Selected Controversies in Selected Controversies in Antiretroviral TherapyAntiretroviral Therapy

Joel E. Gallant, MD, MPH

Johns Hopkins University School of Medicine

When to Start Therapy?When to Start Therapy?

Will We Return to Earlier Therapy?

Availability of more potent, easier, and less toxic regimens

The Move Toward Simpler Regimens3-drug regimens: 1996 and 2005

1996: ddI + d4T + SQV

-SQV: 6 q8h with fatty food

-ddI: 2 bid ½ hr ac or 2 hrs pc

-d4T: 1 pill bid

-24 pills/d, 5 doses

-significant long-term toxicity

2005:TDF/FTC or ABC/3TC + EFV

-2 pills qd

-no food restrictions

-no long-term toxicity anticipated

One Pill, Once Daily Triple Combination Regimen?

tenofovir + emtricitabine + efavirenz

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

Boosted PI

NNRTI

NRTI

Unboosted PI

Collated Results of HAART Studies

Bartlett JA et al. Abstract 586.

Previous analysis emphasized relation b/w pill burden and response

Updated analysis: pill burden less important

Highlights efficacy of boosted-PI and NNRTI regimens

0

15

30

45

60

75

90

105

120

135

150

Med

ian

CD

4+ In

crea

se

97

119 120 121127 125

150Median CD4+ increase

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 increase in later years

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

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

24.8 23.017.3

12.4 10 8 8.4

0

10

20

30

40

50

1996 1997 1998 1999 2000 2001 2002

% with > 500 copies/mL

60

70

80

90

100

% W

ith

VL

> 5

00 o

n A

RT

What Degree of Adherence is Needed? Data From Unboosted PIs

Adherence to a PI-containing regimen correlates with HIV RNA response at 3 months

% V

L <

400

co

pie

s/m

L

PI Adherence, % (MEMS caps)

0

20

40

60

80

100

< 70 70–80 80-90 90–95 > 95

Paterson DL, et al. Ann Intern Med. 2000;133:21-30.

Adherence and Virologic Suppression:NNRTIs vs. unboosted PIs

Bangsberg DR et al. 12th CROI, 2005. Abstract 616.

PINNRTI

0-53 54-73 74-93 94-1000

20

40

60

80

100

% V

L <

400

co

pie

s/m

L

% Adherence (Pill Count)

0-53 54-73 74-93 94-1000

20

40

60

80

100

% Adherence (Electronic Measurement)

109 indigent patients in San Francisco: 56 on unboosted PIs, 53 on NNRTIs VL < 400 reliably seen with NNRTI if adherence > 54%, but with unboosted

PI, only with very high adherence Predictors of VL < 400: NNRTI use, adherence, high CD4 nadir, time on Rx

Will We Return to Earlier Therapy?

Availability of better, easier, and less toxic regimens Conflicting cohort data: some studies show benefit

with earlier therapy

Cohort Studies Supporting Earlier Therapy

Swiss Cohort: Better prognosis with initiation of HAART at CD4 >3501

HOPS: Trend toward lower mortality in pts treated with CD4 351-5002

ALIVE: Survival of HIV+ IDUs only approximated that of HIV- IDUs when HAART initiated at CD4 >3503

1. Opravil M, et al. AIDS 2002; 2. Palella FJ, et al. Ann Intern Med 2003; 3. Wang C, et al. J Infect Dis 2004

Will We Return to Earlier Therapy?

Availability of more potent, easier, and less toxic regimens

Conflicting cohort data: some studies show benefit with earlier therapy

Risk of prolonged HIV exposure independent of CD4? (dementia, NHL, PML, KS)

Will We Return to Earlier Therapy?

Availability of more potent, easier, and less toxic regimens

Conflicting cohort data: some studies show benefit with earlier therapy

Risk of prolonged HIV exposure independent of CD4? (dementia, NHL, PML)

Maintain options for intermittent therapy

Intermittent CD4-Guided TherapyThe BASTA Study

Maggiolo F, et al. 43rd ICAAC, Chicago, September 2003, H-448

• 18/76 (24%) restarted HAART at least once

• 95% in STI group have maintained CD4 >400 at 20 months of follow-up

• Better lipid profiles in STI group:

• Only nadir CD4 <350 cells/mm3 predicted time to restart HAART

• Cost of care in STI group decreased by ~€300/month

114 patients:CD4 >800 cells/mm3

HIV RNA <50 c/mL

Continuous therapy(n=38)

Restart therapy when CD4 <400 cells/mm3

(n=76)

Characteristics:3.2 prior ARV regimens

57 mo of prior ARVPre-ARV RNA: ~100,000 c/mL

The BASTA Study: Maggiolo’s Conclusion

“…“…therefore, we should start therapy therefore, we should start therapy earlier so we can stop.” earlier so we can stop.”

CD4-Guided Intermittent TherapyC

D4

Cou

nt

CD4 Treatment threshold

= on HAART Time

Treatment interruption (years)

CD4 nadir = strongest predictor of time off therapy

Will We Return to Earlier Therapy?

Availability of more potent, easier, and less toxic regimens

Conflicting cohort data: some studies show benefit with earlier therapy

Risk of prolonged HIV exposure independent of CD4? (dementia, NHL, PML)

Maintain options for intermittent therapy Preserve R5-tropic status

How Will We Use New Agents?How Will We Use New Agents?

Targets for Antiretroviral Therapy

Reverse Reverse Transcriptase Transcriptase

InhibitorsInhibitors

Protease Protease InhibitorsInhibitors

Integrase Integrase InhibitorsInhibitors

EntryEntryInhibitorsInhibitors

PIsPIs

NRTIs,NRTIs,NNRTIsNNRTIs

Attachment Attachment Inhibitors, Inhibitors, Coreceptor Coreceptor AntagonistsAntagonists

Maturation Maturation InhibitorsInhibitors

Fusion Fusion InhibitorInhibitor

NRTIs/NtRTIs» SPD 754 (DOTC)

» Amdoxovir (DAPD)

» D-D4FC

» Alovudine (MIV 310)

» Racivir (+/–FTC)

» SN1212

» Compound X

Protease inhibitors» TMC114

» GW0385

» P-1946

Entry inhibitors» Aplaviroc

» Maraviroc

» Vicriviroc

» BMS-488043

» TNX-355

» NB-2, NB-64

» T-649

NNRTIs» TMC125» GW678248

(prodrug = GW695634)» TMC278» BILR 355 BS» CSIC» DAPY/DATA» UC781» TMC120 (as microbicide)

New Antiretrovirals in Development

CCR5 Inhibitors in Development

OaLb0203 -2.0

-1.5-1.0

-0.5

0

0.5

Placebo 15Placebo 0725 mg QD50 mg BID100 mg QD

100 mg BID150 mg Fast150 mg Fed300 mg QD300 mg BID

0 5 10 15 20 25 30 35 40

Time (days)

10 mg BIDPlacebo

25 mg BID50 mg BID

HIV-infected volunteers (N = 48)

0.5

0.0

-0.5

-1.0

-1.5

0 5 10 15 20 25 30

Days

Dosing Period Washout Period

Vicriviroc (SCH-417690)

Maraviroc (UK-427857)

Dosing

Greater risk of postural hypotension

Me

dia

n V

L C

ha

ng

e F

rom

B

L (

log

10 c

op

ies

/mL

)

-1.8-1.6-1.4-1.2

-1-0.8-0.6-0.4-0.2

5 10 15 20 25 30

00.2

0

Placebo200 QD

0.4

Day

200 BID 400 QD 600 BID

Dosing

Most common AE: minor, self-limiting GI

events

Aplaviroc (GW873140)

Me

dia

n V

L C

ha

ng

e F

rom

B

L (

log

10 c

op

ies

/mL

)

Me

dia

n V

L C

ha

ng

e F

rom

B

L (

log

10 c

op

ies

/mL

)

Increasing Prevalence of X4- or R5/X4-Tropic Virus At Lower CD4 Counts

CCR5: Pts with early stage HIV-disease tend to

have pure R5-tropic virus

CXCR4: With advanced disease, X4- or dual-

tropic virus emerges Associated with more rapid clinical and

immunologic progression

CCR5 inhibition: could select for more virulent X4-tropic virus

Moyle G, et al. Abstract 1135, 44th ICAAC, Washington, 2004

16 16 14.8

41.9 40

0

10

20

30

40

50

60

70

80

> 300

248

Pre

val

en

ce

of

X4

or

R5

/X4

, % 90

100

> 201-300

104

> 101-200

81

> 51-100

31

< 50

50

CD4 count

n =

Emergence of R5/X4 Virus During Maraviroc Monotherapy: Selection of Baseline Variants

Lewis ME, et al. ICAAC 2004. Abstract 584b.

0

20

40

60

80

100

Prescreen

% o

f E

nve

lop

e C

lon

es

Day 1 Day 11

n = 67R5X4R5/X4

Day 40 Day 203 Day 251 Day 308 Day 373

n = 118

n = 52 n = 63

n = 46 n = 44 n = 49 n = 48

0

20

40

60

80

100

% o

f E

nve

lop

e C

lon

es

R5R5/X4

Day 1 Day 11 Day 40

n = 97

n = 68n = 91

Tropism assay threshold ~ 10%

Treatment selects for preexisting minority variants

Patient A

Patient B

CCR5 Inhibitors for Initial Therapy

PROs: Naïve patients less likely to have X4- or R5/X4-tropic virus Well tolerated and convenient in early trials

CONs: Tough competition (e.g. 1 pill qd, well tolerated, with minimal

long-term toxicity) May require tropism screening: more expensive if used up-front

before initial therapy in all patients

Which agent(s) would it replace?

CCR5 Inhibitors for Experienced Patients

PROs: Effective against NRTI-, NNRTI-, and PI-resistant virus May be synergistic with other entry inhibitors (e.g. ENF) Cost of tropism assay easier to justify in subset of patients failing therapy

CONs: Greater likelihood of X4- or R5/X4-tropic virus with more treatment

experience or more advanced disease Efficacy with dual-tropic virus depends on activity of other drugs in

regimen, which decreases with greater treatment experience.

Integrase Inhibitors: Short-term Monotherapy with L-870,810

Randomized, double-blind, placebo-controlled, 10-day dose-finding study 200 mg BID (n=7) vs 400 mg BID (n=17) vs placebo (n=6)

Development stopped due to preclinical toxicity, but proof of concept demonstrated Other candidate being evaluated Little S, et al. 12th CROI, # 161

Days since randomization

On therapy Post therapy

Δ f

rom

bas

elin

e H

IV

RN

A

log 1

0 c/

mL

–2

–1

0

1

2

1 3 8 10 17 24

–2

–1

0

1

2

L-000870810 200 mg L-000870810 400 mg Placebo

How Will We Use Integrase Inhibitors?

Too soon to tell…» Depends on potency, convenience,

tolerability, toxicity» Unlike CCR5 inhibitors, there appear to be

no other specific considerations that argue for earlier or later use

Can “2nd Generation” Agents Move to the Head of the Line?

Yes: LPV/r started out as a “salvage drug” but became a 1st-

line PI because of greater potency, durability, and lack of resistance with failure

Other examples: TDF, ABC

What does it take to become 1st-line in a class? Advantages with respect to tolerability, toxicity,

convenience, durability, and/or resistance profile

The Potential for Earlier Use of 2nd Generation Agents

PIs » Tipranavir: unlikely because of higher RTV dose, greater PI toxicity, pill

burden, bid dosing» TMC 114: more likely than TPV, though still bid with higher pill burden than

current standards

NNRTIs» TMC 125: unlikely because of higher pill burden vs. EFV» TMC 278: low pill burden, potential for earlier use if better tolerated than

EFV

NRTIs» D-d4FC: qd dosing, but need data on resistance profile with failure

Tipranavir/Ritonavir Superior to Lopinavir/Ritonavir in RESIST Studies

TPV/r superior to LPV/r at Week 24 in PI-experienced patients In subgroups in each arm receiving same total number of active drugs,

TPV/r arm remained superior

Cooper D, et al. ICAAC 2005, Abstract 560.

45.335.2 39.636.1

10.721.4

0

20

40

60

80

100

LPV/rNaive

LPV/r Experienced

Overall

45.735.8 39.639.6

13.121.4

0

20

40

60

80

100

LPV/r Susceptible

LPV/rResistant

Overall

TPV/rLPV/r

% W

ith

VL

≥1

log

10 c

/mL

P < .05 P < .0001 P < .05 P < .0001

TPV Mutation Score vs IAS-USA Protease Gene Resistance Mutations

Many mutations (13, 35, 43, 58, 74, 83) have not been associated with resistance to other PIs Major mutations (D30N, G48V, N88D, L90M) associated with other PIs do not contribute to

TPV mutation score

 10

 

S

C

SAMV

TTAVVIR

SFSTLVALLFMI

MDVAICVpVLLVVIIIINIRF

 9088848277 7371  63 545350484746 36 3332302420 IAS-USA

LNIVVCALIFIGIMMLVDLKL

VV

TMR

VLPKEAVLTIGFMV

 848382 74 69 5854   474643363533   2013 10TPV

IVTHQIIMKMELKI

Score 

D

N

V

L

Relationship of TPV Score to TPV Phenotype Results and Response

Valdez H, et al. Resistance Workshop 2005. Abstract 27.

-2

-1

0

-3

Med

ian

Ch

ang

e in

VL

at

Wk

24*

(lo

g10

co

pie

s/m

L)

0-1 2-3 4-5 6-7 8-9

-2.10(n = 144)

-0.89(n = 242)

-0.45(n = 260)

-0.49(n = 68)

-0.08(n = 4)

TPV Score

Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 14.7-52.5

*24-week data from patients in RESIST-1 and -2 given TPV/r

POWER1: Virologic Response to TMC114/r

LB0102

Time (weeks)

Pat

ien

ts w

ith

HIV

-1 R

NA

< 5

0 co

pie

s/m

L (

%)

0

1 2 4 8 12 16 20 24

TMC114/r 400 QD (n = 64)TMC114/r 800 QD (n = 63)TMC114/r 400 BID (n = 63)TMC114/r 600 BID (n =65)Comparator PIs (n = 63)

P < .001 for all doses80

60

20

40 43%48%49%53%

18%

100

New Trends in Resistance and New Trends in Resistance and Drug SequencingDrug Sequencing

Sequencing therapy in 2006 and beyond: how many tries do you get?

• One of many plausible scenarios:2 NRTIs + 1 NNRTI

→ 3 NRTIs + 1 PI/r → 1 PI/r + CCR5 inhibitor +/- NRTIs → integrase inhibitor + ENF + other CCR5 inhibitor +/-PI/r → maturation inhibitor + other entry inhibitor(s) + ?

• Problems:• People who fail initial therapy today were probably non-adherent with

simple regimens• The “first shot’ may always be the “best shot”• Infection with resistant virus can eliminate many sequences

Resistance Mutations:What’s “In” and What’s “Out” in 2005

OUT TAMs

» Selected by ZDV and d4T, which will be used less frequently in initial therapy

» Usually absent with initial failure» Impact of generic ZDV?

PI mutations» Typically absent with early failure of boosted PIs

Resistance Mutations:What’s “In” and What’s “Out” in 2005

IN M184V

» 3TC and FTC are used in all initial regimens» M184V emerges quickly with failure

NNRTI mutations» NNRTIs used widely for initial therapy» NNRTI resistance emerges quickly with failure

K65R, L74V» Still not widely seen, but more likely to be selected by today’s regimens» May not be preventable with early modification

ENF mutations» Emerge rapidly with non-suppressive ENF-containing therapy

GS934: Efficacy and Tolerability48-week data

Pozniak AL, et al. IAS 2005. Abstract WeOa0202.

Excluding pts with baseline NNRTI resistance

FTC + TDF 80% vs AZT/3TC 70% (P = .021)

AEs leading to D/C

FTC + TDF + EFV

(n = 257)

AZT/3TC + EFV

(n = 254)

Any AE 10 (4%) 23 (9%)*Anemia 0 14 (6%)

Nausea 1 (1%) 4 (2%)

Fatigue 0 3 (1%)

Vomiting 0 2 (1%)

Dermatitis 2 (1%) 0

Neutropenia 0 2 (1%)

Differences in efficacy primarily due to differences in discontinuation due to AEs

* P = .016

Pat

ien

ts w

ith

HIV

-1 R

NA

<

400

co

pie

s/m

L [

TL

OV

R]

(%)

77%

68%

P = .034

FTC + TDF + EFV AZT/3TC + EFV(ITT n = 509)

0

20

40

60

80

BL 8 16 24 32 40 48

100

Weeks

GS934: Resistance Analysis

BL NNRTI resistance mutations ↓ response, whereas BL NRTI resistance mutations had little impact» 2/22 (9%) with BL NNRTI-R had VL < 400 at Wk 48» 12/13 (92%) with BL NRTI-R had VL < 400 at Wk 48

Resistance Mutations at Wk 48

FTC + TDF + EFV(n = 244)

ZDV/3TC + EFV(n = 243)

Resistance analysis, n (%) 12 (5%) 23 (10%)

Population n (% mITT, % RAP) n (% mITT, % RAP)

Any resistance mutations 9 (4%, 75%) 17 (7%, 77%)

Any EFV-R 9 (4%, 75%) 16 (7%, 73%)

Any M184V/I 2 (1%, 17%) 7 (3%, 32%)

Any TAM 0 1 (< 1%, 5%)

K65R 0 0

McColl D, et al. IAS 2005. Abstract TuPp0305. % mITT, % of patients in modified intent-to-treat analysis; % RAP, % in patients with resistance testing

“Nuke-Sparing Regimens”: The Latest Thing or Old News?

Rationale was based on concerns about inevitable mitochondrial toxicity with NRTIs

Role of NRTIs on Change in Limb Fat (ACTG 5005)

*P<0.05 between groups; †P<0.05 within groups. Dube M, et al. 2002; 4th Lipo Wkshp. Abstract 27.

IQR

** *

†

††

†

††

N=156; analysis by intent to treat

Me

dia

n %

ch

ang

e f

rom

ba

sel

ine

-30

-20

-10

0

10

20

Study Week

AZT/3TC ddI+d4T

Entry 16 32 48 64 80

“Nuke-Sparing Regimens”: The Latest Thing or Old News?

Rationale was based on concerns about inevitable mitochondrial toxicity with NRTIs» These concerns have subsided with greater use of

“mitochondria-friendly” NRTIs (TDF, ABC, 3TC, FTC)

RAVE Study: Switch Thymidine Analog to ABC or TDF

Suppressed patients with self-defined lipoatrophy on thymidine analog (TA)

105 pts randomized to replace TA with TDF or ABC

Total limb fat increased to similar extent in both arms over 48 weeks

Moyle G, et al. 12th CROI, 2005, Abstract 44LB.

Ch

ang

e i

n f

at

mas

s (g

) b

y D

EX

A,

Wk

48

393522

1061

316

791

1046

0

200

400

600

800

1000

1200

Limb Trunk Total Fat

TDFABC

Within-group change in limb fat from baseline: TDF P = .01, ABC P = .001

GS 903E: Impact of Switching off d4T on Lipids and Limb Fat

96-week open-label extension phase of 903 study» Data from subgroup of pts given d4T for 144 weeks who

switched to open-label TDF for 48 weeks

Madruga JVR, et al. IAS 2005. Abstract TuPe2.2b12.

Mea

n C

ha

ng

e in

Fas

tin

g

Lip

ids

at W

eek

48 (

mg

/dL

)

TGs TC LDL HDL

-80

-60

-40

-20

0

-72

-38

-16

-1

Mea

n T

ota

l L

imb

Fa

t (k

g)

p = 0.005

0

4.2

4.4

Wk 96 Wk 144 Wk 48post-switch

P < .0014.6

4.8

5.05.02

(n = 74)

4.60(n = 74)

d4T TDF

“Nuke-Sparing Regimens”: The Latest Thing or Old News?

Rationale was based on concerns about inevitable mitochondrial toxicity with NRTIs» These concerns have subsided with greater use of “mitochondria-

friendly” NRTIs (TDF, ABC, 3TC, FTC)

Recent data show greater toxicity with PI/NNRTI regimens (e.g. LPV/r + EFV)

Could new classes (e.g. CCR5 inhibitors) replace NRTIs?» Depends in part on long-term safety of TDF and ABC

Study 934

Serum Creatinine: week 48

Maximum Confirmed Toxicity Grade (mg/dL)a

FTC/TDF(n = 257)

CBV(n = 254)

Grade 1 (>1.5 - 2.0) 0 1 (<1%)

Grade 2 (2.1 - 3.0) 0 1 (<1%)

Grade 3 (3.1 - 6.0) 0 0

Grade 4 (>6.0) 0 0

a. Confirmed toxicity grade = 2 consecutive visits

‡

Arribas, J, et al. 18th International Conference on Antiviral Research, April 10, 2005. Barcelona, Spain

# on TDF 335 304 247 185

# on NRTI 403 369 297 172

*

*

0

20

40

60

80

100

120

0 90 180 270 360 450 540Days

GF

R (

ml/

min

/1.7

32 )

TDFNRTI

The Hopkins Cohort: TDF and Renal Function

Gallant JE, et al. 3rd IAS, Rio de Janeiro, 2005

Decline in ClCr independently associated with TDF use, baseline CD4<50, and duration of therapy

No association with age, race, sex, HIV transmission group, HTN, diabetes, HIV RNA, use of LPV/r or other specific ARV agents, or prior use of adefovir

Although statistically significant, clinical significance unclear: no difference in discontinuation

Majority of TDF-treated subjects remain on TDF and will continue to be followed

Johns Hopkins Cohort Conclusions

Gallant JE, et al. 3rd IAS, Rio de Janeiro, 2005

When to Use the New Agent

Too soon:» New drug used in combination with partially

active drugs despite relatively preserved CD4

Case 1

45-year-old man with multi-class resistance» Phenotype shows partial susceptibility to:

– TPV (FC 3.8)– TDF (FC 1.3)– ddI (FC 1.4)

CD4 326, VL 52,000 He is switched to TPV/r + TDF + ddI + ENF

When to Use the New Agent

Too soon:» New drug used in combination with partially

active drugs despite relatively preserved CD4 Too late:

» Use of new drug deferred until patient resistant to all other available drugs

Case 2

36-year-old man with treatment failure 1998: Began AZT/3TC + EFV 2000: Switched to ABC + 3TC + SQV/RTV

because of failure with NNRTI resistance Current status:

»CD4 180 (down from 240 three months ago)»VL 40,230 (increased from 13,452 3 months ago)»Phenotype: Susceptible to TDF, ddI, d4T, APV, LPV

Case 2

36-year-old man with treatment failure 1998: Began AZT/3TC + EFV 2000: Switched to ABC + 3TC + SQV/RTV

because of failure with NNRTI resistance Current status:

»CD4 180 (down from 240 three months ago)»VL 40,230 (increased from 13,452 3 months ago)»Phenotype: Susceptible to TDF, ddI, d4T, APV, LPV

Started on LPV/r + FPV + TDF + ddI

TORO: % w/ VL <400 c/mL through Week 48

(ITT, D/C + Switch = Failure)Patients on LPV/r with LPV susceptibility and > 2 other susceptible agents in OB

Draft

0102030405060708090

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Study Week

% o

f P

atie

nts

ENF-based regimens (n=98)Regimens without ENF (n=59)

TORO: Change in VL from BL(D/C=Censored)

-3

-2

-1

0

0 4 8 12 16 20 24

Weeks Since Switch or BL

Med

ian

Pla

sm

a H

IV-1

RN

A

Lo

g C

han

ge f

rom

Baseli

ne

ENF+OB Switch

When to Use the New Agent

Too soon:» New drug used in combination with partially

active drugs despite relatively preserved CD4 Too late:

» Use of new drug deferred until patient resistant to all other available drugs

Just right:» New drug combined with other active new

agents, or use deferred until other new agents available

% with VL < 50 at Week 24 (ITT NC=F)

67% (n = 27)16% (n = 25)

37% (n = 27)8% (n = 39)

48% (n = 40)5% (n = 56)

45% (n = 38)5% (n = 42)

31% (n = 16)0% (n = 13)

ENF Used (Naive)

ENF Not Used

3 Primary PI Mut

TMC114 FC > 4

No Sensitive ARV in OBR

0 20 40 60 80

TMC114/r 600/100 BIDControl

47% (n = 64)9% (n = 74)

Overall

100

Katlama C, et al. CROI 2005, Abstract 164.

Subgroup Analyses of Response to TMC114/r 600/100 mg BID

“Salvage Therapy Only Works When it’s Not Really Salvage Therapy”

-Joep Lange

www.hopkins-hivguide.org