Articles
Cabotegravir plus rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a randomised, phase 2b, dose-ranging trial

https://doi.org/10.1016/S1473-3099(15)00152-8Get rights and content

Summary

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-nucleoside 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 HIV-1-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.

Funding

ViiV Healthcare and Janssen Research and Development.

Introduction

Over the past two decades, novel drugs for HIV-1 antiretroviral therapy have improved long-term viral suppression.1 The discovery of integrase strand transfer inhibitors (INIs) has provided important treatment options for patients with HIV/AIDS. Approved first-generation INIs (raltegravir and elvitegravir) are effective and generally well tolerated.2, 3, 4, 5 Clinical resistance to these first-generation INIs has, however, been reported in treatment-naive and previously treated patients.6, 7, 8, 9, 10, 11, 12 Dolutegravir is a second-generation INI with an improved resistance and administration profile.13 These advances might be further augmented by the development of longacting injectable antiretroviral drugs and regimens with the potential to improve adherence and thereby increase the options for treatment or prophylaxis.

Research in context

Evidence before this study

We searched PubMed, with combinations of the search terms “integrase strand transfer inhibitor” (INI), “integrase inhibitor”, “non-nucleoside reverse transcriptase inhibitor”, “raltegravir”, “dolutegravir”, “elvitegravir”, “rilpivirine”, “two drug HIV therapy”, “long acting”, and “HIV pre-exposure prophylaxis”, with no restrictions on language or publication date. Several small retrospective and uncontrolled studies using INIs plus non-nucleoside reverse transcriptase inhibitors (NNRTIs) as dual HIV-1 therapy have been reported. Results from these studies suggested long-term viral suppression from well tolerated regimens, which warranted further investigation and confirmation in larger randomised controlled studies. Longacting parenteral versions of cabotegravir and rilpivirine are being developed with promising preclinical and clinical pharmacology profiles.

Added value of this study

LATTE 24-week induction results confirm rapid and robust viral suppression with cabotegravir plus dual nucleoside reverse transcriptase inhibitors (NRTIs), a profile that has been well established for other drugs within the INI class. The two-drug maintenance regimen of cabotegravir plus rilpivirine showed viral suppression for an additional 72 weeks similar to the three-drug regimen of efavirenz plus dual NRTIs with similar safety and tolerability and an impressive resistance profile. Results from the LATTE study confirm, for the first time within a randomised controlled trial, the safety and durability of a two-drug INI plus NNRTI regimen after induction therapy in an antiretroviral-naive adult population.

Implication of all the available evidence

Current three-drug combination antiretroviral therapy regimens might result in treatment modification or interruption because of side-effects, toxicities, or complicated administration profiles. New HIV-1 antiretroviral agents need to be developed with a focus on improved safety, efficacy, and resistance profiles, and more convenient administration to enable patient adherence. In view of the potential for long-term side-effects of dual NRTIs and pharmacologically boosted protease-inhibitor regimens, a well tolerated, simplified two-drug therapy that offers sustained viral suppression while avoiding these classes might be particularly desirable within the ageing population with HIV infection and in patients with comorbidities, including renal and cardiovascular disease. Results from LATTE are fundamental for further assessment of parenteral formulations of cabotegravir and rilpivirine towards the increase in treatment options for patients and health-care providers.

Cabotegravir (GSK1265744) is an INI and structural analogue of dolutegravir with potent anti-HIV-1 activity, a half-life of about 40 h when dosed orally, and a low propensity for drug interactions.14 Oral doses of cabotegravir have been generally well tolerated in early trials of healthy and HIV-1-infected individuals.15 Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with in-vitro activity against HIV-1 wild type and resistant to some NNRTIs.16 Oral rilpivirine at 25 mg once a day has been approved for use in antiretroviral-therapy-naive patients and in some virologically suppressed patients as a replacement antiretroviral treatment regimen. No significant pharmacokinetic interactions occurred between oral cabotegravir and oral rilpivirine,14 lending support to the investigation of a two-drug regimen for the maintenance of viral suppression. Parenteral longacting formulations of cabotegravir and rilpivirine are in clinical development with the goal to establish the safety and efficacy of a two-drug injectable regimen with a dosing interval of at least 4 weeks. So far, both longacting formulations have been generally well tolerated, alone and together, with longlasting plasma exposures after intramuscular injection.17, 18, 19

In the 24-week induction phase of Long-Acting antireTroviral Treatment Enabling (LATTE), a phase 2b study, we assessed viral suppression (HIV-1 RNA <50 copies per mL) by oral cabotegravir plus nucleoside reverse transcriptase inhibitors (NRTIs) compared with efavirenz plus NRTIs. In the maintenance phase of LATTE, we assessed a two-drug oral antiretroviral treatment regimen (cabotegravir plus rilpivirine) for maintenance of viral suppression for an additional 72 weeks compared with a three-drug efavirenz-based antiretroviral therapy.

Section snippets

Study design and participants

LATTE is a phase 2b, randomised, multicentre, parallel-group, partly masked induction and maintenance study in HIV-1 infected antiretroviral-therapy-naive adults at 49 sites in Canada and the USA. Eligible patients (aged ≥18 years) had HIV-1 infection with screening plasma HIV-1 RNA copies of at least 1000 per mL, had a CD4 cell count of at least 200 per μL, were antiretroviral treatment naive (≤10 days of previous treatment), and had no major drug-resistance-associated mutations.20 Exclusion

Results

Of 324 patients who were screened, 244 antiretroviral-therapy-naive patients were randomly allocated to one of the four treatment regimens; 243 patients received at least one dose of study drug and were included in the analysis (intention-to-treat exposed population; figure 1). Baseline demographics and disease characteristics were balanced across treatment groups (table 1). The maintenance phase had 207 patients (intention-to-treat maintenance-exposed population) and no meaningful differences

Discussion

At week 24 of the induction phase of LATTE, virological response rates were higher in the cabotegravir group than in the efavirenz (control) group because of fewer viral non-responders and adverse-event-related withdrawals in the cabotegravir group. All treatment groups had viral suppression until the end of 72 weeks of maintenance therapy (week 96), with overall suppression rates remaining numerically higher for cabotegravir groups. Response rates at week 96 increased with cabotegravir doses,

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