Viral response in stable patients switching to fosamprenavir/ritonavir monotherapy (the FONT Study)

Abstract

ObjectiveThe aim of the study was to evaluate the efficacy of fosamprenavir/ritonavir (FPV/r) monotherapy in plasma and reservoirs in virologically suppressed patients. MethodsA 48-week, prospective, single-arm pilot trial was carried out (trial registration: ISRCTN78584791). Patients receiving triple therapy [FPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least the previous month], with viral load (VL) o40 HIV-1 RNA copies/mL and no previous virological failure (VF) on protease inhibitors (PIs), were included in the trial and received FPV/r monotherapy (700/100 mg/12 h). VL and FPV/r levels [by liquid chromatography-tandem mass spectrometry (LC/MS/MS); limit of detection (LOD) 0.5 ng/mL] in cerebrospinal fluid (CSF) were determined at week 24. VF was defined as VL 440 copies/mL in three consecutive samples or 4500 copies/mL in two samples. ResultsEnrolment was prematurely stopped because of a high percentage of VF. Twenty patients (45% men; median age 43.5 years) were included in the trial. Nine patients (45%) presented therapeutic failure [seven (35%) had VF, and two discontinued therapy]. Resistance testing was available in five patients. One patient presented major PI mutations (54L, 32I and 47V) in addition to one minor mutation (13V), whereas two patients had minor PI mutations (10V 1 36I and 71T, respectively). The patient with major PI mutations switched from FPV/r to darunavir/r and VL was re-suppressed. In the other six patients with VF, VL was re-suppressed after the reintroduction of NRTIs. VL was o40 copies/mL in all CSF samples (n 5 10). Median amprenavir plasma levels were 2.5 mg/mL (range 0.7-8.6 mg/mL) at week 24 and 2.5 mg/mL (range 0.4-3.8 mg/mL) at VF. The CSF amprenavir concentration was 28.1 ng/mL (range 6.39-83.6 ng/mL), exceeding the reported 50% inhibitory concentration (IC 50 ) range for CSF in nine of 11 patients. ConclusionsThe high percentage of patients with VF in our study suggests that the use of FPV/r in a simplification monotherapy strategy should be discouraged. Adequate amprenavir levels and undetectable VL in CSF were documented in all samples evaluated. IntroductionSeveral studies have recently explored the benefits of a ritonavir-boosted protease inhibitor (PI/r) given as a single agent in virologically suppressed patients [1][2][3][4][5][6][7] in preventing long-term side effects, facilitating compliance and reducing costs. However, the noninferiority of PI/r monotherapy compared with standard triple therapy has not been consistently demonstrated. For example, noninferiority relative to lopinavir/ritonavir (LPV/r) was achieved only if reintroduction of nucleoside reverse transcriptase inhibitors (NRTIs) was not considered a failure [1], and noninferiority relative to darunavir (DRV)/r was observed in the MONOI study only in the per protocol analysis [2], and in the MONET study at 48 weeks [3] DOI: 10.1111/j.1468-1293.2010.00898.x HIV Medicine (2011 r 2011 British HIV Association 438(ATZ/r) in small studies [6,7]. Fosamprenavir/ritonavir (FPV/...

Therapeutic Amprenavir Concentrations in Cerebrospinal Fluid

“…APV CSF concentrations have not been reported previously other than in a much smaller series with a median CSF APV concentration comparable to the one reported here (19). In this study, APV concentrations in plasma were somewhat variable whereas APV concentrations in CSF were more stable and exceeded the median concentration required to inhibit wild-type HIV in vitro in nearly all specimens regardless of dosing schedules (median, 4.4-fold higher).…”

Central Nervous System HIV Infection in “Less-Drug Regimen” Antiretroviral Therapy Simplification Strategies

“…However, no case of CSF escape occurred at week 24 among 10 patients with suppressed plasma viremia. 13 As discussed above, the CSF APV concentration exceeded the reported IC50% value range in nine of 11 patients. Additional information on neuroprotection on PI monotherapy in simplification strategies comes from the MONOtherapy Inhibitor protease (MONOI) study, which compared DRV/r monotherapy 600/100 mg twice daily to standard triple therapy including DRV/r.…”

“…Two studies, the MOST study and a recently published cross sectional study, have compared LPV/r monotherapy to LPV/r-based triple therapy, 46,69 and two singlearm studies have evaluated monotherapy with ATV/r or fAMP with or without ritonavir. 12,13 The MOST study was a randomized, controlled, openlabel trial, comparing a switch to LPV/r monotherapy to continued treatment for 48 weeks in treated patients with fully suppressed viral loads, and evaluating, as primary endpoint, virological failure in CSF and semen. 46 This study was prematurely stopped after 60% of participants had been enrolled due to virological failure in blood (VL > 400 cells/mL) in six patients on monotherapy versus none in the continued treatment arm.…”

“…Clinical trials in combination antiretroviral therapy-(cART-) experienced, virologically suppressed patients have evaluated monotherapy with ritonavir-boosted lopinavir (LPV/r), 6 darunavir (DRV/r), [7][8][9][10][11] and to a lesser extent, atazanavir (ATV/r) 12 and fosamprenavir (fAMP/r). 13 In general, the virological efficacy of these treatments is slightly lower than that of standard therapy, but the risk of resistance development is minimal and the reintroduction of nucleoside analogues usually leads to resuppression of plasma viral load. 1 Several retrospective studies have evaluated the outcome of two-drug combinations in patients who discontinued nucleoside reverse transcriptase inhibitors (NRTI) for toxicity, including dual combinations of LPV/r, DRV/r, or ATV/r with nonnucleoside reverse transcriptase inhibitors (NNRTIs); raltegravir (RAL); maraviroc (MVC); tenofovir (TDF); RAL in combination with etravirine (ETV); and MVC in combination with DRV/r.…”

Treatment of HIV in the Central Nervous System

“…Amprenavir concentrations in CSF following monotherapy with fosamprenavir/r have been demonstrated to be adequate, but with several CSF viral breakthroughs. 47…”