Posted on May 15, 2020 in: Professional Practice
Shelbye Rose Herbin, Pharm.D., PGY1 Pharmacy Resident, Detroit Receiving Hospital, Detroit
Almost 40 years have passed since the first case of acquired immunodeficiency syndrome (AIDs) was documented. Throughout this time, great strides have been made with the creation of antiretroviral therapy (ART) for the treatment of the human immunodeficiency virus (HIV), which is the cause of AIDS. Adherence to ART regimens is crucial for patients to maintain viral suppression and reduce the risk of drug resistance.1 However, there are many barriers to adherence such as pill burden and side effects including nausea, fatigue and mood alterations. 2,3 Antiviral therapy with three active antiretrovirals from two different drug classes has been the mainstay of therapy for decades for patients living with HIV. Newer agents that have been introduced have a higher potency and genetic barrier to resistance, which has enabled researchers to revisit the idea of two-drug regimens for the use in patients with HIV.4 Additionally, advances in treatment options have also demonstrated the possibility of monthly injectable treatment regimens.
The two-drug regimens currently approved by the Food and Drug Administration (FDA) as complete antiretroviral regimens are dolutegravir-rilpivirine (JULUCA®), for treatment experienced patients, and dolutegravir-lamivudine (DOVATO®), for treatment-naïve patients. Both of these combinations include antiretrovirals with pharmacokinetic profiles suitable for once daily administration.5,6 Dolutegravir-rilpivirine was approved in 2017 and contains the integrase strand inhibitor (INSTI) dolutegravir with the non-nucleotide reverse transcriptase inhibitor (NNRTI) rilpivirine. Dolutegravir and rilpivirine both have a high genetic barrier to resistance and are stable against common resistance mechanisms for their respective class, allowing them to be used as a complete antiretroviral regimen. Dolutegravir also interacts minimally with hepatic enzymes and therefore has fewer drug-drug interactions compared to other antiretrovirals. The approval of dolutegravir-rilpivirine was based on the results from the SWORD-1 and SWORD-2 trials. These two studies included participants ≥ 18 years old, who were treatment experienced and virologically suppressed (viral load < 50 copies/mL) for at least six months. The primary outcome of SWORD-1 and SWORD-2 was the proportion of patients with a plasma viral load of lower than 50 copies/mL at week 48, which was achieved in 95 percent of the study participants in both treatment groups. This confirmed non-inferiority of dolutegravir-rilpivirine to participants who continued on their current ART regimen (CAR).5
Dolutegravir-lamivudine was approved in 2019 and includes the nucleoside transcriptase inhibitor (NRTI) lamivudine, with the INSTI dolutegravir. The approval of dolutegravir-lamivudine was based on the GEMINI-1 and GEMINI-2 trials. Both studies included participants ≥ 18 years old who were treatment naïve. The primary outcome of the GEMINI trials was the proportion of patients with a plasma viral load of lower than 50 copies/mL at week 48. Virological response was achieved in 90 percent of participants in each group and confirmed non-inferiority between dolutegravir-lamivudine and dolutegravir-tenofovir disoproxil fumarate-emtricitabine.6
Cabotegravir-rilpivirine (CABENUVA®) is not FDA-approved but is currently being tested in phase III clinical trials. Cabotegravir is an INSTI that is structurally similar to dolutegravir and is formulated as an oral tablet or a long acting injectable suspension for monthly administration. There are two ongoing phase-III trials for cabotegravir-rilpirivine the ATLAS trial which involves treatment-experienced patients and the FLAIR trial which includes treatment-naïve patients. The primary outcome in both studies is the percent of patients with virologic failure (HIV-1 RNA > 50 copies/mL) at week 48. Preliminary data has shown non-inferiority of cabotegravir-rilpivirine to the participant’s CAR and dolutegravir-abacavir-lamivudine in ATLAS and FLAIR trials, respectively.7,8
HIV treatment is a life-long commitment that patients must endure with a potential heavy pill burden and adverse side effects. Previous attempts at creating two-drug regimens have failed due to the medications inability to reduce viral loads or overcome resistance mechanisms9. When used in combination as two-drug regimens, the newer and more potent antiretrovirals, such as dolutegravir and cabotegravir have the potential to reduce pill burdens, increase adherence and decrease the long-term effects associated with antiretrovirals.