For the first time, patients with new HIV diagnoses have a 2-drug regimen option.
In 2016, the US Centers for Disease Control and Prevention estimated that 45% of all people living with HIV in the United States are over age 50.1 This patient population continues to age due to advances in HIV antiretroviral therapy (ART); with tolerable, highly effective pharmacotherapy options, there is a shift in focus to minimize long-term toxicities of lifelong ART.
This new 2-drug regimen (2DR) comprises dolutegravir and lamivudine (DTG/3TC, [Dovato]) coformulated into 1 daily tablet. It received US Food and Drug Administration (FDA) approval on April 9, 2019, for treatment of HIV in adults with no prior ART history and no known resistance to the individual components. It is the second FDA-approved 2DR (it follows dolutegravir/rilpivirine [Juluca]) but the first approved for use in HIV treatment-naïve patients with no known mutations to the individual components. This medication, though not yet included in HIV treatment guidelines, changes what we know about combination ART and the historically recommended use of at least 3 drugs from at least 2 classes.
DTG/3TC received its approval after the completion of 2 identical phase 3 studies: GEMINI 1 and GEMINI 2.2 Both studies are multicenter, double-blind, randomized, noninferiority, phase 3 trials that enrolled a total of 1441 patients from 192 centers across 21 countries. Participants were treatment-naïve individuals living with HIV who were 18 years or older with an HIV viral load less than 500,000 copies/mL. Patients were excluded if they had preexisting drug resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, or protease inhibitors. Women of childbearing potential were included if they were not pregnant or lactating and were using approved contraception. Patients were randomly assigned (1:1) to receive a 2-drug regimen of dolutegravir plus lamivudine (as 2 tablets) or a 3-drug regimen (3DR) of dolutegravir plus emtricitabine/tenofovir disoproxil fumarate (as 2 tablets). Both the participants and the investigators were blinded to treatment assignment, made possible by overencapsulating the lamivudine and emtricitabine/tenofovir disoproxil fumarate. The primary objective of the GEMINI studies was to prove noninferior virological efficacy of the 2DR when compared with guideline-recommended 3-drug ART.
The pooled analysis of the intention-to-treat-exposed populations of the GEMINI trials showed that dolutegravir/lamivudine met its primary endpoint, with 91% of patients achieving HIV-1 RNA of less than 50 copies/mL by week 48 compared with 93% of patients in the dolutegravir plus emtricitabine/ tenofovir disoproxil fumarate group. Of the 10 (<1%) participants (6 in the 2DR group, 4 in the 3DR group) who met criteria for virological withdrawal, defined as a decrease of HIV-1 RNA of less than 1 log10 copies/mL decrease from baseline or HIV-1 RNA greater than 200 copies/mL after week 24 or confirmed rebound of HIV-1 RNA greater than 20 copies/ mL, no patients developed any treatment-emergent resistance as confirmed by genotypic testing.
Pooled analysis of the GEMINI 1 and 2 trials shows low incidence of reported drug-related adverse events (AEs), with 126 (18%) in the 2DR group and 169 (24%) in the 3DR group. Commonly reported AEs were similar between the 2 groups, with headache, diarrhea, and nasopharyngitis being the 3 most common. Changes in renal and bone turnover biomarkers, which can be attributed to tenofovir disoproxil fumarate, were, not surprisingly, more favorable in the 2DR group compared with the 3DR group. Suicidal ideation and behavior was reported in 2% in both groups—17 participants in the 2DR group and 12 in the 3DR group. Of these patients who reported these toxicities, 13 (76%) and 7 (58%), respectively, had a positive history of depression or suicidal behavior at baseline.
Per the labeling of DTG/3TC, other precautions include patients coinfected with HIV and hepatitis B virus (HBV), hypersensitivity reactions, hepatotoxicity, lactic acidosis and severe hepatomegaly with steatosis, and immune reconstitution syndrome.3 When managing patients who are coinfected with HIV and HBV, an additional agent such as entecavir or tenofovir should be added on for treatment of HBV if using DTG/3TC for HIV treatment. HBV resistance to lamivudine monotherapy reaches 90% at 4 years and is no longer a preferred antiviral therapy for HBV treatment.4 Other more serious AEs, like lactic acidosis and severe hepatomegaly with steatosis, is a precaution that is historically associated with nucleoside analogues but not commonly seen with currently used NRTIs like lamivudine.
Risk of drug—drug interactions with DTG/3TC is minimal compared with other antiretrovirals (ARVs) such as boosted-protease inhibitor-based therapies. Common drug interactions seen with the dolutegravir component of DTG/3TC include metformin (increased metformin levels) and polyvalent cations (decreased dolutegravir levels). More serious and less commonly seen drug interactions can occur with dofetilide (increased dofetilide levels) and rifampin (decreased dolutegravir levels; less commonly seen in the United States).
Studies prior to the GEMINI 1 and 2 trials evaluated dolutegravir/lamivudine as a switch strategy for treatment-experienced patients who have been virally suppressed. DTG/3TC, however, was not studied in this patient population and is indicated only for treatment-naïve patients. De-escalation or switch studies have all been successful; however, patient sample sizes were small, and not all studies were prospective, randomized controlled trials.5-7 Future larger studies to confirm the results are warranted before using DTG/3TC as a simplification or switch strategy.
Currently, the US Department of Health and Human Services HIV guidelines list DTG/3TC as an option for “initial therapy when abacavir, tenofovir alafenamide, and tenofovir disoproxil fumarate cannot be used or are not optimal.”8 This recommendation has not been updated since DTG/3TC was approved by the FDA. That approval gave a 2DR option for the initial treatment of patients newly infected with HIV without a history of ART or drug-resistant mutations affecting dolutegravir or lamivudine. With less HIV ARV drug exposure, there is the benefit of fewer long-term toxicities. Additionally, if half the potentially eligible treatment-naïve patient in the United States were initiated on DTG/3TC, the associated ART cost savings would amount to more than $500 million over 5 years.9
HIV treatment has made significant progress, from past regimens consisting of upward of 10 tablets in the mornings and evenings to the current availability of single-tablet regimens. This lowers the ART pill burden to 1 tablet daily, with even some HIV treatment regimens containing just 2 active agents. This shift toward 2DR for initiation and maintenance of HIV changes how we may approach HIV treatment moving forward. DTG/3TC is an effective regimen for patients with new HIV diagnoses who have no treatment or resistance history. Some advantages and disadvantages comparing it with current recommended initial regimens for most people with HIV can be found in the Table. When 2 drugs can do the same job as 3, why are we still using 3?
Min is a clinical assistant professor with a specialty in HIV pharmacotherapy at Temple University School of Pharmacy in Philadelphia, Pennsylvania. She received a PharmD at the University of Maryland School of Pharmacy in Baltimore and completed a PGY-1 pharmacy practice residency at Penn Presbyterian Medical Center in Philadelphia and a PGY-2 HIV ambulatory care/clinical pharmacogenetics residency at the University of Houston College of Pharmacy in Texas. She is an active member of the American Academy of HIV Medicine.