Presentation on theme: "Failure 6th EACS Advanced HIV Course Montpellier, Sept. 3-5, 2008"— Presentation transcript:
1Failure 6th EACS Advanced HIV Course Montpellier, Sept. 3-5, 2008 Prof. Nathan CLUMECKHead, Department of infectious diseasesSaint-Pierre University HospitalBrussels, Belgium
2Trends in HAART Failure Baseline CharacteristicsPatients With 2nd Virologic Failure(n=5057)Male (%)85HIV RNA (copies/mL)15,723Median CD4 (cells/mm3)222Antiretroviral naïve at HAART initiation (%)31Median time from HAART initiation (years)2.9Prior AIDS-definingevent (%)37Retrospective cohort study (1995 to 2005)33,381 patients on HAART46% had virologic failure28% changed HAART regimen after failure15% experienced a second virologic failure3% diedSlide #37: NA-ACCORD: Trends in Second HAART FailureDeeks and colleagues conducted a retrospective cohort study (1995 to 2005) to determine the frequency of second HAART failure and risk factors for resulting mortality.1A cohort of 33,381 patients on HAART was studied. Of these, 46% had virologic failure, 28% changed HAART regimen after failure, 15% experienced a second virologic failure, and 3% died.1Baseline characteristics of those with second virologic failure are listed in the table.1ReferenceDeeks S, North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the IeDEA. Trends in second virologic failure and predictors of subsequent mortality among ART-experienced patients: North American experience. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 41.Deeks S, et al. 15th CROI. Boston, Abstract 41.
3Trends in HAART Failure Incidence of 2nd VirologicFailure Over TimeAdjusted relative risk of second virologic failure has declined dramaticallyDecreased from 1.46 (96-97) to 0.54 (04-05) per 100 patient-yearsNo improvement in mortalityMedian survival: 7.1 yearsIndependent risk factors associated with increased risk of deathCD4 cell count and HIV RNA level at time of second virologic failureNo associationPrior treatment exposurePre-HAART113.670.7Incidence per 100 patient-yearsSlide #38: NA-ACCORD: Trends in Second HAART FailureThe investigators found a 7.5-times decline in risk of second virologic failure from 1997 to 2005; from 113.6/100 person-years to 15.1/100 person-years. However, mortality following second HAART failure did not improve over time.1HIV RNA levels and CD4 cell counts at the time of second virologic failure were independently associated with an increased risk of death, whereas prior treatment exposure and pre-HAART factors were not.1These results do not take into account the potential impact of new drugs or classes of drugs that were available after 2005; a subsequent analysis is planned.1ReferenceDeeks S, North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the IeDEA. Trends in second virologic failure and predictors of subsequent mortality among ART-experienced patients: North American experience. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 41.41.517.915.1Calender YearDeeks S, et al. 15th CROI. Boston, Abstract 41.
4St-Pierre cohort : Viral load response to first line therapy
6Failure of initial HAART regimens Rate of failure of HAART regimens have decreased in developed countries becauseBetter tolerance of new regimensNew regimens are easier to takeLess pill countOnce dailyNo food/ water restrictions
7EACS definition of failure Confirmed Plasma HIV RNA > 50 copies/ml6 months after starting therapyBut real failure or blip?
8Incidence of low-level viremia more frequent than high-level viremia HIV-1 RNA Level During Follow-up, %Study Cohort(N = 4447)Persistently < 50 copies/mL71.2≥ 1 measurement > 50 copies/mL28.8≥ 1 measurement > 1000 copies/mL6.7van Sighem A, et al. J Acquir Immune Defic Syndr. 2008;48:
9After initial virologic suppression with cART, approximately 30% of patients experienced transient viremia7% classified as high level ( > 1000 copies/mL)Low level viremia( c/mL) is not associated with clinical events, development of high-level viremia, or changes in CD4+ cell countsHigh-level viremia is associated with occurrence of resistance and therapy changesvan Sighem A, et al. J Acquir Immune Defic Syndr. 2008;48:
10Why do therapies fail? Virus Drug Patient Resistance Potency Toxicity Non-adherence.
11AdherenceAdherence may be the single most important factor affecting treatment outcomes to HAARTMany components contribute to non-adherence- patient characteristics- clinical care settings- patient-provider relationships- drug regimens characteristics
12Checking adherenceInterview the patient to evaluate adherence and complianceRe-explain the objectives and modalities of the treatment ant the potential risks of poor adherenceExclude potential drug-drug or drug-food interactionsUse TDM if needed (and if available ...)
13Improving adherence Reduce tablet load (fixed-dose) Remove food restrictions Adapt to P.Reduce dose frequency (qd) way of lifeProvide nurse counsellingProvide pill boxProvide psychological support
14Increasing number of mutations Which Barriers to resistance ?Few change per mutationBUTToxicityNRTIsHigh drug levelsLarge change per mutationNNRTIsANDSmall change per mutationBoosted-PIHigh troughHigh troughToxIncreasing EC50EC50EC50Increasing number of mutationsDale Kempf et al.
15Which first-line ART ?« Boosted protease inhibitors have 60% lower risk of resistance compared with other classes « (Lima et al J Infect Dis July 2008)Factors associated with increased risk:=a higher baseline VL;an NNRTI-based combination;a high but still suboptimal adherence
17Management of failureDecision to change treatment regimen must take into account :the remaining treatment optionsthe level of failure based on kinetics of viral load and CD4 (decreased viral fitness)the past treatment history, including resistance patterns, tolerability and adherence issuesChoice of treatment will be based on the number of active drugs within each class (genotypic testing)
18ARV Failure; a historical perspective, before the 2006-08 new paradigm FirstSecond-thirdMultipleOptionsManySomeFewGoalsVLVL/CD4CD4ActionAdapt or switchWait or switchDo your best …
19Before 2006 : Continue the same therapy Stop therapy in order to revert to a wild type virusUse a PI boosted regimen to try to overcome resistanceRe-cycle previous drugsUse mega – or giga – HAARTUse new investigational agents, if available
20Interruption of Therapy Continuation of Therapy ?Continuation of Therapy
21Option 1 : Continuing therapy Patients with CD4 < 50, failing all 3 classes, who continue therapy show better outcome, particularly those with more drugs (Miller et al., AIDS 2002)This is probably in relationship to viral fitness (Deeks et al., 2002)BUT this strategy may lead to development of further drug resistance, that could preclude the use of a new drug in an existing class
22Option 2 : Stopping therapy The goal is to restore the more sensitive wild type virusOne study (Gighaart) suggests a benefit of this strategy in patients with very low CD4 count, while studies in patients with higher CD4 suggest that this strategy is counter productive
23Median changes in plasma viral load and CD4 cells in failing patients continuing or discontinuing therapyFrom Deeks et al., NEJM, 2001
24Median changes in plasma viral load and CD4 cells before and after switch of resistance in patients discontinuing therapyFrom Deeks et al., NEJM, 2001
25STI in patients with multiple failures GIGHAART, Katlama et al., Boston 200370 patients randomized +/- STI 8 WeeksVL 5.3 log CD4 27/mm3 Median ARV 6.6 yearsResults No STI STIAt W 12/20 median VL SS<400 cp 15% 38%At W 24/32 median CD>50 /mm3 25% 50% NSHIV clinical events 3 5At W48/56 median VLmedian CD
26Option 3 : Use of boosted regimens The aim is to overcome resistance due to suboptimal plasma drug levelRitonavir boosted regimens are widely used but the best results are usually obtained in the early stages of treatment (less mutations)
27Option 4 : Recycle drugsThe goal is to maintain the selective pressure for some specific mutations such as M184VThe mutational effects on viral fitness may now be assessed by a replicative capacity assayPatients with discordance failure (virological but not CD4) harbour viruses with lower replicative capacity (Deeks et al., 2001)
28Option 5 : Use Mega/Giga – HAART The goal is to keep patients, who have no options, alive and well, until new drugs become available
29Option 6 : Use of new drugs Enfuvirtide : Phase 3 Studies in Highly Experienced PatientsVL reductionEnfuvirtide +OB OB pTORO <0.0001TORO <0.0001Injection site reactions were the most frequent AE’s but with low discontinuation rate (3%)Lalezari. NEJM 2003
30Since 2006 :Use a genotype - driven salvage therapy plusUse at least 2 new active agentsNew PI: Tipranavir, DarunavirNew NNRTI: EtravirineCCR5 inhibitorsFusion inhibitors: enfuvirtideIntegrase inhibitorsThe new Paradigme for multi-experienced patients is to reach undetectable viral load
31The « New Paradigme »HIV-1 RNA suppression to < 50 copies/mL should be the therapeutic goal for treatment-experienced HIV-infected patients as defined by :2006 US DHHS2006 International AIDS Society-USA guidelines2007 EACS guidelines
32HIV-1 RNA < 50 copies/mL, % Week 48 Virologic Efficacy of New Drugs Defined as HIV-1 RNA < 50 c/mLStudyDrug RegimenHIV-1 RNA < 50 copies/mL, %TORO Enfuvirtide + OBR OBR aloneRESIST Tipranavir + OBR Comparator PI + OBRPOWE Darunavir/ritonavir + OBR Comparator PI + OBRDUET[4,5]Etravirine + darunavir/ritonavir-containing OBR Placebo + darunavir/ritonavir-containing OBRMOTIVATE Maraviroc QD + OBR Maraviroc BID + OBR Placebo + OBRBENCHMRK[7,8]Raltegravir + OBR Placebo + OBR1. Nelson M, et al. J Acquir Immune Defic Syndr. 2005;40: Hicks CB, et al. Lancet. 2006;368: Clotet B, et al. Lancet. 2007;369: Haubrich R, et al. CROI Abstract Johnson M, et al. CROI Abstract Lalezari J, et al. ICAAC Abstract H-718a. 7. Cooper DA, et al. N Engl J Med In press. 8. Steigbigel R, et al. N Engl J Med In press.
34Virologic response with respect to baseline number of LPV mutation 0–5 mutations6–7 mutationsPercentage of responders8–10 mutationsCalvez et al. Scotsdale resistance meeting, Kempf et al. Scotsdale resistance meeting, 2001
35Tipranavirnonpeptidic PI with potent activity against PI-resistant HIV-1 both in vitro and in vivoApproved in United States and Europe for use in PI-experienced patients in combination with ritonavir
36Saquinavir/ritonavir Amprenavir/ritonavir Study Design RESIST 1 and 2 in which tipranavir plus OBR compared with r-boosted comparator PI (CPI) plus optimized background regimen (OBR)Week 48Tipranavir/ritonavir n = 746Patients failing PI-containing HAART(N = 1483)Baseline genotypic resistance testingPreselection of CPI plus OBR by investigatorCPI ArmLopinavir/ritonavirIndinavir/ritonavirSaquinavir/ritonavirAmprenavir/ritonavirn = 737NRTI, NNRTI, and PI experience for ≥ 3 consecutive months≥ 2 PI-based regimens for ≥ 3 monthsOn PI-based regimen at enrollment≥ 1 documented primary PI mutation (30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, 90M)≤ 2 mutations at codons 33, 82, 84, and 90
37Tipranavir/Ritonavir (n = 746) Outcome at Week 48Tipranavir/Ritonavir (n = 746)CPI/Ritonavir (n = 737)P ValueTreatment response, %33.615.3< .0001In patients using ENF48.520.0< .0001*In patients using first-time ENF58.521.6HIV-1 RNA < 400 copies/mL, %30.413.843.218.5HIV-1 RNA < 50 copies/mL, %22.810.228.414.1Mean HIV-1 RNA reduction, log10 copies/mL (SD)1.14 (1.30)0.54 (1.02)Mean CD4+ cell count increase, cells/mm3 (SD)45 (104)21 (89)ENF, enfuvirtide; IQR, interquartile range.*Comparison between use and nonuse of enfuvirtide within treatment arm.
38Patient OutcomesSeveral factors significantly and independently associated with treatment response to tipranavir/ritonavir:ENF use: Odds Ratio 4.07 ; P < .0001Higher tipranavir trough concentration ; Odds Ratio , 2.16 ; P < .05Fewer baseline tipranavir mutations (0-2 vs 5-6): Odds Ratio , 0.14; P < .0001Other factors associated with treatment response to tipranavir/r≤ 2 primary PI mutations at baseline: 40.8% vs 31.5% (P = .03)Prior treatment with ≤ 3 PIs: 40.9% vs 30.5% (P = .007)CI, confidence interval.
39Tipranavir/Ritonavir (n = 749) Other OutcomesIncidence of exposure-adjusted adverse events similar between armsSignificantly higher triglycerides, ALT/AST, and cholesterol in the tipranavir/ritonavir armAdverse Events and Grade 3/4 Laboratory Abnormalities, n (Rate per 100 Patient-Years)Tipranavir/Ritonavir (n = 749)CPI/Ritonavir (n = 737)P ValueAny adverse event leading to study discontinuation90 (12.4)48 (10.6)--Triglycerides184 (30.8)94 (23.1)< .0001ALT71 (10.1)15 (3.3)AST45 (6.3)13 (2.9).002Cholesterol31 (4.3)3 (0.7)ALT, alanine aminotransferase; AST, aspartate aminotransferase.
40Tipranavir-r : Conclusions in highly experienced P. Associated with significantly superior treatment outcomes vs r-boosted CPI plus OBR through 48 weeks of treatmentTreatment response rate significantly higher with tipranavir/rSignificantly longer time to treatment failure with tipranavir/rInclusion of enfuvirtide in OBR increased likelihood of effective treatment outcomesSafety profile similar to that of other r-boosted Pis
41Disadvantages of Tipranavir-r 4 pills (2 Tipra+2 RTV 100mg) BIDLiver toxicityLipid profile is worsenedDrug-drug interaction:no other PI allowedEtravirine not allowed
42DarunavirDarunavir/ritonavir a potent boosted PI active against wild-type and many PI-resistant viruses
43POWER 1 and 2 : Study Design Investigator-selected CPI(s) + OBRDRV/RTV 400/100 mg QD+ OBRPI-, NRTI- and NNRTI-experienced 1 PI mutationPI-based regimenVL > 1000 copies/mLInvestigator-selected CPI(s)+ OBR (without NNRTIs)DRV/RTV 800/100 mg QD+ OBRDRV/RTV 400/100 mg BID+ OBRDRV/RTV 600/100 mg BID+ OBRDRV/RTV 600/100 mg BID provided greatest virologic response in Wk 24 analysis; Now ,FDA-approved dose for treatment-experienced ptsVL, viral load; OBR, optimized background regimen (NRTIs ± enfuvirtide)Lazzarin A, et al. IAC Abstract TUAB0104.
44POWER 1 and 2 : VL < 50 c/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 (%)40121020124812162024283236404448WeeksLazzarin A, et al. IAC Abstract TUAB0104.
45POWER 1 and 2: VL < 50 c/mL at Week 48 by Baseline Subgroups 46Overalln = 12010ENF Used (Naive)n = 35n = 365811ENF Not Usedn = 6144n = 7010DRV/RTV 600/100 BID≥ 3 Primary PI Mutn = 5544n = 745CPI/RTVNo Sensitive ARVs in OBRn = 2520n = 18≥ 1 Active Agent in OBRn = 4454n = 111120406080100Patients With VL < 50 copies/mL at Wk 48 (ITT, NC = F) (%)Lazzarin A, et al. IAC Abstract TUAB0104.
46Effect of Baseline DRV Fold Change on Response to DRV Baseline fold-change to DRV (by Antivirogram) was strong predictor of Week 24 response in POWER 1, 2, and 3100Distribution of pts by baseline DRV FC806050Patients With VL < 50 copies/mL at Wk 24 (%)40252013n =2556548FC ≤ 10FC 11-40FC > 40Baseline DRV FCDeMeyer S, et al. Resistance Workshop Abstract 73.
47Effect of Baseline DRV-associated Mutations on Response to DRV 11 PI resistance mutations associated with reduced responseV11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V100Distribution of pts by baseline # of DRV mutations806460Patients With VL < 50 copies/mL at Wk 24 (%)504240222010n =67941135841123≥ 4Baseline No. of DRV MutationsDeMeyer S, et al. Resistance Workshop Abstract 73.
48Relationship Between Activity of OBR and Response to DRV/RTV 600/100 Highest rates of VL < 50 copies/mL in pts with ≥ 2 active agents in OBRNo incremental benefit of active ENF if ≥ 1 active NRTI in OBRPhenotypic susceptibility score (PSS) of OBR also predicted VL < 50 at Wk 24PSS ≤ 0.5: 34%PSS : 49%PSS > 1.5: 52%Characteristic of OBRVL < 50 at Wk 24, %# of active agents26146≥ 249Type of active agentActive ENF only43≥ 1 active NRTI, no ENF51≥ 1 active NRTI + active ENF531. Pozniak A, et al. BHIVA, Abstract P3.2. Vangeneugden T, et al. Resistance Workshop, Abstract 1138.
49Other Outcomes Most adverse events mild to moderate in severity 25% of patients reported ≥ 1 grade 3 or 4 adverse eventGrade 3-4 Adverse Events With Incidence ≥ 2, %Darunavir/Ritonavir(n = 298)Diarrhea14Nausea10Elevated cholesterol4Elevated triglycerides6Elevated pancreatic amylase7Elevated ALT2Elevated ASTMolina JM, et al. J Acquir Immune Defic Syndr. 2007;46:24-31.
50Summary of Key Conclusions Darunavir/ritonavir 600/100 mg twice daily safe and effective in treatment-experienced patients with drug-resistant HIVRates of virologic suppression is the highest in pts with > 1 active agent in OBRFull susceptibility to darunavir strongest predictor of responseSafety profile of darunavir/r is goodMolina JM, et al. J Acquir Immune Defic Syndr. 2007;46:24-31.
51NNRTIEtravirineactive against wild-type HIV and strains resistant to currently available NNRTIs in phase IIb trials
52DUET-1 and 2 :assess long-term efficacy, safety, and tolerability of etravirine in treatment-experienced patients; 24-week results shownWeek 24Week 48Etravirine 200 mg BID +Darunavir/Ritonavir-containing OBR*(DUET-1: n = 304;DUET-2: n = 295)HIV-infected patients with virologic failure on current HAART regimen, history of ≥ 1 NNRTI RAM, ≥ 3 primary PI mutations, andHIV-1 RNA > 5000 copies/mL(DUET-1: N = 612;DUET-2: N = 591)Placebo +Darunavir/Ritonavir-containing OBR*(DUET-1: n = 308;DUET-2: n = 296)*Investigator-selected OBR included darunavir/ritonavir 600/100 mg twice daily + ≥ 2 NRTIs ± enfuvirtide.1. Madruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
54Description of Analysis Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 24First trial to use HIV-1 RNA < 50 copies/mL as primary endpoint in treatment-experienced patientsSecondary endpoints: HIV-1 RNA < 400 copies/mL at Week 24, change in HIV-1 RNA from baseline, change in CD4+ cell count from baseline, toxicityAnalysisIntent to treat, time to loss of virologic response95% power to detect significanceMadruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
55Significantly more patients achieved HIV-1 RNA < 50 copies/mL with etravirine vs placebo Etravirine treatment resulted in greater CD4+ cell count increases from baseline compared with placebo (statistical significance reached in DUET-1 only)Outcome at Week 24DUET-1DUET-2Etravirine(n = 304)Placebo(n = 308)P(n = 295)(n = 296)HIV-1 RNA < 50 copies/ mL, %5639.0056244.0003HIV-1 RNA < 400 copies/mL,%7451.00017554HIV-1 RNA reduction,log10copies/mL2.41.7< .00012.3Mean increase in CD4+ cell count from baseline, cells/mm38964.00027866.3692Madruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
56HIV-1 RNA < 50 copies/mL at Week 24 (%) Etravirine + OBRPlacebo + OBR100DUET-1DUET-2DUET-1DUET-282808073DUET-1DUET-270686665DUET-1DUET-262615960HIV-1 RNA < 50 copies/mL at Week 24 (%)47444034242097n =45884643451059564116669382646149495112≥ 3Number of Fully Active Agents in OBR (Assessed by PSS)Madruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
57Enfuvirtide Reused or Not Used Enfuvirtide Used de Novo Patients reusing or not using enfuvirtide achieved greater response with etravirine vs placeboFindings unchanged when further stratified by number of baseline NNRTI RAMs and fold change in darunavir susceptibilityAmong patients who used enfuvirtide de novo, no significant difference in response to etravirine compared with placeboOutcome at Week 24, %Enfuvirtide Reused or Not UsedEnfuvirtide Used de NovoDUET-1DUET-2ETR(n = 230)PBO(n = 229)(n = 216)(n = 215)(n = 74)(n = 79)(n = 81)HIV-1 RNA < 50 copies/ mL55*3358*3460567368HIV-1 RNA < 400 copies/mL70*4471*45848678Madruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
58Other Outcomes13 baseline mutations associated with diminished response to etravirine: V90I, L100I, V106I, Y181C/I/V, A98G, K101E/P, V179D/F, G190A/SResponse diminished by ~ 20% in presence of 1 or 2 mutations≥ 3 mutations present at baseline in only 14% of study populationRash most common AE; most mild/moderate (grade 3: 1%; grade 4: 0%)AEs Through Week 24, %DUET-1DUET-2Etravirine(n = 304)Placebo(n = 308)(n = 295)(n = 296)Rash2010149Central nervous system symptoms†1517Nausea12Diarrhea18Psychiatric event‡16Headache1311Combined grade 3 or 4 AEs212827Madruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
59Results at week 48 (CROI 2008) DUET-1 DUET-2 ETRPBOHIV-1 RNA < 50 copies/ mL60396141p<.0001HIV-1 RNA < 400 copies/mL71477248Mean CD4 Change cells/mm31037494.0025.0160Duet 1:Haubrich R Abstract 790Duet 2: Johnson M Abstract 791
60Summary of Key Conclusions Etravirine (TMC125) in combination with an OBR of darunavir/r and optimized NRTIs (with optional enfuvirtide) associated with significantly greater rates of HIV-1 RNA < 50 copies/mL at w48 in highly treatment– experienced (≥ 3 primary PI mutations) patientsEtravirine also superior to placebo in increasing CD4+ cell counts from baselineToxicity comparable in etravirine and placebo arms except rashMadruga JV, et al. Lancet. 2007;370: Lazzarin A, et al. Lancet. 2007;370:39-48.
61Entry InhibitorsLet’s start with the entry inhibitors.
62HIV-1 Entry Inhibitors CD4 binding Coreceptor binding Virus-cell fusionEnfuvirtidegp41CCR5 antagonistsMaravirocVicrivirocTNX-355gp120V3 loopCD4This slide displays the different steps involved in viral entry. This process begins with the binding of HIV gp120 to a CD4+ cell followed by a conformational change that allows the V3 loop of gp120 to interact with the chemokine coreceptors, either CCR5 or CXCR4. A conformational change then occurs that facilitates fusion. The first entry inhibitor to be approved, enfuvirtide, is a fusion inhibitor. In this presentation, I will talk about some of the drugs that have been developed to target both CD4 and CCR5.CellmembraneCCR5/CXCR4(R5/X4)CXCR4 antagonistsFigure adapted from Doms R, et al. Genes Dev. 2000;14:
63Coreceptor Usage of HIV-1 Variants X4X4/R5DualR5CD4CXCR4CCR5This schematic demonstrates the mode of action for HIV via certain chemokine coreceptors. On the far left is X4 virus, which primarily uses the CXCR4 coreceptor. CXCR4 chemokine coreceptors are primarily located on T-cell tumor lines as well as primary lymphocytes in peripheral blood.The R5 virus is located on the far right. These viruses are defined by the use of the CCR5 chemokine coreceptor, which is present on monocytes and macrophages as well as primary lymphocytes. In the middle of the schematic are those viruses designated as X4/R5 dual‑tropic viruses that are actually able to use either one of these chemokine coreceptors. The terms syncytium‑inducing (SI) and nonsyncytium-inducing (NSI) viruses were used before the identification of chemokines as secondary receptors. Syncytium‑inducing viruses were isolated from the blood of patients that demonstrated the ability to induce syncytia in T-cell tumor lines. We now know that this ability correlates highly with the use of the CXCR4 coreceptor. The NSI viruses, on the other hand, are able to infect cells but do not induce syncytia. These viruses are now known to use CCR5.T-cell linesPrimary lymphocytesMonocyte/macrophages
64Association Between Emergence of SI Virus and CD4+ Cell Count NSI virus predominates early in diseaseDual/mixed virus detected in approximately 50% of patients over timeCD4+ cell count decline accelerated following detection of SI in patients in whom NSI-only virus was previously detected800600Mean (SE) CD4+ Cell Count (cells/mm3)400NSI200NSI, nonsyncytium inducing; SE, standard error; SI, syncytium inducing.More than a decade ago, data were presented that suggested there may be a relationship between SI virus—or what we now know are X4 viruses—and the natural history of the disease. Koot and colleagues from a Dutch cohort followed a group of patients over time and performed assays to determine whether there was detectable SI virus. The investigators found that there was a gradual decline in CD4+ cell counts, but with the emergence of the SI viruses a more precipitous decline was seen than that which was seen among patients who did not have this viral population. This observation has been confirmed in many data sets during the last 10‑15 years, and there are now data that suggest very similar findings in people who develop X4 viruses.What is still not clearly defined is whether there exists a cause-and-effect relationship. More specifically, is it the development of these X4 viruses that is actually causing CD4+ cell decline? Although the answer to this question remains unknown, it is important to bear in mind the implications of the association between X4 viruses and CD4+ cell decline when considering the use of CCR5 antagonists. There is the possibility that we might select for X4 viruses with the use of these agents, which could influence the natural history of the disease. This possibility must be taken into account as these drugs move forward in clinical trials and in drug development.NSI → SISI-48-36-24-12122436Time (Months)Koot M, et al. Ann Intern Med. 1993;118:
65MOTIVATE : Maraviroc in Treatment-Experienced Patients With R5 Virus Randomized, double-blind, placebo-controlled, parallel phase IIb/III studiesPrimary endpoint : mean change in VL at Week 242:2:1 randomization;stratified by ENF use and VLPlanned interim analysis Week 24Week 48Maraviroc 150 mg or 300 mg twice daily + OBRR5 virus; ≥ 5000 copies/mL;Triple-class resistant or triple-class experienced patientsMOTIVATE 1 (N = 601)(Canada, US)MOTIVATE 2 (N = 475)(Europe, Australia, US)Maraviroc 150 mg or 300 mg once daily + OBRENF, enfuvirtide; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; OBR, optimized background regimen; R5, CCR5 tropic; TPV, tipranavir; X4, CXCR4 tropic; VL, viral load.The next slide shows recently presented randomized control data from 2 large trials called MOTIVATE 1 and MOTIVATE 2. Combined, these studies evaluated more than 1000 patients, and they used an essentially identical study design. MOTIVATE 1 was performed in Canada and the United States, and MOTIVATE 2 was performed in Europe, Australia, and the United States. These trials randomized highly treatment–experienced patients 2 to 2 to 1 to receive an optimized background regimen with 1 of 2 doses of maraviroc or placebo. The 2 investigational arms were once-daily or twice-daily maraviroc in 2 different doses. Maraviroc is a substrate for cytochrome P450 and is boosted by ritonavir and the NNRTI delavirdine so the patients on those 2 drugs received 150 mg; all others received 300 mg. Patients on tipranavir/ritonavir also received the 300-mg dose because of a drug-drug interaction between tipranavir and maraviroc. The primary planned interim analysis at Week 24 has been presented, and the study is designed to continue until Week 48. The primary endpoint is mean change in HIV-1 RNA at Week 24.For more information about this study, see the Capsule Summary at:Placebo + OBRNelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.
66MOTIVATE 1 and 2 : VL < 400 copies/mL (ITT, NC = F) Placebo + OBR (n = 209)MVC QD + OBR (n = 414)MVC BID + OBR (n = 426)100100MOTIVATE 1MOTIVATE 290908080P < .0001*P < .0001*707060.4%61.3%606054.7%55.5%5050Patients (%)Patients (%)P < .0001*P < .0001*404031.4%303023.1%2020BID, twice daily; ITT, intent to treat; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; NC = F, noncompleter equals failure; OBR, optimized background regimen; QD, once daily; VL, viral load.The data on this slide are of individuals who achieved an HIV-1 RNA of < 400 copies/mL in an intent-to-treat, noncompleter-equals-failure, analysis. MOTIVATE 1 is on the left and MOTIVATE 2 on the right. The data are nearly superimposable, with better viral suppression among those who received once- or twice-daily maraviroc vs those who received placebo.For more information about this study, see the Capsule Summary at:10102468101214161820222424681012141618202224Time (Weeks)Time (Weeks)*P values vs placebo at Week 24.Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.
67MOTIVATE 1 and 2: VL < 50 copies/mL (ITT, NC = F) Placebo + OBR (n = 209)MVC QD + OBR (n = 414)MVC BID + OBR (n = 426)100100MOTIVATE 1MOTIVATE 29090808070706060P < .0001*P < .0001*5050Patients (%)Patients (%)48.5%45.6%4042.2%4040.8%P = .0006*P = .0005*303024.6%202020.9%BID, twice daily; ITT, intent to treat; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; NC = F, noncompleter equals failure; OBR, optimized background regimen; QD, once daily; VL, viral load.The next slide shows the same kind of data for those achieving HIV-1 RNA < 50 copies/mL. Again, the results are essentially superimposable with significantly better viral suppression among those who received the investigational drug with an optimized background regimen vs those who received an optimized background regimen with placebo.For more information about this study, see the Capsule Summary at:10102468101214161820222424681012141618202224Time (Weeks)Time (Weeks)*P values vs placebo at Week 24.Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.
68Combined Analysis: MOTIVATE 1 and 2 MOTIVATE 1 and 2 : VL < 50 c/mL at Wk 24 by Number of Active Drugs in OBRPlacebo + OBRMVC QD + OBRMVC BID + OBR10090Combined Analysis: MOTIVATE 1 and 28070615860555253Patients (%)5043434029301819209BID, twice daily; c/mL, copies/mL; ITT, intent to treat; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; OBR, optimized background regimen; QD, once daily; VL, viral load; Wk, week.This is a combined analysis of MOTIVATE 1 and 2 looking at the proportion of people achieving HIV-1 RNA < 50 copies/mL at Week 24 based on the number of active drugs in the optimized background regimen. These individuals were analyzed by genotypic and phenotypic assays at baseline. Their response based on the number of active drugs in the regimen0, 1, 2, or 3 or moreis shown. All of the groups that received 3 or more active drugs did well because of the high number of active drugs in their regimens. Among those who received 0, 1, or 2 active drugs, better virologic responses were seen in those patients who received maraviroc, either once or twice daily, vs placebo. In those participants who had no other active drugs within their regimen except maraviroc, there is the suggestion that those who received twice‑daily therapy did better than those who received once-daily therapy. However, both maraviroc treatment groups did far better than those who received placebo.For more information about this study, see the Capsule Summary at:103n =35515644130134598810464132121Number of Active Drugs in OBR12≥ 3Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.
69MOTIVATE 1 and 2 : Mean Change in VL at Wk 24 by ENF Use in OBR Placebo + OBRMVC QD + OBRMVC BID + OBRMOTIVATE 1MOTIVATE 2No ENFENF*No ENFENF*n =671301274998107n =50113112416773-0.5-0.5-1.0-1.0-0.97Change in VL, log10 copies/mL-1.12-1.20-1.31-1.5-1.5BID, twice daily; ENF, enfuvirtide; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; OBR, optimized background regimen; QD, once daily; VL, viral load; Wk, week.The next slide looks the mean change in HIV-1 RNA based on enfuvirtide use. Studies often use this drug with the idea that enfuvirtide may be active in many treatment-experienced patients. Looking at MOTIVATE 1 on the left and MOTIVATE 2 on the right, it is clear that there is better virologic suppression in the maraviroc groups (orange and blue) than the placebo groups (green). However, when comparing the group that used enfuvirtide with the group that did not, it is evident that there is not much of a difference.The one thing that was not done in this particular trial is an analysis within the enfuvirtide‑treated group of those who were enfuvirtide experienced and possibly resistant to this drug vs those who were treatment naive. The previous slide suggested that the number of active drugs, which would include enfuvirtide in an enfuvirtide-naive patient, is associated with virologic response, and in general, this may true even though this analysis is not able formally to show that.For more information about this study, see the Capsule Summary at:-2.0-1.97-2.0-2.08-2.08-2.02-2.18-2.17-2.22-2.5-2.5-2.45*Includes all those who received ENF as part of OBR, whether ENF naive or experienced.Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.
70MOTIVATE 1 and 2: Change in CD4+ Count at Time of Failure Mean Change in CD4+ Cell Count in Patients With Treatment FailurePlacebo + OBRMVC QD + OBRMVC BID + OBRAll treatment failures+14 (n = 97)+49 (n = 68)+71 (n = 77)In Patients With Tropism Results at Baseline and FailureR5 R5+15 (n = 80)+61 (n = 18)+138 (n = 17)R5 D/M or X4+67 (n = 4)+37 (n = 31)+56 (n = 32)Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.~ 8% of patients experienced shift in detected tropism between screening and baselineAmong patients with treatment failure, shift in detected tropism more common among maraviroc vs placebo recipientsAmong maraviroc recipients with tropism results at time of failure, approximately 2/3 had dual/mixed or X4 virus detectedBID, twice daily; D/M, dual/mixed tropic; MOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; MVC, maraviroc; OBR, optimized background regimen; R5, CCR5 tropic; QD, once daily; X4, CXCR4 tropic.These data look at CD4+ cell count at the time of virologic failure. There are a few issues that need to be considered with any new drug and some unique issues associated with CCR5 antagonists in particular. For any drug, it is important to think about the possibility of true drug resistance. In the case of CCR5 antagonists, one must also consider the possibility of a shift in the viral population from R5 virus only at baseline to a population of dual/mixed-tropic virus.As mentioned earlier, it is important to be sure that if dual/mixed-tropic viruses emerge, this event is not associated with adverse outcomes. If we look at all treatment failures, CD4+ cell counts were maintained in both maraviroc groups, even among those who experienced virologic failure. The tropism data are even more interesting if one looks at the group of people who had R5 virus only at baseline and at failure. Although the numbers are fairly small, CD4+ cell counts remained high. The most important groups to analyze, however, are those who experienced virologic failure with dual/mixed-tropic or X4 virus. CD4+ cell counts were maintained in this group as well suggesting that, at least in the short term, this shift in tropism was not associated with CD4+ cell count decline.The other thing that is important to note is that if you look at the proportion of people in the different groups that failed with dual/mixed-tropic or X4 virus, only approximately 5% of those who received optimized background regimen with placebo are included in this group. However, approximately 65% or two thirds of those who were treated with CCR5 antagonists ultimately failed with dual/mixed-tropic or X4 virus. Whereas true resistance data were not formally described (there was some suggestion that there may be mutations within the V3 loop), it appears that those who are failing on a CCR5 antagonist are failing with viruses that use the other receptor. The good news is that this does not appear to be associated with a decline in CD4+ cell count.The other interesting observation that came out of this study is that there was minimal variability in the results seen with the tropism assay. All of the patients who wanted to enroll in the study were screened and were included only if they did not have any evidence of X4 or dual/mixed virus (ie, their virus was R5 only). A tropism assay was performed again at study entry, several weeks after the initial screening test but before treatment with a CCR5 antagonist. Approximately 8% of the patents who had R5 virus only at screening were found to have dual/mixed-tropic virus at the time of entry. This has been seen in other studies as well. In fact, there is approximately 5% to 10% of patients who, over time, will have viral populations that switch from R5 virus only to dual/mixed or X4 virus only and then perhaps back and forth again. It is also believed that low levels of dual/mixed-tropic virus are below the sensitivity of the assay may result in a false negative at baseline.For more information about this study, see the Capsule Summary at:
71MOTIVATE 1 and 2 : Adverse Events and Resistance Similar incidence of adverse events in maraviroc and placebo armsSimilar low incidence of hepatotoxicity in maraviroc and placebo armsLymphoma diagnosed in 3 patients in maraviroc arms and 2 patients in placebo armsResistanceMutations seen in V3 loop among patients who failed on the maraviroc arms with R5 virusNo signature R5 mutations have been defined yetMOTIVATE, Maraviroc plus Optimized Background Therapy in Viremic, ART-Experienced Patients; R5, CCR5 tropic.Adverse events and the development of resistance were similar across the treatment groups. Although it is important to remember that these patients all received optimized background regimens, there did not appear to be any difference in adverse events between those who received once-daily or twice-daily maraviroc vs placebo. Similar low levels of hepatotoxicity were found in all of the groups.There was an issue of malignancy raised in an earlier trial. It was suggested that there may have been more malignancies among those who received a CCR5 antagonist when compared with those who did not. That was analyzed very carefully in these 2 studies. In this case, the investigators were unable to see any relationship between malignancies and the use of CCR5 antagonists. In fact, the overall number of malignancies was small and similar results were found in both groups.Regarding resistance, no real data have been formally presented yet. There are in vitro data, however, showing that resistance may develop. This needs to be studied carefully in these trials. Lastly, no signature R5 mutations have been defined at this time.For more information about this study, see the Capsule Summary at:Nelson M, et al. CROI Abstract 104aLB. Lalezari J, et al. CROI Abstract 104bLB.
72Advantages and Disadvantages of CCR5 Antagonists Novel antiretroviral classEffective against NRTI-, NNRTI-, PI-, and ENF-resistant virusSynergistic with ENF in vitroShort-term tolerability data promisingOrally administeredDisadvantagesMay not be effective for significant portion of patient population—those with X4 or D/M virusUncertain risk/implications of emerging D/M or X4 virusLong-term safety and resistance not well definedCost and availability of tropism assayDrug interactions: complexity of dosing with PID/M, dual/mixed tropic; ENF, enfuvirtide.The advantages of CCR5 antagonists include that it is a novel antiretroviral class and it is effective against those with resistance to NRTIs, NNRTIs, enfuvirtide, and PIs. There is some suggestion in vitro that there may be synergy with enfuvirtide. The short‑term tolerability data appear to be quite promising, and it is an orally available drug.Unfortunately, on the other hand, this class of drugs may not be effective for a significant proportion of patients, particularly those in the more advanced stage of disease who may have dual/mixed-tropic virus. There are uncertain risk implications of the emergence of dual/mixed-tropic or X4 virus, although the preliminary data suggest that this class appears to be safe. Long‑term safety and resistance has yet to be defined. There are also issues involving cost and the availability of a tropism assay, which will be a vital tool in determining for which patients these drugs are appropriate.
74Integrase Enzyme Viral enzyme essential to replication of both HIV-1 and HIV-2IntegrationFollows reverse transcription, where DNA copy of HIV-1 RNA synthesized after infectionEssential step before viral DNA can be transcribed back into viral RNAIncorporates or “integrates” viral DNA into host cell’s DNA
75BENCHMRK 1 & 2 Phase III : RAL in Treatment-Experienced Pts Week 48 current analysisWeek 156 planned follow-upHIV-infected patients with triple-class resistance and HIV-1 RNA > 1000 copies/mLBENCHMRK 1 (N = 350;Europe, Asia/Pacific, Peru)BENCHMRK 2 (N = 349;North, South America)Raltegravir 400 mg BID + OBR*(BENCHMRK 1: n = 232;BENCHMRK 2: n = 230)Placebo + OBR*(BENCHMRK 1: n = 118;BENCHMRK 2: n = 119)*Investigator-selected OBR based on baseline resistance data and history; inclusion of DRV and TPV permitted.Cooper DA, et al. CROI Abstract 788.Steigbigel R, et al. NEJM359:339, July 24, 2008
76BENCHMRK 1: BL Characteristics Raltegravir + OBR(n = 234)Placebo + OBR(n = 118)Mean HIV-1 RNA, log10 copies/mL4.64.5Median CD4+ cell count, cells/mm3140105AIDS diagnosis, %9489Median duration of ARV exposure, yrs1110GSS = 0, %3029GSS = 1, %3341PSS = 0, %1918PSS = 1, %First-time use of DRV in OBR, %2725First-time use of ENF in OBR, %2120GSS, genotypic sensitivity score; HBV, hepatitis B virus; HCV, hepatitis C virus; OBR, optimized background regimen; PSS, phenotypic sensitivity score; SD, standard deviation.Steigbigel RT, et al. N Engl J Med7676
77BENCHMRK 2 : BL Characteristics Raltegravir + OBR(n = 230)Placebo+ OBR(n = 119)Mean HIV-1 RNA, log10 copies/mL4.7Median CD4+ cell count, cells/mm3102132AIDS diagnosis, %9192Median duration of ARV exposure, yrs10GSS = 0, %2027GSS = 1, %4440PSS = 0, %19PSS = 1, %3428First-time use of DRV in OBR, %4550First-time use of ENF in OBR, %GSS, genotypic sensitivity score; HBV, hepatitis B virus; HCV, hepatitis C virus; PSS, phenotypic sensitivity score; SD, standard deviation.Steigbigel RT, et al. N Engl J Med7777
78BENCHMRK 1 & 2: Efficacy by BL HIV-1 RNA and CD4+ Cell Count Patient Group, %HIV-1 RNA < 50 copies/mL at Week 48*Raltegravir + OBR(n = 443)Placebo + OBR(n = 228)All patients6434HIV-1 RNA at BL, copies/mL> 100,00048 (n = 156)16 (n = 76)≤ 100,00073 (n = 287)43 (n = 152)CD4+ cell count at BL, cells/mm3≤ 5050 (n = 139)20 (n = 75)> 50 to ≤ 20067 ( n = 167)39 (n = 82)> 20076 (n = 136)44 (n = 71)*Virologic failures carried forward.Steigbigel RT, et al. N Engl J Med
79BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL at Week 48, Overall and by GSS* *The genotypic sensitivity score is the total number of antiretroviral drugs used as part of the optimized background therapy to which a patient's HIV was fully susceptible, as determined with the use of genotypic resistance testing.RaltegravirPlaceboSubgroupnPatients (%)44364Total22834GSS:1124565316667For 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 drugs1923715875≥ 2685920406080100David A. Cooper et al. N Engl J Med797979
80BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL at Week 48 by BL PSS* * The phenotypic sensitivity scorePSSnPatients (%)Raltegravir + OBRPSS = 0 (based on lower cutoff)6551442Placebo + OBRPSS = 0 (based on upper cutoff)3352128PSS = 1 (based on lower cutoff)PSS = 1 (based on lower cutoff)PSS = 1 (based on lower cutoff)PSS = 1 (based on lower cutoff)137616929PSS = 1 (based on upper cutoff)71485413PSS ≥ 2 (based on lower cutoff)2217110848PSS ≥ 2 (based on upper cutoff)PSS ≥ 2 (based on upper cutoff)313701534320406080100David A. Cooper et al. N Engl J Med
81BENCHMRK 1 & 2: Virologic Failure, Resistance Through Week 48 Virologic failure generally associated with mutations at Q148 or N155, in combination with at least 1 other mutationVirologic failure*: BENCHMRK 1 (n = 50); BENCHMRK 2 (n = 48)Virologic failure defined as< 1 log10 ↓ HIV-1 RNA from BL and > 400 c/mL at Week 16 or> 1 log10 ↑ HIV-1 RNA above nadir or > 400 c/mL from nadir after response of < 400 c/mL (on 2 consecutive measurements ≥ 1 week apart)*In patients for whom integrase genotypic data were available.David A. Cooper et al. N Engl J Med
82BENCHMRK 1 & 2: Adverse Events Through Week 48 Clinical adverse eventsRaltegravir groups: 89%Placebo groups: 87%Considered treatment related in each group: 54%Laboratory adverse eventsRaltegravir groups: 23%Placebo groups: 22%Considered treatment related: 14% and 13%, respectivelyMost common drug-related clinical adverse events in both treatment groupsDiarrhea, nausea, headacheMost common drug-related laboratory adverse eventsIncreased serum lipid, aminotransferase, creatinine levelsSteigbigel RT, et al. N Engl J Med
83EACS Management of virologic failure If Plasma HIV RNA confirmed > 500/1000 copies/ml, change regimenas soon as possible: what to change will depend on the resistancetesting results:No Resistance mutations found: re-check for adherence, perform TDMResistance mutations found: switch to a suppressive regimen based on drug history; multidisciplinary experts discussion advisedGoal of new regimen:Plasma HIV RNA < 400 c/ml after 3 monthsPlasma HIV RNA < 50 c/ml after 6 months
84EACS In case of resistance mutations demonstrated General recommendations :Use 2 or preferably 3 active drugs in the new regimen (including active drugs from previously used classes)Any regimen should use at least 1 drug from a class not used previously e.g. fusion, integrase or CCR inhibitorDefer change if < 2 active drugs available, based on resistance data, except in patients with low CD4 count (<100/mm3) or with high risk of clinical deterioration for whom the goal is the preservation of immune function through partial reduction of Plasma HIV RNA (> 1 log reduction) by recycling.If limited options, consider experimental and new mechanistic drugs, favouring clinical trials (but avoid functional monotherapy)Treatment interruption is not recommended
85EACS In case of resistance mutations demonstrated Optimisation of new regimen :Avoid NNRTI in NNRTI-experienced patients; Etravirine potentially active in selected NNRTI-resistance profilesConsider continuation of 3TC or FTC even if documented resistance mutation (M184V/I)Select other potentially active NRTI(s), on treatment history and full resistance (past and present) evaluationSelect 1 active ritonavir-boosted PI. If at all possible avoid double boosted PIsAlways check for drug-drug-interactions, and when necessary perform TDM of drugs of new regimen if availableIf many options are available, criteria of preferred choice include : simplicity of the regimen, toxicity risks evaluation, drug-drug-interactions, future salvage therapy
86Estimated Timeline for Availability of New Antiretrovirals CXCR4 inhibitorsEntry inhibitors(anti-gp120, CCR5)GS-9137Maturation inhibitorsVicrivirocIntegrase inhibitorsMaravirocTNX-355MK-0518Bevirimat20062007200820092010EtravirineTMC278PIsBrecanavirNNRTIApricitabineNRTI
87Conclusions (1)Failure of therapy is multifactorial.The virologic failure is a progressive increase of HIV RNA that further leads to a decrease in CD4 cells.Prevention of therapeutic failure starts as soon as first-line therapy detect defect in adherence due to any reasons.Identification of therapeutic failure should mobilize treating HIV physicians.
88Conclusions (2)An optimal analysis of the failing situation must be performed with ARV history and resistance assays results .an « expert group » decision is the ideal situation.Do not jeopardize any chance for success therapy by using a single new potent drugCombining new drugs is the only solution to multi salvage situations
89The near future of Antiretroviral therapy ? …at least and unfortunately in developped countries only …
90TRIO Study : Combining Raltegravir, Darunavir and Etravirine 24 Week Phase II, non-comparative, Multicenter TrialAll pts viremic on current regimen (n=103)HIV RNA > 1000 /mL, any CD4 countDocumented multidrug-resistant virus≥ 3 NRTI mutations≥ 3 major PI mutationsSusceptible to DRV : ≤ 3 DRV mutations*Previous virologic failure on NNRTIsSusceptible to ETR : < 3 ETR NNRTI mutationsAll initiate Raltegravir, Darunavir and Etravirine (naïve to all)Additional ARVs allowed : NRTIs and ENF (based on clinical judgment)Yazdanpannah, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THAB0406.9090
91TRIO Study : Baseline Characteristics HIV RNA log10, copies/ml, median (IQR)4.0(3.6 – 4.6)CD4 cells/mm3, median (IQR)255(132 – 350)# mutations at screening, median (IQR)Major PI4(3 – 5)NRTIs5(4 – 6)NNRTIs1(0 – 2)% with 0 / 1 / 2 / 3 mutationsDRV4% / 31% / 30% / 35%ETR34% / 31% / 31% / 3%Additional ARVs in Optimized Background Regimen:None 14%NRTIs 83%Enfuvirtide (most – 10/12 - ENF naive) 12%Yazdanpannah, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THAB0406.9191
92TRIO Study : Primary Outcome at 24 Weeks (ITT, M=F) 90%(95% CI:85% to 96%)% Pts with HIV RNA <50 cp/ml (95% CI)Weeks00020408121620241030405060708090100Yazdanpannah, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. ThAB0406.9292
95Episodes of low-level viremia less likely associated with clinical event or change in therapy than episodes of high-level viremiaLow-level viremiaWithout clinical event or therapy change : 79.6%Change in therapy occurred : 13.9%High-level viremiaWithout clinical event : 41.7%Change in therapy occurred : 52.3%CD4+ cell counts increased during periods of virologic suppression but decreased during episodes of high level viremiavan Sighem A, et al. J Acquir Immune Defic Syndr. 2008;48:
96Viremia : Low level 50-1000 cp/ml High level >1000 cp/ml After achieving virologic suppression, many patients experience transient, measurable viremia while on antiretroviral therapy [1,2]Transient viremia is associated withLow-level viral replicationActivation of latently infected cells and subsequent viral productionRise in target cell availability1. Easterbrook PJ, et al. AIDS. 2002;16: Havlir DV, et al. JAMA. 2001;286:
97Nucleosides Analogues (NRTI) Resistance very commonmutations archived indefinitelycross-resistance between NRTIs ++AZT-D4T- high cross-resistance> 3 TAMs including T215 F D4T efficacyDDI- antiviral efficacy if 3TAMS including T215 FAbacavir- antiviral efficacy if 4 mut. among 41,67,74,184,210,215
98Nucleosides Analogues (NRTI) resistance 3TC induces M184V. high level of resistance for intrinsic antiviral activityM184V reduces viral fitnessM184V prevents accumulation of other mutations(K65R)Data suggest a benefit to maintain M184V in a regimen
99Management of failure on first line therapy Failure is defined as the detection of a viral load greater than 50 copies > 6 months after the initiation of a first treatment regimenInterview the patient to evaluate adherence and complianceRe-explanation of the objectives and modalities of the treatment and the potential risks of poor adherenceExclusion of potential drug-drug or drug-food interactionsRe-Test viral load : If detectable :- Resistance testing- Therapeutic drug monitoring
100Adding new drugs / drugs with a remaining sensitivity is a key issue in the succes of a salvage regimen
101Management of virologic failure General measures (1) If 50< Plasma HIV RNA < copies/mlCheck for adherenceCheck Plasma HIV RNA 1 to 2 months laterImprove boosted PI's PK (if applicable)
102Management of virologic failure General measures (2) Perform resistance testing (if plasma HIV RNA levels > copies/ml) and obtain historical resistance testing for archived mutationsReview antiretroviral historyIdentify treatment options, active, potentially active drugs/combinations
103Failure in (multi)experienced patients Patients who have been treated suboptimally in the past, have a long treatment history and have developed sequential resistance complex pattern of resistance which makes viral suppression difficultPatients who have been unable to comply to and/or to tolerate their previous regimens less complex pattern of resistance but compliance and tolerability issues for the long term
104Resistance testing : impact on treatment Decision to change treatment regimens must take into account :the remaining treatment optionsthe level of failure based on kinetics of viral load and CD4 (decreased viral fitness)the past treatment history, including resistance patterns, tolerability and adherence issuesCo-infections and comorbidities
105Treatment interruption in salvage therapy : a case for caution May be associated with rapid decline of CD4Need to optimalize OI prophylaxisOptimal time for re-initiation of therapy is not established
106HIV Replication Cycle and Drug Targets Entry inhibitorsReverse transcriptase inhibitorsProtease inhibitors3′-processing inhibitorsStrand transfer inhibitorsCurrent antiretrovirals target (a) entry of HIV into the host cell and the viral enzymes (b) reverse transcriptase and (c) protease. Integrase, the third viral enzyme, catalyzes 2 steps in the viral replication cycle. First, integrase catalyses the processing of the 3′-ends of the viral DNA (3′-processing) (d); integrase then remains bound in a complex with the viral DNA ends in the preintegration complex (PIC). Second, after the PIC enters the host nucleus, integrase catalyses the insertion (strand-transfer) of the viral DNA ends into host chromosomes (e).Pommier Y, et al. Nat Rev Drug Discov. 2005;4:106106
107Percentage of Patients with Plasma HIV-1 RNA Levels of Less Than 400 or Less Than 50 Copies per Milliliter during the BENCHMRK Studies, According to Study GroupFigure 1. Percentage of Patients with Plasma HIV-1 RNA Levels of Less Than 400 or Less Than 50 Copies per Milliliter during the BENCHMRK Studies, According to Study Group. Percentages are shown for patients in the BENCHMRK-1 study (Panel A), patients in the BENCHMRK-2 study (Panel B), and patients in the combined studies (Panel C). The data, based on standard and ultrasensitive assays, are for the patients included in the analysis counting noncompletion as treatment failure. I bars represent 95% confidence intervals.Steigbigel RT et al. N Engl J Med 2008;359:107
108BENCHMRK 1 : Patients With HIV-1 RNA < 50 c/mL at Week 48 Raltegravir + OBR (n = 232)Placebo + OBR (n = 118)P ValueHIV-1 RNA < 50 c/mL (NC = F), %6531< .001HIV-1 RNA < 400 c/mL (NC = F), %7436Mean change in HIV-1 RNA vs BL, log10 c/mL-1.7-0.7Mean change in CD4+ cell count vs BL, cells/mm312049BL, baseline; DRV, darunavir; ENF, enfuvirtide; NC = F, noncompleter = failure; OBR, optimized background regimen.*P value derived from a logistic regression model adjusted for BL HIV-1 RNA level (log10), first ENF use in OBR, first DRV use in OBR, active PI in OBR.Steigbigel RT, et al. N Engl J Med108108
109BENCHMRK 2 : Patients With HIV-1 RNA < 50 c/mL at Week 48 Raltegravir + OBR (n = 232)Placebo + OBR (n = 119)P ValueHIV-1 RNA < 50 c/mL (NC = F), %6034< .001HIV-1 RNA < 400 c/mL NC = F), %7138Mean change in HIV-1 RNA vs BL, log10 c/mL-1.8-0.9Mean change in CD4+ cell count vs BL, cells/mm39840BL, baseline; DRV, darunavir; ENF, enfuvirtide; NC = F, noncompleter = failure; OBR, optimized background regimen.*P value derived from a logistic regression model adjusted for BL HIV-1 RNA level (log10), first ENF use in OBR, first DRV use in OBR, active PI in OBR.Steigbigel RT, et al. N Engl J Med109109
110TRIO Study : Combining Raltegravir, Darunavir and Etravirine 24 Week Phase II, non-comparative, Multicenter TrialAll pts viremic on current regimen (n=103)HIV RNA > 1000 /mL, any CD4 countDocumented multidrug-resistant virus≥ 3 NRTI mutations (2006 IAS list)≥ 3 major PI mutations (2006 IAS list)Susceptible to DRV (using 1st Power algorithm): ≤ 3 DRV mutations*Previous virologic failure on NNRTIsSusceptible to ETR (using 1st Tibotec analysis of ETR RAMs): < 3 ETR NNRTI mutationsAll initiate Raltegravir, Darunavir and Etravirine (naïve to all)Additional ARVs allowed : NRTIs and ENF (based on clinical judgment)* V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89VYazdanpannah, et al. 17th IAC; Mexico City, Aug 3-8, 2008; Abst. THAB0406.110110
111Option 6 : «Continuous» genotypic - driven salvage therapy The goal is to achieve a selective pressure by using a genotypic-driven salvage therapy that is changed as soon as emergence of new resistant variants is documented Maggiolo et al. (Barcelona 2000) multi class experienced patients - VL every 2 months - Therapy changed if VL > , based on genotype - Over 24 months, VL contained below copies and CD4 increase of 84 cells (with max. 4 drugs)
112POWER 3 : VL < 50 copies/mL at Week 24 by ITT-TLOVR POWER 3: ongoing phase III open-label study, DRV/RTV 600/100 mgSafety analysis similar to POWER 1 and 270POWER 1 (n = 65)60POWER 2 (n = 66)5350POWER 3 (n = 327)4040Patients With VL < 50 copies/mL (%)39302010B/L24812162024Weeks1. Molina JM, et al. IAC Abstract TUPE Madruga V, et al. IAC Abstract TUPE0062.112
113J Acquir Immune Defic Syndr. 2007;46:24-31. POWER 3 Study Confirms Safety and Efficacy of Darunavir/Ritonavir in Treatment-Experienced PatientsJ Acquir Immune Defic Syndr. 2007;46:24-31.POWER 1 and 2 studies demonstrated efficacy and safety of darunavir/ritonavir in treatment-experienced individualsParallel dose-ranging trials in treatment-experienced patientsCurrent POWER 3 study designed to provide additional data on efficacy and safety of darunavir/ritonavir 600/100 mg in treatment-experienced, HIV-infected patients
114Description of Current Analysis Data for RESIST 1 and 2 pooled in current analysis, given similar study design and patient demographicsPatients assessed at Weeks 2, 4, 8, 16, 24, 32, 40, and 48 for clinical and laboratory evaluationsPrimary endpointsTreatment response, defined as confirmed reduction in HIV-1 RNA ≥ 1 log10 copies/mL at Week 48Time to treatment failureSafety assessed via adverse-event monitoringAdverse events and laboratory abnormalities graded according to Division of AIDS grading scaleTotal cholesterol abnormalities graded according to Common Toxicity Criteria ScaleIntent-to-treat analyses using noncompletion-equals-failure and last-observation-carried-forward methods114
115Main FindingsDarunavir/ritonavir plus OBR associated with substantial virologic responses and immunologic improvement at Week 24Outcome at Week 24Patients> 1 log10 copies/mL reduction in HIV-1 RNA, %65HIV-1 RNA < 400 copies/mL, %57HIV-1 RNA < 50 copies/mL, %40Mean change in HIV-1 RNA, log10 copies/mL-1.65Mean change in CD4+ cell count, cells/mm3+80Molina JM, et al. J Acquir Immune Defic Syndr. 2007;46:24-31.
116BLQ Study : DRV/RTV + ENF in Triple-Class Experienced Patients 142 triple-class-experienced, DRV/RTV-naive and ENF-naive patients with HIV-1 RNA > 2000 copies/mLSwitched from failing regimen to DRV/RTV (600/100 mg BID), ENF (90 mg SC BID), and other investigator-selected antiretroviralsSingle arm, nonrandomized designOverall, 60% achieved HIV-1 RNA < 50 copies/mL at Week 24No difference in response according to baseline DRV susceptibilityBaseline Phenotypic Susceptibility to DarunavirHIV-1 RNA < 50 copies/mL at Week 24, %Categorical cutoffsFC < 10 (n = 87)64.4FC (n = 19)57.9FC > 40 (n = 8)62.5BID, twice daily; BLQ, below the level of quantitation; DRV, darunavir; ENF, enfuvirtide; FC, fold change; RTV, ritonavir; VL, viral loadDe Jesus E, et al. ICAAC Abstract 367.116
117Various Causes of failure - Non-adherence : Side effectsComplex regimensLifestyle conflicts- Toxicity- Pharmacologic variations : drug-drug interaction pregnancy- Infection with resistant HIV-1 strains- Selection of resistant HIV-1 strains