Association of Incomplete Adherence to Antiretroviral Therapy With Cardiovascular Events and Mortality in Virologically Suppressed Persons With HIV: The Swiss HIV Cohort Study

Abstract

Background Incomplete antiretroviral therapy (ART) adherence, even if sufficient to maintain viral suppression, is associated with enhanced inflammation in persons living with HIV (PLWH). However, its clinical implications remain unknown. Methods PLWH enrolled in the Swiss HIV Cohort Study without history of cardiovascular disease (CVD), who initiated ART between 2003-2018, and had viral suppression (<50 copies/mL) for ≥6 months, were evaluated. The association between incomplete self-reported ART adherence (≥1 or ≥2 missed doses in the last month) and (1) any CVD event (myocardial infarction, revascularization, cerebral hemorrhage, stroke, and/or death due to CVD event), or (2) non-CVD-related death was evaluated using adjusted Cox proportional hazards models. Results 6,971 PLWH (74% male) were included in the analysis; median (IQR) age was 39 (32,47) years. Median (IQR) follow-up was 8 (4,11) years, with 14 (8,23) adherence questionnaires collected per participant. In total, 205 (3%) participants experienced a CVD event and 186 (3%) non-CVD-related death. In an adjusted competing risk model where missing data were imputed, missing ≥1 ART doses showed an increased, but not statistically significant, risk in CVD events (HR: 1.23; 95% CI: 0.85-1.79; p=0.28). Non-CVD-related mortality showed a statistically significant increased risk with missing ≥1 ART doses (HR: 1.44; 1.00-2.07; p=0.05 and missing ≥2 ART doses (HR: 2.21; 1.37-3.57; p=0.001). Conclusions Incomplete ART adherence was significantly associated with an increased risk for non-CVD-related mortality in PLWH with virologic suppression. This highlights the potential role of non-adherence to ART as a driver of non-AIDS clinical outcomes.

High residual inflammation despite HIV viral suppression: Lessons learned from real‐time adherence monitoring among people with HIV in Africa

“…The possible clinical implications of our findings should be highlighted. First, they emphasize the continued importance of ART adherence in both achieving and sustaining viral suppression, but also potentially in reducing the overall burden of non‐AIDS disease and mortality [14,39,40]. Second, given the limited efficacy of existing interventions aimed at reducing systemic residual inflammation in virologically suppressed PWH [18], medication adherence could become the focus of future study as a clinically relevant intervention to reduce inflammation.…”

“…Previous research established that < 100% (and, in particular, < 85%) ART adherence, while potentially sufficient to sustain viral suppression, has been associated with a 10–20% increase in biomarkers of residual systemic inflammation, immune activation and coagulopathy [11–13], and with overall mortality [14] in diverse populations, including PWH in sub‐Saharan Africa [15,16]. However, in most of these studies ART adherence was quantified using self‐report (which usually overestimates adherence [17]).…”

Prevalence and Characteristics of HIV-Associated Stroke in a Tertiary Hospital Setting in South Africa

“…Lack of adherence has been associated with biomarkers of chronic inflammation and has been implicated to increase the risk of non-CVD mortality in PLWH, even in those with virologic suppression. 41 Two Malawian studies have hypothesized potential immune reconstitution as a reason for stroke in the period near ART initiation: the first found 20% (n = 12) of patients with an adjusted OR for stroke of 15.6, 20 and the second found 25% (n = 16 of 64) of patients with stroke within 6 months of ART initiation. 33 Our data may support this increased stroke risk because of possible immune reconstitution and inflammation activation, with many of those initiating or reinitiating ART in the lower CD4 group.…”

Beyond HIV viral load: application of pharmacologic measures to identify ART adherence mismatch

“…4 While this “forgiveness” to more potent drugs is advantageous, it results in less-than-optimal adherence that cannot be identified by relying on HIV VL alone, and has been found to have deleterious consequences, as it has been associated with heightened inflammation, immune activation, coagulopathy, and mortality. 5–7…”

“…4 While this "forgiveness" to more potent drugs is advantageous, it results in less-than-optimal adherence that cannot be identified by relying on HIV VL alone, and has been found to have deleterious consequences, as it has been associated with heightened inflammation, immune activation, coagulopathy, and mortality. [5][6][7] Pharmacologic measures of adherence are objective and can avoid subjective biases. 1 However, they are dependent on the pharmacokinetics of the parent drug or metabolite that is quantified in the body fluid or matrix of interest.…”