By Liz Highleyman

Epzicom Tablet

Truvada Tablet

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-boosted atazanavir (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

• 57 patients in the abacavir/lamivudine arm and 26 in the tenofovir/emtricitabine arm experienced virological failure.

• 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).

• In a secondary cross-sectional analysis with prior virological failures and regimen changes included, 75% (69%-80%) of patients in the abacavir/lamivudine arm and 80% (74%- 85%) in the tenofovir/emtricitabine arm achieved HIV RNA < 50 copies/mL at week 48 (p = 0.20).

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

• There were considerably more instances of regimen modification in the abacavir/lamivudine arm compared with the tenofovir/emtricitabine arm.

• 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).

• AEs were predominantly general body aches and blood lipid increases.

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

• There were no myocardial infarctions in either arm.

• 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

• By 48 weeks, 87%-95% of participants across all regimens did not experience virological failure.

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

• Safety outcomes were similar regardless of viral load strata.

These results led to researchers to conclude that, "Using the efficacy and safety endpoint defined in ACTG 5202, this analysis of 6 clinical trials showed that the efficacy of [abacavir/lamivudine]-containing regimens was robust in antiretroviral-naive patients irrespective of baseline viral load."

GlaxoSmithKline, Infectious Diseases MDC, U.S. HIV Collaborative Studies, Research Triangle Park, NC.

HEAT Findings

GSK's HEAT trial (Head-to-head Epzicom and Truvada), like ACTG 5202, aimed to determine which regimen is best for initial antiretroviral therapy. As its name suggest, HEAT directly compared abacavir/lamivudine vs tenofovir/emtricitabine, with all participants taking the same third drug, lopinavir/ritonavir (Kaletra). Investigators presented 96-week findings in a poster last week; 48-week data from HEAT[LINK TO 2/5/08 ARTICLE] were presented at the 2008 Conference on Retroviruses and Opportunistic Infections in February.

HEAT included 688 treatment-naive participants; most (82%) were men, half were white, and 36% were black. Patients started with a plasma HIV RNA level > 1000 copies/mL, and were stratified as having greater or less than 100,000 copies/mL. The baseline CD4 count was about 200 cells/mm3. This study also did not perform HLA-B*5701 screening at baseline.

As previously reported, at 48 weeks, 68% of patients in the abacavir/lamivudine arm and 67% in the tenofovir/emtricitabine arm had HIV RNA < 50 copies/mL in an intent-to-treat (ITT) analysis, missing = failure (M=F) analysis.

Results

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

• 60% vs 58%, respectively, maintained HIV RNA < 50 copies/mL in an ITT, M=F analysis.

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

• Treatment discontinuations were uncommon, and occurred at a similar rate in both groups.

• Lipid changes were similar in both arms.

• No patients in the abacavir/lamivudine arm experienced kidney failure, compared with 1% in the tenofovir/emtricitabine arm.

• 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.