2Antiretroviral Therapy Objectives Stop HIV disease evolutionRestore immunityStop HIV immune activationControl HIV replication in compartments and reservoirsReduce risk of resistance emergenceReduce transmissionThis can only be obtained with maximal viral suppression
3Control of viral replication has to be maximal Individual levelHealthStop disease progressionOptimize immune restorationPrevent resistanceOptimize survivalDaily normal life- to have children- Maximal reduction of sexual transmission riskPopulation levelReduced transmissionprogressive control and decrease of epidemics- Decrease in tuberculosisLonger durability of efficacy of first lines ARTDecrease of global cost of HIV
4Viral replication has to maximally suppressed Maximal suppression of HIV required toPrevent disease progresionDecrease immune activationPrevent resistanceWhich level of viral suppression ?1000 cp/ml : clinical benefit 200 cp/ml : clinical and immunological 50 cp/ml : resistanceTomorrow : 1 cp ?Which benefitson reservoirs and activation ?
5Management of treatment failure Epidemiology of ART failureDiagnosis of ART failureReasons for ART failureConsequences of ART failureManagement of ART failure
6Epidemiology of ART failure Overall ART failure in developping countries has decreased over time !!Better understanding of reasons for failureUse of virological monitoringMore effective and better tolerated drugsGreater number of drug classesLack of report of treatment failure in RSL may be only dueto lack of access to viral load or drugs …
7Second line failure in MSF programmes Cross-sectional study in 27 ART sites in RLCRoutine CD4 monitoringVL for second line only in 4 sitesFirst line: > 95% D4T; < 15% EFVSecond line: > 70% LPV/r; 30% TDF; 28% DDIInclusion criteria:Adults who were ART naive when starting 1st lineSwitch from NNRTI-based FL to PI-based SLAt least 6 months on SLPujades et al. CROI
8Diagnosis of 2nd line failure in MSF 2 16.1 % Clinical symptoms : new stage 3 or 4 event after 6 months of ART4.1% Immunological parameters :decline of CD4 to or below baseline value, ordecline of ≥50% from on treatment peak value after 6 months of ART; orCD4 <100 cells/µl after 1 year of ART; with measurement confirmed within 3 months1.7% Virological failure : HIV RNA >10,000 copies/ml; with confirmed within 3 monthsAny criteria of failure: 18.8% after a median of 22 monthsPujades et al. CROI
9Second line failure in Khayelitsha MSF 25% virological failure at 2 years on 2nd lineAdd references to first line!Time in years to next confirmed failure after switch (2 x >=5000 copies/mL)Boulle et al. (unpublished)9
10Mortality on second line in Khayelitsha 10% on 2nd line had died within 2 yearsBoulle et al. (unpublished)
11Ressource Limited countries : Risk factors for treatment failure First line failure :concurrent TB treatment,self reported poor adherence during the previous weekSecond line failure:Changing 1 NRTI instead of 2Other PI than LPV/rattending a public clinicnot having a refrigerator at homeTB treatmentNo association with sex, type of clinic, duration of treatment, age, educational level, being unemployed, income level.El Khatib. AIDS. 2010; Pujades et al. CROI
12Diagnosis of ART failure viral loadBQL50cp/ml Considerabsolute viral load :duration of virologic failure4213- low < copies/ml- moderate copies/ml- high > copies/ml
13Mechanisms for Virological Failure Inadequate ARV potency/resistance Poor compliance Drug- drug interactionsLow plasma drug concentrationsinsufficient to control viral replicationDevelopment of viral resistance
14Reasons for treatment failure Resistant VirusesInadequate treatment/prescriptions : dosage, drug interactions ,Patients :- poor adherence- toxicity- self treatment interruptions- transient lost to follow upLong life therapy is an individual challenge !!
15Prevention of adherence problems Education to long life treatmentPatient should be THE actor of his therapy- provide their results regularlyProvide long enough prescriptionConsider minor intolerance..Social reasonsPsychological distress
16Consequences of persistent replicative viremia Accumulation and archive of resistanceImmune activation induced by HIV replicationDecrease of CD4HIV disease progressionIncreased risk of HIV transmissionResistant virus transmission
17Cross-sectional study of patients >12 m. on ART in Soweto. First Line RX L1Second line Rx L2Viraemia12%33%R to NRTI64%29%R to NNRTI81%54%R to PI2%6%El Khatib. AIDS. 2010
18International recommendations : When to switch: Consider any viral load above < 50 as to be investigatedViral load > 400 cp/ml / tretment failureVL > 50 cp/ml repeatedlyVL>50 cp/ml : Blip ..try to understand whyCurrent drugs allow full viral suppression .So always try to understand why a VL is not < 20 cp/ml
19New 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.
20Step 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 failure2 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
21Step 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 neededNumber of CD4 cells : clinical risk of progression?Patient:- commitment to Rx, socio-psychological context ..
22Step 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 /pastLonger the virus has replicated ..greater is the risk for resistanceHigher the viral load has been ..higher may be the level of resistanceNOW: What really active drugs left ?
23Management 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 patientsLevel of resistance ?Longer the virus has replicated ..greater is the risk for resistanceHigher the viral load has been ..higher may be the level of resistanceHigher VL is, more viral potency needed to control virusAt least 2 active drugs
24New WHO recommendations 2009:Second line ART 1. A boosted protease inhibitor (PI/r) plus two nucleosideanalogues (NRTIs) are recommended for second-line ART.2. ATV/r and LPV/r are the preferred boosted PI’s for secondlineART.3. Simplification of second NRTI options is recommended.• If d4T or AZT has been used in first-line, use TDF + 3TCor FTC as the NRTI backbone in second-line.• If TDF has been used in first-line, use AZT + 3TC as theNRTI backbone in second-line.
25Combination of active drugs : the only way to success
26Recently Approved New or Novel Antiretroviral Agents Mature virusPIsDarunavir TipranavirEntry inhibitorsCCR5 inhibitorsMaravirocVicrivirocReverse transcriptase inhibitorsEtravirineThis is a summary of some of the recently approved new or novel antiretroviral agents, starting with the entry inhibitor maraviroc, a novel CCR5 antagonist; the next-generation NNRTI etravirine, which is active against most NNRTI-resistant viruses; and the integrase inhibitor raltegravir. Some newer PIs include darunavir and tipranavir, which were developed specifically for activity against PI-resistant virus.Integrase inhibitorsRaltegravirElvitegravir2626
27Raltegravir is highly and fastly effective BENCHMRK - Percent of Patients With HIV RNA <50 copies/mL (95% CI)STARTMRK – Percent of Patients With HIV RNA <50 copies/mL (95% CI) (Non-Completer = Failure)100mL86%WeeksPercent of Patients withHIV RNA <50 Copies/mL24812162432404820608010082%Non-inferiorityp-Value<0.00162%8060Percent of Patients withp<0.001HIV RNA <50 Copies/4033%20248121624324048Weeks281279278280282Raltegravir 400 mg b.i.d.*Efavirenz 600 mg q.h.s.*232231230229118117Raltegravir*Placebo*
28BENCHMRK-1 & -2: Raltegravir in Treatment-Experienced Patients Current Analysis:Week 48Planned follow-up:Week 156Raltegravir 400 mg BID + OBR*(BENCHMRK-1: n = 232;BENCHMRK-2: n = 230)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)*Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted.1. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.
30BENCHMRK-1 & -2: HIV-1 RNA < 50 c/mL at Week 48, Overall and by GSS SubgroupPercent of PatientsnRaltegravir44364Total22834PlaceboGSS:11245653Virologic failures carried forward.For patients with GSS=1, 4 ART agents represented at least 80% of the active agents in OBT: darunavir (52%, 52% in raltegravir and placebo groups, respectively), enfuvirtide (8%, 16%), tenofovir (12%, 6%), and tipranavir (11%, 11%).Rates of virologic suppression also greater with RAL vs placebo when analyzed by baseline PSSSimilar results when assessing PSS by number of fully active drugs and by number of fully or partially active drugs1666719237158≥ 2756859204060801001. Cooper DA, et al. CROI Abstract Steigbigel R, et al. CROI Abstract 789.30
31Raltegravir Resistance Three pathways defined by primary mutations at 143, 148, and 155Replicative capacity decreased with 155Secondary mutations lead to higher resistanceQ148 pathway is preferredQ ndary mutationshigher levels of resistanceless impact on RC (replication capacity)Mixed populations generally resolve to Q148Virus population can switch from N155 to Q148Low genetic barrier to resistanceCumulative mutationsCross resistance with EVGHazuda et al ICAAC 2008
32Raltegravir : summary Disadvantages High PotencyFast antiviral effectExcellent toleranceFew drug drug interactionsNo metabolic effectsDisadvantagesLow genetic barrier to resistance : rapid emergence of RNeed active companion drugsBID regimen32
33Darunavir : a new PI generation A drug potent at all stages of HIV diseaseVirologic robustnessGood tolerabilityPotential for QD if no resistance to DRVPrezista binding within HIV-1 proteaseKey pointPrezista fits neatly into and has a very stable position in the catalytic pocket in the HIV-1 protease enzyme (numbers on figure represent the distance in Ångströms between Prezista and the amino acids that make up the protease).Data on file. Tibotec BVBA, Mechelen, Belgium.A key drug in the context of RSL countriesmutation frequency33
34POWER 1 and 2: CV VL < 50 copies/mL at Week 48 (ITT-TLOVR) 100DRV/RTV 600/100 mg BID80*P < .001 vs comparator PI/RTV.Control45*46*60Patients With VL< 50 c/mL (%)40121020124812162024283236404448WeeksNot 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 TUAB0104.34
35Darunavir 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.Primary endpoint: HIV-1 RNA <400 copies/mlTreatment phase (96 weeks)Screening phase (4 weeks)DRV/r 600/100mg bid + OBRRollover or follow-up phase after 1 and 4 weeksTreatment-experienced, LPV-naïveVL ≥1,000 copies/mLStable HAART (≥12 wks) or STI (≥ 4 wks)TITAN is an ongoing, randomised, controlled trial. It is an international 96-week study, with primary analysis at Week 48.Patients were screened for eligibility and had to be:treatment experienced but naïve to lopinavirhave documented HIV infectionhave a viral load of greater than one thousand copies per mLto have been on stable HAART therapy or off treatment for 12 weeks or more.A total of 595 patients were randomised to treatment of either, darunavir 600mg with 100mg ritonavir or lopinavir 400mg, again with the same low dose of ritonavir.Both treatments were administered twice daily, and all patients also received an optimised background regimen. This consisted of at least 2 to 3 antiretrovirals from the NRTI and NNRTI classes.LPV/r patients were allowed to switch to new formulation upon its approval by the regulatory authorities. At the time of this analysis 18% had switched top the new formulation.BackgroundPatients co-infected with chronic hepatitis B or C were allowed to enter the trial if their condition was clinically stable and they were not expected to require hepatitis treatment during the study period.Randomisation was performed using a centralised system to ensure balance across treatments groups and across two stratification factors (the use of an NNRTI in the OBR and screening plasma viral load of <50,000 or 50,000 copies/mL).Darunavir was administered as 300-mg tablets, ritonavir as 100-mg capsules and lopinavir-ritonavir as 133.3/33.3-mg capsules. During the study, a new formulation of lopinavir-ritonavir (200/50-mg tablet) became available. The study protocol was amended to allow patients randomised to lopinavir-ritonavir to switch to the new formulation as soon as it was approved by local regulatory authorities; subsequently, all patients on this arm would be switched to the new formulation.Patients who experienced virological failure (defined as plasma viral load >400 copies by week 16 or beyond) or a treatment-related grade 4 AE or a confirmed grade 4 laboratory abnormality were eligible to participate in the planned rollover phase. Results of the 48-week primary analysis are reported here.LPV/r* 400/100mg bid + OBR785 screened, 595 patients randomised and treated
36Patients with VL <400 copies/mL (% [95%CI]) TITAN: confirmed virological response (<400 copies/mL) up to Wk 48 (PP-TLOVR)10090807060504030201077%*68%Patients with VL <400 copies/mL (% [95%CI])DRV/r (n=286) LPV/r (n=293)*Estimated least square mean difference in response vs LPV/r = 9% (95% CI 2;16); p<0.001BAS481216243648Time (weeks)PP – per protocol
37TITAN: Less virological failures with DRV/r than with LPV/r – Week 96 14%41/29826%76/297102030DRV/rLPV/rVFs (%)Never suppressedReboundersp0.001*n=28Note: VFs included “rebounders” (patients who had VL >400 copies/mL after an initial virologic suppression) and patients who were “never suppressed” (patients who lost or never achieved HIV-1 RNA <400 copies/mL after Week 16)Week 48 analysis: 31 VFs in the DRV/r arm and 65 VFs in the LPV/r arm*Exact Chi-Squared Test
38Effect of Baseline Resistance on Response to DRV* Number of BL PI Resistance-Associated Mutations6050Correlates to FC > 10< 4040% With HIV-1 RNA < 50 copies/mL302010CPIDarunavir≤ 567891011≥ 12BL mutations associated with diminished responseV11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V, and L89VPresence associated with a higher number of PI mutationsDRV response remained higher than that of CPI*Analysis excludes ENF-treated patientsDe Meyer S, et al. CROI Abstract 157.
39Darunavir : Virologic efficacy % HIV RNA < 50 copies/ml à S48 1008084 %78 %6071 %60 %% Patients avec CV <50 copies/mL)4045 %2011 %POWERTITANARTEMISDRV800/100 q.dDRV600/100 b.i.dDeJesus E et al, 47th ICAAC chicago 2007Valdez-Madruga J, et Al. Lancet 2007; 370: 49-58Clotet B. et al. The Lancet 2007, 369 :39
40Etravirine 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)1020304050607080901002481216243248p<0.000140
41DUET-1 and -2: Predictors of response and resistance at failure 1725123< 50 copies/mL (%)102030405060708090100≥ 4No. of Baseline ETR Mutations1686755841ETR + OBR4438121/16164/14773/12159/15737/6417/6813/326/247/283/1813 mutations associated with ETR resistance- V90I- L100I- V106I- Y181C/I/V≥ 3 ETR mutations impacts ETV sensitivity ; uncommon 14% of patients at baselineMost common ETR RAM at failure :V179F/I and Y181C/IPlacebo + OBR- V179D/F- G190A/S- A98G- K101E/PETR, etravirine; OBR, optimized background regimen.As etravirine is a NNRTI, one might predict that a subset of HIV-infected people with existing NNRTI resistance would have virus that is cross-resistant to the next-generation agents. To be eligible for the DUET-1 and DUET-2 trials, subjects had to be NNRTI-experienced and have documented evidence of NNRTI mutations either in the past or at the time of screening. In a subanalysis, the investigators examined the screening genotypes of the enrolled patients and were able to demonstrate a relationship between 13 specific mutations and etravirine response (listed on the slide). The figure on the right-hand portion of the slide shows that among patients who received etravirine plus an OBR, there was a stepwise attenuation in the virologic response when an increasing number of baseline etravirine resistance-associated mutations (RAMs) were present. When there were 3 or more present, the virologic response was no better than the response observed in the overall placebo group. However, only approximately 14% of the patients who were enrolled in the DUET studies actually had 3 or more of the etravirine RAMs, so the overwhelming majority would have been predicted to have a virologic response. It is worth noting that K103N is not one of the etravirine RAMs because this drug was developed to have activity against viruses with K103N.Patients (%)Cahn P, et al. ICAAC Abstract H Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics; 2008.4141414141
42MOTIVATE 1 and 2: MVC in Treatment-Experienced Patients With R5 Virus Randomized, double-blind, placebo-controlled, phase IIb/III study2:2:1 randomization;stratified by ENF use and HIV-1 RNA < or 100,000 c/mLWeek 24planned endpoint analysisWeek 48Patients 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)MVC* 150 mg or 300 mg BID + OBR(n = 426)MVC* 150 mg or 300 mg QD + OBR(n = 414)ART, antiretroviral therapy; ARV, antiretrovirals; DLV, delavirdine ; ENF, enfuvirtide; FDA, US Food and Drug Administration; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; OBR, optimized background regimen; R5, CCR5 tropic; TPV, tipranavir; X4, CXCR4 tropic.Placebo + OBR(n = 209)*Patients receiving PI (except TPV) or delavirdine received 150 mg; all others received 300 mg.Hardy D, et al. CROI Abstract 792.424242
43MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48 100Placebo + OBT (n = 209)90MVC QD + OBT (n = 414)80MVC BID + OBT (n = 426)7060Patients With HIV-1 RNA < 50 c/mL (%)5045.5%*4043.2%*302016.7%10*P < vs placebo4812162024283236404448Time (Weeks)Hardy D, et al. CROI Abstract 792.
44MOTIVATE 1&2 Change in HIV-1 RNA and CD4 Week-0.53-2.30-2.41-3-2.5-2-1.5-1-0.54812162024324048PBO (N=209)MVC QD (N=414)MVC BID (N=426)1201051008980Median change from baseline in HIV RNA (log10 copies/ml)Median change from baseline in CD4+ T-Cell Count (cells/mm3)5960402024812162024324048WeekRapid decrease in HIV RNA > 2 log by W4Rate of < 50 cp/ml : 45% in MVC vs 17% in OBTRapid increase in CD4 > 60 cells by W4
45Control of viral replication in treatment experienced patients Lesson 1: Any new drug shouldbe combined with active drugs…at least 2 active compoundsLesson 2 : Earlier is bettera failing strategy should be modifiedeven in case of low VL and high CD4 -Lesson 3 : Less access to new drugs you have more potent should be the regimen
46Which treatment after 1st line treatment failure AZT or D4T/3TCABC/3TCTDF/FTCABC/3TCTDF/FTCAdherence= Principal raison d’échecTreatment adherence =main issue2 NRTI+PI/r++Lopi/rAtaza/rPI/r QDDRV/rATV/rLPV/rAZTor D4T/3TCABC/3TCTDF/FTC2 NRTI+NNRTINNRTIEFVETVOu+EFV
47Which treatment after 2nd line treatment failure AZT or D4T/3TCABC/3TCTENO/FTCNRTI=ARV histoireIPLPV/r – ATV/r=EFV /NVPNNRTI=2 new drugs /classes DRV/ETVPI/RAL2 NRTI+ DRV/r2 NRTI+ ETVOther
48TRIO: DRV/r + ETR + RAL in highly-experienced viraemic patients (96 week study) 103 patients enrolled11009080702.4log10copies/ml(-1.9 to -2.9)60Patients with HIV RNA <50 copies/mL and 95% CI (%)HIV RNA delta from week 0 (log 10 copies/mL) median and IQR-150403090%(95% CI; 85%–96%)-2This is a Phase II non-comparative multi-center trialPatients enrolled in this study received raltegravir, etravirine and darunavir and may have also received NRTIs and/or enfuvirtide, based on the physician’s discretionThe primary endpoint of the study was the 24 week viral suppression defined as an HIV RNA below 50 cp/mlslideFollow-up until 96 weeks of these patients is ungoing2010-32481216202424812162024Time (weeks)Time (weeks)Intent to treat analysisYazdanpanah Y, et al. 17th IAC [Presentation THAB0406].4848
49How to combine new drugs in patients with resistant viruses ? PIETVIf no NRTIs RLow viral replicationor ?+PIETV+VL and resistanceTarget Maximal viral suppressionDRVRAL++ETVRALDRV+
50Major role for HIV clinical team Every patient should have access to viral load monitoringAny detectable viral load means virological failureAny failure should be investigated- compliance- drug interactions or inadequate dosages- résistanceAny virological failure should lead to intervention- compliance issues and reinforce education- change ARV therapy
51Conclusion Art failure: not a fatality Access to viral load monitoring: mandatory tool for long term successTraining to management of ART failurePotent and safe drugs needed to control and prevent ART failure.51