August 16, 2019 Sweta Gupta
In the NAMSAL ANRS 12313 trial, researchers compared a dolutegravir-based regimen with a low-dose efavirenz-based regimen for the treatment of HIV-1 infection.
A dolutegravir-based regimen was found to be non-inferior to a low-dose efavirenz regimen (400 mg dose) in terms of viral suppression at week 48 in treatment-naïve adults with HIV-1 living in a resource-limited setting, according to study results recently published in The New England Journal of Medicine.
En esta fase 3, ensayo abierto, multicéntrico (NAMSAL; ClinicalTrials.gov Identifier: NCT02777229), los investigadores asignaron al azar a adultos con VIH-1 en una proporción 1: 1 para recibir dolutegravir o efavirenz 400 mg (tratamiento de referencia), ambos combinado con tenofovir disoproxil fumarato y lamivudina, como terapia antirretroviral de primera línea . Los participantes con un nivel de ARN del VIH-1 de al menos 1000 copias / ml se inscribieron en 3 hospitales en Yaundé, Camerún, entre julio de 2016 y agosto de 2017. El punto final primario fue la proporción de participantes con una carga viral <50 copias / ml en la semana 48. La no inferioridad de dolutegravir a dosis bajas de efavirenz se probó con un margen de 10 puntos porcentuales.
A total of 613 participants (mean age, 37 years; 65.9% women) received ≥ 1 dose of the assigned regimen. The median baseline viral load was 5.3 log10 copies/ml, and 66.4% of participants had a baseline viral load ≥100,000 copies/ml.
En la semana 48, 231 de 310 participantes (74.5%) en el grupo de dolutegravir y 209 de 303 participantes (69.0%) en el grupo de dosis bajas de efavirenz tenían una carga viral <50 copias / mL. La diferencia entre los grupos de tratamiento fue de 5,5 puntos porcentuales (IC del 95%, -1,6 a 12,7), cumpliendo el criterio de no inferioridad (p <0,001). Entre aquellos con una carga viral basal de ≥100,000 copias / ml, se observó una carga viral de <50 copias / ml en 137 de 207 participantes (66.2%) en el grupo de dolutegravir y en 123 de 200 participantes (61.5%) en el grupo de dosis bajas de efavirenz, con una diferencia de 4,7 puntos porcentuales (IC del 95%, -4,6 a 14,0), lo que demuestra la no inferioridad.
Cuando se utiliza un umbral de carga viral de <200 copias / ml, los resultados cumplen los criterios de no inferioridad y superioridad. Los resultados mostraron que 276 de 310 participantes (89.0%) en el grupo de dolutegravir y 253 de 303 participantes (83.5%) en el grupo de dosis bajas de efavirenz tuvieron supresión viral, con una diferencia de 5.5 puntos porcentuales (IC 95%, 0.1-11.0 )
Of the 404 women exposed to the trial drugs, 6.2% became pregnant during the trial (13 in the dolutegravir group and 12 in the low-dose efavirenz group). All children were born live with no reported birth defects.
Se observó un aumento medio mayor en el peso corporal en el grupo de dolutegravir frente al grupo de dosis bajas de efavirenz (5,0 kg frente a 3,0 kg; p <0,001). Del mismo modo, la obesidad ocurrió más en el grupo de dolutegravir frente al grupo de dosis bajas de efavirenz (12,3% frente a 5,4%; p = 0,004).
The researchers acknowledged "concerns related to the use of dolutegravir in women of childbearing age, and [that] the risk of obesity needs to be explored further."
Virologic failure (defined as a viral load >1000 copies/mL) occurred more frequently in the low-dose efavirenz group compared to the dolutegravir group (16 vs. 3). However, none of the 3 participants in the dolutegravir group had drug resistance mutations at baseline or acquired them during the trial. In the low-dose efavirenz group, 6 of 16 participants had drug resistance mutations at baseline (5 had mutations conferring resistance to efavirenz and 1 to lamivudine, tenofovir, and efavirenz). Of the remaining 10 participants who did not have drug resistance mutations at baseline, 8 acquired them (2 acquired mutations conferring resistance to efavirenz, 3 to lamivudine and efavirenz, and 3 to lamivudine, tenofovir, and efavirenz).
The researchers observed a high level of integrase polymorphism, primarily with E157Q and T97A mutations (8% and 6%, respectively). “Although these mutations are suspected of decreasing the efficacy of integrase inhibitors, no effect on viral suppression was identified in the dolutegravir group,” the researchers noted. “However, long-term follow-up studies would help to further evaluate the effect of these mutations, especially those associated with the persistently low viremia observed in a subgroup of our test population.”
Reference
NAMSAL ANRS 12313 Study Group. Dolutegravir-based or low-dose efavirenz-based regimen for the treatment of HIV-1 [published online July 24, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1904340
https://www.infectiousdiseaseadvisor.com/home/topics/hiv-aids/efficacy-of-dolutegravir-vs-low-dose-efavirenz-regimens-for-hiv-1/