Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection

Abstract

BACKGROUND Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, −0.4 percentage points; 95% confidence interval [CI], −2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, −3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, −10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials

“… 12 , 13 Both compounds are formulated as LA agents to be administered intramuscularly (IM), with oral formulations of RPV and a new formulation of CAB in development. 13 These oral formulations have been used during an oral lead-in phase in the ATLAS 14 and FLAIR 15 studies to assess safety and tolerability before study participants transitioning to LA therapy with CAB and RPV. This 2-drug oral combination therapy of CAB and RPV was assessed in the LATTE (NCT01641809) study and shown to provide similar antiviral activity compared with efavirenz plus dual NRTIs.…”

“…ATLAS (NCT02951052) 14 and FLAIR (NCT02938520) 15 are ongoing randomized, open-label, multinational phase 3 studies. These studies demonstrated that monthly injections of CAB + RPV LA were noninferior based on the primary endpoint (participants with plasma HIV-1 RNA ≥50 copies/mL at week 48) compared with a control group who continued their oral current antiretroviral regimen (CAR).…”

Prevention and treatment of SHIVAD8 infection in rhesus macaques by a potent d -peptide HIV entry inhibitor

“…Studies are under way to formulate CPT31 in a depot that could be used in such a context. Additionally, this formulation could be paired with other long-acting drugs, such as nanocrystals of cabotegravir (GSK744; GlaxoSmithKline) and/or rilpivirine (TMC278; Tibotec) ( 19 , 20 ), ibalizumab ( 21 ), or promising antibodies and small-molecule inhibitors (Merck’s islatravir/MK-8591 and Gilead’s GS-6207) in clinical development ( 22 , 23 ). To fully evaluate CPT31’s therapeutic potential, it will be important to evaluate its efficacy when administered with other antiretrovirals to identify optimal combinations.…”

Prevention and Treatment of SHIVAD8 Infection in Rhesus Macaques by a Potent D-peptide HIV Entry Inhibitor

“…Studies are underway to formulate CPT31 in a depot that could be used in such a context. Additionally, this formulation could be paired with other long-acting drugs, such as nanocrystals of cabotegravir (GSK744, GlaxoSmithKline) and/or rilpivirine (TMC278, Tibotec) (Orkin et al, 2020; Swindells et al, 2020), ibalizumab (Emu et al, 2018), or promising antibodies and small molecule inhibitors (Merck’s islatravir/MK-8591 and Gilead’s GS-6207) in clinical development (Coelho et al, 2019; Schurmann et al, 2020). To fully evaluate CPT31’s therapeutic potential, it will be important to evaluate its efficacy when administered with other antiretrovirals to identify optimal combinations.…”