COMMENTARY

Two- vs Three-Drug Initial Therapy for HIV: GEMINI-1 and GEMINI-2

Paul E. Sax, MD

Disclosures

November 26, 2018

Hi. This is Dr Paul Sax from Brigham and Women's Hospital and Harvard Medical School.

Today I'd like to discuss the GEMINI studies, which were just published in the Lancet.[1] The GEMINI studies ask the question of whether a two-drug regimen of dolutegravir and lamivudine could be as effective as a standard three-drug regimen of dolutegravir plus TDF/FTC.

It was a multicenter clinical trial, conducted at multiple sites around the world. It enrolled about 1400 eligible participants. To be eligible, participants had to have no major baseline resistance mutations, be negative for hepatitis B surface antigen, and have a viral load < 500,000 copies/mL. The people who enrolled in this study were typical of those in treatment-naive studies—about 80% were men, 20% had a viral load > 100,000 copies/mL, and 5%-10% had a CD4+ cell count < 200 cells/µL.

What did the study results show? They showed that both study arms did exceptionally well: Virologic success was achieved in 90%-94% in both study arms, depending on which study they were in. (GEMINI-1 and GEMINI-2 were identical studies.) In addition, the patients who had baseline viral loads > 100,000 copies/mL responded equally well in both study arms. There was a numerical advantage to the three-drug study arm in patients with CD4+ cell counts < 200 cells/µL, but the reasons for failure among patients in the two-drug arm did not appear to be virologic failure. Overall, virologic failures were exceptionally rare in both study arms, and importantly, no study individuals developed resistance to any of the study drugs.

These results are very encouraging, showing that a two-drug initial regimen of dolutegravir and lamivudine is plausible and very effective. It also has major advantages in terms of drug exposure. There might be a little less exposure with the new safer version of tenofovir that is now available (tenofovir alafenamide). Nonetheless, these findings show that combining a drug with a higher resistance barrier (such as dolutegravir) and a drug with such good potency and tolerability (such as lamivudine) is very much a viable strategy.

It would not be useful for patients who do not have access to testing for baseline resistance or hepatitis B surface antigen. As a result, it may have limited international use as initial therapy, because those tests are not regularly done.

Also, it is possible that patients who are on the fringes of medication adherence could be more vulnerable to treatment failure with two drugs rather than three, as was seen in the pilot study, ACTG A5353,[2] of this same strategy. There was one patient who had very poor medication adherence and developed resistance to both components of the dolutegravir-lamivudine regimen.

What do I see as the future for this treatment? In many ways, it is perhaps going to be best used as a switch strategy. The GEMINI studies were of initial therapy, and right now, with the trend toward starting people on HIV therapy the same day we see them (often before the test results are back), it's probably easiest to use a three-drug regimen because you don't need the results of hepatitis B or genotype testing to do that, especially if you use a dolutegravir- or bictegravir-containing regimen.

As a switch therapy, the two-drug regimen could be very attractive. The question of whether you can switch patients safely to dolutegravir-lamivudine is being studied in the upcoming TANGO study, the results of which are expected next year. Thanks so much for listening.

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