Current Clinical Controversies in the Treatment of HIV/AIDS Paul E. Sax, MD Clinical Director,...

Current Clinical Controversies in the Treatment of HIV/AIDS

Paul E. Sax, MDPaul E. Sax, MD

Clinical Director, Division of Infectious Diseases and HIV Program

Brigham and Women’s HospitalAssociate Professor of Medicine

Harvard Medical SchoolBoston, Massachusetts

2

Faculty:Content Development and Training

Calvin J. Cohen, MD, MSResearch Director, CRI New England

Clinical Instructor, Harvard Medical SchoolBoston, Massachusetts

Edwin DeJesus, MD, FACPInfectious Disease Consultants

Medical Director, Orlando Immunology CenterOrlando, Florida

Paul E. Sax, MDClinical Director, Division of Infectious Diseases and HIV Program

Brigham and Women's HospitalAssociate Professor of Medicine, Harvard Medical School

Boston, Massachusetts

Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants

should be able to:— Describe and discuss current controversies regarding

HIV treatment— Identify key studies that potentially can improve

outcomes with HIV treatment — Summarize the clinical data supporting methods for

improving the health and management of HIV-infected patients

4


1. When to Start: 2009 DHHS Guidelines

2. What to Start: 2009 DHHS Guidelines

3. Benefits and Limits of Simplification

4. Adoption of Opt-out Testing

5. Potential Strategies for HIV Prevention

6. The Importance of Non-AIDS Co-Morbidities

5

2009 DHHS Guidelines: Recommendations for Initiation of ART in Naïve Patients

Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.

Strength of Recommendation: A = Strong; B = Moderate; C = Optional Quality of Evidence for Recommendation: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion

Note: HIV RNA >100,000 c/mL and decline of CD4+ count > 100 cells/mm3 per year favor starting ART

Clinical CategoryCD4 Cell Count

(cells/mm3)2009 DHHSGuidelines Strength-Quality

AIDS-defining illness Any value TreatA-I

Asymptomatic

<350 Treat

350 to 500 Treat A/B-II: 55% A vs. 45% B

>500 Treat/Optional B/C-III: 50% B vs. 50% C

Pregnancy, HIV-associated nephropathy, HIV/HBV when HBV treatment indicated

Any value Treat A-III

6

SMART: Influence of CD4+ Count and Treatment on Clinical Event Rate

Last CD4+ Cell Count (cells/mL)

<250 250–349

350–499 ≥500 Overall

Immediate ART

Person-yrs (%)*

10 (2.6)

30 (7.9)

109 (28.8)

230 (60.7)

379(100)

Rate** 10.4 6.7 1.8 0.0 1.3

Deferred ART

Person-yrs (%)*

19 (6.4)

65 (21.7)

118 (39.5)

97 (32.4) 299 (100)

Rate** 16.0 9.2 7.6 3.1 7.0

Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018.Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018.

Opportunistic Disease and Death

Cum

. Pro

babi

lity

(X10

0) 25

Months

Deferred ARTImmediate ART

HR = 4.38 (95%CI, 1.45–13.2); P=.009

5

20

10

15

00 84 12 16 20 24 28 32 36

Serious Non-AIDS (CV, Renal, CA)

HR = 7.05 (95% CI, 1.58–31.5); P=.01

36

Cum

. Pro

babi

lity

(X10

0)

Deferred ARTImmediate ART

5

20

10

25

15

00 84 12 16 20 24 28 32

Months *Time spent in the CD4+ cell count category censored at event**per 100 person years

7

NA-ACCORD: Risk of Death with ART Deferral

351-500 CD4+ >500 CD4+

RR 95% CI P RR 95% CI P

Deferral of ART 1.7 1.3, 2.3 <0.001 1.9 1.4, 2.8 <0.001

Female Sex 1.2 0.9, 1.6 0.24 1.9 1.3, 2.6 <0.001

Older Age(per 10 years) 1.7 1.5, 1.9 <0.001 1.8 1.6, 2.1 <0.001

Baseline CD4 count (per 100 cells/mm3) 1.1 0.7, 1.8 0.59 0.9 0.9, 1.0 0.03

● HIV RNA was not an independent predictor of mortality● Exclusion of IDU or HCV did not affect overall relative risk● Rate of virologic suppression (<500 c/ml) higher in pts who started ART earlier

Kitahata M, et al. New Engl J Med 2009;360:1815-26.

8

ART-CC: When Should ART be Started?

Hazard ratios for AIDS or death, adjusted for lead time/unseen events

Sterne J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 72LB.

44

Haz

ard

Rat

io f

or

AID

S o

r D

eath

Haz

ard

Rat

io f

or

AID

S o

r D

eath

22.5.5

11

500500 400400 300300 200200 100100 00CD4 Threshold (cells/mm3)CD4 Threshold (cells/mm3)

Comparison Hazard Ratio (95% CI)

276-375 vs 376-475 1.19 (0.96 to 1.47)

251-350 vs 351-450 1.28 (1.04 to 1.57)

226-325 vs 326-425 1.21 (1.01 to 1.46)

9

Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count

normalization with earlier therapy

1. Moore R, et al. Clin Infect Dis. 2007;44(3):441-446; 2. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start

1000

800

600

400

200

0

0 48 96 144 192 240 288 336

ATHENA National Cohort2

Weeks From Starting ART

<5050-200200-350350-500≥500

Years on ART

Johns Hopkins HIV Clinical Cohort1

Mea

n C

D4

Cel

l C

ou

nt

(cel

ls/m

m3)

0 1 2 3 4 5

200

400

600

800

0

1000

<200

201-350

>350

10

● Patients initiating ART should be willing and able to commit to lifelong treatment and understand the benefits and risks of ART and the importance of adherence

● Patients and clinicians may defer therapy based on clinical or personal circumstances

● The decision to defer should depend on CD4 count and viral load

● Deferring therapy may be considered for:- Adherence barriers- Comorbidities that complicate or prohibit ART- Elite controllers/Long-term nonprogressors

2009 DHHS Guidelines: Conditions Where Deferral of Therapy Might be Considered

Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.

11








12

DHHS Guidelines: TDF/FTC a part of all Preferred Regimens for Treatment-Naïve Patients

Preferred Regimens

• EFV/TDF/FTC• ATV/r + TDF/FTC• DRV/r (once daily) + TDF/FTC• RAL + TDF/FTC[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]

AlternativeRegimens

• EFV + (ABC or ZDV)/3TC• NVP + ZDV/3TC• ATV/r + (ABC or ZDV)/3TC• FPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• LPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• SQV/r + TDF/FTC

AcceptableRegimens

• EFV + ddI + (3TC or FTC)• ATV + (ABC or ZDV)/3TC

InsufficientData

• MVC + ZDV/3TC• RAL + (ABC or ZDV)/3TC• (DRV/r or SQV/r) + (ABC or ZDV)/3TC

Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

13

Studies Comparing ABC/3TC and TDF/FTC

A5202 HEAT ASSERT

Sponsor NIAID GSK GSK

Sample Size 1858 (797 HIV RNA > 100,000 c/mL)

688 385

Blinding Double-Blind Double-Blind None

3rd Drug EFV or ATV/r LPV/r QD EFV

Primary Endpoint Time to Virologic Failure*

<50 c/mL at 48 wks Change in GFR at wk 48 by MDRD

HLA-B*5701 Testing Permitted, not required No Required, only negative pts enrolled

Key Results For those with HIV RNA >100,000 c/mL, study stopped early due to higher rate of virologic failure with ABC/3TC

ABC/3TC non-inferior

No difference in eGFR; proportion <50 c/mL favored TDF/FTC (71% vs. 59%; difference 11.6%, 95% CI 2.2-21.1); Total hip and lumbar spine BMD decline more with TDF/FTC

*Confirmed >1000 c/mL between wks 16-24, >200 c/mL wk 24 on)

14

No. at Risk

ABC-3TC 398 363 313 267 222 188 137 87 49 20

TDF-FTC 399 361 321 284 236 204 160 104 65 23

A5202: Time to Virologic Failure in Patients with Baseline HIV RNA >100,000 c/mL

Sax PE, et al. NEJM 2009;361:2230-2240.

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108

Weeks since Randomization

Pro

ba

bil

ity

of

No

Vir

olo

gic

F

ail

ure

(%

)

TDF-FTC (26 events)

ABC-3TC (57 events)

P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72)

Probability of No Virologic Failure

15

A5202: Virologic Failure According to Baseline Characteristics

Sax PE, et al. NEJM 2009;361:2230-2240.

ABC-3TC

(N=398)

TDF-FTC

(N=399)

Sub GroupEvents/person-yr at risk (Events per 100

person-yr)Hazard ratio (95%)

P Value for interaction

Overall 57/398 (14.82) 26/399 (6.34) 2.33 (1.46-3.72) <0.001

Sex 0.04

Male 50/331 (15.41) 18/345 (5.24) 3.00 (1.74-5.17)

Female 7/67 (11.63) 8/54 (11.97) 0.85 (0.30-2.39)

Age 0.07

30yr 3.24 (1.73-6.08)

40yr 2.08 (1.28-3.39)

Race or ethnic group 0.55

White 18/170 (10.33) 8/202 (3.63) 2.82 (1.22-6.53)

Black 26/112 (26.71) 12/94 (13.93) 1.94 (0.96-3.90)

Hispanic 9/103 (8.87) 6/93 (6.59) 1.35 (0.48-3.83)

HIV-1 RNA 0.20

5.5 log10 copies/mL 2.64 (1.58-4.40)

6.0 log10 copies/mL 3.39 (1.60-7.22)

CD4 count 0.007

50 cells/mm3 3.54 (1.97-6.36)

200 cells/mm3 1.68 (0.98-2.88)

Genotype tested at screen 0.02

Yes 22/175 (14.05) 3/166 (1.99) 7.21 (2.15-24.20)

No 35/223 (15.35) 23/233 (8.88) 1.71 (1.00-2.91)

0.04 1.00 25.00

ABC-3TC Better TDF-FTC Better

16

HEAT: Virologic Failure by Baseline HIV-1 RNA Using A5202 Efficacy Endpoint

8790 9087

0

20

40

60

80

100

<100,000 ≥100,000

ABC/3TC

TDF/FTC

Perc

ent w

ithou

t Viro

logi

c Fa

ilure

n = 188 155 140205

Pappa K, et al. 17th IAC, Mexico City, 2008. Abst. THAB0304.Young B, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1233.

41%

63%

18%

19%18%

4%22%

15%

0%

20%

40%

60%

80%

100%

ABC/3TC TDF/FTC

Pro

po

rtio

n o

f S

ub

ject

s w

ith

VF

≥500,000 c/mL

250,000 - <500,000 c/mL

100,000 - <250,000 c/mL

<100,000 c/mL

~59%~59%

~37%~37%

17

ASSERT: Proportion of Subjects with HIV-1 RNA <400 and <50 copies/ml by Visit (TLOVR)

Observed analysis: ≥90% in both arms achieved <50c/ml at Week 48

77%71%67%59%

CD4 cell count increase 150 c/mm3 at Wk 48 in both arms

Pro

po

rtio

n(%

)

0

10

20

30

40

50

60

70

100

0 24 48

Week

36124

80

90

W48 difference for % <400 cps/ml was 9.5% (95% CI: 0.6,18.4)

W48 difference for % <50 cps/ml was 11.6% (95% CI: 2.2, 21.1)

ABC/3TC FDC QD: HIV-1 RNA <400 copies /mL TDF/FTC QD: HIV-1 RNA <400 copies /mL

ABC/3TC FDC QD: HIV-1 RNA <50 copies /mL TDF/FTC QD: HIV-1 RNA <50 copies /mL

Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1.

18

ASSERT: Adjusted Mean Change in eGFR (MDRD)

Subjects at Visit

TDF/FTC QDABC/3TC QD 192 158 144

193 176 167

Ch

an

ge

fro

m B

L i

n G

RF

by

MD

RD

(m

L/m

in/1

.73

m2

)

-8

-6

-4

-2

0

2

4

6

8

0 24 48

Week36124

172181

155173

135159

ABC/3TC QD TDF/FTC QD


nAdjusted

Mean S.E. Diff.95% CI forDifference P-value

ABC/3TC FDC QD 174 0.22 0.890

TDF/FTC FDC QD 184 1.18 0.828 0.953(-1.445, 3.351)

0.435

19

ASSERT: % Change from Baseline in Hip and Spine Bone Mineral Density


ABC/3TC: -1.90%TDF/FTC: -3.55%= -1.68 ; 95% CI (-2.26, -1.09)

ABC/3TC: -1.59%TDF/FTC: -2.41%= -0.84 ; 95% CI (-1.61, -0.06)

SubjectsABC/3TC: 176 134 117 182 141 125TDF/FTC: 180 156 138 183 165 143

0

-1

- 2

- 3

- 4

0 24 48

Total Hip0

-1

- 2

- 3

- 4

0 24

P<0.001

Lumbar Spine

48

P=0.036

week week

% c

han

ge

in B

MD

% c

han

ge

in B

MD

20

D:A:D Study: NRTIs and Risk of MI

Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abstract 44LB.; Sabin C, et al. Lancet. 2008;371:1417-26..

* Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddC)

ZDV ddI ddC d4T 3TC ABC TDF#PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157#MI: 523 331 148 405 554 221 139

1.9

1.5

1.2

1

0.8

0.6

Recent Exposure*: yes/noCumulative Exposure: per year

**

Rel

ativ

e R

isk

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)

21

VA Case Registry: Use of ABC or VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MITDF in Last Regimen and Risk of MI

Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.

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)

NRTI in last regimenduring obs. period

ABC TFV Both ABC and TFV

Haz

ard

rat

io

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

22

DHHS Guidelines:Criteria for Preferred PI

● The following criteria distinguish between preferred and alternative PIs:1. Superior or noninferior virologic efficacy compared to another

PI regimen, with at least 48-week data published;2. No more than 100mg of ritonavir per day;3. Once-daily dosing;4. Low pill count; and5. Good tolerability

● Using these criteria, ATV/r QD and DRV/r QD are preferred PIs


23

DRV/r and ATV/r in ARV-Naïve Patients: Higher Response Rates than LPV/r

Adapted from: 1. Mills A, et al. AIDS May 29, 2009 [Epub ahead of print]; 2. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d

*Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012)

ARTEMIS1

(ITT, TLOVR)*96 weeks

LPV/r QD or BID

DRV/r 800/100 QD

79

71

n=343n=346

0

20

40

60

80

100

CASTLE2

(ITT, NC=F)96 weeks

ATV/r300/100 QD

LPV/r400/100 BID

6874

0

20

40

60

80

100

n=443 n=440Pat

ien

t P

erce

nt

<50

co

pie

s/m

L

24

ARTEMIS: DRV/r Better Tolerated than LPV/r

Grade 2–4 adverse events*≥2% incidence, n (%)

DRV/r (N=343)

LPV/r (N=346)

Mean exposure (weeks) 95.0 91.4

Any grade 2–4 AE at least possibly related 80 (23) 119 (34)

GI AEs (all AEs) 23 (7) 52 (15)

Diarrhea 14 (4)‡ 38 (11)

Nausea 6 (2) 10 (3)

Rash (all types) 9 (3) 5 (1)

*Excludes laboratory abnormalities reported as adverse events; ‡p<0.001 vs LPV/r; no other AEs showed a statistically significant difference between the two treatment arms

Mills A, et al. AIDS May 29, 2009 [Epub ahead of print].

25

CASTLE:ATV/r Better Tolerated than LPV/r

a Through 96 weeksb Excluding lab abnormalities reported as AEs

Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d.

ATV/rn = 441n (%)

LPV/rn = 437n (%)

Serious Adverse Events (SAEs) 63 (14) 50 (11)

Grade 2-4 treatment-related AEsa 133 (30) 140 (32)

Grade 2-4 treatment-related AEs 3%a,b

Jaundice 18 (4) 0

Nausea 18 (4) 33 (8)

Diarrhea 11 (2) 54 (12)

26

Comparing PI Lipid Profiles

*Significantly different from LPV/r: P<0.0001 ATV/r vs. LPV/r; p<0.001 DRV/r vs. LPV/r (TC+TG)

Molina J, et al. 48th ICAAC/46th IDSA. Abst. H-1250d; Mills A, et al. Ibid. Abst. H-1250c; Walmsley S, et al. 11th EACS. Abst. PS1/4; Pulido F, et al. 47th ICAAC. Abst. H-361.

Mean (CASTLE) or Median (ARTEMIS)Total Cholesterol and Triglyceride Level Increases at 96 Weeks

*

100 mg RTV QD

200 mg RTV QD

** *19

14

26

18

36

55

35

56

0

10

20

30

40

50

60

Total Cholesterol Triglycerides

CASTLE: ATV/r + TDF/FTC

ARTEMIS: DRV/r + TDF/FTC

CASTLE: LPV/r + TDF/FTC

ARTEMIS: LPV/r + TDF/FTC

Lip

id V

alu

es

mg

/dl

27

D:A:DExposure to PIs and Risk of MI

D:A:D Study includes 33,308 patients, 580 with MI

Lundgren J, et al. CROI 2009, abstract 44, 2/8/2009

1.9

1.131.1

1

0.9

MI

RR

Per

Yea

r (9

5%C

I)

IDV NFV LPV/r SQV

68,469298

56,529197

37,136150

44,657221

PYFU:MI:

PI*

* Approximate test for heterogeneity: P=0.02Note: Insufficient number of pts on DRV/r and ATV/r to assess those agents

28

Cumulative exposure (per additional year)

No. exposed

No. exposed

cases OR [ 95% CI ] P value

Saquinavir 324 92 0.96 0.80 – 1.15 0.669

Indinavir 497 146 1.10 0.98 – 1.24 0.117

Nelfinavir 453 131 1.12 0.98 – 1.28 0.110

Lopinavir 290 94 1.37 1.09 – 1.72 0.006

Amprenavir/Fosamprenavir 117 46 1.52 1.19 – 1.95 0.001

ANRS:Exposure to PIs and Risk of MI

● Nested, case-control study to evaluate association between risk of MI exposure to NRTIs and PIs

● Over 115,000 HIV-infected patients enrolled between 1989 and 2006- Cases: 289 Patients with a first definite or probable MI prospectively

reported between January, 2000 and December, 2006- Matched Controls: For each MI case, up to 5 controls with no history

of MI matched for age, sex and clinical center

Lang S, et al .16th CROI; Montreal, Canada; February 8-11, 2009. Abst . 43LB.

Note: Insufficient number of pts on DRV/r and ATV/r to assess those agents

29

RAL: Pros and Cons

● PROs- New class

- No baseline resistance in ARV-naïve pts

- Well Tolerated

- Relatively few significant drug interactions

- Established efficacy in experienced pts

- No apparent teratogenicity

- No lipoatrophy based on early (48 week) data

● CONs- BID

- No long-term data

- No randomized data with NRTIs other than TDF/FTC

- PK/PD relationship unclear

- Resistance data still emerging

- No second generation agent available

30

100

80

60

40

20

00 8 16 24 32 40 48 60 72 84 96

Immunologic: 240 vs. 225 cells/mm3 (95% CI -13,+42)

Study Week

% P

ati

en

ts w

ith

HIV

RN

A L

ev

els

<5

0 C

op

ies

/mL

86%

82%

81%

79%

Non-inferiorityP-Value <0.001

STARTMRK: RAL and EFV Have Similar Virologic Efficacy Through 96 Weeks

Patients with HIV RNA <50 c/mL Through 96 Weeks (Non-Completer = Failure)

Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.

RAL + TDF/FTC EFV + TDF/FTC

31

STARTMRK: Adverse Events

● Overall adverse events similar between arms● CNS events higher in EFV arm, but

- were transient, mild and occurred within first 48 weeks- Led to few discontinuations- Rates of depression were similar between groups

AEs RAL (%) EFV (%) P value

Overall AE 266 (94.7) 275 (97.5) 0.086

Drug Related AE 132 (47) 220 (78) <0.01

Serious Clinical AE 40 (14) 34 (12) 0.457

Deaths 3 (1) 0

Malignancies 3 (1) 11 (4)

CNS 81 (29) 171 (61) <0.001


32

STARTMRK: Mean Change in Metabolic Parameters to Week 96

Change in TC/HDL ratio was RAL -0.18 and EFV -0.04 (p=0.192)Change in TC/HDL ratio was RAL -0.18 and EFV -0.04 (p=0.192)

-10

-5

0

5

10

15

20

25

30

35

40

45

T Chol HDL LDL TG

Mea

n C

han

ge

(mg

/dl)


P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001


33

STARTMRK: Mean Change in DEXA Morphological Parameters to Week 48

0

5

10

15

20

25

Appendicular Trunk Total

Me

an

% C

ha

ng

e in

Fa

t fr

om

B

as

elin

e


DeJesus E, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1571.

34

Recent Studies Comparing Non-Preferred to Preferred ARVs

Overall virologic failures: NVP QD 11.2%, NVP BID 12.8%, ATV/r 14.0%

Pat

ien

ts (

%)

wit

h H

IV R

NA

<50

c/m

L

ITT: 95% CI= -5.9% to 9.8%; p=0.63

67 65

0

20

40

60

80

100

ATV/rNVP (QD/BID)

1. Soriano V, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924c;2. Heera J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009. Abst. TUAB103.

ARTEN: Comparison of NVP and ATV/r in ARV-naïve pts starting at CD4+ <400 (Men)

and <250 (Women) (N=569)1

MERIT-ES: Comparison of EFV and MVC in ARV-Naïve Patients with an R5 screening

result by enhanced Trofile assay2

6259

0

20

40

60

80

100

MVCEFV

Week 48 <50 c/mL Week 96 <50 c/mL

• D/C for AEs: 15.5% EFV vs. 6.1% MVC

• Virologic failures: 5.9% EFV vs. 12.5% MVC

Pat

ien

ts (

%)

wit

h H

IV R

NA

<50

c/m

L

35








36

Potential Treatment Simplification Strategies

● Substitution of co-formulation for individual agents (e.g., EFV + TDF/FTC to EFV/TDF/FTC)

● Substitution for a single component of the regimen (e.g., ENF to RAL) to improve tolerability or decrease/prevent toxicity

● Dose or regimen de-escalation (e.g., Discontinuation of RTV or PI/r monotherapy)

● Maximizing the use of PK properties to achieve less drug exposure (e.g., FOTO)

37

Simplification Improves Adherence

* Using the Mixed Effect ModelDeJesus E, et al. ICAAC, San Francisco, 2009. # H1572

Analysis of Three Once-daily HAART Regimens by Daily Pill Burden*Analysis of Three Once-daily HAART Regimens by Daily Pill Burden*

QD

do

seQ

D d

ose

TDF + FTC + EFV TDF/FTC + EFV TDF/FTC/EFV

0 192144Week 9648

3 pills 1 pill2 pills

Extension phaseExtension phase

Daily Pill Burden Comparison P Value

1 vs. 2 0.2304

1 vs. 3 0.0005

2 vs. 3 0.0262

Once-Daily RegimensTDF + FTC + EFV

(n=238)TDF/FTC + EFV

(n=162)TDF/FTC/EFV

(n=157)

Daily Pill Burden 3 2 1

Dose Duration (study wks) BL → 96 97 - 144 145 – 240

Mean Adherance Rate (%) 95.6 97.0 97.9

38

EASIER: Quality of Life After Switch from Enfuvirtide to Raltegravir

Boulet T, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PE 7.2/2.

ENF + OBT HIV RNA <400 c/mL(Stable > 3 mos.)

Screening Randomization 1:1SWITCH RAL + OBT

MAINTENANCE ENF +OBTRAL + OBT

–W4 –W1 D0 W24 W48

-1.3

-5.3-4.7

2

5.84.8

-6

-4

-2

0

2

4

6

8

Significant Changes in Quality of Life From BaselineMaintenance Arm RAL arm

Physical Summary Pain Social Functioning

P=0.003 P=0.02P=0.001

Me

an

sc

ore

ch

an

ge

fro

m B

as

eli

ne

to

We

ek

24

BetterHRQoL

WorseHRQoL

39

SWITCHMRK 1 & 2:Study Design

● Identical, multicenter, double-blind, randomized, active-controlled studies

● Enrolled pts with HIV RNA <50 c/mL on LPV/r BID regimen in combination with at least 2 NRTIs- No limit on number of prior

ART regimens- Prior virologic failure not an

exclusion- No lipid lowering therapy

for at least 12 weeks

● Randomized (1:1) to continue LPV/r or switch to RAL

Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.

SWITCHMRK 1 SWITCHMRK 2

RAL

(N=174)

LPV/r

(N=174)

RAL

(N=176)

LPV/r

(N=178)

HIV RNA

≤ 50 c/mL94.3% 92.5% 96.0% 95.5%

Mean CD4 (cells/mm3) 478 508 471 482

LPV/r ≤ 1 yr 16.7% 17.8% 17.6% 18.5%

Median yrs prior ART(min, max)

3.3

(0.3, 22.3)

3.6 (0.5,

20.2)

3.7 (0.5,19.2)

4.6 (0.6,16.3

)

Median # prior ART(min, max)

5.0

(4.0, 16.0)

5.0 (2.0, 5.0)

5.5 (3.0,13.0)

6.0 (4.0,14.0

)

40

● Statistically significant improvements in total cholesterol, non-HDL cholesterol and triglycerides were observed following switch to RAL

● Further Analysis underway to assess factors associated with failure after switch to RAL- Previous Resistance: 84% with confirmed HIV RNA >50 c/mL) in the RAL group were not on 1st

ART regimen; 66% with history of VF on prior regimen(s)- NRTI Backbone: Virologic failure rate higher on ABC/3TC than TDF/FTC

SWITCHMRK 1 and 2:Virologic Outcomes (NC = F)

Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.

Per

cen

t H

IV R

NA

<50

Co

pie

s/m

L

50

60

70

80

90

100SWITCHMRK 1

0 4 8 12 24Weeks

81%

87%

(95% CI) : -6.6 (-14.4, 1.2)

0 4 8 12 24Weeks

94%

88%

(95% CI) : -5.8 (-12.2, 0.2)

SWITCHMRK 2

41

SWITCHMRK 1 and 2:Lower Response with ABC than TDF

http://www.emea.europa.eu/humandocs/PDFs/EPAR/isentress/Isentress-H-860-II-10-AR.pdf

Study 032: <50 copies/mL (Observed Failure)* Difference in percent

response

% (95 CI)

Raltegravir Lopinavir/r

Population n/N % (95 CI) n/N % (95 CI)

Total 139/154 90.3 (84.4, 94.4) 152/162 93.8 (88.9, 97.0) -3.6 (-10.0, 2.5)

Concurrent background ART

TDF** 72/79 91.1 (82.6, 96.4) 69/75 92.0 (83.4, 97.0) -0.9 (-10.4, 8.8)

ABC** 20/25 80.0 (59.3, 93.2) 22/23 95.7 (78.1, 99.9) -15.7 (-35.9, 4.1)**The difference in response was similar in study 033 (-12.9 % for ABC vs -4.6% for TDF)**plus FTC or 3TC

42

MONET: Simplification to DRV/r QD Monotherapy

Arribas J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUAB106.

N=2562NRTIs + PI/r or NNRTI

HIV RNA<50 X 6 monthsNo h/o VF; DRV naive

N=2562NRTIs + PI/r or NNRTI

HIV RNA<50 X 6 monthsNo h/o VF; DRV naive

DRV/r 800/100 mg QD + 2 NRTI* (n = 129)

DRV/r 800/100 mg QD (n = 127)

96 wks96 wks

DRV/r + 2NRTIs DRV/r

HIV RNA < 50copies / mL, ITT, TLOVER,S=F 85.3% 84.3%

HIV RNA < 50 at last visit 97.7% 97.6%

Primary PI mutation 1 1

Grade 2-4 GI AEs ≥ 2% incidence 3.9% 5.5%

Grade 2-4 GI AEs ≥ 2% incidence( all types ) 1.6% 1.6%

ALT > 5 x ULN 1.6% 4.8%

Total Cholesterol > 300mg / dL, sustained 1.6% 4.8%

43

IMANI III: Lopinavir/r QD Monotherapy

● 48 week open-label pilot study

● Evaluated efficacy, safety and tolerability of LPV/r QD monotherapy in pts with undetectable VL while in active follow-up post IMANI I or after completion of IMANI II (LPV/r BID in ARV-naïve patients)

LPV/r QD monotherapy for simplification: Caution warranted until results from larger ongoing

studies evaluated

Gathe J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 4/5.

IMANI III

31 Subjects

IMANI I

4 Subjects

IMANI II

27 Subjects

2 protocol defined

failures at Week 36

1 LFTU at

Week 48

27 Subjects

Week 48

SubjectBaseline

Mutations Week VLOn Treatment

Mutations

007 L63P 36 4,145M461, I54V, I62V, L63P,

V82A

021L63P, A71T

36 3,582L10V, V32I,

M46I/W, I47V, L63P, A71T

44

DHHS Guidelines:Regimen Simplification

● Switching patients with an extensive treatment history from LPV/r to RAL should be done with caution

● RAL can safely substitute for ENF in patients not previously treated with integrase inhibitors

● Any drug substitution may introduce unanticipated adverse effects or drug-drug interactions

● PI/r monotherapy studies have reported mixed results and should not be regarded as a clinical strategy until further data are available


45








46

Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm

2009 DHHS Guidelines: Opt-out Testing

● Patients must be identified early in the course of HIV infection, making earlier initiation of therapy an option

● Most HIV-infected patients are not diagnosed until they are at much later stages of disease

● For the current treatment guidelines to have maximum impact, opt-out testing per current CDC recommendations is essential

47

CDC Recommendation for HIV Testing in Adults and Adolescents

● Routine, voluntary, HIV screening for all persons aged 13–64 years, not based on risk

● Opt-out HIV screening• Opportunity to ask questions and option to decline

● Consent for HIV test is part of general consent for care• Separate consent not recommended• Prevention counseling not required in conjunction with HIV screening

● Low-prevalence setting• If yield from screening <0.1%, continued routine screening not warranted

Branson BM et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.

48

Removing Written Consent Increases HIV Testing Rates

● After HIV testing opt-out policy change, rate of HIV tests per 1000 patient-visits increased 4.38 (CI, 2.17–6.60, p<0.001)

● No increase in ordering of other tests (hematocrit or creatinine) or of HIV testing in control setting without policy change

● Increase occurred across all patient populations and led to a rise in newly-diagnosed HIV

Zetola PLoS One. 2008;3(7):e2591

20

15

10

5

0

HIV

Te

sts

per

1,0

00

pat

ien

t -v

ts

0 6 12 18 24 30 36

MonthsJuly 2004 June 2007

Before Policy After Policy

SFGH HIV Tests

50

40

30

10

0Te

sts

per

1,0

00 v

isit

s

0 6 12 18 24 30 36



Creatinine Tests

20

20

15

10

5

0

HIV

Te

sts

per

1

0,0

00

Lab

ora

tory

t

0 6 12 18 24 30 36



Control University-based Medical Center HIV Tests

Hematocrit Tests

50

40

30

10

0Te

sts

per

1,0

00 v

isit

s

0 6 12 18 24 30 36



20

49

Changing HIV Testing Laws: Impact on Survival

● Comparison of diagnosis rates in states with opt-out vs. opt-in testing

● In states with opt-out testing, HIV is diagnosed at a higher CD4 cell count better treatment outcomes

● Computer-based simulation model of HIV disease applied to these data

● If all remaining states switched to opt-out, potential national survival gain would be > 600,000 life years

April M, et al. 47th IDSA Meeting, Philadelphia, 2009. Abst. 1254

50

HIV Testing Expansion: Earlier Diagnosis, Higher CD4 Counts

● Program to expand testing in medical and jail settings in Washington, DC began in 2006

● Since program began, patients diagnosed with higher CD4 counts at initial testing

● During first 18 months of program, increase in median CD4+ count at diagnosis to 332 cells/mm3

Median CD4+ Countat Time of Testing

215

187 198220

262

332

183

0

50

100

150

200

250

300

350

2001 2002 2003 2004 2005 2006 2007

Year of HIV Diagnosis

Me

dia

n C

D4

Co

un

t

Hader S, et al. 16th CROI; 2009; Montreal. Abstract 57.

51

Adoption of Opt-out Testing

Opt in Opt out

Written consent required: n= 8 (MA, MI, NE, OR, NY, PA, WI, RI)

Mahajan AP, et al. Ann Intern Med 2009;150:263-9.

52

Why is Opt-out Screening Not Being Implemented in All States?

● Need to reduce stigma and discrimination before universal testing

● Before universal testing there must be universal prevention counseling for HIV-negative and treatment and care for HIV-positive

● Broad testing leading to increase in numbers of HIV- positive patients entering into care could potentially have grave consequences due to a lack of funding and healthcare resources

● While it is everyone’s human right to know their HIV status, they also have the right to decide when and where they will be HIV tested

The Global Network of People living with HIV, Scaling up HIV Testing: Different perspectives; http://www.gnpplus.net/component/option,com_docman/task,cat_view/gid,245/Itemid,53/?mosmsg=You+are+trying+to+access+from+a+non-authorized+domain.+%28search.yahoo.com%29; Accessed 12/10/09

53








54

First Positive HIV Vaccine Trial

● 16,401 patients enrolled from 2003-2005 in Thailand in placebo-controlled trial

● Intervention: Canarypox ALVAC-HIV and glycoprotein 120 AIDSVAX B/E (“boost)

● Intervention reduced infection by 30%

Rerks-Ngarm S et al. N Engl J Med 2009.

0.00.10.20.30.40.50.60.70.80.91.0

0 0.5 1 1.5 2 2.5 3 3.5

Years

Prob

abili

ty o

f HIV

-I In

fect

ion

(%)

PlaceboPlacebo

VaccineVaccine

Intention-to-analysisIntention-to-analysis Modified Intention-to-analysisModified Intention-to-analysis

0.00.10.20.30.40.50.60.70.80.91.0

0 0.5 1 1.5 2 2.5 3 3.5

Years

Prob

abili

ty o

f HIV

-I In

fect

ion

(%)

P<0.05

55

Many PrEP Trials Pending

Study/Location

Sponsor/ Funder

Population (mode of exposure) Intervention arms (s)

Status/ExpectedCompletion

US Extended Safety Trial (CDC 4323)United States

CDC 400 gay/men and other men who have sex with men (penile/rectal)

Daily oral TDF Fully enrolled/2009Fully enrolled July 2007Final data analysis Q1/10

Bangkok Tenofovir Study(CDC 4370)Thailand

CDC 2,400 injecting drug users (parenteral)

Daily oral TDF Enrolling/20101st interim analysis Q4/09

CAPRISA 004South Africa

CAPRISA, FHI, CONRAD, USAID,LIFElab

1,200 heterosexual women (vaginal)

Coitally dependent topical tenofovir gel

Fully enrolled/20101st interim analysis in Q4/082nd interim analysis in Q3/09

iPrExBrazil, Ecuador, Peru,South Africa, Thailand, US

NH, BMGF 3,000 gay men and other men who have sex with men (penile/rectal)

Daily oral TDF/FTC Enrolling/20111st interim analysis in Q4/09

TDF2 (CDC 4940)Botswana

CDC 2,000 heterosexual men and women (penile and vaginal)

Daily oral TDF/FTC

(switched from TDF Q1 2007)

Enrolling 2012

Partners PrEPKenya, Uganda

BMGF 3,900 serodiscordant heterosexual couples (penile and vaginal)

Daily oral TDF & daily oral TDF/FTC

Enrolling 2012

FEM-PrEPKenay, Malawi, South Africa, Tanzania, Zambia

FHI, USAID, BMGF

3,900 heterosexual women (vaginal)

Daily oral TDF/FTC Enrolling 2012

VOICE (MTN 003)South Africa, Uganda, Zambia, Zimbabwe, additional sites to be determined

MTN, NIH 5,000 heterosexual women (vaginal)

Daily oral TDF; daily oral TDF/FTC; daily topical tenofovir gel

Enrolling 2013

IAVI E001 and E002Kenya, Uganda

IAVI 150 serodiscordant couples and at-risk men and women (vaginal and penile/rectal)

Daily oral TDF/FTC; intermittent oral TDF/FTC (twice weekly – coital dosing)

Planning/2010Anticipated start Q3/2009

Ongoing ARV based Prevention (Oral PrEP and Topical Microbicide) Trials (September 2009)

BMGF-BI & Melinda Gates Foundation; CAPRISA – Centre for the AIDS Programme of Research in South Africa; CDC – US Centers for Disease Control and Prevention; FHI – Family Health International; FTC – emtricitabine; IAVI – International AIDS Vaccine Initiative; MTN – Microbicide Trials Network; NIH – US National Institute of Health; Q1-4 – quarters 1-4; TDF – tenofovir disoproxil fumarate; USAID – United States Agency for International Development

56

A Major PrEP Issue:Is it Cost-Effective in the US?

● Computer simulation of HIV acquisition, detection, and care to model PrEP among MSM at high risk of HIV in US

● Model assumed 50% PrEP efficacy and TDF/FTC $753/month● Base-case: $298,000/Quality-adjusted life year (QALY) – not

generally considered cost-effective by US standards

Paltiel AD, et al. Clin Infect Dis 2009;48:806-815..

$0 $100,000 $200,000 $300,000 $400,000 $500,000+ $0 $100,000 $200,000 $300,000 $400,000 $500,000+

TDF Resistance (0%-100%)

ART Efficency Reduction (0%-15%)

PrEP Toxicity (None Extreme scenario)

Cohort age (30-34)

HIV Testing Frequency (Never-Annual)

PrEP Cost Multiplier (0.1-1.0)

HIV Injection Incidence Multiplier (0.3-2.0)

PrEP Efficiency (90%-20%)

Incremental Cost per QALY

57

2009 DHHS Guidelines: Preventing Secondary Transmission of HIV

● Essential tools for prevention of sexual and blood-borne transmission of HIV include:- Consistent and effective use of ARV therapy, resulting in a

sustained reduction in viral load;- Consistent condom usage;- Safer sexual and drug use practices; and- Detection and treatment of STIs

● Medical visits provide an opportunity to:- Reinforce HIV prevention messages;- Discuss sexual- and drug-related risk behaviors;- Diagnose and treat intercurrent STIs; and

- Develop open communication between provider and patient


58

HIIV Treatment Reduces the Risk of Transmission

ARV StatusCY

ObservationNo. LinkedInfections

InfectionRate (C-Y)

Infection RateRatio (95% CI)

Not on ARV 5,062 171 3.4/100 ---

On ARV 547 4 0.7/100 0.21 (0.08, 0.59)

On ARV –conservative*

547 6 1.0/100 0.32 (0.14, 0.73)

● Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05)● Both ART and change in behavior independently reduced HIV

transmission

*Includes 2 partners who seroconverted in the same 3-month interval when the HIV-infected partner initiated ARVs

2,993 couples were followed for a median of 512 days

HIV-free Survival of HIV-negative partners,by ARV status of HIV+ Partner

0

2073920

500

1035475

1000

598256

1500

25269

2000

806

2500

00

0.0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al P

rob

ab

ilit

y

Days

Off ARV On ARV

CensoredLogrank P<.0001

Sullivan P, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 52bLB.

59

Potential Impact of “Test and Treat” Strategy on HIV Epidemic and Use of ART

Granich R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPL101.

Strategy: Universal ARTART if CD4+ <350 cells/mm3No ART

0.0000.0050.0100.0150.020

Inc

ide

nc

e/y

ea

r

0.00

0.05

0.10

0.15

Pre

va

len

ce

0.00

0.05

0.10

0.15

1980 2000 2020 20400.000

0.005

0.010

Mo

rta

lity

/ye

ar

0.000

0.005

0.010

1980 2000 2020 2040

HIV ART

Pro

po

rtio

n o

f ad

ole

scen

ts a

nd

ad

ult

s 15

yea

rs o

r o

lder

0.0000.0010.0020.0030.0040.005

60

Concerns Regarding Using “Test and Treat” Strategy

1. Crepaz N et al. JAMA 2004;292:224-236; 2. Vernazza PL, et al. AIDS 2000;14:117-21; 3. Marcelin, A-G, et al. AIDS 2008;22:1673-81.

HIV RNA detected in semen of 7/145 (5%) of men with VL <40 c/mL

#

HIV RNA in seminal

plasma (c/mL) ARV combination

1 940 ZDV, 3TC, IDV, RTV

2 257 3TC, EFV, LPV/r

3 1230 ZDV, 3TC, LPV/r

4 255 TDF, FTC, AZT

5 802 ZDV, 3TC, IDV, RTV

6 267 FTC, ATV, RTV

7 620 TDF, FTC, EFV

HIV in semen in ARV naïve and ARV treated men with VL <400

0%

20%

40%

60%

80%

100%

HIV-RNA HIV-DNA

Pe

rce

nta

ge

of

pa

tie

ns

wit

h

de

tec

tab

le H

IV i

n s

em

en Controls (drug naïve ) n=55

Effective treatment n=114

P<0.0001P<0.0001

P<0.01P<0.01

● Patients who believe that ART or an undetectable viral load protects against transmitting HIV have higher rates of unprotected sex (OR 1.82; 95% CI, 1.52-2.17)1

● While HIV RNA significantly lower in semen of pts on ART with an undetectable plasma HIV RNA, still detectable in some2,3

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62

Life Expectancy of ARV-treated Patients by CD4 Nadir

Depending on when HAART is started, life expectancyduring modern HAART era is 10 to 30 years less than that

in uninfected patients

CD4+ Nadir (cells/mm3) < 100 100-200 >200

Life expectancy at age 20 (years)

32 42 50

ART-Cohort Collaboration. Lancet. 2008;372:293-299 (see also Lohse N, et al. Ann Intern Med. 2007;146:87-95 and Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-77.)

Life Expectancy by CD4+ Nadir When HAART Started

63

Kaplan RC, et al. Clin Infect Dis. 2007; 5:074-1081.

Traditional Health Related Risk Factors More Prevalent Among HIV-positive Patients

0 10 20 30 40 50 60 70 80

0 10 20 30 40 50 60 70 80

Prevalence, % (95% CI)

High LDL Level

Low HDL Level

HighTriglycerides Level

Hypertension

Smoking

Overweightor Obese

Diabetes

HIV+ Men

HIV- Men

HIV- Women

HIV+ Women

64

Many Non-AIDS Events Appear to be Higher in Treated HIV Disease than Controls

● Cardiovascular disease1-4

● Cancer (non-AIDS)● Bone fractures/osteopenia5,6

● Left ventricular dysfunction● Liver failure7

● Kidney failure● Cognitive decline (controversial)8

● Frailty9

1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2. Hsue P, et al. Circulation. 2004;109:316-319. 3. Mary-Kraus M, et al. AIDS. 2003;17:2479-2486. 4. Grinspoon SK, et al. Circulation. 2008;118:198-210. 5. Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8. McCutchan JA, et a. AIDS. 2007;21:1109-1117. 9. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286

65

Many Factors Contribute to Non-AIDS Events Being More Common In HIV

Behavior

Pre-HAARTHarm

HAARTToxicity

PersistentImmuneDefects

PrematureAging

Deeks and Phillips, BMJ 2009

66

Association Between Current CD4 Cell Count and Non-AIDS Complications

StudyNon-AIDS

malignancies Renal disease/death CVD events/deathLiver disease/

death

FIRST Yes Yes Trend, NS No

D:A:D Yes Yes Trend, NS Yes

CASCADE Yes NA Yes Yes

SMART Trend, NS Trend, NS Trend, NS Yes

Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.

Is Lower Current CD4 Cell Count Significantly Associated With Increased Risk of non-AIDS Events?

67

DHHS Guidelines: T-cell Activation and Inflammation

● Early untreated HIV infection associated with sustained high-level inflammation and T-cell activation which are associated with disease progression

● ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation- Persistent inflammation, as represented by levels of IL-6, may be

associated with risk of death

● These observations support earlier use of ART:- Treatment decreases the level of inflammation and T-cell

activation; and- Degree of residual inflammation and/or T-cell dysfunction during

ART is higher in patients with lower CD4 cell nadirs and earlier treatment may result in less residual immunological perturbations


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Current Clinical Controversies in the Treatment of HIV/AIDS Paul E. Sax, MD Clinical Director,...

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Transcript of Current Clinical Controversies in the Treatment of HIV/AIDS Paul E. Sax, MD Clinical Director,...