By Liz Highleyman

Abacavir/ lamivudine (Epzicom)

Atazanavir (Reyataz)

Tenofovir/ emtricitabine (Truvada)

Recently presented data have offered conflicting evidence concerning the relative effectiveness of nucleoside reverse transcriptase inhibitor (NRTI) backbone combinations.

As previously reported, the ACTG A5202 study showed that among patients with a high baseline viral load (HIV RNA ? 100,000 copies/mL), those taking abacavir plus lamivudine (the drugs in the Epzicom fixed-dose coformulation) with either boosted atazanavir (Reyataz) or efavirenz (Sustiva) were more likely to experience virological failure -- and to do so more rapidly -- than those taking tenofovir plus emtricitabine (the drugs in the Truvada combination pill).

However, the HEAT study -- a head-to-head comparison of Epzicom versus Truvada in combination with lopinavir-ritonavir (Kaletra) -- and a retrospective analysis of 6 previous abacavir trials conducted by manufacturer GlaxoSmithKline found that the backbones had similar efficacy.

New data presented this week at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Washington, DC, provide further support for both sides of the debate. (The HEAT and GlaxoSmithKline trial review results were presented again as posters at ICAAC.)

ARIES

The ARIES (Atazanavir/Ritonavir Induction/Simplification) study enrolled participants at the same time as ACTG A5202 and used the same regimen as the A5202 abacavir/lamivudine arm. This open-label study included more than 500 treatment-naive participants in North America with a viral load of at least 1000 copies/mL at screening and any CD4 cell count. Most (83%) were men, the median age was 38 years, 63% were white, 32% were black, and the median CD4 count was 199 cells/mm3. More than half (56%) had baseline viral load > 100,000 copies/mL.

Participants were pre-screened with the HLA-B*5701 genetic test for abacavir hypersensitivity. Of the initial 725 patients screened, 41 (5.7%) were found to be HLA-B*5701 positive and excluded from the trial.

All patients initially started taking abacavir/lamivudine plus 300/100 mg ritonavir-boosted atazanavir (Reyataz), then at week 36, they were randomly assigned to either stay on the same regimen or else switch to 400 mg/day atazanavir and discontinue ritonavir.

Virological failure was defined as failure to achieve HIV RNA < 400 copies/mL by week 30 or confirmed rebound to > 400 copies/mL. The researchers performed an additional analysis of the A5202 primary efficacy endpoint of viral load > 1000 copies/mL between weeks 16 and 24 -- an unusual time frame, as most trials do not report virological response before 24 weeks -- or > 200 copies/mL at or after week 24.

Results

• In a pre-planned intent-to-treat analysis at week 36, 410 out of 515 patients (80%) achieved HIV RNA < 50 copies/mL.

• o Among those with baseline viral load < 100,000 copies/mL: 190 out of 227 (84%);

• Among those with baseline viral load > 100,000 copies/mL: 220 out of 288 (76%).

• 422 of 515 patients (82%) achieved HIV RNA > 200 copies/mL in a time to loss of virological response (TLOVR) analysis:

• Among those with baseline viral load < 100,000 copies/mL: 193 out of 227 (85%);

• Among those with baseline viral load > 100,000 copies/mL: 229 out of 288 (80%).

• Looking at the primary A5202 endpoint, the overall percentage was 97%:

• Among those with baseline viral load < 100,000 copies/mL: 98%;

• Among those with a baseline viral load > 100,000 copies/mL: 95%.

• 15 patients (3%) experienced virological failure (1% failed to achieve virological response and 2% experienced viral rebound).

• 5 failures (2%) in patients with baseline viral load < 100,000 copies/mL;

• 10 failures (4%) in people with >100,000 copies/mL.

• The average CD4 count increase from baseline was 171 cells/mm3.

• 86% of participants completed 36 weeks of therapy, while 14% dropped out.

• 142 patients (28%) experienced moderate to severe (grade 2-4) drug-related adverse events, most commonly hyperbilirubinemia (elevated blood bilirubin, a known side effect of atazanavir; 13%) and diarrhea (4%).

• Less than 1% were diagnosed with a clinically suspected abacavir hypersensitivity reaction.

These findings led the investigators to conclude, "The combination of [abacavir/lamivudine + atazanavir/ritonavir] demonstrated potent antiviral activity through 36 weeks of follow-up in this population of [antiretroviral therapy]-naive subjects."

Based on the ACTG A5202 endpoint, they continued, "similar virologic success rates were achieved irrespective of viral load strata."

Since the proportions of patients with low and high baseline viral load achieving HCV RNA suppression below 200 and 400 copies/mL were closer than the percentages achieving < 50 copies/mL by week 36, the researchers suggested that high viral load patients might be slower to respond, but typically eventually achieved full suppression.

"These results further support that the combination of Epzicom and atazanavir/ritonavir is a generally well-tolerated treatment regimen for HIV-infected patients initiating therapy with a high viral load," said Mark Shaefer, PharmD, Director of Clinical Development at GlaxoSmithKline, in a press release issued by the company.

Thomas Jefferson Univ., Philadelphia, PA; Univ. of Colorado, Denver, CO; Orlando Immunology Ctr., Orlando, FL; Southwest Infectious Disease Association, Dallas, TX; Clinique Med. L'Actuel, Montreal, Canada; GSK, Research Triangle Park, NC.

12-trial Meta-analysis

Andrew Hill from the University of Liverpool in the U.K. and Will Sawyer from SEARCH in Bangkok, Thailand, conducted a meta-analysis of prior clinical trials comparing the efficacy of the abacavir/lamivudine and tenofovir/emtricitabine NRTI backbones as part of a first-line regimen containing a ritonavir-boosted protease inhibitor (PI).

The researchers performed a systematic MEDLINE search of the medical literature, identifying 12 relevant clinical trials published between January 1, 2000 and March 1, 2008, with a total of 4896 treatment-naive patients. HEAT was included, but ACTG A5202 was not, since data from the low viral load arm have not yet been released.

In 21 treatment arms, participants used abacavir/lamivudine (n = 1556) or tenofovir/emtricitabine (n = 3340) with a boosted PI. There were no significant differences between abacavir/lamivudine and tenofovir/emtricitabine recipients with regard to baseline CD4 count (195 vs 204 cells/mm3, respectively) or viral load (5.0 and 4.9 log10, respectively).

For each NRTI backbone and boosted PI combination, the percentages of patients with HIV RNA < 50 copies/mL at week 48 by standardized intent-to-treat "non-completer = failure" TLOVR analysis were combined using inverse-variance weighting. The effect of baseline HIV RNA, CD4 cell count, and choice of NRTI backbone were assessed using a weighted analysis of covariance.

Results

• The efficacy of first-line HAART correlated with baseline HIV RNA and CD4 count.

• Across all studies, 75% of patients with baseline viral load > 100,000 copies/mL achieved virological response compared with 69% of those with < 100,000 copies/ml.

• Use of tenofovir/emtricitabine was associated with higher rates of HIV RNA suppression < 50 copies/mL for each of the 3 boosted PIs with available data:

• Lopinavir/ritonavir:

• Tenofovir/emtricitabine (n = 2285): 74%;
• Abacavir/lamivudine (n = 722): 66%.

• Fosamprenavir (Lexiva)/ritonavir:

• Tenofovir/emtricitabine (n = 53): 75%;
• Abacavir/lamivudine (n = 722): 67%.

• Atazanavir/ritonavir:

• Tenofovir/emtricitabine (n = 493): 79%;
• Abacavir/lamivudine (n = 112): 77%.

• Tenofovir/emtricitabine data were available for saquinavir(Invirase)/ritonavir (n = 166; 65%) and darunavir(Prezista)/ritonavir (n = 343; 84%), but there was no abacavir/lamivudine comparison data.

• Overall response rates for people with baseline HIV RNA < 100,000 copies/mL were 79% for tenofovir/emtricitabine and 70% for abacavir/lamivudine (P = 0.0001).

• For those with baseline HIV RNA > 100,000 copies/mL, the corresponding rates were 71% and 66%, respectively, a difference that did not reach statistical significance (P = 0.0995).

Based on these findings, the researchers concluded, "This systematic meta-analysis of standardized HIV RNA < 50 copy efficacy data, using the FDA TLOVR algorithm, suggests higher efficacy for first-line use of a [tenofovir/emtricitabine] NRTI backbone, relative to use of [abacavir/lamivudine]."

"This apparent difference in efficacy was seen for patients with baseline HIV RNA levels below and above 100,000 copies/mL," they added.

They noted that when using the TLOVR endpoint, a majority of treatment "failures" are due to discontinuations for reasons other than poor virological response. Therefore, they stated, "apparent differences in treatment efficacy between trials might be influenced by differences in trial procedures to manage adverse events, or maintain adherence."

A caveat to these findings is that the studies generally did not employ HLA-B*5701 screening -- which only recently became widely available -- so the differences in TLOVR response rates may reflect a higher drop-out rate in the abacavir/lamivudine arms due to suspected hypersensitivity reactions.

Liverpool Univ., Liverpool, UK; SEARCH Thailand, Bangkok, Thailand.

10/31/08

References

K Squires, B Young, E Dejesus, and others. Atazanavir/Ritonavir (ATV/r) + Abacavir/Lamivudine (ABC/3TC) in Antiretroviral (ART)-Naive HIV-1 Infected HLA-B*5701 Negative Subjects Demonstrates Efficacy and Safety: the ARIES Trial. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1250a.

B Young, K Smith, P Patel, and others. Characterization of Virologic Failure (VF) Over 96 Weeks by Drug Resistance and Antiviral Response in ART Naïve Patients Receiving Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) Each with Lopinavir/Ritonavir QD in the HEAT Study. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1233.

KA Pappa, F Ha, H Brothers, and others. Six Abacavir/Lamivudine (ABC/3TC) Clinical Trials Show Robust Virologic Responses in ART-Naïve Patients for Baseline (BL) Viral Loads (VL) of ?100,000c/mL and <100,000c/mL. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1251.

AM Hill and WS Sawyer. Effects of NRTI Backbone on Efficacy of First-line Boosted Pi Based Haart - Meta-analysis of 12 Clinical Trials in 4896 Patients. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1254.

Other source

GlaxoSmithKline. Similar Virologic Success Rates for Patients on EPZICOM Irrespective of Viral Load Strata Seen in ARIES Study. Press release. October 26, 2008.