Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment

Abstract

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.gov No. NCT01815736), we randomized virologically suppressed (HIV-1 RNA <50 copies/ml) adults (2:1) to receive a once-daily, single-tablet regimen containing elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and TAF group or to continue one of four TDF-containing regimens (TDF group) for 96 weeks. We evaluated efficacy (HIV-1 RNA <50 copies/ml using the FDA snapshot algorithm) and prespecified bone and renal endpoints at week 96. We randomized and treated 1,436 participants in this study (TAF n = 959, TDF n = 477). At week 96, TAF was superior to TDF in virologic efficacy, with 93% on TAF and 89% on TDF having HIV-1 RNA <50 copies/ml (difference 3.7%, 95% confidence interval: 0.4%-7.0%). Improvements in hip and spine bone mineral density for those assigned to TAF versus TDF continued through week 96 (p < .001). Significant improvements in urine protein or albumin to creatinine ratios were also seen among those in the TAF group versus TDF through week 96 (p < .001). There were no cases of investigator-reported proximal renal tubulopathy in the TAF group as compared with one case in the TDF group. Switching to EVG/COBI/FTC/TAF (E/C/F/TAF) was associated with statistically significant efficacy and safety advantages over remaining on a standard-of-care TDF-based regimen.

Antiviral activity of HIV‐1 integrase strand‐transfer inhibitors against mutants with integrase resistance‐associated mutations and their frequency in treatment‐naïve individuals

“…These data suggest that these mutations may help restore the fitness of viruses with major INSTI DRMs with an effect on susceptibility to EVG. However, none of these mutations have been observed to develop in clinical studies of EVG in treatment‐naïve subjects or in virologically suppressed subjects switching to E/C/F/TAF (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) after up to 3 years of treatment, suggesting a potential genetic barrier to the development of these mutations. Importantly, the coexistence of these minor INSTI DRMs along with major INSTI DRMs in the mutants tested did not affect the susceptibility to BIC and DTG, indicating a lack of cross‐resistance to these drugs.…”

Switching regimens in virologically suppressed HIV‐1‐infected patients: evidence base and rationale for integrase strand transfer inhibitor (INSTI)‐containing regimens

“…In this study, assessments were made for bone mineral density (BMD) and renal function. Hip and spine BMD significantly improved in the switch group at 48 and 96 weeks . Significant improvements in renal function were seen in patients who switched from TDF‐based regimens to EVG/COBI/FTC/TAF .…”

“…Hip and spine BMD significantly improved in the switch group at 48 and 96 weeks . Significant improvements in renal function were seen in patients who switched from TDF‐based regimens to EVG/COBI/FTC/TAF . Excluding patients switched from EFV/FTC/TDF, mean serum creatinine in those assigned to the TDF (control) group rose compared with the switch to TAF group (2.9 vs .…”

“… SWITCHMRK SPIRAL STRATEGY‐PI STRATEGY‐NNRTI STRIIVING (unpublished at the time of submission) GS‐US‐292‐0109 (GS Study 109) …”

“…• SWITCHMRK [30] • SPIRAL [31][32][33][34][35] • STRATEGY-PI [40,45,46] • STRATEGY-NNRTI [39,42,43] • STRIIVING (unpublished at the time of submission) [36,37] • GS-US-292-0109 (GS Study 109) [38,47] Three of these studies assessed a switch to raltegravir (RAL) (SWITCHMRK and SPIRAL) or elvitegravir (EVG)/ cobicistat (COBI) (STRATEGY-PI) in patients who had received only PI/r-based regimens; two studies assessed a switch from multiple third agents to EVG/COBI (GS Study 109) or dolutegravir (DTG) (STRIIVING). The STRATEGY-NNRTI study assessed a switch to the fixed dose INSTI- Patients with a history of virological failure were eligible to enter SWITCHMRK and SPIRAL but were excluded from the other studies (Table 1).…”