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Switch to PI/r monotherapy
 PIVOT Study
PIVOT Study: switch to PI/r monotherapy
 Design
HIV-infected patients
> 18 years
Stable Triple ART (NNRTI or PI/r)
HIV RNA < 50 c/mL > 24 weeks
CD4 > 100/mm3
Randomisation
1:1
Open-label
Triple therapy
*
N = 296
PI/r monotherapy **
(selected by investigator)
N = 291
Continuation of ongoing
triple therapy ***
Randomisation was stratified by centre and baseline ART regimen (NNRTI or PI/r)
* Prompt reintroduction of NRTIs (switch PI/r to NNRTI allowed) for protocol-defined viral rebound
(3 consecutive HIV RNA > 50 c/ml) ; further management with combination therapy as in the triple therapy group
** PI substitution during follow-up allowed
*** Switches for toxic effects, convenience, and viral load failure allowed
 Objective
– Primary outcome : non-inferiority of the PI/r-mono group in loss of future drug options,
defined as new intermediate-level or high-level resistance to ≥ 1drug in contemporary
use to which patient’s virus was considered to be sensitive at trial entry ; 2-sided 95%
CI for the difference in maintaining all future drug options during 3 years with upper
limit of 10%, 85% power
PIVOT
Paton
NI. Lancet
HIV
2015;2e:417-26
Paton
N, CROI
2014,
Abs. 550LB
PIVOT Study: switch to PI/r monotherapy
Baseline characteristics
Triple therapy
PI/r monotherapy
43
45
22%
25%
71% / 25%
66% / 30%
HCV antibody positive
2%
5%
Prior AIDS
20%
19%
512 / 181
516 / 170
36 months
38 months
NNRTI at entry
EFV
NVP
ETR
54%
40%
14%
0
53%
39%
13%
1%
PI/r at entry
ATV/r
LPV/r
DRV/r
SQV/r
FPV/r
46%
20%
10%
8%
5%
2%
47%
20%
17%
4%
5%
1%
65%, 27%, 7%
61%, 28%, 11%
Median age, years
Female
White / Black
CD4/mm3, median (IQR) at baseline / at nadir
Median duration of undetectable HIV RNA at baseline
NRTI at entry : TDF/FTC, ABC/3TC, other
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26
PIVOT Study: switch to PI/r monotherapy
 PI/r monotherapy group
–
–
–
–
–
DRV/r: 80%
LPV/r: 14%
ATV/r: 6%
Saquinavir/r < 1%
58% still on PI/r monotherapy at trial end
(72% of follow-up time on monotherapy)
– Reasons for reintroduction of combination regimens
•
•
•
•
23% for protocol-defined confirmed viral rebound
4% for viral rebound not meeting protocol criteria
5% for toxic effects
7% for other or unknown reasons
 Median duration of follow-up : 44 months
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26
PIVOT Study: switch to PI/r monotherapy
Primary endpoint
 Definition : Loss of future drug options, defined as new intermediate-level or
high-level resistance to one or more drugs to which the patient’s virus was deemed
sensitive at trial entry (Kaplan-Meier estimate at 3 years)
Triple therapy
N = 291
PI/r monotherapy
N = 296
Difference
(95% CI)
N = 2 (0.7%)
N = 6 (2.1%)
1.4% (-0.4 to 3.4)
Loss of future options during the full
trial period
1.8%
2.1%
0.2% (-2.5 to 2.6)
Loss of future options during the full
trial period (excluding possible
archived mutations)
1.5%
1.0%
-0.4% (-2.9 to 1.4)
Primary endpoint*
N=4
Lost drug options
- NVP, EFV
- 3TC, FTC, ATV, SQV,
FPV, TPV
- 3TC, FTC, NVP, EFV,
ETR, RPV
- 3TC, FTC, ABC, TDF,
NVP, EFV, ETR, RPV
N=6
-
ATV
SQV
SQV
NVP,EFV
NVP, EFV
ZDV
* non-inferiority met
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26
PIVOT Study: switch to PI/r monotherapy
Viral rebound and resuppression
Time to viral rebound
Time to viral resuppression after
change of ART in the PI-mono group
Without VL resuppression (%)
Without VL rebound (%)
100
80
60
40
HR = 13,9 ; 95 % CI : 6,8-28,6
p < 0,0001
OT
PI-mono
20
0
0
24
48
72
96
120
144
168
192
216
240
10
80
60
median time : 3.5 weeks
40
20
0
0
Weeks from randomisation
291
296
24
36
Weeks from ART change
Number at risk
OT
PI-mono
12
Number at risk
289
281
287
240
283
220
280
216
279
210
276
208
247
183
133
100
64
53
10
67
11
1
0
 Confirmed viral rebound (Kaplan-Meier estimate) during follow-up
– PI/r monotherapy : 35.0% vs triple therapy : 3.2% (difference : 31.8%)
(95% CI : 24.6 to 39.0, p < 0.0001)
– Rebound on PI/r monotherapy : 24 per 100 person-years during 1st year,
6 per 100 person-years in subsequent years
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26
PIVOT Study: switch to PI/r monotherapy
Secondary outcomes, n (%)
Triple therapy
N = 291
PI/r monotherapy
N = 296
Death
1 (0.3%)
6 (2.0%)
AIDS-defining event
1 (0.3%)
1 (0.3%)
Serious non-AIDS event
7 (2.4%)
12 (4.1%)
+ 93
+ 100
Clinical grade 2 or 4 adverse event
16.8%
22.0%
eGFR < 60 mL/min/1.73 m2 during follow-up
9.7%
5.1% (p < 0.033)
Symptomatic peripheral neuropathy
15.5%
15.9%
Facial lipoatrophy
8.2%
12.1%
Abdominal fat accumulation
17.2%
20.6%
10 year cardiovascular disease risk, mean change
+ 1.32
+ 1.59
Mean change in CD4/mm3
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26
PIVOT Study: switch to PI/r monotherapy
 Conclusion
– In patients who have achieved viral load suppression with combination
treatment, a maintenance strategy of PI/r monotherapy, with reintroduction of
combination treatment in the event of viral load rebound, was non-inferior to
continuous combination treatment for preservation of future treatment options
during 3–5 years
• Regular viral load monitoring and prompt reintroduction of combination treatment for
rebound needed
• Absolute number of patients who lost future drug options with PI/r monotherapy was
very low (only 1 patient with resistance to ATV)
• No change in overall clinical outcomes or frequency of toxic effects
– Much higher proportion of patients in the PI/r monotherapy group with viral
rebound
• Rapid resuppression of viral load by reintroduction of combination treatment
• No adverse effect on CD4 change
– Protease inhibitor monotherapy is an acceptable alternative for long-term
clinical management of HIV infection
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26