HTB

High efficacy from switching to bictegravir/F/TAF in virally suppressed participants – including analyses by baseline drug resistance

Simon Collins, HIV i-Base

Several studies at IAS 2019 presented data on switching to bictegravir/FTC/TAF (B/F/TAF).

Paul Sax from Brigham and Women’s Hospital, Boston, presented results from a randomised double-blind phase 3 study (4030) switching people with undetectable viral load on stable dolutegravir (DTG)-based ART (plus either FTC/TDF or TFC/TAF).

The study randomised565 participants to B/F/TAF (n=284) or DTG+F/TAF (n=281). Although history of integrase resistance was an exclusion criteria, documented drug resistance to NRTI, NNRTI and protease inhibitors was allowed.

Approximate baseline characteristics included median age 50 years (IQR: 20 to 79), 85% men. 70% white, 22% Black/African and 22% Hispanic/Latino. Median CD4 count was about 640 cells/mm3(IQR: 460 to 885).

At week-48, viral load was <50 copies/mL by snapshot analysis in 93% vs 91% in the B/F/TAF vs DTG+F/TAF arms respectively. The results for primary endpoint of viral failure (>50 copies/mL) was <1% vs 1% (n=1 vs 3), meeting criteria for non-inferiority (diff. –0.7%, 95% CI: –2.8 to 1.0) using 4% margin. Sensitivity analyses using <20 copies/mL cut-off reported undetectable viral load in 91% vs 86% overall and 64% vs 60% for target not detected (B/F/TAF vs DTG + F/TAF).

Adverse events were similar between arms, including leading to drug continuation (n=6 in each arm (2.1%) and including grade 3.4 laboratory abnormalities. No significant differences in lipids were reported between arms with similar use of lipid lowering drugs at baseline through to week-96.

There were also no differences in rates of viral suppression between arms in the 24% participants with previous NRTI resistance: K65R or >2 thymidine analogue mutations (TAMS) (94% vs 93%) or other NRTI (87% vs 87%). No participants in either group with previous NRTI resistance developed detectable viral load over 48 weeks and there were no newly emergent integrase-related mutations. Further results on drug resistance in this study were included in a separate poster. [2]

Another two posters provided similar reports of viral suppression with baseline drug resistance.

Andreatta et al looked at drug resistance in 510 participants in the control arms of two switch studies who rolled over into the open label extension (OLE) to receive B/F/TAF for a median of 60 weeks (IQR: 48 to 72). [3]

Cumulative baseline genotypic data were available for NRTI in 73% (373/510) and integrase in 49% (248/510), with primary mutations in 11% (41/373) and 3.6% (9/248), for NRTI and integrase respectively. DNA genotyping detected previously undocumented M184V/I in 5.4% (20/373), and TAMs were observed in 8.0% (30/373).

However,99% (503/510) of participants had viral load < 50 copies/mL at last visit, including 95% (19/20) with archived M184V/I, 100% (30/30) with TAMs, and 100% (9/9) with integrase resistance. No new resistance was detected during the OLE in the five participants who met criteria for resistance testing.

Acosta et al presented a second poster looked at low level baseline resistance using deep sequencing in 1270 treatment-naive participants in a further two studies. [4]

Additional primary resistance mutations not found by population sequencing were detected in 3.7%, 3.7%, 4.2% and 5.8% for NRTI, integrase, NNRTI and PI-associated mutations, respectively. Overall, participants with low-frequency resistance mutations had viral load < 50 copies/mL at week 96 at similar rates similar to the overall study.

In women, Cissy Kityo from the Joint Clinical Research Centre in Kampala presented results 96-week phase 3 results from 470 women on stable selected ART regimens who were randomised (1:1) to either switch to once-daily B/F/TAF or remain on their current ART. At week-48, participants in the control arm were switched to B/FTAF until week-96. [5]

This was an open-label study with sites in the Dominican Republic, Russian Federation, Thailand, Uganda, and the US. Baseline regimens at entry was elvitegravir/cobicistat/F/TAF (54%), E/C/F/TDF (43%) or atazanavir + ritonavir + F/TDF (5%).

Baseline characteristics at randomisation included median age 40 years (range: 21 to 64), median CD4 count 701 cells/mm3(IQR: 539 to 895) and baseline eGFR was 100 (IQR: 83 to 117). Ethnicity included black/African (37%), white (28%), Asian (22%) and Hispanic/Latino (15%). Only six women had viral load that was detectable >50 copies/mL.

Although B/F/TAF looks to have produced high rates or viral suppression these results were presented as as Missing = Excluded analysis (M=E), rather than by more strict Missing=Failure (M=F) analyses. Unsurprisingly, >98% virologic outcomes were reported for both timepoints in both arms (as on-treatment analyses tend to do). For example, 234 women were originally randomised to B/F/TAF but at week-96 the denominator for the 99.5% success reported is based on only 208 women (207 of whom had viral load <50 copies/mL).

Side effects were reported for almost the whole study (462/470) but only for the time on B/F/TAF (ie without the week-48 results from the control arm.

Overall, most side effects were grade 1/2. Grade 3/4 adverse events (AEs) were reported by 7% (n-31/462) of women using B/F/TAF, with 6% (n=27/462) judged related to study drugs. Serious AEs were reported by 5% (24/462) but only led to one study discontinuation.

No new cases of drug resistance were reported to B/F/TAF in either group through to week-96. One person on E/C/F/TAF in the control arm with viral rebound and the M184V mutation resuppressed after switching to B/F/TAF.

Small improvements were linked switching from TDF-containing combinations to TAF and although no lipid changes were reported as significant, again, this was only reported for B/F/TAF exposure and not for the control arm at week 48.

Finally, Jean-Michel Molina from Saint Louis Hospital, Paris, presented 24-week results in 86 HIV positive participants older than 65 years who switched to open-label B/F/TAF from E/C/F/TAF or a TDF-based regimens. Follow-up in this study will continue out to week 96.

Baseline characteristics included: mean age 70 years (range 65-80), 13% were female, and 99% were white. Median weight was 78 kg (range: 49 to 110) and eGFR was 76 mL/min (range: 40 to 130). Baseline ART was E/C/F/TAF for  91% (78/86) of participants.

At week-24, 98% participants remained <50 copies/mL, again using Missing=Excluded (M=E) analysis – as 2 participants had missing data and 2 discontinued (with last viral load <5- copes/mL).

Tolerability was good with no grade 3/4 events and no change in weight, although median eGFR declined by –4.5 mL/min at week 12 and was then stable out to week 24.

comment

These studies support high efficacy of B/F/TAF as a switch option in different populations including continued viral suppression with baseline mutations.

It is unclear why results are being presented as observed rather than full intent-to-treat analyses, when at least both should be presented.

References

  1. Sax P et al. Switching to a single-tablet regimen bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) from dolutegravir (DTG) plus emtricitabine and either tenofovir alafenamide or tenofovir disoproxil fumarate (F/TAF or F/TDF). 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract MOAB0105.
    http://programme.ias2019.org/Abstract/Abstract/1225
  2. Acosta R et al. Keeping the pressure on archived NRTI resistance: Switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) triple therapy in study 4030. 10th IAS Conference on HIV Science. Mexico City, 21–24 July 2019. Poster abstract MOPEB241.
    http://programme.ias2019.org/Abstract/Abstract/3907
  3. Andreatta K et al. Previously undocumented preexisting resistance and maintenance of virologic suppression in HIV-1 RNA-suppressed patients switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF). 10th IAS Conference on HIV Science. Mexico City, 21–24 July 2019. Poster abstract MOPEB243.
    http://programme.ias2019.org/Abstract/Abstract/721
  4. Acosta R et al. Low-frequency resistance variants in ART-naïve participants do not affect bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) triple therapy treatment outcome. 10th IAS Conference on HIV Science. Mexico City, 21–24 July 2019. Poster abstract MOPEB242.
    http://programme.ias2019.org/Abstract/Abstract/3778
  5. Kityo C et al. Longer-term (96-week) efficacy and safety of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in women. 10th IAS Conference on HIV Science. Mexico City, Mexico. 21–24 July 2019. Oral abstract MOAB0106.
    http://programme.ias2019.org/Abstract/Abstract/1210
  6. Molina J-M et al.  A phase 3b, multicenter, open-label study switching from an Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide(E/C/F/TAF) or a Tenofovir disoproxil fumarate containing regimen to Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in virologically-suppressed, HIV-1 infected subjects aged ≥65 years. 10th IAS Conference on HIV Science. Mexico City, 21–24 July 2019. Poster abstract MOPEB238.
    http://programme.ias2019.org/Abstract/Abstract/1453

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