Rationale

Access to antiretroviral therapy (ART) in low-income and middle-income countries has been scaled-up effectively over recent years. Despite these advances, the number of patients failing on their first-line regimen is increasing thereby requiring a switch to second-line treatment to reduce accumulation of drug-resistance mutations, disease progression, human immunodeficiency virus (HIV) transmission, and death. Publicly funded programmes tend to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors (NRTIs) for first-line ART; however, there is a need for further data on the best treatment options for people with HIV-1 who have virological failure with this first-line regimen. WHO guidelines recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a ritonavir-boosted protease inhibitor (PI); atazanavir plus ritonavir (ATV+RTV) or lopinavir (LPV)/RTV are the preferred boosted PI options.

Several studies have been conducted or are currently underway to investigate novel treatment strategies (i.e. NRTI-sparing regimens) in patients requiring second-line ART. There are currently no studies ongoing to explore the potential option of PI-sparing second-line ART. This strategy, especially with the availability of agents from non-PI classes with a high barrier to resistance, may have some advantages over PI-based regimens, particularly from a safety and tolerability perspective. This study compares a second-line regimen of dolutegravir (DTG) plus two NRTIs with a WHO-recommended regimen of LPV/RTV plus two NRTIs.

Objectives

Primary Objective

To demonstrate non-inferior antiviral activity at 48 weeks of a DTG containing regimen (DTG 50 mg once daily + two NRTIs) compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV-1 infected patients failing first line therapy.

Secondary Objectives

To demonstrate non-inferior antiviral activity at 24 weeks of a DTG containing regimen (DTG 50 mg once daily + two NRTIs) compared to a recommended WHO standard of care regimen for second line treatment, LPV/RTV + two NRTIs, in HIV- 1 infected patients failing first line therapy;

To evaluate the antiviral and immunological activity and incidence of disease progression (HIV-associated conditions, AIDS and death) of DTG compared to LPV/RTV over time;

To assess the development of viral resistance in subjects meeting confirmed virologic withdrawal criteria; To evaluate the safety, tolerability, and laboratory parameters of DTG compared to LPV/RTV over time;

To compare the effects of DTG and LPV/RTV on fasting lipids over time;

To compare the effects of DTG and LPV/RTV on the occurrence of gastrointestinal adverse events over time;

To compare the change in gastrointestinal symptom rating score for subjects treated with DTG and LPV/RTV over time;

To compare the satisfaction with treatment of patients with DTG compared to the LPV/RTV over time;

To compare patients’ adherence with DTG compared to the LPV/RTV over time;

To evaluate the effect of patient demographics and baseline characteristics (e.g. demographic factors, HIV-1 subtype, baseline CD4+ cell count) on response to DTG compared to LPV/RTV over time.

Study Design

This study is a Phase IIIb, randomised, open-label, active-controlled, multicenter, parallel group, non-inferiority study. Approximately 612 adult patients with confirmed virologic failure (HIV-1 RNA 400 copies/mL [c/mL] on two occasions) on their first antiretroviral regimen consisting of one NNRTI + two NRTIs will be recruited. Subjects will be randomised 1:1 to receive DTG 50 mg once daily or LPV/RTV (800/200 mg once daily or 400/100 mg twice daily, in accordance with investigator decision and local label), each added to an investigator selected background regimen consisting of two NRTIs. The background regimen shall be constructed by the investigator based on viral resistance testing at Screening and be composed of at least one fully active NRTI plus one more NRTI which may or may not be active. In consultation with the medical monitor, lamivudine (3TC) may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC (e.g. M184V). 3TC cannot be added to regimens that include FTC.

Randomisation will be stratified by Screening plasma HIV-1 RNA (≤100,000 c/mL or >100,000 c/mL) and number of fully active NRTIs in the investigator selected study background regimen (2 versus <2).

The study will comprise a Screening Phase (approximately 28 to 42 days), a Randomised Phase (Day 1 to Week 48 plus a 4-week treatment extension), and a Continuation Phase.

The 4-week treatment extension up to Week 52 within the Randomised Phase is to allow for the collection of a confirmatory viral load measurement in subjects presenting with HIV-1 RNA ≥50 c/mL at the Week 48 visit. The primary efficacy endpoint corresponds to viral load measurements collected within a ± 6 week window around the Week 48 visit (including data from the Week 52 visit), as per the FDA’s Snapshot algorithm, and for this reason, the primary analysis is denoted as occurring at Week 48 with the understanding that data from the Week 52 visit may be included.

The primary analysis at Week 48 will take place after the last subject completes 52 weeks on therapy (Day 1 to Week 48 plus a 4-week treatment extension). An interim analysis and data cut will be conducted after the last subject completes 24 weeks on therapy, with the intent to provide an earlier assessment of efficacy to inform the Sponsor and clinicians. A switch from LPV/RTV 800/200 mg once daily to 400/100 mg twice daily and the opposite switch and a single change of one of the background NRTIs for toxicity or tolerability management is allowed. Any NRTI change must ensure a fully active NRTI is still present based on Screening resistance testing. A switch from 3TC to emtricitabine (FTC) (or vice versa) will not be considered a background NRTI change and is permitted. No other dose reductions, modifications in dosage, or changes in the frequency of dosing will be allowed in this study.

Subjects randomised to receive DTG who successfully complete 52 weeks of treatment will continue to have access to DTG (Continuation Phase) until it is either locally approved and commercial supplies are available to patients (e.g. through public health services), the patient no longer derives clinical benefit, or the patient meets a protocoldefined reason for discontinuation. Subjects randomised to the LPV/RTV arm will receive LPV/RTV through their Week 48 visit and during the 4-week treatment extension only, after which they will complete the study and will need to have alternate arrangements in place to access antiretroviral medication.

An IDMC has been instituted to perform periodic reviews of the accumulating data to ensure that subjects are not being sub-optimally treated. The IDMC completed two of the three pre-planned analyses. Prior to interim analysis #3, the IDMC conducted an ad-hoc review of trial data and observed significant, clinically relevant differences between treatment arms in favour of DTG. The IDMC recommended to the sponsor that the LPV/RTV treatment arm be discontinued and subjects currently receiving LPV/RTV in the study be switched to a regimen with DTG as the third drug, if considered appropriate by the Investigator. As per Protocol Amendment No. 2, subjects randomised to the LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the 4-week treatment extension (see above), or (ii) switch to the DTG arm prior to study completion at Week 52 and continue to have access to DTG in the Continuation Phase until DTG is either locally approved and commercial supplies are available to patients (e.g. through public health services), the patient no longer derives clinical benefit, or the patient meets a protocol-defined reason for discontinuation. Subjects originally randomized to DTG and receiving DTG in the Randomised Phase or in the Continuation Phase are not affected by this IDMC recommendation and Protocol Amendment No. 2.