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Eighth International Congress on Drug Therapy and HIV Infection

Glasgow, UK / November 12-16, 2006

Reported by: Sharon L. Walmsley, MD, FRCPC

Division of Infectious Diseases UHN-Toronto General Hospital

Associate Professor of Medicine University of Toronto Toronto, Ontario

The safety and efficacy of protease inhibitor (PI) boosting depends in part on the pharmacokinetic profile and drug exposure of the boosted agent. The important pharmacokinetic parameters are likely to include the Cmax achieved, elimination half-life and the area under the curve (AUC) but may vary with different agents. The ALERT study compares the efficacy, safety and tolerability of ritonavir (RTV)-boosted fosamprenavir (FPV) to RTV-boosted atazanavir, both given once daily in combination with the tenofovir/emtricitabine (TDF/FTC) fixed-dose tablet.

ALERT STUDY DESIGN

ALERT is the first open-label, prospective study in which once-daily FPV at the standard dose of 1400 mg together with a reduced dose of RTV (100 mg vs. the usual 200 mg) has been evaluated for treating naive HIV patients compared to atazanavir/r 300/100 mg. All patients received TDF/FTC 300/200 mg q.d. Fifty-three patients were randomized to each treatment arm, 79% and 89% of whom were male. All patients had an entry viral load >1000 copies/mL. There were no CD4+ cell count restrictions.

The primary end point of the study was the proportion of HIV patients with plasma viral load <50 copies/mL after 48 weeks of treatment. Secondary end points included the proportion of patients with plasma viral load <50 copies/mL at 24 weeks (the interval of the present interim analysis); the proportion with plasma viral load <400 copies/mL at 24 and 48 weeks; change from baseline in CD4+ cell counts at 24 and 48 weeks; HIV treatment-emergent resistance patterns; and the difference between treatment arms in incidence, type and severity of adverse events.

STUDY RESULTS

Baseline characteristics of the patients included the following: median age 40 years in both groups; HIV RNA viral load 4.88 log10 copies/mL in both arms; median CD4+ cell count 161/mm3 in the FPV/r cohort vs. 188/mm3 among those given ATV/r; cholesterol levels 160 mg/dL (4.1 mmol/L) and 153 mg/dL (3.9 mmol/L), respectively, with triglycerides at 120 mg/dL (1.35 mmol/L) and 124 mg/dL (1.39 mmol/L); normal estimated glomerular filtration rates (eGFR) ³90 mL/min according to the Modification of Diet in Renal Disease (MDRD) equation were 36% and 40%, respectively.

Three patients discontinued TDF/FTC due to declining renal function (i.e. eGFR change >25% below baseline or eGFR <50 mL/min). Four patients in the FPV/r arm and three in the ATV/r arm had discontinued their study drug protocol by week 24. Discontinuations among FPV/r-treated participants were due to non-response (one patient), severe rash (one patient), loss to follow-up (one patient) and protocol violation (one patient). In the ATV/r arm, one patient developed Kaposi’s sarcoma and dropped out and two were lost to follow-up.

At that time, by intention to treat analysis based on missing/discontinued equals failure, 79% (42/53) vs. 83% (44/53), respectively, had viral loads <50 copies/mL and 89% (47/53) in both treatment groups had viral loads <400 copies/mL. By observed analysis, 84% (42/50) of FPV/r-treated patients, in contrast to 88% (44/50) of those taking ATV/r, had HIV RNA viral load <50 copies/mL, respectively, and 94% (47/50) in both groups had viral loads <400 copies/mL (Figures 1 and 2). Median CD4+ count change amounted to 110 vs. 134 cells/mm3, respectively, for FPV/r and ATV/r between week 0 and week 24.

Figure 1. Viral Load (<50 copies/mL)

d (<400 copies/mL)

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ALERT co-investigator Dr. Kimberly Smith, Division of Infectious Disease, Rush University Medical Center, Chicago, Illinois, concluded that FPV/r and ATV/r provided similar rates of virologic suppression and immunologic improvement at week 24 in this interim analysis of the ALERT study.

One of the reasons for investigating the 100 mg RTV boosting dose is to assess the impact of that lower dose on metabolic changes, including changes in lipids. Most PIs are associated with at least slight elevations in lipids, which is likely related in part to the dose of RTV but also to the backbone NRTI agents used. In previous work, moderate effects have been reported with boosted FPV and ATV. Regarding median fasting lipids at week 24, Dr. Smith noted that median total cholesterol increased from 160 mg/dL (4.1 mmol/L) at baseline to 177 mg/dL (4.6 mmol/L) at 24 weeks in the FPV/r group relative to ATV/r patients, among whom it increased from a median 153 mg/dL (3.9 mmol/L) at baseline to 180 mg/dL (4.6 mmol/L) at 24 weeks. Median triglycerides rose from a 116 mg/dL (1.3 mmol/L) baseline level to 160 mg/dL (1.8 mmol/L) with FPV/r and from 127 mg/dL (1.4 mmol/L) to 133 mg/dL (1.5 mmol/L) in the ATV/r treatment group. There were small increases in LDL and HDL in both cohorts.

Also at week 24, the proportion of patients with eGFR ³90 mL/min was 30% vs. 24%, respectively. Protocol required TDF/FTC discontinuation when GFR decreased more than 25% below baseline or to <50 mL/min, and three patients were discontinued due to declining renal function, both in the FPV/r arm, and switched to individual components of abacavir/lamivudine. Severe or grade 3-4 adverse events occurred in 13% and 49%, with the difference driven by bilirubin-associated adverse events, Dr. Smith reported.

Dr. Smith remarked that the trend for declining renal function observed in this trial would suggest a need for increased renal function monitoring when TDF/FTC is administered with RTV-boosted PIs to naive patients with reduced renal function.

Dr. Michael Youle, Director, Clinical HIV Research, Royal Free Hospital, London, UK, characterized ALERT as a very helpful study. The data are compelling, he commented, in that there was no difference between FPV/r q.d. and ATV/r q.d., thus providing an option to patients who do not wish to risk developing hyperbilirubinemia. As expected, there was a higher risk of treatment-related adverse events with ATV/r due mainly to the observed bilirubin increases (Table 1). In terms of the lipid differences, there were no data to suggest any differences between the two treatment grou
e 1. Treatment-related Adverse Events by Overall Frequency (>4%)

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CORROBORATIVE FINDINGS

The rationale for the ALERT trial is supported by the findings of pharmacokinetic studies. In a trial evaluating different boosting doses of RTV on the pharmacokinetics of the FPV metabolite amprenavir (APV) in healthy volunteers, investigators found no differences in area under the plasma APV vs. time curve (AUC) or minimum APV concentration (Cmin) when FPV 600 mg b.i.d. was given with either RTV 50 or 100 mg b.i.d., or with RTV 100, 200 or 1200 mg q.d., suggesting that once-daily 100 mg RTV may be sufficient to boost FPV, especially in ARV-naive patients, where the IC50 of virus would be anticipated to be wild-type.

Because the clinical use of APV/r was largely limited by pill size and high pill burden, the authors of the more recent COL10053 study assessed plasma APV pharmacokinetics and tolerability with FPV 1400 mg q.d. co-administered with RTV 100 or 200 mg in healthy volunteers. According to Dr. Peter Ruane, Light Source Medical, Los Angeles, California (Antimicrob Agents Chemother 2006 Nov 6 [Epub ahead of print]), low-dose RTV inhibits first-pass metabolism of PIs, which can result in increased absorption of the PI, reduce its hepatic metabolism, or both. That leads to more prolonged plasma half-lives and eventually higher plasma concentrations of the boosted PI, potentially resulting in lower pill burden and fewer daily administrations. Studies have regularly demonstrated that patient compliance is inversely proportional to increasingly complicated regimens with multiple daily doses and heavy pill burdens.

The multicentre, randomized, crossover pharmacokinetic study Dr. Ruane headed compared steady-state plasma APV concentrations, safety and tolerability of FPV in standard once-daily 1400 mg doses boosted with 100 or 200 mg RTV. It demonstrated that at those doses, the 1400/100 mg q.d. combination delivers plasma AUC0-tau and Cmax values equivalent to those delivered by FPV 1400 mg q.d. plus RTV 200 mg q.d., and that the lower boosting dose is associated with an improved safety profile. Although the geometric least square (GLS) mean trough concentrations (Ctau) was 38% lower for FPV/r 1400/100 mg q.d., it remained sixfold above the mean APV protein binding-adjusted IC50 value for wild-type virus and 2.5-fold above the historic Ctau value of unboosted FPV 1400 mg b.i.d.

Dr. Ruane reported that even the lowest APV Ctau observed with FPV/r 1400/100 mg q.d. was nearly threefold higher than the mean APV protein binding-adjusted IC50 value for wild-type virus. The GLS mean Ctau for FPV/r 1400/100 mg q.d. was slightly lower than the mean APV protein binding-adjusted IC50 value for multiple PI-resistant HIV.

The COL10053 study findings suggest that FPV1400 mg with low-dose RTV 100 mg q.d. provides a superior adverse event and fasting lipid profile than the same regimen with a RTV 200 mg q.d. dose. The lower dose supplies adequate plasma exposure of APV for treating PI-naive HIV-1-infected patients. Moreover, there were fewer gastrointestinal adverse events with RTV 100 mg, which was not unexpected, given earlier reports of more gastrointestinal distress events accompanying doses above 200 mg.

It has also been noted that frequency of administration may affect the RTV dose necessary for maximum boosting. With high-dose FPV at 1400 mg b.i.d., 200 mg RTV b.i.d. resulted in an 18% lower plasma APV exposure compared with b.i.d. high-dose FPV combined with RTV 100 mg b.i.d.

Dr. Ruane concluded that co-administration of FPV 1400 mg with reduced-dose RTV 100 mg q.d. offers a better short-term, adverse event-triglyceride profile than standard FPV/r 1400/200 mg q.d. dosing and that the reduced-dose RTV regimen produces sufficient plasma APV exposure for treating HIV-1-infected, PI-naive patients. In view of these findings, further investigations of the efficacy, safety and resistance profile of FPV 1400/RTV 100 mg q.d. in such individuals is underway.

SUMMARY

The ALERT study interim findings presented clinical evidence supporting the case for reduced-dose boosting with RTV combined with FPV when compared to ATV/r in ARV-naive hosts. The encouraging results were reflected in fewer severe adverse events (other than bilirubinemia) and similar virologic suppression and lipid changes between the two cohorts. In COL10053, Dr. Ruane and colleagues offered additional evidence for a lower RTV dose, resulting in a reduced pill burden and improved patient compliance without sacrificing efficacy. The final results of the controlled trial are awaited to confirm these early observations.