss to follow-up or treatment discontinuation

% with > 500 copies/mL

100

90

80

70

60

% With VL >500 on ART

50

40

30

24.8

23.0

17.3

20

12.4

10

8.4

8

10

0

1996

1997

1998

1999

2000

2001

2002

Lampe F, et al. CROI 2005. Abstract 593


Unadjusted and adjusted risk ratios of virological failure by year of starting cart

Unadjusted and adjusted risk ratios of virological failure by year of starting cART

1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age, risk group, pre-HAART VL and CD4 count, previous AIDS; Adjusted 2$ =adjusted for all above factors plus starting regimen as defined by 3rd drug and nucleoside combination.

Lampe et al, Arch Intern Med 2006;166:521-528


Cohort data

Cohort Data

Improved outcomes with earlier antiretroviral therapy

HIV and non-HIV clinical events associated with CD4 cell counts above 200


Haart and survival based on initial cd4 cell count

HAART and Survival Based on Initial CD4 Cell Count

Cumulative Probability of AIDS/Death by CD4 Count at Initiation of ART

  • Modeled data from ART Cohort Collaborative

  • 10,855 pts, >61,000 person-years of F/U

  • 934 progressed to AIDS or died

  • IDUs excluded from model

101-200 cells/mm3201-350 cells/mm3351-500 cells/mm3

0.12

0.10

0.08

Probability of AIDS or Death

0.06

0.04

0.02

0.00

3

0

4

5

1

2

Years Since Initiation of HAART

Antiretroviral Therapy (ART) Cohort Collaboration. AIDS 2007;21:1185-97.


Hops cohort early uninterrupted art associated with improved outcomes

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

HOPS Cohort: Early, Uninterrupted ARTAssociated with Improved Outcomes

Incidence per 1,000 patient years by pre-HAART CD4 count

and % time on HAART (n = 4,421)

Opportunistic Infections

Mortality

71.5

HAART < 95% of time HAART > 95% of time

HAART < 95% of time HAART > 95% of time

*

55.9

* P = 0.05 for difference by % HAART use

* P = 0.05 for difference by % HAART use

47.8

37.8

38.5

Incidence per 1,000 Person-Years

Incidence per 1,000 Person-Years

*

*

*

26.1

25.5

22.3

21.4

20.1

16.2

15.9

14.2

*

11.5

10.4

*

7.5

7.3

7.2

5.4

2.4

0-49 50-199 200-349 350-499 500+

0-49 50-199 200-349 350-499 500+

CD4 category

CD4 category

CD4 Cell Count Category

Lichtenstein K, et al. CROI 2006. Abstract 769.


Pre haart cd4 predicts progression to aids johns hopkins cohort

900

800

700

600

CD4 cells/mm³

500

400

300

200

100

0

0

Yr 1

Yr2

Yr3

Yr 4

Yr 5

Yr 6

Pre-HAART CD4 Predicts Progression to AIDS: Johns Hopkins Cohort

  • Johns Hopkins HIV Cohort

  • Patients with virologic suppression for up to 6 yrs (N=280)

  • Only patients with baseline CD4 >350 returned to near normal CD4 count levels

  • Rate of progression to AIDS or death significantly higher over time in patients with CD4 <200 and 201-350 vs. >350

1.5%*†

12%*

13%*

*% developing AIDS over 6 years of study

† P < .05 compared with CD4+ < 200

Moore RD, et al. IAC 2006. Abstract THPE0109.


Caveat

Caveat

  • Remember Bias of Cohort Studies

    • Complex or non adherent patient may have therapy delayed

      • Bias by indication

    • Lead time bias


Hiv associated complications that are less cd4 dependent

HIV-Associated Complications that are Less CD4-Dependent

  • Neurocognitive impairment

  • Non-Hodgkin’s lymphoma

  • Peripheral neuropathy

  • HPV-associated dysplasia/cancer

  • Kaposi’s sarcoma

  • HIV-associated nephropathy


D a d study cd4 count associated with risk of non hiv related death

RR of death according to immune function and specific cause

100

Overall

HIV

Malignancy

Liver

Heart

RR

10

1.0

>500

<50

50–99

100–199

200–349

350–499

CD4 count

0.1

D:A:D Study: CD4 Count Associated with Risk of Non-HIV Related Death

  • >23,000 pts in Europe, Australia, USA

  • 1248 (5.3%) deaths 2000–2004 (1.6/100 person-years)

    • Of these, 82% on ART

  • Both HIV- and non–HIV-related mortality* associated with CD4 depletion

*Liver-related: Chronic viral hepatitis, liver failure (other); malignancy-related: malignancy, non-AIDS hepatitis; heart-related: MI, other CVD, other heart disease

Weber R et al. 12th CROI; 2005; Boston. Abstract 595.


Cd4 t cell count associated with risk of aids and non aids related malignancies

CD4+T-cell Count Associated with Risk of AIDS and Non-AIDS-related Malignancies

  • Risk factors for fatal AIDS-defining malignancies (ADM) and non-ADM in the D:A:D study

    • Of 1246 deaths, 112 ADM and 193 non-ADM related

  • 4 most common non-ADM: lung, GI, hematologic, anal

  • Risk of ADM and non-ADM increased as CD4 cells decrease

  • Additional risk factors

    • ADM: Prior AIDS event (RR 2.43, P<0.0001)

    • Non-ADM: Older age (RR 1.53/5 years older, P<0.0001), current smoking (RR 2.42, P<0.0001), active HBV (RR 1.89, P=0.008)

D’Arminio Monforte A et al. 14th CROI; 2007; Los Angeles. Abstract 84.


Malignancies and cd4 t cell count

Malignancies and CD4+ T-cell Count

D’Arminio Monforte A et al. 14th CROI; 2007; Los Angeles. Abstract 84.


Cd4 t cell and risk of clinical events

CD4+ T-Cell and Risk of Clinical events

Multivariate HR/100 CD4 Cell Increase*

  • Evaluation of impact of CD4+ count on OI and non-OI events

    • Compared latest CD4 count in FIRST study (n=1397) with risk

    • Median BL CD4 163 cells/uL, mean increase of 238 cells/uL

    • Median F/U 5 years

  • Higher latest CD4 associated with lower risk of OI and non-OIs

  • Tx strategies should minimize time spent at lower CD4 counts

1.2

1

1

0.92

0.83

0.81

0.78

0.76

0.8

0.58

Hazard Ratio

0.6

0.4

0.2

0

OI

CV

Liver

Renal

Non-OI

Reference

Malignancy

P value

<0.01

<0.01

0.06

0.40

0.08

<0.01

Baker J et al. 14th CROI; 2007; Los Angeles. Abstract 37.

*Adjusted for: age, sex, race, prior AIDS, hepatitis B and C, baseline CD4 & RNA, and latest RNA


Cascade sero conversion cohort

CASCADE: Sero-conversion Cohort

  • N=9,858; med. F/U 8 yrs post-seroconversion

  • 597 deaths, >50% non-AIDS-related

  • Current & nadir CD4 and time with CD4 <350 assoc. with:

    • AIDS deaths

    • Non-AIDS deaths: Infections, liver disease, malignancy

Marin B, et al.Sydney 2007, #WEPEB019


Randomized studies

Randomized Studies

There are none!


Clinical trial data supporting earlier therapy

SMART1

Subset: ART-naïve or not on ART at randomization

Immediate ART: n=249 (131 naïve)

Deferred ART: n=228 (118 naïve)

Greater risk of OI, OI/death, serious non-AIDS event with deferred ARV

>5-fold increased risk with deferred ARV

25

HR=5.08 (95% CI: 1.91-13.5) p=0.001

20

Cum. probability (X100)

15

10

5

0

0

4

8

12

16

20

24

28

32

38

Months

Clinical Trial Data Supporting Earlier Therapy

Composite endpoint1

Deferred ART

Immediate ART

1. Emery S, et al.4th IAS, Sydney 2007, #WEPEB018;


Early therapy

Early Therapy

Greater Toxicity?

Greater Resistance?


Risk of fat loss accumulation with nrtis pis increases with time on arvs

Risk of Fat Loss/Accumulation with NRTIs + PIs Increases with Time on ARVs

Kaplan-Meier Curve Showing

Progression to Any Lipodystrophy

  • Prospective study of 494 ARV-naïve patients starting HAART (Oct ’96-Sept ’99)

  • 85 subjects (17%) developed fat changes after median of 18 mo.

    • 21% central obesity

    • 34% subcutaneous lipoatrophy

    • 45% mixed

    • 11.7 cases per 100 person-years

  • Associated laboratory changes*

    • CD4 cell count 

    • Plasma HIV RNA 

    • Triglyceride level 

    • Cholesterol level 

Any lipodystrophy

Lipodystrophy with subcutaneous lipoatrophy

Lipodystrophy with central obesity

25

20

15

% of patients

10

5

0

06121824

Time since starting HAART (months)

Numbers at risk494 433 333 246136

Martinez E et al. Lancet. 2001;357:592-598.

*All P values 0.001.


Incidence of myocardial infarction increases with duration of combination art d a d study

Incidence of Myocardial Infarction Increases with Duration of Combination ART (D:A:D Study)

8

7

6

5

Incidence per

1000 Person-Years

4

3

2

1

0

Exposure (y):None<11-22-33-4 >4

Relative Risk:0.241.01.341.731.982.55

No. of events3914223147

No. of person-y 571441404801584772208477

Friis-Møller N et al. N Engl J Med. 2003;349:1993-2003.


When to start when to stop what to start

Relative Rate of MI according to NNRTIExposure(adjusted for PI exposure)

Adjusted RR* per year of NNRTI: 1.05 [0.98-1.13]

  • : Adjusted for sex, age, cohort, calendar year, prior CVD, family history of CVD, smoking, body-mass index, PI exposure

Friis-Moller et al, CROI 2006, oral 144


Hops more toxicity with later initiation of therapy

HOPS: More Toxicity with Later Initiation of Therapy

  • More NRTI toxicity (anemia, neuropathy, renal insufficiency) with initiation of ART at lower CD4 counts

Lichtenstein CROI 2005


Unc cfar db triple class resistance

UNC CFAR DB Triple Class Resistance


When to start when to stop what to start

Triple-class antiretroviral drug resistance (TC-DR) incidence rates (cases/1000 person-years) stratified by first HAART regimen

TCDR=4

N=34

PY=176

TCDR=15

N=184

PY=756

Incidence rate of TC-DR (cases/1000 PY)

TCDR=2

N=65

PY=316

TCDR=2

N=110

PY=659

TCDR=1

N=227

PY=713

TCDR=0

N=53

PY=244

TCDR=0

N=116

PY=258

EFV

PI/r

NFV

PI/NNRTI

NVP

DLV

IDV

PI

First HAART regimen


Hops more resistance with later initiation of therapy

Major mutations 50% less likely in pts starting with CD4 >350 vs <200, despite greater treatment exposure

p=0.076

p=0.007

p=0.051

p=0.103

60

50

Patients (%)

40

30

20

10

0

Any

mutation

(n=78)

NRTI mut.

among

NRTI-exp

(n=77)

NNRTI mut.

among

NNRTI-exp

(n=37)

PI mut.

among

PI-exp

(n=48)

0-199 cells/mm3

200-349 cells/mm3

>350 cells/mm3

HOPS: More Resistance with Later Initiation of Therapy

GT mutations and virologic failure

Uy JP, et al. 4th IAS, Sydney 2007, #WEPEB017


Transmission

Transmission


Hiv rna level affects probability of hiv transmission

HIV RNA Level Affects Probabilityof HIV Transmission

5

No GUD

GUD

4.5

4

3.5

3

Probability of Transmission/1000 Coital Acts

2.5

2

1.5

1

.5

0

<1700

1700-

12,500-

38,500+ GUD

Log Viral Load (c/mL)

GUD = genital ulcer disease.

Gray R, et al. Lancet. 2001;357:1149-1153.


Art induced reduction in plasma hiv rna associated with decreased levels in semen

ART-Induced Reduction in Plasma HIV RNA Associated with Decreased Levels in Semen

Controls (drug naive)

n=55

Effective ART

n=114

100

P<0.0001

80

60

P=0.01

detectable HIV in semen

Patients (%) with

40

20

0

HIV-RNA

HIV-DNA

Vernazza PL et al. AIDS. 2000;14:117-121.


The impact of art on hiv transmission among hiv serodiscordant couples

The Impact of ART on HIV Transmission Among HIV Serodiscordant Couples

  • ART offered in Kigali, Rwanda since 2003

  • 1034 serodiscordant couples followed

  • 248 “index cases” receiving ART (CD4<200)

  • In spite of counseling, 42 seroconversions

  • Only 2/42 seroconversions with partner on ART

  • HIV-negative individuals whose partners are on ART are less likely to seroconvert compared with those whose partners are not on ART(OR = 0.19; 95% CI:0.05-0.80)

Kayitenkore K et al. XVI IAC; 2006; Toronto. Abstract MOKC101.


Current dhhs guidelines for initiating art chronic infection

Current DHHS Guidelines for Initiating ART: Chronic Infection


Indications for haart regardless of cd4 cell count

Indications for HAARTRegardless of CD4 Cell count

  • HBV co-infection that requires therapy

    • Entecavir not longer an option

  • HIV Associated Nephropathy

  • Pregnancy

  • Discordant couples?

    • Perhaps if fully informed


Dhhs guidelines

DHHS Guidelines


Potential benefits of early therapy cd4 350 cells mm

Maintain higher CD4; prevent irreversible immune system damage

Decrease risk of HIV-associated complications

eg, TB, NHL, KS, peripheral neuropathy, HPV-associated malignancies, HIV-associated cognitive impairment

Decrease risk of nonopportunistic conditions and non-AIDS associated conditions

eg, CV, renal, and liver disease; malignancies; infections

Decrease risk of HIV transmission

Potential Benefits of Early Therapy (CD4 >350 cells/mm³)


Potential risks of early therapy cd4 350 cells mm

ARV-related side effects and toxicities

Drug resistance (due to ART failure)

Inadequate time to learn about HIV, treatment, and adherence

Increase in total time on ART; greater chance of treatment fatigue

Current ART may be less effective or more toxic than future therapies

Transmission of ARV-resistant virus, if incomplete virologic suppression

Potential Risks of Early Therapy (CD4 >350 cells/mm³)


Once treatment is started can we stop

Once Treatment is Started, Can We Stop?


Consequences of stopping art smart trial

Continuous antiretroviral therapy throughout follow-up*

(n = 2752)

ART stopped/deferred† until CD4+ <250 cells/mm3 then started to increase CD4+ to >350 cells/mm3

(n = 2720)

Consequences of Stopping ART: SMART Trial

HIV-1-infected patients with CD4+ cell count > 350 cells/mm3

(N = 5472)

95.4% treatment experienced

El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.

*Mean follow-up 16 months

†The protocol also permitted antiretroviral therapy to be initiated/reinitiated if symptoms of disease from HIV infection developed or the percentage of CD4+ lymphocytes (CD4+ percentage) was less than 15%.


Smart primary endpoint and components

SMART: Primary Endpoint and Components

#Pts w/ Events

Relative Risk (95% CI)

Endpoints

Death from any cause or Opportunistic Disease167

2.6

1.8

Death from any cause85

6.6

Serious opportunistic disease 15

1.7

Severe Complications* 104

0.1

1

10

Favors VS ►

(viral suppression)

Favors DC

(drug conservation)

*CVD, Renal, Hepatic Events (fatal/nonfatal)

El-Sadr W et al. N Engl J Med. 2006; 355:2283-2296.


Smart why did the sti arm have more clinical progression

N= 5472; randomized trial comparing continuous treatment (VS) to “STI” arm (DC):

Stop meds CD4 >350

Restart CD4 <250

Trial halted Jan 2006

2.63 greater risk of OI/death in DC versus VS arm

Greater risk of DC strategy explained by:

Lower CD4 count

Higher viral load at higher CD4 counts

Implications for “When to Start?”

SMART: Why Did the “STI” Arm Have More Clinical Progression?

Event Risk by Time Updated CD4 Count1

OI/Death by Arm During Study (%)

Time Spent at Different CD4 Strata2

31.7

Follow-Up Time (%)

8.2

7.2

1.7

3.1

0.8

VS Group

DC Group

1. Lundgren J, et al. Presented at: XVI IAC; August 13-18, 2006;Toronto, Canada. Abstract WEAB 0203;

2. El Sadr W, et al. Presented at: XVI IAC; August 13-18, 2006;Toronto, Canada. Abstract WEAB0204.


Trivacan study

Trivacan Study

  • Treatment Naïve patients in Abidjan

  • Randomized to continuous ARV treatment or CD4 guided interruption or timed interruption of therapy

  • Therapy held for CD4 > 350 and resumed when CD4 < 250

  • CD4 guided arm stopped on DSMB review

    • 110 received continuous treatment

    • 216 received CD4 guided therapy

Lancet. 2006 Jun 17;367(9527):1981-9


Trivacan time to severe morbidity or death

Trivacan: Time to severe Morbidity or Death


Trivacan study1

Trivacan Study

Continuous

CD4 guided


What to start with

What to Start With?


Initial treatment preferred components

Initial Treatment: Preferred Components

*Avoid in pregnant women and women with significant pregnancy potential.

**Emtricitabine can be used in place of lamivudine and vice versa.

NNRTI Option

NRTI Options

  • Tenofovir + emtricitabine**

  • Zidovudine + lamivudine**

OR

+

PI Options


Initial treatment alternative components

Initial Treatment: Alternative Components

*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400 cells/mm³

**Atazanavir must be boosted with ritonavir if used in combination with tenofovir

NNRTI Option

NRTI Options

  • Abacavir + lamivudine

  • Didanosine + (emtricitabine or lamivudine)

OR

PI Options


Initial treatment other possible options

Initial Treatment: Other Possible Options

ARV drugs or regimens

Rationale

These are considered acceptable but inferior to preferred or alternative components. They may be used in special circumstances.

*Should not be given to pregnant women.


Arvs not recommended in initial treatment 1

ARVs Not Recommended in Initial Treatment (1)


Arvs not recommended in initial treatment 2

ARVs Not Recommended in Initial Treatment (2)


Arv medications should not be offered at any time

ARV Medications: Should Not Be Offered at Any Time

  • ARV regimens not recommended:

    • Monotherapy (except possibly zidovudine used to prevent perinatal HIV transmission)

    • Dual NRTI therapy

    • 3-NRTI regimen (except abacavir/lamivudine/ zidovudine and possibly lamivudine/zidovudine + tenofovir

    • NRTI-sparing regimens


Arv medications should not be offered at any time1

ARV Medications: Should Not Be Offered at Any Time

  • ARV components not recommended:

    • Didanosine + stavudine

    • Stavudine + zidovudine

    • Emtricitabine + lamivudine

    • Atazanavir + indinavir

    • Saquinavir as single PI (unboosted)


Arv medications should not be offered at any time2

ARV Medications: Should Not Be Offered at Any Time

  • ARV components not recommended:

    • Efavirenz in pregnancy and in women with significant potential for pregnancy*

    • Nelfinavir in pregnancy and in women with significant potential for pregnancy*

    • Nevirapine initiation in women with CD4 >250 cells/mm³ or men with CD4 >400 cells/mm³

* Women who are trying to conceive or who are not using effective and consistent contraception.


Actg 5142 study design

ACTG 5142Study Design

Primary Study Objectives

Time to virologic failure*

Time to regimen completion†

753 Patients randomized in open label design

Major inclusion criteria:

ART naïve, Any CD4 or HIV RNA >2000 c/mL

LPV/r + NRTI

EFV + NRTI

LPV/r + EFV

*Virologic failure defined as early (rebound or lack of suppression by 1 log10) or late (failure to suppress to <200 c/mL or rebound); †Regimen Completion defined as virologic failure or d/c secondary to any treatment related discontinuation of any component

Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006; Toronto, Canada. August 13–18, 2006; Abstract THLB0204.


Actg 5142 96 week outcomes itt

ACTG 514296-Week Outcomes (ITT)

CD4+ Cell Count Change from BL:

+239 vs +285 vs +268P =.01)

EFV vs LPV: P = .006

EFV vs LPV/EFV: P = .5

LPV vs LPV/EFV: P =.13

EFV vs LPV: P = .003

EFV vs LPV/EFV: P = .123

LPV vs LPV/EFV: P = .183

Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006;Toronto, Canada. Abstract THLB0204.


Arv resistance mutations preliminary analysis

ARV Resistance Mutations (Preliminary Analysis)

*Some genotype assays pending.

†30N, 321, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V, 90M.

‡P <.05 vs LPV/EFV.

§ P <.05 vsEFV.

¶ P <.05 vs LPV.

Riddler S, et al. Presented at: XVI IAC; August 13-18, 2006;Toronto, Canada. Abstract THLB0204.


Haubrich r et al croi 2007 abstract 38 actg 5142

Haubrich R, et al. CROI; 2007. Abstract 38 (ACTG 5142)

  • Significantly lower incidence of lipoatrophy at 96 weeks for NRTI-sparing vs NRTI-containing regimens

  • Lipoatrophy incidence comparable with TDF-containing vs NRTI-sparing regimen

  • Incidence of lipoatrophy in NRTI arms lower with LPV/r vs EFV regardless of NRTI used

  • Total cholesterol, high density lipoprotein (HDL), and non-HDL increases similar between LPV/r and EFV + 2 NRTI arms

  • Triglycerides at 96 weeks significantly higher with LPV/r vs EFV + 2 NRTIs

  • Serum lipid changes greater with stavudine (d4T) - vs TDF-containing regimens


Lipoatrophy b y r andomized group

Lipoatrophyby Randomized Group

n = 173

9

17

n = 166

32

n = 171

P Values at Week 96

LPV/EFV vs LPV: .023

LPV/EFV vs EFV: <.001

LPV vs EFV: .003

7

n = 197

10

n = 191

21

n = 188

Lipoatrophy (>20% Limb Fat Loss) (%)

Haubrich R, et al. Presented at: 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 38.


Lipoatrophy b y nrti

Lipoatrophy by NRTI

9

n = 136

27

n = 117

42

n = 84

P Values at Week 96

ZDV vs TDF: <.001

d4T vs TDF: <.001

d4T vs ZDV: .038

n = 153

8

16

n = 133

26

n = 93

% Lipoatrophy (>20% Limb Fat Loss)

ZVD = ziclovidiine.

Haubrich R, et al. Presented at: 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 38.


How many nrtis actg 5095 study design

How Many NRTIs?ACTG 5095: Study Design

  • Phase III, randomized, double–blind, placebo–controlled study to evaluate a) ZDV/3TC + EFV, b) ZDV/3TC/ABC + EFV and c) ZDV/3TC/ABC

  • ZDV/3TC/ABC found to be inferior and discontinued

ART-naïve patientsN = 765, Compared for 3 years

ZDV/3TC/ABC/EFV

ZDV/3TC/EFV

Virologic Failure99 patients

Virologic Failure94 patients

Results at Year 3

90% <200 (P = .59)85% <50 (P = .39)

92% <200 (P= .59)88% <50 (P = 0.39)

ABC = abacavir.

Gulick R, et al. JAMA. 2006;296:769-781.


Actg 5095 time to virologic response

ACTG 5095Time to Virologic Response

Confirmed HIV RNA <200 c/mL

1.0

ZDV/3TC/ABC+EFV

0.8

ZDV/3TC+EFV

0.6

Probability of No Response

0.4

0.2

0

0

24

48

72

96

120

144

168

Time (wk)

No difference of probability of not failing among patients with HIV RNA >100,000 c/mL

Gulick R, et al. JAMA. 2006;296:769-781.


Actg 5095 impact of baseline values and risk of virologic failure at 3 years on efv

0.35

0.35

0.66

0.66

1.0

1.0

1.75

1.75

2.85

2.85

ACTG 5095 Impact of Baseline Values and Risk of Virologic Failure at 3 Years on EFV

By Baseline HIV RNA Level

≥300,000

100,000-299,999

30,000-99,999

<30,000

By Baseline CD4 Cell Count

≥500

350-499

200-349

50-199

<50

Ribaudo H, et al. Presented at: XVI IAC; August 13–18, 2006; Toronto, Canada Abstract THLB0211.


What nrtis gs 934 study design

What NRTIs? GS 934: Study Design

Noninferiority Trial, Primary Endpoint <400 c/mL at Week 96TLOVR

ARV-naïve patientsrandomized 1:1

Stratification by

HIV RNA >10,000 c/mL Any CD4 count

TDF QD

FTC QD

EFV QD

(n = 255)

CBV BID

EFV QD

(n = 254)

Week 144

Week 144

Adequate Renal and Hepatic Function at baseline

FTC/TDF Fixed dose combination tablet was not used

CBV = carbovir.

*FDA-required endpoint, similar to ITT Missing = Failure, Switch = Failure.

Requires confirmation for success, used by FDA for presentation in U.S. Prescribing Information of newly approved antiretrovirals.

Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.


Proportion 50 c ml tlovr

B

L

8

1

6

2

4

3

2

4

0

4

8

6

0

7

2

8

4

9

6

Proportion <50 c/mL (TLOVR)

9

0

8

0

TDF+FTC+EFV 67*

7

0

r

e

6

0

d

CBV+EFV 61*

5

0

Responder (%)

pon

4

0

3

0

Res

P = .16

%

2

0

*95% CI: (-2.3%, +15.0%)

1

0

0

Time (wk)

Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.


Mean absolute change in cd4 count from baseline

Mean Absolute Change in CD4 Count From Baseline

270 TDF+FTC+EFV

30

0

)

3

m

25

0

m

20

0

237 CBV+EFV

Mean Change (cells/mm3)

15

0

10

0

P = .036

5

0

0

Mean Change (cells/

B

L

8

1

6

2

4

3

2

4

0

4

8

6

0

7

2

8

4

9

6

Time (wk)

n = 255 238 234 223 218 209 199 177 184 172166

n = 254 222 216 199 188 175 164 145 149 149 142

Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.


Resistance development through week 96

Resistance Development Through Week 96

P =.017

P = .036

Excludes patients with baseline NNRTI-R mutations (n = 487).

Gallant JE, et al. Presented at: XVI IAC; August13–18, 2006; Toronto, Canada. Abstract TUPE0064.


Initial treatment strategies pi based regimens

Initial Treatment Strategies:PI-based Regimens


Klean study lpv r vs fpv r both with 3tc and abc qd

KLEAN Study: LPV/r vs FPV/r, Both With 3TC and ABC QD

Phase IIIb, randomized (1:1), open-label, 48-wk study conducted at 131 sites in the US, Europe, and Canada

FPV/r 700 mg/100 mg

BID + ABC/3TC(600 mg/300 mg) FDC QD

n = 434

ART-naïve subjects

LPV/r 400 mg/100 mg

BID + ABC/3TC(600 mg/300 mg) FDC QD

n = 444

  • Entry criteria

    • HIV-1 RNA 1000 c/mL

    • No CD4 cell count restrictions

  • Stratified by entry HIV-1 RNA <100,000 c/mL or 100,000 c/mL

  • KLEAN had 90% power to detect noninferiority of FPV/r to LPV/r within a 12% difference

FDC = fixed-dose combination.

Eron J, et al.Presented at: 16th IAC; August 13–18, 2006; Toronto, Canada. Abstract THLB0205.


Klean study hiv 1 rna 50 c ml at wk 48

KLEAN Study: HIV-1 RNA <50 c/mL at Wk 48

Proportion of Subjects

CD4+ <50 cells/mm3

CD4+ 50-199 cells/mm3

HIV-1 RNA ≥100,000 c/mL

HIV-1 RNA <100,000 c/mL

CD4+ ≥200 cells/mm3

TLOVR

FPV/rn =43419723767163204

LPV/r n =44420923580152212

Eron J, et al.Presented at: 16th IAC; August 13–18, 2006; Toronto, Canada.Abstract THLB0205.


Klean results median fasting lipids mg dl at baseline and wk 48

KLEAN Results: Median Fasting Lipids (mg/dL) at Baseline and Wk 48

Cholesterol

Triglycerides

Baselinen=363377363377

Wk 48n=287294287294

Use of lipid-lowering medications was similar in the FPV/r and LPV/r groups (11%).

Eron J, et al.Presented at: 16th IAC; August 13–18, 2006; Toronto, Canada.Abstract THLB0205.


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