Transcript Le opzioni di terapia e il follow

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
CD4
cells/m
m3
WHO 131
DHHS 132
IAS-USA 123
EACS 134
CNA-SIMIT
135
BHIVA 136
GESIDA 147
CNS-ANRS 138
AIDS-defining
or symptoms
Any
value
Treat (AI)
Treat (AI)
Treat (AI)
Treat
Treat (AI)
Treat (AI)
Treat (AI)
Treat (AI)
Pregnancy
Any
value
Treat (AI)
Treat (AI)
Treat (AI)
Treat
Treat (AI)
Treat (AI)
Treat (AI)
Treat (AI)
HBV, HCV
Any
value
Treat HBV
(AIII)
Treat (AI-II)
Treat
(AII/CIII)
Treat or
consider only
if CD4
<500/mm3
Treat (AI-II)
Treat or
consider only
if CD4
<500/mm3
Treat (AII)
Treat (AIII)
Other clinical
conditions
Any
value
TB
HIVAN
HIVAN
HIVAN,
Malignancies,
HAND
HIVAN,
Malignancies,
HAND, CVD
HIVAN,
Malignancies,
HAND
HIVAN,
Malignancies,
HAND, CVD
Malignancies
Asymptomatic
<350
Treat (AI)
Treat (AI)
Treat (AI)
Treat
Treat (AI)
Treat (AI)
Treat (AI)
Treat (AI)
Asymptomatic
350–
500
Treat (AII)
Treat (AII)
Treat (AI)
Consider
treatment
Treat (AII)
Generally
defer
Treat (AII)
Treat (AII)
Asymptomatic
>500
Defer
Treat as
moderate
(BIII)
Treat as
moderate
(BIII)
Consider
treatment
Treat only on
individual
basis (AII/BIII)
Generally
defer
Treat as
moderate
(BIII)
Treat as
moderate
(BIII)
Prevent sexual
transmission
Any
value
Treat (AI-II)
Consider
treatment
Treat PHI
(BIII)
Consider
treatment
Treat (AI-II)
Consider
(GPP)
Treat (AI-II)
Treat (AI/BIII)
Clinical
category
1.
2.
3.
4.
5.
6.
7.
8.
Treat (AI)
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
NA-ACCORD
Mid-point life expectancy estimates at age 20 years in three
calendar periods, 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. PLoS One, 2014
HIV Outpatient Study (HOPS)
Median CD4 count, cells/mm3
Higher CD4 Count at ART Initiation Predicts Greater LongTerm Likelihood of CD4 Count Normalization
•
≥ 500
350-499
200-349
50-199
< 50
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.
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
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.
The SPARTAC Trial Investigators, N Engl J Med, 2013
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
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
DHHS 2014
Initiating Antiretroviral Therapy in Treatment-Naive Patients
(Last updated May 1, 2014; last reviewed May 1, 2014)
The Continuum of HIV Care in Various Settings
Engagement in HIV Care
United States1
British Columbia, Canada2
France3
1,178,350 ~11,000 149,900
100%
100 100 100
80%
941,950
80
86
81
60%
725,302
79
74
62
480,395
40%
41
20%
0%
56
60
426,590
45
36
No
data
HIVinfected
HIVdiagnosed
Linked to
HIV care
Retained in
HIV care
On ART
52
328,475
28 32
Suppressed
viral load*
•
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
*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
1
0
The model of HIV continuum of care
2. Asymptomatic individuals
either receive a diagnosis
before progressing to AIDS or
do not.
6. Undiagnosed and
unlinked individuals
progress to AIDS–
never treated, from
which they either
die or present for
treatment
1. Acutely infected individuals flow
into asymptomatic undiagnosed.
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. Clin Infect Dis, 2014
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 postantiretroviral therapy
compartment.
What to Start: Comparison of Updated 2012-2014 Guidelines
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
Regimen
* Only if HIV-RNA <100.000 c/mL; # Only if HIV-RNA <100.000 c/mL and CD4 >200 cell/mm3.
1.
2.
3.
4.
5.
6.
7.
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
ACTG 5202 ABC/3TC vs TDF/FTC high viral load stratum
ABC/3TC vs. TDF/FTC: primary virologic endpoint
(High viral load stratum at DSMB action)
Hazard Ratio
ABC/3TC vs. TDF/FTC with
EFV
HR 2.46 (95% CI 1.20, 5.25)
ATV/r
HR 2.22 (95% CI, 1.19, 4.14)
-4
Favors ABC/3TC
Daar, E. et al. 17th CROI, San Francisco, CA, 2010, presentation 59LB.
1
Favors TDF/FTC
5
Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or
TDF/FTC, Even for High BL VL
HIV-1 RNA < 50 c/mL at Wk 48 by FDA
Snapshot Analysis (%)
• In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or DTG,
including with high BL HIV-1 RNA*
ABC/3TC
100
88
91
TDF/FTC
81
86
82
76
72
64
80
60
40
20
n/
N=
0
225/
257
306/
335
< 100k
36/
42
72/
88
100K - < 250K
13/
16
29/
38
250K - 500K
Baseline HIV-1 RNA (c/mL)
*Pooled data from both INSTIs.
Eron J, et al. Glasgow 2012. Abstract P204.
13/
18
18/
28
> 500K
Snapshot at 48 weeks by baseline
HIV-1 RNA and NRTI background therapy
Favours Favours
DRV/r
DTG
Baseline ≤100,000 c/mL
ABC/3TC at Day 1
TDF/FTC at Day 1
DTG
50 mg QD
(%)
DRV/r
800/100 mg
QD (%)
134
228
89
88
88
86
25
97
92
94
67
71
n
Baseline >100,000 c/mL
ABC/3TC at Day 1
TDF/FTC at Day 1
–20
–10
0
10
20
30
40
50
60
Difference in proportion (DTG–DRV/r; unadjusted)
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
Linee-guida CNA-SIMIT 2013
Regimi 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 = Optional
Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials or observational cohort
studies with long-term clinical outcomes; III = Expert Opinion
What data do we have in treatment-naive patients ?
PI
RPV
ECHO15
2NN14
NNRTI
NVP
EFV
THRIVE16
INSTI
STARTMRK1
DTG
SPRING19
RAL
DRV/r
EVG/c‡
ATV/r
ATADAR8
LPV/r
ArTen12
ACTG 520213
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.
Virologic Suppression at Wk 48 by Baseline HIV1 RNA
STARTMRK[1]
SPRING-2[4]
Difference, % (RAL-EFV) and 95% CI
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
-20
Difference, % (DTG-RAL) and 95% CI
-10
0
20
10
Difference, % (EVG/COBI-EFV) and 95% CI
-15 -10
In favor of EVG/COBI
-5
0
5
30
-20
-10
10
15
-5
In favor of EVG/COBI
0
5
20
30
In favor of DTG
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
0
10
20
30
FLAMINGO[5]
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
-15 -10
10
Difference, % (DTG-EFV) and 95% CI
Study 103[3]
In favor of ATV/RTV
≤ 100,000 c/mL
> 100,000 c/mL
0
SINGLE[4]
Study 102[2]
In favor of EFV
≤ 100,000 c/mL
> 100,000 c/mL
In favor of DTG
In favor of RAL
≤ 100,000 c/mL
> 100,000 c/mL
In favor of RAL
10
15
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DRV/RTV
≤ 100,000 c/mL
> 100,000 c/mL
-20
-10
In favor of DTG
0
10
20
30
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;379:24292438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract H1464a.
40
ECHO/THRIVE Post Hoc Analysis: Wk 96 Efficacy by
Baseline VL and CD4+ Count
Rilpivirine
HIV-1 RNA < 50 copies/mL (%)
100
84
80
80
71
Efavirenz
76
100
73
80
69
65
60
60
40
40
20
20
0
n = 368 329
249 270
≤ 100k
69 83
> 100k > 500k
≤ 500k
By Baseline HIV-1 RNA
(copies/mL)
Cohen CJ, et al. AIDS. 2013;27:939-950.
0
71
75
81 79
85
79
56
n = 34 36
< 50
194 175
313 307
144 164
50 200 ≥ 350
< 200
< 350
By Baseline CD4+ Count (cells/mm3)
STaR: EPA vs. ATR – Week 96
EPA Maintains Significant Difference in Virologic
Suppression vs. ATR at Low BLVL Through 96 Weeks
RPV/FTC/TDF at Week 48
RPV/FTC/TDF at Week 96
100
EFV/FTC/TDF at Week 48
EFV/FTC/TDF at Week 96
89
HIV-1 RNA <50 c/mL , %
82
80
80
79
82
76
71
75
Favours
ATR
Favours
EPA
BL HIV-1 RNA
60
≤100,000 c/mL
W48
W96
40
1.1
7.2
0.2
7.6
13.4
15.1
p=0.046
>100,000 c/mL
20
0
W48
231/ 204/ 205/ 178/
260 250 260 250
≤100K
107/ 116/
134 142
102/ 106/
134 142
>100K
W96
-11.1
-1.8
1.5
-8.7
-12%
7.5
11.6
p=0.78
0
12%
Baseline HIV-1 RNA, c/mL
Cohen C, et al. EACS 2013; Brussels, Belgium. #LBPE7/17
BLVL = Baseline Viral Load
VA Study: STR vs. MTR
Adherence Results
100%
STR
90.0%
77.5%
80%
% of Patients
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)]
MTR
75.0%
55.7%
60%
40%
20%
0%
≥80%
≥95%
Adherence Threshold
*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
Rao GA, et al. ICAAC 2013. Denver, CO. #H-1464
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 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).
Antiretroviral therapy
adherence rate,
virological response, and
pill burden. Area of circle
is proportional to the
sample size. Blue, oncedaily regimens; orange,
twice-daily regimens.
Nachega JB, et al. Clin Infect Dis, 2014
ACTG 5257
Primary Endpoint Analyses at Wk 96
Virologic Failure
•
Regimens equivalent in
time to VF
Tolerability Failure

Significantly greater
incidence of treatment
failure with ATV/RTV vs
RAL or DRV/RTV
–
In part due to high
proportion of pts with
hyperbilirubinemia
20
Favors RAL
ATVRTV vs RAL
15% (10-20)
Favors RAL
DRV/RTV vs RAL
7.5% (3.2-12.0)
Favors DRV/RTV
ATV/RTV vs DRV/RTV
7.5% (2.3-13.0)
Favors DRV/RTV
ATV/RTV vs DRV/RTV
9.2% (5.5-13.0)
ATV/RTV vs DRV/RTV
-2.2% (-6.7 to 2.3)
10

Considering both efficacy
and tolerability, RAL
superior to either boosted
PI
DRV/RTV superior to
ATV/RTV
DRV/RTV vs RAL
3.6% (1.4-5.8)
DRV/RTV vs RAL
5.6% (1.3 -9.9)
0

Favors RAL
ATV/RTV vs RAL
13% (9.4-16.0)
ATV/RTV vs RAL
3.4% (-0.7 to 7.4)
-10
Composite Endpoint
-10
0
10
20
-10
0
10
20
Difference in 96-Wk Cumulative Incidence (97.5% CI)
Landovitz R, et al. CROI 2014, Boston (MA). Abst.#85
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.
Primary Endpoint at Week 96 by
Baseline Characteristics
Primary Endpoint
Overall analysis: RAL+DRV+RTV non inferior to TDF/FTC+DRV+RTV
N
N with primary endpoint
RAL+ DRV+
RTV
FTC/TDF
+DRV+RTV
401
404
76 (19%)
61 (15%)
V1. Regiment change for insufficient response
1
0
<100,000 c/ml
n = 530 -3.9
HIV RNA ≥400 c/ml W24*
1
0
≥100,000 c/ml
n = 275 -0.05
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
8.6
-1.1
<1 log10 c/ml HIV RNA reduction W18*
27
•
•
n = 805
FTC/TDF
+DRV+RTV
17.4%
13.7%
Baseline HIV-1 RNA
V2. HIV RNA ≥50 c/ml at W32*
•
Overall
RAL+
DRV+
RTV
7%
3.5
19.3
36%
7%
27%
p = 0.09*
Baseline CD4+
30.8
4.7
<200/mm3
n = 123
≥200/mm3
n = 682 -3.4 6.3
39.0%
21.3%
13.6%
12.2%
p = 0.02*
9
-10
0
10
20
30
Difference in Estimated Proportion
In planned subgroup analysis the outcome for patients with low
(95% CO) RAL – FTC/TDF; Adjusted
3
CD4 (<200/mm ) RAL+DRV+RTV was inferior to
FTC/TDF+DRV+RTV
Comparable safety
Raffi F,et al. CROI 2014; Boston (MA). Abst. #84LB
Genotypic resistance: RAL (n=5) FTC/TDF (n=0)
ENCORE1
A 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
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.
Abgrall S, et al. The ART Cohort Collaboration, AIDS, 2013
Linee-guida CNA-SIMIT 2013
Ottimizzazione 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
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
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
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
Proportion of Subjects, %
100
93.7
89.9 92.1
FDA Snapshot at 48 Weeks
RPV/FTC/TDF
(immediate switch, Day 1 to W24)
90
80
RPV/FTC/TDF
(immediate switch, Day 1 to W48)
PI+RTV+2NRTIs
(delayed, Day 1 to W24)
70
60
RPV/FTC/TDF
(delayed switch, W24 to W48)
50
40
30
20
10
0
0.9
Virologic Suppression
(HIV-1 RNA <50 c/mL)
5
Virologic
Failure
1.3
5.4 5
6.6
No Data
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
STRATEGY-PI Study
Switching 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/mL at 48 wks
Arribas J, et al. CROI 2014, Boston (MA). Abst.551LB
The puzzle of emerging HIV-associated
conditions (HANA)
from High KP, et al. J Acquir Immune Defic Syndr, 2012
Metabolic disease in HIV infection
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)
Recent trials investigating the effects of antiretroviral therapy on lipids
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
Mean of changes from Baseline in Fasting Lipid Profile (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 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.
Ofotokun I, et al. CROI 2014, Boston (MA). Abst.#746
Change from Baseline in Fasting Lipids
Study 102 and 103 – Week 96
* STB vs ATR
12
12
11
0.4
(P=0.002)*
8
8
6
5
0.2
5
0
0.0
Total
Cholesterol
LDL
(P=0.003)^
20
16
0.4
15
10
5
8
0.0
Triglycerides
ATR
ATV/r + TVD
No difference in change in TC to HDL ratio at Week 48 or 96
0.2
4
0
HDL
STB
0.6
(mmol/L)
16
Median Change at Wk 96
(mg/dL)
18
15
10
0.6
(P=0.064)*
20
STB vs ATV/r+TVD
25
(mmol/L)
Median Change at Wk 96
(mg/dL)
25
^
(P=0.001)*
D:A:D: MI rate
MI rate/100 PYRS (95% CI)
Stratified by cumulative exposure to any ATV, ATV with ritonavir, and ATV without ritonavir
Years of exposure
Any ATV
PYFU 37005
ATV with RTV
PYFU 31232
ATV without RTV
PYFU 9611
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.
d’Arminio Monforte A, et al. CROI 2012; Poster#823.
ARV’s and the kidney
ARV
Alteration of renal function
(generally not treatment-limiting)
• Tubular dysfunction
• Rapid eGFR decline
• Proteinuria (non-glomerular)
• Incident CKD
Treatment-limiting renal disease
•
•
•
•
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
COBI/EVG
•
•
Incident CKD/CKD progression
Inhibition of creatinine secretion
•
•
•
None reported
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
TDF
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
Risk factors for kidney disease in the HIVpositive population
Ethnicity
Family
history
Age
Decreased CD4 cell count
Increased viral load
HIV
KD Risk
ART
= Modifiable
= Non-modifiable
Hypertension
Diabetes
Hepatitis C
Gupta et al. Clin Infect Dis 2005;40:1559–85.
D:A:D Non-ARV Predictors of
Advanced CKD/ESRD
Univariate
Multivariate
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
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.
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
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
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
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
Guidelines Differ about PI/r Monotherapy
Recommendations
Guidelines
EACS 2013[1]
PI/r monotherapy with qd DRV/r or bd LPV/r might represent an option in persons with
intolerance to NRTIs or for treatment simplification or in illicit drug users with documented
frequent interruption of cART. Such a strategy only applies to persons without history of
failure on prior PI-based therapy and who have had HIV-VL < 50 copies/mL in at least the
past 6 months and who do not have chronic HBV.
IAS-USA 2012[2]
Ritonavir-boosted protease inhibitor monotherapy is associated with an increased risk of
virologic failure and is not recommended when other options are available (A1a).
DHHS 2014[3]
The rationale for this strategy is to avoid NRTI toxicities and decrease costs, while taking
advantage of the high barrier to resistance of RTV-boosted PIs. RTV-boosted PI
monotherapy maintains virologic suppression in most patients, but at slightly lower rates
than standard therapy that includes 2 NRTIs. Low-level viremia,
generally without the emergence of PI resistance, appears to be more common with
monotherapy. There are rare reports of central nervous system virologic escape, sometimes
with clinical symptoms, in patients on RTV-boosted PI monotherapy. On the basis of the
results from these studies, RTV-boosted PI monotherapy should generally be avoided.
ITA CNA-SIMIT 2013[4]
Simplification to monotherapy with PI/r (DRV/r or LPV/r) in the case of toxicity [AI] or
prevention NRTI toxicity [BI], in selected patients with no history of VF or PI resistance
mutations, no anemia, no HCV coinfection, with undetectable viremia for at least 6 months,
good immunological recovery and CD4 nadir >100 cells, may represent an acceptable
option for optimizing ARV treatment in virologically suppressed patients.
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
Seminario Nadir 2014 - Iniziativa resa possibile grazie al supporto di Janssen-Cilag
.