Stop HIV disease evolution Restore immunity Stop HIV immune activation Control HIV replication in compartments and reservoirs Reduce risk of resistance emergence Reduce transmission This can only be obtained with maximal viral suppression Antiretroviral Therapy Objectives
Control of viral replication has to be maximal Individual level Health –Stop disease progression –Optimize immune restoration –Prevent resistance –Optimize survival Daily normal life - to have children - Maximal reduction of sexual transmission risk Population level - Reduced transmission progressive control and decrease of epidemics - Decrease in tuberculosis - Longer durability of efficacy of first lines ART -Decrease of global cost of HIV
Viral replication has to maximally suppressed Maximal suppression of HIV required to –Prevent disease progresion –Decrease immune activation –Prevent resistance Which level of viral suppression ? 1000 cp/ml : clinical benefit 200 cp/ml : clinical and immunological 50 cp/ml : resistance Tomorrow : 1 cp ? Which benefits on reservoirs and activation ?
Management of treatment failure Epidemiology of ART failure Diagnosis of ART failure Reasons for ART failure Consequences of ART failure Management of ART failure
Epidemiology of ART failure Overall ART failure in developping countries has decreased over time !! Better understanding of reasons for failure Use of virological monitoring More effective and better tolerated drugs Greater number of drug classes Lack of report of treatment failure in RSL may be only due to lack of access to viral load or drugs …
Second line failure in MSF programmes Cross-sectional study in 27 ART sites in RLC Routine CD4 monitoring VL for second line only in 4 sites First line: > 95% D4T; < 15% EFV Second line: > 70% LPV/r; 30% TDF; 28% DDI Inclusion criteria: –Adults who were ART naive when starting 1 st line –Switch from NNRTI-based FL to PI-based SL –At least 6 months on SL Pujades et al. CROI
–16.1 % Clinical symptoms : new stage 3 or 4 event after 6 months of ART –4.1% Immunological parameters : decline of CD4 to or below baseline value, or decline of 50% from on treatment peak value after 6 months of ART; or CD4 <100 cells/µl after 1 year of ART; with measurement confirmed within 3 months –1.7% Virological failure : HIV RNA >10,000 copies/ml; with confirmed within 3 months Any criteria of failure: 18.8% after a median of 22 months Pujades et al. CROI Diagnosis of 2 nd line failure in MSF 2
Time in years to next confirmed failure after switch (2 x >=5000 copies/mL) Second line failure in Khayelitsha MSF 25% virological failure at 2 years on 2 nd line Boulle et al. (unpublished)
10% on 2 nd line had died within 2 years Mortality on second line in Khayelitsha Boulle et al. (unpublished)
Ressource Limited countries : Risk factors for treatment failure First line failure : –concurrent TB treatment, –self reported poor adherence during the previous week Second line failure: –Changing 1 NRTI instead of 2 –Other PI than LPV/r –attending a public clinic –not having a refrigerator at home –TB treatment No association with sex, type of clinic, duration of treatment, age, educational level, being unemployed, income level. El Khatib. AIDS. 2010; Pujades et al. CROI
Diagnosis of ART failure viral load BQL 50cp/ml Consider absolute viral load : duration of virologic failure low < copies/ml - moderate copies/ml - high > copies/ml
Mechanisms for Virological Failure Low plasma drug concentrations insufficient to control viral replication Inadequate ARV potency/resistance Poor compliance Drug- drug interactions Development of viral resistance
Reasons for treatment failure Resistant Viruses Inadequate treatment/prescriptions : dosage, drug interactions, Patients : - poor adherence - toxicity - self treatment interruptions - transient lost to follow up Long life therapy is an individual challenge !!
Prevention of adherence problems Education to long life treatment Patient should be THE actor of his therapy - provide their results regularly Provide long enough prescription Consider minor intolerance.. Social reasons Psychological distress
Consequences of persistent replicative viremia Accumulation and archive of resistance Immune activation induced by HIV replication Decrease of CD4 HIV disease progression Increased risk of HIV transmission Resistant virus transmission
Cross-sectional study of patients >12 m. on ART in Soweto. First Line RX L1Second line Rx L2 Viraemia12%33% R to NRTI64%29% R to NNRTI81%54% R to PI2%6% El Khatib. AIDS. 2010
International recommendations : When to switch: Consider any viral load above < 50 as to be investigated Viral load > 400 cp/ml / tretment failure VL > 50 cp/ml repeatedly VL>50 cp/ml : Blip..try to understand why Current drugs allow full viral suppression. So always try to understand why a VL is not < 20 cp/ml
New WHO 2009 recommendations: When to switch: Where available, use viral load (VL) to confirm treatment failure. Where routinely available, use VL every 6 months to detect viral replication. A persistent VL above copies/ml confirms treatment failure. When VL is not available, use immunological criteria to confirm clinical failure.
Step 1 : To diagnose a situation of virological failure 1 Confirm viral replication - Blips is defined as VL between 50 and 200 cp/ml - Isolated blip should not be considered as failure 2 Evaluate adherence : - the main reason for early failure or rebound after VL< 50cp/ml is discontinuation of therapy - many situations in life where a » compliant « patients will stop transitorily treatment - Monitoring plasma drug concentration at time of virological failure may help to understand certain situations
Step 2 : To analyse a situation of virological failure 2 Evaluate type and duration of virogical failure : - rebound after undetectability - persistant replication /intermittent replication - level of viral replication ? Higher is VL …more antiviral potency needed Number of CD4 cells : clinical risk of progression? Patient: - commitment to Rx, socio-psychological context..
Step 3: To evaluate what sensitive drugs are left (2 ) PAST : what resistance has been accumulated ? - Prior History of ARV, CD4 and VL - Resistance testing : current /past Longer the virus has replicated..greater is the risk for resistance Higher the viral load has been..higher may be the level of resistance NOW: What really active drugs left ?
Management of treatment failure : to analyse and to understand Treatment history ? VL and CD4 at baseline ? Adherence to therapy ? High viral load may indicate defect in adherence..smoothly ask patients Level of resistance ? Longer the virus has replicated..greater is the risk for resistance Higher the viral load has been..higher may be the level of resistance Higher VL is, more viral potency needed to control virus At least 2 active drugs
New WHO recommendations 2009:Second line ART 1. A boosted protease inhibitor (PI/r) plus two nucleoside1. A boosted protease inhibitor (PI/r) plus two nucleoside analogues (NRTIs) are recommended for second-line ART. 2. ATV/r and LPV/r are the preferred boosted PIs for secondline2. ATV/r and LPV/r are the preferred boosted PIs for secondlineART. 3. Simplification of second NRTI options is recommended.3. Simplification of second NRTI options is recommended. If d4T or AZT has been used in first-line, use TDF + 3TC If d4T or AZT has been used in first-line, use TDF + 3TC or FTC as the NRTI backbone in second-line. or FTC as the NRTI backbone in second-line. If TDF has been used in first-line, use AZT + 3TC as the If TDF has been used in first-line, use AZT + 3TC as the NRTI backbone in second-line. NRTI backbone in second-line.
Combination of active drugs : the only way to success
Recently Approved New or Novel Antiretroviral Agents Mature virus CCR5 inhibitorsM aravirocVicr iviroc Entry inhibitors Reverse transcriptase inhibitors E travirine Integrase inhibitors Raltegravir Elvitegravir PIs Darunavir Tipranavir
Raltegravir is highly and fastly effective STARTMRK – Percent of Patients With HIV RNA <50 copies/mL (95% CI) (Non-Completer = Failure) Raltegravir 400 mg b.i.d.* Efavirenz 600 mg q.h.s.* p< % 33% Weeks Percent of Patients with HIV RNA <50 Copies/ mL BENCHMRK - Percent of Patients With HIV RNA <50 copies/mL (95% CI) Raltegravir* Placebo*
BENCHMRK-1 & -2: Raltegravir in Treatment- Experienced Patients HIV-infected patients with triple- class resistance and HIV-1 RNA > 1000 copies/mL (BENCHMRK-1: N = 352; BENCHMRK-2: N = 351) Placebo + OBR* (BENCHMRK-1: n = 118; BENCHMRK-2: n = 119) Raltegravir 400 mg BID + OBR* (BENCHMRK-1: n = 232; BENCHMRK-2: n = 230) Planned follow-up: Week 156 *Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted. Current Analysis: Week Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.
BENCHMRK-1 & -2: HIV-1 RNA < 50 c/mL at Week 48, Overall and by GSS 0 GSS: Raltegravir n Percent of Patients Placebo Total 1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789. Subgroup
Raltegravir Resistance Three pathways defined by primary mutations at 143, 148, and 155 Replicative capacity decreased with 155 Secondary mutations lead to higher resistance Q148 pathway is preferred Q ndary mutations higher levels of resistance less impact on RC (replication capacity) Mixed populations generally resolve to Q148 Virus population can switch from N155 to Q148 Low genetic barrier to resistance -Cumulative mutations -Cross resistance with EVG Hazuda et al ICAAC 2008
32 Raltegravir : summary Disadvantages Low genetic barrier to resistance : rapid emergence of R Need active companion drugs BID regimen Advantages High Potency Fast antiviral effect Excellent tolerance Few drug drug interactions No metabolic effects
mutation frequency Darunavir : a new PI generation A drug potent at all stages of HIV disease Virologic robustness Good tolerability Potential for QD if no resistance to DRV A key drug in the context of RSL countries
DRV/RTV 600/100 mg BID *P <.001 vs comparator PI/RTV. 45* 12 46* Weeks 12 Control Patients With VL< 50 c/mL (%) Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit. Lazzarin A, et al. IAC Abstract TUAB0104. POWER 1 and 2: CV VL < 50 copies/mL at Week 48 (ITT-TLOVR)
Darunavir TITAN: Study design Treatment-experienced, lopinavir (LPV)-naïve, HIV-1-infected patients were randomised (1:1) to DRV/r 600/100mg bid, or LPV/r 400/100mg bid, plus optimised background therapy ( 2 NRTIs/NNRTIs) for 96 weeks. 785 screened, 595 patients randomised and treated Screening phase (4 weeks) Treatment phase (96 weeks) Treatment-experienced, LPV-naïve VL 1,000 copies/mL Stable HAART (12 wks) or STI ( 4 wks) DRV/r 600/100mg bid + OBR LPV/r* 400/100mg bid + OBR Rollover or follow-up phase after 1 and 4 weeks Primary endpoint: HIV-1 RNA <400 copies/ml
TITAN: confirmed virological response (<400 copies/mL) up to Wk 48 (PP-TLOVR) PP – per protocol Patients with VL <400 copies/mL (% [95%CI]) 77%* 68% BAS Time (weeks) DRV/r (n=286) LPV/r (n=293) 16 *Estimated least square mean difference in response vs LPV/r = 9% (95% CI 2;16); p<0.001
TITAN: Less virological failures with DRV/r than with LPV/r – Week 96 14% 41/298 26% 76/ DRV/rLPV/r VFs (%) Never suppressed Rebounders Week 48 analysis: 31 VFs in the DRV/r arm and 65 VFs in the LPV/r arm n=28 p 0.001* *Exact Chi-Squared Test
Effect of Baseline Resistance on Response to DRV* BL mutations associated with diminished response –V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V, and L89V –Presence associated with a higher number of PI mutations –DRV response remained higher than that of CPI De Meyer S, et al. CROI Abstract 157. *Analysis excludes ENF-treated patients % With HIV-1 RNA < 50 copies/mL CPI Darunavir Number of BL PI Resistance-Associated Mutations Correlates to FC > 10< 40
POWER % Darunavir : Virologic efficacy % HIV RNA < 50 copies/ml à S48 % Patients avec CV <50 copies/mL) ARTEMIS TITAN DRV 600/100 b.i.d DRV 800/100 q.d 71 % 84 % 11 % 60 % 78 % DeJesus E et al, 47 th ICAAC chicago 2007 Valdez-Madruga J, et Al. Lancet 2007; 370: Clotet B. et al. The Lancet 2007, 369 :
Etravirine DUET study : Efficacy Response (<50 copies/mL) at Week 48 (ITT-TLOVR) CV < 50 c/ml at W48 according to active molecules in OBT (PSS) 61% 40% Patients with viral load <50 copies/mL at Week 48 (%) (± 95% CIs) Time (weeks) Placebo + BR (n=604) ETR + BR (n=599) p<0.0001
DUET-1 and -2: Predictors of response and resistance at failure 13 mutations associated with ETR resistance - V90I - L100I - V106I - Y181C/I/V 3 ETR mutations impacts ETV sensitivity ; uncommon 14% of patients at baseline Most common ETR RAM at failure :V179F/I and Y181C/I Patients (%) Cahn P, et al. ICAAC Abstract H-717. Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics; Placebo + OBR - V179D/F - G190A/S - A98G - K101E/P < 50 copies/mL (%) No. of Baseline ETR Mutations ETR + OBR /161 64/147 73/121 59/157 37/64 17/68 13/32 6/24 7/28 3/18
MOTIVATE 1 and 2: MVC in Treatment- Experienced Patients With R5 Virus Randomized, double-blind, placebo-controlled, phase IIb/III study Placebo + OBR (n = 209) MVC* 150 mg or 300 mg QD + OBR (n = 414) MVC* 150 mg or 300 mg BID + OBR (n = 426) 2:2:1 randomization; stratified by ENF use and HIV-1 RNA < or 100,000 c/mL Week 24 planned endpoint analysis Week 48 *Patients receiving PI (except TPV) or delavirdine received 150 mg; all others received 300 mg. Patients infected with R5; HIV-1 RNA 5000 copies/mL; stable ART or no ART for 4 weeks; previous ART experience with 1 agent ( 2 for PIs) from 3 of the 4 antiretroviral drug classes for 6 months or documented resistance to members of 3 of 4 classes (N = 1049) Hardy D, et al. CROI Abstract 792.
MOTIVATE 1 and 2: Combined Virologic Efficacy at Week Patients With HIV-1 RNA < 50 c/mL (%) Time (Weeks) Placebo + OBT (n = 209) MVC BID + OBT (n = 426) MVC QD + OBT (n = 414) 16.7% 43.2%* 45.5%* *P <.0001 vs placebo Hardy D, et al. CROI Abstract 792.
MOTIVATE 1&2 Change in HIV-1 RNA and CD4 Median change from baseline in HIV RNA (log 10 copies/ml) Median change from baseline in CD4+ T-Cell Count (cells/mm 3 ) Week Week PBO (N=209) MVC QD (N=414) MVC BID (N=426) Rapid decrease in HIV RNA > 2 log by W4 Rate of < 50 cp/ml : 45% in MVC vs 17% in OBT Rapid increase in CD4 > 60 cells by W4
Control of viral replication in treatment experienced patients Lesson 1: Any new drug should be combined with active drugs… at least 2 active compounds Lesson 2 : Earlier is better a failing strategy should be modified even in case of low VL and high CD4 - Lesson 3 : Less access to new drugs you have more potent should be the regimen
Which treatment after 1 st line treatment failure 2 NRTI + PI/r 2 NRTI + NNRTI AZT or D4T/3TC ABC/3TC TDF/FTC Lopi/r Ataza/r AZTor D4T/3TC ABC/3TC TDF/FTC EFV Adherence = Principal raison déchec ABC/3TC TDF/FTC + PI/r QD DRV/r ATV/r LPV/r Ou NNRTI EFV ETV + + Treatment adherence = main issue
A R V histoire IP NRTI 2 new drugs /classes DRV/ETV PI/RAL = AZT or D4T/3TC ABC/3TC TENO/FTC LPV/r – ATV/r = = EFV /NVP 2 NRTI + DRV/r 2 NRTI + ETV NNRTI Other Which treatment after 2nd line treatment failure
TRIO: DRV/r + ETR + RAL in highly-experienced viraemic patients (96 week study) 90% (95% CI; 85%–96%) Time (weeks) Patients with HIV RNA <50 copies/mL and 95% CI (%) patients enrolled Yazdanpanah Y, et al. 17th IAC [Presentation THAB0406] log 10 copies/ml (-1.9 to -2.9) Time (weeks) HIV RNA delta from week 0 (log 10 copies/mL) median and IQR Intent to treat analysis
ETVPI DRV PI How to combine new drugs in patients with resistant viruses ? VL and resistance ± ETV RAL DRV RAL + or ? ETV If no NRTIs R Low viral replication + Target Maximal viral suppression
Every patient should have access to viral load monitoring Any detectable viral load means virological failure Any failure should be investigated - compliance - drug interactions or inadequate dosages - résistance Any virological failure should lead to intervention - compliance issues and reinforce education - change ARV therapy Major role for HIV clinical team
Conclusion Art failure: not a fatality Access to viral load monitoring: mandatory tool for long term success Training to management of ART failure Potent and safe drugs needed to control and prevent ART failure.