Pharmacist, HIV and HCV Medicine
Albany Medical Center
Regional Pharmacy Director
Northeast/Caribbean AIDS Education and Training Center (AETC)
Albany, New York
John Faragon, PharmD, BCPS, AAHIVP, has disclosed that he has received fees for non-CME activities from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV.
A New Drug Application was recently filed with the FDA for what may become the first 2-drug single-tablet regimen (STR) for initial treatment of HIV. I’m encouraged by the clinical trial data supporting this new STR and am eager to see how this combination may fit into future paradigms for HIV therapy.
Is This a New Era in ART Initiation?
Guidelines from the International Antiviral Society (IAS)-USA and DHHS recommend the use of 3 drugs for the initial treatment of HIV. Initial regimens for most patients should include an INSTI plus 2 NRTIs; however, evidence for the role of an investigational 2-drug option, dolutegravir (DTG)/lamivudine (3TC), for use in treatment-naive patients with HIV infection has emerged from 2 large, randomized clinical trials demonstrating similar efficacy to a 3-drug initial HIV regimen. On October 17, 2018, a New Drug Application was submitted to the FDA for DTG plus 3TC with an anticipated Prescription Drug User Fee Act action date of April 2019. Currently, DTG/rilpivirine is available as an STR approved for use as a switch option in patients with virologic suppression on their current regimen, but this combination is not approved for use as an initial ART regimen.
The GEMINI Trials
The 2-drug combination of DTG plus 3TC was initially evaluated in the single-arm, 20-patient PADDLE study where it demonstrated high efficacy in treatment-naive patients. The results of the PADDLE study led to the large, international phase III trials GEMINI-1 and -2, which randomized more than 1400 treatment-naive patients to receive either DTG plus 3TC or DTG plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Baseline characteristics included median CD4+ cell counts of 427-438 cells/mm3 and median HIV-1 RNA levels of 4.43-4.46 log10 copies/mL in both studies. A small proportion (8% to 9%) of patients had CD4+ cell counts < 200 cells/mm3 and 20% to 21% of patients had HIV-1 RNA > 100,000 copies/mL at baseline. Most patients in the study were men (85%) and nearly 70% were white.
At Week 48, 90% (320/356 in GEMINI-1) to 93% (335/360 in GEMINI-2) of patients receiving the 2-drug DTG plus 3TC regimen had HIV-1 RNA < 50 copies/mL vs 93% (332/358 in GEMINI-1) to 94% (337/359 in GEMINI-2) of those receiving the 3-drug regimen, demonstrating noninferiority of DTG plus 3TC according to the predefined -10% noninferiority margin (pooled treatment difference for HIV-1 RNA < 50 copies/mL: -1.7%; 95% CI: -4.4% to 1.1%). There was no significant difference in virologic response rates to either regimen of patients with baseline HIV-1 RNA > 100,000 copies/mL vs ≤ 100,000 copies/mL. Among patients treated with DTG plus 3TC, virologic efficacy was numerically lower for those with baseline CD4+ cell counts ≤ 200 cells/mm3 (79%; 50/63) vs patients with baseline CD4+ cell counts > 200 cells/mm3 (93%; 605/653) in the Snapshot analysis but not in the treatment-related discontinuation equals failure analysis (98% in both groups). No new primary mutations associated with INSTI or NRTI resistance were reported in patients with virologic failure, and adverse events were similar in both treatment arms. Because TDF was not used in the DTG plus 3TC arms of the studies, renal and bone biomarkers favored the 2-drug vs 3-drug regimen at 24 weeks.
The GEMINI studies provide evidence supporting the efficacy of DTG plus 3TC as a 2-drug regimen for treatment-naive patients. Despite excellent efficacy, tolerability, and barrier to drug resistance, the question remains if DTG plus 3TC will perform as well in clinic settings as it did in the GEMINI trials. Although 3-drug regimens containing abacavir (ABC), tenofovir alafenamide (TAF), or TDF have been the standard of care for many years, providers managing patients at risk for or with preexisting renal or cardiovascular disease may want to select a regimen that avoids these medications. DTG plus 3TC was studied in patients with stable renal function (creatinine clearance < 50 mL/min was an exclusion criterion for GEMINI trials); therefore, it is currently unclear if the combination can be used in patients with creatinine clearance < 50 mL/min. Lamivudine should be dose adjusted in the case of renal impairment, however some data suggest that this may not be required. For providers concerned about cardiovascular disease risk in patients receiving ABC or in patients with intolerance to ABC and/or tenofovir, DTG plus 3TC could provide another effective option. I think the biggest limitation of DTG plus 3TC is its lack of efficacy against HBV infection, a characteristic that may be especially important in settings with limited resources.
Pharmacists working with individuals living with HIV, especially in community and retail settings, are often tasked with managing drug-drug interactions. An additional advantage of the DTG plus 3TC 2-drug regimen is that this combination has a lower risk of drug-drug interactions when compared with other 2-drug regimens that contain ritonavir or cobicistat as pharmacokinetic boosting agents. However, DTG does have drug-drug interaction potential with certain medications. For example, anticonvulsants known to induce CYP3A4 should be avoided in patients receiving DTG; use of dofetilide is contraindicated in combination with DTG; and metformin levels are increased with concomitant DTG. Despite these limitations, DTG-containing ART regimens as well as other unboosted INSTI-containing ART regimens are associated with generally lower risk of drug-drug interactions relative to many other ART regimens. For pharmacists providing recommendations for initial HIV treatment, DTG plus 3TC would offer an option for patients with significant renal, bone, or cardiovascular disease risk where providers may not want to include ABC, TAF, or TDF as part of the regimen.
I am generally conservative in working with my providers when asked to give recommendations for ART in our patients. Although clinical trial data help to inform our decisions, patients in real-world clinic settings do not always experience the same outcomes as those participating in clinical trials because study populations in clinical trials may not match the patient population in our clinics. Current guidance recommends ABC/3TC, FTC/TAF, or FTC/TDF as components of initial ART regimens; therefore, I think 3-drug regimens will remain the standard of care for most patients. However, GEMINI-1 and -2 offer strong evidence that an initial 2-drug strategy of DTG plus 3TC provides efficacy, potency, and a similar safety profile to 3-drug regimens in treatment-naive patients.
How do you think the potential availability of a 2-drug STR for initial HIV treatment might fit into your practice? Please share your thoughts in the comments box.