High Prevalence of Pulmonary Arterial Hypertension in a Cohort of Asymptomatic HIV-Infected Patients

Abstract

HIV infection is considered a risk factor for the development of pulmonary arterial hypertension (PAH) and the estimated prevalence of PAH in developed countries is 0.5%. The aim of this study was to determine the prevalence of PAH in a cohort of HIV-infected patients and the related factors. We undertook an observational study of a consecutive cohort of asymptomatic HIV-infected patients. Data were recorded about factors of cardiovascular interest and factors related to HIV infection. All the patients underwent a transthoracic echocardiogram (Vivid S6, GE Healthcare). PAH was considered to be a pulmonary arterial systolic pressure (PASP) >40 mm Hg. The study included 194 patients (85.2% men) with a mean age of 47.0 years, 94% of whom were on antiretroviral therapy (ART). The mean CD4 lymphocyte count was 495/mm³. The mean duration of HIV infection was 131.5 months, and 28.4% had experienced an AIDS event. PAH was present in five patients (2.6%) and 14 were in the gray zone (PASP of 36–40 mm Hg). These five patients were men, the route of transmission was homosexual, and they were all on ART. They were also older than the patients without PAH (57.7 vs. 46.4 years, p=0.02) and had been on ART for longer (180.0 vs. 92.5 months; p=0.01). No association was found with any of the other parameters. The prevalence of PAH in this cohort of patients was greater than in other published series. The only associations found were with older age and longer ART time.

Introduction

T he generalization of highly-active antiretroviral therapy (ART) has led to an important reduction in the morbidity and mortality of patients infected with the human immunodeficiency virus (HIV).¹ The chronification of HIV and the reduction in opportunistic events have resulted in the emergence of other disorders in the HIV-infected population, including cardiovascular complications,^2,3 among which is pulmonary arterial hypertension (PAH). Not only is HIV infection now an established risk factor for the development of PAH,^4

–7 it has also been suggested to be an independent risk factor for death in these patients.^4,8,9 The estimated prevalence of HIV-associated PAH in developed countries is 0.5%, though the real prevalence may be greater as most studies do not include asymptomatic patients.^{7,8,10

–14} Although HIV-associated PAH has been related to particular factors such as parenteral drug abuse and the degree of immunosuppression, fewer data exist about the characteristics of patients with HIV-associated PAH in the era of ART.^7
–9 Doppler echocardiography is a very useful technique for the diagnosis of PAH,¹⁵ as well as for discarding congenital, valvular, and myocardial disease. It can therefore be considered a good method for screening. The aim, therefore, of this study was to determine the prevalence of PAH in a cohort of asymptomatic HIV-infected patients in our area, as well as the related factors.

Materials and Methods

We undertook an observational study of a consecutive cohort of asymptomatic HIV-infected patients on regular follow-up at the Infectious Diseases Unit of this hospital who attended the office between April and July 2011. All the patients were older than 18 years of age. Patients were excluded if they had prior known structural heart disease of any etiology and if they were pregnant or lactating. The study was approved by the Research and Ethics Committee of our center. All the patients were informed about the nature of the study and consented to participate. All the patients completed a questionnaire about cardiovascular risk factors, toxic habits, lung disease, medication, and family history. Exercise tolerance was established according to the New York Heart Association (NYHA) classification¹⁶ and the patients underwent a physical examination to determine their weight, height, waist circumference, and blood pressure. HIV-related data included the route of transmission, the time since diagnosis, AIDS events, viral load, nadir, and current CD4 lymphocyte count, ART and its duration, and coinfection with hepatitis B virus or hepatitis C virus.

All the patients underwent an electrocardiogram and an echocardiogram. The transthoracic echocardiograms were all done by the same echocardiographer, blinded to the data on the clinical history of the patients. The echocardiographer interpreted the results in real time according to the protocol described in the clinical practice guidelines of the American Society of Echocardiography.^17,18 The device used was a Vivid S6, from GE Healthcare. The echocardiographic parameters measured were (1) pulmonary arterial systolic pressure (PASP), which in the absence of obstruction of the right ventricular (RV) outflow tract or pulmonary stenosis should be equal to the RV systolic pressure, estimated by the maximum velocity (V) of the tricuspid regurgitation and the pressure (P) of the right atrium (RA) according to the following formula: RVSP=4V ²+DBP. The diastolic blood pressure (DBP) was estimated from the size and degree of inspiratory collapse of the inferior vena cava. PAH was considered to be absent when the PASP was <36 mm Hg, in the gray zone when it was 36–40 mm Hg, mild when it was 41–50 mm Hg, moderate when it was 51–60 mm Hg, and severe when it was >60 mm Hg. (2) In the absence of tricuspid regurgitation, the mean pulmonary arterial pressure (mPAP) was calculated from the pulmonary flow acceleration time (AT) with pulsed Doppler, according to the formula mPAP=79−(0.45AT); and when the AT was <120 ms the formula used was mPAP=90−(0.62AT). In this case, PAH was defined as an mPAP >25 mm Hg.

The qualitative variables are expressed in percentages and contrast associations analyzed by the Chi square test (χ²) or the Fisher test. The quantitative variables are expressed as the mean±standard deviation and the differences were analyzed by the Student's t test after verifying that the quantitative variables followed a normal distribution (Kolmogorov–Smirnov test). When there were more than two groups to be compared, a one-way or multiway analysis of variance (ANOVA) was used, according to the case. The multivariate analysis for the event-related variables was done with the Cox proportional hazards model. The odds ratios were determined and the 95% confidence intervals calculated for the significant variables. In all cases the contrasts were done bilaterally and significance was set at p<0.05. The statistical analysis was done with SPSS 17.0.0 (SPSS, Inc., Chicago, IL).

Results

Of the 207 patients invited to participate in the study, 194 accepted and provided signed consent. The mean PASP, which could be estimated in 115 patients (59.3%), was 31.4±4.7 mm Hg, with five patients being diagnosed with PAH. In the remaining 79 patients (40.7%) the mPAP was estimated due to absence of tricuspid regurgitation, with a mean of 14.0±5.5 mm Hg; no PAH was detected in any of these patients. Thus, the prevalence of PAH was 2.6%, with 14 patients (7.2%) in the gray zone. Table 1 shows the characteristics of the patients with and without PAH. The patients with PAH were older and had been exposed to ART for longer. Table 2 shows the characteristics of the five patients with PAH. These five patients all underwent an exhaustive study to discard the presence of an autoimmune, respiratory, or thromboembolic disorder as a systemic cause of PAH. Other cardiac causes were also ruled out by echocardiographic study of the left ventricular mass, diastolic function, and valvulopathy.

Table 1.

Characteristics of the Patients (N=194)

Characteristics	PAH (n=5)	No PAH (n=189)	p
Sex (men)	5 (100)	161 (85.2)	0.352
Age (years)	56.3±7.6	46.1±9.4	0.017
Smoking	0 (0)	112 (59.3)	0.029
Alcohol	1 (20)	42 (22.2)	0.906
Other drugs	0 (0)	27 (14.3)	0.362
HCV coinfection	0 (0)	52 (27.7)	0.169
Hypertension	2 (40)	32 (17)	0.183
DM	1 (20)	16 (8.5)	0.368
Prior pulmonary disease	0 (0)	23 (12.2)	0.406
AIDS event	1 (20)	52 (27.5)	0.710
Time with HIV (months)	159.6±92.4	122.5±88.4	0.356
Time on ART (months)	149.3±79.2	83.3±67.2	0.032
ART	5 (100)	178 (94.2)	0.579
VL <50 copies/mm³	5 (100)	166 (87.8)	0.406
CD4/mm³	363.3±126.7	545.5±259.5	0.113

The quantitative variables are expressed as mean±standard deviation and the qualitative variables as n (%).

PAH, pulmonary hypertension; HCV, hepatitis C virus; DM, diabetes mellitus; AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; ART, antiretroviral therapy; VL, viral load.

Table 2.

Characteristics of the Patients with Pulmonary Hypertension (N=5)

Case	Sex	Age	Risk	AIDS	CD4	VL <50	PASP	HTN	DM	NYHA
1	Male	57	HMX	No	172	Yes	43	Yes	Yes	I
2	Male	59	HMX	Yes	328	Yes	41	No	No	I
3	Male	67	HMX	No	391	Yes	43	Yes	No	I
4	Male	48	HMX	No	411	Yes	43	No	No	I
5	Male	50	HMX	No	516	Yes	43	No	No	I

HMX, homosexual; AIDS, acquired immunodeficiency syndrome; VL, viral load; PASP, pulmonary artery systolic pressure; HTN, hypertension; DM, diabetes mellitus; NYHA, New York Heart Association (functional grade of dyspnea).

Discussion

The prevalence of PAH in this series of asymptomatic HIV-infected patients with a good immunovirological status was 2.6%. The prevalence of PAH in HIV-infected patients is greater than that found in the general population. A French registry estimated the prevalence of PAH to be 5–25 cases per million population, with the prevalence of idiopathic pulmonary arterial hypertension being 5.9 cases per million population.⁶ Nevertheless, this figure varies widely in the different series, ranging from 0.46%¹⁰ up to 57%.¹⁹ This variability is related to the epidemiological and clinical characteristics of the study population, the methods used to estimate the PASP, and the cut-point selected to define PAH. For example, the prevalence rises markedly with a low cut-point such as 30 mm Hg.¹⁹ We based our study on the guidelines for the diagnosis and treatment of PAH¹⁵ and, considering that the patients were asymptomatic, we decided to set the cut-point at 40 mm Hg, defining a safe gray zone. The prevalence of tricuspid regurgitation in the general population also varies greatly, from 15% to 80%,^20
–22 which has important repercussions for the estimation of the PASP. To overcome this issue, we used an alternative method to estimate the mPAP with the pulmonary acceleration time; this has been defended as an accurate measurement in recent studies.²³

The factors related to PAH in our study were older age and time on ART, though no association was found with any particular drug group. Although the pathophysiology of HIV-associated PAH is unknown, the virus itself is thought to affect the pulmonary vasculature, favored by the presence of accompanying disorders (hepatitis C virus, hypertension, diabetes) or ART in patients with special susceptibility or an aberrant cell response.⁷ Other series have related HIV-associated PAH with the use of ritonavir¹⁹ or a worse immunovirological status.²⁴ The only associations found in our cohort were with age and the time of exposure to ART, though as there were only five cases these results should be treated with caution. PASP is known to increase with age, at the rate of 0.8 mm Hg per decade of life, with an age of 50 years or older being related to a high PASP. McQuillan et al.²⁵ suggested that the upper limit of normal in this age group should be 40 mm Hg.

Despite the limitations of this study, the characteristics of the patients were similar to those of any current HIV-infected cohort in developed countries. The study also provides useful information to contrast with other studies, some of which had a smaller sample than ours or were done before the general use of ART, with different echocardiographic techniques and based on criteria that are now obsolete.

In summary, the prevalence of PAH in this cohort of asymptomatic HIV-infected patients with a good immunovirological status was related to age and the time on ART. Nonetheless, prospective studies comparing the situation with that in the general population are needed to show the weight of the HIV infection and its treatment in these disorders.

Footnotes

Author Disclosure Statement

No conflicts of interests exist.

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