Dolutegravir + lamivudine comparable with dolutegravir + tenofovir/emtricitabine as initial treatment for HIV-1
The combination of dolutegravir + lamivudine appeared noninferior to dolutegravir + tenofovir/emtricitabine in reducing viral load in treatment-naïve patients with HIV-1 infection, according to the phase III GEMINI-1 and GEMINI-2* trials presented at AIDS 2018.
“GEMINI-1 and -2 results demonstrate noninferior virologic efficacy for the two-drug regimen dolutegravir + lamivudine versus the three-drug regimen dolutegravir + tenofovir/emtricitabine at week 48,” said study author Professor Pedro Cahn from Fundación Huésped and Buenos Aires University Medical School in Buenos Aires, Argentina.
“These data support dolutegravir + lamivudine as an effective option for the treatment of HIV-1 infection,” he said.
The identical multinational, double-blind GEMINI-1 and GEMINI-2 trials included adult patients with HIV-1 infection (screening HIV-1 RNA viral load 1,000–500,000 c/mL) who had not received previous antiretroviral therapy. They were randomized to receive once-daily oral doses of dolutegravir (50 mg) + lamivudine (300 mg; n=356 and 360 in GEMINI-1 and GEMINI-2, respectively, mean age 32 years, 16 percent female) or dolutegravir (50 mg) + tenofovir/emtricitabine (300/200 mg; n=358 and 359 in GEMINI-1 and GEMINI-2, respectively, mean age 33 years, 14 percent female) for 144 weeks, following which patients in the dolutegravir + lamivudine group will receive the drug combination in the continuation phase of the trial.
At baseline, median HIV-1 RNA viral loads were 4.43 and 4.46 log10 c/mL for dolutegravir + lamivudine and dolutegravir + tenofovir/emtricitabine recipients, respectively, while median CD4+ cell counts were 427.0 and 438.0 cells/mm3, respectively. About 80 percent of patients had viral loads of ≤100,000 log10 c/mL while <10 percent had CD4+ cell counts of ≤200 cells/mm3.
At week 48, response rates (percentage of patients who achieved viral load of <50 c/mL) to either drug regimen were high at 90 and 93 percent among patients on dolutegravir + lamivudine and dolutegravir + tenofovir/emtricitabine, respectively, in GEMINI-1 and 93 and 94 percent, respectively, in GEMINI-2.
In terms of reducing viral load to <50 c/mL at 48 weeks, the dolutegravir + lamivudine combination was noninferior to the dolutegravir + tenofovir/emtricitabine combination in both the GEMINI-1 (adjusted treatment difference, -2.6, 95 percent confidence interval [CI], -6.7 to 1.5) and GEMINI-2 trials (adjusted treatment difference, -0.7, 95 percent CI, -4.3 to 2.9). [AIDS 2018, abstract 13210]
CD4+ cell counts also improved at a similar rate in patients on dual vs triple therapy (adjusted mean change from baseline, 224 vs 218 cells/mm3) at week 48.
Six patients on dual and four on triple therapy met the criteria for confirmed virologic withdrawal (CVW) at 48 weeks. There was no incidence of treatment-emergent nucleoside reverse transcriptase inhibitor or integrase strand transfer inhibitor resistance mutations in patients with CVW in either group in either trial.
Adverse event (AE) incidence was comparable between patients on dolutegravir + lamivudine and dolutegravir + tenofovir/emtricitabine (76 percent vs 81 percent), with headache (10 percent in each group), diarrhoea (9 percent vs 11 percent), and nasopharyngitis (8 percent vs 11 percent) the most frequently occurring AEs. Drug-related AEs were less frequent in the dual compared with the triple therapy group (18 percent vs 24 percent). Fifteen and 16 patients in the dual and triple therapy groups, respectively, withdrew due to AEs.
Changes in plasma or serum and urine markers favoured the dual therapy group, as did changes in bone markers at 48 weeks (p<0.001 for all biomarkers tested).
“The requirement for lifelong antiretroviral therapy for HIV infection has highlighted interest in two-drug regimens to minimize cumulative drug exposure [as] lower antiretroviral drug exposure may translate to less long-term drug toxicity,” said Cahn.
“The potency, safety, and high resistance barrier of dolutegravir make it an optimal core agent for two-drug regimens [while] the safety, tolerability, and efficacy of lamivudine make it an attractive partner for initial HIV-1 treatment,” he said.