Antiretroviral therapy adherence and exploratory proteomics in virally suppressed people with HIV and stroke

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PROJECT SUMMARY Antiretroviral therapy (ART) has dramatically changed the health outcomes of people with HIV (PWH). Newer ART regimens with more robust viral suppression may allow complacency creep for imperfect adherence, given the regimen forgiveness for achieving suppressed viral loads despite imperfect adherence. In turn, imperfect adherence may lead to ongoing viral replication below the clinically-relevant suppression threshold, driving inflammation and premature aging. Accumulating data indicate that underlying inflammation strongly contributes to PWH continuing to develop non-communicable diseases (NCD) despite viral suppression, with studies showing a 2-fold increased risk of a significant NCD, HIV-associated stroke, compared to people without HIV. HIV-associated stroke is associated with major mortality, morbidity, and healthcare economic burden. The current investigators found a stroke prevalence of 6.2% in South African PWH with suppressed viral loads compared to people without HIV. PWH were almost 10 years younger, had less traditional cardiovascular risk factors, and were predominantly female, despite being virally suppressed to <200 copies/mL. Additionally, HIV was found to be the predominant risk factor for young stroke (≤45 years) in a Malawian case-control study of 222 PWH and 503 population controls with acute stroke, with an adjusted odds ratio of 5.57 (2.43-12.8). However, none of these studies examined imperfect adherence as a risk factor for stroke. Research on the treatment success of ART focuses primarily on perfect or near-perfect adherence strategies to suppress HIV viral loads to below clinically-relevant thresholds, currently defined as <200 copies/mL. In clinical practice, however, adherence to ART is often imperfect, with a cohort study from South Africa and Uganda showing that despite most participants being classified as virally suppressed, adherence across several categories of PWH was poor. This was confirmed in a study of 64 virally suppressed participants in whom 47% had detectable viremia between 0-50 copies/mL despite adherence rates over the preceding two months of 93% (82%-98%) using unannounced pill counts. Others have shown that lower concentrations of intracellular tenofovir diphosphate (TFV-DP) on dried blood spots (DBS), an objective drug concentration biomarker indicating cumulative adherence over the preceding 8 weeks, was associated with a 2-fold higher odds of viremia between 20-200 copies/mL. Investigating imperfect ART adherence in virally suppressed PWH with stroke offers an opportunity to gain new insights into a potential modifiable factor to reduce stroke. This exploratory study will obtain important preliminary data on the association between stroke and ART adherence, as well as the novel approach of testing candidate proteomic biomarkers for the identification and prediction of stroke in virally suppressed PWH. We will test the hypothesis that imperfect ART adherence sufficient to suppress HIV viral loads to <200 copies/mL is insufficient to control viremia below this threshold, and is associated with inflammation leading to stroke.