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TDF/FTC-to-ABC/3TC Switch Maintains Viral Suppression, Eases Bone Markers
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53rd ICAAC, September 10-13, 2013, Denver
Mark Mascolini
A switch from tenofovir/emtricitabine (TDF/FTC) to abacavir/lamivudine (ABC/3TC), both with atazanavir/ritonavir, maintained viral suppression through 48 weeks in a noninferiority analysis and improved bone and kidney markers. Four people in the ABC/3TC arm (2%) and one in the TDF/FTC arm (1%) had study-defined virologic failure by week 48.
Questions about the antiviral impact of ABC/3TC in maintenance therapy emerged in a 333-person Spanish study of nucleoside-experienced people with a viral load below 200 copies for at least 6 months on a 3TC-containing regimen [2]. The investigators randomized them to switch to ABC/3TC or TDF/FTC. At week 48 the virologic failure rate was higher in the ABC/3TC group, and ABC/3TC did not meet noninferiority criteria for efficacy compared with TDF/FTC [2]. In two randomized trials that enrolled antiretroviral-naive people, ABC/3TC did not control HIV as well as TDF/FTC [3], especially in people with a pretreatment viral load above 100,000 copies [4].
The new trial, ASSURE, differed from all these earlier studies. ASSURE enrolled 296 people with a confirmed viral load below 75 copies for at least 6 months while taking TDF/FTC plus atazanavir/ritonavir and randomized them in a 2-to-1 ratio to switch to ABC/3TC or continue TDF/FTC, both while maintaining atazanavir/ritonavir. TDF/FTC plus atazanavir/ritonavir could be a first-line regimen or a first or second switch regimen, as long as virologic failure did not cause the switch. Everyone had an estimated glomerular filtration rate (eGFR) at or above 50 mL/min.
In the ABC/3TC and TDF/FTC groups, median age stood at 44 and 42 years, 78% and 81% of participants were men, and 61% and 57% were white. Median baseline viral load lay below 40 copies both groups, and median CD4 count measured 492 in people assigned to ABC/3TC and 480 in those assigned to TDF/FTC.
At 24 weeks ABC/3TC met the primary endpoint of virologic noninferiority to ABC/3TC. A week-48 time-to-loss-of-virologic-response (TLOVR) analysis determined that 152 of 199 people randomized to ABC/3TC and 77 of 97 randomized to maintain TDF/FTC had a viral load below 50 copies (76.4% versus 79.4%, nonsignificant at P = 0.564). In an observed analysis, 91.1% taking ABC/3TC and 96.3% taking TDF/FTC had a sub-50 load at 48 weeks (P = 0.134).
Four people in ABC/3TC group and 1 in the TDF/FTC group (2% versus 1%) met criteria for virologic failure (consecutive viral loads above 400 copies). Two of these 5 people, both taking ABC/3TC, had resistance-associated mutations and reduced susceptibility to study drugs at virologic failure. CD4 counts rose significantly more with ABC/3TC than with TDF/FTC (median 90, interquartile range [IQR] 3 to 181, versus 47, IQR -32 to 121, P = 0.026).
Seventeen people randomized to ABC/3TC and 6 randomized to maintain TDF/3TC had any drug-related adverse events through 48 weeks, but this difference was not significant (9% versus 6%, P = 0.645). The same proportion in each study arm, 45%, had any grade 2 to 4 adverse event. Eight people (4%) taking ABC/3TC and 2 (2%) taking TDF/FTC had an adverse event leading to withdrawal from the study.
Incidence of any grade 2 to 4 lab toxicity was significantly lower with ABC/3TC (50% versus 69%, P = 0.003), as was incidence of any grade 3 or 4 event (19% versus 36%, P = 0.001). Median eGFR rose (improved) 0.8 mL/min with ABC/3TC and fell 1.3 mL/min with continued TDF/FTC, but this difference lacked significance (P = 0.566).
Renal urine beta-2 microglobulin/creatinine ratio declined (improved) significantly after the switch to ABC/3TC (P < 0.001) and did not change with continued TDF/FTC. Bone markers alkaline phosphatase, c-telopeptide, osteocalcin, and parathyroid hormone also dropped significantly with ABC/3TC (P < 0.001) but did not change with TDF/FTC. Serum calcium levels stayed flat after the switch to ABC/3TC, while vitamin D levels fell 4 ng/mL, a nonsignificant change.
Two markers of inflammation (high-sensitivity C-reactive protein and IL-6) and a coagulation marker (d-dimer) did not change significantly in either study arm. "Good" high-density lipoprotein cholesterol rose slightly with ABC/3TC and fell slightly with TDF/FTC through 48 weeks (P = 0.013 for between-group difference), and no other lipid values changed significantly in either group.
The ASSURE investigators concluded that "simplification to ABC/3TC plus atazanavir from an atazanavir/ritonavir-containing regimen maintained viral suppression, was well-tolerated, and led to improvements in specific bone and renal biomarkers through 48 weeks."
References
1. Wohl D, Bhatti L, Small CB, et al. Simplification to abacavir/lamivudine (ABC/3TC) + atazanavir (ATV) from tenofovir/emtricitabine (TDF/FTC) + ATV/ritonavir maintains viral suppression and improves bone biomarkers: 48 week ASSURE study results. 53rd ICAAC. September 10-13, 2013. Denver. Abstract H-665.
2. Martínez E, Arranz JA, Podzamczer D, et al. A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression. J Acquir Immune Defic Syndr. 2009;51:290-297.
3. Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55:49-57.
4. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009;361:2230-2240.
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