Pulmonary arterial hypertension (PAH) results from chronic obstruction of small pulmonary arteries, leading to right ventricular failure and ultimately death. Infection with HIV is an established risk factor for PAH [1–3], which may arise regardless of the mode or stage of HIV infection, and degree of immunodeficiency [4–6]. Survival is worse in patients with PAH associated with HIV infection (PAH-HIV), compared with either HIV-infected patients without PAH  or patients with idiopathic PAH . Mortality in patients with PAH-HIV is usually related to pulmonary vascular disease, rather than other complications of HIV infection; PAH is considered an independent predictor of death [4,5,8].
Therapeutic management of HIV infection and PAH has improved considerably over the past decade. The availability of highly-active antiretroviral therapy (HAART) has markedly improved the prognosis of HIV-positive patients , whereas the prevalence of PAH-HIV, estimated at 0.5%, is unchanged [6,8]. HAART has been suggested to improve survival of PAH-HIV patients [2,10], but its impact on severity and outcome of PAH remains controversial [11,12].
PAH therapy has also advanced in recent years , with the availability of targeted therapies such as prostanoids, phosphodiesterase type-5 inhibitors and endothelin receptor antagonists [5,14–20]. Evidence to support best management of PAH-HIV is however still lacking [21,22].
Characteristics and outcomes of patients with PAH-HIV in the current era of HAART and specific PAH therapies are unknown. The aims of the present study were to report characteristics of all consecutive patients referred to our institution with a diagnosis of PAH-HIV in the current therapeutic era; to describe long-term outcomes of these patients; and to identify prognostic factors.
Analyses were performed on patients admitted consecutively to our centre, from all over France, for initial evaluation of PAH during the study period (from October 2000 to January 2008), who were infected with HIV. Patients with potentially confounding associated risk factors for PAH were excluded from the present analysis.
PAH was diagnosed by right heart catheterization (RHC), defined as mean pulmonary arterial pressure (mPAP) at rest more than 25 mmHg, pulmonary capillary wedge pressure (PCWP) less than 15 mmHg and pulmonary vascular resistance (PVR) more than 250 dyn s/cm5. Acute vasodilator testing with inhaled nitric oxide was performed in all patients, as previously described . An acute response was defined as a decrease in mPAP more than 10 mmHg to less than 40 mmHg with normal or elevated cardiac output .
All clinical characteristics at diagnosis and follow-up were stored in the Registry of the French Network of Pulmonary Hypertension. This registry was set up in agreement with French legislation (French Commission Nationale de l'Informatique et des Libertés) and all patients provided written informed consent. This study was approved by the Ile de France VII/CHU Bicêtre Institutional Review Board.
Criteria for treatment
In the absence of specific recommendations for PAH-HIV, initiation of specific PAH therapies was guided by recommendations for idiopathic PAH  and physician's judgment. In patients not receiving HAART − defined as a combination of at least three drugs, including nucleoside reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors – at time of PAH diagnosis, HAART was initiated irrespective of HIV viral load or CD4+ lymphocyte count [2,10].
All patients received nonspecific supportive therapies in accordance with current guidelines, including oral anticoagulants to maintain an international normalized ratio of 1.5–2.5 (unless contraindicated), diuretics to control symptoms of right heart failure, and long-term oxygen therapy if hypoxemia was present [21,22,25]. Calcium-channel blocker therapy was initiated only in patients with an acute response to nitric oxide .
Evaluation and follow-up
Baseline evaluation included measurement of HIV parameters, New York Heart Association functional class (NYHA FC) assessment, nonencouraged assessment of 6-min walk distance (6MWD) and RHC. Assessment was repeated 3–6 months after initiation of therapy, and then 3–6 months after each change in therapeutic regimen or in the event of clinical deterioration. In addition, noninvasive assessments were repeated every 4–6 months thereafter and RHC was conducted annually.
Analysis was performed using Statview version 5.0 (SAS Institute, Cary, North Carolina, USA). Data were expressed as median [1st–3rd quartile] values. A nonparametric Kruskal–Wallis one way analysis of variance followed by a Mann–Whitney U-test was used for comparisons between the three groups of patients, according to baseline NYHA FC. A nonparametric Wilcoxon signed-rank test was used for comparisons between baseline values and those obtained at last evaluation on first-line therapeutic regimen, in the following groups and subgroups: patients who did and did not receive specific PAH treatment upon diagnosis of PAH (the ‘PAH therapy’ and ‘HAART only’ groups, respectively), and the subgroup of patients not initially on any antiretroviral therapy who were given HAART alone at PAH diagnosis. Chi-squared testing was used for comparisons of discrete data between two or more groups or subgroups.
Date of PAH diagnosis was used as the baseline for survival estimates. Patients lost to follow-up were censored at the date of last visit. Probability of survival in each group was calculated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors for survival were determined by performing univariate and multivariate analyses. Univariate analysis based on the proportional hazards model was used to examine the relationship between survival and selected demographics, medical history, and haemodynamic variables at time of PAH diagnosis. For continuous variables, patients were separated into two groups on both sides of the median value. The results were expressed as hazard ratios with 95% confidence intervals (CI). Multivariate analysis based on the Cox proportional hazards regression model was used to examine the independent effect of each variable on survival, controlling for possible confounders. Variables with P ≤ 0.10 in the univariate analysis without colinearity were included in the multivariate model.
Of 944 consecutive patients admitted to our centre for evaluation of PAH between October 2000 to January 2008, 122 (12.9%) were infected with HIV. Of these patients, 45 had associated risk factors for PAH other than HIV infection and were excluded from the present analysis. These patients comprises four with anorexigen exposure, three with congenital heart disease, 34 with cirrhosis and/or portal hypertension, and four with secondary causes of PAH, such as postembolic pulmonary hypertension (n = 2) and PAH secondary to primary lung disease (n = 2). The 77 remaining patients (8.2% of all patients seen during the study period) had HIV infection as their only PAH risk factor.
Patient characteristics at time of pulmonary arterial hypertension diagnosis
Patient demographics, clinical characteristics and haemodynamics are shown in Table 1. The most frequent risk factor for HIV was intravenous drug use (IDU; 36%). Thirty-eight patients (49%) had a history of viral hepatitis, but none had cirrhosis or portal hypertension. At time of PAH diagnosis, 38 patients (49%) had undetectable viral load (defined by HIV RNA < 50 copies/ml) and 61 (79%) had a CD4+ lymphocyte count more than 200 cells/μl. HIV infection at time of PAH diagnosis was discovered in only one patient. The duration of HIV infection before diagnosis of PAH was longer in patients in NYHA FC IV at PAH diagnosis compared with patients in FC II or III. The median time interval between onset of symptoms and diagnosis of PAH was 6 months [4–12].
The 62 patients receiving HAART at time of PAH diagnosis, did so in the following combinations; 37 (60%) two NRTIs and a protease inhibitor, nine (14%) three NRTIs, and 16 (26%) two NRTIs and a NNRTI. Thirty-four (55%) of these patients had undetectable viral load, and 50 patients (81%) had a CD4+ lymphocyte count more than 200 cells/μl.
Among the 62 patients already on HAART, 42 received specific PAH therapy after baseline evaluation, and 20 remained on HAART alone. HAART was initiated in the 15 patients not receiving it at PAH diagnosis (two NRTIs plus a protease inhibitor in all cases). At time of PAH diagnosis, these 15 patients had HIV load of 4.2 [3.4–4.8] log10 copies/ml and CD4+ cell count of 279 [120–500] cells/μl. Eight of these patients also received specific PAH therapy after baseline evaluation, seven received HAART alone.
At time of PAH diagnosis, 50 patients received specific PAH therapy, the remaining 27 patients did not. Baseline characteristics of both patient subgroups are shown in Table 2. Specific PAH therapy comprises intravenous epoprostenol in three patients; inhaled iloprost in one and bosentan in 45 patients. The only patient who responded acutely to nitric oxide was given a calcium channel antagonist.
Evolution on first-line therapeutic regimen
Evolution of the main functional and haemodynamic parameters from baseline to last evaluation is shown in Fig. 1. The seven patients not initially on any antiretroviral therapy and who were given HAART alone at PAH diagnosis remained on this treatment for 10 [5–41] months. In these patients, 6MWD increased by 18% [6–33%] (P = 0.04), but haemodynamic parameters did not change significantly, median change in cardiac index was −7% (range: −36%, 40%) and median change in PVR was +4% (range: −48%, 69%).
During follow-up of the 27 patients who were not given specific PAH therapy at PAH diagnosis, seven received bosentan, one received epoprostenol, and 19 received no specific PAH therapy. Among these 27 patients, 19 (70%) had undetectable viral load and 22 (83%) had a CD4+ lymphocyte count more than 200 cells/μl at last evaluation on first-line therapy.
Forty-two of 50 patients treated with specific first-line PAH therapy remained on monotherapy during follow-up. Treatment regimens were changed from epoprostenol to bosentan, epoprostenol to iloprost, bosentan to iloprost, and bosentan to sildenafil, respectively in each of four patients. Combinations of targeted therapies were given to two patients (epoprostenol or sildenafil added to bosentan in one patient each). Bosentan was discontinued due to elevation of liver enzymes in two patients (4.4%) who remained on HAART alone. Of these 50 patients, 39 (78%) had undetectable viral load and 44 (88%) had a CD4+ lymphocyte count more than 200 cells/μl at last evaluation on first-line therapy.
The patient with an acute response to inhaled nitric oxide at baseline was alive on calcium-channel blocker therapy at the study cut-off date (duration 93 months). Functional and haemodynamic parameters in this patient were improved at last evaluation compared with baseline.
At the cut off date (1st May 2008), the mean duration of follow-up was 41 [22–61] months. Forty-nine patients were alive, 26 had died, and two were lost to follow-up. Of the reported deaths, 15 were attributable to consequences of PAH (including right heart failure and sudden death), 11 were attributable to HIV infection or other diagnoses. Patients with poor HIV control were more likely to die from causes other than PAH; in the subgroup of patients with CD4+ less than 200 cells/μl at time of PAH diagnosis (n = 16), two died from PAH and eight from other causes. By comparison, 13 died from PAH and three from other causes in the subgroup of 61 patients with CD4+ more than 200 cells/μl (P < 0.01).
In the subgroup of patients who did not receive first-line specific PAH therapy (n = 27), 12 (44%) patients died: seven deaths were attributable to PAH, five to other causes. Fourteen (28%) of the patients who received specific PAH therapy first-line (n = 50), died: eight deaths were attributable to PAH, six to other causes.
Overall survival rates with 95% CI were 88% (81–95%), 84% (76–93%), 72% (62–84%), and 63% (50–75%) at 1, 2, 3 and 5 years, respectively (Fig. 2a). Survival was not statistically different between patients in NYHA FC II and III, and appeared dramatically worse for patients in NYHA FC IV (Fig. 2b).
Factors associated with mortality
On univariate analysis, a history of right-sided heart failure, baseline NYHA FC IV, and cardiac index less than 2.8 l/min per m2 (corresponding to the median value) were associated with poor survival. Two additional variables − a detectable HIV viral load and a CD4+ lymphocyte count less than 200 cells/μl − were significantly related to an increased risk of death (Table 3).
On multivariate analysis, only cardiac index less than 2.8 l/min per m2 and CD4+ lymphocyte count less than 200 cells/μl were independently related to poor survival (Table 3).
This study provides a full description and a comprehensive longitudinal analysis of a large population of PAH-HIV patients in the modern therapeutic era. The main observations of this study were that in PAH-HIV patients, long-term HAART without additional specific PAH therapy may improve 6MWD, but is unable to improve haemodynamic parameters in most patients, and that prognosis in PAH-HIV is mainly related to CD4+ lymphocyte count and cardiac function.
Our patient series represented 8.2% of all consecutive patients admitted to our centre for initial evaluation of PAH during the study period. These patients were referred to our centre from all over France and were therefore likely to be representative of the French PAH-HIV patient population. In a previous report of data collected from 17 French university hospitals (from October 2002–October 2003) 6.2% of all consecutive patients with PAH exhibited PAH-HIV (n = 42); 86% of these patients were followed at the French reference centre, and PAH-HIV patients represented 8.4% of all patients seen in the reference centre .
In our series, the proportion of patients with HIV infection via IDU was lower compared with previous PAH-HIV patient series [2,5,10]. IDU was the cause of HIV infection in about 35% patients in our series, which is more frequent than reported for HIV-infected patients without PAH . IDU acquired HIV infection was not found to be a factor associated with survival, in accordance with previous reports showing that these patients have no clinical, functional, or haemodynamic particularities compared with patients with PAH related to HIV infection from another route of transmission [4–6].
In contrast with previously reported series in which only a minority of patients received HAART and a majority had CD4+ lymphocyte counts less than 200 cells/μl at PAH diagnosis [2,5,7,8,10], most patients in our series were on HAART at diagnosis of PAH and had well controlled HIV infection. This observation confirms that PAH can develop in patients with well controlled HIV infection, and that HAART (including protease inhibitors) is unable to prevent the development of PAH in HIV-infected patients. In our series, haemodynamics at baseline tended to be less impaired compared with previous reports, although duration of HIV infection before PAH diagnosis was longer (approximately 5 years, 6.4 years and 11 years, in the series by Petitpretz et al. , Nunes et al. , and the current study respectively) and the time interval between the onset of symptoms and the diagnosis of PAH was similar (approximately 6 months) [2,5,7,8,10]. This suggests that HAART may help to delay and to attenuate the development of PAH in HIV-infected patients. This hypothesis is in line with recent data from the Swiss HIV Cohort Study, which showed a decline in the incidence of PAH-HIV from 0.21% in 1995 to only 0.03% in 2006 and an apparent reciprocal relationship between this decline and the increase in CD4+ cell counts observed over a similar period .
Presently, the effects of HAART on functional and haemodynamic parameters in PAH-HIV patients remain controversial. Barbaro et al.  observed that HAART improved 6MWD without significant changes in haemodynamics measured by RHC. In contrast, Opravil et al. and Zuber et al. [2,10] reported that HAART improved right ventricular systolic pressure over right atrial pressure measured by echocardiography. However, patients in these two studies did not have PAH confirmed by RHC [2,10], which is an important limitation of these studies . In this study, we report that long-term, first-line HAART (10 [5–41] months in 7 patients) improved 6MWD but had no significant effect on haemodynamic parameters measured by RHC. This result is in line with data from a 12-week study reported by Barbaro et al. . Individual data for seven patients also indicated that the effect of HAART on haemodynamic parameters was highly variable between patients, resulting in improvements or near-normalization in some cases, and stability or deterioration in others. This variability suggests that careful functional and haemodynamic follow-up might be warranted in PAH-HIV patients receiving first-line HAART without specific PAH therapy.
Guidelines are not currently available for specific PAH therapies in PAH-HIV . Contrary to previous recommendations , our data suggest that an acute vasoreactivity test with inhaled nitric oxide might be performed in all PAH-HIV patients at diagnosis of PAH, because long-term response to calcium-channel blockers, although less frequent than in other forms of PAH (one patient in our series), may be present in PAH-HIV. Our current practice is to only give continuous intravenous epoprostenol to patients in NYHA FC IV and patients remaining in NYHA FC III with low cardiac index on bosentan, sildenafil or both. In contrast with other patient series in which epoprostenol was the only available specific PAH treatment, bosentan was the first-line therapy given to patients in NYHA FC II–III with impaired cardiac index, and to patients in NYHA FC IV who refused or were unable to receive intravenous epoprostenol. Sildenafil was given to patients who did not tolerate bosentan, or given in combination with bosentan in cases of insufficient response to bosentan monotherapy. Patients in NYHA class II–III with normal or elevated cardiac index were not given specific PAH therapy. These patients (27/77) had very stable functional and haemodynamic parameters over a long period of time, strongly contrasting with the rapid worsening reported in historical series of patients who received neither HAART nor specific PAH therapy [7,8]. However, a recent controlled study indicated that if untreated, patients with mildly symptomatic PAH can progressively deteriorate, and that bosentan treatment of these patients can improve haemodynamics and prevent clinical deterioration .
The mean follow-up duration of 42 months in the present study allowed an adequate evaluation of survival. Survival estimates of 88, 72, and 63% at years 1, 3, and 5, respectively, are much better than those observed in previous PAH-HIV patient series [2,5,7]. Nevertheless, the current survival rate of patients without PAH-HIV after the first diagnosis of an AIDS-defining opportunist infection (approximately 85% at 5 years) is much higher than current survival of PAH-HIV patients with similar CD4+ cells counts . In line with previous series, 15 of the 26 deaths were caused by PAH [5,7]. On univariate analysis, we found that factors related to HIV control (i.e., CD4+ lymphocyte count and HIV load) and factors related to severity of PAH (i.e., history of right heart failure, NYHA FC and cardiac index) were associated with survival. Similar to observations in idiopathic PAH and portopulmonary hypertension, multivariate analysis found that preservation of right ventricular function (evidenced by an improved cardiac index) was independently associated with improved survival [29,30]. In accordance with the study by Nunes et al. , our multivariate analysis also indicated that a low CD4+ lymphocyte count was independently associated with poor survival. CD4+ lymphocyte count is a prognostic factor in HIV-infected patients without PAH , and in line with this, most deaths observed in patients with CD4+ less than 200 cells/μl were related to complications other than PAH.
There are some limitations to this study. It is a retrospective analysis with possible biases; particularly the existence of a specific impact of HAART on progression of PAH cannot be definitively excluded. For instance 45% of patients receiving HAART at PAH-HIV diagnosis had a detectable viral load, whereas only 25% on HAART had detectable viral load at last evaluation. A more effective HAART regimen could therefore have participated in the improvement of PAH. The specific effect of HAART on PAH needs evaluation in a long-term, placebo-controlled randomized trial in PAH-HIV patients, such a study would however be impossible for ethical reasons . PAH-HIV is a rare disease, thus patient numbers in subgroups of this study were small, and analyses of these may therefore be regarded cautiously. Given the complexity and frequent changes of antiretroviral drug regimens in HIV-infected patients, a drug–drug interaction may have had relevant consequences; the study was not designed to address this question. Adverse effects of specific PAH therapies were however infrequent in our population, bosentan was the only PAH-specific therapy discontinued for safety reasons, and at a similar frequency to that observed in patients with PAH due to other aetiologies . As the co-administration of protease inhibitors and sildenafil can increase serum sildenafil levels, protease inhibitors were avoided in the two patients in our series who received sildenafil . Additionally, the number of patients with undetectable viral load tended to increase, even in patients who received PAH specific therapy, suggesting the absence of an adverse effect of the association of antiretroviral drugs and PAH specific therapy on HIV control.
In summary, our data indicate that in the modern era of HAART and specific PAH therapy, survival of PAH-HIV patients was dramatically improved compared with all previous series. However, PAH remains a complication of HIV infection that burdens the prognosis of HIV-infected patients. Data from the current series indicate that HAART is very unlikely to improve haemodynamic parameters in PAH-HIV patients. Whether specific PAH therapy might be of benefit to HIV-infected patients with mildly symptomatic PAH remains to be determined and should stimulate future studies.
All authors participated in the design of the study. B.D. and M.G. performed data collection. B.D., M.G., D.M., G.S., M.H. and O.S. participated in data analysis and interpretation. B.D. prepared the article, which was circulated among all co-authors. A final draft was prepared incorporating the suggestions from all authors. The authors thank Dr Mohammed Bennaceur and Ms Laurence Rottat from the Department of Clinical Research of the Antoine Béclère Hospital for technical assistance. Editorial support was provided by Elements Communication Ltd, funded by Actelion Pharmaceuticals, France.
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