Assessing cardiovascular liabilities associated with HIV therapeutics

National Institute Of Environmental Health Sciences

Investigators

Abstract

HIV infections remain prevalent with almost 38 million people affected worldwide. In the US alone the current HIV positive population is estimated to be between 1 and 3.5 million individuals, with about 30,000 new cases being diagnosed every year (UNAIDS/WHO and hiv.gov). HIV is also a disease that affects the American population based on race differentially, with Blacks/African Americans accounting for a higher proportion of new HIV diagnoses per year compared to other races/ethnicities. For example, in 2018, blacks/African Americans accounted for 13% of the US population but 42% of the 37,832 new HIV diagnoses in the United States and dependent areas. In the past 30 years antiretroviral therapies (ART) have aided in the management of the acquired immune deficiency syndrome (AIDS) resulting from HIV, changing the disease from a fatal infection in the early 90s to a chronically managed condition in the mid-2000s. Patients on ART take the drugs daily throughout life. ART is recommended for everyone that is HIV positive, including pregnant mothers and their newborns who are directly administered these drugs up to 6-weeks after birth as prophylaxis. ART is also recommended to high risk individuals who are HIV negative such as injectable drug users, same-sex couples and heterosexual couples comprised of an infected and a non-infected partner (including partners of HIV positive individuals who may become pregnant). Although not curative, these medicines help reduce the risk of HIV transmission. ART have also allowed HIV-positive individuals to live longer, posing a new set of concerns about the long-term health effects associated with chronic exposure to these medicines. A modelling study estimates that 73% of HIV patients will be aged 50 years in 2030. Of these, 78% are predicted to develop cardiovascular disease (CVD, Smit et al., 2015), partially because of increased age as a risk factor and partly due to HIV-specific liabilities, including daily intake of ART. The initial medicines used to treat HIV consisted of nucleotide reverse transcriptase inhibitors (NRTIs), which aimed at blocking viral replication. While successful in diminishing viral titers, these drugs led to severe adverse health effects associated with off-target mitochondrial toxicity, which were most notable in the heart and skeletal muscle (Margolis et al., 2014). After these findings, new classes of drugs targeting additional pathways within the HIV life cycle have been developed, including less toxic NRTIs. Currently, there are more than 25 different medications in six different classes for the treatment of HIV. Despite the efforts to increase safety, adverse effects remain a concern for patients chronically exposed to ART since the newer drugs have been shown to significantly alter lipid profiles, induce lipodystrophy, increase weight gain and insulin resistance or cause vascular inflammation and lactic acidosis - all of which can increase the risk of CV complications. Also, ARTs are most often administered in a cocktail which contain 2-3 drugs (cART); NRTIs remain a staple of combination therapies despite some remaining degree of mitochondrial toxicity (Eggleton and Nagalli, 2020). The phenotype of cardiomyopathy in the HIV-positive population has changed after the implementation of cART. Initially, it was characterized by myocarditis associated with opportunistic viral infections in immunocompromised patients. It is now defined as asymptomatic systolic or diastolic dysfunction that is detected by echocardiography (Hsue and Waters, 2019). It is also noteworthy that epidemiological studies have identified that individuals infected with HIV are at an increased risk of CVD, including sudden cardiac death (Tseng et al., 2012), acute myocardial infarction (MI, Freiberg et al., 2013), stroke (Chow et al., 2012), peripheral artery disease and heart failure with either reduced or preserved ejection fraction (Freiberg et al., 2017). While the state of chronic low-grade inflammation associated with the remaining presence of the virus despite ART is likely involved in this increased risk, the extent to which cART itself contributes to these effects is unknown. Data on the effects of cART on HIV-negative individuals is scarce because most clinical trials recruit HIV positive subjects. Nevertheless, a small clinical study involving 42 healthy volunteers exposed to dolutegravir, the ART most recommended to pregnant mothers due to safety, suggested a small increase in QT interval. QT prolongation is normally associated with arrhythmia. As far as animal studies involving HIV therapeutics, most have focused on humanized models in which the virus is present (Nixon et al., 2017). Thus, there is a need to understand the long-term, stand-alone potential adverse health effects of chronic exposure to cART, including in the CV system. The molecular, biological, and functional effects of the combination therapies, as is the therapeutic standard, are still poorly understood. This is because drug makers may not be required to test them all in combination for FDA approval. Thus, it remains unclear whether the combined exposures to ART lead to higher or equal adverse health outcomes as compared to single therapy. The proposed molecular and biochemical assessment of tissues (heart) in this study will help in filling this gap of knowledge while anchoring future in vitro studies. There is also concern about exposures of pediatric populations. The pediatric literature is relatively sparse (McComsey and Leonard, 2004), but the data currently available on the effects of HIV infection and ART on children suggests that subclinical abnormalities of cardiac structure and function may result in symptomatic cardiomyopathy in adulthood, particularly as they become exposed to other CV risk factors such as smoking, obesity and diabetes (Lipshultz et al., 2013). Thus, what is needed are actionable insights into potential adverse health effects of cART by investigating early life stage susceptibilities and comparing to the effects in the adults. Also needed is the evaluation of potential mechanisms that can inform/predict these adverse health outcomes.