Reports

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46th Interscience Conference on Antimicrobial Agents and Chemotherapy

San Francisco, California / September 27-30, 2006

In the late-breaking trial of once-daily (q.d.) regimens, boosted fosamprenavir (FPV) was compared to boosted atazanavir (ATV), both of which were recently added to the list of IAS-USA Panel Guidelines of preferred protease inhibitors (PIs) (Hammer et al. JAMA 2006;296:827-43). The addition of FPV to the preferred list was largely based on results of the KLEAN (Kaletra versus Lexiva with Epivir and Abacavir in ART-Naïve patients) trial, which found FPV 700 mg b.i.d. boosted by ritonavir 100 mg to provide similar efficacy and safety when compared to lopinavir 400 mg b.i.d .boosted by ritonavir 100 mg (when both were combined with abacavir [ABC] and lamivudine. In the new trial, the comparison was between the q.d. regimens of FPV 1400 mg boosted by ritonavir 100 mg or ATV 300 mg boosted by ritonavir 100 mg when both were combined with tenofovir and emtricitabine.

As reported by Dr. Kimberly Smith, Division of Infectious Disease, Rush University Medical Center, Chicago, Illinois, “High rates of virologic suppression were achieved with both regimens”. Describing 24-week results in the late breaker presentation the ALERT trial, she indicated that the q.d. boosted FPV was at least as safe as q.d. boosted ATV. In fact, lipid changes were similar but the rate of grade 3 or 4 side effects was substantially lower on FPV/r (14 vs. 49%) primarily because of the substantial rate of hyperbilirubinemia in the ATV arm.

The efficacy of the q.d. FPV regimen against ATV, which is the only PI currently approved for q.d. use, is important because this is the first trial to evaluate q.d. FPV boosted with only 100 mg ritonavir rather than the previously studied 200-mg dose. Predicted to be effective by pharmacokinetics (PK) analyses, the FPV/r regimen with the lower ritonavir dose has the potential to circumvent side effects, including hypercholesterolemia and renal toxicity. The current trial is planned for 48 weeks, but the 24-week data have provided an initial indication that these two q.d. regimens are at least equivalent.

The primary end point of this open-label comparison, which randomized 106 treatment-naïve patients, is the proportion with a viral load <50 HIV RNA copies/mL at 48 weeks. In the 24-week analysis, the proportion did not differ significantly on an intention-to-treat (79% for FPV vs. 83% for ATV) or per-protocol (84% and 88%, respectively) analysis. On a per-protocol basis, the proportion of patients with a viral load < 400 copies/mL was 94% in both arms. There was also no significant difference in immunological recovery, which exceeded 125 CD4+ cells/mm3 by week 24 in both groups. Total cholesterol levels increased by a modest 0.43 mmol/L in both arms. LDL increased by 0.10 mmol/L on FPV and by 0.13 mmol/L on ATV/r, while HDL increased by 0.08 mmol/L on FPV/r and by 0.18 on ATV/r.

Low Virologic Failure Rate

Virologic failure was observed in two patients randomized to FPV/r and one patient randomized to ATV/r, but one of the FPV/r patients had resistant HIV at baseline. Only seven of the patients randomized in this study had discontinued therapy by 24 weeks. The majority of these patients was lost to follow-up or protocol violation. The study is notable for its representative patient sample. According to Dr. Smith, more than 50% of the patients were African-American or Hispanic. The median age at the time of randomization was 40. If sustained at 48 weeks, the efficacy and safety of q d. FPV/r relative to q.d. ATV/r should provide substantial support for expanding the list of q.d. PI-based regimens.

These findings are consistent with a previous randomized study in which a q.d.regimen containing FPV/r (with a 200-mg dose of ritonavir) was compared to a b.i.d. regimen containing nelfinavir. While HIV suppression at <50 copies/mL or <400 copies/mL was slightly but not statistically better on FPV/r, virologic failure was far less common on FPV/r.

“When you look across trials that included q.d. arms with a PI, the development of PI resistance mutations has been very low. In the study comparing FPV to nelfinavir, PI resistance mutations were observed in 8% of patients on twice-daily nelfinavir vs. 0% on q.d. boosted FPV,” reported Dr. Eric Daar, Chief, Division of HIV Medicine, Harbor-UCLA Medical Center, Torrance, California. Referring to the SOLO study (Gathe et al. AIDS 2004;18:1529-37), he noted that the virologic failure rate at 48 weeks was 17% in the nelfinavir arm vs. 7% in FPV/r cohort.

In the SOLO trial, part of the advantage of FPV over nelfinavir, which was among the most commonly prescribed PIs at the time of the study, was likely due to the better PK of a boosted PI, which is typically associated with higher minimum concentrations (Cmin) and area-under-the-curve (AUC) values than unboosted PIs.

Optimal Use of Therapeutic Drug Monitoring

The opportunity to provide more individualized therapy is strengthened by the growing number of laboratories equipped to provide reliable therapeutic drug monitoring (TDM). According to Dr. David Burger, Radboud University Medical Center, Nijmegen, The Netherlands, “TDM may not ever be routine in all patients, but it can be very useful in specific groups and for specific agents either to confirm that drug levels are adequate or that they are not excessive.” He noted that TDM is especially attractive in patients with HIV because many antiretroviral drugs have a relatively narrow therapeutic window. There is considerable variability between patients in how these compounds are metabolized and pharmacologic response cannot be otherwise measured on a short-term basis.

TDM may allow some regimens with less relative potency to be used in selected populations by verifying that the medications are being delivered in adequate concentrations. For example, a comparative trial suggesting that triple nucleoside reverse transcriptase inhibitor (NRTI) regimens may have a role when used appropriately in selected treatment-naïve patients may provide a caveat to current recommendations to avoid triple NRTIs for first-line therapy.

Triple Regimen Applicability

According to Dr. Princy N. Kumar, Acting Chief, Division of Infectious Diseases, Georgetown University Medical Center, Washington, DC, “Our data would support the use of a triple NRTI in selected patients, particularly those with a viral load of <100,000 HIV RNA copies/mL at baseline. ” Presenting results of the ACTION study, which randomized 279 treatment-naïve patients at 46 sites in North America to a q.d. regimen of ABC/lamivudine/zidovudine (ZDV) or a q.d. regimen of ATV/lamivudine/ZDV, Dr. Kumar reported that the two regimens were comparable except in those with a high baseline viral load.

At the end of 48 weeks, the proportion of patients who achieved a viral load <50 copies/mL was 62% in the triple NRTI group vs. 59% in the ATV group. However, when patients were stratified by baseline viral load, results diverged. In those with a baseline HIV count <100,000 copies/mL, 66% of those receiving triple NRTI and 59% of those receiving the ATV-based regimen achieved a viral load <50 copies/mL. In contrast, the proportion fell to 39% on triple NRTI therapy but climbed to 60.2% on ATV-based therapy among those with a HIV count >100,000 copies/mL. Although the triple NRTI therapy “clearly underperformed” in those with a higher baseline viral load, the comparable efficacy in those with a low relative viral load suggests that the triple NRTI regimen “remains a viable option as initial therapy” in a carefully selected subpopulation. Such a strategy might be particularly attractive with close monitoring to ensure that adequate drug levels are being achieved so that HIV levels remain adequately suppressed.

Summary

New findings have provided insight about the relative role of currently available treatment options for management of HIV in treatment-naïve patients. The 24-week data from a direct comparison of q.d. FPV/r and ATV/r indicate that q.d. options for PI-based regimens are likely to expand, while a direct comparison of a q.d. triple NRTI regimen and ATV suggest that individualization of treatments can be considered. The use of less potent regimens in selected patients may be particularly attractive with the use of TDM to verify adequate drug levels.