Commentary
Currently, the mainstay of HIV pharmacotherapy is a 3-drug regimen consisting of 2 nucleoside reverse transcriptase inhibitors in combination with 1 drug from another class, with an integrase strand transfer inhibitor being the preferred third drug.6 Despite the improved tolerability of contemporary ARVs, there remains concern among HIV practitioners regarding potential toxicities associated with cumulative drug exposure, specifically related to nucleoside reverse transcriptase inhibitors. As a result, there has been much interest in evaluating 2-drug ARV regimens for HIV treatment in order to reduce overall drug exposure.7-10
The 48-week results of the GEMINI-1 and GEMINI-2 trials, published in early 2019, further expand our understanding regarding the efficacy and safety of 2-drug regimens in HIV treatment. These identically designed studies evaluated once-daily dolutegravir and lamivudine for HIV in a treatment-naive population. This goes a step further than the SWORD-1 and SWORD-2 trials, which evaluated once-daily dolutegravir and rilpivirine as a step-down therapy for virologically suppressed individuals and led to the U.S. Food and Drug Administration (FDA) approval of the single-tablet combination regimen dolutegravir/rilpivirine (Juluca).10 Therefore, whereas the SWORD trials evaluated a 2-drug regimen for maintenance of virologic suppression, the GEMINI trials assessed whether a 2-drug regimen can both achieve and maintain virologic suppression.
The results of the GEMINI trials are promising for a future direction in HIV care. The rates of virologic suppression achieved in these trials are comparable to those seen in the SWORD trials.10 Furthermore, the virologic response seen in the GEMINI trials is comparable to that seen in similar trials that evaluated a 3-drug ARV regimen consisting of an integrase strand transfer inhibitor–based backbone in ART-naive individuals.11,12
A major confounder to the design of this trial was that it included TDF as one of the components in the comparator arm, an agent that has already been demonstrated to have detrimental effects on both renal and bone health.13,14 Additionally, the bone biomarker results were inconclusive, and the agents’ effects on bone would have been better demonstrated through bone mineral density testing, as had been done in prior trials.
Applications for Clinical Practice
Given the recent FDA approval of the single-tablet combination regimen dolutegravir and lamivudine (Dovato), this once-daily 2-drug ARV regimen will begin making its way into clinical practice for certain patients. Prior to starting this regimen, hepatitis B infection first must be ruled out due to poor efficacy of lamivudine monotherapy for management of chronic hepatitis B infection.15 Additionally, baseline genotype testing should be performed prior to starting this ART given that approximately 10% of newly diagnosed HIV patients have baseline resistance mutations.16 Obtaining rapid genotype testing may be difficult to accomplish in low-resource settings where such testing is not readily available. Finally, this approach may not be applicable to those presenting with acute HIV infection, in whom viral loads are often in the millions of copies per mL. It is likely that dolutegravir/lamivudine could assume a role similar to that of dolutegravir/rilpivirine, in which patients who present with acute HIV step down to a 2-drug regimen once their viral loads have either dropped below 500,000 copies/mL or have already been suppressed.
—Evan K. Mallory, PharmD, Banner-University Medical Center Tucson, and Norman L. Beatty, MD, University of Arizona College of Medicine, Tucson, AZ