The ASSURE study: HIV‐1 suppression is maintained with bone and renal biomarker improvement 48 weeks after ritonavir discontinuation and randomized switch to abacavir/lamivudine + atazanavir

Abstract

Objectives HIV treatment guidelines endorse switching or simplification of antiretroviral therapy in therapy‐experienced patients with suppressed viraemia; ritonavir discontinuation may also enhance tolerability and reduce long‐term adverse events (AEs). This open‐label, multicentre, noninferiority study enrolled HIV‐1‐infected, treatment‐experienced adults with confirmed HIV‐1 RNA ≤ 75 HIV‐1 RNA copies/mL currently receiving tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC + ATV/r) for ≥ 6 months with no reported history of virological failure.MethodsParticipants were randomized 1:2 to continue current treatment or switch to abacavir/lamivudine + atazanavir (ABC/3TC + ATV). Endpoints included the proportion of participants with HIV‐1 RNA < 50 copies/mL by time to loss of virological response (TLOVR), AEs, fasting lipids, and inflammatory, coagulation, bone and renal biomarkers.ResultsAfter 48 weeks, 76% (152 of 199) of ABC/3TC + ATV‐treated and 79% (77 of 97) of TDF/FTC + ATV/r‐treated participants had HIV‐1 RNA < 50 copies/mL (TLOVR; P = 0.564). Other efficacy analyses yielded similar results. Rates of new grade 2–4 AEs were 45% in both groups, but an excess of hyperbilirubinaemia made the rate of treatment‐emergent grade 3–4 laboratory abnormalities higher with TDF/FTC + ATV/r (36%) compared with ABC/3TC + ATV (19%). Most fasting lipid levels remained stable over time; high‐density lipoprotein (HDL) cholesterol increased modestly in ABC/3TC + ATV‐treated participants. Bone and renal biomarkers improved significantly between baseline and week 48 in participants taking ABC/3TC + ATV and were stable in participants taking TDF/FTC + ATV/r. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups.ConclusionsThe ABC/3TC + ATV treatment‐switch group had similar viral suppression rates up to 48 weeks to the TDF/FTC + ATV/r comparator group, with lower rates of moderate‐ to high‐grade hyperbilirubinaemia and improvements in bone and renal biomarkers.

Switching to abacavir versus use of a nucleoside‐sparing dual regimen for HIV‐infected patients with tenofovir‐associated renal toxicity

“…However, the ASSURE (A Simplification Study of Unboosted Reyataz with Epzicom) trial showed a nonsignificant improvement in eGFR after switching from TDF to abacavir (+0.8 vs . −1.3 in those who continued TDF), but significantly better evolution in tubular proteinuria . A significant improvement in eGFR, albuminuria and phosphataemia was also found in a recent study where TDF was switched to abacavir, regardless of whether or not patients continued with atazanavir .…”

“…In the ASSERT (KIVEXA Vs TRUVADA, Both Administered With Efavirenz, In ART-Naive Subjects) study, the use of TDF was associated with a significant increase in tubular proteinuria in comparison with the use of abacavir, but there were no differences in eGFR [19], as observed in the STEAL (Simplification with Tenofovir-Emtricitabine or Abacavir-Lamivudine) study [20]. However, the ASSURE (A Simplification Study of Unboosted Reyataz with Epzicom) trial showed a nonsignificant improvement in eGFR after switching from TDF to abacavir (+0.8 vs. À1.3 in those who continued TDF), but significantly better evolution in tubular proteinuria [21]. A significant improvement in eGFR, albuminuria and phosphataemia was also found in a recent study where TDF was switched to abacavir, regardless of whether or not patients continued with atazanavir [22].…”

“…Secondly, follow‐up was short, and therefore there are no data on the long‐term evolution of renal toxicity, compared with the risk of virological failure after switching treatments. However, previous randomized studies with strategies used in this study have shown a high virological efficacy when switching therapies . Finally, the number of patients was low for each different cART regimen, and comparisons between specific drugs or different dual regimens were not possible.…”

The protease inhibitors and HIV-associated bone loss

“…While the effects of the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) on bone resorption and BMD are well established [25–28*, 29, 30*], the effects of the PIs on BMD are less clear. However, most studies suggest an association between PI use and BMD loss [15, 31**–35*].…”

Bone Loss in HIV Infection

“…Both cART-naïve and virologically suppressed HIV-infected patients exposed to TDF experience 1–3% more bone loss than those exposed to other NRTIs in [57–61]. Additionally, reversible TDF-associated bone loss has been observed in healthy, HIV-uninfected men and women taking TDF for pre-exposure prophylaxis (PrEP) [62–64], thus confirming the effects of TDF on bone beyond what can be attributed to viral or immune factors.…”