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Senior Consultant, Infectious Diseases
Hospital Juan Fernández
Director, Fundación Huesped
Professor of Infectious Diseases
Buenos Aires University Medical School
Buenos Aires, Argentina
Pedro Cahn, MD, PhD, has disclosed that he has received funds for research support and consulting fees from Merck and ViiV and fees for non-CME/CE services from Gilead Sciences, Merck, and ViiV.
The 1996 IAS conference, held in Vancouver, British Columbia, opened a new era in our struggle against HIV: the birth of HAART, highly active antiretroviral therapy. Since then, 3-drug combinations comprising 2 NRTIs plus a boosted PI, an NNRTI, or an INSTI became standard of care, and strategies aiming to reduce drug burden consistently failed to show noninferiority vs 3-drug HAART.
That situation changed with the GARDEL study, the first randomized clinical trial to demonstrate noninferiority of a 2-drug regimen—boosted lopinavir (LPV) plus lamivudine (3TC)—vs boosted LPV plus 2 NRTIs. Similar results were obtained with another 2-drug regimen consisting of boosted darunavir (DRV) plus 3TC in the ANDES study.
The GEMINI-1 and GEMINI-2 studies were designed to evaluate the safety and efficacy of the 2-drug regimen of dolutegravir (DTG) plus 3TC compared to a 3-drug regimen of DTG plus 2 NRTIs, tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC), in treatment-naive adults. These studies met the primary endpoint at Week 48, with DTG/3TC demonstrating noninferiority based on the proportion of participants with plasma HIV-1 RNA < 50 copies/mL. Noninferiority was maintained through 96 weeks with no cases of treatment-emergent resistance and similar overall adverse event profiles between the 2 treatment arms.
At the HIV Glasgow 2020 virtual meeting, we saw new data from the GEMINI studies confirming the long-term durability of DTG/3TC. At Week 144, 82% (584/716) of participants in the DTG/3TC arm had HIV-1 RNA < 50 copies/mL compared with 84% (599/717) of participants receiving DTG plus TDF/FTC. These results were consistent across the prespecified strata of baseline viral load below and above 100,000 copies/mL and in participants with baseline CD4+ cell counts > 200 cells/mm3. However, among participants with a CD4+ cell count ≤ 200 cells/mm3, a slightly lower response rate was observed with the 2-drug vs the 3-drug regimen (67% vs 76%, respectively). Of note, the majority of snapshot failures in these participants (including discontinuations for other reasons) were for nontreatment-related reasons. Also, the number of participants with CD4+ cell count ≤ 200 cells/mm3 was small (n = 63 in the DTG/3TC arm and n = 55 in the DTG plus TDF/FTC arm). It is notable that the recently updated EACS ART guidelines do not include a CD4+ cell count restriction for the use of DTG/3TC in treatment-naive patients, nor do the DHHS ART guidelines.
The newest data from the GEMINI program also confirm the high genetic barrier to treatment-emergent resistance with DTG/3TC. The rate of protocol-defined confirmed virologic withdrawal (CVW) was 1.7% (12/716) in the DTG/3TC arm and 1.3% (9/717) in the DTG plus TDF/FTC arm. None of these participants developed treatment-emergent resistance mutations. One participant receiving DTG/3TC who did not have CVW but with reported nonadherence to treatment developed M184V and R263R/K resistance mutations before discontinuing the study. After study discontinuation, this patient switched to DTG plus DRV/cobicistat and regained viral suppression. Regarding safety and tolerability, the rate of drug-related adverse events was lower with DTG/3TC vs DTG plus TDF/FTC (20% vs 27%; relative risk: 0.76; 95% CI: 0.63-0.92), and changes in markers of bone and renal health were more favorable with DTG/3TC.
The safety and efficacy of DTG/3TC was also explored in the TANGO study, designed to assess whether virologically suppressed people with HIV can reduce the number of medicines in their treatment regimen while maintaining viral suppression. Participants receiving a tenofovir alafenamide (TAF)–based regimen of at least 3 drugs were randomized to switch to DTG/3TC or continue their baseline regimen. At the HIV Glasgow 2020 virtual meeting, investigators presented Week 96 data, demonstrating continued noninferiority of DTG/3TC for the primary endpoint of the proportion of participants with plasma HIV-1 RNA ≥ 50 copies/mL using the FDA Snapshot algorithm. No participants receiving DTG/3TC (0/369, 0%) and 3 participants (3/372, < 1%) who continued to receive a TAF-based regimen met the criteria for protocol-defined virologic failure. No participants in either treatment group developed resistance mutations. The overall rate of adverse events was similar between regimens, but the rate of grade 2-5 drug-related adverse events was numerically higher in the DTG/3TC arm vs the DTG plus TDF/FTC arm (6% vs 2%, respectively). This is not unusual in switch studies; the switch arm is typically associated with a numerically higher incidence of adverse events because patients are being exposed to newer drugs, whereas the continuation arm has already been stably receiving their continued regimen.
In summary, a 2-drug ART strategy using DTG/3TC showed long-term efficacy and safety, both in treatment-naive patients and in those switching from virologically suppressive TAF-based regimens, further demonstrating the utility of this simplified regimen for patients living with HIV.
How are you incorporating DTG/3TC into your practice? Answer the polling question and join the discussion by posting in the comments box. For more coverage of the 2020 virtual HIV Glasgow meeting, download a highlights slide deck from my colleagues Monica Gandhi, MD, MPH, and Renslow Sherer, MD; listen to an audio recap of key studies from Dr. Sherer; and review a text- and slide-based module featuring expert insights on additional study data from HIV Glasgow 2020 designed for international clinicians managing HIV patient care around the world.