HIV/AIDS Unit Director
Infectious Diseases Division
Geneva University Hospitals
University of Geneva
Alexandra Calmy, MD, FMH, PhD, has disclosed that she has received fees for non-CME/CE services from Gilead Sciences.
After several years of research evaluating dual ART combinations, more recent studies have shown that INSTI plus NRTI options can effectively and safely suppress HIV in both first-line and maintenance settings. Here, I review some of the key factors I weigh when considering these options in my clinical practice.
A New First-line Treatment Option
For the first time, efficacious 2-drug ART is a guideline-recommended option for treatment-naive patients. Based on 48-week primary endpoint data from the phase III GEMINI trials, the FDA and European Medicines Agency approved the single-tablet regimen dolutegravir/lamivudine for persons with HIV and no known or suspected resistance to either drug in mid-2019.
Data subsequently presented at the 10th IAS Conference on HIV Science and IDWeek 2019 demonstrated that this combination continued to be noninferior to 3-drug ART in treatment-naive individuals through 96 weeks of treatment. The regimen was well tolerated in clinical trials, with few long-term adverse events and a reassuring lack of emergent resistance.
It should be noted that GEMINI-1/2 only enrolled individuals with baseline HIV-1 RNA ≤ 500,000 copies/mL. Although dolutegravir/lamivudine prescribing information sets no limitations for its use based on HIV-1 RNA level or CD4+ cell count, international guidelines do contain restrictions that align more closely with trial entry criteria.
Because lamivudine is active against hepatitis B virus but associated with resistance during long-term use, all potential candidates for dolutegravir/lamivudine treatment must be tested for hepatitis B surface antigen (HBsAg) before initiating this dual regimen. This additional testing can slow the prescription of dual ART, which must be weighed against the WHO recommendation for rapid ART initiation. However, this can be addressed by starting a patient on a 3-drug regimen, then switching to dual ART after HBsAg negativity is confirmed.
Nearly all regimens exhibit some limitation that must be considered when selecting ART. Ultimately, the availability of multiple options for tailoring first-line therapy must be balanced against the need to start ART quickly before every patient characteristic is known.
Dual Therapy as Maintenance ART
In the maintenance setting, use of simplified therapy can be even easier given that the patient characteristics and history are generally already known to the clinician and candidacy is, therefore, more readily assessable. As maintenance therapy, 2-drug ART may be a good option when patients have multiple comorbidities and there is a desire to limit potential drug–drug interactions or toxicities (eg, with NRTIs).
The primary INSTI-based regimens being used in this setting include dolutegravir plus rilpivirine, lamivudine, or emtricitabine. When considering switching patients off regimens that are currently well tolerated, it should be noted that this can be accompanied by new adverse events, which may include neuropsychiatric events and/or weight gain. Ongoing monitoring should be adopted to avoid the potential for regimen discontinuation.
Key Considerations With an ART Paradigm Shift
Although we are in a very good position now to consider dual therapy as a treatment option, there are some potential limitations including their use in settings not evaluated long term in fully powered clinical trials, such as advanced disease or pregnancy. We also do not know how these regimens penetrate sanctuary sites, such as lymph nodes, and we have limited inflammatory marker data.
In addition, a paradigm shift from triple to dual therapy brings about key clinical questions, such as: Is better adherence needed? Should HIV-1 RNA be monitored once or twice yearly, or more frequently, and how will this affect patient satisfaction? How should treatment failure with 2-drug regimens be managed—by obtaining a genotype and/or adding another drug? Can we propose a dual therapy regimen in the absence of a well-documented patient history?
Dual therapy is now incorporated into DHHS and EACS ART guideline recommendations for first-line and maintenance treatment. However, in my view, the information lacking for certain patient categories or clinical situations must be available before we can be completely confident in its widespread use.
Our recently presented Swiss SIMPL’HIV study was aimed at obtaining real-world data on the use of dual therapy by avoiding CD4+ cell count and HIV-1 RNA enrollment restrictions, and including patients with baseline M184V mutations. The selected regimen for this ART switch study was dolutegravir plus emtricitabine, chosen in part for the longer intracellular half-life of emtricitabine. As presented at EACS 2019, switching to dolutegravir plus emtricitabine was noninferior to continued ART through 48 weeks. In addition, the 2-drug regimen was well tolerated, quality of life improved, and the rates of weight gain as an adverse event were comparable between groups. We look forward to additional data to help confirm the safety and efficacy of its use in real-world settings.
Have you begun integrating dual therapy in your practice? Join the discussion by posting a comment. For more details on this and other key issues in ART management, review the associated video module and slides from a recent live symposium held at EACS 2019.