Dual Antiretroviral Therapy—All Quiet Beneath the Surface?

Abstract

Infection with the human immunodeficiency virus (HIV) is characterized by progressive depletion of CD4+ lymphocytes cells as a result of chronic immune activation. Next to the decreases in the number of CD4+ cells which leads to opportunistic infections, HIV-related immune activation is associated with several prevalent comorbidities in the HIV-positive population such as cardiovascular and bone disease. Traditionally, combination antiretroviral therapy (cART) consists of three drugs with activity against HIV and is highly effective in diminishing the degree of immune activation. Over the years, questions were raised whether virological suppression could also be achieved with fewer antiretroviral drugs, i.e., dual- or even monotherapy. This is an intriguing question considering the fact that antiretroviral drugs should be used lifelong and their use could also induce cardiovascular and bone disease. Therefore, the equilibrium between drug-induced toxicity and immune activation related comorbidity is delicate. Recently, two large clinical trials evaluating two-drug cART showed non-inferiority with respect to virological outcomes when compared to triple-drug regimens. This led to adoption of dual antiretroviral therapy in current HIV treatment guidelines. However, it is largely unknown whether dual therapy is also able to suppress immune activation to the same degree as triple therapy. This poses a risk for an imbalance in the delicate equilibrium. This mini review gives an overview of the current available evidence concerning immune activation in the setting of cART with less than three antiretroviral drugs.

Ageing with HIV: Challenges and biomarkers

“…But there is controversy on whether these alternative ART regimens may also have a detrimental effect on immune activation. 47 Although the global benefit of ART in PLWH is beyond doubt, the appearance of these drug-related toxicities can affect their health, ageing, and survival. The real contribution of current antiretrovirals to cellular injury is yet to be defined.…”

Changes in Inflammatory and Atherogenesis Biomarkers With the 2-Drug Regimen Dolutegravir Plus Lamivudine in Antiretroviral Therapy–Experienced, Virologically Suppressed People With HIV-1: A Systematic Literature Review

“…Effective antiretroviral therapy (ART) has been shown to reduce systemic inflammation caused by human immunodeficiency virus (HIV) infection, although not to the levels of HIV-negative populations [ 1–4 ]. Even in the setting of maintained ART-mediated virologic suppression, HIV may be associated with some degree of persistent inflammation, contributing to an increased risk of non-AIDS-related comorbidities such as cardiovascular disease and cancer [ 2 , 3 , 5 , 6 ]. HIV-related inflammation may be driven by a variety of factors including ongoing viral replication and persistent low-level viremia (HIV reservoirs and sanctuary sites), coinfections, and bacterial translocation [ 2 , 3 , 6 , 7 ].…”

“…Even in the setting of maintained ART-mediated virologic suppression, HIV may be associated with some degree of persistent inflammation, contributing to an increased risk of non-AIDS-related comorbidities such as cardiovascular disease and cancer [ 2 , 3 , 5 , 6 ]. HIV-related inflammation may be driven by a variety of factors including ongoing viral replication and persistent low-level viremia (HIV reservoirs and sanctuary sites), coinfections, and bacterial translocation [ 2 , 3 , 6 , 7 ]. Moreover, other host-specific considerations such as comorbidities (eg, obesity, diabetes mellitus, metabolic syndrome [eg, insulin resistance and hyperlipidemia], and hypertension), lifestyle factors (eg, smoking and substance abuse), and sex differences (eg, menopause) have also been associated with the pathogenesis of inflammation in people with HIV (PWH) and may further contribute to persistent inflammation despite ART-mediated suppression [ 1 , 5 , 7 , 8 ].…”

“…Potential biomarkers of HIV-related inflammation (eg, C-reactive protein [CRP], interleukin-6 [IL-6]), monocyte and macrophage activation (eg, soluble CD14 [sCD14], soluble CD163 [sCD163]), and atherogenesis and hypercoagulation (eg, D-dimer) have been linked to increased risk of mortality and non-AIDS-related events in PWH [ 1 , 5 , 6 ]. Observations from the Strategies for Management of Anti-Retroviral Therapy (SMART) study showed that elevated baseline levels of inflammatory biomarkers were independently associated with increased risk of cardiovascular disease and mortality [ 9 , 10 ].…”

“…Furthermore, persistently low CD4 + /CD8 + ratio (≤0.4) has been associated with systemic inflammation in ART-treated PWH, which may be linked to an increased risk of non-AIDS-defining morbidity and mortality [ 7 , 12 ]. Other biomarkers of cellular activity such as those for T-cell activation (HLA-DR + and CD38 + ), proliferation (Ki-67), and apoptosis (annexin-V + ) have also been studied in HIV-1 [ 6 , 13 ]. Although several presumed biomarkers of inflammation and atherogenesis have been investigated in HIV, precise correlations of each marker with specific clinical events are largely unknown and a high degree of overlap exists in the processes they are supposed to monitor [ 2 ].…”