MODERATO trial: dual antiretroviral maintenance regimen in West and Central Africa

The challenges of antiretroviral maintenance dual therapy

Since the mid-1990s, the use of three active antiretroviral drugs belonging to at least two different classes of medication has been the standard of care for treating HIV in people living with HIV. However, patients are now living for several decades with continuous exposure to antiretroviral drugs, which increases the cumulative risk of adverse effects, metabolic toxicities and target organ damage associated with ageing. The growing proportion of people living with HIV who are over 50 years of age makes these issues particularly important. In this context, therapeutic simplification aims to reduce the number of molecules administered while maintaining virological efficacy. Several national and regional guidelines now recommend the use of antiretroviral dual therapy or 2DR (2-Drug Regimen) for people with undetectable viral loads. The potential benefits of the 2DR approach include reduced lifetime exposure to drugs, smaller tablets, better tolerance, lower risk of drug interactions and specific toxicities, and cost savings.

The World Health Organisation now recommends, under certain conditions, the use of dolutegravir/lamivudine (DTG/3TC) as a treatment simplification strategy (1), particularly in resource-limited countries. However, data from clinical trials conducted in sub-Saharan Africa remained limited, particularly about the actual efficacy and operational feasibility of these strategies in various healthcare settings.

It was in this context that the MODERATO trial was designed, led by Prof. Serge Paul Eholié and Dr Roland Landman, in collaboration between the Treichville University Hospital and Félix Houphouët-Boigny University in Abidjan, as well as the IMEA-CHU Bichat Claude Bernard in Paris, the University of Bordeaux and the PAC-CI/Prisme-CI programme. Promoted by Inserm-ANRS MIE, this multicentre trial was conducted in Burkina Faso, Cameroon and Côte d’Ivoire.

The MODERATO trial demonstrates the feasibility of dual therapy in controlled patients

The 96-week results demonstrate that dual therapy is non-inferior to standard triple therapy for maintaining virological suppression (2). In the intention-to-treat analysis, the virological success rate was 95% in the dual therapy arms compared to 98% in the triple therapy arm. Ten virological failures were observed in the dual therapy groups compared with four in the triple therapy group. The change in CD4+ count was comparable between groups.

Adverse events were similar (12% versus 9%). However, greater weight gain was observed in the dual therapy groups: +3.7 kg in the DTG/3TC arm and +2.6 kg in the ATV/r arm, compared with +0.6 kg in the TLE group (3). On the other hand, no significant changes were observed in major metabolic parameters, including lipid profile or renal function.

MODERATO trial methodology

The MODERATO trial is the first study in West and Central Africa to evaluate the non-inferiority of a dual maintenance therapy (DTG/3TC or boosted atazanavir [ATV/r] + 3TC) compared to a triple therapy (3DR, tenofovir/3TC/efavirenz, TLE, or tenofovir/3TC/dolutegravir, TLD) in people living with HIV-1.

Between November 2020 and December 2024, 480 patients were enrolled in three countries (Burkina Faso, Cameroon and Côte d’Ivoire). All had been on antiretroviral therapy (TLE or TLD) for at least 2 years, with no history of virological failure or hepatitis B, and a CD4+ count above 200/mm³ ^³at enrolment. The primary endpoint was success defined as maintaining an undetectable viral load at S96 (< 50 copies/mL), according to the FDA Snapshot algorithm.

Patients were randomly assigned: 160 to each of the two 2DR arms and 160 to the 3DR arm: 149 to the TLE arm and 11 to the TLD arm. The median age was 50 years, with a median treatment duration of 9 years and a median CD4+ count of 736/mm³

Implications and perspectives

The MODERATO trial represents a major advance in clinical HIV research in sub-Saharan Africa. It demonstrates for the first time that a dual-therapy strategy can be successfully implemented in resource-limited settings among virologically suppressed patients.

These results support recent recommendations from the World Health Organization and help address the lack of data from low- and middle-income countries. Beyond clinical efficacy, reducing the number of drugs could improve treatment adherence, limit long-term toxicities (with the exception of weight gain), and lower the costs of national HIV treatment programs—an important issue for the sustainability of healthcare systems.

However, the issue of weight gain in patients receiving dual therapy needs to be further investigated in order to identify associated factors and implement measures for at-risk individuals, thereby preventing metabolic complications.

References

1. WHO updated recommendations on HIV clinical management: recommendations for a public health approach ; 2025. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789240119468
2. Fadiga F et al. First experience of dual antiretroviral maintenance regimen in West and Central Africa compared with continuing 3-drug current antiretroviral regimens (CARs): week 96 results from the MODERATO trial (ANRS -MIE 12372). IAS 2025, abstract OAB0103.
3. Fadiga F et al. Evolution of weight under Dual Therapy without Tenofovir Compared to Triple Therapy: Week 96 Results from the MODERATO Trial (ANRS -MIE 12372). CROI 2026, abstract