2005 Asilomar HIV/AIDS Medical Update

David H. Spach, MDClinical Director, Northwest AIDS Education and Training Center

Professor of Medicine, Division of Infectious DiseasesUniversity of Washington, Seattle

DHS/PP

HIV/AIDS: 2005 Antiretroviral Therapy Update

• Hepatitis C & HIV Co-Infection Update

• Hepatitis B & HIV Co-Infection Update

• New Antiretroviral Guidelines

• New Medications

• Future Medications

DHS/PP

HCV and HIV Co-Infection Update

DHS/PP

HCV Therapy: Terminology

DHS/PP

Treatment (48 Weeks)

Post-Treatment (24 Weeks)

End of Treatment Response (ETR)HCV RNA undetectable

Early Virologic Response (EVR)HCV < 100 copies/ml

ORHCV RNA decrease > 2 log

Sustained Virologic Response (SVR) HCV RNA undetectable

Week 12 Week 48 Week 72Week 0

Case History: HCV Rx

• A 38-year-old HIV and HCV co-infected man is evaluated for treatment of HCV. Labs- CD4 cell count 486 cells/mm3 (on no ARV Rx)- HCV genotype 1- HCV RNA level of 2,000,000 copies/ml- Liver Bx: Metavir Stage 3 fibrosis

• What would be the preferred therapy for his hepatitis C?

1. Interferon + Ribavirin x 24 weeks2. Peginterferon + Ribavirin x 24 weeks 3. Peginterferon + Ribavirin x 48 weeks4. Peginterferon + Ribavirin x 96 weeks

DHS/PP

Progression of HCV Treatment SuccessSustained Virologic Response

From: Strader DB, et al. Hepatology 2004;39:1147-71. DHS/PP

6

16

3442 39

55

0

20

40

60

80

100S

us

tain

ed

Vir

olo

gic

Re

sp

on

se

(%

)

IFN (24w)

INF (48w)

INF/RIB(24w)

INF/RIB(48w)

PEG(48w)

PEG/RIB(48w)

Treatment of HCV in HIV-Infected PersonsAPRICOT TRIAL (“Pegasys”)

12

20

40

7

14

29

20

36

62

0

20

40

60

80

100

SV

R a

t Wee

k 72

(%)

All Genotypes Genotype 1 Genotypes 2 & 3

INF + RBV

PEG-INF

PEG-INF + RIB

Background - N = 868 - All with baseline biopsy

Evaluation - SVR: HCV RNA <50 IU/ml at week 72

Regimens (48 Weeks of Therapy) - INF alpha-2a + Ribavirin - PEG-IFN alpha-2a - PEG-IFN alpha-2a + Ribavirin

Study Design SVR: 24 Week Post-Treatment

From: Torriani FJ, et al. N Engl J Med 2004;351:438-50.DHS/PP

Dosing- Interferon alpha-2a: 3 million IU sq 3x/week - Peginterferon alpha-2a: 180 ug sq q week- Ribavirin: 800 mg PO qd

Treatment of HCV in HIV-Infected PersonsACTG A5071 Study (“Pegasys”)

12

27

6

14

33

73

0

20

40

60

80

100

SV

R 2

4 W

eeks

Pos

t-Tr

eatm

ent (

%)

All Genotypes Genotype 1 Genotypes 2 & 3

INF + RBV

PEG-INF + RIB

Background - N = 133 - All with baseline biopsy

Evaluation - SVR: HCV RNA < 60 IU/ml at week 72

Regimens (48 Weeks of Therapy) - INF alpha-2a + Ribavirin - PEG-IFN alpha-2a + Ribavirin

Study Design SVR: 24 Week Post-Treatment

From: Chung R, et al. N Engl J Med 2004;351:451-9.DHS/PP

Dosing- Interferon alpha-2a: 6 million IU sq 3x/week x 12 weeks, then 3 million IU sq 3x/week- Peginterferon alpha-2a: 180 ug sq q week- Ribavirin: 800 mg PO qd

Results of HCV & HIV Co-Infection Treatment Trials Peginterferon + Ribavirin x 48 Weeks

DHS/PP

40

29

62

27

14

73

27

15

43

0

20

40

60

80

100

Su

sta

ine

d V

iro

log

ic R

es

po

ns

e (

%)

APRICOT ACTG 5071 RIBAVIC

Overall

Genotype 1

Genotypes 2,3

Peginterferon-2a Peginterferon-2a Peginterferon-2b

Case History: HCV Rx

• The patient (HCV Genotype 1) is started on Peginterferon alpha-2b plus Ribavirin. His 12 week HCV RNA level is 1,300,000 copies/ml (baseline pretreatment HCV RNA was 2,000,000).

• What can we predict regarding the sustained virologic response (SVR) based on this 12 week HCV RNA value?

1. The 12 weak early virologic response (EVR) does NOT reliably predict SVR in HIV-infected patients2. He has approximately a 30% chance of having a SVR 3. He has approximately a 15% chance of having a SVR4. He has less than 10% chance of having a SVR

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12 Week Early Virologic Response (EVR) Predicts SVR APRICOT TRIAL (“Pegasys”)

From: Torriani FJ, et al. N Engl J Med 2004;351:438-50. DHS/PP

3037

56

0 0 20

20

40

60

80

100S

us

tain

ed

Vir

olo

gic

Re

sp

on

se

(%

)

(+) EVR (-) EVR)

All Genotypes

INF + RIB

PEG-INF

PEG-INF + RIB

12 Week EVR- HCV RNA < 50 copies/ml

OR- HCV RNA decrease > 2 log

Case History: HCV Rx

• A 34-year-old HIV and HCV co-infected woman is evaluated for treatment of HCV. Labs- CD4 cell count 510 cells/mm3 (on no ARV Rx)- HCV genotype 3- HCV RNA level of 1,860,000 copies/ml- Liver Bx: Metavir Stage 3 fibrosis

• What would recommend for therapy in this HIV-infected patient with HCV genotype 3?

1. Peginterferon + Ribavirin x 12 weeks 2. Peginterferon + Ribavirin x 24 weeks 3. Peginterferon + Ribavirin x 48 weeks4. Peginterferon + Ribavirin x 72 weeks

DHS/PP

Peginterferon + Ribavirin for HCV Genotypes 2 or 3 48 Weeks versus 28 Weeks (Romance 2 Trial)

60

90

0

20

40

60

80

100

SV

R R

ates

(%)

28 Weeks 48 Weeks

Treatment Duration

Background - N = 128 - HCV & HIV Co-Infected - All with HCV genotype 2 or 3 - CD4 > 200 and HIV RNA < 10,000

Regimen - Peginterferon alpha-2a + Ribavirin

Evaluation - Week 24: HCV RNA (57% HCV RNA -) - Those with (-) HCV RNA randomized to stop therapy or receive 24 more weeks

Study Design SVR: 24 Week Post-Treatment

From: Zanini B, et al. 3rd IAS Path & Treatment. 2005: MoPpLB0103.DHS/PP

Case History: HCV Rx

• A 29-year-old HCV and HIV co-infected woman is started on Peginterferon alpha-2a (180 ug sq once weekly) plus Ribavirin (400 mg bid) for HCV genotype 1. After 6 weeks of therapy, her Hb decreases from 14 to 10 g/dL. All other labs without a significant change. She weighs 71 kg.

• What would you recommend doing regarding the patient’s development of anemia?

1. No change needed; Hb likely will improve in next 4 weeks2. Decrease ribavirin dose to 600 mg3. Start recombinant erythropoetin 40,000 units sq weekly4. Decrease Peginterferon to 150 uq sq once weekly

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Ribavirin Dosing During Therapy

• Impact of Ribavirin Dosing on SVR- Near or optimal ribavirin dose associated with better SVR

• Ribavirin Target Dosing- Dose > 800 mg/d OR > 10.6 mg/kg/d- Most critical in first 20 weeks

• Use Recombinant Erythropoeitin/Epotin Alpha (Epogen;Procrit)- Initiate for Hb < 12 g/dL- Dose: 40,000 sq 1 x/w & increase to 60,000 sq/w if needed

DHS/PP

HCV Therapy: Future Needs

• Improved Initial Response Rates with Genotype 1

• Better Tolerated Therapy- Viramidine (Ribavirin prodrug); less anemia- Peptide aptemers (Inhibit HCV NS3 serine protease)

• Less Frequent Injections- Albumin Interferon

• Therapies for Peginterferon + Ribavirin Non-Responders- Maintenance PEG-INF- Valopictadine (NM 283) + PEG-INF?

DHS/PP

DHS/Viral/PP

Viramidine

Viramidine

Adenosine DeaminaseNH3

Liver Ribavirin

Inactive MetaboliteICN3297 Adenosine Deaminase

Case History: HCV Rx & Interaction with ARV Meds

• Which of the following is TRUE regarding treatment of HCV in a HIV-infected person taking antiretroviral therapy?

1. Stavudine will increase ribavirin levels and increase the severity of anemia.

2. Ribavirin will increase the intracellular concentration of didanosine’s active metabolite and thus increase the risk of didanosine-related toxicity.

3. Didanosine will increase interferon levels and increase the degree of leukopenia.

4. Lopinavir-ritonavir is contraindicated in persons on peg-interferon because of the increased risk of hepatotoxicity.

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Ribavirin and Didanosine Interaction

DHS/PP

HBV and HIV Co-Infection Update

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HIV/HBV: Initiating HBV Therapy

• A 36-year-old caucasian man with HIV and HBV co-infection: • CD4 520, VL 18,000; Never on HAART. • Persistent 3-5x increase in ALT/AST levels.• HBsAg+; HBeAg+; HBV DNA: 6 x 108 IU/ml.• Liver biopsy not performed

• Which of the following drugs has significant activity against Hepatitis B virus but NOT HIV?

1. Entecavir (Baraclude)2. Ribavirin (Rebetol, Copegus) 3. Emtricitabine (Emtriva)4. Valacyclovir (Valtrex)

DHS/HIV/PP

DHS/HBV/PP

FDA-Approved Therapies for HBV Infection

Drug Approval Dose in HIV-Infected Patients

Interferon-alpha-2b 1991*5-6 x 106 U sq qd or 9-10 x 106 U sq 3x/week

Peginterferon-alpha 2a 2005 180 ug sq qweek x 48 weeks

Lamivudine 1998 100 mq PO qd

Adefovir 2002 10 mg PO qd

Entecavir 2005 0.5-1.0 mg PO qd

*Dose given for HBeAg+ (duration 4-6 months) Dose for HBeAg(-): 5-6 x 106 3x/week x 48 weeks

DHS/HBV/PP

Non FDA-Approved Therapies for HBV

Drug Status Dose

Tenofovir 300 mg PO qd

Emtricitabine 200 mg PO qd

Peginterferon alpha 2b1.5 ug/kg sq qweek(max 100 ug sq qweek)

DHS/HIV/AIDS/PP

Entecavir (Baraclude)

• Classification: nRTI (guanosine analogue)

• Active against HBV: wild-type & Lamivudine-resistant

• Dosing- 0.5 mg and 1.0 mg tablets- Initial Rx: 0.5 mg PO qd- Lamivudine-resistant/failure: 1.0 mg PO qd

• Efficacy: Improves liver histology & degree of fibrosis

• Adverse Effects: flare of hepatitis when drug stopped

• HIV Activity: Entecavir does not have activity against HIV

Peginterferon-alpha-2a vs Lamivudine vs BothHBeAg-Negative Chronic HBV

43 44

29

59 60

44

0

20

40

60

80

100

Pat

ien

ts (

%)

Virologic Biochemical

PegINF PegINF + Lamivudine Lamivudine

Methods - N = 537 adults - HBeAg(-), chronic HBV

Regimens (48 Weeks of Therapy) - PegINF-alpha-2a: 180 ug qweek - Lamivudine: 100 mg PO qd - PegINF-alpha-2a + Lamivudine

Major Measurements - Virologic: HBV DNA < 20,000 - Biochemical: Normalization of ALT - Loss of HBsAg

Study Design Response: 24 Weeks Post Rx

From: Marcellin P, et al. N Engl J Med 2004;351:1206-17.

HIV/HBV: Initiating HBV Therapy

• The following 3 patients are co-infected with HBV and HIV. All 3 patients have HBsAg(+), persistent elevations of ALT (> 2-3x), and HBV DNA levels > 106. None of the patients have ever received ARV Rx or HBV Rx. Regarding treatment, assume they are willing, able, and adherent.

• Patient 1: CD4 490, HIV RNA=23,000; HBeAg(+).

• Patient 2: CD4 524; HIV RNA=38,000; HBeAg(-).

• Patient 3: CD4 210; HIV RNA = 112,000; HBeAg(+).

• QuestionHow would you approach treatment of HBV infection is these 3 patients?

DHS/HIV/PP

Chronic HBV & HIV: Initiating HBV TherapyRecommendations from an International Panel

DHS/HIV/PP

HBeAg (+)

No

Yes

Peginterferon

Yes

Tenofovir plus

Lamivudine (or Emtricitabine)plus

NNRTI or PINo

Entecavir or Adefovir

HIV ARV Indicated

From: Soriano V, et al. AIDS 2005;19:221-40.

HIV/HBV: Monitoring Response

• A 41-year-old woman with HIV and HBV co-infection: • CD4 220, VL 88,000; Never on HAART. • Labs show 3-4x increase in ALT/AST levels.• HBsAg(+); HBeAg(+); HBV DNA: 4 x 109 IU/ml.• Started on Tenofovir-DF + Lamivudine + Efavirenz

• In terms of HBV infection and treatment, which of the following is the LEAST LIKELY goal to achieve during therapy?

1. HBV DNA level decrease to less than 5,000 copies/ml2. HBeAg becomes negative and anti-HBe becomes positive3. HBsAg becomes negative and anti-HBsAg becomes positive4. The progression to cirrhosis is delayed

DHS/HIV/PP

HBV Therapy: Goals

• Delay/Stop progression of liver cirrhosis

• Decrease (but not eliminate) risk of HCC

• Suppress HBV DNA

• Cause ALT to normalize

• Shift HBeAg(+) to HBeAg(-) & HBeAb(-) to HBeAb(+)

• Shift HBsAg(+) to HBsAg(-) & HBsAb(-) to HBsAb(+): Rare

• Eradicate HBV: Rare

DHS/HIV//PP

HBV: Loss of Response with NRTIs Resistance to NRTIs

DHS/HIV//PP

HBV Reverse Transcriptase Mutations

From: Nunez M, et al. Lancet ID 2005;5:374-82.

HIV/HBV: Screening for HCC

• A 53-year-old man with HIV and HBV co-infection and has known cirrhosis.

• CD4 420, VL < 50 copies/ml• Taking Tenofovir + Emtricitabine + Ritonavir + Atazanavir • Labs show normal ALT/AST levels.• HBsAg(+); HBeAg(+); HBV DNA: 1500 IU/ml (baseline 14,000,000).

• Which of the following is TRUE regarding hepatocellular carcinoma?

1. The patient no longer has risk since his HBV DNA level is < 10,000 copies/ml?2. His risk is lower since he has cirrhosis3. His risk is higher because he has HBeAg+4. His risk is lower because he is older than 45

DHS/HIV/PP

Chronic HBV: Risk Factors for HCC

• Age > 45

• Male gender

• Detectable HBV DNA

• HBeAg (+)

• Presence of cirrhosis

• Co-infection with HCV

DHS/HIV//PP

Chronic HBV & Risk of HCC

12

10

8

6

4

2

0

Per

cent

cum

ulat

ive

inci

denc

e

0 1 2 3 4 5 6 7 8 9 10

Year

HBsAg+, HBeAg+

HBsAg+, HBeAg-

HBsAg-, HBeAg-

Yang HI, et al. N Engl J Med. 2002;347:168-74.

n=11,893 men, Taiwan

Chronic HBV: Screening for HCC2004 AASLD Guidelines

• “HBV carriers at high risk for HCC such as men over 45 years, persons with cirrhosis, and persons with a family history of HCC, should be screened periodically with both AFP and US.”

• “While there are insufficient data to recommend routine screening in low-risk patients with chronic HBV infection, periodic screening for HCC with AFP in carriers from endemic areas should be considered.”

DHS/HIV//PP

From: Lok AS, McMahon BJ. 2004 AASLD Guidelines

Chronic HBV: Screening for HCC2005 HIV-HBV International Panel

• “Screening for this neoplasia (HCC) with ultrasonography and alpha-fetoprotein should be performed in all HBV/HIV cirrhotic patients every 6 months.”

DHS/HIV//PP

From: Soriano V et al. AIDS 2005:19:221-40.

Antiretroviral TherapyNew DHHS Guidelines

DHS/PP

DHHS Panel: 2004 Antiretroviral Guidelines Initial Therapy: Preferred Regimens

Picture

Efavirenz+

Lamivudine+

Zidovudine or Stavudine or Tenofovir

Source: www.aidsinfo.nih.gov

PI-Based Regimens

Lopinavir/Ritonavir (Kaletra)+

Lamivudine +

Zidovudine or Stavudine

NNRTI-Based Regimens

DHS/PP

Case History: Initiating Antiretroviral Therapy

• A 34-year-old HIV-infected man presents for follow-up with a CD4 count of 316 cells/mm3 and an HIV RNA = 72,000 copies/ml. His most recent CD4 count 3 months ago was 323 cells/mm3.

• He is motivated to take antiretroviral therapy if you think it would be indicated for him. He has never taken any meds for his HIV disease.

• Assume the patient is likely to have excellent adherence. Would you recommend starting ARV therapy now?

1. Yes2. No, but you would have started if HIV RNA > 100,000 copies/ml3. No, you would wait until CD4 count less than 300 cells/mm3.4. No, you would wait until CD4 count less than 200 cells/mm3.

DHS/PP

2005 ARV Guidelines: Recent Major Changes

• List 5 or more changes in the DHHS guidelines that have

occurred in the past 12 months?

1.

2.

3.

4.

5.

DHS/PP

2005 ARV Guidelines: Recent Major Changes

• Major Changes since September 2004:

1. HIV RNA “threshold” changed from 55,000 to 100,000

2. Stavudine move from preferred to alternative

3. Emtricitabine added as a preferred drug in PI- and NNRTI-based regimens

4. Nevirapine NOT recommended (even as alternative) regimen for initial

ARV Rx in women with CD4 > 250 and men with CD4 > 400

5. Rifampin can NOT be used safely with ritonavir-boosted PI regimens

6. Tenofovir + Didanosine should NOT be used together for initial Rx

7. Once daily Lopinavir-Ritonavir (6 capsules qd) added for ARV-naïve patients

DHS/PP

DHHS Panel: 2005 Antiretroviral Guidelines Initial Therapy: Preferred Regimens

Picture

Efavirenz+

Lamivudine or Emtricitabine+

Zidovudine or Tenofovir

Source: www.aidsinfo.nih.gov

PI-Based Regimens

Lopinavir-Ritonavir+

Lamivudine or Emtricitabine +

Zidovudine

NNRTI-Based Regimens

DHS/PP

From: Gathe J et al. 11th CROI:2004: Abstract 570.

TDF-FTC + (LPV-RTV qd or LPV-RTV bid) Study 418

Patients (N = 109) - ARV naïv - HIV RNA > 1,000 copies/ml - Randomized trial

Regimens - Backbone: Tenofovir + Emtricitabine - Lopinavir-Ritonavir (800/200 mg qd) - Lopinavir-Ritonavir (400/100 mg bid)

Study Design HIV RNA < 50 copies/ml: 48 Weeks

7064

9085

0

20

40

60

80

100

Pat

ient

s (%

)ITT Observed

TDF-FTC + LPV-r (qd)

TDF-FTC + LPV-r (bid)

DHS/PP

Diarrhea- 16% in qd regimen- 5% in bid regimen

Starting Antiretroviral Therapy

0

200

400

600

800

1000

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Years

CD

4 C

ell C

ou

nt

Acute HIV Infection

Year 1

350

200 200

350

DHS/PP

Antiretroviral TherapyNewer Medications

DHS/PP

Tenofovir plus Emtricitabine (Truvada)

• Classification: nRTI

• Dose: 1 pill qd (Tenofovir 300 mg + Emtricitabine 200 mg)

• Meal Restrictions: none

• Preliminary 24 week data from Study 934 very promising

• Adverse Effects: well-tolerated

DHS/PP

From: Pozniak AL et al. 3rd IAS Path & Treatment. 2005: Abstract WeOa0202.

TDF + FTC + EFV versus ZDV + 3TC + EFVStudy 934

Patients (N = 509) - ARV naïve, HIV RNA > 10,000 copies/ml - Randomized trial Regimens - Tenofovir + Emtricitabine + Efavirenz - Zidovudine + Lamivudine + Efavirenz

Study Design Results: 48 Weeks (ITT)

81

7077

68

0

20

40

60

80

100

Pat

ient

s (%

)< 400 < 50

HIV RNA (copies/ml)

TDF + FTC + EFV ZDV + 3TC + EFV

DHS/PP

Tipranavir (Aptivus)

• Which of the following is NOT TRUE regarding the use of Tipranavir (Aptivus) in a patient who is highly antiretroviral therapy experienced and has failed several previous regimens?

1. It should always be used with Ritonavir2. If tolerated, it should be combined with Lopinavir-Ritonavir3. Response rates are significantly better if used with Enfuvirtide4. Tipranavir has been associated with cases of severe liver toxicity

DHS/PP

DHS/PP

Tipranavir-r versus LPV-r in PI-Experienced Patients

35

17

58

26

70

2931

18

0

20

40

60

80

100

Pat

ient

s (%

)

Overall ENF-Na•ve ENF-Exp

Tipranavir + Ritonavir

Lopinavir-Ritonavir

Tipranavir + Ritonavir + Enfuvirtide

Lopinavir-Ritonavir + Enfuvirtide

Background - Tipranavir is novel nonpeptidic PI - Patients failing PI-containing HAART - HIV RNA > 1,000 copies/ml - > 2 PI mutations

Regimens - Optimized background regimen - With/without Enfuvirtide - Randomized to CPI-r* versus Tip-r**

Study Design HIV RNA Reduction > 1 log10

From: Cooper D, et al. 12th CROI. 2005: Abstract 560.

*Most chose LPV-r: subset analysis of LPV-r**Tipranavir 500 mg bid + Ritonavir 200 mg bid

DHS/ARV Rx/PP

Response to Tipranavir-Ritonavir in Advanced Salvage

10

100

1000

10000

100000

1000000

0 1 2 3 4 5 6

Months

HIV

RN

A

50 50

Tipranavir-Ritonavir + OBR

Tipranavir-Ritonavir + OBR + Enfuvirtide

-45

-70

-49-40

-81

-43

-100.0

-80.0

-60.0

-40.0

-20.0

0.0

20.0

40.0

60.0

80.0

100.0

% C

hang

e C

ombi

ned

with

TP

R-r

AUC Cmin

Amprenavir

Saquinavir

Lopinavir

DHS/PP

Pharmacokinetics of Tipranavir Combined with other PIs

Background - N = 173 - Patients failing PI-containing HAART - HIV RNA > 1,000 copies/ml - > 3 PI mutations (33, 82, 84, 90)

Regimens (OBR in All Arms) - TPR/RTV/Control (500/200) bid - TPR/AMP/RTV (500/600/200) bid - TPR/SQV/RTV (500/1000/200) bid - TPR/LPV/RTV (500/400/100) bid

Study Design Tipranavir-r Effect on PIs

From: Walmsley S, et al. 15th International AIDS Conference, 2004: Abstract WeOrB1236.

Strategic Use of Enfuvirtide/T-20 (Fuzeon)

• Early Virologic Failure - Likely to be very effective with other new medications

• Late Virologic Failure - Highly likely to fail if used as the only new effective drug added to failing regimen

• Recommendation - Defer until you have at least two effective agents available

DHS/PP

DHS/HIV/ARV Rx/PP

Antiretroviral TherapyFuture Medications

From: Murphy RL, et al. 11th CROI. 2004. Abstract 137.DHS/ ARV Rx /PP

D-d4FC (Reverset) ARV-Naïve: Monotherapy Dose-Ranging Study

Background - D-d4C is novel cytidine analog NRTI - Active against NRTI-resistant isolates Patients (N = 30) - ARV naive - CD4 count > 50 cells/mm3

- HIV RNA > 5,000 copies/ml Regimens - D-d4FC: 50 mg qd - D-d4FC: 100 mg qd - D-d4FC: 200 mg qd - Placebo: qd

Study Design Results: Day 10 Data

-1.67 -1.74 -1.77

-3

-2

-1

0

1

2

Ch

ang

e in

HIV

RN

A (

log

10)

D-d4FC: 50 mg qd D-d4FC: 100 mg qd D-d4FC: 200 mg qd

Serious Adverse Events: None

From: Cohen C, et al. 3rd IAS Path & Treatment. 2005: Abstract WeOaLB103. DHS/ ARV Rx /PP

D-d4FC (Reverset) ARV-Experienced: Monotherapy Dose-Ranging Study

Background - D-d4C is novel cytidine analog NRTI - Active against NRTI-resistant isolates Patients (N = 199) - ARV experienced (failing) - HIV RNA > 2,000 copies/ml Regimens - D-d4FC: 50 mg qd - D-d4FC: 100 mg qd - D-d4FC: 200 mg qd - Placebo: qd

Study Design Results: Day 14 Data

-0.4-0.3

-0.7

-0.03

-1.0

-0.5

0.0

0.5

1.0

Ch

ang

e in

HIV

RN

A (

log

10)

D-d4FC: 50 mg qd

D-d4FC: 100 mg qd

D-d4FC: 200 mg qd Placebo

DHS/PP

TMC114/r in Late Salvage Therapy

4648

5559

16

30 31

38

47

10

0

20

40

60

80

100

Pat

ient

s (%

)

HIV RNA < 400 HIV RNA < 50

TMC114/r: 400/100 qd

TMC114/r: 800/100 qd

TMC114/r: 400/100 bid

TMC114/r: 600/100 bid

CPI

Background - TMC114 is novel PI - N = 497 enrolled - Heavily 3-class experienced - Multiple PI resistance mutations

Regimens - Background regimen optimized - Enfuvirtide use similar in all groups - TMC-114 plus Ritonavir (dose-ranging) - CPI = Control Protease Inhibitor

Study Design 24 Week ITT Data

From: Katlama C, et al. 12th CROI. 2005:Abstract 164LB.

Subgroup Analysis of TMC-114/r600/100 mg bid - Enfuvirtide Used (naïve): HIV RNA < 50 in 67% - Enfuvirtide not Used: HIV RNA < 50 in 37%

*ITT (Missing = Failure)

DHS/HIV/PPFrom: Levy J. N Engl J Med 1996;335:1528-30.

HIV Cell Binding and Entry

DHS/HIV/PPFrom: Levy J. N Engl J Med 1996;335:1528-30.

HIV Cell Binding and Entry

CD4 CellHIV

Inhibitors of HIV Cell Binding and Entry

CCR5

CXCR4

CD4

DHS/PP

Fusion Domain

Vicriviroc (SCH 417690)Maraviroc (UK427,857)GW873140PRO 140

Enfuvirtide (T-20)

AMD-070

PRO 542BMS-806TNX355

Fusion Domain

gp120

DHS/PP

Maraviroc (UK-427,857): CCR5 Receptor Antagonist

Novel entry inhibitor (CCR5 Inhibitor)

Provides 1.5 log decrease as monotherapy

Dosing with food decreases absorption

Other CCR5 blockers retain activity against Maraviroc-resistant virus

Good safety profile

Optimal dose unknown

DHS/PP

Maraviroc: Summary of Studies Performed

Background - Review of 6 studies- All with multiple dose Maraviroc - N = 195 (66 of whom HIV-infected)

Regimens - Maraviroc (dose ranging)

Toxicity- No major toxicity < 300 mg bid

Study Design 10 day Data: HIV RNA Change

From: McHale M. 3rd IAS Path & Treatment. 2005: Abstract TuOa20.04.

* Capravirine levels boosted 2-fold by NFV

-1.60-1.84

-3

-2

-1

0

1

2

Ch

ang

e in

HIV

RN

A (

log

10)

Maraviroc: 300 mg qd

Maraviroc: 300 mg bid

Vicriviroc (SCH 417690): CCR5 Receptor Antagonist

From: Schumann D, et al. CROI 2004:140LB.

HIV-Infected Volunteers: N =48

HIV

RN

A C

ha

ng

e f

rom

Ba

se

lin

e(l

og

10 c

op

ies

/ml)

CD4 count > 200 cells/mm3

No ARV Rx for > 8 weeks

DHS/ARV Rx/PP

HIV Infection: Natural History

0

200

400

600

800

1000

0 2 4 6 8 10 12 14

Years

CD

4 C

ell C

ou

nt

AIDS

Year 1

R5 HIV R5 HIV R4 HIV R5 HIV

CD4 CellR5 HIV

HIV Cell Binding and Entry

CCR5

CXCR4

CD4

DHS/PP

CD4 CellR5 HIV

HIV Cell Binding and Entry

CCR5

CXCR4

CD4

DHS/PP

CD4 CellR5 HIV

CCR5

CXCR4

CD4

DHS/PP

R4 HIV

HIV Cell BindingPotential Shift from R5 HIV to R4 HIV

CD4 Cell R5 HIV

HIV Cell BindingPotential Shift from R5 HIV to R4 HIV

CCR5

CXCR4

CD4

DHS/PP

R4 HIV

CD4 CellR4 HIV

HIV Cell Binding and Entry

CCR5

CXCR4

CD4

DHS/PP