1. HIV-1 dynamics Perelson et.al. Science 271:1582 (1996) Infected CD4 + lymphocytes Uninfected, activated CD4 + lymphocytes HIV-1 t 1/2 - 1.6 days t 1/2 - 6 hrs Long lived cell populations > 99% Latently Infected CD4 + lymphocytes < 1% CD4 + lymphocytes - defective virus < 1%

2. Observations - viral dynamics u it takes 2.6 days to produce a new generation of viral particles u estimated total HIV production is 10.3 x 10 9 virions per day u at least 99% of the virus pool is produced by recently infected cells u retroviral therapy should be able to reduce viral load within a few days

3. HIV-1 RNA in plasma Mellors et.al. Science 272:1167 (1996) HIV-1 RNA CD4 + cells 01200600 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

4. HIV-1 RNA in plasma Mellors et.al. Science 272:1167 (1996) Proportion surviving 1 0.5 0 Time (yrs) 0 5 10 Baseline HIV-1 RNA < 4500 4500-13000 13000-36000 > 36000 Kaplan-Meier curves There is a strong time- dependent prognostic relation between HIV-1 RNA and clinical outcome

5. HIV-1 RNA in plasma of neonates Shearer et.al. NEJM 336:1337 (1997) HIV-1 RNA Age - months 02412 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 (p=0.006) nonrapid rapid

6. Receptors for HIV Receptors for HIV (Levy J. NEJM 1996;335:1529) HIV virus Fusion CCR5 CD4 CXCR4 CELL SURFACE gp41 - gp120 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

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 trials Combination therapy trials ACTG 175 NEJM 335:1081 (1996) Methods u RCT- 52 centres & 2467 participants (CD4 200-500/mm 3 u 4 treatment arms - ZDV vs ddI vs ZDV + ddI vs ddI + ddC u End points - >50 % decline in CD4; AIDS; death u Median FU 143 weeks - 565 reached an end-point Results u 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) u combination therapy appeared superior to monotherapy

9. Combination therapy trials Combination therapy trials NuCombo (NEJM 1996;335:1099) Methods u RCT (21 sites and 1102 participants) u Men and women - CD4 counts < 200 / mm 3 u 3 treatment arms (ZDV; ZDV + ddI; ddI + ddC) u End points - disease progression; death u Median FU 35 months - 64% reached an endpoint Results u 66% of ZDV group reached an endpoint compared to 62% of ZDV + ddI and 63% of ddI + ddC u No difference

10. Combination therapy trials Combination therapy trials Delta Trial: Lancet 348:283 (1996) & 350:983 (1997) Methods u RCT -175 centres & 3207 participants (CD4 < 350 / mm 3 ) u 3 treatment arms (ZDV vs. ZDV + ddI vs. ZDV + ddC) u End points - AIDS; death u Median FU 30 months - 51% reached an endpoint Results u 26% ZDV group reached an endpoint compared to 18% ZDV + ddI (RHR 0.67); 21% ZDV + ddC (RHR 0.79); u A greater effect was found in those without previous ZDV u High rates of early ZDV resistance in all groups

11. Protease inhibitor trial Protease inhibitor trial Hammer et.al, ACTG 320 NEJM 337:725 (1997) Methods u RCT (40 sites & 1156 participants) u CD4 counts < 200 / mm 3 & previous ZDV therapy u RCT - 2 arms (ZDV + LAM vs ZDV + LAM + Indinavir) u End points - AIDS; death u Median FU 38 weeks - only 8% reached an endpoint Results u 6% IND group reached an endpoint compared to 11% ZDV + LAM (RHR 0.5, 95% CI 0.3-0.8) u The CD4 & HIV-RNA responses paralleled clinical results u Indinavir useful in late disease

12. Protease inhibitor trial Protease inhibitor trial Gulick et.al. NEJM 337:734 (1997) Methods u RCT (97 participants) with previous ZDV therapy u CD4 - 50 to 400/ mm 3 & >20,000 copies of HIV RNA/ml u 3 arms (INDINAVIR vs ZDV/ LAM vs IND/ ZDV/LAM)  End points -  CD4;  HIV RNA u FU 24 weeks (terminated early) Results u 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 u monitor plasma viral load and CD4 u initiate treatment before immunodeficiency becomes apparent u aim to reduce plasma viral load to undetectable levels u use combination of at least 2 drugs u change to a new combination if plasma viral load rebounds despite continued therapy

14. Problems with therapy u limited availability u very expensive (3 drugs ~ $25,000 / yr) u poorly tolerated - reduced compliance u multiple drug interactions u viral resistance - occurs in both exposed and non-exposed individuals u data from clinical trials very limited

15. Therapy recommendations (IAS-USA 1997) u Preferred: 2 nucleoside analogues plus a protease inhibitor example: ZDV + ddI + indinovir u Alternative 1: 2 nucleoside analogues + non-nucleo. RT inhibitor example: ZDV + 3TC + nevirapine u Alternative 2: 2 nucleoside analogues example: ZDV + ddI or 3TC + d4T u Not recommended any monotherapy