2005 Asilomar HIVAIDS Medical Update David H' Spach, MD Clinical Director, Northwest AIDS Education

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2005 Asilomar HIV/AIDS Medical Update
David H. Spach, MDClinical Director, Northwest
AIDS Education and Training CenterProfessor of
Medicine, Division of Infectious
DiseasesUniversity of Washington, Seattle
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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

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HCV and HIV Co-Infection Update
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HCV Therapy Terminology
Week 12
Week 48
Week 72
Week 0
Treatment (48 Weeks)
Post-Treatment (24 Weeks)
Early Virologic Response (EVR)HCV lt 100
copies/mlORHCV RNA decrease gt 2 log
End of Treatment Response (ETR)HCV RNA
undetectable
Sustained Virologic Response (SVR) HCV RNA
undetectable
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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

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Progression of HCV Treatment SuccessSustained
Virologic Response
From Strader DB, et al. Hepatology
2004391147-71.
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Treatment of HCV in HIV-Infected PersonsAPRICOT
TRIAL (Pegasys)
Study Design
SVR 24 Week Post-Treatment

• Background - N 868 - All with baseline
  biopsy
• Evaluation - SVR HCV RNA lt50 IU/ml at week 72
• Regimens (48 Weeks of Therapy) - INF alpha-2a
  Ribavirin - PEG-IFN alpha-2a - PEG-IFN
  alpha-2a Ribavirin

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

From Torriani FJ, et al. N Engl J Med
2004351438-50.
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Treatment of HCV in HIV-Infected PersonsACTG
A5071 Study (Pegasys)
Study Design
SVR 24 Week Post-Treatment

• Background - N 133 - All with baseline
  biopsy
• Evaluation - SVR HCV RNA lt 60 IU/ml at week 72
  
• Regimens (48 Weeks of Therapy) - INF alpha-2a
  Ribavirin - PEG-IFN alpha-2a Ribavirin

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
From Chung R, et al. N Engl J Med
2004351451-9.
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Results of HCV HIV Co-Infection Treatment
Trials Peginterferon Ribavirin x 48 Weeks
Peginterferon-2a
Peginterferon-2a
Peginterferon-2b
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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)
12 Week EVR- HCV RNA lt 50 copies/ml OR- HCV
RNA decrease gt 2 log
From Torriani FJ, et al. N Engl J Med
2004351438-50.
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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

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Peginterferon Ribavirin for HCV Genotypes 2 or
3 48 Weeks versus 28 Weeks (Romance 2 Trial)
Study Design
SVR 24 Week Post-Treatment

• Background - N 128 - HCV HIV Co-Infected
  - All with HCV genotype 2 or 3 - CD4 gt 200 and
  HIV RNA lt 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

From Zanini B, et al. 3rd IAS Path Treatment.
2005 MoPpLB0103.
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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
  patients 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 gt 800 mg/d OR gt
  10.6 mg/kg/d- Most critical in first 20 weeks
• Use Recombinant Erythropoeitin/Epotin Alpha
  (EpogenProcrit)- Initiate for Hb lt 12 g/dL-
  Dose 40,000 sq 1 x/w increase to 60,000 sq/w
  if needed

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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?

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• Viramidine

Adenosine Deaminase
NH3
Viramidine
Ribavirin
Liver
Inactive MetaboliteICN3297
Adenosine Deaminase
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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 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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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)

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FDA-Approved Therapies for HBV Infection
Dose given for HBeAg (duration 4-6 months)
Dose for HBeAg(-) 5-6 x 106 3x/week x 48 weeks
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Non FDA-Approved Therapies for HBV
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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

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Peginterferon-alpha-2a vs Lamivudine vs
BothHBeAg-Negative Chronic HBV
Study Design
Response 24 Weeks Post Rx

• 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 lt
  20,000 - Biochemical Normalization of ALT -
  Loss of HBsAg

From Marcellin P, et al. N Engl J Med
20043511206-17.
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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 (gt 2-3x), and HBV
  DNA levels gt 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 RNA23,000 HBeAg().
• Patient 2 CD4 524 HIV RNA38,000 HBeAg(-).
• Patient 3 CD4 210 HIV RNA 112,000 HBeAg().
• QuestionHow would you approach treatment of HBV
  infection is these 3 patients?

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Chronic HBV HIV Initiating HBV
TherapyRecommendations from an International
Panel
HIV ARV Indicated
No
Yes
HBeAg ()
Tenofovir plusLamivudine (or
Emtricitabine)plus NNRTI or PI
No
Yes
Peginterferon
Entecavir or Adefovir
From Soriano V, et al. AIDS 200519221-40.
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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

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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

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HBV Loss of Response with NRTIs Resistance to
NRTIs
HBV Reverse Transcriptase Mutations
From Nunez M, et al. Lancet ID 20055374-82.
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HIV/HBV Screening for HCC

• A 53-year-old man with HIV and HBV co-infection
  and has known cirrhosis.
• CD4 420, VL lt 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 lt
  10,000 copies/ml?2. His risk is lower since he
  has cirrhosis3. His risk is higher because he
  has HBeAg4. His risk is lower because he is
  older than 45

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Chronic HBV Risk Factors for HCC

• Age gt 45
• Male gender
• Detectable HBV DNA
• HBeAg ()
• Presence of cirrhosis
• Co-infection with HCV

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Chronic HBV Risk of HCC
12 10 8 6 4 2 0
n11,893 men, Taiwan
HBsAg, HBeAg
Percent cumulative incidence
HBsAg, HBeAg-
HBsAg-, HBeAg-
0 1 2 3 4 5 6 7 8 9 10
Year
Yang HI, et al. N Engl J Med. 2002347168-74.
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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.

From Lok AS, McMahon BJ. 2004 AASLD Guidelines
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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.

From Soriano V et al. AIDS 200519221-40.
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Antiretroviral TherapyNew DHHS Guidelines
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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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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 gt 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.

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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.
  

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2005 ARV Guidelines Recent Major Changes

• Major Changes since September 20041. HIV RNA
  threshold changed from 55,000 to 100,000 2.
  Stavudine move from preferred to alternative3.
  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 gt 250 and
  men with CD4 gt 400 5. Rifampin can NOT be used
  safely with ritonavir-boosted PI regimens6.
  Tenofovir Didanosine should NOT be used
  together for initial Rx7. Once daily
  Lopinavir-Ritonavir (6 capsules qd) added for
  ARV-naïve patients

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DHHS Panel 2005 Antiretroviral Guidelines
Initial Therapy Preferred Regimens
PI-Based Regimens
NNRTI-Based Regimens
EfavirenzLamivudine or Emtricitabine
Zidovudine or Tenofovir
Lopinavir-RitonavirLamivudine or Emtricitabine
Zidovudine
Picture
Source www.aidsinfo.nih.gov
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TDF-FTC (LPV-RTV qd or LPV-RTV bid) Study 418
Study Design
HIV RNA lt 50 copies/ml 48 Weeks

• Patients (N 109) - ARV naïv - HIV RNA gt
  1,000 copies/ml - Randomized trial
• Regimens - Backbone Tenofovir
  Emtricitabine - Lopinavir-Ritonavir (800/200 mg
  qd) - Lopinavir-Ritonavir (400/100 mg bid)

Diarrhea- 16 in qd regimen- 5 in bid regimen
From Gathe J et al. 11th CROI2004 Abstract
570.
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Starting Antiretroviral Therapy
Acute HIV Infection
350
350
200
200
Year 1
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Antiretroviral TherapyNewer Medications
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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 48 Weeks (ITT)

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

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

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Tipranavir-r versus LPV-r in PI-Experienced
Patients
Study Design
HIV RNA Reduction gt 1 log10

• Background - Tipranavir is novel nonpeptidic
  PI - Patients failing PI-containing HAART - HIV
  RNA gt 1,000 copies/ml - gt 2 PI mutations
• Regimens - Optimized background regimen -
  With/without Enfuvirtide - Randomized to CPI-r
  versus Tip-r

Most chose LPV-r subset analysis of
LPV-rTipranavir 500 mg bid Ritonavir 200 mg
bid
From Cooper D, et al. 12th CROI. 2005 Abstract
560.
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Response to Tipranavir-Ritonavir in Advanced
Salvage
Tipranavir-Ritonavir OBR
Tipranavir-Ritonavir OBR Enfuvirtide
50
50
DHS/ARV Rx/PP
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Pharmacokinetics of Tipranavir Combined with
other PIs
Study Design
Tipranavir-r Effect on PIs

• Background - N 173 - Patients failing
  PI-containing HAART - HIV RNA gt 1,000 copies/ml
  - gt 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

From Walmsley S, et al. 15th International AIDS
Conference, 2004 Abstract WeOrB1236.
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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 TherapyFuture Medications
DHS/HIV/ARV Rx/PP
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D-d4FC (Reverset) ARV-Naïve Monotherapy
Dose-Ranging Study
Study Design
Results Day 10 Data

• Background - D-d4C is novel cytidine analog
  NRTI - Active against NRTI-resistant isolates
• Patients (N 30) - ARV naive - CD4 count gt
  50 cells/mm3 - HIV RNA gt 5,000 copies/ml
• Regimens - D-d4FC 50 mg qd - D-d4FC 100
  mg qd - D-d4FC 200 mg qd - Placebo qd

Serious Adverse Events None
From Murphy RL, et al. 11th CROI. 2004.
Abstract 137.
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D-d4FC (Reverset) ARV-Experienced Monotherapy
Dose-Ranging Study
Study Design
Results Day 14 Data

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

From Cohen C, et al. 3rd IAS Path Treatment.
2005 Abstract WeOaLB103.
DHS/ ARV Rx /PP
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TMC114/r in Late Salvage Therapy
Study Design
24 Week ITT Data

• 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

ITT (Missing Failure)
Subgroup Analysis of TMC-114/r600/100 mg bid -
Enfuvirtide Used (naïve) HIV RNA lt 50 in 67 -
Enfuvirtide not Used HIV RNA lt 50 in 37
From Katlama C, et al. 12th CROI. 2005Abstract
164LB.
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HIV Cell Binding and Entry
DHS/HIV/PP
From Levy J. N Engl J Med 19963351528-30.
57
HIV Cell Binding and Entry
From Levy J. N Engl J Med 19963351528-30.
DHS/HIV/PP
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Inhibitors of HIV Cell Binding and Entry
Enfuvirtide (T-20)
HIV
CD4 Cell
Vicriviroc (SCH 417690)Maraviroc
(UK427,857)GW873140PRO 140
Fusion Domain
gp120
CCR5
PRO 542BMS-806
CD4
TNX355
CXCR4
AMD-070
Fusion Domain
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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

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Maraviroc Summary of Studies Performed
Study Design
10 day Data HIV RNA Change

• 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 lt 300 mg bid

Capravirine levels boosted 2-fold by NFV
From McHale M. 3rd IAS Path Treatment. 2005
Abstract TuOa20.04.
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Vicriviroc (SCH 417690) CCR5 Receptor Antagonist
HIV-Infected Volunteers N 48
HIV RNA Change from Baseline(log10 copies/ml)
CD4 count gt 200 cells/mm3 No ARV Rx for gt 8 weeks
From Schumann D, et al. CROI 2004140LB.
62
HIV Infection Natural History
R5 HIV
R5 HIV
R4 HIV
R5 HIV
AIDS
Year 1
DHS/ARV Rx/PP
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HIV Cell Binding and Entry
CD4 Cell
R5 HIV
CCR5
CD4
CXCR4
DHS/PP
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HIV Cell Binding and Entry
CD4 Cell
R5 HIV
CCR5
CD4
CXCR4
DHS/PP
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HIV Cell BindingPotential Shift from R5 HIV to
R4 HIV
CD4 Cell
R5 HIV
CCR5
CD4
R4 HIV
CXCR4
DHS/PP
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HIV Cell BindingPotential Shift from R5 HIV to
R4 HIV
CD4 Cell
R5 HIV
CCR5
R4 HIV
CD4
CXCR4
DHS/PP
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HIV Cell Binding and Entry
CD4 Cell
R4 HIV
CCR5
CD4
CXCR4
DHS/PP