Initial Antiretroviral TherapyInitial Antiretroviral Therapy

Joel E. Gallant, MD, MPHJohns Hopkins University School of Medicine

A Brief History of Antiretroviral Therapy

! Early 80�s: No antiretroviral therapy

A Brief History of Antiretroviral Therapy

! Early 80�s: No antiretroviral therapy! Late 80�s: AZT monotherapy

A Brief History of Antiretroviral Therapy

! Early 80�s: No antiretroviral therapy! Late 80�s: AZT monotherapy! Early 90�s: Sequential NRTI

monotherapy and dual-NRTI therapy

A Brief History of Antiretroviral Therapy

! Early 80�s: No antiretroviral therapy! Late 80�s: AZT monotherapy! Early 90�s: Sequential NRTI

monotherapy and dual-NRTI therapy! Late 90�s: HAART: �Hit hard, hit early�

■ IDV / 3TC / AZT

● IDV

∆ AZT / 3TC

Gulick RM. Merck 035 NEJM 1997;337:734

Mortality From 1990-2004 in the Johns Hopkins HIV Clinical Cohort

Lau B, et al. Lau B, et al. CROI Denver, CO, 2006

Mortality and Use of Protease Inhibitors by Patients with CD4 <100, US 1994-1997

Palella, NEJM 1998

A Brief History of Antiretroviral Therapy

! Early 80�s: No antiretroviral therapy! Late 80�s: AZT monotherapy! Early 90�s: Sequential NRTI

monotherapy and dual-NRTI therapy! Late 90�s: HAART: �Hit hard, hit early�! Early 00�s: Deferral of therapy

0.0010.01

0.11

10100

100010000

Freq

uenc

y(IU

PM)

Frequency of Latently Infected CD4 Cells as a Function of Time on HAART

-

t ½ = 44.2 months73.4 years

0.00010.00001

3 4 5 6 7 80 1 2

Time on HAART (years)

Siliciano R, et al.

Adherence and Emergence of Resistant Virus Strains

Old View New View

Probability of resistance

0% Adherence 100%

Based on Friedland GH, et al. 1999;13(suppl 1):S61-S71.

Metabolic and Morphologic Complications of Antiretroviral Therapy

� Hyperlipidemia� Insulin resistance, hyperglycemia, &

diabetes� Lipoatrophy� Fat accumulation� Lactic acidosis� Osteopenia and osteoporosis (?)� Osteonecrosis & avascular necrosis (?)

Lipodystrophy

Prognosis of Antiretroviral-Naïve Patients:ART Cohort Collaboration

Prognosis of Antiretroviral-Naïve Patients:ART Cohort Collaboration

� Time to AIDS defining events or death� 12,040 patients followed at 12 centers starting HAART

Probability of AIDS-free survival

1.000.950.900.850.800.75

Years from starting HAART0 1 2 3

0-49

50-68

100-198

200-349≥350

CD4 cell count at baseline

0.95

0.90

0.85

0.80

0.75Years from starting HAART

0 1 2 3

≥5

4-4.99

1.00

3-3.99>3

Log HIV RNA at baseline

Egger, et al. 41st ICAAC, Chicago 2001.

Guidelines For Initial Therapy

(TDF or AZT) + (3TC or FTC) + (EFV or LPV/r)

2004

2 NRTIs + PI, NNRTI, or 3rd

NRTI2002

2 NRTIs + PI or NNRTI19992 NRTIs + PI19972 NRTIs1995AZT/ddI1992AZT1987

GUIDELINESYEAR

ACTG 5095: AZT/3TC/ABC vs. EFV-Based Therapy

Gulick R, et al. N Engl J Med

NFV vs. LPV/r: Time to Virologic Failure by Baseline Viral Load

87%

68%

57%

41%40%

Nelfinavir

0%

20%

40%

60%

80%

100%

0 24 48 72 96Weeks

Perc

ent r

espo

ndin

g

<20,000 (n=68)20,000-65,000 (n=66)65,000-150,000 (n=66)150,000-350,000 (n=64)>350,000 (n=63)

Baseline viral load (log10 copies/mL)

90%85%80%74%67%

Lopinavir/ritonavir

0 24 48 72 96Weeks

<20,000 (n=62)20,000-65,000 (n=66)65,000-150,000 (n=66)150,000-350,000 (n=72)>350,000 (n=60)

Baseline viral load (log10 copies/mL)

King M et al. 9th CROI, Seattle, 2002, #470

TDF vs. d4T (plus EFV/3TC): Gilead 903 � 144 week data

0

20

40

60

80

100

0 24 48 72 96 120 144

% P

atie

nts

with

VL

< 50

c/m

L

Weeks

73%69%

ITT Missing=Failure

TDF+3TC+EFVd4T+3TC+EFV

Gallant JE, et al. JAMA 2004

TDF+FTC vs. AZT/3TC (with EFV): GS 934: 48-week data

TDF+FTC 80%*CBV 70%*

% w

ith H

IV R

NA

<50

c/m

L

*95% CI: (+1.6%, +16.6%); p = 0.02

0

20

40

60

80

100

BL

HIV RNA <50 c/mL, TLOVR (n=487)

8 16Week

24 32 40 48

Gallant JE, et al, N Engl J Med 2006; 354:251-60.

Lessons Learned in the HAART Era

! A �new� drug may not be an �active� drug» Extensive cross-resistance within drug classes

! Addition of a 1 active drug to a failing regimen is monotherapy and results in drug resistance

! Continuing a failing regimen leads to accumulation of resistance and loss of options

Antiretroviral Drug Approval:1987 - 2006

0

5

10

15

20

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005

AZT ddIddC d4T

3TCSQV

RTVIDVNVP

NFVDLV

EFVABC

APVLPV/r

TDF

TPVENFATV FPV

DRV?

When to Start TherapyWhen to Start Therapy

DHHS Guidelines: When to Start Treatment

Defer therapy< 100,000> 350Asymptomatic

Most clinicians recommend deferring therapy, but some

clinicians will treat.

≥ 100,000> 350Asymptomatic

Treatment should be offered following full discussion of pros and cons of treatment.

Any value200-350Asymptomatic

TreatAny value< 200Asymptomatic

TreatAny valueAny valueAIDS-defining illness or severe symptoms*

General GuidelinesViral LoadCD4 Count

Clinical Category

* Severe symptoms = unexplained fever or diarrhea > 2-4 wks, oral candidiasis, or > 10% unexplained weight loss.

DHHS guidelines. http://AIDSinfo.nih.gov. Accessed November 11, 2004.

Collated Results of HAART Studies

0 10 20 30 40 50 60 70 80 90 100% With VL < 50 at Week 48

Boosted PI

NNRTINRTI

Unboosted PI

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

" Updated analysis: pill burden less important

" Highli and NNRTI regimens

ghts efficacy of boosted-PI

Bartlett JA et al. Abstract 586.

Treatment Responses in 1st Year of HAARTImproving Over Time

! 5 clinic cohorts in Europe and Canada, N=4143! Treatment-naive; started HAART 1996-2002! ↓ risk of virologic failure, ↑ med. CD4 increase in later years

» In recent years, most �failure� due to loss to follow-up or treatment discontinuation

0153045607590105120135150

97

119 120 121127 125

150Median CD4 increase

Lampe S, et al. 12th CROI, 2005, Abstract 593

24.8 23.017.3

12.4 10 8 8.4

01020304050

1996 1997 1998 1999 2000 2001 2002

% with VL > 500 c/mL

60708090

100

% W

ith V

L >

500

on A

RT

Med

ian

CD

4 In

crea

se

HAART and Survival Based on Initial CD4 Count

! Modeled data from ART Cohort Collaborative

! 10,855 patients included! 934 progressed to AIDS or died! IDUs excluded from model

Sterne J, et al. CROI 2006. Abstract 525.

Progression and Death According to CD4 Count (cells/mm3)

1.26 (0.94-1.68)

2.93 (2.41-3.57)

Hazard ratio for AIDS or death (95% CI)

< 350 vs 351-500

< 200 vs 201-350

1.52 (1.10-2.10)

3.68 (3.01-4.51)

Hazard ratio for AIDS (95% CI)

Cumulative Probability of AIDS/Death According to CD4 Count at Initiation of HAART

Years Since Initiation of HAART

0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Prob

abili

ty o

f AID

S or

Dea

th

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3

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)

CD4 Cell Count Category

MortalityOpportunistic Infections80

70

60

50

40

30

20

10

0

80

70

60

50

40

30

20

10

00-49 50-199 200-349 350-499 500+0-49 50-199 200-349 350-499 500+

CD4 categoryCD4 category

HAART < 95% of timeHAART > 95% of time

* P = 0.05 for difference by % HAART use

HAART < 95% of timeHAART > 95% of time

* P = 0.05 for difference by % HAART use

Inci

denc

e pe

r 1,0

00 P

erso

n-Ye

ars

Inci

denc

e pe

r 1,0

00 P

erso

n-Ye

ars

71.5

47.8

38.5

25.521.4

15.9 14.211.5

7.2 7.5

*

*

55.9

26.1

37.8

22.3 20.1

10.416.2

5.4 7.32.4

**

**

Lichtenstein K, et al. 13th CROI, 2006; #769.

CD4 Response Based on Baseline CD4 CountJohns Hopkins

HIV Clinical Cohort

Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

Years on HAART

Mea

n C

D4

Cou

nt

! Magnitude of CD4 increase greatest if therapy started at low CD4 counts, but greater likelihood of CD4 count normalization with earlier therapy

0 1 2 3 4 5

200

400

600

800

0

1000ATHENA National Cohort

1000

800

600

400

200

00 24014448 96 192 288 336

Weeks From Starting HAART

Viral Load and Heterosexual Transmission of HIV-1

Quinn, et al. NEJM 2000;342:921-929

Recommended regimens fortreatment-naïve patients: DHHS 7/05

Preferred regimensLPV/r +LPV/r +

(3TC or FTC) + (ZDV) (3TC or FTC) + (ZDV) EFV* +EFV* +

(3TC or FTC) + (ZDV or TDF)(3TC or FTC) + (ZDV or TDF)Alternative regimens

PIPI--basedbased(ZDV, d4T, TDF, ABC or ddI) + (3TC or FTC) + :(ZDV, d4T, TDF, ABC or ddI) + (3TC or FTC) + :

ATV (w/ RTV for TDF)ATV (w/ RTV for TDF)FPVFPV

FPV + RTVFPV + RTVIDV + RTVIDV + RTV

LPV/rLPV/rNFV NFV

SQV + RTVSQV + RTV

NNRTINNRTI--basedbasedEFV* + (3TC or FTC) + (ddI, d4T, or ABC)EFV* + (3TC or FTC) + (ddI, d4T, or ABC)

NVP + (3TC or FTC) + (ZDV, d4T, ddI, ABC, or NVP + (3TC or FTC) + (ZDV, d4T, ddI, ABC, or TDFTDF

Triple NRTI**Triple NRTI**ABC + 3TC + (ZDV or d4T)

*EFV safety in pregnancy not established � avoid in pregnant women or women with pregnancy potential**Only when an NNRTI- or a PI-based regimen cannot or should not be used as first-line therapywww.aidsinfo.nih.gov

Decreasing Use of Thymidine Analogs for Initial Therapy

! AZT/3TC or d4T/3TC → TDF/FTC or ABC/3TC! Once daily therapy with coformulated products! Well tolerated! No mitochondrial toxicity (lipoatrophy, lactic acidosis)! No anemia or neuropathy! Better lipid profiles (TDF)! TDF: nephrotoxicity! ABC: hypersensitivity

Improvements in PI Therapy

! Once-daily therapy common (LPV/r, FPV/r, ATV/r)! Decreasing pill burden (2-4 pills/d)! GI tolerability improving! Metabolic toxicity no longer universal! RTV boosting standard: no PI resistance with

failure

Increasing Use of Once-Daily Therapy

EFV orATV* orATV/r orFPV/r or

LPV/r

TDF/FTCor

ABC/3TC+

*don�t use unboosted ATV with TDF

www.hopkins-hivguide.org