CROI 2021 HIV-1 updates: 144-week GEMINI-1, GEMINI-2 and 96-week TANGO results

Dr. Chloe Orkin
Queen Mary University, London
UK
Dr. Paul Benson
Be Well Medical Center, Berkley
Michigan, US
06 May 2021

Latest international guidelines recommend dolutegravir plus lamivudine (DTG + 3TC) in adults with HIV-1 infection as initial antiretroviral therapy (ART) and in the viral suppression setting. This recommendation is based on 96-week results of the GEMINI-1 and -2 and 48-week results of the TANGO studies, which demonstrated the noninferiority of DTG + 3TC vs DTG plus tenofovir disoproxil fumarate and emtricitabine (DTG + TDF/FTC) and vs continuing a tenofovir alafenamide (TAF)–based regimen. Consistent with primary analyses, updated 144-week results of the GEMINI-1 and -2 studies and 96-week results of the TANGO study, presented recently at the Conference on Retroviruses and Opportunistic Infections 2021 (CROI 2021), showed continuous virologic suppression with DTG + 3TG.

DHHS, EACS and IAS guidelines on management of adults with HIV-1

Current guidelines of the US Department of Health and Human Service (DHHS), European AIDS Clinical Society (EACS) and International Antiviral Society (IAS) recommend the once-daily DTG + 3TC regimen as initial ART and for opti-mizing ART in the viral suppression setting for adults with HIV-1 infection based on noninferior efficacy vs DTG + TDF/FTC in the 96-week results of the GEMINI-1 and -2 studies and vs a TAF-based regimen in the 48-week results of the TANGO study.[Panel on Antiretroviral Guidelines for Adults and Adolescents, Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV; EACS Guidelines, version 10.1, October 2020; JAMA 2020;324:1651-1669]

GEMINI-1 & -2: DTG + 3TC for ART-naïve adults with HIV-1

In the ongoing, multicentre, noninferi-ority, phase III GEMNI-1 and -2 studies, 1,441 ART-naïve adults (median age, 33 years; male, 85.3 percent; baseline HIV-1 RNA >100,000 copies/mL, 20.4 percent; CD4+ cell count ≤200 cells/mm3, 8.2 percent) with HIV-1 infection with HIV-1 RNA ≤500,000 copies/mL were randomized (1:1) to receive the two-drug regimen of DTG 50 mg + 3TG 300 mg (n=719) or the three-drug regimen of DTG 50 mg + TDF 300 mg/FTC 200 mg (n=722). [Lancet 2019;393:143-155; J Acquir ImmuneDefic Syndr 2020;83:310-318]

Week 96: DTG + 3TC noninferior to DTG + TDF/FTC

At week 96, DTG + 3TC demonstrated noninferiority to DTG + TDF/FTC in virologic suppression, based on the proportion of patients with HIV-1 RNA <50 copies/mL (Snapshot algorithm, -10 percent noninferiority margin; 86.0 percent vs 89.5 percent; adjusted difference, -3.4 percent; 95 percent confidence interval [CI], -6.7 to 0.0007) in the pooled analysis. [J Acquir Immune Defic Syndr 2020;83:310-318]

Week 144: Durable virologic suppression with DTG + 3TC

“Noninferiority of DTG + 3TC to  DTG + TDF/FTC in virologic suppression was maintained at week 144 [82 percent vs 84 percent; adjusted difference, -1.8; 95 percent CI, -5.8 to 2.1],” reported Professor Chloe Orkin of the Queen Mary University, London, UK. [Orkin C, et al, CROI 2021, abstract 414]

At week 144, 12 patients in the DTG + 3TC group and nine patients in the DTG + TDF/FTC group met the protocol-defined confirmed virologic withdrawal (CVW) criteria (ie, if a second and consecutive HIV-1 RNA value met any of the following definitions: decrease from baseline in HIV-1 RNA of <1 log10 copies/mL, unless HIV-1 RNA <200 copies/mL, by week 12; confirmed plasma HIV-1 RNA ≥200 copies/mL at or after week 24; or confirmed rebound with HIV-1 RNA ≥200 copies/mL after confirmed consecutive HIV-1 RNA <200 copies/mL).

“No treatment-emergent integrase strand transfer inhibitor [INSTI] or nucleoside reverse transcriptase inhibitor [NRTI] resistance mutation was observed,” said Orkin.

“Of note, a non-CVW participant in the DTG + 3TC group who was reported to have intermittent nonadherence to treatment developed M184V mutation at week 132 [HIV-1 RNA 61,927 copies/mL] and R263R/K mutation at week 144 [HIV-1 RNA 135 copies/mL], conferring a 1.8-fold change in susceptibility to DTG,” she continued.

Subgroup analysis showed consistent noninferiority in virologic suppression with DTG + 3TC vs DTG + TDF/FTC at week 144 across demographic and baseline disease subgroups and compared with the overall population. (Figure 1)

“Although the response rate with DTG + 3TC vs DTG + TDF/FTC [67 percent vs 76 percent; treatment difference, -9.7] was lower among patients with CD4+ ≤200 cells/mm3, most treatment nonresponses were unrelated to virologic efficacy or treatment regimen,” Orkin noted.

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“Rates of adverse events [AEs] with DTG + 3TC across demographic and baseline disease subgroups, including change in weight and body mass index from baseline, were consistent with those in the overall population at week 144,” noted Orkin.

TANGO: Switch to DTG + 3TC for ART-experienced adults with HIV-1

In the TANGO study, 741 adults living with HIV-1 with virologic suppression (HIV-1 RNA <50 copies/mL) for >6 months who were taking a three-drug or four-drug TAF-based regimen were randomized (1:1) to switch to DTG  50 mg + 3TC 300 mg fixed-dose combination tablet (n=369) or to remain on the TAF-based regimen (n=372). The majority of patients were male (DTG + 3TC, 93.2 percent; TAF-based regimen, 91.1 percent), with a median CD4+ cell count of 682 cells/mm3 in the DTG + 3TC group and 720 cells/mm3 in the TAF-based regimen group. INSTI, such as elvitegravir/cobicistat, was the most common class of third agent used at baseline (DTG + 3TC, 78.3 percent; TAF-based regimen, 79.6 percent). [Clin Infect Dis 2020;71:1920-1929]

Week 48: DTG + 3TC noninferior to TAF-based regimen

At week 48, both the primary and the key secondary endpoints were met. Results showed noninferiority in antiviral activity with DTG + 3TG vs the TAF-based regimen in terms of the proportion of patients with HIV-1 RNA  ≥50 copies/mL (primary endpoint; Snapshot algorithm, 4 percent noninferiority margin; 0.3 percent vs 0.5 percent; adjusted difference, -0.3; 95 percent CI, -1.2 to 0.7) and the proportion of patients with HIV-1 RNA <50 copies/mL (key secondary endpoint; Snapshot algorithm, -8 percent noninferiority margin; 93.2 percent vs 93.0 percent; adjusted difference, 0.2; 95 percent Cl, -3.4 to 3.9) .

Week 96: Durable virologic suppression with DTG + 3TC

Noninferiority of viral suppression with DTG + 3TC vs a TAG-based regimen was sustained at week 96 for the primary endpoint (<1 percent vs 1 percent; adjusted difference, -0.8; 95 percent CI, -2.0 to 0.4) and the key secondary endpoint (86 percent vs 79 percent; adjusted difference, 6.8; 95 percent CI, 1.4 to 12.3). [Benson P, et al, CROI 2021, abstract 417]

“Per-protocol analysis demonstrated superiority of DTG + 3TC vs a TAF-based regimen with  respect to the primary endpoint [n=0/348 vs 4/351; adjusted difference, -1.1; 95 percent CI, -2.3 percent to 0.0 percent; p=0.044],” said Dr Paul Benson of Be Well Medical Center, Berkley, Michigan, US.

“No cases of CVW [defined as HIV-1 RNA ≥50 copies/mL followed by a second consecutive HIV-1 RNA  ≥200 copies/mL] were reported with DTG + 3TC through week 96, whilst three CVW cases were reported in the TAF-based regimen group. No resistance mutation was observed,” said Benson.

Efficacy of DTG + 3TC was com-parable across demographic, baseline regimen and baseline CD4+ cell count subgroups, and consistent with that in the overall population, confirming its noninferiority vs continuing a TAF-based regimen. (Figure 2)

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“At week 96, rates of AEs with DTG + 3TC across the subgroups were consistent with that in the overall population and with its prescribing information,” said Benson.

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