scholarly journals 877. North American Phase 3/3b Experience with Long-Acting Cabotegravir and Rilpivirine: Efficacy, Safety, and Virologic Outcomes

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S530-S531
Author(s):  
Babafemi O Taiwo ◽  
Darrell Tan ◽  
Parul Patel ◽  
Paula Teichner ◽  
Joseph Polli ◽  
...  
Keyword(s):  
Treatment Guidelines ◽  
Virologic Failure ◽  
Descriptive Analysis ◽  
Injection Site Reaction ◽  
Treatment Preference ◽  
Virologic Suppression ◽  
Research Support ◽  
Phase 3 ◽  
Long Acting ◽  
Hiv 1

Abstract Background Cabotegravir (CAB) plus rilpivirine (RPV) is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virologic suppression. CAB+RPV LA dosed every 4 weeks (Q4W) or every 8 weeks (Q8W) demonstrated noninferior efficacy in multinational Phase 3/3b trials. This post hoc descriptive analysis summarizes efficacy, virologic outcomes, safety, and treatment preference for US and Canadian (CAN) participants through Week (W) 48. Methods This analysis focuses on data for US/CAN participants naive to CAB+RPV (n=376) from the larger pooled population of the ATLAS, FLAIR, and ATLAS-2M Phase 3/3b studies (N=1245). Endpoints included the proportion of participants with plasma HIV-1 RNA ≥ 50 and < 50 c/mL at W48 (FDA Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥ 200 c/mL), safety, and treatment preference through W48. Results 376 US/CAN participants received CAB+RPV LA Q4W or Q8W. Median (range) age was 39y (20–74); 14.9% were female, 66.0% were White. At W48, 93.1% (350/376) maintained virologic suppression (HIV-1 RNA < 50 c/mL), 1.9% (7/376) had HIV-1 RNA ≥ 50 c/mL, and 0.8% (3/376) met the CVF criterion, consistent with the overall global pooled population (Table 1). Two of the three participants with CVF had ≥ 2 of the three baseline factors (archived RPV resistance-associated mutations [RAMs], HIV subtype A6/A1, body mass index [BMI] ≥ 30 kg/m2) previously associated with CVF. Among the US/CAN participants with a single baseline factor, none met CVF. Overall, archived RPV RAMs were observed in 3.2% (12/376), HIV subtype A6/A1 in 1.1% (4/376), and BMI ≥ 30 kg/m2 in 26.3% (99/376) of participants. Safety and injection site reaction findings were similar to the overall pooled population (Table 2). Most participants (120/134, 89.6%) preferred LA over oral dosing (7/134, 5.2%). Table 1. Snapshot outcomes following CAB+RPV LA Q4W and Q8W at Week 48 in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M (ITT-E population) Table 2. Safety summary through Week 48 following CAB+RPV LA Q4W and Q8W or comparator ART in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M Conclusion In US/CAN Phase 3/3b trial participants, CAB+RPV LA was highly effective and well tolerated, with outcomes consistent with the overall pooled population. Baseline prevalence of archived RPV RAMs and subtype A6/A1 was low and aligned with regional prevalence/surveillance data. CAB+RPV LA provides a tolerable and effective injectable LA treatment option for virologically suppressed US/CAN individuals with HIV. Disclosures Babafemi O. Taiwo, MBBS, Gilead (Consultant)Merck (Consultant)ViiV Healthcare (Consultant) Darrell Tan, MD PhD, Abbvie (Grant/Research Support)Gilead (Grant/Research Support)GlaxoSmithKline (Scientific Research Study Investigator)ViiV Healthcare (Grant/Research Support) Parul Patel, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paula Teichner, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Joseph Polli, PhD, FAAPS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christine L. Talarico, M.S., GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Bryan Baugh, MD, Janssen, Johnson & Johnson (Employee, Shareholder) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Matthew Bosse, DO, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

scholarly journals 833. Efficacy and Safety of Long-Acting Cabotegravir + Rilpivirine in Participants with HIV/HCV Co-infection: ATLAS-2M 48-Week Results

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S508-S509
Author(s):  
Ronald D’Amico ◽  
Paul Benn ◽  
Shanker Thiagarajah ◽  
Susan L Ford ◽  
Eileen Birmingham ◽  
...  
Keyword(s):  
Research And Development ◽  
Injection Site ◽  
Virologic Failure ◽  
Hcv Rna ◽  
Virologic Suppression ◽  
Efficacy And Safety ◽  
Modes Of Transmission ◽  
Long Acting ◽  
Chronic Hcv ◽  
Hiv 1

Abstract Background The phase IIIb ATLAS-2M study demonstrated non-inferiority of long-acting (LA) cabotegravir (CAB) + rilpivirine (RPV) dosed every 8 weeks (Q8W) compared with every 4 weeks (Q4W) for maintenance of virologic suppression. Hepatitis C virus (HCV) co-infection occurs in ~6% of people with HIV due to shared modes of transmission. We report efficacy and safety of CAB + RPV LA in participants with HIV/HCV co-infection in ATLAS-2M. Methods Participants with HIV-1 RNA < 50 c/mL receiving CAB + RPV LA Q4W (transitioned from ATLAS [NCT02951052]) or oral comparator ART were randomized 1:1 to receive CAB + RPV LA Q4W or Q8W. Baseline HCV RNA was assessed by polymerase chain reaction. Participants with symptomatic chronic HCV infection requiring treatment within 12 months or liver enzymes not meeting entry criteria were excluded. Week 48 assessments included proportion with HIV-1 RNA ≥50 and < 50 c/mL (Snapshot algorithm), general and hepatic safety, and pharmacokinetics. Results HIV/HCV co-infection was present in 10 (1%) of 1045 participants, 60% of whom were female at birth. At Week 48, 9/10 (90%) and 972/1035 (94%) participants with HIV/HCV co-infection and HIV mono-infection, respectively, had HIV-1 RNA < 50 c/mL (adjusted difference, 4.1; 95% CI, −14.5 to 22.6). No participants with HIV/HCV co-infection had HIV-1 RNA ≥50 c/mL (vs 14/1035 [1%] with HIV mono-infection) or confirmed virologic failure through Week 48 (vs 10 [1%] with HIV mono-infection); 1/10 (10%) discontinued for reasons other than adverse events (AEs). Excluding injection site reactions (ISRs), AEs and serious AEs were reported in 4 (40%) and 0 participants with HIV/HCV co-infection, respectively; the only AE reported in >1 participant was injection site pain (n=5; 50%). In participants with HIV/HCV co-infection, all ISRs were grade 1/2; none led to withdrawal. No hepatic laboratory abnormalities were reported in participants with HIV/HCV co-infection through Week 48; rates were low in those with HIV mono-infection (Table). Plasma CAB and RPV concentrations were similar between groups. Conclusion CAB + RPV LA was effective and well tolerated in this small cohort of participants with HIV and asymptomatic HCV co-infection. Disclosures Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paul Benn, MB ChB FRCP, ViiV Healthcare (Employee) Shanker Thiagarajah, MB ChB, GlaxoSmithKline (Employee, Shareholder) Susan L. Ford, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Eileen Birmingham, MD, MPH, Janssen Research and Development (Employee, Shareholder) Ojesh R. Upadhyay, MPH, MBA, GlaxoSmithKline (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Kati Vandermeulen, M.SC., Janssen Research and Development (Employee) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

scholarly journals Phase 3 Randomized, Controlled Trial of Switching to Fixed-dose Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor-based Regimens in Virologically Suppressed Adults: Week 48 Results

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S735-S735 ◽  
Author(s):  
Eric Daar ◽  
Edwin DeJesus ◽  
Peter Ruane ◽  
Gordon Crofoot ◽  
Godson Oguchi ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Drug Interactions ◽  
Controlled Trial ◽  
Fixed Dose ◽  
Virologic Suppression ◽  
Research Support ◽  
Phase 3 ◽  
Tenofovir Alafenamide ◽  
Hiv 1 ◽  
Research Grant

Abstract Background Boosted protease inhibitor regimens (bPIs) are effective and often used in HIV-infected individuals with difficulties with adherence, but they can have drug–drug interactions and GI adverse effects. Bictegravir (B), a novel, potent integrase strand transfer inhibitor with a high barrier to resistance and low potential for drug–drug interactions, was coformulated with the recommended nucleoside reverse transcriptase inhibitor backbone emtricitabine (FTC)/tenofovir alafenamide (F/TAF) and demonstrated high efficacy and tolerability in randomized studies in treatment-naïve adults. This randomized Phase 3 study assesses efficacy and safety of switching to B/F/TAF from a multi-tablet regimen containing a bPI. Methods HIV-infected adults suppressed on regimens of boosted atazanavir (ATV) or darunavir (DRV) + abacavir/lamivudine (ABC/3TC) or FTC/tenofovir disoproxil fumarate (TDF) were randomized 1:1 to continue their current bPI regimen or switch to open-label coformulated B/F/TAF (50/200/25 mg) once daily. Primary endpoint was proportion with HIV-1 RNA ≥50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% confidence intervals (CI) using a margin of 4%. Secondary endpoints included proportion with HIV-1 RNA <50 c/mL and safety measures at W48. Results A total of 577 participants were randomized and treated with B/F/TAF (n = 290) or current bPI regimens (n = 287): 17% women, 26% Black, median age 48 years. Most were receiving a bPI with FTC/TDF (85%) at screening. At W48, switching to B/F/TAF was noninferior to continuing bPI with 1.7% in each group having HIV-1 RNA ≥50 c/mL (difference −0.0%; 95.002% CI −2.5% to 2.5%, P = 1.00); the proportion with HIV-1 RNA <50 c/mL was 92.1% in B/F/TAF vs. 88.9% in bPI. No participant on B/F/TAF developed resistance to study drugs. One participant on DRV/ritonavir + ABC/3TC developed a treatment-emergent L74V mutation. Incidence of grade 3 or 4 AEs was similar (B/F/TAF 4%, bPI regimens 6%). No renal discontinuations or tubulopathy cases occurred with B/F/TAF. Conclusion Adults switching to B/F/TAF from a boosted PI maintained high rates of virologic suppression without resistance. B/F/TAF was safe and well tolerated. Disclosures E. Daar, Bristol-Myers Squibb: Consultant, Consulting fee. Gilead Sciences, Inc.: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Janssen: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. Teva Pharmaceuticals: Consultant and Scientific Advisor, Consulting fee. ViiV: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research support. E. DeJesus, Abbott Laboratories; Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann LaRoche, Idenix, Janssen, Merck, Pfizer, Sangamo, Taimed, Tobira, and Vertex: Grant Investigator, Research grant. Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex: Scientific Advisor, Consulting fee. P. Ruane, Gilead: Investigator, Scientific Advisor and Shareholder, Consulting fee and Research support. Merck: Speaker’s Bureau, Speaker honorarium. Boehringer: Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. Janssen: Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. Abbott: Investigator, Scientific Advisor and Speaker’s Bureau, Research support and Speaker honorarium. Idenix: Investigator, Research support. ViiV: Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. BMS: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium. G. Crofoot, Gilead: Investigator and Scientific Advisor, Advisory honorarium and Research grant. ViiV: Investigator and Scientific Advisor, Advisory honorarium, Research grant and Research support. C. Creticos, Thera Technologies and ViiV Healthcare: Scientific Advisor, Consulting fee. Gilead sciences, Merck, and ViiV Healthcare: Investigator, Research support. Pfizer: Speaker’s Bureau, Speaker honorarium. J. K. Rockstroh, Abbvie: Consultant and Investigator, Consulting fee and Speaker honorarium. Gilead: Consultant, Investigator and Scientific Advisor, Consulting fee and Speaker honorarium. ViiV: Scientific Advisor, Consulting fee. Janssen: Investigator and Speaker at educational event, Speaker honorarium. J. M. Molina, Gilead, ViiV, Merck, Janssen, BMS and TEVA: Scientific Advisor, Speaker honorarium. Y. P. Liu, Gilead: Employee and Shareholder, Salary and Shareholder. K. Andreatta, Gilead: Employee and Shareholder, Salary and Shareholder. H. Graham, Gilead Sciences: Employee and Shareholder, Salary. A. Cheng, Gilead: Employee and Shareholder, Salary. H. Martin, Gilead Sciences: Employee, Salary. E. Quirk, Gilead: Employee and Shareholder, Salary

scholarly journals Impact of Integrase Sequences From HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine

2022 ◽  
Author(s):  
Jerry L. Jeffrey ◽  
Marty St. Clair ◽  
Ping Wang ◽  
Chunfu Wang ◽  
Zhufang Li ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Fold Change ◽  
Effective Capacity ◽  
Virologic Suppression ◽  
Subtype B ◽  
Long Acting ◽  
Breakthrough Experiments ◽  
The Impact ◽  
Hiv 1

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine vs daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

scholarly journals 887. High Rates of Virologic Suppression Achieved in HIV-1–Infected Adults Rapidly Starting Antiretroviral Therapy (ART) with the Single-Tablet Regimen (STR) of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) 800/150/200/10 mg Regardless of Baseline Disease Characteristics: Week 48 Subgroup Analyses From the Phase 3 DIAMOND Trial

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S21-S21 ◽  
Author(s):  
Gregory D Huhn ◽  
Moti Ramgopal ◽  
Gordon Crofoot ◽  
Joseph Gathe ◽  
Sareh Seyedkazemi ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Study Drug ◽  
Virologic Suppression ◽  
Open Label ◽  
Phase 3 ◽  
Art Initiation ◽  
Disease Characteristics ◽  
Laboratory Results ◽  
Intent To Treat ◽  
Hiv 1

Abstract Background Rapid initiation of ART requires that clinicians start therapy prior to having baseline laboratory Results. High rates of virologic suppression and retention were reported in the DIAMOND trial. Efficacy and safety are presented, according to baseline disease characteristics. Methods DIAMOND (ClinicalTrials.gov: NCT03227861), a phase 3, single-arm, open-label, prospective, multicenter study, assessed efficacy/safety of D/C/F/TAF in rapid initiation. Adults enrolled within 14 days of diagnosis and started D/C/F/TAF without baseline laboratory results; investigators reviewed results as they became available. Primary endpoint was virologic suppression (HIV-1 RNA < 50 copies[c]/mL; intent-to-treat (ITT); Food and Drug Administration [FDA] snapshot) at Week 48. Virologic suppression <50 c/mL and <200 c/mL were also assessed via an observed analysis, excluding patients with missing data. Results Overall, 109 patients were enrolled; 25% had HIV-1 RNA ≥100,000 c/mL and 21% had CD4+ < 200 cells/μL (Table 1). 21% of patients started therapy within 24 hours of diagnosis. At Week 48, 84%, and 88% of patients had HIV-1 RNA <50 c/mL and <200 c/mL (FDA snapshot), respectively. In the observed analysis, 96% and 100% of patients had HIV-1 RNA <50 c/mL and <200 c/mL, respectively, at Week 48. Earlier ART initiation, HIV-1 RNA <100,000 c/mL, and CD4+ >200 cells/μLwere associated with numerically higher virologic suppression rates (ITT-FDA snapshot; Table 2). No patient discontinued due to lack of efficacy or met protocol-defined virologic failure (PDVF) criteria. In the observed analysis, virologic suppression rates were consistent across all subgroups; all patients were suppressed <200 c/mL at Week 48. One patient discontinued due to an adverse event (AE); incidences of grade 3/4 (10%) and serious (9%) AEs were low, with no serious AEs related to study drug and no deaths. Conclusion In the first phase 3 study of an STR in a rapid initiation model, no patients rapidly starting D/C/F/TAF discontinued therapy due to lack of efficacy or had PDVF through 48 weeks. High rates of virologic suppression were achieved and maintained with a variety of baseline characteristics, and treatment was safe and well tolerated, indicating D/C/F/TAF as a preferred ART option for patients rapidly starting treatment. Disclosures All Authors: No reported Disclosures.

scholarly journals 887. Implementation of Long-acting Injectable Cabotegravir/Rilpivirine for HIV-1 Treatment at a Ryan White-funded Clinic in the U.S. South

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S535-S535
Author(s):  
Lauren F Collins ◽  
Lauren F Collins ◽  
Della Corbin-Johnson ◽  
Meron Asrat ◽  
Tonya Rankins ◽  
...  
Keyword(s):  
Virologic Failure ◽  
Panel Member ◽  
Proton Pump Inhibitor Therapy ◽  
Source Distribution ◽  
Virologic Suppression ◽  
Screening Criteria ◽  
Medication Access ◽  
Ryan White ◽  
Long Acting ◽  
Hiv 1

Abstract Background In January 2021, the first ever long-acting injectable (LAI) antiretroviral therapy (ART), cabotegravir/rilpivirine (CAB/RPV), was approved for maintenance HIV-1 treatment in select patients with virologic suppression. LAI-ART has the potential to improve ART adherence, reduce HIV stigma, and promote equity in care outcomes, however, implementation in real-world settings has yet to be evaluated. Methods We launched a pilot LAI-ART program at the largest Ryan White-funded HIV clinic in the Southeast. From 4/14/21 to 5/14/21, providers referred patients interested and willing to switch to LAI-CAB/RPV who met screening criteria. Our interdisciplinary LAI team (Clinician-Pharmacy-Nursing) verified clinical eligibility (HIV-1 &lt; 200 c/ml ≥6 months and no history of virologic failure, resistance to either drug, or chronic HBV infection) and pursued medication access for 28-day oral lead-in and monthly injectable CAB/RPV. We describe demographic and clinical variables of referred PWH and early outcomes in accessing LAI-ART. Results Among 42 referrals, median age was 40.5 (Q1-Q3, 32-52) years, 83% were men, and 76% Black. Payor source distribution was 26% Private, 19% Medicare, 10% Medicaid, and 45% ADAP. At the time of referral, median CD4 count was 583 (Q1-Q3, 422-742) cells/mm3 and median sustained HIV-1 RNA &lt; 200 c/ml was 1427 (Q1-Q3, 961-2534) days. A total of 35 patients (74%) met clinical eligibility for LAI-CAB/RPV, including 4 patients who required a transition off proton pump inhibitor therapy to accommodate oral RPV. Ineligible PWH were excluded due to evidence of RPV resistance (n=5), possible RPV hypersensitivity (n=1), and HIV non-suppression (n=1). The table summarizes the process of pursuing LAI-ART access for the initial 10 enrollees by insurance status. Conclusion Our experience implementing LAI-ART at a Ryan White-funded HIV clinic in the Southern U.S. has been challenged by substantial human resource capital to attain drug, delayed therapy initiation due to insurance denials, and patient ineligibility primarily due to concern for potential RPV resistance. These barriers may perpetuate disparities in ART access and virologic suppression among PWH and need to be urgently addressed so that LAI-ART can be offered equitably. Disclosures Lauren F. Collins, MD, MSc, Nothing to disclose Bradley L. Smith, Pharm.D., AAHIVP, Gilead Sciences, Inc (Advisor or Review Panel member) Wendy Armstrong, MD, Nothing to disclose Jonathan Colasanti, MD, Integritas CME (Consultant, develop and deliver CME content around Rapid Entry/Rapid ART)

scholarly journals 884. Patient Adherence to Long-Acting Injectable Cabotegravir + Rilpivirine Through 48 Weeks of Maintenance Therapy in the Phase 3 ATLAS and FLAIR Studies

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S20-S20 ◽  
Author(s):  
Paula Teichner ◽  
Amy Cutrell ◽  
Ronald D’Amico ◽  
David Dorey ◽  
Sandy Griffith ◽  
...  
Keyword(s):  
Patient Adherence ◽  
Adverse Event Reporting ◽  
Virologic Suppression ◽  
Viral Load Suppression ◽  
Phase 3 ◽  
Pivotal Phase ◽  
Oral Dosing ◽  
Injection Site Reactions ◽  
Long Acting ◽  
Hiv 1

Abstract Background Cabotegravir (CAB) and rilpivirine (RPV) are under development as a novel long-acting (LA) regimen for maintenance of HIV virologic suppression. Pooled Week 48 data from pivotal Phase 3 trials demonstrated noninferiority of CAB LA + RPV LA vs. current antiretroviral regimen (CAR) on the primary endpoint, proportion of subjects with HIV-1 RNA ≥50 c/mL (1.9% and 1.7%, respectively). Adherence to dosing visits, use of oral dosing (bridging) to cover planned missed injections and injection tolerability were examined for subjects in the ATLAS and FLAIR studies. Methods Virologically suppressed subjects (HIV-1 RNA < 50 c/mL) were randomized to switch to CAB LA + RPV LA or to continue CAR. On-time injections occurred Q4 weeks within a +7-day dosing window of the projected dosing date. Adherence to LA therapy was calculated as the number of on-time injection visits divided by the number of expected dosing visits through Week 48. Injection visits outside the pre-specified window and missed injection visits with/without the use of oral dosing were quantified. Injection tolerability was assessed via adverse event reporting. Results A total of 14,682 injections of CAB and RPV were administered to 581 subjects during 6,920 injection visits. 98% of injection visits took place within the allowed ±7-day dosing window with 3,194 (46%) on the projected dosing date. Forty-six (<1%) injection visits were early and 106 (2%) were late. Oral bridging was used in 16 subjects overall; 8 planned missed injection visits were successfully covered, with no change to virologic suppression status. No subject with HIV-1 RNA ≥ 50 c/mL at Week 48 had missed/late injection visits. 25% (3,663/14,682) of injections were associated with local injection site reactions (ISRs). The most common ISR was pain (3,087/3,663 = 84%). Most ISRs were grade 1–2 (99%), short duration (median 3 days), with few associated discontinuations (<1%). Conclusion Subjects receiving CAB LA + RPV LA demonstrated high rates of adherence to injection visits through week 48, with 98% of injections occurring within the ±7-day dosing window. Oral bridging with CAB and RPV was an effective strategy for maintaining viral load suppression to cover missed injection visits. Injections were well-tolerated with few associated discontinuations. Disclosures All Authors: No reported Disclosures.

scholarly journals 1035. Patient-Reported Outcomes on Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy: FLAIR 96-Week Results

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S548-S548
Author(s):  
Vasiliki Chounta ◽  
Enrique Bernal ◽  
Johan Lombaard ◽  
Harold P Katner ◽  
Sharon Walmsley ◽  
...  
Keyword(s):  
Treatment Satisfaction ◽  
Patient Reported Outcomes ◽  
Hiv Treatment ◽  
Virologic Suppression ◽  
Research Support ◽  
Treatment Groups ◽  
Patient Reported ◽  
The Difference ◽  
Long Acting ◽  
Hiv 1

Abstract Background In the phase 3 FLAIR study, switching to monthly injectable long-acting (LA) cabotegravir (CAB) + rilpivirine (RPV) was noninferior to continued daily oral dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) for the maintenance of virologic suppression over 96 weeks in adults with HIV-1. Key patient-reported outcomes (PROs) through Week 96 are presented. Methods In FLAIR, ART-naive adult participants received induction therapy with oral DTG/ABC/3TC for 20 weeks. Those with HIV-1 RNA &lt; 50 c/mL at 16 weeks were randomized (1:1) to continue DTG/ABC/3TC or receive monthly CAB + RPV LA injections after a 4-week lead-in with daily oral CAB + RPV through Week 96. Treatment satisfaction (HIV Treatment Satisfaction Questionnaire status version [HIVTSQs]) and acceptability of injections (Perception of Injection [PIN] Questionnaire) up to Week 96 were secondary endpoints. Results A total of 566 participants were randomized (median age, 34 years; 22% female); baseline characteristics were similar between treatment groups. At Week 96, significantly greater improvement from baseline in total treatment satisfaction score was observed in the CAB + RPV LA vs DTG/ABC/3TC treatment group (adjusted mean difference, 2.3 [95% CI, 1.1-3.5]; P&lt; 0.001), further increasing from Weeks 24 (2.1 [0.9-3.3]) and 44 (0.7 [−0.4, 1.9]). Key drivers for the difference in HIVTSQs between treatment groups were items assessing convenience, flexibility, and satisfaction to continue with LA therapy. In participants receiving CAB + RPV LA, mean score for the “Acceptability of ISRs” dimension of PIN (scale, 1-5) significantly decreased (improved) from Week 5 to Weeks 41, 48, and 96 (2.08 to 1.71, 1.66, and 1.71, respectively; P&lt; 0.001 for all). In addition, 82% and 85% of LA participants, respectively, rated pain and local reactions due to injections as “totally” or “very acceptable” at Week 96. Conclusion At Week 96, FLAIR participants receiving LA therapy reported greater improvement in treatment satisfaction compared with participants continuing on daily oral medication as well as overall good acceptability of injections with improvement over time. Overall, these results support monthly CAB + RPV LA as an alternative to daily oral regimens for adults with HIV-1. Disclosures Vasiliki Chounta, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sharon Walmsley, FRCPC, MD, MSC, GSK (Grant/Research Support)ViiV Healthcare (Grant/Research Support) David Dorey, MMATH, GlaxoSmithKline Inc. (Employee, Shareholder) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

scholarly journals 1021. HIV-1 RNA Blips and Low-Level Replication During Phase III/IIIb Cabotegravir + Rilpivirine Long-Acting Studies Are Similar to Oral 3-Drug Therapy and Not Associated with Week 48 Virologic Outcome

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S540-S541
Author(s):  
Christine L Talarico ◽  
Sterling Wu ◽  
Ojesh R Upadhyay ◽  
Marty St Clair ◽  
Veerle Van Eygen ◽  
...  
Keyword(s):  
Viral Load ◽  
Virologic Failure ◽  
Phase Iii ◽  
Individual Study ◽  
Treatment Groups ◽  
Qualitative And Quantitative ◽  
Low Level ◽  
Long Acting ◽  
Study Participants ◽  
Hiv 1

Abstract Background Phase III/IIIb studies demonstrated cabotegravir (CAB) + rilpivirine (RPV) long-acting (LA) dosed every 4 weeks (Q4W) was noninferior to current antiviral regimen (CAR) (FLAIR and ATLAS) and CAB + RPV LA dosed every 8 weeks (Q8W) was noninferior to Q4W (ATLAS-2M) through Week 48 (W48). HIV-1 ribonucleic acid (RNA) blips (viral load [VL] ≥50 to &lt; 200 c/mL) are common during antiretroviral therapy (ART) and generally not associated with subsequent virologic failure (2 consecutive HIV-1 RNA ≥200 c/mL). We compared the frequency of HIV-1 RNA blips and low-level qualitative and quantitative HIV-1 RNA replication among participants treated with CAB+RPV LA and oral CAR and assessed impact on virologic outcome. Methods Plasma samples collected at study visits were analyzed for HIV-1 RNA viral load using the Abbott RealTime HIV-1 assay and qualitative target detected (TD) or target not detected (TND) outcomes were provided for HIV-1 RNA &lt; 40 c/mL. The HIV-1 SuperLow assay (bioMONTR Labs) was used to measure HIV-1 RNA &lt; 2 c/mL at Baseline and W48. Results The proportion of participants with HIV-1 RNA blips was similar overall between Q4W CAB + RPV LA and CAR arms in FLAIR (38/283 [13%] vs 39/283 [14%]) and ATLAS (17/308 [6%] vs 23/308 [7%]). Presence of HIV-1 RNA blips in either arm was not associated with virologic non-response at W48 (HIV-1 RNA ≥50 c/mL per US Food and Drug Administration Snapshot). In ATLAS-2M, HIV-1 RNA blips were observed in 32/523 (6%; Q4W) and 18/522 (3%; Q8W) of participants, with W48 virologic nonresponse in 2 Q4W and 0 Q8W participants. TD outcomes at individual study visits were comparable between study arms for the 3 studies. At W48, the proportion of participants with HIV-1 RNA &lt; 2 c/mL was similar to Baseline and similar between treatment groups in all studies. Conclusion The proportions of study participants with HIV-1 RNA blips, TD viral load results, and HIV-1 &lt; 2 c/mL were similar between the Q4W and Q8W CAB+RPV LA and the oral 3-drug CAR arms through W48 in phase III/IIIb studies. HIV-1 RNA blips did not predict virologic nonresponse (Snapshot analysis) at W48. Disclosures Christine L. Talarico, M.S, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sterling Wu, PhD, GlaxoSmithKline (Employee, Shareholder) Marty St. Clair, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Veerle Van Eygen, MSc, Janssen Pharmaceutica NV (Employee) Krischan J. Hudson, PhD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Conn M. Harrington, BA, ViiV Healthcare (Employee) Jan van Lunzen, MD, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder)

scholarly journals Population Pharmacokinetics of Doravirine and Exposure-Response Analysis in Individuals with HIV-1

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Ka Lai Yee ◽  
Aziz Ouerdani ◽  
Anetta Claussen ◽  
Rik de Greef ◽  
Larissa Wenning
Keyword(s):  
Virologic Failure ◽  
Phase 1 ◽  
Fixed Dose ◽  
Response Analysis ◽  
Population Pharmacokinetic ◽  
Phase 3 ◽  
Once Daily ◽  
Intrinsic Factors ◽  
Exposure Response ◽  
Hiv 1

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1) infection. A population pharmacokinetic (PK) model was developed for doravirine using pooled data from densely sampled phase 1 trials and from sparsely sampled phase 2b and phase 3 trials evaluating doravirine administered orally as a single entity or as part of a fixed-dose combination of doravirine-lamivudine-tenofovir disoproxil fumarate. A one-compartment model with linear clearance from the central compartment adequately described the clinical PK of doravirine. While weight, age, and healthy versus HIV-1 status were identified as statistically significant covariates affecting doravirine PK, the magnitude of their effects was not clinically meaningful. Other intrinsic factors (gender, body mass index, race, ethnicity, and renal function) did not have statistically significant or clinically meaningful effects on doravirine PK. Individual exposure estimates for individuals in the phase 2b and 3 trials obtained from the final model were used for subsequent exposure-response analyses for virologic response (proportion of individuals achieving <50 copies/ml) and virologic failure. The exposure-response relationships between these efficacy endpoints and doravirine PK were generally flat over the range of exposures achieved for the 100 mg once-daily regimen in the phase 3 trials, with a minimal decrease in efficacy in individuals in the lowest 10th percentile of steady-state doravirine concentration at 24 h values. These findings support 100 mg once daily as the selected dose of doravirine, with no dose adjustment warranted for the studied intrinsic factors.

scholarly journals Long-term Outcomes in a Large Randomized Trial of HIV-1 Salvage Therapy: 96-Week Results of AIDS Clinical Trials Group A5241 (OPTIONS)

2019 ◽  
Vol 221 (9) ◽  
pp. 1407-1415 ◽  
Author(s):  
Rajesh T Gandhi ◽  
Karen T Tashima ◽  
Laura M Smeaton ◽  
Vincent Vu ◽  
Justin Ritz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Salvage Therapy ◽  
Virologic Failure ◽  
Virologic Suppression ◽  
Cumulative Activity ◽  
Antiretroviral Medications ◽  
Resistant Group ◽  
Aids Clinical Trials ◽  
Hiv 1

Abstract Background Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of &gt;2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. Methods Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. Results At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA &lt;200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA &lt;200 copies/mL at week 96. Conclusions HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of &gt;2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. Clinical Trials Registration NCT00537394.

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