Boosted darunavir plus lamivudine matches three-drug regimen

A combination of darunavir/ritonavir and lamivudine was just as effective as the same combination plus tenofovir, according to 24-week results of the ANDES study presented last month by Professor Pedro Cahn at the 9th IAS Conference on HIV Science in Paris (IAS 2017).

Darunavir boosted by ritonavir or cobicistat is recommended as an option for first-line treatment in United States and European guidelines due to its high barrier to resistance.

Professor Cahn’s Argentinean research group has been investigating the use of two-drug regimens consisting of boosted protease inhibitors or integrase inhibitors combined with lamivudine. These regimens offer potential advantages, saving money and sparing potential long-term side-effects of tenofovir, the drug most commonly employed as the third agent in first-line antiretroviral treatment.

The GARDEL study showed that the combination of lopinavir/ritonavir plus lamivudine was non-inferior to the three-drug combination of lopinavir/ritonavir, lamivudine and a nucleoside or nucleotide analogue after 48 weeks of follow-up.

An Italian study, ATLAS, reported last year that the combination of atazanavir/ritonavir and lamivudine was non-inferior to atazanavir/ritonavir and two nucleoside or nucleotide reverse transcriptase inhibitors after 48 weeks of follow-up.

The GEMINI 1 and 2 studies are currently investigating whether the combination of the integrase inhibitor dolutegravir with lamivudine is non-inferior to three-drug treatment with dolutegravir, tenofovir and emtricitabine. If successful, the combination of dolutegravir and lamivudine could be the cheapest drug combination available for treatment in lower-income and lower-middle income countries, due to the low costs of manufacturing both drugs.

However, patent restrictions may not permit the sale of a generic version of dolutegravir in some upper-middle income countries. Use of a boosted protease inhibitor combined with lamivudine may offer an attractive option for first-line treatment.

The ANDES study randomised 145 previously untreated people with HIV in Argentina to receive either darunavir/ritonavir (800/100 mg once daily) plus lamivudine (300mg once daily) (n = 75) or darunavir/ritonavir (800/100mg once daily) plus tenofovir (300mg) and lamivudine (300mg) (n = 70). The study population was predominantly male (91%), men who have sex with men (73%) and relatively young (median age 30). Just under a quarter of participants had a high viral load (> 100,000 copies/ml) and the median CD4 cell count was 383 cells/mm³.

In this study, participants received a fixed-dose combination of darunavir/ritonavir manufactured by the Argentinean generic drug maker Richmond Laboratories and a generic form of lamivudine. The generic darunavir product is licensed in Argentina as bioequivalent to the branded product Prezista plus ritonavir and is marketed as Virontar N.

The primary outcome of the study is the proportion of participants in each study arm with a viral load below 50 copies/ml by intent-to-treat analysis at week 48. Professor Cahn presented results of a secondary endpoint, the proportion of participants with a viral load below 400 copies/ml at week 24.

There was no significant difference in viral suppression at week 24 – 97% in the triple-drug arm and 95% in the two-drug arm – and only one virological failure, in the three-drug arm. Four participants in the two-drug arm discontinued treatment for other reasons (one due to rash, one due to a serious adverse event unconnected to the study drug, one withdrew from the study and one was lost to follow-up).

Drug-related grade 2 or 3 adverse events occurred more frequently in those who received three-drug therapy (21 vs 11 events), with neurologic and gastrointestinal adverse events largely accounting for the difference. Rash occurred with similar frequency in each study arm (8 vs 7.1%). There were no drug-related serious adverse events.

The study is continuing to a second phase in which 190 additional participants will be randomised and all participants will be followed for 48 weeks to determine if the combination of darunavir/ritonavir and lamivudine is non-inferior to three-drug therapy in longer-term follow-up.