Two-Drug Regimens for HIV—Current Evidence, Research Gaps and Future Challenges

Abstract

During the last 30 years, antiretroviral treatment (ART) for human immunodeficiency virus (HIV) infection has been continuously evolving. Since 1996, three-drug regimens (3DR) have been standard-of-care for HIV treatment and are based on a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The effectiveness of first-generation 3DRs allowed a dramatic increase in the life expectancy of HIV-infected patients, although it was associated with several side effects and ART-related toxicities. The development of novel two-drug regimens (2DRs) started in the mid-2000s in order to minimize side effects, reduce drug–drug interactions and improve treatment compliance. Several clinical trials compared 2DRs and 3DRs in treatment-naïve and treatment-experienced patients and showed the non-inferiority of 2DRs in terms of efficacy, which led to 2DRs being used as first-line treatment in several clinical scenarios, according to HIV clinical guidelines. In this review, we summarize the current evidence, research gaps and future prospects of 2DRs.

Dual Antiretroviral Regimens for HIV – Here to Stay

“…This study demonstrated non-inferiority at 48 weeks between the 2D and 3D regimens (88.9% vs. 92.7%) [6]. Despite these earlier studies, many concerns remained about the durability of the regimens, the inability to utilize them in certain populations such as pregnant women or those with tuberculosis, the concern about adequate suppression of viral reservoirs, the paucity of studies in naïve patients, and some conflicting data that did not show non-inferiority [3].…”

“…Initial attempts starting around 2000 combined boosted protease inhibitors(PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) but still showed higher levels of toxicity and/or lower efficacy than triple-drug regimens and led to studies simplifying to a regimen containing a boosted PI and an NRTI [3]. Such switch studies included the open-label GARDEL study, which enrolled 416 patients naive to therapy comparing boosted lopinavir (LPV/r) and lamivudine (3TC) to LPV/r and 2NRTIs [4], and the ATLAS-M study [5], comparing boosted atazanavir (ATV/r) and 3TC in 266 virologically suppressed patients to ATV/r and 2NRTIs; both studies showed non-inferiority by intent to treat analysis.…”

“…The durability of suppression is one concern, and the data reviewed above support the non-inferiority of the virologic response for certain two-drug regimens compared to three-drug regimens as far out as 144 weeks. Additional concerns include the possibility of treatment-emergent resistance mutations, low-level viremia, or variability in controlling inflammation and immune activation [3].…”

Therapeutic drug monitoring and virological response at week 48 in a cohort of HIV‐1‐infected patients switching to dolutegravir/rilpivirine dual maintenance therapy (ANRS‐MIE‐BIRIDER study)

“…6 The aims are to limit cumulative lifetime drug exposure along with associated adverse events related to these drugs while limiting the risk of drug-drug interaction. [7][8][9] Despite these advantages, a small percentage of PLWHA on dual therapy experience virological failure. [10][11][12] We can hypothesize that these poor outcomes might be partly associated with inadequate drug exposure and therapeutic drug monitoring (TDM) is then an additional tool in management of PLWHA, which can clarify patients' drug exposures, enabling rational adjustment of their medications or adherence interventions.…”

“…This dual therapy is a single tablet, pill burden reducing strategy, which avoids the use of nucleos(t)ide reverse transcriptase inhibitors and boosted protease inhibitors in non‐HBV coinfected patients 6 . The aims are to limit cumulative lifetime drug exposure along with associated adverse events related to these drugs while limiting the risk of drug–drug interaction 7–9 . Despite these advantages, a small percentage of PLWHA on dual therapy experience virological failure 10–12 .…”