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Does HIV Really Augment the Frequency or Mortality Risk of Increased Pulmonary Artery Systolic Pressures?

In theUnited States, about 49%of the 1.2million persons livingwithHIV infection have their circulating HIV viral load durably suppressed by antiretroviral therapy (1). Modeling suggests that such individuals could have life expectancies of 74 years compared with 80 years for the general population (2). Although improved survival for persons with HIV infection is indeed good news, an important question is whether these projections will be accurate. It is well documented that persons with HIV infection, even if virologically suppressed, have enhanced states of inflammation as measured by elevated C-reactive protein, D-dimer, IL-6, and other proinflammatory cytokine concentrations (3). An enhanced inflammatory state likely accelerates progression of comorbidities and could make estimates of survival overly optimistic. It is instructive to look at the causes of death in persons whose HIV viral load is below the current level of detection. Three recent studies suggest that cardiovascular disease has joined liver disease andmalignant neoplasms as themajor causes of death (4–6). Readers of this journal are likely familiar with literature suggesting that persons with HIV infection and durable HIV viral suppression have enhanced risks of coronary artery and cerebrovascular disease, not all of which is attributable to traditional risk factors such as tobacco use, hypertension, dyslipidemia, and diabetes. Readers might not be as familiar with literature suggesting an association of HIV infection with sudden cardiac death, diastolic dysfunction, atrial fibrillation, and pulmonary hypertension (7–10). In this issue of the Journal (pp. 923–932), Brittain and colleagues report their investigation of the frequency and clinical significance of elevated pulmonary artery systolic pressure (PASP) in VACS (Veterans Aging Cohort Study) (11). They studied a convenience sample of patients who were referred for any reason for echocardiography between 2003 and 2012 and compared those individuals with HIV infection with matched control subjects without HIV infection. Only those veterans with a reported PASP measured by echocardiogram were included. Measurements of PASP and left ventricular ejection fraction range were obtained using a custom information extraction system. Although additional echocardiographic data such as diastolic function and right ventricular function would have been informative, most of these data had significantmissing values or could not be obtained. Patients were followed for an average of 4 years. No clinical data on causes of death were provided. Are elevated PASPs more frequent among persons with HIV infection who are durably suppressed by a variety of antiretroviral regimens than in matched control subjects without HIV infection? The paper by Brittain and colleagues clearly states that PASP values were similar between veterans with HIV infection and veterans without HIV infection (366 15 mm Hg vs. 366 14 mm Hg; P = 0.99), as was the prevalence of increased PASP (28% vs. 27%, respectively; P = 0.58). We know that HIV infection is an independent risk factor for the occurrence and impact of coronary artery disease. Are the effects of HIV and PASP additive in contributing to mortality, or are they synergistic? Table 3 of the paper by Brittain and colleagues demonstrates fully adjusted mortality risks for patients with and without elevated PASPs and with and without HIV infection. The authors did not calculate the difference in mortality risk that elevated PASP confers on persons with versus those without HIV infection. A back-of-the-envelope calculation suggests that the effect of HIV infection among veterans with PASP greater than 40mmHg is 1.18 (95% confidence interval [CI], 1.00–1.39) for the entire group and 1.77 (95% CI, 0.82–3.83) for the subgroup with no prevalent comorbidities. These confidence intervals overlap with those for veterans with PASP less than or equal to 40 mm Hg, who have mortality risks of 1.35 (95% CI, 1.21–1.50) for the entire group and 2.06 (95% CI, 1.45–2.94) for the subgroup with no comorbidities. Therefore, the effects of HIV and PASP greater than 40 mm Hg appear to be additive, but there is no statistical evidence that elevated PASP exacerbates the impact of HIV on mortality. Of course, there are no data in this study about the causes of death in these patients. The article by Brittain and colleagues provides considerable data about the prevalence of elevated PASP in this selected population. It would be instructive to have more information about left atrial size, left ventricular mass, diastolic function, and right ventricular function. At higher PASPs consistent with pulmonary hypertension, an estimated resting PASP is less relevant than determinants of right ventricular function in terms of prognosis (12). None of the available data provide compelling evidence that persons with HIV infection should be screened or treated any differently for such elevated pulmonary artery pressures, although there is always the caveat that drug–drug interactions must be carefully assessed when any new drugs are prescribed for persons receiving antiretroviral therapy. Future work delineating the causes of death for persons with HIV infection who have elevated PASP, assessing related morbidity, and improving our understanding of the biological basis for HIV as a possible cause of PASP elevation or as an exacerbating factor would be welcome. A precision medicine approach (13) linking phenotypes with biological mechanisms might be useful to delineate risk factors, causality, and mortality. n