- Category: Approved HIV Drugs
- Published on Wednesday, 10 October 2012 00:00
- Written by Liz Highleyman
Substituting abacavir/lamivudine (the drugs in Epzicom) for tenofovir/emtricitabine (the drugs in Truvada) and dropping the ritonavir (Norvir) booster with atazanavir (Reyataz) maintains undetectable HIV viral load and improves biomarkers of bone loss, researchers reported at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) last month in San Francisco.
The 4-drug regimen of tenofovir, emtricitabine, ritonavir, and atazanaviris highly effective for controlling HIV. But ritonavir causes gastrointestinal and metabolic side effects, and taking fewer total drugs is more convenient and may save money on prescription co-pays. Tenofovir can cause kidney and bone toxicity; abacavir has been linked to heart attacks in some studies, though this was not seen in a recent FDA meta-analysis.
David Wohl from the University of North Carolina at Chapel Hill and colleagues conducted an open-label non-inferiority study in which participants were randomly assigned (1:2) to either remain on their baseline regimen of tenofovir/emtricitabine plus atazanavir/ritonavir or switch to abacavir/lamivudine plus unboosted atazanavir.
The ASSURE study included 296 participants in the U.S. and Puerto Rico who had been on tenofovir/emtricitabine plus atazanavir/ritonavir for at least 6 months and had confirmed HIV RNA < 75 copies/mL. Most (about 80%) were men, about 60% were white, about 35% were black, about one-quarter identified as Hispanic/Latino, and the median age was about 43 years. At baseline the median CD4 T-cell count was high, at about 490 cells/mm3, and only 7% had < 200 cells/mm3. About 9% were coinfected with hepatitis C. Kidney function was normal at baseline (creatine clearance > 50 mL/min).
- The primary 24-week TLOVR analysis showed that the 2 regimens worked equally well, with 86.9% in the simplification arm and the 86.6% in the unchanged arm having HIV RNA < 50 copies/mL.
- The treatment difference of 0.33% demonstrated that switching treatment was non-inferior to staying on the baseline regimen.
- 6 people (3%) in the simplification arm and 1 person (1%) in the unchanged arm experienced virological failure.
- 2 people in the simplification arm and 1 person in the unchanged arm had 2 consecutive viral loads > 400 copies/mL and underwent drug-resistance testing.
- 1 person in the simplification arm and 1 in the unchanged arm had no NRTI or NNRTI resistance mutations, but had protease inhibitor resistance mutations; 1 person in the simplification arm had resistance to all 3 drug classes.
- Median CD4 cell gains at 12 weeks were similar, but levels continued to rise in the simplification arm, resulting in a significantly larger gain at 24 weeks, 48 vs 8 cells/mm3, respectively.
- Rates of study discontinuation were similar in the 2 arms, 10% and 9%, respectively; 4% and 2%, respectively, discontinued due to adverse events.
- Both regimens were generally safe and well-tolerated, with most adverse events being mild-to-moderate (grade 1-2).
- The only grade 2-4 adverse event seen in at least 5% of study participants was upper respiratory tract infections, 4% in the simplification arm and 6% in the unchanged arm.
- 1 person with several cardiovascular risk factors experienced an acute myocardial infarction, which was not considered related to study drugs.
- Elevated total bilirubin levels -- a known side effect of atazanavir -- was 3 times more common in the unchanged (boosted atazanavir) arm, 16% vs 47% (4% vs 25%, respectively, with grade 3-4 elevation).
- Total and LDL (bad) cholesterol and triglyceride levels did not change significantly in either arm, while HDL (good) cholesterol rose a bit in the simplification arm.
- No significant changes in levels of the inflammatory biomarkers hsCRP, IL-6, or D-dimer were seen in either treatment arm.
- Urine beta-2-microglobulin/creatinine ratio decreased significantly in the simplification arm while remaining stable in the unchanged therapy arm, but the more commonly used kidney markers creatinine clearance and GFR did not change in either group.
- Bone biomarkers bone osteocalcin, alkaline phosphatase, parathyroid hormone, and C-telopeptide all decreased significantly in the simplification arm, but stayed the same in the unchanged therapy arm.
"In this randomized multicenter study, simplification to [abacavir/lamivudine + atazanavir] was as effective as maintaining treatment-experienced subjects on a regimen of [tenofovir/emtricitabine + atazanavir/ritonavir]," the investigators summarized.
"Significantly greater emergent or worsening grade 2-4 laboratory toxicities, driven by total bilirubin, [were] observed in the [tenofovir/emtricitabine + atazanavir/ritonavir] group," they continued. "Significant improvements [were] observed in bone biomarkers...[and] renal urine beta-2-microglobulin/creatinine ratio in the [abacavir/lamivudine + atazanavir] group."
"These data support simplification to [abacavir/lamivudine + atazanavir] as a treatment option in virologically suppressed, treatment-experienced subjects," they concluded.
This analysis showed that 1 person had a suspected abacavir hypersensitivity reaction despite testing negative for HLA-B*5701, a genetic variation linked to hypersensitivity; symptoms resolved upon abacavir discontinuation.
The researchers reported separately that only 3% of a diverse population of HIV positive people in the U.S. and Puerto Rico who were screened for ASSURE tested positive for HLA-B*5701. In accordance with previous studies, most HLA-B*5701 positive participants were white (11 people or 85%) and 2 (15%) were black. The number of Asian or other race participants was small, and none tested HLA-B*5701 positive.
D Wohl, L Bhatti, CB Small, et al. Simplification to Abacavir/Lamivudine (ABC/3TC) + Atazanavir (ATV) from Tenofovir/Emtricitabine (TDF/FTC) + ATV/Ritonavir (RTV, /r) Maintains Viral Suppression and Improves Bone Biomarkers. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-556c.
CB Small, D Wohl, DA Margolis, et al. Prevalence of HLA-B*5701 Allele in HIV-Infected Subjects in North America and Reductions in Risk for Development of Abacavir Associated Hypersensitivity Reaction. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-895.