New Concepts and Recent Developments in HIV Therapeutics ...

Institute of Human Virology

New Concepts and Recent Developments in HIV Therapeutics

September 27 2004

Robert R. Redfield MDDirector Clinical Care and Research



Impact of Anti-retroviral Therapy in the US

• Major impact on mortality and morbidity of HIV infection– In 2003 some patient’s with HIV will live a natural lifetime as a direct

consequence of durable antiretroviral therapy

• >90% reduction in perinatal HIV infection

• Significant treatment failure in experienced clinics secondary to the development of drug resistance

• Increase morbidity and mortality secondary to drug induced toxicities

• Increase transmission of anti-retroviral drug resistant virus

• Significant “swings” in consensus recommendation related to use of anti-retroviral therapy


Evolution of Treatment: Main Steam Approaches

• AZT mono-therapy• Combination NRTI therapy• Triple drug regimens (2 NRTI and 1 PI)• Combination PI’s with or without 1 NRTI)• Three drug RTI (2NRTI,1NNRTI) regimens

• Three NRTI regimens• PK enhanced PI regimens• Four RTI regimens


Evolution of Treatment: Main Steam Approaches

• Salvage and Deep therapy• Fusion Inhibitors• Under Investigation

– Entry inhibitors• Chemokine antagonist• Strategies to alter chemokine and co-receptor dynamics

– Intergrase Inhibitors– Combination of chemotherapeutic drugs with candidate

therapeutic vaccines– Cycle Therapy

• Structured Interrupted Treatment• Maintenance Therapy with cell cycle agents

– Use of cytostatic agents– Induction Maintenance therapy


Mainstream Treatment Strategy: 2000

• Sequential combination chemotherapy (rational ART sequencing based on concerns of cross resistance)

• Preservation of future treatment options

• Expanded use of Viral Load monitoring

• Use of resistance testing in selected clinical settings (viral rebound, new infection) to steer drug selection

• Delay use of ART ( due to high risk of viral failure and toxicity)


Real Life Settings Demonstrates Limited Durability in Clinical Cohort Studies

(1 year Antiretroviral Treatment Success Rates)

• Baltimore (JHU) 37% • Cleveland Clinic 47%• San Francisco (UCSF) 50%• Amsterdam 60%

Ref: Lucas Annal 1999, Deeks AIDS 1999 , Casado AIDS 1998)

• Baltimore (JHU) 36% (18 months)– 1999-2003 ARV naïve

Ref: Lucas JAIDS 2003


Key Factors for Improved Durability:• Working Hypothesis: Events that occur in during the

initial induction of viral control largely determine the durability of antiretroviral induced viral control.

• Key Factors

– Role of compartment specific ART

– Role of enhanced treatment support especially during induction of viral control – impact of drug side effect profile on adherence

– Use of high Mutation Threshold Regimens

• Does the use of low mutation drugs during induction of viral control contribute to limited durability?

– Use of antiretroviral drugs in regimen with similar

pk profiles


Case 1

• Patient is 37 year old black female with at history of HIV infection diagnosed in 1989.

• She remained asymptomatic with CD 4 cell count in the range of 437- 526.

• In 2000, she re-engaged in care with her PMD. She remained asymptomatic; CD4 count 444, VL 67,000.

• After discussion with her doctor she began on treatment with AZT, 3TC and Nelfinavir.


Case 1 continued

• Patient did well; viral load declined to <400 copies.

• After 3 months on treatment viral load ranged 1,300-27,000.

• After 5 months Viral genotype was preformed. (RT mutations noted at 184. 211, 215 )

• Plasma from 3 month sample demonstrated RT mutation at 184.


New Concepts

•Concept of Compartment Specific Mono-therapy


HIV infection occurs inactivated and resting PMBC. Does state of cell cycle impact antiviral activity of approved antiretroviral drug?


What is the Impact of Cell Cycle on the Anti-Viral Activity of RT Inhibitors?

AZT has potent antiviral Activity in activated HIV infected cells

0 0.03 0.1 0.3 1 40

1000

2000

3000

4000

5000

HIV

-1 p

24 a

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AZT –Activated Cell Infection


Cell Cycle and AZT Antiviral ActivityAZT limited antiviral Activity in resting HIV infected cells

0 0.03 0.1 0.3 1 40

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AZT - Resting Cell Infection

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Cell Cycle and DDI antiviral activity DDI has limited antiviral Activity in activated HIV infected cells

0 0.1 0.3 1 3 100

1000

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DDI - Activated Cell Infection

HIV

-1 p

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Cell Cycle and DDI antiviral activity

DDI has antiviral activity in only resting HIV infected cells

0 0.1 0.3 1 3 100

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DDI-Resting Cell Infection

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-1 p

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1000

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Abacavir- Activated Cell Infection

HIV

-1 p

24 a

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gen

(n

g/m

l)Cell Cycle and Antiviral Activity: Abacavir


0 0.04 0.14 0.4 1.3 40

100

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300

400

500

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Abacavir- Resting Cell Infection

HIV

-1 p

24 a

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Cell Cycle and Antiviral Activity: Abacavir


Impact of Cell Cycle on Antiviral Activity of Approved Antiretroviral Drugs 2004

• Cell Cycle Dependent Drugs– AZT, D4T ( activated cells)– DDI (resting cells)– Combivir, Trizavir (activated cells for AZT)– Protease Inhibitors (activated cells)

• Cell Cycle Independent Drugs– 3TC, FTC, Abacavir– Tenofovir– Truvada– Epzicom– NNRTIs


New Concepts

Did wide scale use of compartment specific “mono-therapy” in the late 1990’s contributed to limited durability of early 2NRTI PI based regimens?


Case 2

• Patient is a 23 year old white male who was diagnosed with HIV infection after he presented in 2002 to his PMD for a medical evaluation increasing fatigue. He had several different sexual partners in NYC between 1982-1984; however, he has not been involved in sexual activity since his partner got sick with AIDS in 1992.

• His CD4 ranged 190-256 cells/mm3 and viral load ranged 368,000-478,000 copies/ml. After extensive discussion with his PMD he began treatment with AZT, 3TC and Sustiva.

• After 12 week viral load was 12,000 copies/ml.• Genotype was drawn.• Patient did not return to clinic until 8 weeks later.• At 20 weeks post treatment his viral load was 47,000 copies/ml.

Genotype was repeated.


Case 2

• Genotype at 12 weeks– 184V

• Genotype at 20 weeks– 184V

– 103N


How Quickly Resistance Can Occur How Quickly Resistance Can Occur Depends on the Viral LoadDepends on the Viral Load

Viral LoadViral LoadDays Before Mutation Days Before Mutation

ArisesArises300,000300,000 0.10.1

30,00030,000 11

3,0003,000 1010

300300 100100

3030 1,0001,000Adapted from Siliciano, 2002


New Concepts

Does the wide scale use of low mutation threshold 3TC and NNRTI “protected” by a thymidine analog (AZT or DT4) contributed to limited durability of these regimens?


New Concepts

• Concept of Specific NRTI-NRTI interaction


Recent Developments

• High failure Rates for selected 3NRTI based regimens – D4T, DDI Abacavir- Gerstoff et.al AIDS 2003

– Tenofovir, Abacavir, 3TC – Farthing et. Al 2nd ISA Paris 2003

– Tenofovir abacavir, 3TC- Gallant et al ICAAC Chicago 2003

– Tenofovir, DDI, 3TC – Jemsek personal communication/Gilead Warning letter 2003


RIBOSE-5P + ATP

PRPP

GUANINE GUANOSINE MP INOSINE MP ADENOSINE MP

DEOXYGUANOSINE DP DEOXYADENOSINE DP

DEOXYGUANOSINE TP DEOXYADENOSINE TP

DNA DNA

IMP dehydrogenase

ADA

Mycophenolic Acid

HGPRTase

PRPP

Salvage Pathway

PRPP Synthetase

DeNovo Pathway

Ribonucleotide reductase

Hydroxyurea

Ribonucleotide reductase

AS

Therapeutic Strategies to Target Cellular Enzymes and Cell Cycle


Early Virologic Response*: COL40263 vs ESS30009

0

20

40

60

80

100

VL<100,000c/mL

VL>100,000c/mL

Overall

ESS30009

COL40263

ESS30009 N = 80 N = 22 N = 102COL40263 N = 36 N = 52 N = 88

(ABC/3TC + TDF QD)

(ABC/3TC/ZDV + TDF QD)

* Based on early virologic non-response criteria used in ESS30009:1: <2 log drop from baseline by week 8 and HIV-1 RNA 50 copies/mL by week 8 2: 1 log increase above nadir at or before 8 weeks

56%

83%

32%

71%

51%

76%

Elion R, et al. 11th CROI, San Francisco 2004, #53.


New Concepts

• Concept of Dynamic Adherence Threshold


Correlation Between Adherence* and Virologic Suppression† (N = 84)

% Patients With

HIV-1 RNA<400

copies/mL

Level of Adherence, %

*Adherence was measured by MEMScaps electronic pill monitoring device.†P = .00001.Data from Paterson et al. Poster presented at: 6th Conference on Retroviruses and Opportunistic Infections; January 31–February 4, 1999; Chicago, Ill. Poster 92.

70

60

50

40

30

20

10

0

80

90

>95 90–95 80–90 70–80 <70


Relationship Between Adherence and HIV Suppression

*Series of 886 treatment-naive HIV patients;CD4 cell count <500 x 106 cells/L or plasma viral load >5000 copies/mL.

†Prospective, observational study of 81 HIV patients.‡MEMS, Medication Events MonitoringSystem.

1. Low-Beer S et al. JAIDS. 2000;23:360-361. Letter. 2. Paterson DL et al. Ann Intern Med. 2000;133:21-30.

2


Consistency in viral rebound dynamics

Davey et al. PNAS 1996

Davey et al. demonstrated in 18 patients that mean time to viral load rebound above 50copies/ml and 500copies/ml was 11 and 18 days respectively.


New Concept Dynamic Adherence Threshold

• Key variables– in vivo replication kinetics

–mutation threshold of regimen

– pk profile of regimen


“JACQUES Initiative”

• J Joint

• A AIDS

• C Community-wide• Q Quest for

• U Unique and

• E Effective treatment

• S Strategies

A program designed by and for the community.


The JACQUES Initiative (J.I.) A new care delivery model

Integrating treatment preparation, clinical management and treatment support for long term treatment success

Jacques Initiative

J.I. Staff serves as an extension to

referring provider

Clinical ManagementTreatment Preparation

Treatment Support

Directly Observed Therapy (DOT)Our staff will assist and observe the

medicine being taken on site or in the community.

HIV 101 WorkshopLife Skills Workshop

Care Partner Supported (CP) - This option is for someone who chooses to be supported by a friend or relative, not HIV positive

Treatment Partner (TP) - This system is modeled as a buddy system where two HIV positive people plan together to support each other with therapy

Treatment Coach Observed/Supported – A coach from our staff will observeand/or support you with therapy

Weekly Observed Therapy (WOT) – This option involves a weekly exchange ofa pre-filled pill box


New Concepts

• Treatment Preparation– Patient and support system

• Targeted Treatment Support– Intensive daily treatment support for first 6-12 weeks and then de-

intensify

– Menu of treatment support options

– Role of Treatment Specialist and Treatment Coaches

– Integrate support groups into treatment care plan

– Proactive treatment interruption prior to treatment failure when co-morbidities flair such as relapsed SA and depression


Case 4

• Patient presented (in 1997) as a 33 year old Hispanic male with a 12 year history of HIV infection complicated with PML associated with significant neurological impairment. CD 4 <20 cells/mm3; Viral load >750,000.

• Patient had a history of antiretroviral in the late 1980’s early 1990’s to include use of AZT, DDI, 3TC; however he has not used AVR sense 1994.

• Patient was treated with Nelfinavir, Saquinavir and Sustiva.• Over the next 6 years, the patient experienced progressive

CD4 immune reconstitution (CD 4 450-625 range) associated with sustained viral suppression (VL < 50 copies/ml

• After over 6 years, in 2002 simplification of patients regimen was considered.


Case 4

• Patient was placed on Tenofovir, DDI , 3TC

• Viral load 2 weeks 763, at 4 weeks 3890, 6 weeks 58,000. CD4 cell count dropped to 269

• Viral genotype at week 4 demonstrated multiple RT mutations consistent with previous NRTI history

• High input genotype 2 week sample confirmed multiple RT mutations.

• Initial PI NNRTI regimen was restarted. Patient re-suppressed. VL remains < 50 copies. CD4 cell count continues to increase (620-700 range 1/2004)


ACTG 398: HIV-1 RNA response (logACTG 398: HIV-1 RNA response (log1010 copies/ml) by NNRTI copies/ml) by NNRTI

Experience and NNRTI mutationsExperience and NNRTI mutations


New Concepts

• Resistance is unforgiving.

• What is the long term consequences of development of specific mutations associated with decreased antiviral susceptibility?

• Consider the implication related to PEPFAR and MTCTP plus programs unfolding in Africa


Case 5

• Patient is a 19 year old African female in labor (2003) HIV diagnosis was confirmed three years earlier when she tested HIV positive during delivery of her first child. She and her child were treated with single dose Nevirapine as part of MTCT program in Cameroon.

• Her CD4 cell count was 220; viral load 78,000 copies.ml.


Case 5

• During delivery she and her newborn completed AZT MTCT program. After recovering from childbirth she discussed ARV treatment option with her PMD and was started on Trizavir and Sustiva.

• Viral load at 6 weeks was > 50 copies. By 6 months CD4 cell count had increased to 315.

• At 14 months viral load was 3500. Repeat at month 15 was 127,000.


Case 5

• Viral genotype demonstrated 184V, 103N, 181Y and several TAM’s.

• Plasma from 6, 12 and 24 weeks was evaluated for variants– 6 week genotype: 181Y

– 12 week genotype 181Y

– 24 week genotype 181Y, 103N, 184V


Response to d4T/3TC/NVP in mothers based on previous history of single-dose NVP

No NVPNo NVP

NVPNVPNo MutationNo Mutation

NVP + NVP + MutationMutation

42

139

81

37

112

58

28

110

50

0%

30%

60%

90%

Baseline 3 months 6 months

7%2% 0%

86% 88%

79%86%

80%

68%

Jourdain G, et al. 11Jourdain G, et al. 11thth CROI 2004 Abstract #41 CROI 2004 Abstract #41

% W

ith

Vir

olo

gic

Su

pp

ress

ion

% W

ith

Vir

olo

gic

Su

pp

ress

ion <400 copies/mL

1% 0% 0%

59%

44% 43%

75%

53%

34%

<50 copies/mL

* Significant

*

*


New Concepts

•Could the current MTCT program negatively impact general ART programs. If so how could this be minimized?

•Use alternative MTCT regimen –Single drug with high mutation threshold and or limited pk profile as single dose drug–Use drugs with matched pk profile


Stopping drugs with different half lives

0 24 483612

Time (hours)

Dru

g c

on

cen

trat

ion

Zone of potential replication

IC90

IC50

Last Dose

Day 1Day 1 Day 2Day 2

MONOTHERAPY

S. Taylor et al. 11th CROI Abs 131


New Concepts

• Use regimens with similar Pk profile

• Prolong tail of NNRTI post single dose NVP or discontinuation of NNRTI

• Long acting may not always be better. Needs to be combined with drugs with similar pk profile


Durability: Key Variables

• Potency of primary regimen• Treatment Adherence especially during the

induction of viral control• PK profile of regimen • Background Resistance• Mutation threshold of ARVs used especially during

induction of viral control


Key Factors for Improved Durability:• Working Hypothesis: Events that occur in during the

initial induction of viral control largely determine the durability of antiretroviral induced viral control.

• Key Factors

– Role of compartment specific ART

– Role of enhanced treatment support especially during induction of viral control – impact of drug side effect profile on adherence

– Use of high Mutation Threshold Regimens

• Does the use of low mutation drugs during induction of viral control contribute to limited durability?

– Use of antiretroviral drugs in regimen with similar

pk profiles


Key Factors for Improved Durability:

Prevent Chronic Toxicity – major cause of ARV regimen changes– Minimize long term drug induced toxicity

– Minimize mitochondrial toxicity

– Minimize development of chronic metabolic toxicity

– Minimize drug induced changes in body habitus changes


New Approaches to Treatment under Investigation at IHV: Targeting Host Cell Pathways for

Therapeutic Potential

• Modulating Cell Cycle– Antiretroviral activity and Cell Cycle– Use of cell cycle agents

• Use of inhibitors of cellular enzymes to potentate nucleoside analogs• Use of S phase agents to potentate nucleoside analogs • Modification of chemokine and co-receptor dynamics CCR5• Inhibitors of specific CD kinases

• Targeting cellular receptors– Entry Inhibitors ( CCR5 antagonist)– Role of sialic acid and sialidase inhibitors

• Therapeutic Vaccines: non-structural protein targets and cell receptor HIV envelope complexes


HIV Pathogenesis

• CCR5 co-receptor usage and HIV – CCR5 co-receptor using virus key in HIV transmission– CCR5 co-receptor using virus dominant in early HIV

infection

• CCR5 co-receptor beta chemokines dynamics and HIV– Decrease infection rate of delta 32 CCR5 host– Decrease infection rate among risk populations with

increase basal beta chemokine production

• Inter-relationship between increase cellular activation and increase CCR5


High expression of activation markers and CCR5 inadvanced HIV-1 infection:

Percent CD4

Percent CD4

Disease progression


CCR5 expression predicts disease progression

CCR5

CXCR4

: PRESEROCONVERSION 5 YEARS AFTER SEROC.

Van Rij et al. (2003) AIDS Res Hum Retrov 19:389.

“low” CCR5

“high” CCR5

“low” CCR5

“high” CCR5

“high” CXCR4

“high” CXCR4


Strategies to Alter CCR5 co-receptor Dynamics

• Block CCR5 receptor (antagonist/antibody)

• Augmentation of Beta-Chemokine production and/or extracellular Beta-Chemokine levels

• Change or alter CCR5 expression


Proof of Concept: In vivo anti-HIV activity of prototype CCR5 antagonist SCH C: “Monotherapy” in HIV Infected Volunteers


Rapamycin

• Rapamycin is a marcocyclic lactone produced by Streptomyces hygroscopicus

• Inhibits T Lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (IL-2,IL-4 and IL-15) stimulation

• Binds to immunophilin K binding protein 12 to generate an immunosuppressive complex

• Inhibits progression of cell from G1 to S phase• Approved for use in US as an immunosuppressive

agent used in solid organ transplantation


RAPA inhibits CCR5-using HIV-1

0

20

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100

p24

(ng/

ml)

No RAPARAPA 0.01 nMRAPA 0.1 nMRAPA 1 nM

IIIb ADA BaL JRCSF JRFL SF162

0.20.40.60.81.01.2

MT

T (

O.D

. 490)

0 .01 .1 1RAPA (nM)


M 100 10 1 0

RAPA (nM)

CCR5

18S

1 10 100 100010000FL2-H

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# C

ells

1 10 100 100010000FL2-H

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# C

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1 10 100 100010000FL2-H

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ells

1 10 100 100010000FL2-H

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ells

1 nM RAPA 100 nM RAPA

10000

Rapamycin inhibits CCR5 expression (RNA and protein levels)


RAPA-mediated reduction of CCR5 expression results in accumulation of

beta-chemokines

0

10000

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i nes

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/ml )

RAPA (nM): 0 1 10 1000

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CR

5RAPA (nM): 0 1 10 100

RANTES

MIP 1∞

MIP 1ß


10

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100000

RAPA (nM): 0 1 10 100

No TAK 779

0.1 nM TAK 779p2

4 (p

g/m

l)


Potential Role in Treatment of HIV Infection

• Synergize with CCR5 antagonist• Primary treatment for early infection alone or

in conjunction with other therapy• Strategy to decrease dependency on standard

ART–Cycle therapy–De-intensification–Role in induction maintenance

• Increase durability of primary ARV regimens


Potential Role in Prevention of HIV Infection

• Block mother to child transmission breast milk transmission

• Role in chemoprophylaxis

• Potential in increase efficacy of marginal preventive vaccine

• Potential in increase immunogenicity of HIV vaccine


Clinical Translation to evaluate role of G1 cell cycle agents: Proof of Concept Trials in progress at IHV

• Phase 1 Pilot Study Rapamycin in Healthy Volunteers ( completed Fall 2003)

• Phase 1 Pilot Study: Monotherapy with Rapamycin in HIV infected volunteers with CD4 counts > 350 cells/mm

– Enrollment closed– Study visits competed June 2004, analysis in progress

• Phase 1 Pilot: Prolonged Cycle Therapy (ART plus HU cycled with HU alone

– Initial 3 week cycle closed to enrollment ( Spring 2004)– Initiation of 4 week cycle ( Spring 2004) actively enrolling

• Phase 1 Pilot: Treatment De-intensification-HADIT study using Tenofovir and HU: Actively enrolling


New Approaches to Treatment: Targeting Host Cell Pathways for Therapeutic Potential

• Modulating Cell Cycle– Antiretroviral activity and Cell Cycle– Use of cell cycle agents

• Use of inhibitors of cellular enzymes to potentate nucleoside analogs

• Use of S phase agents to potentate nucleoside analogs • Modification of chemokine and co-receptor dynamics CCR5• Inhibitors of specific CD kinases

• Targeting cellular receptors– Entry Inhibitors ( CCR5 antagonist)– Role of sialic acid and sialidase inhibitors

• Therapeutic Vaccines: non-structural protein targets and cell receptor HIV envelope complexes


•Inhibition of HIV-1 by targeting cellular components:

Key Advantage: Viral drug resistance is much less likely to emerge under drug pressure

• Targeting of cellular enzymes in nucleotide biosynthesis pathways: Ribonucleotide Reductase (hydroxyurea), IM Dehydrogenase (Mycophenolic acid), Resveratrol

• Targeting of virus coreceptors: CCR5 (Rapamycin and other G1 cell cycle agents)

• Targeting of Cyclin Dependent Kinases


(Full-length viral transcripts. Virus production)

(Short viral transcripts. No virus production)

Tat is essential for HIV-1 replication

HIV provirus


Inhibition of HIV-1 by targeting CDKs with Indirubin

• Indirubin is a compound extracted from the medicinal herb Isantis tinctoria. Its use is approved in China for the treatment of Chronic Mielogenous Leukaemia (CML)

• Indirubin exerts anticancer activity by inhibiting CDKs


10000

20000

30000

IM0IM.25IM.5IM1IM2IM4

0.0

0.1

0.2

0.3

0.4

day 7 day 13 day 21 day 28

RT

(C

PM

)

MT

T (

O.D

. 490)

day

28

a) b)

IM (µM):0 0.2 0.5 1 2 4


M 16 8 4 0

IR (µM)

M 16 8 4 0

IR (µM)

Multiple-splicedHIV-1 transcripts

Full-length, unsplicedHIV-1 transcripts

Indirubin inhibits HIV-1 by blocking synthesis of full-length, unspliced viral transcripts


0

50

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200

0.0

0.2

0.4

0.6

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1.0

p 24

(ng

/ml)

MT

T (

O.D

. )

74V,4

1L,1

06A,2

15Y

(RTM

DR)46

I,63P

,82T

,184

V

(PI R

esist

ant)

103N

,181

C

(NNRT R

esist

ant)

305R

,308

P,31

6V,3

21E

(SCH-C

Res

istan

t)

wild ty

pe(d

rug

sens

itive

)

No IM1µM IM

4µM IM

74V,4

1L,1

06A,2

15Y

(RTM

DR)46

I,63P

,82T

,184

V

(PI R

esist

ant)

103N

,181

C

(NNRT R

esist

ant)

305R

,308

P,31

6V,3

21E

(SCH-C

Res

istan

t)

wild ty

pe(d

rug

sens

itive

)

IM inhibits drug-resistant HIV-1


Clinical Development Status to evaluate role of CDK 9 inhibitors as Novel Treatment

Strategy for HIV

• IND under development• Phase 1 Pilot Proof of concept trial under

development– patient population: patients with MDRV and 3 class

cross class ARV drug resistance

– Planned start date late fall 2004


New Directions in Antiretroviral Therapy• Development of specific regimens for specific clinical situation

– Treatment Naïve: • Development of Induction Maintenance regimens

• Use of new fixed dose combinations

– Viral suppressed: • De-intensification regimens

– Deep Salvage: • Bridging regimens

• New class of agents

– Regimens designed for initiation of treatment early in disease course• Therapeutic strategies that target CCR5

• Chemotherapy Induction/Maintenance

• Role of new fixed dose combinations

New Concepts and Recent Developments in HIV Therapeutics ...

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