Boosted darunavir plus lamivudine matches three-drug regimen

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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 by Professor Pedro Cahn from the Fundacion Huesped, clinical research, Buenos Aires, Argentina, 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 US and European guidelines due to its high barrier to resistance.

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. 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.

Abstract
Background: Following the results of the GARDEL trial, dual therapy (DT) has been explored in different studies. Generic fixed dose combinations (FDC) of Darunavir/ritonavir (DRV/rtv) 800/100 mg and Tenofovir/Lamivudine(TDF/3TC) are available in Argentina. This study compares DRV/rtv plus 3TC to standard-of care triple therapy (TT) based on these same drugs plus Tenofovir (TDF).
Methods: ANDES is a randomized, open-label, phase IV study, designed to assess the antiviral efficacy, safety and tolerability of DT with DRV/rtv (800/100 mg) FDC, plus 3TC (300 mg), compared to TT with DRV/RTV (800/100 mg) plus TDF/3TC (300/300mg) FDC in treatment-naïve HIV-1 infected patients. Primary endpoint: proportion of patients with viral load (pVL) < 50 copies/mL at week 48. Preplanned analyses at week 24, measured by the proportion of patients with pVL < 400 copies/mL (ITT-exposed analysis, FDA snapshot algorithm) are reported. ClinicalTrials.gov Identifier:NCT02770508. Results: Out of 182 patients screened, 145 were randomized to receive: DT (n:75) or TT (n:70). Screening failure rate 20%. At baseline: 91% were male; median age 30 years; CDC stage A: 92%; 24% had pVL >100,000 copies/mL. At week 24, 94.7% (n:71) of patients receiving DT and 97.1% (n:68) receiving TT were responders (pVL < 400 copies/mL), difference -2.5 % (95% CI:-7.9-2.9) Patients with baseline pVL >100,000 copies/mL (n:35) showed 100% response in both arms. One patient had virological failure at W24 due to non-compliance (control arm). Mean CD4+ increases were similar in both arms (DT=206 cells/mm3; TT=204 cells/mm3).Sixty-seven grade 2-3 possible/probable related adverse events (AEs) were reported in 51 patients (36%), most frequent were gastrointestinal (22%) and rash (14%). AEs incidence was similar in both arms; one patient was discontinued due to a drug-related grade 3 adverse event (rash).
Conclusions: A generic combination of DRV/RTV in fixed-dose plus 3TC showed non-inferiority to a generic triple drug regimen of DRV/RTV plus TDF/3TC at 24 weeks. These results, if confirmed at week 48, may provide further evidence about the potential efficacy of dual therapy based on 3TC and a drug with a high genetic barrier.

Authors
O Sued, MI Figueroa, A Gun, W Belloso, D Cecchini, G Lopardo, D Pryluka, MJ Rolon, V Fink, S Perez Lloret, P Cahn

Aidsmap material
IAS 2017 abstract


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