Iniziare la terapia per poi personalizzarla: valutare ‘ il presente ’ a 360 gradi
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Transcript of 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 Antinori9 Maggio 2014
Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag.
When to start cART? 2012-2014 Guidelines Update
1. WHO consolidated guidelines onthe use of antiretroviral drugs for treating and preventing HIV infection. June 20132. DHHS Guidelines 2013 Available at http://aidsinfo.nih.gov/guidelines 3. ARV Treatment of Adult HIV Infection. 2012 Recommendation of the IAS-USA panel. JAMA 2012;308:387-402.4. EACS Guidelines 2013. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf.5. 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; 6. BHIVA Guidelines 2012-Updated 2013. HIV Medicine (2014), 15 (Suppl. 1), 1–857. 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 20148. CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013
NA-ACCORDMid-point life expectancy estimates at age 20 years in three
calendar periods, overall and by characteristics
Samji H, et al. PLoS One, 2014
Life expectancy estimates for the general population at age 20 years in 2009 were59.7 and 57.0 years for men and 63.9 and 61.7 years for women, in Canada and the U.S., respectively.
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.
Palella F, et al. CROI 2014; Boston (MA). Abst.#560.
Med
ian
CD4
coun
t, ce
lls/m
m3
≥ 500350-499200-34950-199< 50
HIV Outpatient Study (HOPS)
Relationship between current CD4 and AIDS-defining illness with a CD4 count ≥500 cells/μL
Relationship 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
SPARTAC Trial
Primary end point according to interval between seroconversion and randomization
The SPARTAC Trial Investigators, N Engl J Med, 2013
366 HIV individuals with PHI.Primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation.
Value of viremia copy years in deciding optimal timing of ART initiation in adults with HIV
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.
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.
Olson AD, et al. CROI 2014, Boston (MA). Abst.#558
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 arelisted 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
DHHS 2014Initiating Antiretroviral Therapy in Treatment-Naive Patients
(Last updated May 1, 2014; last reviewed May 1, 2014)
Nodata
The Continuum of HIV Care in Various SettingsEngagement in HIV Care
• 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
1. Adapted from CDC, MMWR 2011;60:1618-16232. 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. #10265. Novak R, et al. CROI 2013; Atlanta, GA. #1032a 6. Horberg M, et al. CROI 2013; Atlanta, GA. #1033
*US ≤200 copies/mL, BC and France < 50 copies/mL
0%
20%
40%
60%
80%
100%
HIV-infected
HIV-diagnosed
Linked toHIV care
Retained inHIV care
On ART Suppressedviral load*
100 100 100
8086
81
62
79
41
56
74
3645
60
28 32
52
1,178,350 ~11,000 149,900
941,950
725,302
480,395426,590
328,475
United States1
British Columbia, Canada2
France3
10
The model of HIV continuum of care
Birger RB et al. Clin Infect Dis, 2014
1. Acutely infected individuals flow into asymptomatic undiagnosed.
2. Asymptomatic individuals either receive a diagnosis before progressing to AIDS or do not.
3. Tested, ineligible individuals eventually become eligible as their CD4 counts drop, but may be lost to follow up before attaining eligibility.
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.
5. Unsuppressed individuals move into a dead-end AIDS post-antiretroviral therapy compartment.
6. Undiagnosed and unlinked individuals progress to AIDS–never treated, from which they either die or present for treatment
What to Start: Comparison of Updated 2012-2014 GuidelinesRegimen CNA-SIMIT 20131 DHHS 20142 IAS 20123 EACS 20134 BHIVA 20135 GESIDA 20146 CNS-ANRS 20137
EFV/TDF/FTC Preferred Recommended Recommended Recommended Preferred Preferred Preferred
EFV + ABC/3TC Preferred* Recommended* Recommended* Recommended* Alternative* Alternative* Preferred*
NVP + TDF /FTC Alternative Not recommended Alternative Alternative Alternative Alternative Alternative
RPV + TDF/FTC Preferred* Recommended# Alternative Recommended* Alternative* Preferred* Preferred*
ATV/r + TDF/FTC Preferred Recommended Recommended Recommended Preferred Preferred Preferred
ATV/r + ABV/3TC Preferred* Recommended* Recommended* Recommended* Alternative* Preferred* Preferred*
DRV/r + TDF/FTC Preferred Recommended Recommended Recommended Preferred Preferred Preferred
DRV/r + ABV/3TC Preferred Alternative Alternative Recommended Alternative* Alternative Alternative
LPV/r + TDF/FTC Alternative Alternative Alternative Alternative Alternative Alternative Alternative
LPV/r + ABV/3TC Alternative Alternative Alternative Alternative Alternative* Alternative Alternative
RAL + TDF/FTC Preferred Recommended Recommended Recommended Preferred Preferred Alternative
RAL+ABV/3TC Preferred Alternative Recommended Alternative Preferred Alternative
EVG/COBI/TDF/FTC Preferred Recommended Alternative Preferred Preferred
DTG + TDF/FTC Preferred Recommended Preferred
DTG + ABV/3TC Preferred Recommended Preferred
* Only if HIV-RNA <100.000 c/mL; # Only if HIV-RNA <100.000 c/mL and CD4 >200 cell/mm3.
1. 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; 2. DHHS Guidelines 2014 Available at http://aidsinfo.nih.gov/guidelines 3. ARV Treatment of Adult HIV Infection. 2012 Recommendation of the IAS-USA panel. JAMA 2012;308:387-402.4. EACS Guidelines 2013. Available at http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf.5. BHIVA Guidelines 2012-Updated 2013. HIV Medicine (2014), 15 (Suppl. 1), 1–856. 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 20147. CNS-ANRS. Prise en charge médicale des personnes vivant avec le HIV. Rapport 2013
ABC/3TC vs. TDF/FTC: primary virologic endpoint(High viral load stratum at DSMB action)
Hazard Ratio
1 5-4 Favors TDF/FTCFavors ABC/3TC
ABC/3TC vs. TDF/FTC with
EFV
ATV/r HR 2.22 (95% CI, 1.19, 4.14)
HR 2.46 (95% CI 1.20, 5.25)
Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB.
ACTG 5202 ABC/3TC vs TDF/FTC high viral load stratum
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*
Eron J, et al. Glasgow 2012. Abstract P204.
< 100k 100K - < 250K 250K - 500K > 500K0
20
40
60
80
100
HIV
-1 R
NA
< 50
c/m
L at
Wk
48 b
y FD
A Sn
apsh
ot A
naly
sis
(%)
86
n/N =
88
225/257
91
306/335
36/42
82
72/88
81
13/16
76
29/38
72
13/18
64
18/28
Baseline HIV-1 RNA (c/mL)
TDF/FTCTDF/FTCABC/3TCABC/3TC
*Pooled data from both INSTIs.
DTG 50 mg QD
(%)
DRV/r800/100 mg
QD (%)
Baseline ≤100,000 c/mL
ABC/3TC at Day 1 TDF/FTC at Day 1
8988
Snapshot at 48 weeks by baseline HIV-1 RNA and NRTI background therapy
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
Adapted from Clotet B, et al. Lancet, 2014
Baseline >100,000 c/mL
ABC/3TC at Day 1TDF/FTC at Day 1
9294
6050403020100–10–20
FavoursDRV/r
FavoursDTG
n
134228
2597
8886
6771
Difference in proportion (DTG–DRV/r; unadjusted)
Linee-guida CNA-SIMIT 2013Regimi raccomandati per l’inizio della cART
DHHS 2014 – What to start(Last updated May 1, 2014; last reviewed May 1, 2014)
Rating of Recommendations: A = Strong; B = Moderate; C = OptionalRating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohortstudies with long-term clinical outcomes; III = Expert Opinion
What data do we have in treatment-naive patients ?
NVP
ARTEMIS 6,7
LPV/r
EFV
DRV/r
ACTG 51422
Sierra-Madero3
EVG/c‡
Study 102* 11
ArTen12
DTG
STARTMRK
1
ECHO15
THRIVE16
2NN14
ATV/r
CASTLE,4,5ACTG 520213
Stud
y 103
10
PI
NNRTI
INSTI
RALSPRING19
SINGLE20
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.
FLAMINGO 21
ATADAR8
RPV
ACTG52
57* ACTG5257 *
Virologic Suppression at Wk 48 by Baseline HIV-1 RNA
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.
≤ 100,000 c/mL> 100,000 c/mL
SPRING-2[4]
3020100-20 -10
Difference, % (DTG-RAL) and 95% CI
In favor of RAL In favor of DTG
≤ 100,000 c/mL> 100,000 c/mL
SINGLE[4]
3020100-20 -10
Difference, % (DTG-EFV) and 95% CI
In favor of DTGIn favor of EFV
Study 102[2]
FLAMINGO[5]
≤ 100,000 c/mL> 100,000 c/mL
3020100-20 -10
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DTGIn favor of DRV/RTV
40
≤ 100,000 c/mL> 100,000 c/mL
Difference, % (EVG/COBI-EFV) and 95% CI
In favor of EFV In favor of EVG/COBI
Study 103[3]
-15 -10 -5 5 10 150
≤ 100,000 c/mL > 100,000 c/mL
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
In favor of ATV/RTV In favor of EVG/COBI
≤ 100,000 c/mL> 100,000 c/mL
STARTMRK[1]
3020100-20 -10
Difference, % (RAL-EFV) and 95% CI
In favor of EFV In favor of RAL
-15 -10 -5 5 10 150
ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by Baseline VL and CD4+ Count
Cohen CJ, et al. AIDS. 2013;27:939-950.
HIV
-1 R
NA
< 50
cop
ies/
mL
(%)
By Baseline CD4+ Count (cells/mm3)
84
71
≤ 100k
Rilpivirine Efavirenz
8076
> 100k -≤ 500k
56
71
< 50
6975
50 -< 200
81 7985
79
200 - < 350
≥ 350
By Baseline HIV-1 RNA (copies/mL)
0
20
40
60
80
100
0
20
40
60
80
100
n = 368 329 249 270 n = 34 36 194 175 313 307 144 164
65
73
69 83
> 500k
STaR: EPA vs. ATR – Week 96 EPA Maintains Significant Difference in Virologic
Suppression vs. ATR at Low BLVL Through 96 Weeks
BLVL = Baseline Viral Load
BL HIV-1 RNA
≤100,000 c/mL
>100,000 c/mL
7.6
Baseline HIV-1 RNA, c/mL
231/260231/260
204/250204/250
107/134107/134
116/142116/142
205/260
178/250
102/134
106/142
0-12% 12%
FavoursATR
FavoursEPA
7.21.1 13.4
0.2 15.1W48
W96 p=0.046p=0.046
-11.1 -1.8 7.5
-8.7 1.5 11.6W48
W96p=0.78p=0.78
Cohen C, et al. EACS 2013; Brussels, Belgium. #LBPE7/17
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-1464Rao GA, et al. ICAAC 2013. Denver, CO. #H-1464
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
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.
Antiretroviral therapy adherence rate, virological response, and pill burden. Area of circle is proportional to the sample size. Blue, once-daily regimens; orange, twice-daily regimens.
Meta-analysis of randomized controlled trials. RCTs comparing once daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study quality was rated using the Cochrane risk-of-bias tool.Nineteen studies met inclusion criteria (N = 6312 adult patients).
Nachega JB, et al. Clin Infect Dis, 2014
ACTG 5257Primary Endpoint Analyses at Wk 96
• Regimens equivalent in time to VF
Landovitz R, et al. CROI 2014, Boston (MA). Abst.#85
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
Virologic Failure Tolerability Failure Composite Endpoint
Difference in 96-Wk Cumulative Incidence (97.5% CI)
0-10 10 20
ATV/RTV vs RAL3.4% (-0.7 to 7.4)
DRV/RTV vs RAL5.6% (1.3 -9.9)
ATV/RTV vs DRV/RTV-2.2% (-6.7 to 2.3)
0-10 10 20
ATVRTV vs RAL15% (10-20)
DRV/RTV vs RAL7.5% (3.2-12.0)
ATV/RTV vs DRV/RTV7.5% (2.3-13.0)
Favors RAL
Favors DRV/RTV
Favors RAL
0-10 10 20
ATV/RTV vs RAL13% (9.4-16.0)
DRV/RTV vs RAL3.6% (1.4-5.8)
ATV/RTV vs DRV/RTV9.2% (5.5-13.0)
Favors RAL
Favors DRV/RTV
NEAT001/ANRS143. First Line RAL+DRV+RTV is Non-Inferior to FTC/TDF+DRV+RTV
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.
Raffi F,et al. CROI 2014; Boston (MA). Abst. #84LB
RAL+ DRV+RTV
FTC/TDF +DRV+RTV
N 401 404
N with primary endpoint 76 (19%) 61 (15%)
V1. Regiment change for insufficient response
<1 log10 c/ml HIV RNA reduction W18* 1 0
HIV RNA ≥400 c/ml W24* 1 0
V2. HIV RNA ≥50 c/ml at W32* 27 28
V3. HIV RNA ≥50 c/ml after W32* 32 22
C1. Death 3 1
C2. AIDS event 5 3
C3. SNAIDS event 7 7
*Confirmed by a subsequent measurement
Primary EndpointPrimary Endpoint at Week 96 by
Baseline Characteristics
RAL+ DRV+RTV
FTC/TDF +DRV+RTV
Overall n = 805 17.4% 13.7%
Baseline HIV-1 RNA
<100,000 c/ml n = 530 7% 7%
≥100,000 c/ml n = 275 36% 27%
Baseline CD4+
<200/mm3 n = 123 39.0% 21.3%
≥200/mm3 n = 682 13.6% 12.2%
Overall analysis: RAL+DRV+RTV non inferior to TDF/FTC+DRV+RTV
-10 0 10 20 30
-3.4 6.3
4.7 30.8
-0.05 19.3
-3.9 3.5
-1.1 8.6
Difference in Estimated Proportion(95% CO) RAL – FTC/TDF; Adjusted
9
p = 0.09*
p = 0.02*
• 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)
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
High rates of treatment modification or interruption in the first years of ART
Abgrall S, et al. The ART Cohort Collaboration, AIDS, 2013
21,801 patients from 18 cohorts in Europe and North America starting ART.
Stacked Cumulative Incidence Functions of class change, substitution addition of drugs within class, switch to nonstandard regimen, interruption and death, estimated using competing risk methods.
Figures below the graph are the estimated cumulative incidence of each event at 1, 2 and 3 years, with 95% Cis.
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
Simplification of ARV therapy to a single tablet regimen consisting of EFV/FTC/TDF
De Jesus E, et al. J Acquir Immune Defic Syndr, 2009
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.
Efavirenz and chronic neuropsychiatric symptoms
In 32 patients treated with EFV and matched controls, symptoms of depression, anxiety and stress were assessed by the Depression Anxiety and Stress Scale (DASS). Mean duration of the last ARV regimen was 14+5 months for EFV group and 24+14 months in the control group.
In the EFV group, 19 patients (58%) reported unusual dreams in the past 7 days compared with 10 (32%) in the control group (P=0.049). No significant differences were observed with regard to quality of sleep, number of awakenings per night or fatigue.
Rihs TA, et al. HIV Med, 2006
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
SPIRIT. Virologic Suppression at Weeks 24 and 48 FDA Snapshot Analysis – ITT Population
RPV/FTC/TDF (immediate switch, Day 1 to W48)RPV/FTC/TDF (immediate switch, Day 1 to W48)
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
Prop
ortio
n of
Sub
ject
s, %
(HIV-1 RNA <50 c/mL)(HIV-1 RNA <50 c/mL)
RPV/FTC/TDF (immediate switch, Day 1 to W24)RPV/FTC/TDF (immediate switch, Day 1 to W24)
PI+RTV+2NRTIs (delayed, Day 1 to W24)PI+RTV+2NRTIs (delayed, Day 1 to W24)
0.95.4
RPV/FTC/TDF (delayed switch, W24 to W48)RPV/FTC/TDF (delayed switch, W24 to W48)
92.1
1.36.65 5
93.789.9
0102030405060708090
100
Virologic Suppression Virologic Failure
No Data
FDA Snapshot at 24 Weeks FDA Snapshot at 48 Weeks
STRATEGY-PI Study
Switching to E/C/F/TDF from PI+RTV+FTC/TDF resulted in significantly higher rates of virological suppression
Arribas J, et al. CROI 2014, Boston (MA). Abst.551LB
Primary end point: FDA Snapshot <50 copies/mL at 48 wks
The puzzle of emerging HIV-associated conditions (HANA)
from High KP, et al. J Acquir Immune Defic Syndr, 2012
Metabolic disease in HIV infection
Recent trials investigating the effects of antiretroviral therapy on lipids
Metabolic diseases probably develop at the intersection of traditional risk factors (such as obesity, tobacco, and genetics) and HIV-specifi c and ART-specific contributors (including chronic inflammation and immune activation)
Lake JE & Currier JS. Lancet Infect Dis, 2013
SPIRIT
Change in fasting lipids from baseline to week 24 and week 48
Palella F, et al. AIDS, 2014
A5257. INSTI produced a more favorable lipid profile than ATVr or DRVr
Following ART initiation, fasting TG, non-HDL-C, and calculated LDL-C increased in the 2 RTV boosted PI arms, and decreased or remained stable in the RAL arm.All pairwise comparisons between the ATV/RTV or DRV/RTV arm and the RAL arm showed greater increases with ATV/RTV or DRV/RTV treatment compared to RAL; no differences between ATV/RTV and DRV/RTV treatment were apparent.As-treated and sensitivity analyses excluding subjects on lipid lowering agents did not change results.
Mean of changes from Baseline in Fasting Lipid Profile (mg/dL) Over Time.
Ofotokun I, et al. CROI 2014, Boston (MA). Abst.#746
Change from Baseline in Fasting Lipids Study 102 and 103 – Week 96
0
5
10
15
20
25
0.0
0.2
0.4
0.6
Med
ian
Ch
ang
e at
W
k 96
(mg
/dL
)
(mm
ol/L
)
Total Cholesterol
LDL HDL Triglycerides
ATV/r + TVDSTB
(P=0.001)*
(P=0.064)*
(P=0.002)*
* STB vs ATR
(P=0.003)^
0
5
10
15
20
25
0.0
0.2
0.4
0.6
Med
ian
Chan
ge a
t W
k 96
(mg/
dL) (mm
ol/L)
ATR
12
18
8
12
16
11
68
54
8
16
^ STB vs ATV/r+TVD
No difference in change in TC to HDL ratio at Week 48 or 96
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 r
ate/
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.
ARV Alteration of renal function (generally not treatment-limiting)
Treatment-limiting renal disease
TDF • Tubular dysfunction• Rapid eGFR decline • Proteinuria (non-glomerular)• Incident CKD
• AKI (rare)• Tubulo-interstitial nephritis (rare)• Tubular disease/FS (uncommon)• CKD with progressive eGFR decline
ATV/r • Inhibition of creatinine secretion• Tubular dysfunction• Rapid eGFR decline• Incident CKD
• AKI (rare)• Tubulo-interstitial nephritis (rare)• Nephrolithiasis (uncommon)• CKD with progressive eGFR decline
LPV/r • Incident CKD/CKD progression • None reportedCOBI/EVG • Inhibition of creatinine secretion • AKI (rare)
• Tubular disease/FS (uncommon)
COBI/ATV • Inhibition of creatinine secretion • AKI (rare)• Tubular disease/FS (uncommon)
DTG • Inhibition of creatinine secretion • None reported
RPV • Inhibition of creatinine secretion • None reported
ARV’s and the kidney
Post F, 2013
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. J Infect Dis, 2013
AgeFamily history
ART Diabetes
HIV Hypertension
Hepatitis C
Ethnicity
KD Risk
= Modifiable= Non-modifiable
Risk factors for kidney disease in the HIV-positive population
Gupta et al. Clin Infect Dis 2005;40:1559–85.
Decreased CD4 cell count Increased viral load
D:A:D Non-ARV Predictors of Advanced CKD/ESRD
Gender female vs male
Ethnicity African vs Caucasian
HIV transmission IDU vs MSM
Prior AIDS yes vs no
HBV pos vs neg
HCV pos vs neg
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
Univariate Multivariate
0.25 0.5 1 2 4 8Advanced CKD/ESRD IRR (95%CI)
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.
Ryom L, et al. AIDS, 2014
Lower chance to maintain viral suppression after switching to PI/r monotherapy
Mathis S., et al. PLoS One, 2011
PIVOT. PI/r monotherapy switch strategy for long-term HIV management
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%.
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.
Paton N, et al. CROI 2014; Abst.#550LB
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
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), 20131. 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
Guidelines Differ about PI/r Monotherapy Recommendations
Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag.