Virologic and Lipoprotein Changes after Halving Ritonavir Boosting in HIV-Infected Patients Stabilized on Once-Daily Fosamprenavir plus Abacavir/Lamivudine ()
1. Introduction
Fosamprenavir, the phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, is frequently used as a component of combination antiretroviral therapy in HIV-infected patients. Fosamprenavir-containing regimens offer the flexibility of dosing either once-daily or twice-daily without regard to food or fluid requirements [1]. Once-daily fosamprenavir regimens can be prescribed only for antiretroviral-naïve patients and must be co-administered with low-dose ritonavir. The latter serves to inhibit the CYP3A4 hepatic metabolism of amprenavir, thereby increasing amprenavir plasma concentrations/exposure, elimination half-life, and antiretroviral activity [2].
The initial once-daily ritonavir boosting dose to be approved in the United States for co-use with fosamprenavir was 200 mg. This approval was based on the findings of the SOLO study, a clinical trial that evaluated fosamprenavir/ritonavir 1400 mg/200 mg once daily plus abacavir/lamivudine 300 mg/150 mg twice daily and showed that 69% of 322 antiretroviral-naïve patients treated were able to achieve a viral load <400 copies/mL at 48 weeks [3]. As ritonavir is associated with doserelated adverse gastrointestinal events and unfavorable lipid changes [4-6], using the lowest ritonavir boosting dose to push amprenavir concentrations to well within the clinically effective range would be expected to optimize the tolerability of fosamprenavir/ritonavir regimens. In view of this, a ritonavir boosting dose lower than 200 mg once daily—100 mg once daily—was investigated in studies of patients receiving once-daily fosamprenavircontaining regimens [7-16].
COL10053 showed that once-daily ritonavir 100 mg boosting of fosamprenavir 1400 mg provided a mean plasma amprenavir trough concentration (Ct) of 0.86 µg/mL [17], which is 6-fold higher than the mean amprenavir protein binding-adjusted 50% inhibitory concentration (IC50) for wild-type virus (0.146 μg/mL) [18] and 2.5- fold above the historical Ct value observed with unboosted fosamprenavir 1400 mg twice daily (0.35 μg/mL) [19]. The results of this pharmacokinetic study led to Food and Drug Administration approval of ritonavir 100 mg once daily for boosting fosamprenavir 1400 mg oncedaily-based regimens in treatment-naïve HIV populations in the United States [20].
There are limited data available describing whether changes in efficacy or safety occur when HIV-infected patients stabilized on a fosamprenavir/ritonavir 1400 mg/ 200 mg once-daily regimen have their ritonavir boosting dose reduced to 100 mg once daily. The purpose of COL101295 was to explore the clinical sequelae of such a switch over 24 weeks when it follows 28-week treatment induction with fosamprenavir/ritonavir 1400 mg/200 mg once daily plus abacavir/lamivudine 600 mg/300 mg once daily in antiretroviral-naïve, HIV-infected patients. In addition, an analysis of the effect of treatment on lipid particles was conducted.
2. Methods
In this 52-week, phase 4, open-label, single-center pilot study, 26 antiretroviral-naïve, HIV-infected patients with viral load >1000 copies/mL and any CD4+ cell count received induction treatment with fosamprenavir/ritonavir 1400 mg/200 mg plus abacavir/lamivudine 600/300 mg once daily for 28 weeks. Patients who achieved a viral load <50 copies/mL at week 28 were given maintenance therapy for 24 subsequent weeks with half the ritonavir dose (100 mg) plus the usual fosamprenavir, lamivudine and abacavir doses. Fosamprenavir was administered as two 700-mg tablets of Lexiva® (GlaxoSmithKline, Research Triangle Park, North Carolina), abacavir 600 mg as two 300-mg tablets of Ziagen® (GlaxoSmithKline, Research Triangle Park, North Carolina), lamivudine as two 150-mg tablets of Epivir® (GlaxoSmithKline, Research Triangle Park, North Carolina), and ritonavir as one or two 100-mg soft-gel capsules of Norvir® (Abbott Laboratories, North Chicago, Illinois).
The primary study endpoints were the proportion of patients achieving a viral load <50 copies/mL at the end of the induction and maintenance periods, and change from baseline in CD4+ count and safety/fasting lipid profile at these time points. Viral load (HIV-1 RNA) and CD4+ were measured at baseline (week 0), weeks 4, 12, 16, 20, 24 and 28 (induction period), and at weeks 32, 40, 48, and 52 (maintenance period) using the Roche Amplicor MONITOR Ultrasensitive assay (version 1.5; LLOQ 50 copies/mL) (Roche Diagnostics, Branchburg, New Jersey) and HIV-1 MONITOR Version 1.0 polymerase chain reaction assay (LLOQ, 400 copies/mL) (Roche, Nutley, New Jersey). Virologic failure was said to occur, and require the patient discontinuing their study treatment regimen, if viral load remained >200 copies/ mL at induction-week 24 or if there were two consecutive viral load levels of ³1000 copies/mL observed within a 1- to 2-week period after at least two consecutive (separated by 1-2 weeks) viral load values of <200 copies/mL). CD4+ T lymphocyte cell count was assessed by flow cytometry.
Patients were monitored for adverse events, laboratory abnormalities, and any HIV-related illnesses at baseline (week 0) and weeks 4, 12, 16, 20, 24, 28, 32, 40, 48, and 52. NMR (LipoMed Inc., Cambridge, Massachusetts) was used to measure the quantity and size of LDL, HDL, IDL, and VLDL/chylomicron particles at baseline, week 28 (end of induction), and week 52 (end of maintenance). Adherence was assessed by pill count (pills counted in returned vials of study medication) by the study site personnel at each patient visit and by patient self-report. Statistics were primarily descriptive in the observed population, and included change from baseline in viral load, CD4+ count, lipids, and lipoproteins, and tabulation of adverse events and abnormal laboratory values. A Fisher exact test was performed to compare the total adverse event incidence at week 28 of the induction regimen with that at week 24 of the maintenance regimen (week 52 of study). A P value of <0.05 for this comparison was considered statistically significant.
3. Results
3.1. Patient Characteristics
The baseline characteristics of the patient population are shown in Table 1. Fifteen patients completed the 28- week induction phase, and 12 completed both the induction and maintenance study phases. Fourteen patients
Table 1. Characteristics of the study population.
prematurely discontinued due to loss to follow-up (6), protocol violation (4), moving away (2), or suspected abacavir-related hypersensitivity reaction (2).
3.2. Efficacy
In the 15 patients who completed the induction phase, 11 (73%) had a viral load <50 copies/mL and 12 (80%) a viral load of <400 copies/mL at induction-week 28. In the 12 completers of both treatment phases, 10 (83%) patients had a viral load level <50 copies/mL (Figure 1(a)) and 11 (92%) a viral load of <400 copies/mL by maintenance-week 24 (Figure 1(b)). CD4+ count increased from a baseline median of 110/mm3, to 292/mm3 at induction-week 28, and finally to 296/mm3 at maintenance-week 24 (Figure 1(c)).
(a)
(b)
(c)
Figure 1. Change in viral load with respect to proportion of patients achieving HIV-1 RNA <50 copies/mL (a) and <400 copies/mL (b); Change in CD4+ cell count is shown in (c).
3.3. Safety
Adverse events generally were reported during the first 4 weeks of the study, with few reports subsequently. Potentially drug-related adverse events included abdominal discomfort (1), anemia (1), depression (1), odynophagia (1), rash (3), hypercholesterolemia (1), and hypertriglyceridemia (2) during induction, and hypercholesterolemia and hypertriglyceridemia (2) during maintenance. The incidence of adverse events at maintenance-week 24 did not differ from that at induction-week 28 (P > 0.05). Lipid analysis showed that median fasting total-cholesterol, LDL-cholesterol, and triglycerides remained below National Cholesterol Education Program (NCEP) cut-off levels [21] (Figure 2). No hypolipidemic medications were prescribed during the study. The greatest increase in median total-cholesterol levels occurred between baseline and induction-week 28 (from 130 to 177 mg/dL), as was the case with LDL-cholesterol (from 78 to 107 mg/dL), HDL-cholesterol (from 33 to 41 mg/dL), triglycerides (from 93 to 145 mg/dL), and the total-cholesterol: HDL-cholesterol ratio (from 3.9 to 4.3) (Figure 3). After reducing the ritonavir boosting dose to 100 mg once daily, little or no change was seen over the ensuing 24-week maintenance period in median total-cholesterol (+6 mg/dL [to 183 mg/dL at week 24]), LDL-cholesterol (+7 mg/dL [to 114 mg/dL]), HDL-cholesterol (+2 mg/dL [to 43 mg/dL]), and total-cholesterol: HDL-cholesterol ratio (no change, remaining 4.3), although triglycerides fell notably (−26 mg/dL [to 119 mg/dL]).
3.4. Lipoprotein Particle Analysis
Table 2 compares lipid particle concentrations at baseline, end of induction, and end of maintenance. Between baseline and the end of the induction phase, total VLDL/ chylomicron particles doubled in quantity and subclasses of these particles increased by 62% to 166%. Following