1 / 47

Iniziare la terapia per poi personalizzarla: valutare ‘ il presente ’ a 360 gradi

Iniziare la terapia per poi personalizzarla: valutare ‘ il presente ’ a 360 gradi. Andrea Antinori 9 Maggio 2014. Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag. When to start cART? 2012-2014 Guidelines Update.

shel
Download Presentation

Iniziare la terapia per poi personalizzarla: valutare ‘ il presente ’ a 360 gradi

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Iniziare la terapia per poi personalizzarla: valutare ‘il presente’ a 360 gradi Andrea Antinori 9 Maggio 2014 Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag .

  2. When to start cART? 2012-2014 Guidelines Update • WHO consolidated guidelines onthe use of antiretroviral drugs for treating and preventing HIV infection. June 2013 • DHHS Guidelines 2013 Available at http://aidsinfo.nih.gov/guidelines • ARV Treatment of Adult HIV Infection. 2012 Recommendation of the IAS-USA panel. JAMA 2012;308:387-402. • EACS Guidelines 2013. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf. • Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1, 2013. Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf; • BHIVA Guidelines 2012-Updated 2013. HIV Medicine (2014), 15 (Suppl. 1), 1–85 • GESIDA. Documento de consenso de Gesida/Plan Nacional sobre el SIDA respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana. Actualización enero 2014 • CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

  3. NA-ACCORDMid-point life expectancyestimatesatage 20 years in threecalendarperiods, overall and by characteristics Life expectancy estimates for the general population at age 20 years in 2009 were 59.7 and 57.0 years for men and 63.9 and 61.7 years for women, in Canada and the U.S., respectively. Samji H, et al. PLoSOne, 2014

  4. HIV Outpatient Study (HOPS) Higher CD4 Count at ART Initiation Predicts Greater Long-Term Likelihood of CD4 Count Normalization • Progressively higher CD4 counts at ART initiation were associated with greater long-term CD4 gains, greater likelihood of achieving CD4 > 750 (“normalization”), increased unadjusted survival rates, higher CD4 at death, and decreased likelihood of deaths from both AIDS and non-AIDS causes. Median CD4 count, cells/mm3 ≥ 500 350-499 200-349 50-199 < 50 Palella F, et al. CROI 2014; Boston (MA). Abst.#560.

  5. Relationship between current CD4 and AIDS-defining illness with a CD4 count ≥500 cells/μLRelationship with current viral load and antiretroviral treatment. COHERE. A total of 12,135 ADIs occurred at a CD4 count of ≥200 cells/μL among 207,539 persons with 1,154,803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0–21.1 per 1000 PYFU) with current CD4 200-349 cells/μL to 4.1 per 1000 PYFU (95% CI, 3.6–4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/μL. Persons with a current CD4 of 500–749 cells/μL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10–1.32). Mocroft A, et al. Clin Infect Dis, 2013

  6. SPARTAC TrialPrimary end point according to interval between seroconversion and randomization 366 HIV individuals with PHI.Primary end pointwas a CD4+ count of lessthan 350 cells per cubicmillimeter or long-term ART initiation. The SPARTAC Trial Investigators, NEnglJMed, 2013

  7. Value of viremia copy years in deciding optimal timing of ART initiation in adults with HIV Using 2011 CASCADE data of individuals with well estimated dates of HIV seroconversion, we created a sequence of ‘trials’ in which individuals were classified as initiating or deferring ART. 6497 individuals contributed ≥1 baseline ‘trial’; 3089 (48%) initiated ART and 293 (5%) acquired AIDS/died. Figure. Adjusted hazard ratios for the effect of initiation vs. deferring ART on time from SC to AIDS/death by a) viremia copy years pooling CD4 stratum, b) viremia copy years with CD4<350 cells/mm3and c) viremia copy years with CD4≥350 cells mm3 Pooling CD4 strata, hazard ratios for the effect of initiating ART on time from seroconversion to AIDS/death decreased as VCYyear increased, with a 63% reduced risk of AIDS/death for those initiating ART when VCY exceeded 100,000. At CD4<350 cells/mm3, there was an overall reduction in the risk of AIDS/death in all VCY groups (all HR < 1) for those initiating vs. deferring ART with no evidence that this benefit varied by VCY (p=0.78). At CD4 ≥ 350 there was a trend for increasing benefit of initiation vs. deferral with increasing VCY, with the largest benefit seen in the VCY ≥ 100,000 c/mL group (HR, 95% CI= 0.56, 0.35-0.90, p(heterogeneity) = 0.16). Results were qualitatively similar for CD4 strata ≥ 500 cells mm3. Olson AD, et al. CROI 2014, Boston (MA). Abst.#558

  8. Four opportunities for HIV prevention The four stages of infection risk are listed at the top of the fi gure. Potential interventions during each stage are listed within each box. The timeline for the intervention is listed in the arrows below the intervention boxes. STD=sexually transmitted diseases. ART=antiretroviral therapy. PrEP=pre-exposure prophylaxis. TDF/FTC=tenofovir disoproxil fumarate co-formulated with emtricitabine. PEP=post-exposure prophylaxis. Cohen MS, et al. Lancet, 2013

  9. DHHS 2014Initiating Antiretroviral Therapy in Treatment-Naive Patients(Last updated May 1, 2014; last reviewed May 1, 2014)

  10. The Continuum of HIV Care in Various SettingsEngagement in HIV Care United States1 1,178,350 ~11,000 149,900 British Columbia, Canada2 100% 100 100 100 France3 • To achieve a reduction in HIV transmission, HAART programs must ensure the effectiveness and quality of a cascade of services from testing and referral to care to ensuring ongoing adherence to HAART2 • Large US cohorts have found that women, IVDU, younger and non-white patients were less likely to achieve virologic suppression, and may require targeted outreach along the cascade of care4,5,6 941,950 80% 86 81 80 79 725,302 74 60% 62 60 56 480,395 52 426,590 40% 45 41 328,475 36 32 28 20% Nodata 0% HIV-infected HIV-diagnosed Linked toHIV care Retained inHIV care On ART Suppressedviral load* *US ≤200 copies/mL, BC and France < 50 copies/mL 1. Adapted from CDC, MMWR 2011;60:1618-1623 2. Adapted from Nosyk B, et al. CROI 2013; Atlanta, GA. #1029 3. Costagliola D, et al. CROI 2013; Atlanta, GA. #1030 4. Althoff K, et al. CROI 2013; Atlanta, GA. #1026 5. Novak R, et al.CROI 2013; Atlanta, GA. #1032a 6. Horberg M, et al. CROI 2013; Atlanta, GA. #1033

  11. The model of HIV continuum of care 1. Acutely infected individuals flow into asymptomatic undiagnosed. 2. Asymptomatic individuals either receive a diagnosis before progressing to AIDS or do not. 1 2 4. Tested-eligible individuals can be lost to follow-up or not linked to treatment, or be linked to treatment and then either be virologically suppressed or not suppressed. 3 4 6 6. Undiagnosed and unlinked individuals progress to AIDS–never treated, from which they either die or present for treatment 5 5. Unsuppressed individuals move into a dead-end AIDS post-antiretroviral therapy compartment. 3. Tested, ineligible individuals eventually become eligible as their CD4 counts drop, but may be lost to follow up before attaining eligibility. Birger RB et al. ClinInfectDis, 2014

  12. What to Start: Comparison of Updated 2012-2014 Guidelines * Onlyif HIV-RNA <100.000 c/mL; # Onlyif HIV-RNA <100.000 c/mL and CD4 >200 cell/mm3. • Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1, 2013 Available at: http://www.salute.gov.it/imgs/C_17_pubblicazioni_1301_allegato.pdf; • DHHS Guidelines 2014 Available at http://aidsinfo.nih.gov/guidelines • ARV Treatment of Adult HIV Infection. 2012 Recommendation of the IAS-USA panel. JAMA 2012;308:387-402. • EACS Guidelines 2013. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf. • BHIVA Guidelines 2012-Updated 2013. HIV Medicine (2014), 15 (Suppl. 1), 1–85 • GESIDA. Documento de consenso de Gesida/Plan Nacional sobre el SIDA respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana. Actualización enero 2014 • CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013

  13. ABC/3TC vs. TDF/FTC: primary virologic endpoint(High viral load stratum at DSMB action) ACTG 5202 ABC/3TC vs TDF/FTC high viral load stratum Hazard Ratio ABC/3TC vs. TDF/FTC with HR 2.46 (95% CI 1.20, 5.25) EFV ATV/r HR 2.22 (95% CI, 1.19, 4.14) Favors ABC/3TC Favors TDF/FTC -4 1 5 Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB.

  14. Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or TDF/FTC, Even for High BL VL • In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG, including with high BL HIV-1 RNA* ABC/3TC TDF/FTC 81 86 91 100 72 88 82 76 64 80 60 HIV-1 RNA < 50 c/mL at Wk 48 by FDA Snapshot Analysis (%) 40 20 n/ N = 225/ 257 306/ 335 36/ 42 72/ 88 13/ 16 29/ 38 13/ 18 18/ 28 0 > 500K 250K - 500K 100K - < 250K < 100k Baseline HIV-1 RNA (c/mL) *Pooled data from both INSTIs. Eron J, et al. Glasgow 2012. Abstract P204.

  15. Snapshot at 48 weeks by baseline HIV-1 RNA and NRTI background therapy FavoursDRV/r FavoursDTG • DTG-based therapy showed statistical superiority in subjects with baseline HIV-1 RNA >100,000 c/mL overall and comparable efficacy independent of NRTI backbone through all viral load strata Baseline ≤100,000 c/mL n ABC/3TC at Day 1 134 89 88 TDF/FTC at Day 1 228 88 86 Baseline >100,000 c/mL ABC/3TC at Day 1 25 92 67 97 TDF/FTC at Day 1 94 71 –20 –10 0 10 20 30 40 50 60 Difference in proportion (DTG–DRV/r; unadjusted) Adapted from Clotet B, et al. Lancet, 2014

  16. Linee-guida CNA-SIMIT 2013Regimi raccomandati per l’inizio della cART

  17. DHHS 2014 – What to start(Last updated May 1, 2014; last reviewed May 1, 2014) Rating of Recommendations: A = Strong; B = Moderate; C = Optional Rating of Evidence: I = Data from randomizedcontrolled trials; II = Data from well-designednonrandomized trials or observationalcohort studies with long-termclinicaloutcomes; III = Expert Opinion

  18. What data do we have in treatment-naive patients ? NVP RPV EFV 2NN14 ECHO15 THRIVE16 PI NNRTI SINGLE20 STARTMRK1 Study 102*11 INSTI DTG RAL EVG/c‡ SPRING19 ACTG5257* ACTG5257* RPV FLAMINGO21 Study 10310 DRV/r ATV/r ArTen12 ATADAR8 ACTG 520213 CASTLE,4,5 ARTEMIS6,7 LPV/r ACTG 51422 Sierra-Madero3 • Adapted from: 1. Lennox JL, et al. Lancet 2009;374:796−806; 2. Riddler SA, et al. NEJM 2008;358:2095–106; 3. Sierra-Madero J, et al. JAIDS 2010;53:582–8; 4. Molina J-M, et al. Lancet 2008;372:646–55; 5. Molina J-M, et al. JAIDS 2010;53:323–32; 6. Ortiz R, et al. AIDS 2008;22:1389–97; 7. Mills AM, et al. AIDS 2009;23:1679─88; 8. Martínez E, et al. CROI 2013; Oral presentation 772; 9. Gallant JE, et al. JID 2013 [Epub ahead of print]; 10. DeJesus E, et al. Lancet 2012;379:2429–38; 11. Sax PE, et al. Lancet 2012;379:2439–48; 12. Soriano V, et al. Antivir Ther 2011;16:339–48; 13. Daar ES, et al. Ann Intern Med 2011;154:445–56; 14. van Leth F, et al. Lancet 2004;363:1253–63; 15. Molina J-M, et al. Lancet 2011;378:238–46; 16. Cohen CJ, et al. Lancet 2011;378:229–37; 17. European Medicines Agency http://www.ema.europa.eu (Accessed Apr 2013) 18. ATRIPLA SmPC Available at: http://www.ema.europa.eu Last updated 12/02/2013 (Accessed Apr 2013); 19. Raffi F, et all. Lancet Infect Dis. 2013 Nov;13(11):927-35; 20 Walmsley S et all. 52 ICAAC, September 9-12, 2012 H-556b; 21. Feinberg J et al. 52 ICAAC, September 9-12, 2012, H-1464a.

  19. Virologic Suppression at Wk 48 by Baseline HIV-1 RNA STARTMRK[1] SPRING-2[4] Difference, % (RAL-EFV) and 95% CI Difference, % (DTG-RAL) and 95% CI In favor of DTG In favor of EFV In favor of RAL In favor of RAL ≤100,000 c/mL ≤100,000 c/mL >100,000 c/mL >100,000 c/mL -20 -10 -20 0 20 30 -10 0 20 30 10 10 SINGLE[4] Study 102[2] Difference, % (DTG-EFV) and 95% CI Difference, % (EVG/COBI-EFV) and 95% CI In favor of DTG In favor of EFV In favor of EFV In favor of EVG/COBI ≤100,000 c/mL ≤100,000 c/mL >100,000 c/mL >100,000 c/mL -20 -10 5 15 -10 -15 -5 0 10 0 20 30 10 Study 103[3] FLAMINGO[5] • Difference , % (DTG-DRV/RTV) and 95% CI Difference, % (EVG/COBI-ATV/RTV) and 95% CI In favor of DRV/RTV In favor of DTG In favor of EVG/COBI In favor of ATV/RTV ≤100,000 c/mL ≤100,000 c/mL >100,000 c/mL >100,000 c/mL -20 -10 5 15 -15 -5 0 10 -10 0 20 30 40 10 1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet. 2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract H1464a.

  20. ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count RilpivirineEfavirenz 100 100 85 84 81 80 79 79 80 80 75 76 73 71 71 69 65 56 60 60 HIV-1 RNA < 50 copies/mL (%) 40 40 20 20 69 83 249 270 n = 368 329 n = 34 36 194 175 313 307 144 164 0 0 ≤ 100k > 100k -≤ 500k > 500k < 50 50 -< 200 200 - < 350 ≥ 350 By Baseline CD4+ Count (cells/mm3) By Baseline HIV-1 RNA (copies/mL) Cohen CJ, et al. AIDS. 2013;27:939-950.

  21. STaR: EPA vs. ATR – Week 96 EPA Maintains Significant Difference in Virologic Suppression vs. ATR at Low BLVL Through 96 Weeks Favours ATR Favours EPA BL HIV-1 RNA ≤100,000 c/mL >100,000 c/mL 7.2 1.1 13.4 W48 W96 0.2 7.6 15.1 p=0.046 -1.8 7.5 -11.1 W48 W96 1.5 -8.7 11.6 231/ 260 204/ 250 205/ 260 107/ 134 116/ 142 102/ 134 106/ 142 178/ 250 p=0.78 -12% 12% 0 Baseline HIV-1 RNA, c/mL BLVL = Baseline Viral Load Cohen C, et al. EACS 2013; Brussels, Belgium. #LBPE7/17

  22. VA Study: STR vs. MTRAdherence Results • *Calculated using pharmacy claims data [medication possession ratio (MPR)] = [sum of days supply to all HAART regimen components (excluding days of last fill)/last fill date-first fill date] X 100%; • **Odds ratio adjusted for covariates at study entry: age, race, geographic region, Charlson comorbidity index, mental health disorders, drug/alcohol abuse disorders, index year, treatment-naïve status, undetectable viral load HAART regimen patients (N=15,602) in VA cohorts evaluating the adherence and hospitalisation impact of receiving single-tablet regimen [STR (n=6,191)] or multiple tablet regimen [MTR; ≥2 tablets/day (n=9,411)] from Jan 2006 - July 2012 Adherence* results • At a threshold of ≥95%, a significantly higher proportion of STR vs. MTR patients were adherent (75.0% vs. 55.7%, P<0.001) • At 80% threshold STR vs. MTR: 90.0% vs. 77.5%, P<0.001 • After adjusting for covariates at study entry, STR patients were two times significantly more likely to be adherent compared to MTR patients [Odds ratio** (95% CI): ≥ 80%=2.16 (1.92,2.43); ≥95%=1.98(1.81,2.17)] Rao GA, et al. ICAAC 2013. Denver, CO. #H-1464

  23. Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with OD vs BID regimens. Meta-analysis of randomizedcontrolled trials. RCTscomparing once daily vs twice-daily ART regimensthatalsoreported on adherence and virologicalsuppressionwereincluded. Studyqualitywasratedusing the Cochranerisk-of-biastool. Nineteenstudiesmetinclusioncriteria (N = 6312 adultpatients). Antiretroviraltherapyadherence rate, virologicalresponse, and pillburden. Area of circleisproportional to the sample size. Blue, once-dailyregimens; orange, twice-dailyregimens. Nachega JB, et al. ClinInfectDis, 2014

  24. ACTG 5257Primary Endpoint Analyses at Wk 96 Virologic Failure Tolerability Failure Composite Endpoint • Significantly greater incidence of treatment failure with ATV/RTV vs RAL or DRV/RTV • In part due to high proportion of pts with hyperbilirubinemia • Considering both efficacy and tolerability, RAL superior to either boosted PI • DRV/RTV superior to ATV/RTV Favors RAL Favors RAL ATV/RTV vs RAL3.4% (-0.7 to 7.4) ATV/RTV vs RAL13% (9.4-16.0) ATVRTV vs RAL15% (10-20) Favors RAL DRV/RTV vs RAL3.6% (1.4-5.8) DRV/RTV vs RAL5.6% (1.3 -9.9) DRV/RTV vs RAL7.5% (3.2-12.0) Favors DRV/RTV Favors DRV/RTV ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3) ATV/RTV vs DRV/RTV9.2% (5.5-13.0) ATV/RTV vs DRV/RTV7.5% (2.3-13.0) -10 0 10 20 -10 0 10 20 -10 0 10 20 Difference in 96-Wk Cumulative Incidence (97.5% CI) • Regimens equivalent in time to VF Landovitz R, et al. CROI 2014, Boston (MA). Abst.#85

  25. Results: Primary endpoint incidence over 96 weeks was 17.4 % (RAL) vs. 13.7 % (FTC/TDF); adjusted absolute difference was 3.7% (non-inferior), upper 95% CI of 8.6% was below the pre-specified 9% margin. NEAT001/ANRS143. First Line RAL+DRV+RTV is Non-Inferior to FTC/TDF+DRV+RTV Primary Endpoint at Week 96 by Baseline Characteristics Primary Endpoint Overall analysis: RAL+DRV+RTV non inferior to TDF/FTC+DRV+RTV 8.6 -1.1 -3.9 3.5 -0.05 19.3 p = 0.09* 30.8 4.7 -3.4 6.3 p = 0.02* 9 -10 0 10 20 30 *Confirmed by a subsequent measurement Difference in Estimated Proportion(95% CO) RAL – FTC/TDF; Adjusted • In planned subgroup analysis the outcome for patients with low CD4 (<200/mm3) RAL+DRV+RTV was inferior to FTC/TDF+DRV+RTV • Comparable safety • Genotypic resistance: RAL (n=5) FTC/TDF (n=0) RaffiF,et al. CROI 2014; Boston (MA). Abst. #84LB

  26. ENCORE1A reduced dose of 400 mg efavirenz is non-inferior to the standard dose of 600 mg, when combined with TDF/FTC during 48 weeks in ART-naive adults with HIV-1 infection 630 patients (efavirenz 400=321; efavirenz 600=309). 32% were women; 37% were African, 33% were Asian, and 30% were white. The mean baseline CD4 cell count was 273 cells per μL (SD 99) and median plasma HIV-RNA was 4.75 log10 copies per mL (IQR 0.88). The proportion of participants with a viral load below 200 copies per mL at week 48 was 94.1% for efavirenz 400 mg and 92.2% for 600 mg (difference 1.85%, 95% CI −2.1 to 5.79). Encore1 Study Group, Lancet, 2014

  27. High rates of treatment modification or interruption in the first years of ART 21,801 patients from 18 cohorts in Europe and North America starting ART. Stacked Cumulative IncidenceFunctions of classchange, substitutionaddition of drugswithinclass, switch to nonstandardregimen, interruption and death, estimatedusingcompetingriskmethods. Figuresbelow the graph are the estimated cumulative incidence of eacheventat 1, 2 and 3 years, with 95% Cis. AbgrallS, et al. The ART Cohort Collaboration, AIDS, 2013

  28. Linee-guida CNA-SIMIT 2013Ottimizzazione della cART Il termine ottimizzazione della cART è utilizzato per indicare strategie finalizzate al miglior risultato possibile, attraverso switch terapeutici anche differenti fra loro e con scopi e razionali diversi, ma sempre in condizioni di soppressione virologica (HIV-RNA < 50 copie/mL). Sono immaginabili tre principali modalità di ottimizzazione: • Riduzione del numero di farmaci antiretrovirali; • Riduzione del numero di dosi/somministrazioni e di compresse giornaliere, ma sempre ricorrendo ad uno schema di triplice terapia; • Altre strategie di ottimizzazione, che ricorrono ad uno schema di triplice terapia, non necessariamente inquadrabili nel razionale del precedente punto. Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1. Novembre 2013

  29. Simplification of ARV therapy to a single tablet regimen consisting of EFV/FTC/TDF Percentage of patients with virologic response vs. HIV-1 RNA thresholds for the time to loss of virologic response (TLOVR) analysis. Black-shaded columns are patients randomized to the single tablet regimen of EFV/FTC/TDF; gray-shaded columns are patients randomized to SBR. De Jesus E, et al. J Acquir Immune Defic Syndr, 2009

  30. Efavirenz and chronic neuropsychiatric symptoms In 32 patientstreated with EFV and matchedcontrols, symptoms of depression, anxiety and stress wereassessed by the DepressionAnxiety and Stress Scale (DASS). Meanduration of the last ARV regimenwas 14+5 months for EFV group and 24+14 months in the control group. In the EFV group, 19 patients (58%) reportedunusualdreams in the past 7 dayscompared with 10 (32%) in the control group (P=0.049). No significantdifferenceswereobserved with regard to quality of sleep, number of awakenings per night or fatigue. Rihs TA, et al. HIV Med, 2006

  31. 92.1 RPV/FTC/TDF (delayed switch, W24 to W48) 6.6 1.3 SPIRIT. Virologic Suppression at Weeks 24 and 48 FDA Snapshot Analysis – ITT Population Switching to RPV/FTC/TDF was non-inferior* to remaining on PI+RTV+2NRTIs for 24 weeks (difference 3.8, 95% CI [-1.6, 9.1]). Similar rates of virologic suppression were also seen with 48 weeks of treatment with RPV/FTC/TDF FDA Snapshot at 24 Weeks FDA Snapshot at 48 Weeks 93.7 100 89.9 RPV/FTC/TDF (immediate switch, Day 1 to W24) RPV/FTC/TDF (immediate switch, Day 1 to W48) 90 PI+RTV+2NRTIs (delayed, Day 1 to W24) 80 70 60 Proportion of Subjects, % 50 40 30 20 5.4 5 5 10 0.9 0 Virologic Suppression Virologic Failure No Data (HIV-1 RNA <50 c/mL) CD4 count change (cells/mm3): Week 24, RPV/FTC/TDF immediate switch +20, PI+RTV+2NRTIs +32, RPV/FTC/TDF delayed switch -7. Week 48, RPV/FTC/TDF immediate switch +10

  32. STRATEGY-PI StudySwitching to E/C/F/TDF from PI+RTV+FTC/TDF resulted in significantly higher rates of virological suppression Primary end point: FDA Snapshot <50 copies/mLat 48 wks ArribasJ, et al. CROI 2014, Boston (MA). Abst.551LB

  33. The puzzle of emerging HIV-associated conditions (HANA) from High KP, et al. JAcquir Immune DeficSyndr, 2012

  34. Metabolic disease in HIV infection Metabolicdiseasesprobablydevelopat the intersection of traditionalriskfactors (suchasobesity, tobacco, and genetics) and HIV-specifi c and ART-specificcontributors (includingchronicinflammation and immune activation) Recent trials investigating the effects of antiretroviraltherapy on lipids Lake JE & Currier JS. Lancet InfectDis, 2013

  35. SPIRITChange in fasting lipids from baseline to week 24 and week 48 Palella F, et al. AIDS, 2014

  36. A5257. INSTI produced a more favorable lipid profile than ATVr or DRVr Mean of changes from Baseline in FastingLipidProfile (mg/dL) Over Time. Following ART initiation, fasting TG, non-HDL-C, and calculated LDL-C increased in the 2 RTV boosted PI arms, and decreased or remainedstable in the RAL arm. Allpairwisecomparisonsbetween the ATV/RTV or DRV/RTV arm and the RAL armshowedgreaterincreases with ATV/RTV or DRV/RTV treatment compared to RAL; no differencesbetween ATV/RTV and DRV/RTV treatment wereapparent. As-treated and sensitivityanalysesexcludingsubjects on lipidlowering agents didnotchangeresults. Ofotokun I, et al. CROI 2014, Boston (MA). Abst.#746

  37. Change from Baseline in Fasting Lipids Study 102 and 103 – Week 96 * STB vs ATR ^ STB vs ATV/r+TVD (P=0.001)* 25 0.6 (P=0.003)^ (P=0.064)* 20 18 16 16 0.4 15 (P=0.002)* 12 12 Median Change at Wk 96 (mg/dL) 11 (mmol/L) 8 10 8 8 6 0.2 5 4 5 0 0.0 Triglycerides Total Cholesterol LDL HDL STB ATR ATV/r + TVD No difference in change in TC to HDL ratio at Week 48 or 96

  38. D:A:D: MI rate Stratified by cumulative exposure to any ATV, ATV with ritonavir, and ATV without ritonavir The rate of MI varied from 2.80 (95% CI: 2.6, 23.0)/1000 PYFU in those with no exposure to ATV to 2.0 (1.2, 3.2)/1000 PYFU in those with >3 years exposure. MI rate/100 PYRS (95% CI) Years of exposure Any ATVPYFU 37005 ATV with RTVPYFU 31232 ATV without RTVPYFU 9611 d’Arminio Monforte A, et al. CROI 2012; Poster#823.

  39. ARV’s and the kidney Post F, 2013

  40. D:A:D Study. ARV Exposure (Per Year) and Incidence Rate Ratios of ceGFR ≤70 and CKD From eGFR >90 • Cumulative TDF (aIRR 1.18 [1.12-1.25] per year) and ATV/r (1.19 [1.09-1.32]) use were independently associated with increased rates of ceGFR ≤70 from eGFR >90, but not with CKD (eGFR <60), whereas lopinavir/r (LPV/r) use was associated with both endpoints (1.11 [1.05-1.17]) and 1.22 [1.16-1.28] respectively. Inconsistent trends were seen with abacavir use. Ryom L, et al. JInfectDis, 2013

  41. Ethnicity Family history Age KD Risk Hypertension HIV ART Diabetes Hepatitis C Risk factors for kidney disease in the HIV-positive population Decreased CD4 cell count Increased viral load = Modifiable = Non-modifiable Gupta et al. Clin Infect Dis 2005;40:1559–85.

  42. D:A:D Non-ARV Predictors of Advanced CKD/ESRD Univariate Multivariate Gender female vs male Ethnicity African vs Caucasian Poisson regression model adjusted for gender, ethnicity, HIV transmission group, enrolment cohort, Prior AIDS, HBV status*, HCV status*, smoking status*, hypertension*, diabetes*, cardiovascular events (CVE)*, baseline year, eGFR, age, current CD4 count*, CD4 Nadir, HIV-1 viral load (VL)*, and use of TDF, ATV/r, ATV, LPV/r, other PI/r and IND. Incidence rate-ratio, IRR. *time-updated. HIV transmission IDU vs MSM Prior AIDS yes vs no HBV posvsneg HCV posvsneg Hypertension yes vs no Diabetes yes vs no Prior CVE yes vs no Smoking non vs current eGFR per 10 ml/min lower Age per 10 years higher CD4 per doubling CD4 Nadir per 100 cells/mm3 higher VL per log10 higher 0.25 0.5 1 2 4 8 Advanced CKD/ESRD IRR (95%CI) Ryom L, et al. AIDS, 2014

  43. Lower chance to maintain viral suppression after switching to PI/r monotherapy Mathis S., et al. PLoSOne, 2011

  44. PIVOT. PI/r monotherapy switch strategy for long-term HIV management We randomised 587 patients who were followed for a median (maximum) of 44 (59) months; 2.7% withdrew or were lost-to follow up. In PIm, 80% selected DRV/r, 14% LPV/r, 7% other PI/r at randomisation. Patients were randomised to maintain ongoing triple therapy (OTT) or switch to a PI monotherapy strategy (PIm) using a ritonavir boosted PI (physician drug choice) with prompt re-introduction of NRTIs if unable to maintain VL suppression <50 copies/ml. Primary outcome: loss of future drug options, defined as new intermediate/high level resistance to ≥1 drug to which the patient’s virus was considered to be sensitive at trial entry Secondary outcomes: included serious disease complications (AIDS, serious non-AIDS, all-cause death), total grade 3/4 adverse events and neurocognitive function change (annual 5-test battery). Analysis: all analyses done as ITT. Tested hypothesis of non inferiority of PIm on the primary outcome, margin 10%. Paton N, et al. CROI 2014; Abst.#550LB

  45. More than 1 year of sustained viral suppression before switching to PI/r mono is related to lower risk of VF Guiguet M, et al. AIDS, 2012

  46. Guidelines Differ about PI/r Monotherapy Recommendations 1. EACS guidelines version 6.0, 2011. 2. Thompson MA, et al. JAMA. 2012;308(4):387-402. 3. DHHS guidelines, 2014. Italian Guidelines (National AIDS Commission, Ministry of Health-SIMIT), 2013

  47. Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag .

More Related