ELDORADO: a therapeutic alternative to first-line dolutegravir

Background and aims of the ELDORADO trial

Dolutegravir (DTG), in combination with two nucleoside analogues (NRTI), is currently recommended by the WHO as first-line treatment for HIV-1. It is used by more than 22 million people living with HIV (PLHIV) worldwide. However, data suggest long-term metabolic side effects, including weight gain, increased blood pressure and an increased risk of type 2 diabetes.

Doravirin (DOR), a non-nucleoside reverse transcriptase inhibitor, is recommended by the European AIDS Clinical Society (EACS) and the International Antiviral Society in the United States (IAS-USA), but remains little used in countries with limited resources. The aim of the ELDORADO trial is to assess whether doravirine could be an effective and better tolerated therapeutic alternative to dolutegravir in people who are new to antiretroviral treatment.

ELDORADO trial: doravirine as an effective therapeutic alternative?

The objective of the ELDORADO trial is to assess the virological non-inferiority of doravirine (combined with tenofovir disoproxil fumarate [TDF] and lamivudine [3TC]) versus dolutegravir (combined with TDF and lamivudine or emtricitabine [FTC]) at week 48. The primary endpoint is the proportion of participants with an HIV-1 viral load <50 copies/mL according to the FDA “snapshot” algorithm.

The trial also aims to demonstrate improved metabolic tolerance of the doravirin-based regimen, particularly with regard to weight gain, glycaemic control and blood pressure.

Secondary outcomes

Other outcomes are also being evaluated as part of this trial. These include :

• virological efficacy at week 96;
• metabolic effects: obesity, overweight, insulin resistance, hypertension, diabetes;
• quality of life;
• development of virological resistance;
• changes in immunovirological parameters (CD4, CD8, ratios);
• adherence to treatment.

A targeted metabolic sub-study

In addition to the main trial, an optional sub-study is being offered to 80 cisgender women, including 10 in France, to explore in greater detail the impact of treatment on adipose tissue (biological analyses, DEXA scanner, subcutaneous biopsy). The aim of this sub-study is to gain a better understanding of the mechanisms underlying the weight gain and metabolic disturbances observed in certain patients.

ELDORADO: towards a diversification of first-line therapeutic options?

The ELDORADO trial is part of an overall reflection on the diversification of first-line therapeutic options, taking into account the long-term effects of ARV treatments. It could help widen access to doravirine in developing countries if its results confirm equivalent efficacy to dolutegravir, with a better safety profile.

Methodology

Study design and timetable

ELDORADO is a randomised, open-label, multicentre, phase III trial involving 610 ARV-naïve participants from 6 countries (Brazil, Cameroon, Ivory Coast, Mozambique, Thailand, France), divided equally into two treatment arms:

• DOR arm: doravirine 100 mg + TDF 300 mg + 3TC 300 mg (1 tablet/day)
• DTG arm: dolutegravir 50 mg + TDF 300 mg + FTC 200 mg or 3TC 300 mg (2 tablets/day)

The trial has a total duration of 4 years, with an inclusion period of 12 months and a follow-up period per participant of 96 weeks. Participants are followed up at seven key points: weeks 4, 12, 24, 36, 48, 72 and 96.

Find out more about the ELDORADO trial methodology