American Journal of Respiratory and Critical Care Medicine

Rationale: The prevalence of HIV-associated pulmonary arterial hypertension (PAH) has not been evaluated since introduction of combined, highly active antiretroviral treatments.

Objectives: To establish the current prevalence of PAH in a large HIV-positive population.

Methods: Prospective study conducted in 7,648 consecutive HIV-positive adults in 14 HIV clinics in France. PAH was identified through screening with a predefined algorithm. Patients with dyspnea unexplained by other causes underwent transthoracic Doppler echocardiography. PAH was suspected if peak velocity of tricuspid regurgitation was greater than 2.5 m/second and was confirmed by right heart catheterization.

Measurements and Main Results: PAH was diagnosed if mean pulmonary arterial pressure at rest was 25 mm Hg or greater (with pulmonary capillary wedge pressure ⩽ 15 mm Hg) or 30 mm Hg or greater on exercise. A total of 739 patients had dyspnea, of which 312 met exclusion criteria and 150 refused to participate. Among the remaining 277, 30 had known PAH and 247 had unexplained dyspnea and underwent echocardiography; PAH was suspected in 18 and confirmed in 5, to give a total of 35 cases. The prevalence was thus 0.46% (95% confidence interval, 0.32–0.64%). All new cases had relatively milder PAH.

Conclusions: The prevalence of HIV-associated PAH is about the same as it was in the early 1990s. Given the current good long-term prognosis of patients with HIV, the severity of PAH in HIV-infected patients, and the absence of predictive factors, careful screening for PAH is warranted for patients with unexplained dyspnea.

Scientific Knowledge on the Subject

One established risk factor for development of pulmonary arterial hypertension (PAH) is HIV infection, with the main symptom, progressive dyspnea, reported in about 85% of patients. In the early 1990s, when highly active antiretroviral treatments (HAART) were not available, prevalence of HIV-PAH was 0.5% (95% confidence interval, 0.10–0.90%).

What This Study Adds to the Field

The prevalence of HIV-associated PAH is about the same as it was in the early 1990s. Given the current good long-term prognosis of patients with HIV, the severity of PAH in HIV-infected patients, and the absence of predictive factors, careful screening for PAH is warranted for patients with unexplained dyspnea.

Pulmonary arterial hypertension (PAH) results from chronic obstruction of small pulmonary arteries, leading to right ventricular (RV) failure and, ultimately, death. One established risk factor for development of PAH is HIV infection (14).

The first case of HIV-associated PAH (HIV-PAH) was reported in 1987 (5), and initial studies in the early 1990s—a time when therapy with a combination of highly active antiretroviral treatments (HAART) was not yet available—indicated a prevalence of 0.5% (95% confidence interval [CI], 0.10–0.90%) (3, 6).

The signs and symptoms of HIV-PAH are nonspecific; the main symptom is progressive dyspnea, which is reported in about 85% of patients (3, 7). Due to the nonspecificity of symptoms, diagnosis is often delayed, with 71–81% of patients diagnosed in New York Heart Association (NYHA) class III–IV (4, 8). The 3-year survival in patients with NYHA class III–IV HIV-PAH is 28%, whereas it is 84% in patients in class I–II (8). The mortality of patients with HIV-PAH is usually related to the pulmonary hypertension itself, rather than to other complications of HIV infection, and PAH is an independent predictor of death in such patients (1, 3, 6, 7).

The prognosis for HIV-positive patients has improved markedly over the last 10 years with the availability of new antiretroviral therapies, including combinations of protease inhibitor and nucleoside/nucleotide reverse-transcriptase inhibitors (NRTIs). However, recent reports are controversial with regard to the impact of HAART on the prevalence and severity of PAH (911).

The objective of this study was to assess the prevalence of PAH in a large population of patients followed for HIV infection in the HAART era in France. Some of the results of this study have been previously reported in the form of abstracts (1214).

This prospective study was conducted in 14 centers in France, chosen on the basis of geographical distribution of HIV infection and having large, active files of patients with HIV. PAH was identified through screening with a predefined algorithm based on clinical symptoms of dyspnea, transthoracic Doppler echocardiography (TTE) and right heart catheterization (RHC) (Figure 1).

Patients

Consecutive male and female HIV-positive adults attending the clinic for regular follow-up were assessed for dyspnea after informed consent was obtained. Exclusion criteria were as follows: patients without dyspnea; patients with dyspnea explained by known severe pulmonary function impairment (severe chronic obstructive pulmonary disease defined by a FEV1 < 60% predicted, acute lung parasitosis, Pneumocystis jiroveci infection, severe lung fibrosis defined by a TLC < 60% predicted, acute cytomegalovirus infection, lymphoid interstitial pneumonia, or lung granulomatosis) or by known severe heart disease (left ventricular ejection fraction < 40%, mitral regurgitation > grade 2, aortic regurgitation > grade 2, aortic surface < 1.5 cm2, or mitral surface < 1.5 cm2); patients with severe anemia (hemoglobin concentration < 7 g/dl for females; < 8 g/dl for males); patients who were hospitalized; patients with other cardiac complications due to HIV infection (myocarditis, pericarditis, or endocarditis), chronic thromboembolic disease (with abnormal perfusion lung scan or pulmonary angiography), or connective tissue disease; and patients who declined to participate. Patients with unexplained dyspnea had to undergo TTE. Patients with known PAH previously diagnosed on RHC were also enrolled, but did not undergo the predefined study procedures.

Dyspnea Assessment

Dyspnea was defined as an NYHA functional class II or higher, and was diagnosed from a standardized questionnaire (15, 16) (Table 1; see also the English translation of the questionnaire in the online supplement).

TABLE 1. TRANSLATION (FROM FRENCH) OF THE DYSPNEA QUESTIONNAIRE COMPLETED BY PARTICIPANTS


Class/No.

Question
NYHA IV
 1Are you breathless at rest?
 2Can you dress without stopping because of symptoms?
 3Can you shower without stopping because of symptoms?
 4Are you breathless when walking at home?
 5Can you walk 50 m on the flat?
NYHA III
 6Are you breathless when you climb up one flight of steps or when you walk less than 100 m at normal pace?
 7Are you breathless when you do cleaning (strip and make bed, mop floors, hang washed clothes, clean windows) or recreational activities (shopping, push a shopping cart, play French bowls [petanques], play golf, push power lawn mower)?
NYHA II
 8Are you breathless when you climb up two flights of steps or when you walk up hill?
 9Are you breathless when you walk quickly or do gardening or slow dancing?
NYHA I
 10
Are you breathless when you perform heavy physical activities (jogging, skiing, cycling, climb two flights of steps when carrying a baby)?

Definition of abbreviation: NYHA = New York Heart Association.

TTE

Patients with unexplained dyspnea were referred to a senior cardiologist, who performed a complete time–motion, bidimensional, and Doppler echocardiography examination. Color-flow Doppler was used to obtain the best possible alignment between the tricuspid regurgitation and the Doppler ultrasound beam (see the online supplement). PAH was suspected in patients with peak velocity of tricuspid regurgitation (VTR) greater than 2.5 m/second. In the event that tricuspid regurgitation was absent, or VTR not measurable, peak velocity of pulmonary regurgitation (VPR) was considered. PAH was suspected if protodiastolic VPR was greater than 2.0 m/second and end-diastolic VPR was greater than 1.2 m/seconds.

RHC

All patients with echocardiographically suspected PAH underwent RHC to confirm the diagnosis, unless they had echocardiographic evidence of left heart disease (see the online supplement). PAH was defined as mean pulmonary arterial pressure () of 25 mm Hg or greater at rest or 30 mm Hg or greater during exercise, with pulmonary capillary wedge pressure of 15 mm Hg or less.

Patients with PAH diagnosed on RHC before the study were also enrolled, but did not undergo TTE nor repeat RHC. Hemodynamic parameters recorded at diagnosis were collected, together with date of diagnosis and treatments received. For other data recorded and ethical considerations, see the online supplement.

Statistical Analysis

All statistical analyses were performed with SAS software version 8.2 (SAS Institute, Cary, NC) (see the online supplement) (17, 18).

Study Population

Over the period from March 2004 to March 2005, 7,648 patients were seen at the clinic for their regular follow-up and completed the dyspnea questionnaire.

Of the 7,648 patients (overall population), 739 presented with dyspnea. A total of 462 out of the 739 patients with dyspnea did not enter the study (312 met exclusion criteria, 116 refused to participate, and 34 refused to undergo study procedures). Among the 277 remaining patients (the per-protocol population), 30 had previously diagnosed PAH and 247 had unexplained dyspnea and underwent all study procedures. The demographics and HIV infection characteristics of the overall population and the per-protocol population are detailed in Table 2.

TABLE 2. COMPARISON OF DEMOGRAPHIC AND DISEASE CHARACTERISTICS OF THE OVERALL AND PER-PROTOCOL POPULATIONS


Characteristic

Overall Population (n = 7,648)

Per-Protocol Population (n = 277)
Age, yr, mean (SD)41.91 (9.56)42.29 (8.90)
Males, %6755
Race, %
 White7573
 Black2426
 Asian11
Mode of HIV infection
 Men having sex with men3123
 IV drugs1626
 Heterosexual contact4344
 Transfusion23
 Undetermined44
Duration of HIV infection, yr, mean (SD)10 (6)10 (6)
Viral load, copies/ml, < 400, %6266
CD4+ count/mm3 < 200, %
13
20

A total of 55% of subjects in the per-protocol population were male, but there were marked differences within ethnic subgroups: of the white patients, 66% were male and 34% female, whereas black patients were more likely to be female (21% males compared with 79% females).

The mean duration of HIV infection was 10 years. A total of 20 patients (7%) were treatment naive with regard to antiretroviral therapy, 18 (7%) had had treatment stopped, and 237 (86%) were currently receiving treatment; data were lacking for 2 subjects. Globally, 71% of patients were receiving HAART: three NRTIs for 30 patients (13%), two NRTIs plus a protease inhibitor for 87 patients (37%), and two NRTIs plus a non-NRTI (NNRTI) for 49 patients (21%). The majority of patients were well controlled: 66% had a viral load of less than 400 copies/ml.

Just over half (52%) of the per-protocol patients were current smokers, with 35% having never smoked and 13% having stopped smoking; 31% were also infected with hepatitis C (36% of whites and 11% of blacks), and 10% with hepatitis B (10% of whites and 10% of blacks). Apart from dyspnea, the most common symptom of patients in the per-protocol population was fatigue (64%), followed by palpitations (39%), anginal pain (12%), lipothymia (near syncope) (11%), hepatalgia on exercise (6%), and syncope (3%).

Doppler Echocardiography Findings

In total, 247 patients underwent TTE: PAH was suspected in 18 and absent in 225, whereas 4 had left-heart disease.

The group of 225 patients with no PAH was composed of 186 (83%) patients with VTR less than 2.5 m/second or end-diastolic VPR less than 1.2 m/second or protodiastolic VPR less than 2 m/second, and 39 patients in whom neither VTR nor VPR could be recorded (17%). These 39 patients had no indirect evidence of pulmonary hypertension, as the size of their right heart chambers was comparable with that of the patients with a VTR of less than 2.5 m/second, and were considered as having no PAH (data not shown).

Differences between patients with suspected PAH (n = 18) and those with no suspicion of PAH (n = 225), in regard to echocardiographic parameters, did not reach statistical significance. However, there was a constant trend toward RV and right atrial enlargement and a lesser RV shortening fraction in patients with echocardiographic suspicion of PAH. The mean end-diastolic RV diameter was 34.85 (±8.08) (mean ± SD) mm in those with suspected PAH and 31.53 (±5.18) mm in those with no PAH (P = 0.12), whereas end-diastolic left ventricular diameter was 43.84 (±5.79) mm compared with 42.04 (± 7.21) mm, respectively (P = 0.30). Diastolic RV area was 17.53 (±7.36) versus 15.04 (±4.38) mm2 (P = 0.35), and systolic RV area was 10.78 (±6.11) versus 8.28 (± 3.08) mm2 (P = 0.32). Percentage shortening of RV surface was 38.25 (±9.41) versus 44.16 (±12.91) (P = 0.13), whereas right atrial surface was 15.73 (±4.83) compared with 13.38 (±3.58) mm2 (P = 0.13).

RHC

All of the 18 patients in whom PAH was suspected underwent RHC. Among them, PAH was confirmed in five cases. No patient with PAH had a VTR of less than 2.8 m/second. Four patients had a over 25 mm Hg at rest and one patient had a of 33 mm Hg on exercise, despite a of 20 mm Hg at rest. One other patient had a of 35 mm Hg on exercise, but was diagnosed as having post–capillary PAH.

Prevalence of PAH

Among the 7,648 patients who attended the clinic, 739 presented with shortness of breath, giving a prevalence of dyspnea of 9.66% (95% CI, 9.00–10.33%).

A total of 30 of the 7,648 patients were previously diagnosed as having PAH, and 5 other patients were found to have PAH through the screening algorithm. Thus, the prevalence of PAH was 35/7,648 (i.e., 0.46% [95% CI, 0.32–0.64%]).

Patients with PAH

The clinical profile of the patients with PAH is compared with that of the patients without PAH in Table 3. There were no clinically remarkable differences between the two groups with regard to age, race, duration of HIV infection (expressed as the time from diagnosis of HIV infection to time of PAH diagnosis in patients with PAH), and ongoing antiretroviral treatment. Patients with PAH were more likely to be males (71% compared with 53% male in patients without PAH; P = 0.04) and intravenous drug abusers (51 vs. 22%; P < 0.0001). There was no overall difference with regard to CD4+ count, but the proportion of patients with a CD4+ count of less than 200/mm3 was significantly higher in those with PAH.

TABLE 3. COMPARISON OF PATIENTS WITH AND WITHOUT PULMONARY ARTERIAL HYPERTENSION PER-PROTOCOL POPULATION


Characteristic

PAH (n = 35)

No PAH (n = 242)

P Value
Age, yr, mean (SD)41.51 (8.04)42.40 (9.03)0.58
Males, %71530.04
Race0.38
 Whites8071
 Blacks1726
 Asians31
 Others02
Mode of HIV infection, %
 Man having sex with men11250.07
 IV drugs5122< 0.0001
 Heterosexual contact29460.05
Duration of HIV infection, yr, mean (SD)10.17 (6.42)9.87 (5.74)0.76
Currently treated with ARV, n (%)30 (86)207 (86)0.98
Ongoing ARV treatment, n (%)0.88
 3 NRTIs3 (10)27 (13)
 2 NRTI + 1 PI11 (38)75 (37)
 2 NRTIs + 1 NNRTI5 (17)43 (21)
 Other10 (34)58 (29)
 Missing14
Viral load, copies/ml, < 400, %66660.98
CD4+ count/mm3 < 200, %
37
18
0.01

Definition of abbreviations: ARV = antiretroviral; IV = intravenous; NNRTI = nonnucleoside reverse-transcriptase inhibitor; NRTI = nucleoside/nucleotide reverse transcriptase inhibitor; PAH = pulmonary arterial hypertension; PI = protease inhibitor.

In the previously diagnosed group, the duration of PAH was 3.0 (± 2.2) years. All newly diagnosed PAH cases had relatively milder PAH. Newly diagnosed cases had lower , lower right atrial pressure (RAP), lower pulmonary vascular resistance (PVR), and slightly higher cardiac index when compared with previously diagnosed cases (for which values at the time of diagnosis are given) (Table 4).

TABLE 4. COMPARISON OF HEMODYNAMIC DATA


Parameter

Known PAH (n = 30)

Newly Diagnosed PAH (n = 5)
, mm Hg46 ± 1330 ± 9
PCWP, mm Hg7 ± 38 ± 4
PVR, Wood units10 ± 44 ± 3
RAP, mm Hg8 ± 64 ± 1
Cardiac index, L/min/m2
3.0 ± 0.8
3.6 ± 0.8

Definition of abbreviations: = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure.

This study is the first prospective, nationwide, multicenter study devoted to PAH in HIV since the availability of HAART. The patients were recruited within the short time frame of 1 year, and all were assessed using a standardized algorithm. To our knowledge, this is the largest cohort studied to date. In this prospective, multicenter study in the HAART era, the prevalence of PAH was found to be 0.46%. This figure is very similar to that from Speich and colleagues of 0.50%, which was obtained before HAART was used (6). More recently, Pugliese and colleagues concluded that use of HAART had decreased the incidence of cardiac involvement in HIV-positive patients; however, their data also showed a higher percentage with PAH within the 498 patients treated with HAART (2%) than in the 544 treated with NRTI (0.7%) (9). The difference in prevalence between Speich and colleagues and Pugliese and colleagues may be related to several factors: Pugliese and colleagues performed a retrospective study of patients in the advanced stage of HIV disease who had been hospitalized from 1989 to 1998; not only did the treatment regimen change over that period, but, with regard to mode of HIV infection, the demographic characteristics changed (9). In comparison, Speich and colleagues studied prospectively a cohort of 1,200 subjects infected with HIV over a 9-month period, and evaluated 74 with cardiopulmonary complaints (6). The studies also differed with regard to methodology for PAH diagnosis: Pugliese and coworkers used electrocardiography and echocardiography (9), whereas Speich and colleagues examined patients by bronchoscopy and/or echocardiography, with echocardiography being performed in 12 of the 74 patients (6). It is of note that the criteria used to diagnose PAH were not described by Pugliese and colleagues; in addition, all patients with clinical signs of cardiac involvement were evaluated with echocardiography, whereas asymptomatic individuals were not routinely assessed in this way (9). In the study by Speich and colleagues, PAH was defined by elevated RV systolic pressure greater than 30 mm Hg over RAP documented by Doppler echocardiography. In these two studies, RHC was never performed to confirm the diagnosis of PAH (6, 9).

One of the strengths of our study is the methodology used to identify patients with PAH. We had a predefined algorithm that included clinical symptoms, TTE, and RHC. The algorithm was derived from the one used in a study in systemic sclerosis (ItinérAIR-Scleroderma) (19). However, given the much lower prevalence of PAH in HIV-infected patients compared with systemic sclerosis, we needed to select a high-risk population: the dyspnea questionnaire allowed us to select such individuals.

The echocardiographer's experience is crucial for the accurate identification of the tricuspid regurgitation jet. Our TTE data were of high quality, as evidenced by the high percentage of patients with a recordable VTR: 208 of 247 patients (84%) undergoing TTE had a recordable VTR or VPR. This percentage is in line with the article by Hachulla and colleagues (19), in which VTR could be determined in 81.5% of patients with systemic sclerosis. We believe it important to stress the fact that PAH has been confirmed in our patients by RHC, which is the gold standard. In our study, PAH was suspected in 18 and confirmed in 5 (28%); the false-positive rate from echocardiography (72%) was rather higher than in the series reported by Hachulla and colleagues, in which PAH was suspected in 33 and confirmed in 18 (55%), giving a false-positive rate of 45%. It is important to note that, in both studies, PAH was suspected in patients with VTR greater than 2.5 m/second. In our study, the false-positive rate might have been reduced if we had chosen a threshold of 2.8 m/second for VTR. When using this threshold, there is no false-negative result (all patients with confirmed pulmonary hypertension had a VTR ⩾ 2.8 m/s), and the false-positive rate is only 11% (only two patients had VTR ⩾ 2.8 m/s without confirmed PAH on RHC). In this patient population, a VTR threshold of 2.8 m/second or greater could dramatically reduce the number of RHCs to confirm or rule out the diagnosis of PAH.

In addition to enrolling a large sample of patients with HIV infection, our patient population was representative of the overall 100,000 HIV-positive patients followed in France (20). In 2002, 70% of patients seen in specialized HIV centers were male (compared with 67% in our registry), the mode of HIV transmission was “men having sex with men,” and intravenous drug abuse in 34.1 and 15.5%, respectively (31 and 16%, respectively, in our registry), CD4+ count was less than 200 in 14.7% (compared with our 13%), and viral load was less than 500 in 59.1% (<400 in 62% of our cohort). Furthermore, our per-protocol patient sample was generally comparable to the total registry, although this subgroup had slightly more severe disease on the basis of CD4+ counts. The treatment of the per-protocol population was consistent with overall national data: the 2002 data showed 76% to be treated (70% with HAART and 6% with other treatments) compared with 86% of our per-protocol population (71% with HAART and 15% with other treatments). Just over half of our per-protocol population were smokers; the high prevalence of smoking was not unexpected, as smoking in the HIV population is recognized as being higher than in the general population in Western Europe (21). Differences in coinfection (hepatitis B and C) in the different ethnic groups were as expected in view of the difference in modes of transmission in whites and blacks.

To identify potential predictive factors, comparison of patients with and without PAH revealed few differences; the most notable difference was a higher proportion with HIV acquired from intravenous drug use in the subset with PAH than in those without PAH. This possible susceptibility has already been described by others (7, 8). However, PAH may be observed in all HIV-positive patients, whatever the mode of HIV infection. Patients with PAH related to HIV infection via intravenous drug abuse have no clinical, functional, or hemodynamic particularities as compared with patients with PAH related to HIV infection from another route of transmission. In the initial diagnostic workup, chronic thromboembolic pulmonary hypertension was ruled out by ventilation/perfusion (V/Q) scan, which was performed in all patients. V/Q scan findings were similar in intravenous drug abusers and in patients with HIV infection from another route of transmission.

Our study proved that PAH can be assessed in all HIV-positive patients in routine clinical practice using a screening algorithm based on dyspnea, TTE, and RHC. The severity of PAH in our newly diagnosed patients was mild; however, such patients need close monitoring, as HIV-PAH patients may have a rapidly progressive disease and a poor prognosis when in NYHA III–IV (8). In accordance with guidelines, PAH-specific therapy needs to be instituted for those in NYHA III–IV (22). Some authors believe that antiretroviral treatment might slow progression of PAH and improve survival (11). A retrospective analysis of all 47 patients in the Swiss HIV cohort study revealed benefits of HAART over NRTIs alone: the RV systolic pressure over RAP gradient increased by a median of 25 mm Hg in 9 patients who had not received therapy, decreased by a median of 3 mm Hg in 12 who received nucleoside analogs, and decreased by a median of 21 mm Hg in 14 who received HAART. HAART decreased mortality due to PAH and other causes (11). However, the impact of HAART on survival is still controversial. Thus, Nunes and colleagues found that the 3-year survival of patients in NYHA class III–IV with HIV-associated PAH treated with HAART and epoprostenol was 52% (8).

We acknowledge that our study has some limitations. First, for feasibility reasons, TTE was performed only in patients with unexplained dyspnea. Second, it should be noted that, for 39 patients, there was no VTR or VPR, and so their risk of PAH was effectively unknown. We considered these patients to have no PAH, as comparison of their right heart parameters on TTE showed them to be similar to those with no TTE-identified risk of PAH. Restricting TTE to those with dyspnea and classifying the 39 patients as we did may have reduced the estimate of the prevalence of PAH. Our prevalence thus represents a minimum. Furthermore, the prevalence remains unknown in those who had a potential reason for dyspnea (anemia, impaired respiratory function, etc.). Finally, the estimated prevalence of 0.46% is conservative, and would probably not be altered by the inclusion of patients with dyspnea who refused to participate. These patients had similar clinical characteristics to those of patients who were included in the study, without any difference in terms of age, sex ratio, percentage of whites, duration of HIV infection, viral load, and CD4 count.

We conclude that the prevalence of HIV-associated PAH is about the same now as it was in the 1990s. Our study showed that a screening algorithm based on a dyspnea questionnaire, TTE, and RHC is applicable in routine clinical practice, and seems to identify patients with less severe PAH, as the severity of disease in our newly diagnosed cases was less than that in the established cases. Given the good long-term prognosis of HIV patients in the HAART era, the severity of PAH in HIV-infected patients, and the absence of predictive factors (apart from intravenous drug use), screening for PAH according to a precise algorithm is warranted in patients presenting with dyspnea not explained by another cause.

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Correspondence and requests for reprints should be addressed to Olivier Sitbon, M.D., Ph.D., Service de Pneumologie Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92141 Clamart, France. E-mail:

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