Elsevier

The Lancet

Volume 390, Issue 10101, 23–29 September 2017, Pages 1499-1510
The Lancet

Articles
Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial

https://doi.org/10.1016/S0140-6736(17)31917-7Get rights and content

Summary

Background

Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks.

Methods

In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir–lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir–lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352.

Findings

Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI −5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [−4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related.

Interpretation

The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated.

Funding

ViiV Healthcare and Janssen R&D.

Introduction

An estimated 36·7 million individuals were living with HIV worldwide at the end of 2015.1 Advances in highly active antiretroviral therapies (ARTs) have improved treatment efficacy for patients with HIV, enhancing patient survival and quality of life.2, 3 However, adherence to medication remains an important challenge; poor compliance can result in treatment failure and the emergence of drug-resistant mutations.4 Long-acting injectable ART might provide some patients with a convenient approach to manage HIV infection that avoids daily oral dosing and the need to keep, store, and transport medications as they undertake their activities of daily living.5

Research in context

Evidence before this study

To establish the background for this study, we searched PubMed publications on the topics of antiretroviral therapy and treatment adherence; long-acting injectable therapies; and the safety, efficacy, and pharmacokinetics of cabotegravir (GSK1265744) and rilpivirine using the keywords “antiretroviral therapy”, “treatment adherence”, “long-acting injectable therapies”, “cabotegravir”, “GSK1265744”, “rilpivirine”, and “TMC-2782”. We also located package inserts and government documents using internet search engines. All searches were updated as of March 7, 2017. A review of this literature shows an ongoing challenge in HIV therapy wherein suboptimal adherence to daily oral medication can lead to treatment failure or the emergence of viral resistance. To date, no long-acting injectable regimen is available to patients with HIV. Cabotegravir is an integrase strand transfer inhibitor with clinically demonstrated activity against the HIV-1 virus and a physiochemistry and pharmacokinetic profile amenable to its formulation and use as a long-acting agent. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor approved as an oral agent for the treatment of HIV-1 infection in combination with other antiretrovirals; its physiochemistry is also appropriate for formulation as a long-acting agent. We did a randomised, open-label, parallel group, phase 2b study (LATTE-2) in patients with HIV-1 viral suppression on oral medication to evaluate the efficacy, safety, and tolerability of cabotegravir plus rilpivirine given as long-acting injections every 4 or 8 weeks, compared with daily oral cabotegravir taken with abacavir and lamivudine.

Added value of this study

The LATTE-2 study is the first to investigate the efficacy and safety of a long-acting injectable antiretroviral therapy for the treatment of HIV-1 infection. An option to treat HIV-1 without the use of daily oral medications represents a paradigm shift in the HIV-1 treatment landscape. The principal finding of the study is that among patients who were suppressed on an oral cabotegravir-based therapy, switching to a long-acting combination of cabotegravir and rilpivirine maintained virological suppression in 90% of patients overall through week 96 following 4-week or 8-week injectable administration at rates comparable to remaining on daily oral cabotegravir-based therapy. The complete week 96 dataset included here provides important evidence for both the durability of virological response and acceptability of intramuscular injections for chronic use with dual antiretroviral therapy in patients infected with HIV-1.

Implications of all the available evidence

To date, the class of integrase strand transfer inhibitors has shown a high level of virological efficacy in clinical studies, which has translated to global widespread successful use. The ability to employ one of these agents, in partnership with one other agent, as an effective long-acting injectable agent has the potential to address the challenges of adherence to daily medication faced by people living with HIV. The daily psychological burden of being discovered as HIV positive can be eased by less frequent or clinic-based medication dosing and might be a preferred option for some patients. Following the advent and proliferation of single-tablet regimens, which themselves constituted a leap forward in dosing convenience, long-acting injectables such as the cabotegravir plus rilpivirine regimen might represent the next revolution in HIV therapy by providing an option that circumvents the burden of chronic daily dosing.

Cabotegravir (GSK1265744) is an analogue of the integrase strand transfer inhibitor (INSTI) dolutegravir that exhibits subnanomolar potency and antiviral activity against a broad range of HIV-1 strains.6 Oral administration of cabotegravir once daily has exhibited acceptable safety and tolerability profiles, a long half-life (40 h), and few drug–drug interactions.7, 8, 9 Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved as a 25 mg once-daily oral medication for HIV-1 treatment.10, 11, 12 In the phase 2b LATTE trial (ClinicalTrials.gov identifier, NCT01641809), a two-drug regimen of once-daily oral formulations of cabotegravir and rilpivirine demonstrated durable viral suppression in patients whose viral load was previously suppressed to less than 50 HIV-1 RNA copies per mL by treatment with cabotegravir and two nucleoside reverse transcriptase inhibitors (NRTIs), providing proof of principle for a two-drug maintenance regimen using an INSTI and NNRTI.13

Long-acting injectable nanosuspension formulations of cabotegravir and rilpivirine are in clinical development.12, 14 Phase 1 clinical studies investigating long-acting cabotegravir and rilpivirine have shown prolonged exposures at least 30 days following gluteal intramuscular injections, enabling dosing at once-monthly or longer intervals.15, 16 Combined administration of long-acting cabotegravir plus rilpivirine produced no clinically significant pharmacokinetic interactions, supporting investigation of these agents as the first-ever long-acting combination ART regimen.16 Here, we report the efficacy and safety of long-acting cabotegravir plus rilpivirine, given as intramuscular injections every 4 weeks or every 8 weeks, compared with that of oral cabotegravir plus abacavir–lamivudine, as maintenance therapy through 96 weeks for individuals who had achieved successful HIV-1 viral suppression with oral cabotegravir plus abacavir–lamivudine.

Section snippets

Study design and participants

LATTE-2 is an ongoing phase 2b, randomised, multicentre, open-label, non-inferiority, parallel-group trial, consisting of a 20-week induction period, 96-week maintenance period, extension period, and long-term follow-up period. The study was done at 50 sites in the USA, Canada, Spain, France, and Germany.

Patients who were HIV-1 positive, were aged 18 years or older, and had no more than 10 days of previous ART treatment, with screening HIV-1 RNA of at least 1000 copies per mL and CD4+ T-cell

Results

The first patient was screened in April 28, 2014, and the last patient's week 96 visit occurred in Nov 10, 2016. Of 386 patients screened, 309 were enrolled in the study (figure 1). 282 (91%) patients were male, average age 36·6 years (SD 10·4). 72 (23%) patients had a baseline CD4+ cell count of no more than 350 cells per mm3, and 60 (19%) patients had a baseline HIV-1 RNA of at least 100 000 copies per mL. Baseline characteristics were balanced among the three dosing groups. 288 patients

Discussion

LATTE-2 is the first study to analyse the efficacy and safety of fully injectable two-drug long-acting ART regimens in patients with HIV-1 infection and contributes to the growing number of studies evaluating simplification to two-drug therapy. Both the long-acting injectable 4-week and 8-week regimens maintained virological suppression at rates comparable to oral daily three-drug ART, with two protocol-defined virological failures occurring among the 230 patients who received long-acting

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    Prof Louis Sloan died in June, 2017

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