2004 Asilomar HIV/AIDS Medical Update David H. Spach, MD Medical Director, Northwest AIDS Education and Training Center Professor of Medicine, Division of Infectious Diseases University of Washington, Seattle

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2004 Asilomar HIV/AIDS Medical Update
David H. Spach, MDMedical Director, Northwest
AIDS Education and Training CenterProfessor of
Medicine, Division of Infectious
DiseasesUniversity of Washington, Seattle
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HIV/AIDS 2004 Antiretroviral Therapy Update

• Hepatitis and HIV Update
• New Antiretroviral Guidelines
• New Medications
• Lipoatrophy

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Hepatitis and HIV Update
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Treatment of HCV in HIV-Infected PersonsAPRICOT
TRIAL
Study Design
SVR 72 Week Data

• Background - N 868 - All with baseline
  biopsy
• Evaluation - SVR HCV RNAlt50 IU/ml
• at week 72
• Regimens - INF alpha-2a Ribavirin - PEG-IFN
  alpha-2a - PEG-IFN alpha-2a Ribavirin

From Torriani FJ, et al. N Engl J Med
2004351438-50.
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Treatment of HCV in HIV-Infected PersonsACTG
A5071 Study
Study Design
SVR 72 Week Data

• Background - N 133 - All with baseline
  biopsy
• Evaluation - SVR HCV RNAlt60 IU/ml
• at week 72
• Regimens - INF alpha-2a Ribavirin - PEG-IFN
  alpha-2a Ribavirin

From Chung R, et al. N Engl J Med
2004351451-9.
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Case History HCV Rx Interaction with ARV Meds

• A 46-year-old HIV-infected man is taking his
  third antiretroviral regimen and this salvage
  regimen consists of stavudine plus didanosine
  plus lopinavir-ritonavir.
• His CD4 count is 410 cells/mm3 and his HIV RNA is
  less than 50 copies/ml.
• He is co-infected with HCV and the plan is to
  treat him with peg-interferon plus ribavirin.

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Case History HCV Rx Interaction with ARV Meds

• Which of the following is TRUE?1. Stavudine
  will increase ribavirin levels and increase the
  severity of anemia.2. Ribavirin will increase
  the intracellular concentration of didanosines
  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
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GB Virus CInteraction with HIV
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Case History GB Virus C

• Which of the following is BEST DESCRIBES GB Virus
  C and HIV?1. It is a hepatitis virus that is
  present in 20 of HIV-infected persons.2. It is
  a rare hepatitis virus that causes acute liver
  failure if an HIV-infected person is already
  infected with hepatitis B virus.3. This virus
  markedly increases the risk of transmission of
  HIV. 4. This virus may delay progression of HIV
  disease by increasing levels of chemokines that
  block HIV entry into cells.

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GB Virus CBackground Information

• First isolated in 1995
• Single stranded RNA flavivirus
• Genetically similar to hepatitis C virus
• NOT a hepatitis virus
• No clear disease state in humans
• Approximate seroprevalence rates (E2 antibody)-
  Healthy US blood donors 16- IDU 70

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GB Virus C and Survival of HIV-Infected
MenKaplan Meier Survival Curve /- GBV-C Viremia)
N 362 HIV-Infected Patients40 positive for
GBV-C viremia
From Xiang J, et. al. N Engl J Med
2001345707-14.
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GB Virus C and Survival of HIV-Infected Men

• GBV-C viremia was significantly associated with
  prolonged survival among HIV-positive men 5 to 6
  years after HIV seroconversion, but not at 12 to
  18 months, and the loss of GBV-C RNA by 5 to 6
  years after HIV seroconversion was associated
  with the poorest prognosis. Understanding the
  mechanisms of interaction between GBV-C and HIV
  may provide insight into the progression of HIV
  disease.

From Williams CF, et. al. N Engl J Med
2004350981-90.
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Molecular Interactions Between HIV GB Virus-C
From Pomerant, RJ, et. al. N Engl J Med
2004350963-5.
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HIV Cell Binding and Entry
CD4 Cell
R5 HIV
CCR5
CD4
CXCR4
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Chemokines Natural Ligand For CCR5
CD4 Cell
R5 HIV
CCR5
CD4
Chemokines
Rantes
CXCR4
MIP-1 alpha
MIP-1 beta
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HIV Cell Binding and Entry
CD4 Cell
R4 HIV
CCR5
CD4
CXCR4
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SDF-1 Natural Ligand For CXCR4
CD4 Cell
R4 HIV
CCR5
CD4
CXCR4
SDF-1
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Inhibition of HIV Replication by GB Virus C
Peripheral Lymphocyte
CD4 Cell
HIV
CCR5
CD4
CXCR4
GB Virus C
From Xiang, J, et. al. Lancet 20043632040-6.
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Inhibition of HIV Replication by GB Virus C
Peripheral Lymphocyte
CD4 Cell
HIV
CCR5
CD4
CXCR4
GB Virus C
From Xiang, J, et. al. Lancet 20043632040-6.
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Inhibition of HIV Replication by GB Virus C
Peripheral Lymphocyte
CD4 Cell
HIV
CCR5
CD4
CXCR4
Rantes
GB Virus C
MIP-1 alpha
MIP-1 beta
SDF-1
From Xiang, J, et. al. Lancet 20043632040-6.
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Inhibition of HIV Replication by GB Virus C
Peripheral Lymphocyte
CD4 Cell
HIV
CCR5
CD4
CXCR4
Rantes
GB Virus C
MIP-1 alpha
MIP-1 beta
SDF-1
From Xiang, J, et. al. Lancet 20043632040-6.
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Antiretroviral Therapy New DHHS Guidelines
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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, you would wait until
  CD4 count less than 300 cells/mm3.3. No, you
  would wait until CD4 count less than 200
  cells/mm3.

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• DHHS Panel 2004 Antiretroviral
  GuidelinesInitial Therapy, Chronically Infected

Clinical Category CD4 Cell Count Plasma HIV RNA Recommendation
Symptomatic(AIDS, severe symptoms) Any value Any value Treat
Asymptomatic, AIDS lt200/mm3 Any value Treat
Asymptomatic gt200/mm3 but lt350/mm3 Any value Generally offered controversy exists.
Asymptomatic gt350/mm3 gt55,000 copies/ml Some experts would recommend initiating therapy.
Asymptomatic gt350/mm3 lt55,000 copies/ml Many experts would defer therapy and observe.
Source http//www.aidsinfo.nih.org
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Starting Antiretroviral Therapy
Acute HIV Infection
350
350
200
200
Year 1
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DHHS Panel 2004 Antiretroviral Guidelines
Initial Therapy Preferred Regimens
PI-Based Regimens
NNRTI-Based Regimens
EfavirenzLamivudine Zidovudine or Stavudine
or Tenofovir
Lopinavir/Ritonavir (Kaletra)Lamivudine
Zidovudine or Stavudine
Picture
Source www.aidsinfo.nih.gov
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Antiretroviral TherapyNewer Medications
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FDA-Approved HIV Antiretroviral Medications in US
FPV
FTC
ATZ
EFV
TDF
LPV-RTV
AMP
ABC
DLV
EFV
NFV
NVP
IDV
RTV
SQV
3TC
d4T
ddC
ddI
AZT
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FDA-Approved HIV Antiretroviral Medications in US
AZT-3TC
AZT-3TC-ABC
ABC-3TC
TDF-FTC
FPV
FTC
ATZ
EFV
TDF
LPV-RTV
AMP
ABC
DLV
EFV
NFV
NVP
IDV
RTV
SQV
3TC
d4T
ddC
ddI
AZT
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HIV Antiretroviral Therapy
Nucleoside Analogue RTI
Entry Inhibitors
RT
HIV RNA
HIV DNA
Nucleus
HIV
Protease Inhibitors
Host Cell
Non-Nucleoside RTI
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Emtricitabine/FTC (Emtriva)

• Classification nRTI
• Activity HIV and HBV
• Dose 200 mg PO qd
• Meal Restrictions none
• Potency in vitro more potent than Lamivudine
• Resistance Profile similar to Lamivudine (M184V)
• Adverse Effects well-tolerated

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Emtricitabine versus Stavudine 301A StudyddI
EFV either Emtricitabine or Stavudine
Study Design
Results 24 Weeks (ITT)

• Patients (N 571 randomized) - ARV naïve,
  HIV RNA gt 5,000 copies/ml - Randomized,
  double-blind - Median HIV RNA 4.8 log10 (both
  groups) - Mean CD4 312 cells/mm3
  (Emtricitabine) - Mean CD4 324 cells/mm3
  (Stavudine)
• Regimens -Emtricitabine ddI EFV -
  Stavudine ddI EFV

Study stopped at 24 weeks after preliminary
analysis
From Saag M, et al. JAMA 2004292180-9.
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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

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TDF FTC EFV versus ZDV 3TC EFVStudy 934
Study Design
Results 24 Weeks (ITT)

• Patients (N 517) - ARV naïve, HIV RNA gt
  10,000 copies/ml - Randomized
• Regimens - Tenofovir Emtricitabine
  Efavirenz - Zidovudine Lamivudine
  Efavirenz

From Gilead Sciences, Press Release Aug 26,
2004.
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Abacavir plus Lamivudine (Epzicom)

• Classification nRTI
• Dose 1 pill qd (Abacavir 600 mg Lamivudine 300
  mg)
• Active component of abacavir (carbovir-P-P-P) has
  long half-life
• Meal Restrictions none
• Adverse Effects hypersensitivity reaction with
  Abacavir

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Plasma Abacavir Intracellular Carbovir-TP PK
Concentration
CBV-TP t1/2 20.64 hours
From Piliero P. JAIDS. 200437S2-12.
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Enfuvirtide/T-20 (Fuzeon)

• Classification fusion inhibitor (36 amino acid
  peptide)
• Dose 90 mg sq bid
• Indications salvage therapy
• Adverse Effects local injection site reactions
• Cost gt 20,000 per year

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Enfuvirtide (Fuzeon) for Drug-Resistant
HIVTORO-1 Study (North South America)
Study Design (TORO-1)
24 Week HIV RNA Data

• Background - N 491 - Very heavily pretreated
• Baseline (Control Group) - Median HIV RNA 5.2
  log10 copies/ml - Median CD4 87 cells/mm3
• Baseline (Enfuvirtide Group) - Median HIV RNA
  5.2 log10 copies/ml - Median CD4 75 cells/mm3
  
• Regimens - Optimized Background (3-5 ARVs) -
  Optimized Background Enfuvirtide

P lt 0.001
P lt 0.001
P lt 0.001
Enfuvirtide (Fuzeon) 90 mg sq bid
From Lalezari JP, et al. N Engl J Med
20033482175-85.
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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

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Antiretroviral TherapyResistance
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K65R Mutation

• Which of the following is TRUE regarding the K65R
  mutation? 1. It reduces the activity of
  abacavir and tenofovir2. It is more likely to
  occur if a patient is taking zidovudine. 3. It
  causes cross resistance to efavirenz and
  nevirapine.4. It is the most important protease
  inhibitor mutation

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Treatment Failure and Development of K65R
MutationSummary of Prospective Studies
.
From Ruane P Luber AD. Med Gen Med 2004631.
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Impact of the K65R Mutation

• Common Resistance Mutation in Triple-NRTI
  Regimens that do not Contain Zidovudine or
  Stavudine
• Reduces Activity of Tenofovir, Lamivudine,
  Abacavir
• Causes Hypersusceptibility to Zidovudine or
  Stavudine

From Ruane P Luber AD. Med Gen Med 2004631.
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Benefit of Lamivudine with M184V Mutation
Study Design
Results

• Patients (N 4) - Highly treatment-experienced
  - Failing antiretroviral regimen - All
  receiving Lamivudine - All with M184V mutation
• Intervention - Stop Lamivudine

Lamivudine Stopped
M184V
- M184V
From Campbell TB, et al. 12th International
Resistance Workshop. 2003. Abstract 140.
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Antiretroviral TherapyLipoatrophy (fat wasting)
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Lipoatropy (Fat Wasting)
Higher Risk
Low Risk
StavudineDidanosine
TenofovirAbacavirLamivudineEmtricitabine
Lipoatrophy
Fat Wasting
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Lamivudine Efavirenz either Tenofovir or
StavudineStudy 903 Toxicity Analysis
Study Design
Limb Fat

• Background - N 600 enrolled - Antiretroviral
  therapy naive - Mean HIV RNA 4.9 log10 -
  Mean CD4 279 cells/mm3
• Regimens - TFV 3TC EFV (n 299) - d4T
  3TC EFV (n 301)

P lt 0.001
P lt 0.001
TFV Tenofovir (Viread)3TC Lamivudine
(Epivir)d4T Stavudine (Zerit)EFV Efavirenz
(Sustiva)
From Gallant JE, et al. JAMA 2004292192-201.
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Lipoatrophy Effects of Switching Nucleoside
AnalogsMITOX Study
Study Design
Week 24 Change in Limb Fat

• Methods - Randomized, open-labeled - 111
  patients with lipoatrophy - Patients on
  stavudine (n 85) - Patients on zidovudine (n
  26)
• Regimen Changes - Switch stavudine/zidovudine
  to abacavir - Continue current regimen (no
  switch)
• Measurements - Dual-energy x-ray
  absorptiometry

P 0.02
From Carr A, et al. JAMA 2002288207-15.
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Lipoatrophy Switching Stavudine to Abacavir or
ZidovudineTARHEEL Study
Study Design
48 Week Data Change in Fat (DEXA)

• Methods (N 118) - Open-labeled switch study
  - Patients on stavudine with lipoatrophy
• Regimen Changes - Switch stavudine to abacavir
  (n 86) - Switch stavudine to zidovudine (n
  32)
• Measurements - Dual-energy x-ray absorptiometry
  (DEXA) - Computerized tomography

Trial to Assess Regression of Hyperlactatemia
Evaluate Established Lipodystrophy
From McComsey G, et al. Clin Infect Dis
200438263-70.
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Poly-L-Lactic Acid/New-Fill (Sculptra)

• Approved by FDA on August 3, 2004
• Indication facial lipoatrophy (facial wasting)
  in HIV-infected persons
• Manufacturer Dermik laboratories (Aventis)
• Mechanism of Action- poly-L-lactic acid
  (PLLADegrades injected into deep dermis-
  Increases fibroblast numbers and collagen
  production
• Adverse Effects- Nodules, redness, swelling,
  bruising

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Polylactic Acid (Sculptra) for HIV-1 Facial
Lipoatrophy
Study Design
Facial Thickness gt 10 mm

• Patients - N 50 - Fat thickness lt 2 mm in
  upper cheek
• New Fill Injections - Bilateral deep dermal
  injections - 0, 2, 4, 6 weeks
• Follow-Up - Ultrasound measurements of face

From Valentin MA, et al. AIDS 2003172471-7.
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Polylactic Acid/New Fill (Sculptra) for HIV
Facial Lipoatrophy
From Valentin MA, et al. AIDS 2003172471-7.
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• Summary

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