Presentation on theme: "Institute of Clinical Infectious Diseases. Catholic University, Rome"— Presentation transcript:
1Institute of Clinical Infectious Diseases. Catholic University, Rome Anti-HIV drugsAndrea De Luca, M.D.Institute of Clinical Infectious Diseases. Catholic University, Rome2nd Division of Infectious Diseases, University Hospital of Siena, Italy
2Goals of antiretroviral therapy HAARTGoals of antiretroviral therapyCD4 +MortalityOpportunisticinfectionsHIV RNAtime
3Probability (%) to develop full blown AIDS in the subsequent 3 years by CD4 counts and HIV RNA levels before and after the introduction of antiretroviral therapyWithouttherapyWiththerapy
5Limitations of antiretroviral therapy morbidity and mortality but…Eradication impossible because of latently infected CD4+ memory T cellsEmergence of drug resistanceLIFE-LONG CHRONIC TREATMENT NECESSARYAdherenceTolerability
6Antiviral potency and development of drug-resistance Risk of developmentof drug-resistancepoorsuboptimalhighPoor pharmacokineticsSuboptimal adherenceDrug pressure selectsresistant virusInadequate drug pressure to selectComplete viral suppressionIncreasing adherenceIn generale, il rischio di selezione di mutanti resistenti aumenta fino a un picco massimo con l’aumentare della pressione selettiva. Una pressione minore (potenza antivirale scarsa) può infatti consentire un sufficiente livello di replicazione virale senza che un’eventuale mutante, per definizione meno efficiente del virus wild-type, prevalga. D’altra parte, una pressione maggiore (attività antivirale elevata) può comportare un’inibizione pressoché totale dell’attività replicativa virale, facendo venire meno il presupposto essenziale per la generazione delle varianti resistenti. Alla condizione di potenza antivirale di livello intermedio, associata a una consistente probabilità di selezione di mutanti resistenti, concorrono vari fattori, fra cui un’imperfetta aderenza e condizioni farmacocinetiche non ottimali.6
8Antiretroviral drugs and classes licensed for use in developed countries Nucleoside/nucleotide RT inhibitorsNon-nucleoside RT inhibitorsProtease inhibitorsFusion inhibitorsIntegrase inhibitorsCCR5 antagonistsZidovudineNevirapineSaquinavir/ritEnfuvirtideRaltegravirMaravirocDidanosineEfavirenz(Ritonavir)(Zalcitabine)(Delavirdine)Indinavir/ritLamivudineEtravirineNelfinavirStavudineFosamprenavir/(rit)AbacavirLopinavir/ritTenofovirAtazanavir/ (rit)EmtricitabineTipranavir/ritDarunavir/rit
9NRTI Historical ARV drugs. Still difficult to avoid Essential component of ART regimens (2 NRTI+ x)Alone: Low/intermediate potency, intermediate genetic barrierClass-toxicity: mitochondrial toxicity (lipoatrophy, peripheral neuropathy, pancreatitis, hyperlipemia)Individual components related to organ-specific toxicities (bone marrow, renal/bone, cardiovascular)
11PI Potent, high genetic barrier (ritonavir-boosted) Class-toxicity: metabolism (lipid, glicidic, lipodystrophy, cardiovascular)Ritonavir toxicity (gastrointestinal, lipids)Lopinavir and fosamprenavir probably cause diarrhea per seSpecific toxicities: hyperbilirubinemia (atazanavir), cutaneous reactions (sulpha component of fosamprenavir and darunavir), nephrolithiasis (indinavir>atazanavir)
12FI, INSTI, CCR5 antagonists All potent drugs but low/intermediate genetic barrier to resistanceFI: injection site reactionsOther drugs: very modest toxicityRaltegravir: CNS/psychiatric, muscleMaraviroc: liver
13ART: Recent /Future developments Goal (virologic suppression) achieved in 85-90% of patients in trials and clinical practice (drug naive and experienced patients)Towards more simple regimens (one pill/day)Increased genetic barrierImproved tolerabilityFurther improvements:Less medium-long term toxicity (metabolic, cardiovascular, renal/bone)PK boosting without ritonavir
14New treatments and strategies for naive patients
15ARTEMIS: Wk 96 Lipid and Anthropometric Substudy Randomized noninferiority trial of DRV/RTV vs LPV/RTV, both with TDF/FTC, in naive ptsDRV/RTV noninferior to LPV/RTV at Wk 48. At Wk 96, DRV/RTV met superiority criteria vs LPV/RTVIn anthropometric analysis at Wk 96, no increase in median midwaist:midhip ratio in either study armChanges in BMI, body weight, midwaist, chest, hip, and circumferences similar between arms and not clinically relevant6056DRV/RTV50LPV/RTV4035Median Increase at Wk 96 (mg/dL)3026201715188105TCLDL-CHDL-CTGStatistically greater % increases in TC, TG in LPV/RTV arm than DRV/RTV arm (P < .001)Baraldi E, et al. IAS Abstract MOPEB034.
17MERIT: Wk 96 Response With MVC vs EFV in Naive Pts MERIT-ES: reanalysis of MERIT trial using enhanced phenotypic tropism assay suggested noninferiority of MVC to EFV when additional pts with D/M-tropic virus identified by enhanced assay excludedWk 96 efficacy analysis included only MERIT-ES populationSimilar proportions in MVC and EFV with VL < 50 copies/mL at Wk 96CD4+ increase at Wk 96 greater with MVC vs EFV (+212 vs +171 cells/mm³)EFV more likely discontinued for AEs: % vs 6.1% on MVCMVC more likely discontinued for insufficient response: 12.5% vs 5.9% on EFVEFV + ZDV/3TCMVC + ZDV/3TCMERITMERIT-ESMERIT-ES100ITT, NC = FModifiedITTTLOVR8069.365.368.368.562.46058.560.760.5HIV-1 RNA < 50 c/mL (%)4020nWk 48Wk 963TC, lamivudine; D/M; dual/mixed; ES, enhanced sensitivity; MERIT, Maraviroc vs Efavirenz Regimens as Initial Therapy; R5, CCR5-utilizing virus; ZDV, zidovudineFor more information about this study, go online to: clinicaloptions.com/HIV/Conference%20Coverage/Cape%20Town%202009/Tracks/Developed/Capsules/TUAB103.aspxHigher levels of dyslipidemia on EFV5/15 pts who discontinued EFV for tolerability developed NNRTI mutations in follow-up1. Saag M, et al. ICAAC/IDSA Abstract 1232a. 2. Heera J, et al. IAS Abstract TUAB Nelson M, et al. IAS Abstract MOPEB040.
18ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients Randomized, double-blind phase III trialsStratification by BL HIV-1 RNA < 100,000 vs ≥ 100,000 copies/mL, NRTI use*Wk 48primary analysisWk 96final analysisRilpivirine 25 mg QD+ TDF/FTC 300/200 mg QD(n = 346)ECHO(N = 690)EFV 600 mg QD + TDF/FTC 300/200 mg QD (n = 344)Treatment-naive,HIV-1 RNA ≥ 5000 copies/mLno NNRTI RAMs,susceptible to NRTIsTHRIVE(N = 678)Rilpivirine 25 mg QD + 2 NRTIs† (n = 340)EFV 600 mg QD + 2 NRTIs† (n = 338)*THRIVE only. †Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC.Cohen C, et al. AIDS Abstract THLBB206.
19ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients HIV-1 RNA < 50 copies/mL at Wk 48 by BL VL6.6 ( )HIV-1 RNA < 50 copies/mL (ITT-TLOVR) at Wk 48100909091848384801006085.684.382.3Patients (%)82.982.881.7408020332/ 368276/ 330162/ 181136/ 163170/ 187140/ 16760Patients (%)PooledECHOTHRIVE40≤100,000 copies/mL-3.6 (-9.8 to +2.5)2010081827980n =686682346344340338807776PooledECHOTHRIVE60Patients (%)4020*P < for noninferiority at -12% margin.246/ 318285/ 352125/ 165149/ 181121/ 153136/ 171Cohen C, et al. AIDS Abstract THLBB206. Graphics used with permission.PooledECHOTHRIVE> 100,000 copies/mL
20ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events Treatment Failure in ECHO and THRIVE15RilpivirineAdverse Events and Discontinuation12EFV9.0Wk 48 Outcome, %Rilpivirine (n = 686)Efavirenz(n = 682)P ValueDC for AE38.0005Most Common AEs of Interest, %Any neurologic AE1738< .0001Any psychiatric AE1523.0002Any rash1496.7Patients (%)64.82.03n =346686682686682VFAEResistance at Virologic FailureWk 48 OutcomeRilpivirine (n = 686)Efavirenz(n = 682)VF with resistance data, n6228No NNRTI or NRTI RAMs,%2943 1 Emergent NNRTI RAM,%6354Most frequent NNRTI RAME138KK103N 1 Emergent NRTI RAMs, %6832Most frequent NRTI RAMM184IM184VCohen C, et al. AIDS Abstract THLBB206. Table used with permission.
21GS-9350–Boosted Elvitegravir + FTC/TDF Noninferior to EFV/FTC/TDF in Naive Pts Cobicistat (GS-9350): investigational CYP3A inhibitor (boosting agent)Elvitegravir: investigational integrase inhibitorGS-9350/EVG/FTC/TDFEFV/FTC/TDFGS-9350/EVG/FTC/TDF (n = 48)EFV/FTC/TDF (n = 23)Treatment-naive pts with CD4+ ≥ 50 cells/mm3, HIV-1 RNA ≥ 5000 c/mL, no NRTI, NNRTI, or PI resistance(N = 71)Wk 24 primary endpoint analysisWk 48100908083ITT, M = F60HIV-1 RNA < 50 c/mL (%)40Wk 24 stratum-weighted difference: +5% (95% CI: -11.0% to 21.1%)204812162024WkCohen C, et al. CROI Abstract 58LB. Reproduced with permission.
22GS-9350–Boosted ATV Virologic Efficacy Similar to ATV/RTV in Naive Pts Phase II study comparing cobicistat (GS-9350) vs ritonavir as boosting agent for atazanavirWk 24 primary endpointGS-9350Wk 48100RTV868084Treatment-naive pts with CD4+ ≥ 50 cells/mm3, HIV-1 RNA ≥ 5000 c/mL, no NRTI, NNRTI, or PI resistance(N = 79)GS-9350–Boosted ATV + FTC/TDF (n = 50)ITT, M = F60HIV-1 RNA < 50 c/mL (%)RTV-Boosted ATV + FTC/TDF (n = 29)40Wk 24 stratum-weighted difference: -1.9% (95% CI: -18.4% to 14.7%)204812162024WkCohen C, et al. CROI Abstract 58LB. Reproduced with permission.
23SPRING-1: S/GSK1349572 vs EFV in Treatment-Naive Patients Wk 16Wk 48Dose-ranging, partially blinded phase IIb trialS/GSK mg QD+ 2 NRTIs QD*(n = 53)S/GSK mg QD(n = 51)S/GSK mg QDEFV 600 mg QD(n = 50)Treatment naive,HIV-1 RNA > 1000 copies/mL,no CD4+ cell count restriction(N = 205)*NRTIs individually selected by trial investigators (TDF/FTC, 67%; ABC/3TC, 33%).†After Wk 48, all patients continue at dose selected for phase III trial.Arribas J, et al. AIDS Abstract THLBB205.
24SPRING-1: Virologic Response to S/GSK1349572 vs EFV at Wk 16 10096%92%90%8050-mg dose chosen for phase III trial6060%HIV-1 RNA < 50 copies/mL (TLOVR), %40Time to < 50 copies/mL shorter for S/GSK dose than EFV (P < .001 for each comparison)20mgmgmgEFV 600 mgBL12481216WksCD4+ cell count increases cells/mm³ on S/GSK vs 116 cells/mm3 on EFVNo serious adverse events related to S/GSKArribas J, et al. AIDS Abstract THLBB205. Graphic used with permission.
25ARTEN: Wk 48 Response to NVP vs ATV/RTV in Naive Pts NVP either once daily or twice daily noninferior to ATV/RTV at Wk 48Rates of AEs similar overall but higher rate of discontinuation due to toxicity in NVP arms (13.6% vs 3.6%)ITT, NC = F100P = .638066.867.065.366.560HIV-1 RNA < 50 c/mL at Wk 48 (%)Outcome at Wk 48, %NVP QD (n = 188)NVP BID (n = 188)ATV/RTV (n = 193)Virologic failure11.212.814.0Investigator-defined virologic failure5.91.6No confirmed response at Wk 485.312.44020n =376193188188Any NVPATV/ RTVNVPQDNVPBIDSoriano V, et al. IAS Abstract LBPEB07.
26HIV-1 RNA < 50 copies/mL (TLOVR) VERxVE: Extended-Release NVP vs Standard NVP in Naive Patients at Wk 48Multicenter, randomized, double-blind, noninferiority study in treatment-naive patientsNVP XR 400 mg QD (n = 508) vsNVP IR 200 mg BID (n = 505)Both combined with TDF/FTCInclusion criteriaHIV-1 RNA > 1000 copies/mLCD4+ cell count < 400 cells/mm3 if male or < 250 cells/mm3 if femaleHIV-1 RNA < 50 copies/mL (TLOVR)Adjusted difference 4.92% (95% CI: to 9.96)100Patients (%)81.08075.9604020NVP IRNVP XRSimilar safety and tolerability for both armsAEs includedStevens-Johnson (n = 5)Hepatitis (n = 14)Rash (n = 21)Gathe J, et al. AIDS Abstract THLBB202.
27PROGRESS: LPV/RTV + RAL vs LPV/RTV + NRTIs in Treatment-Naive Patients Randomized, open-label, multicenter phase III trial in treatment-naive patients with HIV-1 RNA > 1000 copies/mLLPV/RTV 400 mg BID + RAL 400 mg BID (n = 101) vsLPV/RTV 400 mg BID + TDF/FTC 300/200 mg QD (n = 105)Relatively low mean baseline HIV-1 RNA4.25 log10 copies/mL20406080100WksHIV-1 RNA < 40 copies/mL (ITT-TLOVR)81624324883.2%84.8%Difference: -1.6% (95% CI: -12.0% to 8.8%)*Statistically significant difference between arms: Wks 2, 4, 8 P < .002 Wk 16 P = .038*Patients (%)LPV/RTV + RALSimilar CD4+ cell count gain at Wk 48LPV/RTV + RAL: 215 cells/mm³LPV/RTV + NRTIs: 245 cells/mm³Reynes J, et al. AIDS Abstract MOAB0101. Graphic used with permission.
28PROGRESS: Lipids and Adverse Events at Wk 48 Mean increases in TC, TG, and HDL-C from BL to Wk 48 significantly greater in RAL arm vs NRTI armResistance Development at VFLPV/RTV + RALLPV/RTV + NRTIsMet criteria for resistance testing43INSTI mutation (N155H)1NRTI mutations (M184V)LPV/RTV + RALLPV/RTV + NRTIsP = .044+99100Grade 3/4 laboratory events did not differ between arms, except higher risk of CPK > 4 x ULN in RAL arm12.9% vs 3.8% (P = .023)80P = .008+5960Mean Change From BL, mg/dL+4640+29P = .015+1220+8TCTGHDL-CReynes J, et al. AIDS Abstract MOAB0101.
29A4001078: ATV/RTV + MVC vs ATV/RTV + TDF/FTC—Wk 24 Interim Analysis HIV-1 RNA < 50 copies/mL Overall and by BL VLATV/RTV + MVC1009589ATV/RTV + TDF/FTC808081807760Patients (%)4020n =606144391622OverallHIV-1 RNA < 100KHIV-1 RNA 100KCD4 + cell count increases similarATV/RTV + MVC: 195 cells/mm³ATV/RTV + TDF/FTC: 173 cells/mm³Grade 3/4 hyperbilirubinemiaATV/RTV + MVC: 59.3%ATV/RTV + TDF/FTC: 49.2%5 patients in MVC arm, 1 patient in TDF/FTC arm switched to DRV/RTV per protocol for jaundice or scleral icterusMills A, et al. AIDS Abstract THLBB203.
30SPARTAN: Pilot Study of ATV + RAL vs ATV/RTV + TDF/FTC in Naive Pts Randomized, noncomparative, open-label, multicenter pilot study in treatment-naive patients with HIV-1 RNA ≥ 5000 copies/mLATV 300 mg BID + RAL 400 mg BID (n = 63) vsATV/RTV 3001/00 mg QD + TDF/FTC 300/200 mg QD (n = 31)Mean BL HIV-1 RNA: 4.9 log10 copies/mLPrimary Endpoint: HIV-1 RNA < 50 copies/mL Through Wk 24 (CVR*, NC = F)ATV BID + RAL BIDATV/RTV QD + TDF/FTC10074.6%8060Patients (%)4063.3%20BL4812162024Wks*CVR = modified ITT.Kozal MJ, et al. AIDS Abstract THLBB204. Graphic used with permission.
31SPARTAN: Wk 24 ResultsNo significant changes in fasting lipids observed in either arm during study periodTrial terminated at Wk 24 due to resistance data and grade 4 bilirubin abnormalities (21%) with experimental regimen vs control arm (0%)Resistance Through Wk 24, nATV + RAL (n = 63)ATV/RTV + TDF/FTC(n = 30)Virologic failure (HIV-1 RNA > 50 copies/mL)118BL HIV-1 RNA > 250,000 copies/mL4Evaluable for resistance testing * (HIV-1 RNA > 400 copies/mL)61Genotypic and phenotypic RAL resistanceN155H2NAQ148RQ148R + N155H + T97APhenotypic RAL resistance without genotypic evidence of resistanceATV resistanceTDF/FTC resistance*Criteria for resistance testing:HIV-1 RNA ≥ 400 copies/mL at or after Wk 24Rebound to HIV-1 RNA ≥ 400 any time during the studyDiscontinued before achieving HIV-1 RNA < 50 copies/mL after Wk 8 with last HIV RNA ≥ 400 copies/mLKozal MJ, et al. AIDS Abstract THLBB204.
32SENSE: EFV vs ETR in Treatment-Naive Patients Randomized, double-blind trial of treatment-naive patients with HIV-1 RNA > 5000 copies/mLEFV 600 mg QD (n = 78) vsETR 400 mg QD (n = 79)Each with investigator-selected NRTIs (TDF/FTC, ABC/3TC, or ZDV/3TC)Primary endpoint: % of patients with grade 1-4 drug-related treatment-emergent neuropsychiatric AEs at Wk 12Mean change in HIV-1 RNA at Wk 12 similar between arms (-2.9 log10 copies/mL)More drug-related neuropsychiatric AEs in EFV arm vs ETR armDrug-Related Neuropsychiatric AEs100Grade 1-4Grade 2-480P < .001P = .0260Patients (%)46402017175ETREFVETREFV10 patients discontinued in ETR and 8 in EFV arm by Wk 12Gazzard B, et al. AIDS Abstract LBPE19.
34ARIES: Boosted vs Unboosted ATV Maintenance: Wk 84 Results ATV (n = 210)100ATV/RTV (n = 209)86858780.882798060HIV-1 RNA < 50 c/mL at Wk 84 (%)4020Overall ResultsBL HIV-1 RNA < 100,000 c/mLBL HIV-1 RNA ≥ 100,000 c/mLSquires K, et al. IAS Abstract WELBB103. Graphic used with permission.
35SPIRAL: Switch to RAL Noninferior to Maintaining PI/RTV Regimens Patients With VFRAL (n = 4)PI/RTV (n = 6)Prior VF13Prior suboptimal ART2Prior resistance mutations5Resistance test at VF4Mutations3 (PR, RT)Free of Treatment Failure at Wk 48 (ITT, S = F)Patients (%)10089.286.6806040Mean Change From Baseline to Wk 48, %Switch to RALContinue PI/RTVP ValueTriglycerides-22.1+4.7< .0001TC-11.2+1.8LDL-C-6.5+3.0< .001HDL-C-3.2+5.8Total to HDL-C ratio-4.9-1.3< .0520Switch to RALContinue PI/RTVMartinez E, et al. AIDS. 2010;24:
36MONET Trial: 96-Wk Efficacy Results of Switch to DRV/RTV Monotherapy Randomized, open-label trial of switch to DRV/RTV monotherapy vs continuing DRV/RTV HAART in virologically suppressed ptsDRV/RTV monotherapy noninferior vs DRV/RTV HAART at Wk 48Monotherapy NOT noninferior with switch = failure analysis at Wk 96Δ -5.8% (95% CI: -16.0% to +4.4%)If resuppression with intensification included as success, then monotherapy noninferior at Wk 96Δ +1.4% (95% CI: -5.5% to +8.3%)HIV-1 RNA < 50 copies/mL, ITT, TLOVR (%)DRV/RTV monotherapy (n = 127)DRV/RTV + 2 NRTIs (n = 129)Switch allowed100Switch = failure92.190.784.385.380.68074.8604020Wk 48Wk 961. Arribas JR, et al. IAS Abstract TUAB106LB. 2. Rieger A, et al. AIDS Abstract THLBB209.
38Evolving efficacy of antiretroviral regimens in multiexperienced patients (percent <50 copies/ml) 48w96w%
39Pooled DUET 96-Wk Results: ETR + DRV/RTV-Containing OBR in Exp’d Pts Randomized trial of ETR vs placebo, both with DRV/RTV-containing OBR in multiclass-resistant ptsSuperior virologic suppression with ETR at Wks 24 (primary endpoint) and 48Superior virologic suppression maintained at Wk 96 in ETR vs placebo armHigher response with ETR irrespective of number of active agents, baseline ETR FC, weighted score, sex, race, and ageGreater mean change in CD4+ cell count with ETR vs placebo+123 vs +86 cells/mm³ (P < .0001)ETR (n = 599)100Placebo (n = 604)80P < .0001P < .0001605760HIV-1 RNA < 50 c/mL (%)(ITT-TLOVR)39403620Wk 48Wk 96No new safety signals in Wks 48-96New rash in < 1% of ptsCNS adverse effects similar between arms in Wks1. Mills A, et al. IAS Abstract MOPEB Nelson T, et al. IAS Abstract MOPEB038.
40ODIN: QD vs BID Darunavir/Ritonavir + OBR in Treatment-Experienced Patients Stratified by baseline HIV-1 RNA ≤ and > 50,000 copies/mLWk 48Treatment-experienced adults with stable HAART for ≥ 12 wks, HIV-1 RNA > 1000 copies/mL, CD4+ > 50 cells/mm3, no DRV RAMs(N = 590)QD DRV/RTV 800/100 mg + OBR* (n = 294)BID DRV/RTV 600/100 mg + OBR* (n = 296)*OBR included ≥ 2 active NRTIs.Primary PI mutations in < 2% of patients in either armCahn P, et al. CROI Abstract 57.
41ODIN: HIV-1 RNA < 50 copies/mL at Wk 48 Overall and by Screening HIV-1 RNA QD DRV/RTV 800/100 mgBID DRV/RTV 600/100 mg10010078.476.8808072.152.852.870.96060Pts With HIV-1 RNA < 50 copies/mL (%)Pts With HIV-1 RNA < 50 copies/mL (%)404020Difference in response, QD vs BID: ITT = 1.2% (95% CI: -6.1%, 8.5%)20n =22222472724812243648£ 50,000> 50,000WksScreening HIV-1 RNA (copies/mL)Similar CD4+ cell count increase between armsQD DRV/RTV : +100 cells/mm3BID DRV/RTV : +94 cells/mm3Cahn P, et al. CROI Abstract 57. Reproduced with permission.
42ODIN: Virologic Failure Not Statistically Different Between Arms Resistance Emergence in Pts With Virologic Failure and Paired Genotypes/PhenotypesQD DRV/RTV + OBRBID DRV/RTV + OBRDevelopment of new RAMs,* n (%)Primary PI1 (1.7)Any PI7 (11.7)4 (9.5)Loss of susceptibility,† n (%)Darunavir2 (3.4)*Patients with paired baseline/endpoint genotypes evaluated (n = 60 in QD arm and n = 42 in BID arm). †Patients with paired baseline/endpoint phenotypes evaluated (n = 59 in QD arm and n = 41 in BID arm).Cahn P, et al. CROI Abstract 57.
43ODIN: Significantly Lower Rate of Lipid Abnormalities With DRV/RTV QD vs BID AEs,* %QD DRV/RTV + OBR(n = 294)BID DRV/RTV + OBR(n = 296)P ValueSerious AEs5.49.1--Grade 2-4 treatment-emergent laboratory abnormalities*Total cholesterol†10.120.6< .0007LDL-C†9.816.7< .019Triglycerides5.211.0< .014*No significant differences in grade 3/4 AEs, AEs leading to treatment discontinuation, GI AEs, ALT levels, or AST levels.Cahn P, et al. CROI Abstract 57.
44VIKING: Second-Generation INSTI S/GSK1349572 in RAL-Resistant Patients International, multicenter, single-arm, phase II study in 27 patients with RAL resistanceS/GSK mg QD to replace RAL in failing regimen (or added if RAL already d/c) for 10 days of functional monotherapyDay 11-Wk 24: S/GSK mg QD continued and regimen optimizedMedian fold-change in RAL susceptibility at BL: (range: > 166)Median S/GSK572 FC at BL: 1.5 (range: )Stratified by BL integrase genotypeGroup 1: Q148 + ≥ 1 secondary resistance mutations (n = 9)Group 2: All others (N155H and Y143H pathways) and single mutations at Q148 (n = 18)HIV-1 RNA Response at Day 11Group 1 (n = 9)Group 2 (n = 18)< 400 c/mL or ≥ 0.7 log10 c/mL decline, %33100Change from baseline, log10 c/mL-0.72-1.82Day 1 FC to S/GSK572 highly predictive of Day 11 virologic response (r = 0.79; P < .001)Among 18 paired isolates evaluated on Day 1 and Day 11, no evidence of emergent RAL mutationsIn 17 subjects, < 2 FC in susceptibilityIn 1 subject, ~ 6 FC in susceptibilityEron J, et al. AIDS Abstract MOAB0105.
46ART in special populations: patients starting TB therapy for active disease CD4 cell countrecommendationType of ART/comments<350Recommend ART as soon as TB treatment toleratedEFV-based > NVP>350Recommend ART as soon as TB treatment tolerated (data insufficient)EFV-based >NVPunavailable
47SAPiT: Optimal Time to Initiate ART in HIV/TB-Coinfected Patients Early ARTART initiated during intensive or continuation phase of TB therapy(n = 429)HIV-infected patients diagnosed with TB and CD4+ cell count < 500 cells/mm3(N = 642)Sequential ARTART initiated after TB therapy completed(n = 213)ART, antiretroviral therapy; SAPiT, Starting Antiretrovirals at Three Points in Tuberculosis; TB, tuberculosis.One unanswered question in the context of patients who present with acute opportunistic infections has concerned the potential benefits associated with starting antiretroviral therapy promptly vs deferring antiretroviral therapy until after treatment of the opportunistic infection. The trial shown on this slide examined this question in the context of tuberculosis (TB). A previous study conducted by the ACTG demonstrated clinical benefits associated with starting antiretroviral therapy within the first few weeks of diagnosis for a variety of different opportunistic infections, particularly Pneumocystis carinii pneumonia, but patients with TB were excluded from that analysis.The South African SAPiT trial included 642 patients with CD4+ cell counts < 500 cells/mm3 who were recently diagnosed with TB. Patients were randomly assigned 2:1 to initiate antiretroviral therapy at some point during TB therapy, either during the initial intensive 2 months or the subsequent 4-month continuation phase, or to receive sequential therapy by initiating antiretrovirals after completing TB treatment. This analysis compared the pooled group of patients who received antiretroviral therapy during either the intensive or continuous phase of TB therapy vs those receiving sequential therapy.Primary endpoint: all-cause mortality
48SAPiT: Increased Survival With Concurrent HIV and TB Treatment 1.00Early ARTSequential ART0.950.90Survival0.850.80ART, antiretroviral therapy; SAPiT, Starting Antiretrovirals at Three Points in Tuberculosis; TB, tuberculosis.The curves shown on this slide describe survival during the course of intensive, continuous, and post‑TB treatment. The orange line represents patients who started antiretrovirals after completing TB therapy. It is clear that the survival curves of patients who received early vs sequential antiretroviral therapy diverged, but the divergence was greatest following completion of TB therapy. It is interesting that most of the survival difference between the 2 treatment groups seemed to occur somewhat late. As mentioned earlier, data assessing whether there is a survival difference between patients treated with antiretrovirals during the intensive phase vs the continuous phase of TB therapy are awaited.Intensive phase of TB treatment0.75Continuation phase of TB treatmentPost-TB treatment0.70123456789101112131415161718192021222324Months PostrandomizationAbdool Karim SS, et al. CROI Abstract 36a. Graphic reproduced with permission.
49Multivariate Adjusted HR (95% CI) Survival Probability, % (95% CI) CAMELIA: Survival With Early vs Late Therapy in TB-Coinfected Patients (CD4<200)Survival Probability, Early vs Late TherapyLog rank P = .0042Wks From TB Treatment InitiationProbability of Survival1.000.900.800.700.60Early arm wk 2Late arm wk 850100150200250Factors Independently Associated With MortalityFactorMultivariate Adjusted HR (95% CI)PLate therapy1.52 ( ).007BMI ≤ 161.68 ( ).01Karnofsky score ≤ 404.96 ( )< .001`Pulmonary + extrapulmonary TB2.26 ( )< .001NTM2.84 ( )MDR-TB8.02 ( )WkSurvival Probability, % (95% CI)PEarly ArmLate Arm50( )( ).07100( )( ).006150( )( ).002Significantly higher incidence of IRIS with early vs late HAART4.03 vs 1.44 per 100 person-mos, respectively (P < .0001)Blanc FX, et al. AIDS Abstract THLBB206. Graphic used with permission..
50ART in special populations: pregnant women Primarily consider mother’s need of ART and act accordingly (same as guidelines for adults)Used to prevent mother-to-infant transmission as wellAvoid EFV in first trimester (teratogenic)Prevention of MTCT: conflicting data on pros and cons of single dose NVP to mother and infant (negligible reduction in transmission in mothers who breastfeed, selection of resistance to non-nucleosidic RT inhibitors); same applies to other suboptimal therapies
51BAN Study: Both Regimens Equally Effective at Preventing Transmission Maternal HAART and infant NVP regimens both significantly reduced HIV-1 transmission by breastfeeding to infants at Wk 28Grade 3/4 adverse events generally comparable across arms, exceptSignificantly higher rate of neutropenia in women on maternal HAART vs control arm (6.7% vs 2.0%; P < .0001)Substantially higher number of hypersensitivity reactions in infants on NVP vs control arm (16 vs 0 events)Control0.08Maternal HAARTInfant NVP6.4%0.06Estimated Probability of Being HIV Positive0.043.0%0.021.8%0.001481216202428Age (Wks)Control vs maternal HAART: P = .0032Control vs infant NVP: P < .0001Maternal HAART vs infant NVP: P =.1203Chasela C, et al. IAS Abstract WELBC103.Graphic used with permission..
52WHO 2009 recommendations for PMTCT in mothers who do not need ART for their own health