Dataset Information

Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy - naive adults with HIV-1 infection.

ABSTRACT:

Objective

To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2.

Design

Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks).

Methods

Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC.

Results

At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC.

Conclusions

Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).

SUBMITTER: Cahn P

PROVIDER: S-EPMC8654248 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses.SettingOne hundred eighty-seven centers in 21 countries.MethodsGEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ?500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine.ResultsAt week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ?50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine.ConclusionsConsistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

Project description:Abstract Background At Weeks 48 and 96 in the GEMINI-1 and GEMINI-2 studies (Clinicaltrials.gov: NCT02831673 and NCT02831764), the 2DR of DTG+3TC was noninferior to the three-drug regimen of DTG + tenofovir/emtricitabine (TDF/FTC) in achieving plasma HIV-1 RNA < 50 c/mL in treatment-naïve adults. Methods GEMINI-1 and 2 are identical, global, double-blind, multicenter Phase III studies. Participants with screening HIV-1 RNA ? 500.00 c/mL were randomized to once-daily DTG+3TC or DTG+TDF/FTC, stratified by plasma HIV-1 RNA and CD4+ cell count. The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). We present a secondary endpoint analysis of efficacy at Week 96 by baseline disease and demographic characteristics. For the overall population, estimates and confidence intervals were based on a stratified analysis using Cochran–Mantel–Haenszel weights. Results In total, 714 and 719 adults were randomized and treated in GEMINI-1 and -2, respectively. Based on a 10% noninferiority margin, DTG+3TC was noninferior to DTG+TDF/FTC at Week 96 in both GEMINI-1 and -2 and in the pooled analysis. Response rates across baseline HIV-1 RNA subgroups were high and similar in both arms in the pooled analysis, including in participants with baseline HIV-1 RNA >100,000 c/mL (Table 1). Results were also generally consistent regardless of age, gender, or race. In the CD4+ ? 200 cells/mm3 subgroup, response rates were lower in the DTG+3TC group compared with DTG+TDF/FTC; most reasons for nonresponse were unrelated to virologic efficacy or treatment regimen. Across both studies, 11 participants on DTG+3TC and 7 on DTG+TDF/FTC met protocol-defined virologic withdrawal criteria through Week 96; none had treatment emergent integrase-strand-transfer-inhibitor or NRTI resistance mutations. Conclusion In GEMINI-1 and 2, DTG+3TC was noninferior to DTG+TDF/FTC in treatment-naïve adults at Week 96, demonstrating durable efficacy. The results of subgroup analyses of efficacy at Week 96 were generally consistent with overall study results, and further demonstrate that DTG+3TC is an effective initial treatment for HIV-infected patients across a spectrum of disease characteristics and patient populations. The studies are ongoing. Disclosures All Authors: No reported Disclosures.

Project description:A proof-of-concept study was designed to evaluate the antiviral efficacy, safety and tolerability of a two-drug regimen with dolutegravir 50 mg once daily (QD) plus lamivudine 300 mg once daily as initial highly active antiretroviral therapy (HAART) among antiretroviral (ARV)-naive patients.PADDLE is a pilot study including 20 treatment-naive adults. To be selected, participants had no IAS-USA-defined resistance, HIV-1 RNA ?100,000 copies/mL at screening and negative HBsAg. Plasma viral load (pVL) was measured at baseline; days 2, 4, 7, 10, 14, 21 and 28; weeks 6, 8 and 12; and thereafter every 12 weeks up to 96 weeks. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL in an intention to treat (ITT)-exposed analysis at 48 weeks (the FDA snapshot algorithm).Median HIV-1 RNA at entry was 24,128 copies/mL (interquartile range (IQR): 11,686-36,794). Albeit as per protocol, all patients had pVL ?100,000 copies/mL at screening as required by inclusion criteria, four patients had ?100,000 copies/mL at baseline. Median baseline CD4+ T-cell count was 507 per cubic millimetre (IQR: 296-517). A rapid decline in pVL was observed (median VL decay from baseline to week 12 was 2.74 logs). All patients were suppressed at week 8 onwards up to week 24. At week 48, 90% (18/20) reached the primary endpoint of a pVL <50 copies/mL. Median change in CD4 cell count between baseline and week 48 was 267 cells/mm3 (IQR: 180-462). No major tolerability/toxicity issues were observed. Nineteen patients completed 48 weeks of the study, and one patient (with undetectable VL at last visit) committed suicide. One patient presented a low-level protocol-defined confirmed virological failure at week 36, being the only observed failure. This patient had pVL <50 copies/mL at the end-of-study visit without having changed the two-drug regimen. Observed failure rate was 5%. This is the first report of integrase strand transfer inhibitor/lamivudine dual regimen in ARV-naive patients.This novel dual regimen of dolutegravir and lamivudine warrants further clinical research and consideration as a potential therapeutic option for ARV-therapy-naive patients.NCT02211482.

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