Heart Failure and Human Immunodeficiency Virus

What Is Human Immunodeficiency Virus-Associated Heart Failure?

As antiretroviral therapy (ART) has become widely adopted, acquired immune deficiency syndrome (AIDS)–defining infections and malignancies have become less common, and the burden of chronic noncommunicable diseases has increased. Parallel to this transition, human immunodeficiency virus (HIV)–associated heart failure (HF) has evolved from an end-stage AIDS-related complication to a more heterogeneous disease state representing diverse HIV-related pathophysiologies. HF is more common among people living with HIV (PLWH) than in the HIV-uninfected, even after adjustment for demographic and relevant clinical factors. Worse immune function and more HIV viral replication exacerbate HIV-associated HF risk. Traditional cardiovascular risk factors for HF, ranging from hypertension to smoking, are also more common in PLWH, underscoring the role of both traditional and HIV-specific factors in HF pathogenesis. While there is no uniform definition for HIV-associated HF, most society guidelines and recommendations acknowledge that HIV infection carries with it a risk for a unique HF syndrome differentiated from others by the role of HIV infection, immune dysfunction, or ART on the development of HF.

Historical Perspective

Since the first reports of HF due to AIDS-related cardiomyopathy in the mid-1980s, HF has been a known complication of HIV. The initial case reports of cardiac involvement in HIV were notable in that these cases occurred in the absence of Kaposi sarcoma, in which cardiac involvement was common. Throughout the 1980s and 1990s, the presence of HF in PLWH was mainly in the context of myocarditis, opportunistic infections, nutritional deficiencies and/or severe immunosuppression. Most patients had concomitant opportunistic infections. Numerous terms were introduced to describe this syndrome, including AIDS cardiomyopathy, HIV-associated cardiomyopathy, HIV-associated dilated cardiomyopathy, HIV-associated HF, and HIV-associated left ventricular (LV) dysfunction.

In the pre-ART era, HIV-associated HF was classically defined by progressive HIV/AIDS and associated global LV systolic dysfunction. In an observational study of 136 Italian PLWH followed with serial echocardiography from 1988 through 1992, seven (5.1%) developed symptomatic global LV dysfunction over a mean follow-up of 415 days. All patients with incident HF had AIDS, and myocarditis was a prominent feature. In the pre-ART era, very low CD4 count (<100 cells/mm ³ ) was a common factor associated with LV dysfunction and HF. Overall, the prevalence of HIV-associated cardiomyopathy was 30% to 40% based on clinical-pathological studies in the pre-ART era with an annual incidence of 15.9 per 1000 patients.

Prognostically, the syndrome was initially characterized by severe symptoms and high mortality. Median survival was 101 days for patients with dilated cardiomyopathy, compared to 472 days for patients with normal findings on echocardiogram at a similar level of immunosuppression. Gross autopsy findings demonstrated striking four-chamber dilatation, myofibrillar loss, and focal myocarditis. In the wake of this ostensibly new syndrome, researchers at the time foreshadowed, “Cardiac disease secondary to multiple causes can be expected to complicate the clinical course of these patients.”

Although the relative contribution of AIDS cardiomyopathy to HIV-associated HF has declined with wide ART adoption, ART access and adherence are not ubiquitous. Therefore, AIDS cardiomyopathy remains a relevant disease state, particularly in settings with low ART uptake. Sub-Saharan Africa (SSA), for example, accounts for 12% of the global population but is disproportionately affected by HIV with 69% of all adults and 90% of all children living with HIV residing in the region ( see also Chapter 29 ).

Contemporary Shifts in Epidemiology

Access to effective ART has significantly altered the epidemiology of HF in HIV ( Table 30.1 ). The syndrome has shifted from a severe, dilated cardiomyopathy to one that is often minimally symptomatic and accompanied by mildly decreased LV systolic function. While the prevalence of severe systolic dysfunction has definitely diminished, data from the US Veterans Aging Cohort Study (VACS) show that PLWH on ART remain at higher risk of developing HF compared to the uninfected for HF with preserved, reduced, or borderline ejection fraction (EF). HF risk was greater among PLWH despite having a lower burden of traditional risk factors, including hypertension, diabetes, high low-density lipoprotein (LDL) cholesterol, and obesity. In subgroup analyses adjusted for numerous clinical variables, the most common HF phenotype for white, black, and young (<40 years of age) veterans was HF with reduced EF (HFrEF). PLWH with consistently low CD4+ T-cell counts had significantly elevated risk for HFrEF (hazard ratio [HR] 1.87; 95% confidence interval [CI] 1.36–2.57) and HF with preserved EF (HFpEF) (HR 1.87; 95% CI 1.28–2.73) in comparison to PLWH with higher CD4+ T-cell counts; however, compared with uninfected patients, HF risk among PLWH with CD4+ T-cell count greater than 500 cells/mm ³ remained elevated (HR 1.25; 95% CI 1.08–1.43). Consistently detectable viremia was associated with increased risk for HFrEF (HR 1.63; 95% CI 1.28–2.08). In sensitivity analyses, the risk of HF attributed to HIV persisted after restricting the dataset to those without hypertension, alcohol or cocaine abuse, and never smokers, and adjusted for incident myocardial infarction (MI).

Recent analyses suggest that HFpEF is becoming an increasingly common manifestation of HIV-associated HF. In contrast to the global LV dysfunction-predominant manifestation of HF in the pre-ART era, investigators found that HFrEF comprised only 37.1% of incident HF among HIV-infected veterans. Another US Department of Veterans Affairs (VA) study suggests that the HIV-associated risk of HF may be even higher among women (incidence rate ratio 2.5; 95% CI 1.5-4.5, HIV vs. control). Similarly, higher risks were seen for women in an analysis of a large nationally representative electronic health records database ( Fig. 30.1 ).

A substantial portion of PLWH have abnormal diastolic parameters, with or without symptoms. Investigations into asymptomatic cardiac dysfunction among PLWH show a higher prevalence of diastolic dysfunction and higher LV mass index compared with controls. These differences are not solely explained by differences in traditional risk factors and are independently associated with HIV infection.

Pathophysiology of Heart Failure in Human Immunodeficiency Virus

HF reflects a final common pathway of various cardiovascular and systemic disorders. These diverse pathophysiologies are particularly apparent when examining HIV-associated HF. Here, we outline several mechanisms that appear to contribute to HIV-associated HF.

Cardiac Effects of Antiretroviral Therapy

Few interventions in the history of medicine have so dramatically changed the course of human disease as the discovery of effective combination ART for HIV/AIDS. Since the first ART “cocktails” were introduced in the mid-1990s, data from the Centers for Disease Control indicate mortality due to HIV has plummeted from an annual age-adjusted death rate of ∼17 per 100,000 in 1995 to ∼2 per 100,000 in 2014 ( https://www.cdc.gov/hiv/statistics/index.html ). The first generations of these drugs were associated with significant metabolic toxicities, including cardiotoxicity; however, more metabolically friendly regimens composed of new drug classes, such as integrase inhibitors, have since been developed ( Table 30.2 ).

Randomized trials such as SMART (continuous vs. intermittent ART) and START (Strategic Timing of AntiRetroviral Treatment) (early vs. delayed initiation of ART), have consistently pointed to improved outcomes with ART. The benefit appears to extend to cardiovascular disease specific outcomes, although HF is a rare outcome in these trials of younger patients. Thus, despite some toxicity, dramatic declines in clinical cardiomyopathy cases since the pre-ART era would suggest that on balance ART reduces the risk of HF. Here, we review the toxicities and potential benefits of specific ART drugs and drug-classes.