The RADAR Study: Week 48 Safety and Efficacy of RAltegravir Combined with Boosted DARunavir Compared to Tenofovir/Emtricitabine Combined with Boosted Darunavir in Antiretroviral-Naive Patients. Impact on Bone Health

Abstract

BackgroundNRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression.MethodsIn the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48.ResultsUsing an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP).ConclusionThe NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health.Trial RegistrationClinicalTrials.gov NCT 00677300

Bones, Fractures, Antiretroviral Therapy and HIV

“…The RADAR Study, presented at the 2013 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS), presents a cautionary tale [9]. Ritonavir-boosted darunavir (DRV/rtv) was paired with either RAL or tenofovir/emtricitabine (TDF/FTC) in 80 ART-naïve persons.…”

Bone loss in HIV

“…Net differences in percentage change in BMD between groups were significant at 24 weeks at both the spine and hip (spine: −0.91%; p=0.001 and hip: −0.61%; p=0.001)[44**]. Further, in HIV, studies comparing TDF-containing ART and ART without TDF in ART-naïve HIV-infected individuals have consistently shown that ART without TDF leads to less BMD decline over the first 48 to 96 weeks of treatment[45*, 46] as well as less increase in bone turnover markers[47*, 48]. Last, in virologically suppressed, HIV-infected participants, switching from a TDF-containing regimen to an alternative NRTI or an NRTI-sparing regimen also leads to improvement in bone turnover markers, including sclerostin, a selective regulator of bone formation through the Wnt pathway[49*] and results in increase in BMD[50*].…”

Review of integrase strand transfer inhibitors for the treatment of human immunodeficiency virus infection

“…At week 48, 60% (n = 24/40) of the patients in RAL group and 83.7% (n = 36/43) in TDF/FTC group achieved VL <48 copies/ml (difference À23.7%, 95% CI: À42.9 to À5%) p = 0.016. Unlike PROGRESS study, RADAR study showed that RAL in combination with DRV/r does not achieve comparable viral suppression as TDF/FTC plus DRV/r [22]. NEAT001/ANRS143, a randomized, open-label, noninferiority study comparing the same drug regimens as RADAR in treatment-naïve patients with VL >1000 copies/ml, no documented resistance to the study drugs and CD4 cell count <500 cells/mm 3 , found that NRTI-sparing regimen was non-inferior in patients with baseline CD4 cell count >200 cells/mm 3 [23] (TABLE 3).…”