Simplification of Successful Simplification of Successful Antiretroviral Therapy with Antiretroviral Therapy with Nucleoside Analogues: Nucleoside Analogues: Studies and Clinical Practice Studies and Clinical Practice Milos Opravil Opravil Milos Division of Infectious Diseases Division of Infectious Diseases University Hospital University Hospital Zurich, Switzerland Zurich, Switzerland
Rationale for for simplification simplification of PI of PI- -HAART with HAART with NRTI NRTI or or NNRTI NNRTI Rationale Supporting adherence Supporting adherence less pill burden less pill burden no dietary restriction no dietary restriction reduction in adverse events (GIT) reduction in adverse events (GIT) Preventing or reversing metabolic complications Preventing or reversing metabolic complications hyperlipidemia hyperlipidemia fat accumulation fat accumulation Avoiding CYP interactions (NRTI) Avoiding CYP interactions (NRTI) Equal efficacy efficacy and and durability as PI continuation ? durability as PI continuation ? Equal virological virological, also in , also in lymphoid lymphoid tissue tissue immunological immunological Other / / new new toxicity ? toxicity ? Other mitochondrial toxicity toxicity, , lipoatrophy (NRTI) lipoatrophy (NRTI) mitochondrial rash (ABC, NNRTI) rash (ABC, NNRTI) CNS ( (EFV) EFV) CNS liver (NNRTI) liver (NNRTI)
ACTG5095: randomized randomized, double , double- -blind blind study study of 3 of 3 regimens regimens for for the the ACTG5095: initial treatment treatment of HIV: of HIV: zidovudine zidovudine– –lamivudine lamivudine– –abacavir abacavir, , zidovudine zidovudine– – initial lamivudine plus plus efavirenz efavirenz, and , and zidovudine zidovudine– –lamivudine lamivudine– –abacavir abacavir plus plus lamivudine efavirenz efavirenz Gulick et al., NEJM 2004;350:1850 Gulick et al., NEJM 2004;350:1850
ACTG5095: Virologic Virologic failure failure in in pts pts with with at least at least once once ACTG5095: HIV RNA <200 c./ml ./ml – – Less durable effect of triple NRTI Less durable effect of triple NRTI HIV RNA <200 c Gulick et al., NEJM 2004;350:1850 Gulick et al., NEJM 2004;350:1850
Meta- -analysis of 9 randomized controlled trials of simplified analysis of 9 randomized controlled trials of simplified Meta versus continued PI- -based HAART: based HAART: virologic virologic failure failure versus continued PI ABC / ABC / Trizivir Trizivir NNRTI NNRTI Bucher et al., AIDS 2003;17:2451- -2459 2459 Bucher et al., AIDS 2003;17:2451
Meta- -analysis of 3 randomized controlled trials of analysis of 3 randomized controlled trials of Meta simplification to ABC / Trizivir Trizivir: : virologic virologic failure failure simplification to ABC / Bucher et al., AIDS 2003;17:2451- -2459 2459 Bucher et al., AIDS 2003;17:2451
Bucher et al., AIDS 2003;17:2451- -2459 2459 Bucher et al., AIDS 2003;17:2451
Studies tudies in which some patients in which some patients S received sub- -optimal regimens optimal regimens received sub prior to HAART prior to HAART
N EV/ EV/ EF EF A/ A/ A A BA Trial BA Trial N Virol irolo ogic gical f ailure (VF) by previous therapy al f ailure (VF) by previous therapy V NEV EFA A ABA A NEV EF AB N pat tients ients N pa N = 155 5 N = 156 N = 149 49 N = 15 N = 156 N = 1 Suboptimal Suboptimal 5 4 14 4 5 4 1 Rx+ HAART (n= 237) Rx+ HAART (n= 237) Only HAART Only HAART 3 1 2 3 1 2 (n= 223) (n= 223) 8 5 16 8 5 16 Total VF VF Total Martinez et al., NEJM 2003;349:1036 2003;349:1036- -46 46 Martinez et al., NEJM
SMT Study Design SMT Study Design Initial mono/dual NRTI (46%) Continue HIV- -1 RNA undetectable 1 RNA undetectable HIV ≥ ≥ ≥ ≥ 6 ≥ ≥ ≥ ≥ 6 months months induced induced by by PI- -containing containing HAART HAART PI PI-containing Randomize Randomize HAART At screening: screening: At Switch to • negative for 215 ZDV negative for 215 ZDV • ABC + COM resistance mutation resistance mutation (Trizivir >Mar 2000) (PBMC DNA) (PBMC DNA) • <50 HIV <50 HIV- -1 RNA copies/ml 1 RNA copies/ml • Opravil et al., JID 2002;185:1251- -60 60 Opravil et al., JID 2002;185:1251
SMT: Time to virologic virologic failure failure (ITT (ITT analysis analysis) ) SMT: Time to 1.0 0.9 0.8 Proportion not failing 0.7 0.6 P = 0.061 = 0.061 P logrank logrank test test 0.5 0.4 0.3 cont 0.2 simpl 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 132 Weeks N (cont N ( cont.): .): 79 79 79 79 77 77 73 73 68 68 45 45 34 34 25 25 22 22 10 10 3 3 N (simpl N ( simpl.): .): 84 84 80 80 75 75 74 74 71 71 53 53 38 38 24 24 16 16 8 8 3 3 Opravil et al., JID 2002;185:1251- -60 60 Opravil et al., JID 2002;185:1251
Treatment failure failure vs. vs. virologic virologic failure failure Treatment Change of treatment treatment due due to AE to AE or or preference preference Change of • Today Today many many options options • • May May even even be be desirable desirable if if it it improves improves adherence adherence • Virologic failure failure Virologic • More More severe severe because because resistance resistance possible possible: : • decreases future future treatment treatment options options decreases
SMT: Time to virologic virologic failure failure (ITT (ITT analysis analysis) ) SMT: Time to Pre- -treatment treatment with with ZDV ZDV before before HAART HAART predicts predicts virologic virologic failure failure Pre 1.0 Proportion without virologic failure 0.9 0.8 0.7 0.6 0.5 0.4 cont:no prior ZDV 0.3 simp: no prior ZDV 0.2 cont: prior ZDV simp: prior ZDV 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 132 Weeks Opravil et al., JID 2002;185:1251- -60 60 Opravil et al., JID 2002;185:1251
SMT: original study + extended follow- -up up SMT: original study + extended follow Initial m ono/dual NRTI (46% ) randomized comparison Continue HIV- -1 RNA undetectable 1 RNA undetectable HIV ≥ 6 ≥ ≥ ≥ ≥ ≥ ≥ ≥ 6 m m onths onths induced inducedby by PI- -containing containingHAART HAART PI End of PI-containing Random Random ize ize HAART At screening: screening: At Switch to Trizivir • negative for 215 ZDV negative for 215 ZDV • ABC + COM Extended resistance m resistance m utation utation (Trizivir >M ar 2000) Follow-up (PBM C DNA) (PBMC DNA) • <50 HIV <50 HIV- -1 RNA copies/m 1 RNA copies/m l • l
SMT study study: long : long- -term term efficacy efficacy SMT incidence of incidence of virologic virologic failure: failure: 1.0 without virologic failure 0.9 Proportion of patients 3.4/100 PY 3.4/100 PY 0.8 (N = 53) (N = 53) 0.7 0.6 13.5/100 PY 13.5/100 PY (N = 31) 0.5 (N = 31) 0.4 ( P P = 0.008) = 0.008) ( 0.3 No ZDV prior to HAART 0.2 ZDV prior to HAART 0.1 # at risk: 51 44 44 24 24 25 14 14 10 10 0.0 0 1 2 3 4 5 6 Time after switch (years) Opravil et al., AIDS 2004 in print print Opravil et al., AIDS 2004 in
SMT design: original study + extended follow- -up up SMT design: original study + extended follow Initial m ono/dual NRTI (46% ) randomized comparison Continue HIV- -1 RNA undetectable 1 RNA undetectable HIV ≥ 6 ≥ ≥ ≥ ≥ ≥ ≥ ≥ 6 m m onths onths induced inducedby by PI- -containing containingHAART HAART PI End of PI-containing Random Random ize ize HAART At screening: screening: At Switch to Trizivir • negative for 215 ZDV negative for 215 ZDV • ABC + COM Extended resistance m resistance m utation utation (Trizivir >M ar 2000) Follow-up (PBM C DNA) (PBMC DNA) • <50 HIV <50 HIV- -1 RNA copies/m 1 RNA copies/m l • l Virologic failure among all 81 patients without prior ZDV mono/dual thera failure among all 81 patients without prior ZDV mono/dual therapy py Virologic who switched from PI- -regimens to regimens to Trizivir Trizivir: : who switched from PI 2.45/100 PY (95% Poisson CI: 0.90 2.45/100 PY (95% Poisson CI: 0.90 – – 5.33/100 PY) 5.33/100 PY)
Subjects with a history of mainly Subjects with a history of mainly HAART from initiation of therapy HAART from initiation of therapy
TRIZAL: Proportion of Subjects Subjects with with Plasma HIV Plasma HIV- -1 RNA 1 RNA TRIZAL: Proportion of < 50c/ml at at Week Week 48 48 < 50c/ml 100 94% AT 90% AT 80 Percentage of Subjects 75 % ITT 69 % ITT 60 Trizivir (AT) Continued HAART (AT) 40 Trizivir (ITT) Continued HAART (ITT) 20 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Study Week Katlama C et al. HIV Medicine 2003;4:79 C et al. HIV Medicine 2003;4:79- -86 86 Katlama
Switch Maintenance Therapy (Maggiolo Maggiolo) ) Switch Maintenance Therapy ( Virological Failures over 104 Weeks Failures over 104 Weeks Virological No significant differences across the 3 study arms No significant differences across the 3 study arms Maggiolo F et al. CID 2003;37:41 F et al. CID 2003;37:41- -49 49 Maggiolo
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