Failure of antiretroviral therapy and subsequent treatment options
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Failure of Antiretroviral Therapy and Subsequent Treatment Options. Rafael E. Campo, MD Associate Professor of Medicine University of Miami Leonard M. Miller School of Medicine and Jackson Memorial Hospital Miami, FL [email protected]

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Failure of antiretroviral therapy and subsequent treatment options

Failure of Antiretroviral Therapy and Subsequent Treatment Options

Rafael E. Campo, MD

Associate Professor of Medicine University of Miami Leonard M. Miller School of Medicine

and Jackson Memorial Hospital Miami, FL

[email protected]


Failure of antiretroviral therapy and subsequent treatment options1

Failure of Antiretroviral Therapy and Subsequent Treatment Options

  • 1st line regimens

    • What are the recommendations?

    • How frequently do they fail?

    • What resistance can be expected if and once they fail?

    • What role do genetic barriers and pharmacokinetic characteristics of ARV agents play in the selection of resistance?


Failure of antiretroviral therapy and subsequent treatment options2

Failure of Antiretroviral Therapy and Subsequent Treatment Options

  • 2nd line regimens

    • What is in the current ARV armamentarium?

    • What is the possible sequencing of regimens based on the components of the 1st regimen?

    • How likely is success with a 2nd and subsequent regimens?

    • How complex, costly, and efficacious are salvage regimens?

    • What is in the future drug pipeline?


1 st line regimens what are the recommendations

1st line regimens: What are the recommendations?


Recommended arv regimens for treatment na ve patients dhhs october 2005

Recommended ARV Regimens for Treatment-Naïve Patients: DHHS October 2005

Preferred regimens

Efavirenz* +

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

Lopinavir/ritonavir +

(3TC or FTC) + (ZDV)

Alternative regimens

PI-based

Atazanavir + (3TC or FTC)+(ZDV or d4Tor ABC or ddI) or (TDF +RTV 100 mg/d)

Fosamprenavir + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI)

Fosamprenavir/RTV† + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI)

Indinavir/RTV† + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI)

Lopinavir/RTV + (3TC or FTC)+(d4T or ABC or TDF or ddI)

Nelfinavir + (3TC or FTC)+(ZDV or d4T or ABC or TDF or ddI)

Saquinavir§/RTV† + (3TC or FTC)+(ZDV or d4T or ABC)

NNRTI-based

Efavirenz* + (3TC or FTC)

+ (ABC or ddI or d4T)

Nevirapine‡ + (3TC or FTC)

+ (ZDV or d4T or ddI or ABC or TDF)

Triple NRTI**

Abacavir + 3TC + ZDV

*Not recommended for use in 1st trimester pregnancy or women with high pregnancy potential. **Only when a preferred or alternative NNRTI- or PI-based regimen cannot or should be used as initial therapy. † Low-dose RTV (100–400 mg/day). ‡ Use with caution in women with pre-NVP CD4+ counts >250 and men with CD4 counts >400 cells/mm3. §soft gel or hard gel capsules

Available at: http://aidsinfo.nih.gov/guidelines

6 October 2005


1 st line regimens how frequently do they fail

1st line regimens: How frequently do they fail?


Gs 934 tdf ftc efv vs zdv 3tc efv primary week 48 analysis

100

p=0.005

80

FTC + TDF 81%*

ZDV/3TC 70%*

60

% responder

* 95% CI: (+3.4%, +18.1%)

40

Exclude NNRTI-R (n=487): FTC + TDF 84%, ZDV/3TC 73%, p=0.001 (+4.3%, +18.6%)

20

0

BL

8

16

24

32

40

48

GS 934: TDF + FTC + EFV vs ZDV/3TC + EFVPrimary Week 48 analysis

% with HIV RNA <400 c/mL (TLOVR), ITT (n=509)

  • Open-label

  • ART-naïve patients (n=509)

  • Any CD4+ cell count

  • HIV RNA >10,000 c/mL

  • Randomized 1:1

  • Non-inferiority trial

144

weeks

Pozniak A et al. 3rd IAS, Rio de Janeiro 2005, #WeOa0202; Gallant JE et al.NEJM 2006; 354:251-260.


Arv na ve treatment long term follow up

96-week, Latin American extension study enrolling pts completing 144 weeks in GS 903; n=86

92% OT (87% ITT) with VL <50 c/mL

No patient developed K65R mutation through Week 192

Longest running prospective single-arm study; n=100

95% of subjects OT (59% ITT) with VL <50 c/mL

No pt developed LPV or d4T resistance through Week 3603

92%

100

87%

95%

(n=62)

80

% Patients with

HIV RNA <50 c/mL

60

100

HIV RNA <50 c/mL

40

80

20

60

40

0

ITT M = F

0

60

120

180

240

300

360

20

ITT M = Excluded

Week

Week

0

0

24

48

72

96

120

144

168

192

ARV-Naïve Treatment:Long-Term Follow Up

Gilead 903E (EFV + TDF + 3TC)1

% patients with HIV RNA <50 c/mL through Week 192

Abbott 720 (LPV/r + 3TC + d4T [TDF])2% patient with HIV RNA <50 c/mL

through Week 360 (OT)

1 Enejosa J, et al. 10th EACS, Dublin 2005, #PE7.3/13; 2 Murphy R, et al. ibid, #PE7.9/3;

3 Da Silva B, et al. 7th Int Workshop on Adverse Drug Reactions & Lipodystrophy in HIV, Dublin 2005, #63


Mean change in cd4 cell count through 312 weeks

Mean Change in CD4 cell Count through 312 Weeks

+528

cells/µL

Week

N: 1008672 63

Landay A. et al.,3rd IAS, Rio de Janeiro, Brazil, #WePe16.7B04Study 720


Efficacy of modern art virologic and immunologic response by drug class

PI + NRTIs

NRTItriple

NNRTI+ NRTIs

Boosted PI+ NRTIs

0

10

20

30

40

50

60

70

80

90

100

Efficacy of Modern ART: Virologic and Immunologic Response by Drug Class

Week 48 response by drug class

  • ART-naïve patients in clinical trials 1994–2004

  • 13,147 patients in 49 studies

Week 48 HIV RNA <50 c/mL by treatment arm

* p<0.01 vs NRTI and PI

† p<0.05 vs PI

** p<0.01 vs NNRTI, NRTI, and PI

# p<0.05 vs NRTI

  • Caveats:

  • Cross-study comparison

  • CD4+ responses may be impacted by lower baseline CD4+ counts in recent studies

  • Wide range of patient numbers (n=32–405)

Response (%)

Bartlett J, et al. 12th CROI, Boston 2005, #586


1 st line regimens what resistance can be expected if and once they fail

1st line regimens: What resistance can be expected if and once they fail?


First failure and resistance

First Failure and Resistance

  • Drug resistant HIV in this population may be limited: 20-50% of patients may have no evidence of resistance1

  • If present, resistance usually arises to the component(s) of the regimen with the lowest genetic barrier

    • 3TC

    • NNRTI: EFV, NVP, DLV

    • NFV

  • Resistance to unboosted but more potent PIs (e.g. indinavir) might be moderate

  • Resistance to ritonavir-boosted PIs may be very limited

1. Havlir D et al. New Engl J Med 1998; 339:1261-1268.


Resistance at time of first virologic failure

Resistance at Time of First Virologic Failure

3TC

3TC

3TC

3TC

EFV

NNRTI

+

3TC

NFV

Patients (%)

NNRTI

3TC

IDV

TAMs

TAMs

APV

3TC

TAMs

IDV

LPV

(0%)

TAMs

TAMs

(0%)

TAMs

(N/A)

d4T4

3TC

LPV/r

(n=51)

d4T4

3TC

NFV

(n=96)

ZDV1

3TC

ABC

(n=39)

ZDV2

3TC

IDV

(n=17)

ZDV3

3TC

APV

(n=16)

IDV5

EFV

(n=14)

ZDV6

3TC

EFV

(n=24)

1Melby T. 8th CROI, 2001. Abstract 448; 2Havlir D, et al. JAMA. 2000;283:229-234; 3Rusconi S, et al. Antiviral Ther. 1998;3:203-207. 4Kempf D. 10th CROI. Boston, 2003. Abstract 600; 5Holder DJ, et al. 6th CROI. Chicago, 1999. Abstract 492; 6Vavro C, et al. 42nd ICAAC. San Diego, 2002. Abstract H-2052.


Failure of antiretroviral therapy and subsequent treatment options

Genotypes after Virologic Failure of EFV + TDF + 3TC in ART Naïve Patients

TDF/3TC/EFV (n=29 of 299)

d4T/3TC/EFV (n=25 of 301)

Wild-type or as baseline

M184V alone

EFV-R* alone

EFV-R* + M184V

EFV-R* + K65R

EFV-R* + K65R + M184V

EFV resistance = 48%

*K103N, V106M, Y188C/L or G190A/S/E/Q

12 (48%) EFV-R • 8 (32%) M184V • 2 (8%) K65R

16 (55%) EFV-R • 12 (41%) M184V • 7 (24%) K65R

Miller MD, et al. HIV6, Glasgow 2002, #P205


Failure of antiretroviral therapy and subsequent treatment options

Study 863 (LPV/r vs. NFV plus d4T/3TC): Incidence of Resistance at Weeks 24 – 96

HIV RNA above 400 copies/ml

Genotype available

Resistance detected in protease

3TC resistance

LPV/r

(n=326)

74

51

0/51 (0%)

19/51 (37%)

NFV

(n=327)

113

96

41/96 (43%)

79/96 (83%)

  • Absence of resistance to LPV confirmed by phenotypic analysis

Walmsley S, et al. N Engl J Med 2002; 346:2039-46.


Failure of antiretroviral therapy and subsequent treatment options

Barrier to Resistance

for Protease Inhibitors and NRTI’s

Study

Study

Study

418

863

720

HIV RNA above 400 copies/ml

22

74

28

15/22

51/74

18/28

Genotypic results available

0/15

0/51

0/18

Lopinavir

resistance

0/15

NA

NA

TDF resistance

NA

0/51

0/18

TAMS (D4T) resistance

3/15

19/51

3/18

3TC/FTC resistance

§

LPV/r resistance: emergence of primary or active site mutation at protease positions

8, 30, 32, 46, 47, 48, 50, 54, 82, 84, 90, with phenotypic LPV resistance FC> 2.5 vs WT

TDF resistance: emergence of K65R or any TAM (41, 67, 70, 210, 215, 219) in RT

3TC/FTC resistance: emergence of M184V mutation in RT

§

Molina JM, et al.

XV IAC,

Bangkok, Thailand, July 2004;

WePe5701,

Kempf

Antiviral Therapy

2002;7:S119,

D, et al.

Gulick

RM, et al.

HIV7,

Glasgow, UK, Nov. 2004;

#P28


Failure of antiretroviral therapy and subsequent treatment options

Lack of Resistance to fos-APV/RTV: 48-Week Studies in Naïve Subjects (NEAT and SOLO)

  • fos-APV bid (NEAT) and fos-APV/r (SOLO) vs. NFV, all in combination with 3TC and ABC.

  • Analysis of prevalence of resistance to PIs, 3TC, and ABC.

NEAT

SOLO

Elston R, et al. 2ndIAS, Paris 2003, #558


Failure of antiretroviral therapy and subsequent treatment options

1st line regimens: What role do genetic barriers and pharmacokinetic characteristics of ARV agents play in the selection of resistance?


2 nd line and subsequent regimens what is in the current arv armamentarium

2nd line (and subsequent) regimens: What is in the current ARV armamentarium?


Existing classes licensed drugs

Existing Classes : Licensed Drugs


Potential arv regimens

Naïve patient

Experiencedpatient

Highly-

experienced

patient

Success

Failure

Success

Failure

Success

Failure

Potential ARV Regimens

  • 22 antiretroviral agents have been approved in the U.S.

  • Theoretically >600 triple-combinations can be made

  • However, due to cross-resistance and cross-toxicity, a limited number of regimens are available to an individual patient


Failure of antiretroviral therapy and subsequent treatment options

2nd line (and subsequent) regimens: What is the possible sequencing of regimens based on the components of the 1st regimen?


Therapy after failure of 1 st line un boosted pi regimen options

Therapy after Failure of 1st Line, Un-Boosted PI Regimen: Options

  • 2nd PI regimen (sparing NNRTIs)

    • Degree of NRTI resistance will be important

    • Serious consideration should be given to RTV-boosting

  • NNRTI-based regimen

    • Potent but fragile class

    • Degree of NRTI resistance very important

  • Triple class (PI/NNRTI/NRTI)

    • Few options will be left if there are tolerability, compliance, or resistance issues

  • Nucleotide intensification


Therapy after failure of 1 st line nnrti based regimen options

Therapy after Failure of 1st Line, NNRTI-Based Regimen: Options

  • PI-based regimen

    • Degree of NNRTI resistance important

    • Serious consideration should be given to RTV-boosting

  • Triple or quadruple nucleosides/nucleotides

    • Untested efficacy

  • 2nd NNRTI regimen

    • No currently licensed NNRTI can overcome NNRTI resistance; not an option


Therapy after failure of 1 st line triple nrti regimen options

Therapy after Failure of 1st Line, Triple NRTI Regimen: Options

  • PI-based regimen (sparing NNRTIs)

    • Degree of NRTI resistance important

    • Serious consideration should be given to RTV boosting

  • NNRTI-based regimen

    • Potent but fragile class

    • Degree of NRTI resistance very important

  • Triple class (PI/NNRTI/NRTI)

    • Few options will be left if there are tolerability, compliance, or resistance issues

  • NNRTI plus PI


2 nd line and subsequent regimens how likely is success with them

2nd line (and subsequent) regimens: How likely is success with them?


Time to treatment failure and prevalence of drug resistant hiv

Time to Treatment Failure and Prevalence of Drug-Resistant HIV

  • Median time to treatment failure

    • 1st treatment regimen:10.6 months

    • 2nd treatment regimen:8.1 months

    • Subsequent treatment regimens:6.4 months

  • Prevalence of HIV with reduced drug susceptibility among

    • Newly infected patients:14%

    • Patients failing 1st triple combination:75%

    • Patients failing multiple therapies:95%

Little SJ et al. New Engl J Med 2002;347:385-394. Boden D et al. JAMA 1999;282:1135–1141.Haubrich R et al. AIDS 2001;15:609-615.


2 nd line and subsequent regimens how complex costly and efficacious are they

2nd line (and subsequent) regimens: How complex, costly, and efficacious are they?


Toro 1 2 96 week follow up

100

ENF+OB

n=661

OB

n=334

80

All comparisons ENF+OB vs OB p<0.001

60

Patients (%)

51

49

39

40

32.7

30.4

26

21

18.3

16

20

17

15.9

15

12

7.8

6.3

0

96

96

Week

24

48

24

48

24

48

96

CD4+ increase

>50 cells/mm3

VL <400

c/mL

VL <50

c/mL

TORO 1 & 296-week follow-up

% Responders at Weeks 24,1 482 and 96 (ENF+OB only)3

  • Randomized (2:1), open-label trial of ENF (T-20) plus optimized background (OB) vs OB alone

  • Heavily experienced subjects (median 12 ARVs for 7 years)

  • BL HIV RNA 5.1 log10 c/mL

  • CD4 <100 cells/mm3

  • 52% of subjects originally assigned to ENF+OB completed 96 weeks of study

1. Montaner J, et al. 2nd IAS, Paris 2003, #116;

2. Katlama C, et al. ibid, #LB2;

3. Arastéh K, et al. XV IAC, Bangkok 2004, #MoOrB1058

2 visits required to confirm virologic response


Resist 1 and 2 48 week pooled analysis

Open-label, randomized, studies in USA (n=620)1 and Europe/Latin America (n=863)2 of TPV/r

Entry criteria:

>3 months’ therapy with NRTIs, NNRTIs, and PIs

HIV RNA 1000 c/mL on therapy

No CD4+ cell count restrictions

Genotype indicated:

>1 primary PI mutation at codons 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M and

<2 mutations at codons 33, 82, 84, or 90

100

90

80

70

60

50

40

30

20

10

0

Time to treatment failure at Wk 48

(ITT NC=F)

TPV/RTV

CPI/RTV

Estimated probability of remaining event-free

0 12 24 36 48 60 72 84

Weeks of exposure

RESIST-1 and -2: 48-Week Pooled Analysis

*Comparator PI

** Primary endpoint

Cahn P, et al.10th EACS, Dublin 2005, #LBPS3/8


2 nd line and subsequent regimens what is in the future drug pipeline

2nd line (and subsequent) regimens: What is in the future drug pipeline?


Investigational drugs existing classes

Investigational Drugs: Existing Classes


Investigational drugs new classes

Investigational Drugs: New Classes


Integrase inhibitor mk 0518 in patients with triple class art experience

100

200

MK-0518 200

MK-0518 600

80

150

MK-0518 400

OBT Alone

60

100

% patients with HIV RNA <50 c/mL

50

40

Δ from BL in HIV RNA (log10 c/mL)

Δ from BL in CD4+ cell count (cells/mm3)

0

0

20

-1

0

0

2

4

8

12

16

-2

Week

MK-0518 200 mg

40

38

35

31

25

-3

MK-0518 400 mg

42

39

36

31

27

MK-0518 600 mg

42

40

35

32

28

0

2

4

8

12

16

OBT Alone

43

43

36

31

27

Week

Integrase Inhibitor MK-0518 in Patients with Triple-Class ART Experience

  • Results presented for those with 16 weeks + follow-up

  • Only 2 patients lost to follow-up

Proportion of patients (95% CI) with HIV RNA <50 c/mL

Mean change from baseline (95% CI) in HIV RNA and CD4+ cell count

Grinsztejn B, et al. 13th CROI, Denver 2006, #159LB


Pharmacokinetics and antiviral activity of integrase inhibitor gs 9137

800 BID

50/100 QD

400 BID

800 QD

200 BID

1000

GS-9137 Plasma Concentration

100

10

IC

*

50

0

6

12

18

24

Time (h)

mean + SD

* protein binding adjusted, wild type virus

Mean change in HIV RNA

0.0

0.0

-0.5

-0.5

-1.0

-1.0

Placebo

Placebo

Log10 Change HIV-1 RNA

800 QD

800 QD

-1.5

-1.5

200 BID

200 BID

10

400 BID

400 BID

800 BID

800 BID

-2.0

-2.0

50 + RTV QD

50 + RTV QD

Dosing

Dosing

Dosing

-2.5

-2.5

BL

BL

1

1

2

2

3

3

4

4

7

7

10

11

14

14

21

21

Day

Day

Pharmacokinetics and Antiviral Activity of Integrase Inhibitor GS-9137

Steady-state pharmacokinetics

  • Preclinical pharmacokinetics1

    • Metabolized via CYP3A4; moderate inducer

    • 20-fold increased exposure with RTV 100 mg QD, 3-fold with food

  • Randomized, double-blind, placebo-controlled 10-day monotherapy study2

    • Entry criteria: off ARV, CD4+ >200 cells/mm3, HIV RNA 10K-300K c/mL

    • 5 dosing cohorts, n=8 each; 6 active therapy, 2 placebo

    • No drug discontinuations or AEs different from placebo

1. Kawaguchi I, et al. 13th CROI, Denver 2006, #580; 2. DeJesus E, et al. ibid, #160LB


Considerations before selecting art for extensively experienced patients

Considerations Before Selecting ART for Extensively Experienced Patients


Failure of antiretroviral therapy and subsequent treatment options

Considerations Before Selecting ART for Extensively Experienced Patients

  • Low-level viral replication (<10,000 copies/ml) may need to be accepted as an outcome

  • The change to a new regimen after a 3rd or 4th failure should be paused and thoughtful

    • Viral load on a “failing” regimen may still reflect  from set point due to residual antiviral activity of partially active drugs

    • There might be clinically significant immunologic benefits associated with “failing” regimens

  • To “do nothing” (i.e. continue a “failing” regimen) while waiting for new drugs may be a valid option


Questions and discussion

Questions and Discussion


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