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ICAAC 2008: Boosted Atazanavir (Reyataz) and Lopinavir/ritonavir (Kaletra) Are both Highly Effective through 96 Weeks

Long-term clinical trial data show that modern HAART regimens offer continued antiviral efficacy over time, although toxicities remain a concern.

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AIDS 2008: Didanosine (Videx EC) + Emtricitabine (Emtriva) + Atazanavir (Reyataz) Inferior for Initial HIV Treatment: PEARLS Trial

For a variety of reasons, physicians may recommend an alternative initial antiretroviral regimen rather than one of the first-line regimens recommended by current treatment guidelines. A once-daily regimen of didanosine (ddI; Videx-EC), emtricitabine (Emtriva), and unboosted atazanavir (Reyataz) has potential advantages over other alternative regimens, but the efficacy of this combination is unknown.

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ICAAC 2008: Long-term Safety of Investigational CCR5 Antagonist Vicriviroc in Treatment-experienced Patients

Schering-Plough's investigational CCR5 antagonist vicriviroc has demonstrated potent activity against HIV in laboratory studies and clinical trials of treatment-experienced patients. More than 200 patients received vicriviroc in Phase II trials. In a poster presented at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers described long-term safety data from this population.

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AIDS 2008: Are Abacavir/lamivudine (Epzicom) and Tenofovir/emtricitabine (Truvada) Equally Effective?

With more than 20 antiretroviral drugs to choose from, one of the most frequently asked questions is what is the best regimen to start with in terms of efficacy and safety? Currently 2 nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbones are recommended by U.S. HIV treatment guidelines as part of a first-line regimen: abacavir/lamivudine (Epzicom) and tenofovir/emtricitabine (Truvada; also combined with efavirenz in the Atripla pill). While lamivudine and emtricitabine are similar in their structure, activity, and side effects, the differences between abacavir and tenofovir are of more interest.

ACTG A5202

As previously reported, AIDS Clinical Trials Group (ACTG) study A5202 was modified earlier this year after interim data showed that among patients who started with a high viral load (100,000 copies/mL or more), abacavir/lamivudine did not suppress HIV as well as tenofovir/emtricitabine when both were used in combination with either efavirenz (Sustiva) or ritonavir-boostedatazanavir (Reyataz).

At the XVII International AIDS Conference last week in Mexico City, investigators reported data from an analysis of the high viral load patients, who were unblinded after the interim results became known.

This Phase IIIb study initially enrolled 1858 treatment-naive participants, 797 of whom had HIV RNA > 100,000 copies/mL at screening. Most (85%) were men, about half were white, and one-quarter each black and Hispanic. The mean CD4 count was 181 cells/mm3. The median follow-up period was 60 weeks.

Virological failure was defined as confirmed viral load > 1,000 copies/mL at or after 16 weeks and before 24 weeks, or else HIV RNA > 200 copies/mL at or after 24 weeks. The 16-week time frame was unusual in ACTG 5202, as most trials to not report virological response before 24 weeks.

Results

• In an intent-to-treat analysis, time to virological failure was significantly shorter in the abacavir/lamivudine arm than in the tenofovir/emtricitabine arm (HR 2.33; p = 0.0003).

• There were no differences between the arms with regard to CD4 cell changes.

• Patients receiving abacavir/lamivudine had a shorter time to emergence of grade 3/4 adverse events (AEs) compared with those taking tenofovir/emtricitabine (HR 1.87; p < 0.0001).

• Suspected drug hypersensitivity reactions were reported in 7% of participants taking each NRTI backbone.

• There were 2 cases of kidney failure in each arm.

Based on these findings, the researchers concluded, "In subjects entering A5202 with screening HIV RNA > 100,000 copies/mL, there was a significantly shorter time to virological failure and grade 3/4 adverse events" among those randomized to abacavir/lamivudine compared with tenofovir/emtricitabine.

Presenter Paul Sax noted that many of the adverse events were small lipid changes that were "unlikely to be clinically significant." Participants in this trial did not receive HLA-B*5701 genetic screening for susceptibility to abacavir hypersensitivity reactions, since the test had not been validated when the study started. The frequency of suspected hypersensitivity in both arms was high, suggesting that site investigators were highly vigilant since they did not know who was taking abacavir.

Comparisons of the NRTI backbones in the still-blinded lower HIV RNA stratum (< 100,000 copies/mL at baseline), and each regimen's third drug (efavirenz or boosted atazanavir) in both viral load strata, are ongoing.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Harvard School of Public Health, Boston, MA; University of Washington School of Medicine, Seattle, WA; University of Miami School of Medicine, Miami, FL; National Institute of Allergy and Infectious Diseases, Bethesda, MD; ACTG Operations Center, Social & Scientific Systems Inc., Silver Spring, MD; Frontier Science & Technology Research Foundation Inc., Amherst, MA; Bristol-Myers Squibb, New York, NY; Gilead Sciences, Inc., Foster City, CA; GlaxoSmithKline, Research Triangle Park, NC; Abbott Laboratories, Abbott Park, IL; Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA.

GSK Analysis

After the interim ACTG 5202 results were released, abacavir manufacturer GlaxoSmithKline (GSK) performed an analysis of other clinical trials of abacavir/lamivudine-containing regimens that employed the same efficacy endpoint as ACTG5202 -- including the unusually short 16-week time point -- in order to assess the impact of baseline viral load on virological response.

The investigators looked at 48-week efficacy outcomes from 6 clinical trials including a total of 2940 antiretroviral-naive patients, analyzing the data by baseline viral load strata (again, <100,000 or > 100,000 copies/mL). Along with their NRTIs, participants took efavirenz or various boosted protease inhibitors.

The efficacy endpoint was time to virological failure, defined as in ACTG 5202. The safety endpoint was time to onset of the first grade 3/4 sign, symptom, or laboratory abnormality that was at least 1 grade higher than baseline.

Results

• Virological response also did not differ significantly among patients with a high viral load.

• At 96 weeks, abacavir/lamivudine and tenofovir/emtricitabine remained comparable with respect to virological response.

• Median CD4 gains at week 96 were similar, about 450 cells/mm3 in both arms.

• Lipid changes were similar in both arms.

• Looking at biomarkers associated with inflammation, levels of high sensitivity C reactive protein (hsCRP) and interleukin-6 (IL-6) fell slightly after starting therapy, and changes were similar in both groups.

The HEAT investigators concluded that "[Abacavir/lamivudine] is comparable to [tenofovir/emtricitabine] in virologic efficacy and safety when combined with lopinavir/ritonavir through 96 weeks. Both treatment regimens were well tolerated with few discontinuations due to adverse events in either arm."

It remains unclear why ACTG 5202 and HEAT produced disparate results, and further study is needed to definitively say which of these 2 backbones is superior if terms of efficacy and safety, or whether for all practical purposes they are the equal.

Rush University Medical Center, Chicago, IL; Johns Hopkins University School of Medicine, Baltimore, MD; GlaxoSmithKline, Research Triangle Park, NC; Southwest Infectious Disease Associates, Dallas, TX; North Texas Infectious Disease Consultants, Dallas, TX; ID Consultants, Charlotte, NC; Georgetown University, Washington, DC.

8/12/08

References

P Sax, C Tierney, A Collier, and others. ACTG 5202: shorter time to virologic failure with ABC/3TC than TENOFOVIR/FTC in treatment-naive subjects with HIV RNA >100,000. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0303. (Abstract)

K Pappa, J Hernandez, B Ha, and others. ABC/3TC shows robust virologic responses in ART-naive patients for baseline (BL) viral loads of >100,000c/mL and <100,000c/mL by endpoint used in ACTG5202. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THAB0304. (Abstract)

KY Smith, D Fine, P Patel, and others. Similarity in efficacy and safety of abacavir/lamivudine (ABC/3TC) compared to tenofovir/emtricitabine (TENOFOVIR/FTC) in combination with QD lopinavir/ritonavir (LPV/r) over 96 weeks in the HEAT study. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract LBPE1138.

ICAAC 2008: Efficacy and Safety of Boosted Darunavir (Prezista) Are Comparable to Lopinavir/ritonavir (Kaletra) at 96 Weeks: ARTEMIS Trial

Tibotec's second-generation protease inhibitor darunavir (Prezista) was approved in June 2006 for treatment-experienced HIV patients, to be administered at 600 mg boosted with 100 mg ritonavir twice-daily. As previously reported, in the Phase III ARTEMIS trial darunavir/ritonavir demonstrated safety and efficacy comparable to that of lopinavir/ritonavir (Kaletra) at 48 weeks. In a late-breaker session at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008), taking place this week in Washington, DC, researchers presented longer-term 96-week data from the study. Follow-up is scheduled to continue through 192 weeks.Boosted darunavir has also been studied in treatment-naive individuals, and earlier this month received approval for use in this patient population.

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AIDS 2008: Boosted Atazanavir and Lopinavir/ritonavir Have Similar Efficacy, Side Effects Differ across Racial/ethnic Groups

Race-based differences in efficacy and safety have been reported among HIV positive individuals on HAART. However, data on this issue are limited. It is widely known that rates of obesity, diabetes, and the metabolic syndrome are increasing. In addition, studies suggest that certain racial/ethnic groups may be more susceptible to the risks associated with these conditions.

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