Integrase inhibitor bictegravir matches dolutegravir for first-line tx

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Bictegravir, an investigational integrase inhibitor from Gilead Sciences, was highly potent, well tolerated and worked as well as dolutegravir (Tivcay) in a phase 2 clinical trial, according to study results presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Due to their high potency and good tolerability, integrase strand transfer inhibitors are an increasingly important part of initial antiretroviral therapy and are included in most recommended regimens for first-line treatment in European and US HIV treatment guidelines.

Bictegravir (formerly GS-9883) is an investigational integrase inhibitor that can be taken once daily and does not require a booster – unlike Gilead’s older integrase inhibitor elvitegravir, which must be boosted with cobicistat.

As previously reported, bictegravir demonstrated high potency against wild-type and resistant strains of HIV, favourable pharmacokinetics and an improved resistance profile compared to older integrase inhibitors. In a 10-day monotherapy study it reduced viral load by more than 2 log10 in people with HIV.

At CROI Joseph Custodio of Gilead reported that bictegravir was safe and well tolerated at doses ranging from 5mg to 600mg in healthy volunteers. Bictegravir inhibits renal tubule transporters, which lowers creatinine levels and leads to a decline in estimated glomerular filtration rate, but it does not cause actual kidney function impairment, he explained.

Bictegravir is metabolised equally by the CYP3A4 and UGT1A1 pathways. Custodio said it has low potential to be either a ‘victim’ or ‘perpetrator’ of drug-drug interactions.

Bictegravir levels rose by more than 300% when administered with both CYP3A4 and UGT1A1 inhibitors, and fell by up to 75% when given with both CYP3A4 and UGT1A1 inducers. The drug had a half-life of approximately 18 hours, indicating it is suitable for once-daily dosing. Bictegravir had no effect on a common oral contraceptive or ledipasvir/sofosbuvir (Harvoni) for hepatitis C, and administering it two hours before or after minimises interactions with antacids.

Paul Sax of Brigham and Women’s Hospital in Boston and colleagues conducted a phase 2 placebo-controlled clinical trial comparing bictegravir to dolutegravir for initial HIV therapy. The study included 98 previously untreated adults. Almost all were men, more than half were white and the median age was about 32 years. They generally had asymptomatic HIV infection with a median CD4 T-cell count of approximately 450 cells/mm3 and a median viral load of about 4.4 log10 copies/ml at baseline. They had normal kidney function and people with hepatitis B or C co-infection were excluded.

Participants in this double-blind study were randomly assigned (2:1) to receive 75mg bictegravir or 50mg dolutegravir, each with matching placebos. Both drugs were combined with 25mg tenofovir alafenamide (TAF) and 200mg emtricitabine, taken once daily with or without food for 48 weeks. The primary endpoint was the proportion of people with HIV RNA below 50 copies/ml at 24 weeks.

Both treatments were highly effective, with 97% of participants in the bictegravir arm achieving viral suppression at both 24 and 48 weeks, compared to 94% at 24 weeks and 91% at 48 weeks in the dolutegravir arm. Sax noted that given the small numbers, these differences were not statistically significant and this study was not powered to determine full non-inferiority.

One person in the bictegravir arm and two in the dolutegravir arm had HIV RNA above 50 copies/ml at 48 weeks and had their virus sequenced for drug resistance. No significant resistance was detected in either arm.

CD4 counts rose rapidly, as is typical with integrase inhibitors. The mean CD4 cell gain was 258 cells/mm3 in the bictegravir arm and 192 cells/mm3 in the dolutegravir arm, not a statistically significant difference.

Both regimens were generally safe and well tolerated, with no treatment-related serious adverse events and no deaths. The most frequent adverse events were diarrhoea (12% in each arm) and nausea (8% with bictegravir and 12% with dolutegravir). One bictegravir recipient with a previous history of allergic dermatitis stopped treatment early due to hives after 24 weeks.

Estimated glomerular filtration rate declines were -7.0 ml/min in the bictegravir arm and -11.3 ml/min in the dolutegravir arm at week 48, but there were no discontinuations due to kidney-related adverse events and no cases of tubulopathy, according to Sax.

Bictegravir and dolutegravir taken with TAF and emtricitabine “both demonstrated high virologic response rates at week 24 that were maintained at week 48,” the researchers concluded. “Both treatments were well tolerated, and no significant safety signal was detected in either arm.”

These results were promising enough to proceed with phase 3 trials using a single-tablet regimen of bictegravir, TAF and emtricitabine. Custodio noted that optimising the formulation allowed for a lower 50mg bictegravir dose in the coformulation.

Sax said that four phase 3 studies are now fully enrolled. Two of these are similar to the current study but will use the bictegravir single-tablet regimen rather than separate pills. Another is comparing the bictegravir single-tablet regimen against the Triumeq coformulation of dolutegravir, abacavir and lamivudine.

Abstract 1
Bictegravir (BIC) is an investigational, once-daily, unboosted HIV integrase strand transfer inhibitor (INSTI) with potent in vitro activity against most INSTI-resistant variants. BIC is currently in development as a single tablet regimen (STR) coformulated with FTC/TAF for treatment of HIV-1 infection in adults and adolescents. Clinical pharmacology assessments of the PK, ADME and DDI potential were performed.
A single- (SD) and multiple-dose (MD) randomized, double-blind, placebo-controlled (6 active; 2 placebo/cohort) of staggered dose-escalation evaluated SD BIC 5, 25, 50, 100, 300 or 600 mg; or once-daily MD 5, 25, 50, 100 or 300 mg for 14 days (fasted) in healthy volunteers. An ADME/ mass balance study included 8 healthy male subjects dosed with a SD 100 mg plus 100 µCi [14C]-labeled BIC. Blood, urine and feces samples were analyzed for total radioactivity and pooled plasma and excreta samples were radio-profiled. An open-label, six cohort (n=15/cohort), fixed sequence and cross-over study assessed the DDI liability of BIC as a victim through utilization of CYP3A4, UGT1A1, and/or P-gp inhibitors and inducers. Safety was assessed throughout each study.
BIC exposure was dose proportional following SD of 25-100mg. Accumulation at steady-state was approximately 1.6x, consistent with the observed half-life of approximately 18 hours. Following a SD of [14C]-labeled BIC, the total recovery of radioactivity was 95% ± 1.5%, with 60% ± 5.5% from feces and 35% ± 5.0% from urine. Balanced glucuronidation and oxidation contributed to the major clearance pathways of BIC. The DDI study (Table 1) showed increased BIC AUC (61-74%) by CYP3A4 inhibitors voriconazole and DRV/COBI, but showed a greater increase (~4x) by potent dual inhibitors of UGT1A1 and CYP3A4, ATV and ATV+COBI. Coadministration of BIC with a potent CYP3A4/UGT1A1/P gp inducer, rifampin resulted in a 75% decrease of BIC AUC; in contrast, a lesser reduction (38%) was associated with the moderate CYP3A4/P gp inducer, rifabutin. Overall, BIC was well tolerated at all doses studied. No deaths, SAEs, or Grade 3 or 4 AEs were reported. The safety profile for BIC did not differ with increasing doses of SD or MD.
The favorable BIC PK profile supports once daily dosing. The DDI results of BIC are consistent with its ADME profile, in which both CYP3A4 and UGT1A1contributed to BIC elimination. BIC was safe and well tolerated in healthy volunteers.

Heather Zhang, Joseph M Custodio, Xuelian Wei, Hui Wang, Amanda Vu, John Ling, Hal Martin, Erin Quirk, Brian P Kearney

Abstract 2
Because of their potency and safety, integrase strand transfer inhibitors (INSTIs) are widely recommended initial HIV-1 treatments in most major treatment guidelines. Bictegravir (BIC, GS-9883) is a novel, unboosted, once-daily INSTI that demonstrated potent activity in a 10-day monotherapy study and has in vitro activity against most INSTI-resistant viruses.
Treatment naïve, HIV-infected adults were randomized 2:1 to receive blinded treatment once daily with BIC 75 mg or dolutegravir (DTG) 50 mg; both were given with open label emtricitabine 200 mg/tenofovir alafenamide 25 mg (FTC/TAF). Treatments were administered without regard for food for 48 weeks. The primary endpoint was the proportion with HIV RNA
Of 98 patients enrolled, 65 were randomized to BIC+FTC/TAF and 33 to DTG+FTC/TAF. Most subjects were male, had asymptomatic HIV infection, with median HIV-1 RNA 4.4-4.5 log10; baseline characteristics were balanced between arms. Virologic success (HIV-1 RNA 50 c/mL at W48. No viral resistance was detected in the BIC+FTC/TAF arm. Mean CD4 count increases at W48 were 258 cells/µL in the BIC arm and 192 cells/µL in the DTG arm. There were no treatment-related serious adverse events and no deaths. The most commonly reported adverse events were diarrhea (12% in each arm) and nausea (8% BIC, 12% DTG). One subject in the BIC arm discontinued due to an adverse event of urticaria following the W24 visit. Median changes in estimated glomerular filtration by Cockcroft-Gault (GFRCG) at W48 were -7.0 mL/min for BIC and -11.3 mL/min for DTG, with no discontinuations due to renal adverse events.
Bictegravir+FTC/TAF and DTG+FTC/TAF both demonstrated high virologic response rates at W24 that were maintained at W48. No treatment-emergent resistance was detected in the BIC+FTC/TAF arm through W48. Both treatments were well tolerated, and no significant safety signal was detected in either arm. Estimated GFRCG changes were consistent with known inhibition of tubular creatinine transport by BIC and DTG. Further evaluation of BIC for the treatment of HIV infection is warranted.

Paul E Sax, Edwin DeJesus, Gordon Crofoot, Douglas Ward, Paul Benson, Xuelian Wei, Kirsten L White, Hal Martin, Andrew Cheng, Erin Quirk

Background: All recent treatment guidelines recommend integrase strand transfer inhibitors (INSTIs) as components of initial HIV therapy. Bictegravir, a novel, once-daily, unboosted INSTI, showed potent activity in a 10 day monotherapy study and has a high in-vitro resistance barrier. On the basis of these results, we did a phase 2 trial comparing bictegravir with dolutegravir.
Methods: In this randomised, double-blind, phase 2 trial, we recruited previously untreated adults (aged ≥18 years) with HIV-1 infections from 22 outpatient centres in the USA. Eligible patients had HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 counts of at least 200 cells per μL, estimated glomerular filtration rates of at least 70 mL per min, and HIV-1 genotypes showing sensitivity to emtricitabine and tenofovir. We excluded patients if they were hepatitis B-co-infected or hepatitis C-co-infected, had new AIDS-defining conditions within 30 days of screening, or were pregnant. We randomly allocated participants (2:1) to receive oral once-daily 75 mg bictegravir or 50 mg dolutegravir with matching placebo plus the fixed-dose combination of 200 mg emtricitabine and 25 mg tenofovir alafenamide for 48 weeks. We randomly allocated participants via an interactive web system, stratified by HIV-1 RNA concentration. Investigators, patients, study staff giving treatment, collecting data, and assessing outcomes, and the funder were masked to treatment group. The primary outcome was the proportion of participants with plasma HIV-1 RNA concentrations of less than 50 copies per mL at week 24 according to the US Food and Drug Administration-defined snapshot algorithm. We included all participants receiving one dose of study drug in analyses. This trial is registered with, number NCT02397694.
Findings: Between March 23, 2015, and May 21, 2015, we screened 125 patients, randomly allocating and giving study drug to 98 (65 received bictegravir plus emtricitabine and tenofovir alafenamide and 33 received dolutegravir plus emtricitabine and tenofovir alafenamide). At week 24, 63 (96·9%) of 65 in the bictegravir group had HIV-1 RNA loads of less than 50 copies per mL compared with 31 (93·9%) of 33 in the dolutegravir group (weighted difference 2·9%, 95% CI −8·5 to 14·2; p=0·50). Treatment-emergent adverse events were reported by 55 (85%) of 65 participants in the bictegravir plus emtricitabine and tenofovir alafenamide group versus 22 (67%) of 33 in the dolutegravir plus emtricitabine and tenofovir alafenamide group. The most common adverse events were diarrhoea (eight [12%] of 65 vs four [12%] of 33) and nausea (five [8%] of 65 vs four [12%] of 33). One participant taking bictegravir plus emtricitabine and tenofovir alafenamide discontinued because of a drug-related adverse event (urticaria) after week 24. No treatment-related serious adverse events or deaths occurred.
Interpretation: Bictegravir plus emtricitabine and tenofovir alafenamide and dolutegravir plus emtricitabine and tenofovir alafenamide both showed high efficacy up to 24 weeks. Both treatments were well tolerated. Administration of bictegravir, a novel, potent, once-daily INSTI designed to improve on existing INSTI options with the backbone of emtricitabine and tenofovir alafenamide, might provide an advantage to patients.

Paul E Sax, Edwin DeJesus, Gordon Crofoot, Douglas Ward, Paul Benson, Robin Dretler, Anthony Mills, Cynthia Brinson, Julie Peloquin, Xuelian Wei, Kirsten White, Andrew Cheng, Hal Martin, Erin Quirk

Aidsmap material
CROI 2017 abstract 1
CROI 2017 abstract 2
The Lancet HIV abstract

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