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Low-nadir CD4 Count Predicts Failure of Monotherapy Maintenance with Ritonavir-boosted Lopinavir: Results after Premature Termination of a Randomized Study Due to Unexpectedly High Failure Rate in the Monotherapy Arm
C Gutmann1, M Opravil2, S Yerly3, C Fux4, H Furrer4, M Cavassini5, L-A Decosterd5, Bernard Hirschel*3, P Vernazza1, and the Swiss HIV Cohort Study
1Kantonsspital St Gallen, Switzerland; 2Univ Hosp Zurich, Switzerland; 3Univ Hosp Geneva, Switzerland; 4Univ Hosp Bern, Switzerland; and 5Univ Hosp Lausanne, Switzerland
Background: Previous PI-monotherapy studies demonstrated full viral load
suppression over >1 year. Concerns remain regarding activity in
compartments. The MOST study evaluates antiviral activity of ritonavir-boosted
lopinavir (LPV/r) -monotherapy in the genital tract and central nervous system
as well as predictors of virologic failure. Due to unexpected high failure rate
(>20%), the study is terminated prematurely as per protocol.
Methods: Patients
on full viral load suppression have been randomized to either continued
standard therapy or LPV/r-monotherapy for 48 week. At baseline and week 48, viral
load in cerebrospinal fluid (CSF) and genital secretions is measured in all
patients. Failure was defined as a confirmed viral load >400 copiea/mL in a
fully adherent patient.
Results: As
of September 24, 2008, the study was prematurely terminated (60 patients
randomized) because the predefined stopping criteria (6 failures in monotherapy
arm) was reached. Of 60 patients, 29 were randomized to monotherapy. The median
study duration was 11 months. At baseline, all patients had undetectable plasma
viral load; 1 patient had a CSF viral load of 82 copies/mL (randomized to
continued HAART); 6 patients (all in mono-arm) reached the failing criteria.
Mean nadir CD4 count was significantly lower in failing patients than in non-failing
patients on monotherapy (77 vs 166/µL; p <0.01). Lumbar puncture was
performed in 4 failing patients, one additional examination is scheduled. Viral
load in CSF was significantly higher than in blood (see table). Patients
confirmed optimal adherence, but drug levels were extremely low in 2 of 4.
Three failing patients had neurological symptoms at failure (headache,
dizziness, ataxic problems, visual disturbance, concentration problems). Resistance-associated
mutations were absent in all blood and CSF samples tested.
Parameters at failure
|
ID
|
Week
|
Symptom
|
Viral load blood
|
Viral load CSF
|
CD4 at failure
|
Nadir CD4
|
Lopinavir/r (ng/mL) (percentile)
|
|
101
|
12
|
Yes
|
4.3 log
|
5.1 log
|
680
|
60
|
87 (<1)
|
|
108
|
12
|
No
|
4.2 log
|
pending
|
361
|
5
|
Pending
|
|
126
|
12
|
No
|
4.1 log
|
5.0 log
|
380
|
150
|
6388 (25 to 50th)
|
|
302
|
24
|
Yes
|
3.0 log
|
4.2 log
|
130
|
5
|
6438 (50th)
|
|
303
|
6
|
No
|
5.0 log
|
Refused
|
250
|
50
|
4661 (25th)
|
|
713
|
24
|
Yes
|
3.0 log
|
3.7 log
|
710
|
160
|
Undetectable
|
Conclusions: Failure rates during LPV/r monotherapy may be associated with low
nadir CD4 count and appears to involve the central nervous system. Use of
monotherapy should be restricted to clinical studies.
|
