TUAB0102 – Switching from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir alafenamide (TAF)-based regimen: data in virologically suppressed adults through 48 weeks of treatment T. Mills1, J. Andrade2, G. DiPerri3, J. Van Lunzen4, E. Koenig5, R. Elion6, M. Cavassini7, J. Valdez Madruga8, J. Brunetta9, D. Shamblaw10, E. DeJesus11, C. Cohen12, A. Plummer13, Y. Liu13, S. McCallister13
Mm thank you on behalf of the gs us – 9 – oh 109 study team i’m honored to be invited by the conference organizers to present this data to such a distinguished audience my disclosures are listed here kenapa varela phenom id or taff is a novel to novel prodrug 10 milligrams of taff where the pk booster provides comparable efficacy to 300 milligrams of tanaka vo dodge
Aprox well fumarate or tdf but with a 90% reduction in plasma levels previous studies have shown high rates of urologic suppression with a single tablet combination of ecf taff in treatment naive patients these studies also demonstrated an improvement in renal and bone endpoints study – 9 201 o 9 was designed to evaluate the efficacy and safety of a switch to e cf
Taff in bureau logically suppressed patients taking a variety of currently used pdf based regimens this is the largest switch study containing the largest switch study ever done in via logically suppressed patients fifteen hundred and fifty nine patients were screened and 14 hundred and thirty six were enrolled in this randomized open label trial this large number
Of participants gives the study particular statistical power with the number of patients randomized in the study we had a 98% power to establish non inferiority of ecf taft at 48 weeks all participants had maintained hiv viral or less than 50 copies for greater than ninety six weeks on one of three regiments ecf tdf a fav earns ftc tdf or boosted atazanavir boosted
Either with cove assisted or ritonavir and fdc and tdf all patients came from six existing gilead trials participants were randomized to 2-1 to switch to e cf taff or continued their existing tdf regimen the primary end point of the trial was hiv viral load less than 50 copies at 48 weeks the fda snapshot analysis based on characteristics were well matched between
The arms cd4 counts were generally high reflecting at least ninety six weeks of successful prior therapy for the primary efficacy outcome at week 48 the ecf taf treatment group was non inferior to the comparator arms with 97 percent of patients demonstrating a viral load less than 50 copies compared to 93% in the control arm a pre-specified statistical analysis
For superiority can be seen on the right hand side of the slide because the lower bound of the two-sided 95% confidence interval of the difference in response rate was greater than the pre-specified 12 percent margin and also greater than zero switching to e cf taff was both non inferior to maintaining a td f based regimen and also statistically superior there
Were very few virologic failures in either arm but a higher percent of patients in the tdf arm had no urologic data in the week 48 window most of these patients either discontinued due to an adverse event voluntarily withdrew consent or they were taken off the trial of the investigators discretion this slide shows the breakdown of hiv viral outcome data stratified
By prior treatment regimens first we see the composite of all prior regimens note the p-values above the bars and the confidence intervals at the bottom of the slide in here we see the affair ins ftc tdf arm alone with ecf tabs showing superior performance and here we see the booster that is an of your ftc tdf arm again with ecf taf showing a statistically superior
Performance and finally we see the comparison to the ecf tdf arm in which ecf taft demonstrated non-inferiority but no statistical superiority was seen both the ecf tdf arm and the ecf taf arm were highly a active with ninety-seven and ninety-eight percent of patients achieving of our lower less than fifty copies at 48 weeks in a subgroup analysis looking at age sex
Race and adherence there was a consistent trend in bureau logic outcome favoring ecf taf statistically significant differences seen here are marked with an asterisk 25 to 30 percent of participants had some grade 2 to 4 laboratory abnormality at some point during the trial these were again equally seen between both arms with the exception of elevations in bilirubin
Which were seen more commonly in the tdf arm where participants may have been randomized to remain on atazanavir fasting lipids remain relatively unchanged in participants who remained on their tdf regimen as seen here in the orange bars the arrow and the triglyceride bar indicates that triglycerides actually decreased slightly in the tdf arm over 48 weeks but
Overall there was little change in the group that switched to ecf taf there was an increase in total cholesterol ldl hdl and triglycerides there were similar increases in total cholesterol to hdl ratios in both arms similar low numbers that patients in both arms started lipid modifying medications looking at adverse events all grades that occurred in greater than
Or equal to 5% of participants on ecf taf the frequency of these common adverse events were similar in both arms there were few adverse events that led to discontinuation in either arm and they’re listed here you are seeing reported terms for each patient real events have been separated out in the ecf taf arm there were two discontinuation due to renal events one
Participant was critically ill with a prolonged icu stay sepsis and chemotherapy all contributing to acute renal failure one participant had interstitial nephritis or hematuria he was discontinued from the trial the hematuria persisted and the patient was later found have hodgkin’s lymphoma in the tdf farm five participants discontinued due to the reported renal
Events described here discontinuation for other events are shown in the lower portion of the graph participants discontinued from the trial for a variety of reasons in the ecf taf arm there was no eight year elated discontinuation that occurred more than once per reported term the dexa scan results for spine bone mineral density are shown here remembering that
Patients on the study had at least ninety six weeks of tdf treatment in the group that remained on tdf a slight increase in spine bmd was seen through 48 weeks in the group that switched to ecf taf bone mineral density room improved and was significantly higher at weeks 24 and 48 regardless of prior treatment regimen at week 48 there was a greater than 2% difference
In the spine b and d between the arms and here we have the dexa results for hip bmd again in the tdf arm there was a slight decrease in bmd over 48 weeks while in the ecf taf arm there was a significant increase in bmd leading to a 1.6 percent difference in the arms at 48 weeks regardless of prior treatment regimen differences between the arms were statistically
Significant at weeks 24 and 48-hour reported fracture aes were the result of trauma and not considered related to study drug and there were no reports of fragility fractures this graph illustrates the change in osteopenia and osteoporosis diagnosis defined by t score that was seen in the trial if we start with spine we see that baseline 35 percent of participants
Were found to have osteopenia and approximately 7% were osteoporotic in participants who remained on t df these percentages did not change over the forty eight weeks in contrast in the ecf taf arm we saw a marked decrease in the percent of participants with osteopenia and a decrease as well in participants with osteoporosis similar results were seen in the hip
Analyses no change was seen in the arm that remained on tdf while participants who change to taff showed a decrease in the percent of patients with osteopenia while the small number with osteoporosis remained unchanged renal safety results showed significant differences between the arms the upper graph looks at all participants in the trial the purple bars here
Showing that ecf taf group we see significantly higher changes in urine protein to creatinine ratio and album de gratton ratio over 48 weeks if we focus on molecules that are specific markers of proximal tubular function we see highly significant changes in retinol binding protein to creatinine and beta 2 microglobulin to creatinine ratios over 48 weeks in the lower
Part of the slide we see the results from analysis that excluded participants who switched off the non cobe containing regiment of a favored ins ftc and tdf in this analysis changed to e cf taf was compared only to patients previously on ec f td f or boosted atazanavir fdc and td f when patients switched from these kobe or return of your cane containing regimens
To e cf taf there was a significant decrease in serum creatinine and an increase in egfr significant changes were also seen in fashion excretion of phosphate and uric acid changes began by week 2 and persisted to week 48 in conclusion this is to date the largest randomized switch study ever conducted an hiv-positive urological suppress participants in the overall
Primary efficacy analysis participants who switch from their prior regimens to e cf taff were significantly more likely to maintain bureau logic success aes were similar to the comparator arms and there were few discontinuation due to adverse events in the ecf taf arm a statistically significant improvement in bone density was seen with improvements in spine and
Hip bmd and reduc in t-score defined osteopenia and osteoporosis likewise a statistically significant improvement in multiple tests of renal function was seen with reductions in overall protein urea and specific proximal tubular proteinuria as well as significant reductions in creatinine fractional excretion of phosphate and uric acid i would like to extend thanks
To the participants in the trial their partners and their families i would also like to thank the 292 o 109 investigators and the study teams who worked tirelessly on this very large project without whom this study could not have been completed thank you this paper is now open for questions tony if i might start in terms of the renal & bone analysis was
That done separating those who had switched from atazanavir and tanaka vir what i’m wondering is is because the tanaka vir levels may be elevated in the presence of a boosted protease inhibitor are we really seeing the effects of tanaka vir to taff or are we just seeing lower turn off of their levels yes we did subgroup analyses on all of the arms that came into
The trial so patients who came in on a favron space regimen their creatinine’s increased because they were added kobe regimen was added if they came in on boosted out as anivia or with either koba stat or a ton of year their levels increased incrementally very very small amount if they came in on a kobe based regimen with ecf tdf then their creatinine’s actually
Decreased significantly but thinking more about the bone parameters in the end the protein area so as far as the bone goes again the the patients who came in you know we looked across the board i don’t think we did subgroup analyses on the bone i’ll have to check on that but overall there was a decrease in osteopenia and osteoporosis and all the participants in
The trial petrov from come from buddha’s hair is very nice presentation it’s clear that the benefits in terms of toxicity is other results of switching front and or forward to to tough but in terms of the superiority that you showed in biological efficacy isn’t it the result of using a diagram instead of the other compounds yeah what’s the last part pedro i mean
In terms of the biological efficacy that you’re superior for for the new regimen isn’t in the results of using l my degra here instead of the other compounds i think the superiority results were really driven by the fact that we had more discontinuation in the and the comparator arms so i think there was a variety of reasons for that we didn’t have very many
Virologic failures so it was really about discontinuation so that’s what drove the analysis so i think that you know obviously patients came in on a multi pill regimen oftentimes they were promised the option may be of a single tablet regimen so some of those patients obviously drop off of the trial or the investigator discontinued them so i think that’s really
What drove the superiority analysis so again it’s tolerability as opposed to actual pure efficacy but your point is well-taken they all move to an integration hibner which may have been what’s driving it rather than the taf part of it graham so a few years ago we published with the back of their head less effect on retinal binding proteins and offer there in the
Kidney in partnership in that case with the fav ones the big question is looking at these tubular markers is what do they actually correlate with clinically because at the moment we haven’t correlated anything with those renal markers to a clinical outcome so well they may represent something that describes say tubular distress on to natha vir they’ve got to have
A meaningful outcome for them to be something worth prescribing a different drug for so do you have any analyses looking at the correlates with renal or bone outcome and the changes in retinal binding protein or other tubular proteins that may help us draw a clinical correlate with that observation i think that’s a really great question um you know obviously these
Are not necessarily tests that we use clinically on a routine basis and we use them in these trials where we’re trying to differentiate subtle differences in renal function to see if there’s an improvement really with a different drug so i think that those analyses certainly should be done and i think you you know i think about the these renal markers almost like
We think about some of the cardiovascular markers in that we see a difference sometimes we don’t actually know clinically what they mean so i think that certainly needs to be explored further andrew i didn’t maybe i didn’t see it the gfr went up but i didn’t know where they started and where they finished what was baseline and what was the change the the the change
In creatinine that was significant especially in the group that went from ecf tdf to e cf taff was about point one and i don’t know exactly what the egfr was i’m sure we have that date and i’m happy to get that to you okay last question to christina yes a nice presentation tony i was wondering if you break out the results by type of population mainly age can you
Identify the the one would benefit the most and at the world opposite the one car there was no difference because you know giving the renal advantage i think that’s a great question and i think clinically that’s what we all struggle with is who should we allow to remain on their current regimen or who should we think about switching to something new i think that
You know when i look at this data when i look at the improvements especially in the bone markers even when i start patients who are very young on therapy today i think about these long-term effects so i think it would be a nice idea to look i think it’s effective across the board regardless of their age but then that would be a clinical decision about whether for
That individual patient you think it’s important but i think particularly for women for people who are at risk for a bone shoes for people who are at risk for kidney issues i think this provides a really great new option for us for gilead the decision okay thank you very much tony thank you
Transcribed from video
TUAB0102 – Switching from a tenofovir disoproxil fumarate (TDF)-based regimen to a tenofovir … By IAS Conference on HIV Science
