HIV and pulmonary hypertension: CD4 and viral load matter
Authors: Yingying Ding, Na He
Journal: The Lancet Healthy Longevity (2021)

The use of combination antiretroviral therapy (ART) has transformed HIV infection from a fatal illness into a chronic disease. As a consequence, the long-term cardiopulmonary complications, including HIV-associated pulmonary arterial hypertension, have emerged as the primary source of morbidity and mortality, representing an important health-care concern.1Feinstein MJ Hsue PY Benjamin LA et al.Characteristics, prevention, and management of cardiovascular disease in people living with HIV: a scientific statement from the American Heart Association.Circulation. 2019; 140: e98-124Crossref PubMed Scopus (121) Google Scholar HIV-associated pulmonary arterial hypertension is a life-threatening condition characterised by pulmonary vascular remodelling, elevated pulmonary arterial pressure, and right heart failure. It has been suggested that people living with HIV have a higher incidence of pulmonary hypertension than the general population. However, this theory has been speculated based on limited evidence as most published studies are cross-sectional, have small sample sizes, or do not include appropriate comparison groups.2Basyal B Jarrett H Barnett CF Pulmonary Hypertension in HIV.Can J Cardiol. 2019; 35: 288-298Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar Longitudinal studies of pulmonary hypertension in people with HIV infection are needed to evaluate whether the risk of pulmonary hypertension increases with HIV, and especially with worsening HIV infection. The Veterans Aging Cohort Study (VACS) provides a unique opportunity to address this question because of its large sample size, its long follow-up period, and its population with demographically similar participants with and without HIV.3Fultz SL Skanderson M Mole LA et al.Development and verification of a "virtual" cohort using the National VA Health Information System.Med Care. 2006; 44: S25-S30Crossref PubMed Scopus (190) Google Scholar In the Lancet Healthy Longevity, Meredith S Duncan and colleagues4Duncan MS Alcorn CW Freiberg MS et al.Association between HIV and incident pulmonary hypertension in US Veterans: a retrospective cohort study.Lancet Healthy Longev. 2021; (published online June 16.)https://doi.org/10.1016/S2666-7568(21)00116-1Summary Full Text Full Text PDF Google Scholar used data from VACS participants referred for a clinical echocardiogram in whom estimated pulmonary artery systolic pressure (PASP) was reported. The final analytical sample included 13 028 participants (4174 [32%] with HIV and 8854 [68%] without HIV) with baseline PASP measures of 35 mm Hg or less. Median age was 58 years (IQR 52–64) and 12 657 (97%) were male. Incidence of pulmonary hypertension was 28·6 cases per 1000 person-years (95% CI 26·1–31·3) in veterans with HIV and 23·4 cases per 1000 person-years (21·9–24·9) in veterans without HIV (p=0·0004). The risk of incident pulmonary hypertension was higher among veterans with HIV than among veterans without HIV (unadjusted HR 1·25 [95% CI 1·12–1·40], p<0·0001), and such association remained significant after adjusting for potential confounding factors (HR 1·18 [1·05–1·34], p=0·0062). This increased risk of pulmonary hypertension among people living with HIV was similar to that seen in results from previous publications.2Basyal B Jarrett H Barnett CF Pulmonary Hypertension in HIV.Can J Cardiol. 2019; 35: 288-298Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar The study by Duncan and colleagues4Duncan MS Alcorn CW Freiberg MS et al.Association between HIV and incident pulmonary hypertension in US Veterans: a retrospective cohort study.Lancet Healthy Longev. 2021; (published online June 16.)https://doi.org/10.1016/S2666-7568(21)00116-1Summary Full Text Full Text PDF Google Scholar represents the first large-scale longitudinal investigation of the direct effect of HIV on incident pulmonary hypertension and PASP progression outside its indirect effect though heart failure and chronic obstructive pulmonary disease, providing compelling evidence that infection with HIV increases the incidence for pulmonary hypertension. However, the study has some limitations due to the inclusion of only symptomatic patients and to the diagnosis of pulmonary hypertension by echocardiography. The gold standard for diagnosis of pulmonary hypertension is a mean pulmonary artery pressure of 25 mm Hg or more on right heart catheterisation (RHC). However, RHC is an invasive procedure with associated risks, limiting its utility for screening pulmonary hypertension.5D'Alto M Dimopoulos K Coghlan JG Kovacs G Rosenkranz S Naeije R Right heart Catheterization for the diagnosis of pulmonary hypertension: controversies and practical issues.Heart Fail Clin. 2018; 14: 467-477Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar Echocardiography is the most widely used tool for screening pulmonary hypertension, but it has poor specific and sensitivity. According to published data, the use of echocardiographic measurements is likely to overestimate the prevalence of pulmonary hypertension in people with HIV.2Basyal B Jarrett H Barnett CF Pulmonary Hypertension in HIV.Can J Cardiol. 2019; 35: 288-298Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 6Sitbon O Lascoux-Combe C Delfraissy JF et al.Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era.Am J Respir Crit Care Med. 2008; 177: 108-113Crossref PubMed Scopus (336) Google Scholar Evidence is emerging that screening for pulmonary hypertension in high-risk populations will allow early detection and management, which potentially could reduce morbidity and mortality.7Humbert M Gerry Coghlan J Khanna D Early detection and management of pulmonary arterial hypertension.Eur Respir Rev. 2012; 21: 306-312Crossref PubMed Scopus (74) Google Scholar Notwithstanding the limitations, this new evidence suggests that regular echocardiographic screening and monitoring of pulmonary hypertension might be helpful in people living with HIV, because of their increased risk. The effect of ART on the development of pulmonary hypertension, along with the association between CD4 cell count or viral load and pulmonary hypertension, remain controversial, and available data are insufficient to address these associations.8Janda S Quon BS Swiston J HIV and pulmonary arterial hypertension: a systematic review.HIV Med. 2010; 11: 620-634Crossref PubMed Scopus (27) Google Scholar Duncan and colleagues4Duncan MS Alcorn CW Freiberg MS et al.Association between HIV and incident pulmonary hypertension in US Veterans: a retrospective cohort study.Lancet Healthy Longev. 2021; (published online June 16.)https://doi.org/10.1016/S2666-7568(21)00116-1Summary Full Text Full Text PDF Google Scholar assumed that the effects of ART on the pulmonary vasculature are not mediated through HIV viraemia and CD4 count, and they carefully assessed the association between time-varying CD4 count and HIV viral load and incident pulmonary hypertension. Such analytic approach can address the limitation of previous work based on the cross-sectional data, and it can approximate the association of CD4 count and viral load to pulmonary hypertension more closely to the true association. As reported, low CD4 count and high viral load are associated with both the risk of reaching clinical pulmonary hypertension thresholds and PASP progression of more than 10 mmHg, indicating that ART can reduce the risk of pulmonary hypertension through immune restoration and viral control.4Duncan MS Alcorn CW Freiberg MS et al.Association between HIV and incident pulmonary hypertension in US Veterans: a retrospective cohort study.Lancet Healthy Longev. 2021; (published online June 16.)https://doi.org/10.1016/S2666-7568(21)00116-1Summary Full Text Full Text PDF Google Scholar However, the question of whether ART increases the risk of pulmonary hypertension though its impact on insulin resistance and dyslipidaemia remains unanswered, and therefore it is not possible to determine the overall effect of ART on pulmonary hypertension. The work by Duncan and colleagues contributes to our understanding of the causal relationship between HIV and pulmonary hypertension. However, the biological basis for this link remains undefined. Limited available evidence suggests a role of HIV viral proteins and systemic inflammation in the pathogenesis of HIV-associated pulmonary arterial hypertension.9Butrous G Human immunodeficiency virus-associated pulmonary arterial hypertension: considerations for pulmonary vascular diseases in the developing world.Circulation. 2015; 131: 1361-1370Crossref PubMed Scopus (23) Google Scholar It is interesting to note that recent data suggest the role of immunometabolism in HIV pathogenesis, disease progression, and associated non-communicable conditions.10Sáez-Cirión A Sereti I Immunometabolism and HIV-1 pathogenesis: food for thought.Nat Rev Immunol. 2021; 21: 5-19Crossref PubMed Scopus (10) Google Scholar Further research addressing the cellular metabolism underlying HIV-associated pulmonary arterial hypertension might provide novel insights into disease mechanisms and develop new therapeutic strategies. Furthermore, additional efforts are needed to increase the awareness and early detection of this clinical condition in people living with HIV. We declare no competing interests. Association between HIV and incident pulmonary hypertension in US Veterans: a retrospective cohort studyHIV is associated with pulmonary hypertension incidence, adjusting for risk factors. Low CD4 cell count and high HIV viral load contribute to increased pulmonary hypertension risk among veterans with HIV. Thus, as with other cardiopulmonary diseases, suppression of HIV should be prioritised to lessen the burden of pulmonary hypertension in people living with HIV. Full-Text PDF Open Access