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VIEWS: 4 PAGES: 41

  • pg 1
									                                                   Slide 1




What, Where, When, How, and
 Why: Incorporating Newly
 Approved Drugs into HIV
  Therapy (in 30 minutes)
     Charles B. Hicks, MD
   Associate Professor of Medicine
   Duke University Medical Center


                       The International AIDS Society–USA
When changing the antiretroviral             Slide 2

regimen in a treatment-experienced
patient, it is important to:

 1. Use at least two nucleoside RT
    inhibitors
 2. Avoid use of T-20 if possible
 3. Have at least two active agents in the
    new regimen
 4. To use an investigational agent
    whenever possible
Slide 3
Slide 4
                                                                                                              Slide 5
            Approved Antiretroviral Agents
                     1987-2007
                                                     3TC/ZDV                     TDF        3TC/ABC
                                                                                            FTC/TDF
                              ddC         3TC         DLV         ABC

ZDV                     ddI         d4T         NVP         EFV     ABC/3TC/ZDV            FTC        TDF/FTC/EFV




87     88   89   90     91 92 93 94 95          96     97   98    99     00     01   02    03    04    05   06   07



     Nucleoside RTI                  SQV.hgc          NFV               LPV/r             T-20        TPV

Non-nucleoside RTI                                   SQV.sgc      APV                     ATV           DRV
 Protease Inhibitor
                                                RTV                                        FPV                   MVC
     Fusion Inhibitor
     CCR5 Inhibitor                             IDV                                                                 RTG
 Integrase Inhibitor
                                          Slide 6




•In general, new drugs are commercially
developed in ways that lead to the most
rapid approval and commercial release
•In the HIV market, this has generally
meant studies with highly treatment-
experienced patients
•Thus, newly approved antiretroviral
agents are most often indicated for and
used in ARV-experienced populations
                                                                                                                Slide 7
                             Current Guidelines:
                        Changing ARV Therapy in Highly
                            Experienced Patients

     •     If <2 fully active ARVs, consider RTV-boosted PI +
           optimized ARV background and/or use of prior
           ARVs with partial activity
     •     Adding a drug with activity against resistant virus
           (eg, RTV-boosted PI) and drug with new mechanism
           of action (eg, entry inhibitor) + an optimized ARV
           background antiretroviral regimen can provide
           significant activity
     •     In general, adding one active drug to failing regimen
           leads to resistance, but may be necessary in
           patients with advanced disease (eg, CD4 <100) and
           high risk of clinical progression
Adapted from DHHS Guidelines; Revision October 10, 2006. Available at: http://aidsinfo.nih.gov.
Accessed December 13, 2006; Recommendations for the use of antiretroviral therapy (Hammer et al, JAMA, 2006).
Available at http://www.iasusa.org/pub/arv_2006.pdf. Accessed October 8, 2007.
                                Slide 8




New Drugs in Existing Classes

      Protease Inhibitors
                                                       Slide 9

Recommended Dosing of Tipranavir

  AM         Tipranavir 500 mg          ritonavir 200 mg


  PM         Tipranavir 500 mg          ritonavir 200 mg



 • Capsules: 500 mg (2 x 250 mg) co-administered
   with ritonavir 200 mg (2 x 100 mg) BID
 • Dosing with ritonavir is essential to achieve
   effective Tipranavir plasma concentrations
 • Tipranavir capsules should be taken with food




                                                           9
Slide 10
                                                             Slide 11

Darunavir

   Orange, oval-shaped, film-coated tablets containing
    darunavir ethanolate equivalent to 300 mg of darunavir
   Packaged in bottles containing 120 tablets
                                                                                Slide 12
TITAN: DRV+RTV vs LPV/r in treatment
experienced patients
• 48-week analysis from 96-week, randomized, controlled, open-label trial in
  treatment-experienced, LPV-naïve patients
• Randomized to DRV+RTV or LPV/r SGC + 2 or 3 other ARVs
  (NRTIs/NNRTIs)
• Primary outcome: % patients <400 c/mL (non-inferiority); secondary
  endpoints include % <50 c/mL and test for superiority
                                                            DRV          LPV
 Baseline values
                                                          (n=298)      (n=297)
 CD4+ cells/mm3                                              235          230
 HIV RNA log10 c/mL                                          4.3          4.3
 No prior PIs                                               32%          31%
 >2 prior PIs                                               32%          30%
 FC to assigned PI (median) [range]                       0.6 [0-37]   0.8 [0-74]
 OBR 2+ active agents                                       65%          51%


Valdez-Madruga J, et al. 4th IAS, Sydney 2007, #TUAB101
                                                                                                                                                                                           Slide 13
TITAN: Virologic efficacy at Week 48
(ITT-TLOVR)
                                                            HIV RNA <400 c/mL                                                                                  HIV RNA <50 c/mL
 Patients with HIV RNA <400 c/m (%, 95% CI)




                                              100                                                                                                100




                                                                                                     Patients with HIV RNA <50 c/m (%, 95% CI)
                                              80                                                                                                 80
                                                                                              77%*
                                                                                                                                                                                                 71%*
                                                                                              67%
                                              60                                                                                                 60                                              60%

                                                                      DRV+RTV was non-inferior                                                                           DRV+RTV was non-inferior
                                              40                       and superior to LPV/r*                                                    40                       and superior to LPV/r*



                                              20                                                                                                 20
                                                                      DRV+RTV (n=298)
                                                                      LPV/r (n=297)
                                               0                                                                                                  0
                                                    0   4   8 12 16   24        36       48                                                            0   4   8 12 16   24       36        48
                                                                 Time (weeks)                                                                                      Time (weeks)
   *Estimated least-square mean difference in response                                                                         *Estimated least-square mean difference in
   vs LPV/r (95% CI) = 10% (2–17); p=0.0001                                                                                    response vs LPV/r (95% CI) = 11% (3–19); p=0.005
                                                                           CD4+ change: +88 and +81 cells/mm3, p=NS
Valdez-Madruga J, et al. 4th IAS, Sydney 2007, #TUAB101
                                                                                     Slide 14

TITAN: Subgroup and resistance analyses
• New PI mutations: 21% of DRV and 36% of LPV failures
• New NRTI mutations: 14% of DRV and 27% of LPV failures
                               Subgroup analyses at Week 48
                                                                               p
 HIV RNA                                     DRV     LPV   Difference
                                                                          (superiority)
 <50 c/mL
                                             70%     60%     10%              0.013*
 LPV FC <40
 <50 c/mL
                                             70%     63%      7%               0.07*
 LPV FC <10
 <400 c/mL
                                             91%     85%      6%             Not done
 <6 LPV mutations
 <400 c/mL
                                             86%     41%     45%             Not done
 >6 LPV mutations
                                                             *p (non-inferiority) <0.001

De Meyer S, et al. 4th IAS, Sydney 2007, #WEPEB038
                                                                                                                                                                                   Slide 15


           Darunavir + OB + New Class
                                                                                   POWER 1 & 2                                                                          DRV/r
                                       70                                                                                                                               Comparator PI(s)
   Individuals with HIV RNA <50 c/mL




                                       60
       at Week 48 (ITT-TLOVR)(%)




                                                                                                                                                     21 / 36
                                                               39 / 70




                                                                                                       41 / 76
                                       50




                                                                                                                            27 / 61
                                       40
                                            10 / 29




                                       30
                                                                                     8 / 31



                                       20
                                                                         11 / 76




                                       10
                                                                                                                 11 / 85
                                                      0 / 24




                                                                                              0 / 32




                                                                                                                                                               4 / 35
                                                                                                                                      7 / 70
                                        0
                                            11-40                 10                    0                  ≥1             Not used            Used (naïve)

                                                        DRV/r FC                          Sensitive NRTI                                       ENF

FC = fold change in EC50
Walmsley S, et al. XVI IAC (2006). Abst. TUAB0104.
                                                                                  Slide 16


         ARTEMIS: Phase III study design

                                DRV/r 800/100mg qd
689 ARV-naïve
patients             + TDF 300 mg and FTC 200 mg (N=343)
VL>5,000;
no CD4 entry     LPV/r 400/100mg bid or 800/200mg qd
                    + TDF 300 mg and FTC 200 mg (N=346)



                 LPV dosing                     LPV formulation
                 qd =       15%                 Capsule only =                  15%
                 bid =      77%                 Tablet only =                   2%
                 bid/qd =     7%                Capsule/tablet switch = 83%
                 Dosing was based on regulatory approval; switch was made
                 according to local regulatory approval and drug availability
                                                                                                                            Slide 17


                                           ARTEMIS: Viral load <50 copies/mL
                                               to Week 48 (ITT-TLOVR)
Patients with VL <50 copies/mL (% [±SE])



                                           100                                                           DRV/r qd (N=343)

                                            90                                                           LPV/r qd or bid (N=346)
                                                                                                                      84%
                                            80
                                                                                                                      78%
                                            70
                                            60
                                            50
                                            40
                                                                Estimated difference in response vs LPV/r for non-inferiority:
                                            30
                                                                PP = 5.6% (95% CI –0.1;11.3) p<0.001
                                            20                  Estimated difference in response vs LPV/r for superiority:
                                            10                  ITT = 5.5% (95% CI –0.3;11.2) p=0.062

                                            0
                                                 2 4   8   12        16     24                 36                48
                                                                     Time (weeks)
                                                                                                                                                                       Slide 18

                                     ARTEMIS: Confirmed response by baseline
                                        VL or CD4 at Week 48 (ITT-TLOVR)
                                                                              DRV/r qd   LPV/r qd or bid
                   100                                                                                             100
                                                                    †p<0.05   vs LPV/r
Patients with VL <50 copies/mL (%)




                                                                                         Patients with VL <50 copies/mL (%)
                                             86           85                                                                                                 87
                                                                                                                                                                  84
                                          n=194 n=191      n=28      79†                                                                         80
                                 80                                                                                           80    77
                                                                               67                                                                      71
                                                                                                                                            67

                                     60                                                                                       60


                                     40                                                                                       40


                                     20                                                                                       20

                                                                                                                                                                  0

                                      0                                                                                        0
                                              <100,000                ≥100,000                                                        <50        50–200       >200
                                           Baseline viral load (copies/mL)                                                         Baseline CD4 cell count (cells/mm3)
                                     N=      226          226        117        120                                           N=     30     30   111   118   202 198
                                                   †Chi   square analysis
                                                                                                   Slide 19



           ARTEMIS: Median change in absolute
           CD4 cell count to Week 48 (ITT-NC=F)
                                  150
                                                                                        141 cells/mm3
Median change in CD4 cell count




                                                                                        137 cells/mm3
   from baseline (cells/mm3)




                                  120
                                                                              DRV/r qd (N=343)
                                                                              LPV/r qd or bid (N=346)
                                   90


                                   60


                                   30


                                    0
                                        2 4   8   12 16       24         36        48
                                                          Time (weeks)
                           Slide 20




New Drugs in New Classes

    Integrase Inhibitors
                                                                                                                   Slide 21

                  BENCHMRK 1 and 2: RGV in
                Treatment-Experienced Patients
     Randomized, double-blind, placebo-controlled, parallel phase III
      studies
     Primary endpoints: HIV-1 RNA, CD4+ cell counts, and AEs at week 16
                                                        Primary Endpoints:                     Planned Duration:
                                                              Wk 16                                 Wk 48

                 HIV-infected,
            triple-class resistant,                                 RGV 400 mg BID + OBR*
           HIV-1 RNA >1000 c/mL                                      BENCHMRK 1 (n = 232)
                                                                     BENCHMRK 2 (n = 230)
           BENCHMRK 1 (N = 350)
         (Europe, Asia/Pacific, Peru)                                 Placebo + OBR*
           BENCHMRK 2 (N = 349)                                    BENCHMRK 1 (n = 118)
           (North, South America)                                  BENCHMRK 2 (n = 119)


RGV = raltegravir
*Selected investigational ARVs permitted in OBR.
Cooper D, et al. 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 105aLB; Steigbigel R, et al. 14th CROI; February
25–28, 2007; Los Angeles, CA. Abstract 105bLB.                                                                          21
                                                                                                                      Slide 22
                                      BENCHMRK 1 and 2:
                                    VL <50 c/mL (ITT, NC = F)


                                            RGV + OBR                            Placebo + OBR
                     100           BENCHMRK 1                       100             BENCHMRK 2

                     80                                              80
Pts With HIV-1 RNA




                                              61                                                   62
  <50 c/mL (%)




                     60                                              60

                                        P <.001 at wk 16                                      P <.001 at wk 16
                     40                                              40


                     20                        33                    20                            36

                       0                                               0
                           0 2 4    8     12   16          24              0 2 4       8     12   16              24
                                        Time (wk)                                          Time (wk)
     n=                232                    230          158   n=        230                    229             128
     n=                118                     118          81   n=        119                      119               69

Cooper D, et al. 14th CROI; February 25–28, 2007; Los Angeles, CA. Abstract 105aLB; Steigbigel R, et al. 14th CROI;
February 25–28, 2007; Los Angeles, CA. Abstract 105bLB.                                                                    22
Raltegravir (RAL) with TDF and 3TC
in treatment-naïve patients
 • Patients randomized equally to                              HIV RNA <50 c/mL (95% CI) [NC=F]
    TDF/3TC + EFV 600 mg QD or RAL                                 100
    at 100, 200, 400 or 600 mg BID                                     80
      – Mean BL HIV RNA 4.6–4.8 log10 c/mL                             60
                                                                   %
      – Mean BL CD4+ 271–338 cells/mm3                                 40
      – All susceptible at baseline                                    20
                                                                         0
 • AEs similar                                                                0 2 4 8 12 16    24 32         40   48
                                                                                              Week
      – More CNS AEs with EFV                                      RAL100 mg BID (n=39)              RAL 400 mg BID (n=41)
                                                                   RAL 200 mg BID (n=40)             RAL 600 mg BID (n=40)
                                                                   EFV 600 mg QD (n=38)
 Virologic failures
 • RAL, n=5 (3%)                                        Change from BL to Wk 48in fasting lipids
                                                             50
      – Two with integrase mutations; both                                    RAL     EFV
                                                                                                      49.5
                                                                                                             RAL vs RFV:
        N155H, 1 with multiple mutations                     40                                              *p<0.001
                                                                                                             **p=0.016
      – 3TC resistance (n=4)                                 30                                              †p=0.068
                                                     mg/dL

                                                                          20.7
      – K65R (n=1)                                           20
                                                                                                             ††p=0.52



 • EFV, n=1 (3%)                                             10
                                                                                       3.0                   TC:HDL††
      – K65R and G190E                                        0                                              RAL -0.6
                                                                       -2.3                   -1.0           EFV -0.5
                                                             -10                    -7.5

Markowitz M, et al. 4th IAS, Sydney 2007, #TUAB104
                                                                        TC*         LDL**      TG†                      23
                            Slide 24




New Drugs in New Classes

  Entry (CCR5) Inhibitors
                                      Slide 25


                   CCR5 Antagonists Target
  CCR5              HIV Binding and Fusion
  antagonist          With CD4+ T Cells




CD4



   CCR5



               T-cell surface
                                       Slide 26
Binding of CCR5 Antagonist Causes a
Conformational Change




CD4



  CCR5

           CCR5
         antagonist   T-cell surface
                                                                             Slide 27

Tropism Assay Result
                       WHAT IS A TROPISM ASSAY?

                                                                       .




                       TROPISM VIRAL CLASSIFICATION




                                       tropism assays




                                                        Tropism assays can help




                             tropism assays in clinical settings.
                                                                                 Slide 28


Tropism Assay Result
                       WHAT IS A TROPISM ASSAY?



                                                                                 .


                       TROPISM VIRAL CLASSIFICATION




                                      tropism assays




                                                       Tropism assays can help




                             tropism assays in clinical settings.
                                                                                                                  Slide 29
MOTIVATE 1 & 2: Maraviroc for salvage
therapy (24-week results)
                                             OBT + placebo
  Randomization 1:2:2
                                             OBT + maraviroc (150 mg† QD)
  MOTIVATE 1 (n=601)
  MOTIVATE 2 (n=475)
                                             OBT + maraviroc (150 mg† BID)

 • R5 HIV infection; HIV RNA                                                     Baseline characteristics
   ≥5,000 c/mL; stable pre-study                                                     PBO         MVC QD        MVC BID
   ARV regimen, or no ARVs for ≥ 4                                                  M1 / M2      M1–M2          M1–M2
   weeks                                                          n                 118 / 91     232 / 182     235 / 191
                                                                  CD4+
 • Resistance to and/or ≥6 months’                                (cells/mm3)
                                                                                    163 / 174    168 / 174     150 / 182
   experience with ≥1 ARV from                                    HIV RNA
   three classes (≥2 for PIs)                                                      4.84 / 4.89   4.85 / 4.87   4.86 / 4.84
                                                                  (log10 c/mL)
      – 44% screened out as D/M or X4                             OBT 2
                                                                                    66 / 66%      69 / 63       76 / 62
                                                                  active drugs
 † Patients receiving a PI (except TPV) and/or DLV in             ENF in OBT        42 / 45%      43 / 37       46 / 39
 their OBT received 150 mg dose of MVC; all other
 patients received 300 mg dose of MVC

1 Lalezari J, et al. 14th CROI, Los Angeles 2007, #104bLB; 2 Nelson M, et al. ibid, #104aLB
                                                                                                                         Slide 30
MOTIVATE 1 & 2: Maraviroc in ARV-
experienced patients (24-week results)
               Mean change from baseline                                       % HIV RNA <50 c/mL at 24 weeks
                       PBO            MVC QD          MVC BID           60
                      M1 / M2         M1 / M2         M1 / M2                       M1           M2                 48.5
                                                                        50                                   45.6
                                                                                                      42.2                 40.8
  HIV RNA                                                               40
                    -1.03/0.93       -1.82/1.95       -1.95/1.97                                       * **          †     ††
  (log10 c/mL)                                                          30         24.6
                                                                                          20.9
  CD4+                                                                  20
  (cells/mm3)          52/64          107/112          111/102
                                                                        10

                                                                          0
                                                                                    PBO               MVC QD        MVC BID
                                                                              *    p=0.0006
                                                                              **   p<0.0001      All vs PBO
                                                                              †    p<0.0001
                                                                              ††   p=0.0005




1 Lalezari J, et al. 14th CROI, Los Angeles 2007, #104bLB; 2 Nelson M, et al. ibid, #104aLB
                                                                                                                  Slide 31
    Proportion with HIV-1 RNA < 50 copies/mL
    by number of active drugs in OBT*
               100                                                                            Placebo + OBT

                90                                                                            MVC QD + OBT
                                                                                              MVC BID + OBT
                80
                70
                                                                                                      61%
Patients (%)




                60                                                                                          58%
                                                                                                55%
                                                                              52% 53%
                50
                                                      43% 43%
                40

                30                  29%

                              18%                                       19%
                20
                                                 9%
                10
                        3%
                 0
                     N = 35   51    56           44 130 134              59    88 104            64 132         121

Number of active 0                                     1                       2                      ≥3
drugs in OBT*                       Includes all patients who received at least one dose of study medication.
                     *Based on overall susceptibility score, LOCF.
   MOTIVATE 1 & 2—Week 24
                                                                                                       Slide 32

                    A New Class + Optimized Background
                    Maraviroc (<50c/mL)

                                           First ENF        First LPV/r           All Study       Placebo
                                                                                                  Maraviroc BID
                                                                    68%
                                      70

                                      60
   Patients <50 c/mL at Week 24 (%)




                                                 53%         50%                      48%
                                      50

                                      40   36%

                                      30                                        25%

                                      20

                                      10

                                       0
Patient Number                             14    35    34     193   373   385   207   408   419
Nelson M and Lalezari J, et al. 14th CROI (2007). Absts. 104aLB and 104bLB.
                                                                                                     Slide 33


Tropism shifts in MOTIVATE 1 and 2
                                                Mean change in CD4 count from baseline,
                                               cells/mm3 in patients with treatment failure

                                                 Placebo +            MVC QD +             MVC BID +
 Tropism result,                                                        OBT
                                                    OBT                                      OBT
 Baseline → Treatment Failure
                                                  N = 209               N = 414             N = 426
                                                     +14                  +49                  +71
 All treatment failures
                                                   (n = 97)             (n = 68)             (n = 77)
                                                     +15                  +61                 +138
 R5 → R5                                           (n = 80)             (n = 18)             (n = 17)
                                                    +67                   +37                  +56
 R5 → D/M or X4                                    (n = 4)              (n = 31)             (n = 32)
Change in tropism result between screening and baseline (~8%)
      • Response consistent with the results of study 1029 evaluating MVC in patients D/M-tropic virus

Nelson M, et al. CROI 2007. Los Angeles, Calif. Abstract #104aLB.
Data exclude patients who had no tropism result at time of failure and patients with non-R5 virus at baseline.
                                                        Slide 34
MOTIVATE 1 and 2
summary of 24-week interim analyses

 Maraviroc + OBT demonstrated significantly
  greater virologic suppression compared with
  placebo + OBT in this ARV-experienced patient
  population
     – Some patients appear to have greater benefit with
       maraviroc BID; eg, those with no fully active ARVs in
       OBT

 Maraviroc + OBT demonstrated significantly
  greater CD4+ cell count increases compared with
  placebo + OBT
                                                                                          Slide 35
MERIT: Maraviroc (MVC) vs EFV
in ART-naïve patients at Week 48
• ZDV/3TC plus either MVC 300 mg BID                                             Differenc
  or QD* vs EFV                                                       MVC
                                                     48 wks                EFV + e (95% CI
                                                                      BID
    – Eligible: R5 tropic, HIV RNA >2,000            (ITT)†                 CBV    lower
                                                                     + CBV
      c/mL; no EFV, ZDV, 3TC resistance                                           bound)
    – Endpoint: % HIV RNA <50 and 400               HIV RNA           70.6     73.1      -3.0
      c/mL at 48 weeks; non-inferiority             % <400 c/mL                         (-9.5)
      design                                        HIV RNA           65.3     69.3      -4.2
    – N=721; 29% women; mean CD4+ =                 % <50 c/mL                         (-10.9)
      250 cells/mm3; HIV RNA 4.9 log10              CD4+             170      144       26
      c/mL                                          (cells/mm3)                         (+7)
• Discontinuation                                   Category C       6 (1.7)    12       N/A
    – Virologic failure: MVC 11.9% vs EFV           events                     (3.3)
      4.2%                                         *QD arm stopped for inferior activity by DSMB
    – AE: MVC 4.2% vs EFV 13.6%                    †ITT   for all those who received >1 dose
• Summary: Safety established;
  noninferiority established for
  MVC HIV RNA % <400 c/mL
    – Not for % <50 c/mL (crossed preset
      10% threshold)
Clumeck N, et al. 4th IAS, Sydney 2007, #WESS104
                                                                                                     Slide 36

MERIT: 48-week virologic results
                        HIV RNA <50 c/mL by the two prespecified stratifications


                       100                                                 EFV        MVC
        Patients (%)




                        80       NS                p<0.05

                        60

                        40

                        20

                         0
                               <100,000            >100,000        Northern          Southern
                                                                  Hemisphere*       Hemisphere†
                                 Screening HIV RNA
                                       (c/mL)
                                                                                 *North America and Europe
                                                                      †Argentina, South Africa and Australia
                                                              ITT for all those who received at least 1 dose

Clumeck N, et al. 4th IAS, Sydney 2007, #WESS104
                                                                                                                 Slide 37
                                   Prevalence of R5 Use by Baseline
                                       CD4 and HIV RNA Levels

                                  100
       Prevalence of R5 Use (%)




                                                                           92                        89
                                  80                                  85                      84
                                                            82   80                     81
                                                       71                        78

                                  60         67
                                                  60
                                        58

                                  40


                                  20


                                    0                                                                      <5K
                                                                                                        >5-50K
                                                                                                   >50-100K

                                                                                             >100K

N=563.
Moyle G et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy.
Washington, DC: October 30-November 2, 2004. Abstract H-1135.
Slide 38
                                                                                 Slide 39




Timeline for New Antiretrovirals

  Entry inhibitors
  (anti-gp120, CCR5)                     Integrase          CXCR4
                                         inhibitors       inhibitors
  Maturation inhibitors
  Integrase inhibitors              CCR5
                                  inhibitors             PA-457


  2005             2006         2007            2008              2009



                    Darunavir          Etravirine     TMC278
                                                                         PIs
                                                                         NNRTI
Slide 40
                                                                                                              Slide 41

                             Survival gains of ART compared
                             with other disease interventions
                            200
  Survival Gains (months)




                            180
                            160
                            140
                            120
                            100
                             80
                             60
                             40
                             20
                              0
                                  Node +   Node –   2 vessel   3 vessel        BMT         OI Proph      ART
                                                                    1                                     2
                                   Chemo/breast       CABG/PTCA              Lymph-              AIDS Care
                                             1                                   1
                                      cancer                                  oma


1. Wright JC, et al. N Engl J Med 1998:339:380–6; 2. Walensky R, et al. 12th CROI, Boston 2005, #143LB
                                                                                      Wright and Weinstein NEJM 1998

								
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