David A Cooper National Centre in HIV Epidemiology and Clinical Research The University of New South Wales Sydney, Australia
First line standard of care First line in the developing world First line failure Second line Three class failure
Fauci Nature Medicine 2003 First line standard of care Targets for anti-hiv drugs
First line standard of care FEI N(t)RTI NNRTI PI ENF Current drugs and classes AZT ddi ddc d4t 3TC ABV TFV FTC NVP DLV EFV SQV RTV IDV NFV APV LPV/r ATV fapv TPV DRV
DHHS Guidelines, 2004 First line standard of care Recommended regimens for treatment-naive naive patients: DHHS guideline preferred regimens + or + or + or + EFV LPVr 3TC FTC AZT TFV
First line standard of care 100 Gilead 903: week 144 efficacy intent to treat 80 % patients with HIV-1 60 RNA < 50 c/ml 40 TDF + 3TC + EFV d4t + 3TC + EFV 73% 69% 20 0 0 24 48 72 96 120 144 weeks Gallant et al, 2004
First line standard of care Gilead 903: total limb fat 12 10 kilograms 8 6 4 2 TFV+3TC+EFV d4t+3tc+efv 0 96 weeks 144 TDF + 3TC + EFV 128 115 d4t + 3TC + EFV 134 117 Gallant et al, IAC15 2004
Gallant et al, NEJM 2006 First line standard of care Gilead 934: virologic efficacy 100 % 80 responder 60 40 20 proportion with HIV-RNA <50 c/ml (TLOVR) n = 487 TFV+FTC 80%* CBV 70%* *95% CI: (+1.6%, +16.6%); p = 0.02 0 BL 8 16 24 32 40 48 week
First line standard of care 2NN: treatment success and failure 100 75 50 % of patients 25 0 29.1 22.0 20.0 34.5 15.3 11.4 18.9 16.3 56.4 56.3 62.3 46.9 NVP-qd NVP-bd EFV NVP+EFV failure component: (whichever comes first) change Rx disease progression virologic success VL <50 c/ml success: only significant difference: EFV vs NVP+EFV, p< 0.001
First line standard of care 2NN: grade 3 or 4 laboratory toxicities % NVP-qd n=220 NVP-bd n=387 EFV n=400 NVP+EFV n=209 p hepatobiliary lab. toxicity * non-hepatobiliary lab. toxicity 13.2 7.8 4.5 8.6 0.002 8.2 12.9 8.8 9.6 0.161 neutropenia 2.3 3.9 1.8 5.3 amylase 1.8 3.1 3.5 1.4 triglycerides 1.4 1.3 1.3 0.5 alkaline phosphatase 0.5 1.3 0.8 1.9 hepatobiliary: only significant difference: NVP-qd vs EFV, p< 0.001 * elevated AST and/or ALT
First line standard of care 1.0 ACTG 5142: time to virologic failure 0.8 proportion not 0.6 failed 0.4 0.2 adjusted p values LPV/EFV vs LPV 0.13 LPV/EFV vs EFV 0.5 LPV vs EFV 0.006 EFV LPV/EFV LPV proportion not failed - week 96 LPV/EFV 73% LPV 67% EFV 76% 0.0 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 number at risk time in weeks from randomisation LPV/EFV 250 208 187 171 131 58 10 LPV 253 206 180 164 116 62 3 EFV 250 204 183 170 121 60 8 Ridler et al, WAC 2006
First line standard of care PI SQV r IDV NFV APV LPV/r ATV fapv TPV DRV Protease inhibitors - unboosted poor bioavailability complex regimens high pill burden unpredictable efficacy hard to manage toxicity signature resistance common
First line standard of care Protease inhibitors PI SQV/ r IDV - unboosted biovailability improved by ritonavir boosting NFV APV LPV/r ATV/ fapv/ TPV DRV less complex regimens lower pill burden more predictable efficacy less toxicity negligible resistance in naive patients
Walmsley et al, NEJM 2002 First line standard of care M98-863: 863: LPVr versus NFV - efficacy 80 70 60 50 % 40 patients 30 20 10 * 75 *P<0.001 * 67 63 52 baseline characteristics n = 326 327 % male 80 81 mean age, yr 38 37 CD4+, median 232 232 HIV RNA, median (logs) 5.01 4.98 0 <400 cp/ml <50 cp/ml HIV RNA at 48 weeks d4t/3tc/lpvr d4t/3tc/nfv
First line standard of care SQV IDV RTV NFV LPV fapv ATV TPV gastrointestinal + + ++ ++ lipodystrophy ++ ++ + ++ +? hepatitis ++ ++ nephrolithiasis paresthesias bilirubin ++ retinoid effects + rash Side-effect effect profile of protease inhibitors + asthenia + + + + + ++ + drug causes toxicity ++ main toxicity + + ++ ++ Bartlett JG, Medical Management of HIV Infection, JHUSM, 2002
First line standard of care First line in the developing world First line failure Second line Three class failure
Gilks et al, Lancet 2006 First line in the developing world WHO recommended first-line regimens Standard first-line regimen NRTIs NNRTI AZT or d4t or TFV or ABV and 3TC or FTC and EFV or NVP Triple NRTI regimen NRTIs AZT or d4t and TFV or ABV and 3TC or FTC
Beck et al, AIDS 2006 First line in the developing world National guidelines: criteria for starting ART number of countries 20 16 12 8 4 0 44.4% clinical + CD4 or TLC 33.3% clinical + CD4 WHO clinical staging clinical +TLC CD4 only clinical and laboratory criteria CD4 < 200 and consider < 350 TLC < 1200 5.6% 11.1% 5.6% clinical only
Beck et al, AIDS 2006 First line in the developing world National guidelines: major first-line regimens number of countries 28 24 20 16 12 8 69% 54% 24 countries reported that d4t + 3TC + NVP is the preferred first-line antiretroviral regimen 37% 26% 4 0 d4t + 3TC + NVP AZT + 3TC + NVP AZT + 3TC +EFV d4t + 3TC + EFV
First line standard of care First line in the developing world First line failure Second line Three class failure
First-line failure Causes of treatment regimen failure baseline patient factors suboptimal adherence and missed clinic appointments drug side-effects and toxicity pharmacokinetics potency of the ART regimen
First-line failure age year of starting therapy pretreatment HIV RNA level pretreatment CD4 cell count prior AIDS illness Baseline patient factors comorbidities (e.g. depression) active substance use baseline drug resistance prior ART with drug resistance or cross resistance
First-line failure TAHOD: first antiretroviral treatment 100% 80% 60% 40% 20% 0% <=1999 2000 2001 2002 2003 2004 d4t/3tc/nvp 3 or more ARV with NNRTI, no PI (other than d4t/3tc/nvp) 3 or more ARV with PI, no NNRTI 3 or more ARV, NRTI only mono/double ARV n= 388 164 220 367 458 105
First-line failure TAHOD: duration on first antiretroviral treatment 1.0 0.8 0.6 0.4 0.2 0.0 0 1 2 3 year after ARV started d4t/3tc/nvp 3 or more ARV with NNRTI, no PI (other than d4t/3tc/nvp) 3 or more ARV with PI, no NNRTI 3 or more ARV, NRTI only mono/double ARV
First-line failure Virological failure incomplete virological response <400 copies/ml by 24 weeks virologic rebound
First-line failure Clinical and immunological failure failure to increase 25-50 cells/µl above baseline CD4+ cell count over first year decrease to below baseline CD4+ cell count on therapy occurrence or recurrence of HIV-related events after at least 3 months on HAART
First-line failure TAHOD: factors associated with treatment change patients follow up events p n= (years) n= rate HR (95% CI) value total 404 586.9 131 22.3 hemoglobin level prior to treatment normal 61 68.7 21 37.8 1.00 anemia 155 215.9 41 19.0 0.53 (0.32-0.87) 0.013 not tested 188 302.3 64 21.2 0.61 (0.38-0.96) 0.034 hemoglobin tested within 180 days before ART started. normal anemia male Hb > 13g/dl Hb 8-13g/dl female Hb > 12g/dl Hb 8-12g/dl
First-line failure reason for treatment change n= (%) days on treatment median (range) stop treatment permanently n= (%) number of patients 131 (100) 262 (2-1519) 15 (11.5) adverse effect 82 (62.6) 295 (2-1519) patients decision/ request TAHOD: reasons for treatment change 2 (2.4) 18 (13.7) 196 (6-1005) 7 (38.9) treatment failure 5 (3.8) 457 (138-672) 0 (0.0) clinical progression/ hospitalisation 3 (2.3) 85 (34-322) 1 (33.3) compliance difficulties 2 (1.5) 136 (9-262) 0 (0.0) other 18 (13.7) 250 (13-1071) 4 (22.2) not reported 3 (2.3) 211 (88-545) 1 (33.3)
First-line failure TAHOD: treatment change due to adverse effects reason for treatment change days on treatment stop treatment permanently n= (%) median (range) n= (%) adverse effect 82 (62.6) 295 (2-1519) 2 (2.4) lipodystrophy 26 (31.7) 546 (30-1519) 0 (0.0) hepatitis 10 (12.2) 28 (14-1297) 0 (0.0) rash 12 (14.6) 14 (10-108) 0 (0.0) peripheral neuropathy 9 (11.0) 407 (117-532) 0 (0.0) lactic acidosis 6 (7.3) 416 (204-951) 0 (0.0) pancreatitis 5 (6.1) 55 (5-343) 1 (20.0) nausea and vomiting 4 (4.9) 18 (2-49) 0 (0.0) fever 2 (2.4) 19 (11-27) 0 (0.0) allergy 1 (1.2) 61 0 (0.0) insomnia 1 (1.2) 42 0 (0.0) missing 6 (7.3) 68 (21-491) 1 (16.7)
First line standard of care First line in the developing world First line failure Second line Three class failure
Gilks et al, Lancet 2006 Second line WHO recommended second-line regimens Second-line regimen if standard first-line used NRTIs PI ddi or TFV and ABV or 3TC and PI/r with/without AZT Second-line regimen if triple NRTI used NRTIs PI NNRTI ddi and PI/r and EFV or NVP
Second line Gilead 903: development of resistance mutations through week 144 (ITT) TFV+3TC+EFV(n=299) d4t+3tc+efv (n=301) n % of total % of failures n % of total virologic failures 47 15.7% 49 16.3% % of failures any EFV-R* 26 8.7% 55% 24 8.0% 49% any M184V/I 18 6.0% 38% 17 5.6% 35% any K65R 8 2.7% 17% 2 0.7% 4% other NRTI 1 0.3% 2% 4 1.3% 8% wild-type or as baseline 18 6.0% 38% 23 7.6% 47% *EFV-R = efavirenz resistance Miller et al, IAC 2004
Second line Regimens for first failure in developing world initial regimen predicted resistance pattern recommended change d4t/3tc/nvp M184V ± NNRTI mutation ddi/tfv + ABV/3TC + PI/r ± AZT 3NRTIs TAMs M184V NNRTI + PI/r ± ddi
Second line National guidelines: major second-line regimens number of countries 16 42% 12 8 30% 27% 24% 21% 4 0 ABV + ddi + LPVr ABV + ddi + NFV ABV +ddi + SQVr TFV + ddi + LPVr TFV + ddi + NFV Beck et al, AIDS 2006
First line standard of care First line in the developing world First line failure Second line Three class failure
Three class failure PLATO: CD4+ decline with MDR versus wild-type HIV 100 50 CD4+ slope 0 (cells/year) -50 untreated WT (n=205) treated MDR (n=628) - 100 <300 300-10,000- >30,000 10,000 30,000 steady state viral load (copies/ml) Lancet 2004
Three class failure E-184V: 3TC monotherapy with 3TC resistant virus mean HIV-RNA change log 10 copies per ml mean CD4% change 0-50 -100-150 -200-250 -300 0 mean CD4+ T-cell change cells/μl -2-4 -6-8 -10 2 1.5 1 0.5 3TC mono TI p=0.1220 p=0.0001 p=0.0015 0 0 4 8 12 16 20 24 36 48 weeks Castagna et al, AIDS 2006
Three class failure Partial treatment interruptions (n= 53) 1.0 week 2 change in VL change in plasma HIV RNA 0.5 0.0-0.5 NRTI PI NNRTI ENF discontinued treatment class residual activity against 'resistant' variant: NRTIs >> > ENF, PI > NNRTI
Summary: treatment/virus factors despite emergence of drug-resistance, plasma HIV RNA levels can remain below the off-treatment setpoint for years as long as treatment is maintained persistent anti-hiv activity against drug-resistant virus NRTIs >> PI > NNRTIs reduced replicative capacity PI mutations, M184V > NNRTI mutations
presentation by by Dorrie Cooper Instructional designer dorrie@bigpond.net.au
see you in Sydney 22-25 July 2007 Australia has been at the leading edge of HIV research since the early days of the epidemic. It is a privilege for us to welcome our colleagues and friends to the beautiful city of Sydney, for the first IAS meeting to be held in this country. David Cooper, Local Conference Chair www.ias2007.org in partnership with