HIV-1 dynamics Perelson et.al. Science 271:1582 (1996)

1
HIV-1 dynamicsPerelson et.al. Science 2711582
(1996)
Latently Infected CD4 lymphocytes
Infected CD4 lymphocytes
lt 1
gt 99
CD4 lymphocytes - defective virus
t1/2 - 1.6 days
t1/2 - 6 hrs
lt 1
HIV-1
Long lived cell populations
Uninfected, activated CD4 lymphocytes
2
Observations - viral dynamics

• it takes 2.6 days to produce a new generation of
  viral particles
• estimated total HIV production is 10.3 x 109
  virions per day
• at least 99 of the virus pool is produced by
  recently infected cells
• retroviral therapy should be able to reduce viral
  load within a few days

3
HIV-1 RNA in plasma Mellors et.al. Science
2721167 (1996)
Pittsburgh cohort - 186 men enrolled in
1984/85 Baseline CD4 counts and plasma viremia
were poorly correlated (r - 0.27) CD4 counts
are poorly predictive of disease progression and
death
HIV-1 RNA
0
1200
600
CD4 cells
4
HIV-1 RNA in plasma Mellors et.al. Science
2721167 (1996)
Kaplan-Meier curves
Baseline HIV-1 RNA lt 4500
4500-13000 13000-36000 gt 36000
1
0.5
Proportion surviving
0
There is a strong time- dependent prognostic
relation between HIV-1 RNA and clinical outcome
0 5 10
Time (yrs)
5
HIV-1 RNA in plasma of neonatesShearer et.al.
NEJM 3361337 (1997)
Prospective multicentre trial - 106
newborns Plasma HIV-1 RNA increased rapidly
after birth and slowly declined over 24
months Infants with very high viral loads in the
1st month of life were at increased risk for
rapid progression (p0.006)
rapid
HIV-1 RNA
nonrapid
0
24
12
Age - months
6
Receptors for HIV(Levy J. NEJM 19963351529)
HIV virus
CD4 receptor is not enough for binding a Can
manipulate these other receptors to prevent
infection Genetic deletion of these receptors
may explain why some individuals resist
infection
gp41 - gp120
Fusion
CCR5
CD4
CXCR4
CELL SURFACE
7
Antiretroviral Agents

• Nucleoside analogues
• Zidovudine (AZT, ZDV)
• Zalcitabine (ddC)
• Didanosine (ddI)
• Stavudine (d4T)
• Lamivudine (3TC)
• Non-nucleoside reverse
• transcriptase inhibitors

• Protease inhibitors
• Saquinavir (Invirase)
• Ritonavir (Norvir)
• Indinavir (Crixivan)
• Nelfinavir
• VX-478
• Nevirapine
• Delavirdine
• Loviride

not approved in Canada
8
Combination therapy trialsACTG 175 NEJM
3351081 (1996)

• Methods
• RCT- 52 centres 2467 participants (CD4
  200-500/mm3
• 4 treatment arms - ZDV vs ddI vs ZDV ddI vs
  ddI ddC
• End points - gt50 decline in CD4 AIDS death
• Median FU 143 weeks - 565 reached an end-point
• Results
• 32 of ZDV group reached endpoints compared to
  18 ZDV ddI (RHR 0.50) 20 ZDV ddC (RHR
  0.54) 22 ddI (RHR 0.64)
• combination therapy appeared superior to
  monotherapy

9
Combination therapy trialsNuCombo (NEJM
19963351099)

• Methods
• RCT (21 sites and 1102 participants)
• Men and women - CD4 counts lt 200 / mm3
• 3 treatment arms (ZDV ZDV ddI ddI ddC)
• End points - disease progression death
• Median FU 35 months - 64 reached an endpoint
• Results
• 66 of ZDV group reached an endpoint compared to
  62 of ZDV ddI and 63 of ddI ddC
• No difference

10
Combination therapy trialsDelta Trial Lancet
348283 (1996) 350983 (1997)

• Methods
• RCT -175 centres 3207 participants (CD4 lt 350 /
  mm3)
• 3 treatment arms (ZDV vs. ZDV ddI vs. ZDV
  ddC)
• End points - AIDS death
• Median FU 30 months - 51 reached an endpoint
• Results
• 26 ZDV group reached an endpoint compared to
  18 ZDV ddI (RHR 0.67) 21 ZDV ddC (RHR
  0.79)
• A greater effect was found in those without
  previous ZDV
• High rates of early ZDV resistance in all groups

11
Protease inhibitor trial Hammer et.al, ACTG 320
NEJM 337725 (1997)

• Methods
• RCT (40 sites 1156 participants)
• CD4 counts lt 200 / mm3 previous ZDV therapy
• RCT - 2 arms (ZDV LAM vs ZDV LAM
  Indinavir)
• End points - AIDS death
• Median FU 38 weeks - only 8 reached an endpoint
• Results
• 6 IND group reached an endpoint compared to 11
  ZDV LAM (RHR 0.5, 95 CI 0.3-0.8)
• The CD4 HIV-RNA responses paralleled clinical
  results
• Indinavir useful in late disease

12
Protease inhibitor trialGulick et.al. NEJM
337734 (1997)

• Methods
• RCT (97 participants) with previous ZDV therapy
• CD4 - 50 to 400/ mm3 gt20,000 copies of HIV
  RNA/ml
• 3 arms (INDINAVIR vs ZDV/ LAM vs IND/ ZDV/LAM)
• End points - CD4 HIV RNA
• FU 24 weeks (terminated early)
• Results
• ZDV/LAM - no change in HIV-RNA or CD4 84
  resistance to LAM
• IND alone - initial HIV RNA 53 resistance
• 3 drugs - sustained HIV RNA CD4 (16
  resistance)

13
Principles of therapy

• monitor plasma viral load and CD4
• initiate treatment before immunodeficiency
  becomes apparent
• aim to reduce plasma viral load to undetectable
  levels
• use combination of at least 2 drugs
• change to a new combination if plasma viral load
  rebounds despite continued therapy

14
Problems with therapy

• limited availability
• very expensive (3 drugs 25,000 / yr)
• poorly tolerated - reduced compliance
• multiple drug interactions
• viral resistance - occurs in both exposed and
  non-exposed individuals
• data from clinical trials very limited

15
Therapy recommendations (IAS-USA 1997)

• Preferred
• 2 nucleoside analogues plus a protease inhibitor
• example ZDV ddI indinovir
• Alternative 1
• 2 nucleoside analogues non-nucleo. RT inhibitor
• example ZDV 3TC nevirapine
• Alternative 2
• 2 nucleoside analogues
• example ZDV ddI or 3TC d4T
• Not recommended any monotherapy