Background In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine. Methods LATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1. After a 24-week induction phase with cabotegravir + 2 NRTIs, participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL were randomized to receive cabotegravir (10, 30, or 60 mg) + rilpivirine (25 mg) in the maintenance phase through Week 96 and switched to cabotegravir 30 mg + rilpivirine 25 mg in the open-label phase through Week 312. Results Of 160 participants who entered the maintenance phase, 111 completed the study at Week 312. At Week 312, 105 (66%) participants maintained HIV-1 RNA <50 copies/mL, 15 (9%) had HIV-1 RNA >= 50 copies/mL, and 40 (25%) had no virologic data. Eight participants met protocol-defined virologic failure criteria through Week 312, 2 of whom met protocol-defined virologic failure criteria after Week 144. Six participants developed treatment-emergent resistance to 1 or both agents during the study, 3 of whom developed integrase inhibitor resistance substitutions. Two participants (1%) reported drug-related serious adverse events. Few adverse events led to withdrawal during the open-label phase (n = 5, 3%). Conclusions Oral cabotegravir + rilpivirine demonstrated efficacy in the majority of participants and an acceptable safety profile through 6 years of treatment, demonstrating its durability as maintenance therapy for HIV-1. Oral cabotegravir + rilpivirine maintained virologic suppression in the majority of participants and demonstrated an acceptable safety profile through 6 years of treatment, supporting its use as a flexible treatment strategy in people with HIV-1 receiving long-acting cabotegravir + rilpivirine.

Objectives: Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809). Design: A Phase 2b, multicenter, open-label, rollover study. Methods: LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed. Results: Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV. Conclusion: CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

Abstract Background Long-acting (LA) cabotegravir (CAB) and rilpivirine (RPV) injectable suspensions have demonstrated efficacy in phase III studies. POLAR assessed antiviral activity and safety of CAB LA+RPV LA, administered every 2 mos (Q2M), in HIV-1 infected, antiretroviral therapy–experienced adults who completed LATTE and received once-daily oral CAB30mg+RPV25mg treatment. Methods POLAR is a phase IIb, multicenter, open-label, rollover study in 97 virologically suppressed, HIV-infected adults. LATTE participants who completed ≥312 weeks on study, with plasma HIV-1RNA< 50c/mL at screening, were eligible for POLAR and offered the option to switch to CAB LA+RPV LA Q2M or to the oral fixed dose combination of dolutegravir (DTG)/rilpivirine (RPV) once daily, for continued maintenance of HIV-1RNA suppression. 90 participants chose CAB LA+RPV LA and 7 participants chose oral DTG/RPV. The primary outcome measure was proportion of participants with plasma HIV-1RNA≥50c/mL after 12 mos (M12) of therapy. Safety and laboratory measures were assessed throughout the study. Participants selecting LA treatment completed satisfaction and quality-of-life questionnaires at Day 1, M6, and M12. Results At M12, no participant had HIV-1RNA≥50c/mL or protocol defined virologic failure (confirmed plasma HIV-1RNA > 200c/mL). Excluding injection-site reactions (ISRs), nasopharyngitis (11%), upper respiratory tract infection (11%), diarrhea (10%), and pyrexia (10%) were the most commonly reported adverse events (AEs) in the Q2M arm. 10% (9/90) of Q2M participants reported AEs ≥grade 3; 0 were drug related. 2% (2/90) of Q2M participants had AEs leading to withdrawal. 6% (5/90) of participants reported serious AEs (1 considered drug-related). Over 12 mo, 1534 injections were administered; 463 ISRs were reported (30%; all grade 1/2 [84%/16%]); resolution of ISRs occurred after a median of 3 days. Minimal changes in lab parameters were observed in participants across 12 mo. 88% of participants who received LA therapy preferred CAB LA+RPV LA vs oral therapy. Table 1 Table 2 Conclusion CAB LA+RPV LA, administered Q2M, resulted in durable virologic suppression, an acceptable tolerability profile, and high levels of participant satisfaction over the first 12 mo of treatment in POLAR. Disclosures Anthony Mills, MD, Gilead (Grant/Research Support, Advisor or Review Panel member)Janssen Pharmaceutica (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Shionogi (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Gary J. Richmond, MD, FACP, FCCP, Gilead (Scientific Research Study Investigator)TaiMed (Scientific Research Study Investigator)Viv (Scientific Research Study Investigator) Cheryl Newman, MD, Gilead (Grant/Research Support)GlaxoSmithKline (Grant/Research Support, Speaker’s Bureau)ViiV Healthcare (Research Grant or Support, Speaker’s Bureau) Olayemi Osiyemi, M.D, GlaxoSmithKline (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Jerry Cade, MD, Gilead (Consultant, Research Grant or Support, Speaker’s Bureau)Janssen Pharmaceutica (Consultant)Merck (Consultant, Research Grant or Support, Speaker’s Bureau)ViiV Healthcare (Consultant, Research Grant or Support) Cynthia Brinson, MD, Gilead (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Nisha Andany, MD, MPH, FRCPC, Gilead Sciences (Scientific Research Study Investigator)GlaxoSmithKline (Scientific Research Study Investigator)Janssen (Scientific Research Study Investigator) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kenneth Sutton, MA, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Viviana Wilches, HBSc, MBiotech, GlaxoSmithKline (Employee, Shareholder) Jeremy Roberts, MSc, GSK (Employee) Cynthia C. McCoig, MD, ViiV Healthcare (Employee) Kati Vandermeulen, MSC, Janssen Pharmaceutica (Employee, Shareholder) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder)

Abstract Background Third line antiretroviral regimens have been associated with suboptimal virologic suppression, due to drug cross-resistance and regimen complexity. Yet, in treatment-experienced (TE) HIV patients, ART durability is essential for preventing further resistance and decreasing HIV-associated morbidity and mortality. Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved to treat multi-drug resistant (MDR) HIV, may support regimen durability given its directly observed administration. We analyzed the safety, efficacy, and durability of response in 12 patients who started IBA in a Phase 2b study. Methods In TMB-202, 113 patients with MDR HIV received either 2000 mg IBA every 4 weeks (n=54) or 800 mg IBA every 2 weeks (n=59) for 24 weeks with an optimized background regimen (OBR). Of 96 patients who completed TMB-202, 56 transferred into an investigator-sponsored investigational new drug protocol and 12 later moved onto an expanded access protocol, TMB-311, where efficacy and safety were monitored until IBA was commercially available (approval 2018). Results Baseline median viral load (VL) and CD4 count for the 12 patients were 4.4 log10 copies/mL (c/mL) and 135 cells/mL, respectively. The median duration of HIV infection was 22 years (range 18-25). At the completion of TMB-202 11/12 achieved virologic suppression (VL < 200 c/mL) and 8/12 had VL < 50 c/mL. All 12 patients were suppressed (VL < 50 c/mL) at their last TMB-311 visit. Patients gained an average of 99 CD4 cells/mL relative to baseline. There were no treatment-emergent adverse events (TEAE) or therapy discontinuations related to IBA during follow-up. Two patients died from unrelated causes. Overall, the 12 patients remained on IBA for an average of 8.9 years (range 8-9.5), during which 8/12 did not require addition of new ARVs to their OBR to maintain suppression. Figure 1: duration of ibalizumab-based regimen is displayed for the 12 patients. Grey bars represent patients with no addition of new ARVs to OBR. Black bars represent patients with an addition to OBR. Asterisks represent addition of ritonavir only. Conclusion Data from 12 patients who received IBA for an average of 9 years validate the long-term efficacy and safety of IBA in TE patients. Importantly, for most patients, the durability of virologic response was maintained with minimal adjustments to the OBR. Altogether, these data demonstrate the contribution of IBA towards durable viral suppression in TE HIV patients with limited therapeutic options. Disclosures William Towner, MD, Dynavax (Research Grant or Support)Gilead (Grant/Research Support)Merck (Research Grant or Support)Tai Med (Research Grant or Support)ViiV (Research Grant or Support) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member) Colleen McGary, PhD, Theratechnologies (Employee) Mohammed Zogheib, PharmD, MPH, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

Abstract Background Cabotegravir (CAB), an INI, is under development in both oral and long-acting (LA) injectable formulations. LATTE (NCT01641809) was designed to select a daily oral dose of CAB and evaluate a two-drug ART regimen with rilpivirine (RPV), as suppressive maintenance therapy. Results enabled the LATTE-2 (NCT02120352) study to evaluate CAB LA + RPV LA dosed once every 1 or 2 months. Methods Phase 2b, multicentre, partially blinded dose-ranging study in ART-naïve HIV infected adults, randomized 1:1:1:1 to the induction regimen of once-daily oral CAB 10, 30, or 60 mg or efavirenz (EFV) 600 mg with TDF/FTC or ABC/3TC through W24. CAB patients with VL <50 c/mL immediately prior to W24 discontinued NRTIs and began RPV 25 mg as a two-drug oral maintenance regimen through W96. No change was made to the EFV arm. After W96, at the start of the open-label (OL) phase, all patients randomized to CAB were given the option to continue and switch to the sponsor-selected dose of oral CAB 30 mg. EFV patients completed the study at W96. The OL phase was completed at W312 (288 weeks on CAB + RPV). Successful CAB + RPV patients transitioned to the POLAR study (NCT03639311). Results A total of 243 patients were randomized and initiated treatment (ITT-E). Of those randomized to CAB (n = 181), 160 patients began CAB + RPV (W24) and 138 continued into OL phase (W96). One hundred and ten patients successfully completed the study (W312). Among patients who began CAB + RPV at W24, 66% maintained <50 c/mL, 9% had HIV-1 RNA ≥ 50 c/mL, and 25% were categorized as “No Virologic Data” by Snapshot at W312 (ITT-ME). There were 11 protocol-defined virologic failures (PDVF) on CAB; only 2 occurring after W144. Six patients developed treatment emergent (TE) resistance to one or both agents during the study; of which 4 patients developed TE major INI resistance mutations, 3 after W96. The median increase in CD4+ cell count from Baseline was 393 cells/mm3 (−174 to 1118). During the maintenance and OL phases, 4% of CAB patients reported drug-related AEs ≥ Grade 2; SAEs occurred in 9% of CAB patients (none drug related); 3% of CAB patients withdrew due to AEs. 43% of CAB patients who entered maintenance phase reported TE lab abnormalities ≥ Grade 3. Conclusion As maintenance therapy in virologically suppressed patients, the 2DR CAB + RPV provided durable viral suppression through W312. Through 7 years of study, CAB + RPV continues to be generally safe and well tolerated. Disclosures All Authors: No reported Disclosures.

Background In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nudeoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals.Methods In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV4-infected adults (aged >= 18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809.Findings Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60,51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24,149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group.Interpretation Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection.