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CROI 2008: Abacavir/3TC (Epzicom) Matches Tenofovir/Emtricitabine (Truvada) for Treatment-naive Patients: HEAT Study

While there is always much interest in new antiretroviral drug classes, research continues as well on the earliest type of anti-HIV therapy, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). At the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008) this week in Boston, researchers presented data from the HEAT (Head-to-head Epzicom And Truvada) trial, a direct comparison of 2 double-NRTI backbones.

• Abacavir (Ziagen) plus 3TC (Epivir), coformulated in the Epzicom fixed-dose combination pill.

• Tenofovir (Viread) plus emtricitabine (Emtriva), coformulated in the Truvada pill and, with efavirenz (Sustiva), in the Atripla 3-drug combination pill.

Abacavir is generally well tolerated, but can cause hypersensitivity reactions in a small percentage of patients. The risk of such reactions has fallen with the introduction of the HLA-B*5701 genetic test, which shows which patients are at risk and should therefore avoid abacavir.

Tenofovir is widely used (especially as part of the 1-pill once-daily Atripla coformulation) and is also well tolerated, though a small percentage of patients may develop kidney toxicity and some (albeit mixed) data suggest a potential association with bone loss.

The HEAT study evaluated the efficacy and safety of the 2 backbones in combination with lopinavir/ritonavir (Kaletra) soft-gel capsules once daily in patients starting antiretroviral therapy for the first time (the study began before the new "Meltrex" formulation of Kaletra was approved).

The randomized, double-blind, 96-week, non-inferiority trial included 688 treatment-naive participants at multiple U.S. sites. Most (82%) were men and the average age was 38 years; half were white and 36% were African American. Patients started with a plasma HIV RNA level > 1000 copies/mL, as were stratified as having greater or less than 100,000 copies/mL. The baseline CD4 cell counts were 214 cells/mm3 in the Epzicom arm and 193 cells/mm3 in the Truvada arm.

Virological failure was defined as failure to achieve a viral load < 200 copies/mL by week 24, or confirmed rebound to > 200 copies/mL. Patients were allowed to make certain therapy switched due to toxicity and remain in the study. HLA-B*5701 screening for abacavir hypersensitivity was not performed in advance.

The primary efficacy endpoint was the proportion of patients with viral load < 50 copies/mL at week 48; non-inferiority was analyzed using a 12% threshold. The primary safety endpoint will be safety at week 96; the study was only partially unblinded to allow the interim efficacy analysis.

Results

• At 48 weeks, percentages of patients with HIV RNA < 50 copies/mL were as follows:

• 68% in the Epzicom arm and 67% in the Truvada arm in an intent-to-treat analysis with missing = failure and patients who switched included in the analysis (P = 0.91).

• 64% and 62%, respectively, in an intent-to-treat analysis with missing = failure, but patients who discontinued or switched excluded from the analysis.

• 63% and 61%, respectively, in a TLOVR (time to loss of virological response) analysis (P = 0.68).

• 84% and 87%, respectively, in an observed (as-treated) analysis (P = 0.40).

• Percentages with HIV RNA < 400 copies/mL were as follows:

• 75% in the Epzicom arm and 71% in the Truvada arm in an intent-to-treat, missing = failure, switch included analysis (P = 0.25).

• 94% and 92%, respectively, in an observed analysis (P = 0.47).

• Confirmed virological failure occurred in 12% of patients in the Epzicom arm and 11% in the Truvada arm.

• The median increases in CD4 count from baseline were 201 cells/mm3 in the Epzicom arm and 173 cells/mm3 in the Truvada arm.

• Percentages of patients who withdrew from the study early for any reason were 20% in the Epzicom arm and 24% in the Truvada arm.

• 19% and 24%, respectively, discontinued due to adverse events.

• Moderate-to-severe (Grade 2-4) adverse event rates were 45% and 44%, respectively.

• Rates of diarrhea (18% vs 19%), nausea (7% vs 6%), and elevated triglycerides (6% vs 5%) were similar in both arms.

• Elevated cholesterol occurred in 6% of Epzicom patients and 3% of Truvada patients.

• 4% in the Epzicom arm and 1% in the Truvada arm stopped due to a suspected abacavir hypersensitivity reaction.

• 0% and 1%, respectively, developed proximal renal tubular dysfunction (a potential indicator of kidney toxicity), though glomerular filtration rate decreases occurred in 5% of patients in both arms.

• 34% taking Epzicom and 53% taking Truvada developed treatment-emergent resistance mutations.

• M184V or mixtures were the most common mutations in both arms, but were twice as common in the Truvada arm; a few previously unreported M184A mutations were noted in the Truvada arm.

Conclusion

Based in these results, the investigators concluded, "Abacavir/3TC was non-inferior to tenofovir/[emtricitabine] when combined with once-daily lopinavir/ritonavir. Median CD4 increase was greater in the abacavir/3TC arm at week 48."

"Both once-daily treatment regimens were well tolerated with few discontinuations due to adverse events in either arm," they added.

The study is ongoing and 96 week safety will be reported when it becomes available.

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

2/5/08

Reference

K Smith, D Fine, P Patel, and others. Efficacy and Safety of Abacavir/Lamivudine Compared to Tenofovir/Emtricitabine in Combination with Once-daily Lopinavir/Ritonavir through 48 Weeks in the HEAT Study. CROI 2008. Boston, MA. February 3-6, 2008. Abstract 774