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First-line Dolutegravir/3TC Controls HIV in 90% in Small Pilot Trial
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21st International AIDS Conference (AIDS 2016), July 18-22, 2016, Durban, South Africa
Mark Mascolini
Eighteen of 20 previously untreated people reached the primary endpoint of a viral load below 50 copies/mL 48 weeks after starting dolutegravir/lamivudine (DTG/3TC) in the single-arm PADDLE study [1]. Of the 2 participants who did not reach the primary endpoint in this single-center study, one regained viral control after 48 weeks before intensifying DTG/3TC and the other committed suicide before week 48.
PADDLE investigators at the Fundacion Huesped in Buenos Aires noted that their findings must be confirmed in a well-powered randomized trial. Even if results are confirmed, clinicians will have to consider whether a two-pill once-daily regimen makes more sense for a patient than one-pill once-daily coformulations of three antiretrovirals, such as Triumeq (dolutegravir/lamivudine/abacavir). The Fundacion Huesped team argued that treatment with two antiretrovirals could hold advantages in cost and toxicity. The international 217-person GARDEL trial found twice-daily lopinavir/ritonavir plus 3TC virologically noninferior to twice-daily lopinavir/ritonavir plus 3TC and another nucleoside [2].
PADDLE is a phase 4 open-label single-arm trial that recruited 20 antiretroviral-naive people at least 18 years old with a viral load between 5000 and 100,000 copies and a CD4 count at or above 200 [3]. Nonetheless, 4 participants did have a viral load above 100,000 copies when they started DTG/3TC. Everyone took 50 mg of the integrase inhibitor dolutegravir and 300 mg of the nucleoside 3TC once daily. The primary endpoint was the proportion of participants with a viral load below 50 copies at week 48 by the FDA missing-equals-failure snapshot algorithm.
One study participant was a woman and 19 were men, including 15 men who have sex with men. The group had a median age of 34 years (interquartile range [IQR] 31 to 43), and median pretreatment viral load and CD4 count were 24,128 copies (IQR 11,686 to 36,794) and 507 (IQR 296 to 517). Eighteen people had CDC stage A disease and 2 had stage B.
After 8 weeks of DTG/3TC, all 20 participants had a viral load below 50 copies, and all maintained a sub-50 load through 24 weeks. One person committed suicide between week 24 and week 36. At week 36 another participant met criteria for protocol-defined virologic failure. Thus 18 of 20 participants (90%) achieved the primary endpoint of a viral load below 50 copies at week 48. The person with protocol-defined virologic failure had a viral load of 246 copies and no detectable mutations; integrase and protease regions did not amplify. This participant left the study but continued DTG/3TC and regained viral control.
Seven participants had grade 1 adverse events possibly related to dolutegravir (headache, nausea, somnolence, epigastric pain, and diarrhea). One participant had a grade 2 adverse event (headache). Three participants had three grade 2 or 3 lab toxicities: proteinuria, elevated creatine phosphokinase (both at baseline), and hematuria.
References
1. Cahn P, Rolon MJ, Figueroa MI, Gun A, Patterson P, Sued O. Dolutegravir-lamivudine as initial therapy in HIV-infected, ARV naive patients: 48 week results of the PADDLE trial. 21st International AIDS Conference (AIDS 2016). July 18-22, 2016. Durban, South Africa. Abstract FRAB0104LB.
2. Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis. 2014;14:572-580.
3. ClinicalTrial.gov. Dolutegravir-lamivudine as dual therapy in naive HIV-infected patients: a pilot study (PADDLE). ClinicalTrials.gov identifier NCT02211482.
https://clinicaltrials.gov/ct2/show/NCT02211482
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