1. Switch to PI/r monotherapy
ARV-trial.com
Switch to PI/r monotherapy
PIVOT Study 1

2. PIVOT Study: switch to PI/r monotherapy
Randomisation
1 : 1
Open-label
Design
Triple therapy *
PI/r monotherapy **
(selected by investigator)
HIV-infected patients
> 18 years
Stable Triple ART (NNRTI or PI/r)
HIV RNA < 50 c/mL > 24 weeks
CD4 > 100/mm3
N = 296
Continuation of ongoing
triple therapy ***
N = 291
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

3. PIVOT Study: switch to PI/r monotherapy
Baseline characteristics
Triple therapy
PI/r monotherapy
Median age, years 43 45
Female
22%
25%
White / Black
71% / 25%
66% / 30%
HCV antibody positive 2% 5%
Prior AIDS
20%
19%
CD4/mm3, median (IQR) at baseline / at nadir
512 / 181
516 / 170
Median duration of undetectable HIV RNA at baseline
36 months
38 months
NNRTI at entry
EFV
NVP
ETR
54%
40%
14%
53%
39%
13% 1%
PI/r at entry
ATV/r
LPV/r DRV/r
SQV/r
FPV/r
46%
10% 8%
47%
17% 4%
NRTI at entry : TDF/FTC, ABC/3TC, other
65%, 27%, 7%
61%, 28%, 11%
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26

4. 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

5. 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)
Primary endpoint*
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)
Lost drug options
N = 4
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
NVP,EFV
ZDV
* non-inferiority met
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26

6. 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 20 40 60 80
100 24 48 72 96
120
144
168
192
216
240 OT
PI-mono
HR = 13,9 ; 95 % CI : 6,8-28,6 p < 0,0001
Weeks from randomisation
291
296
289
281
287
283
220
280
279
210
276
208
247
183
133 64 53 10
OT PI-mono
Number at risk
Without VL rebound (%)
median time : 3.5 weeks 12 24 36 20 40 60 80 10 67 11 1
Weeks from ART change
Number at risk
Without VL resuppression (%)
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 < )
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

7. 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
Serious non-AIDS event
7 (2.4%)
12 (4.1%)
Mean change in CD4/mm3
+ 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
PIVOT
Paton NI. Lancet HIV 2015;2e:417-26

8. 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