Jarrett2017

CE: Swati; COH/120613; Total nos of Pages: 6;
COH 120613
CURRENT
OPINION HIV-associated pulmonary hypertension
Harish Jarrett and Christopher Barnett
Purpose of review
HIV-associated pulmonary arterial hypertension (HIV-PAH) is a well-recognized severe cardiovascular
complication of HIV infection that confers an adverse prognosis irrespective of the stage of disease. This
review will summarize the available data on HIV-PAH epidemiology and provide insights into the
pathophysiology and therapeutic strategies currently available.
Recent findings
Patients with HIV are several thousand times more likely to develop HIV-PAH compared to the incidence of
idiopathic PAH. Several HIV viral proteins are implicated in the pathogenesis although the exact
mechanism remains unknown. In the past two decades, there have been several new treatment strategies
that appear effective in treating HIV-PAH. Novel pathophysiologic mechanisms implicating the transforming
growth factor b receptor family may offer novel therapeutic targets in the future.
Summary
As antiretroviral therapy continues to improve health outcomes for patients with HIV, there needs to be a
shift in focus of care toward chronic noncommunicable diseases. Among cardiovascular disease-
complicating chronic HIV infection, HIV-PAH is a severe progressive disease that leads to right heart failure
and death. Currently available treatment strategies are effective, however, furthering our understanding of
HIV-PAH will be critical as it is likely to become the commonest cause of PAH worldwide.
Keywords
AIDS, HIV, pulmonary hypertension
INTRODUCTION
HIV surveillance programs estimate that globally
there are over 36 million people infected with
HIV and over 1 million people living with HIV in
the United States [1]. The introduction of highly
active antiretroviral treatment (HAART) has resulted
in a dramatic decline in mortality, a reduction in the
number of acquired immunodeficiency syndrome
and improved long-term survival [2]. This has ush-
ered in a new era for infected individuals who are
increasingly likely to encounter non-AIDs-related
chronic conditions as they live longer [3–5]. The
risk of developing cardiovascular disease is amplified
in these patients due to HAART-associated dyslipi-
demias and insulin resistance as well as the direct
toxic effects of HIV which results in chronic endo-
thelial dysfunction, impaired fibrinolysis and a
chronic inflammatory state [6].
HIV-associated pulmonary arterial hypertension
(HIV-PAH) is a well-recognized cardiovascular com-
plication of HIV infection that is associated with
significant mortality [7]. A prevalence of 0.46% in a
contemporary European cohort suggests that HIV-
PAH could potentially be one of the most common
causes of PAH. As access to HAART continues to
improve [8], a major shift in the cause of death from
infectious to noninfectious diseases is expected
worldwide [9] and HIV-PAH is likely to become a
global healthcare concern in the future.
EPIDEMIOLOGY
Contemporary data suggest that the prevalence of
HIV-PAH is 0.46% (95% confidence interval 0.32–
0.64) [10]. Prospective study of 7648 individuals in
France with HIV who were identified with unex-
plained dyspnea were evaluated with an echocardio-
gram and pulmonary artery catheterization (PAC) to
evaluate for PAH. To date, this remains the largest
study undertaken to understand the prevalence of
HIV-PAH and the only study to use PAC to establish
a diagnosis of PAH. The earliest available data drawn
Medstar Heart and Vascular Institute, Washington, District of Columbia,
USA
Correspondence to Christopher Barnett, Medstar Heart and Vascular
Institute, 110 Irving St NW, Washington, DC 20010, USA.
E-mail: Christopher.Barnett@medstar.net
Curr Opin HIV AIDS 2017, 12:000–000
DOI:10.1097/COH.0000000000000418
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REVIEW
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

COH 120613
from 1200 untreated patients in Switzerland
screened with echocardiography yielded a similar
prevalence of 0.5% [11].
A higher prevalence of PAH is seen when echo-
cardiography is used as the sole diagnostic modality.
In a study of 196 patients in San Francisco General
Hospital where tricuspid regurgitant jet velocity
(TRV) and right atrial pressure were used to estimate
pulmonary artery systolic pressure (PASP), HIV-
infected patients had significantly higher PASP
(median 27.5 mmHg; interquartile range 22–32.5
mmHg) compared to age matched controls (median
22 mmHg; interquartile range 18–25 mmHg). The
study adjusted for age, sex, cigarette smoking, stim-
ulant drug use and injection drug use and revealed
that HIV patients had an increase of 5.1 mmHg in
their mean PASP and were seven times more likely to
have a PASP greater than 30 mmHg (P < 0.001) [12].
Another multicenter cohort of 656 HIV-infected
patients in the United States screened echocardiog-
raphy demonstrated that 57% of patients had evi-
dence of right ventricular pressure greater than 30
mmHg [13]. Quezada et al. [14] demonstrated that
the prevalence of PAH in a cohort of HIV-infected
patients in Spain approached 10% where PAH was
defined as a TRV greater than 2.8 m/s. Similarly,
echocardiographic evaluation of patients attending
HIV clinic in the United States showed that 9.3% of
patients had a TRV greater than 2.5 m/s [7].
PATHOGENESIS
The exact pathogenic mechanism that links HIV to
PAH is not known. Histologically, the features of
concentric intimal fibrosis, medial hypertrophy and
plexiform lesions are seen in up to 78% of patients
with HIV-PAH [15], and this closely resembles
changes seen in noninfectious causes of PAH [16].
Direct cellular infection is unlikely as HIV-1 RNA or
DNA is not seen in human pulmonary vasculature
[17]. The pulmonary endothelium does appear
to serve as a site for antigen presentation which
directly stimulates abnormal apoptosis, growth
and proliferation which can lead to PAH. The HIV
viral protein Gp120 is implicated in HIV-PAH path-
ogenesis as it stimulates the release of a proinflam-
matory cytokine cascade which has proliferative
effects on vascular smooth muscle [18]. Further-
more, it has been shown to target human lung
endothelium, stimulates the secretion of the potent
vasoconstrictor endothelin-1 and increases markers
of apoptosis [17].
Bone morphogenic protein-2 and protein-4 are
members of the transforming growth factor (TGF)
system that have antismooth muscle cell growth
and proliferation effects [19]. TGF-b activation on
the other hand stimulates vasculogenesis, intimal
hyperplasia and medial smooth muscle growth [20].
The observation that specific mutations lead to PAH
provides key insights into the interplay between
bone morphogenic protein receptor-2 (BMPR-2)
and other TGF-b family proteins. Loss of function
mutations in BMPR-2 are associated with familial
PAH [21]. Patients with the gene mutation princi-
pally responsible for hereditary hemorrhagic telan-
giectasia, in activin receptor-like kinase 1, another
member of the TGF-b family, also develop PAH. It
appears that BMPR-2 opposes competing TGF-b sig-
naling thereby preventing the proproliferative
effects of TGF-b [22]. In-vitro BMPR-2 gene expres-
sion is repressed within human macrophages by
transcriptional trans-activator (Tat), a protein
secreted by HIV-infected cells that affects down-
stream BMP-BMPR-2 transcriptional regulation in
a dose-dependent fashion [21]. Exogenous Tat also
stimulates endothelial cell-mediated growth factor
release and induces the production of reactive oxy-
gen species (ROS) [21,23
&
], adding credence to the
hypothesis that HIV viral proteins alter BMPR sig-
naling and endothelial function in ways that can
lead to the development of PAH.
Negative factor (nef), a critical protein encoded
by HIV and Simian Immunodeficiency Virus (SIV)
that plays a role in host cell signaling [24], is seen in
pulmonary and vascular cell types [25]. Primates
infected with SIV-expressing nef develop plexiform
lesions compared to non nef-expressing SIV infec-
tions; colocalization of HIV-nef has been demon-
strated in pulmonary arterial endothelium of
patients with HIV-infected patients with PAH but
not in those without HIV or in those with idiopathic
PAH. Ten genetic polymorphisms in nef have been
demonstrated in patients with HIV which confers a
12-fold increased risk of developing PAH [26].
KEY POINTS
HIV-related proteins and inflammation are implicated
in HIV-PAH conferring a 1000-fold higher risk than the
general population.
The presence of unexplained dyspnea should trigger
evaluation for HIV-PAH including hemodynamic
assessment with PAC.
Once diagnosed, specific therapy should be promptly
initiated by a clinician with the requisite expertise in
PAH.
Furthering our mechanistic understanding of HIV-PAH,
particularly in relation to the role of TGF-b and BMPR2,
is an area that could provide insights into novel
therapeutic targets.
Cardiovascular disease in HIV-infected persons
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COH 120613
HIV-related chronic inflammation and immune
activation may also play a role in HIV-PAH patho-
genesis. There are demonstrably elevated levels of
inhibitors of nitric oxide synthase such as asymmet-
ric dimethylarginine and interleukin-6 in HIV-
infected individuals, findings that have been linked
to elevated pulmonary artery pressures [27].
Concurrent use of stimulants, especially
cocaine, has significant pathogenic effects on pul-
monary vascular endothelium which enhances HIV-
related pulmonary vascular remodeling [28]. In a
similar fashion to Tat, cocaine induces ROS produc-
tion which disrupts cellular tight junctions which
leads to endothelial dysfunction. It also affects the
BMPR axis by enhancing platelet-derived growth
factor signaling, which leads to maladaptive prolif-
eration of pulmonary endothelial cells.
CLINICAL PRESENTATION AND
DIAGNOSIS
The clinical presentation of HIV-PAH can be with
nonspecific and insidious symptoms which can
often be mistakenly attributed to HIV itself. The
resulting lag in diagnosis from time of presentation
can be up to 2 years. The most common presenting
symptoms noted in a series of patients with HIV-
PAH were progressive dyspnea (85%), pedal edema
(30%), nonproductive cough (19%), fatigue (13%),
presyncope and syncope (12%) and chest pain (7%)
[15].
Physical examination is typically unremarkable,
but features of right-sided heart failure and volume
overload may be apparent in advanced cases [15].
The lung examination is usually normal and abnor-
mal findings usually indicate an alternative or con-
current diagnosis. The electrocardiogram may show
evidence of right ventricular hypertrophy with right
axis deviation and right atrial enlargement. Chest
radiography can show the evidence of right ventric-
ular and pulmonary artery enlargement with nor-
mal lung fields. In patients who have signs and
symptoms suggestive of HIV-PAH, the next step in
evaluation will be transthoracic echocardiography
(TTE).
Employing TTE as a screening tool in asymp-
tomatic HIV-infected patients for the presence of
PAH does not appear to be a beneficial or cost-
effective strategy [29]. Accurate PASP measurement
with TTE relies on the precise measurement of peak
TRV. The absence of tricuspid regurgitation, pres-
ence of very large or eccentric jets affect the reliabil-
ity of this method of PASP assessment and the
presence of a low PASP does not exclude the diag-
nosis of PAH (Fig. 1) [30]. Furthermore, the accuracy
and sensitivity of Doppler TTE is poor compared to
the gold standard of invasive assessment with PAC
[31] with inaccurate PASP estimates in 19.7% of
cases and misclassification of one in three patients
with HIV-PAH [32]. Despite the limitations of using
TRV for definitive diagnosis, ancillary anatomic
findings on TTE such as atrial enlargement, abnor-
malities related to right ventricle size and function
can help guide the clinician toward a possible diag-
nosis of PAH. Pulsed wave Doppler analysis provides
an accurate assessment of PASP independent of TRV
[33] and should be utilized when obtaining TRV is
not possible. Examination of right ventricular out-
flow tract Doppler flow velocity envelopes can be
extremely insightful; the presence of mid-systolic
notching and a decrease in the mid-systolic deceler-
ation time closely correlate with the presence of
PAH as well as adverse outcomes [34].
PAC is required for definitive diagnosis and is
mandatory prior to the initiation of PAH-specific
therapy. Accurate hemodynamic assessment is crit-
ical and should be performed by a clinician with
expertise in hemodynamic assessment including
maneuvers such as fluid challenges or exercise
which can unveil occult left ventricular diastolic
dysfunction, a common diagnosis in patients
infected with HIV [35].
TREATMENT
Antiretroviral therapy
Current guidelines recommend that all patients
infected with HIV receive treatment with HAART
regardless of CD4 T-cell counts and viral load
FIGURE 1. Schematic representation of temporal changes in
hemodynamics over the course of pulmonary arterial
hypertension. Reproduced with permission from the
European Respiratory Society [30].
HIV-associated pulmonary hypertension Jarrett and Barnett
1746-630X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-hivandaids.com 3

COH 120613
[36,37]. The efficacy of HAART as it pertains to HIV-
PAH remains unclear. In a murine model of PAH,
protease inhibitors reversed hypoxia-induced PAH
[38]. Retrospective analyses have demonstrated the
reduced incidence of HIV-PAH in the post HAART
era [39,40]. Degano et al. [41] showed that patients
diagnosed with HIV-PAH after 1995 had improved
survival and those with higher CD4 cell counts had a
lower incidence of HIV-PAH. In a comparison of
patients treated with HAART alone versus HAART
and specific PAH therapies, 6-min walk distance
improved in those treated with HAART alone, with-
out a significant improvement in hemodynamics
[41]. The retrospective observational nature of
these studies precludes definitive conclusions from
being drawn and it is widely accepted that HAART
alone is not sufficient for patients who develop
HIV-PAH.
Conventional pulmonary artery systolic
pressure therapy
The first presentation of HIV-PAH can range from
the asymptomatic outpatient to those with cardio-
genic shock from acute decompensated right heart
failure. Appropriate and timely triage to an ICU for
PAC-guided management is critical in this cohort of
patients with high acute morbidity and mortality.
Diuretic therapy remains a mainstay in patients
with evidence of volume overload. Supplemental
oxygen should be used to improve hypoxemia-
mediated pulmonary vasoconstriction both acutely
and long term. Digoxin can be considered in
patients with acute right heart failure and as first-
line therapy in patients with atrial arrhythmias. As
with all PAH patients, a favorable response to acute
vasodilator challenge must be demonstrated prior to
the initiation of oral calcium-channel blockers. This
response has been rarely demonstrated in patients
with HIV-PAH [41–43] and as such, calcium channel
blockers should be used with caution when there is
clear diagnostic certainty.
Pulmonary artery systolic pressure-specific
therapy
Retrospective cohort studies suggest that patients
treated with specific PAH therapies in addition to
HAART have better survival. Few trials exist where
HIV-PAH patients are the main study cohort, and as
a result, treatment algorithms are often extrapo-
lated from studies of other populations [44] and
great care must be taken with treatment decisions
given the potential for significant adverse drug
interactions between classes of HAART and PAH-
specific therapies.
Phosphodiesterase inhibitors
Favorable results have been reported with the treat-
ment of HIV-PAH with phosphodiesterase inhibitors
[45,46]. Sildenafil and tadalafil metabolism depends
on cytochrome P450 CYP3A4 and CYP 2C9 which
are inhibited by ritonavir and other protease inhib-
itors. Significantly elevated serum sildenafil levels
have been demonstrated with concurrent adminis-
tration of indinavir, saquinavir and ritonavir
[47,48]. The clinical relevance of this finding is
unclear as pharmacokinetic studies do not demon-
strate associated hypotension [48], and successful
concurrent use of ritonavir and sildenafil has been
reported [49,50]. Serum tadalafil levels appear to be
less affected by coadministration of protease inhib-
itors, but dose reductions should be considered with
coadministration of ritonavir and tipranavir [51].
Endothelin receptor antagonists
Bosentan (nonselective) and ambrisentan (selective)
block endothelin receptors and have favorable
effects on hemodynamics and exercise capacity in
patients with PAH. Bosentan has been prospectively
studied in 16 patients with HIV-PAH in the
BREATHE-4 trial. After 16 weeks of therapy, New
York Heart Association (NYHA) classification
improved by at least one in 14 patients, significant
improvements in cardiac index (þ0.9 0.7 l/min/
m2
) and reduction in mean PASP were noted and
6MWD improved by 91 60 m. Similar findings
have been demonstrated in 59 patients taking
bosentan for a median of 29 weeks where improve-
ments were seen in symptoms, exercise tolerance
and hemodynamic parameters [52]. Further open-
label study of bosentan þ HAART compared to
HAART alone showed that exercise capacity
improves (15%; range 5–32%, P 0.01), mean PASP
decreases (21%; range 4–38%, P 0.001) and greater
improvements in NYHA functional class (78 versus
33%, P 0.01) are seen [53]. Ambrisentan, although
not specifically studied in patients with HIV-PAH,
appears to have similar efficacy to bosentan and a
more favorable side-effect profile with less liver
function test abnormalities [54,55]. A total of 17
HIV-PAH patients were included across AMB 220,
ARIES-1 and ARIES-2 with two patients discontinu-
ing the drug because of adverse effects [56,57].
Finally, pharmacokinetic studies suggest no signifi-
cant interaction with ritonavir [58,59].
The AMBITION trial evaluated the efficacy
and safety of initial combination therapy with
oral ambrisentan and tadalafil as compared to
monotherapy with either agent in a randomized
double-blind trial involving 500 patients. The like-
lihood of achieving a composite outcome of clinical

COH 120613
failure was significantly lower with upfront combi-
nation therapy [60

]. Nine patients with HIV-PAH
were enrolled in the trial with five receiving combi-
nation therapy and although the number of HIV-
PAH patients is too small for meaningful analysis,
upfront combination therapy will likely be increas-
ingly used in clinical practice.
Prostacyclin Analogues No dedicated trials have
been performed in HIV-PAH patients. The largest
case series reported by Nunes et al. [61] followed 20
patients with NYHA functional class III or IV symp-
toms treated with intravenous epoprostenol therapy
ranging from 6 to 47 months. After 3 months of
therapy, they demonstrated significant improve-
ments in 6MWD (mean increase of 183 m from
baseline), mean PASP, cardiac index and pulmonary
vascular resistance (PVR). Other small series by Agui-
lar et al. [42] (six patients receiving intravenous
epoprostenol) and Cea-Calvo et al. [62] (three
patients receiving subcutaneous treprostinil) dem-
onstrated favorable outcomes. Intravenous or sub-
cutaneous delivery requires the use of an indwelling
catheter which is a major drawback as it increases
the risk of catheter-related infections and has the
potential to be abused as a mode for injection
drug use.
Inhaled prostacyclin analogues (iloprost) offer
alternate delivery method, although the experience
in patients with HIV-PAH is limited to eight patients
in whom inhaled iloprost decreased PVR by 31% and
improved cardiac index by 21% without significant
adverse events.
The first-in-class oral selective prostacyclin
receptor agonist selexipag was studied in a phase
3, randomized, double-blind placebo-controlled
trial of 1156 patients of whom 10 were diagnosed
with HIV-PAH [63

]. Despite an overall favorable
outcome overall, the small number of HIV-PAH
patients precludes any meaningful conclusions
being drawn in this specific population.
CONCLUSION
The presence of PAH is an independent risk factor
for mortality in patients with HIV infection. As we
shift our focus toward the chronic noninfectious
complications of HIV largely because of the success
of HAART, the presence of new or unexplained
dyspnea should trigger evaluation for HIV-PAH
including hemodynamic assessment with PAC.
HIV-PAH should be managed by a clinician with
expertise in the management of PAH in collabora-
tion with HIV specialists. HIV is undoubtedly a risk
factor for developing PAH and although to-date the
exact mechanism remains unknown, HIV proteins,
chronic immune activation and concurrent drug
effects are implicated in studies to date. The role
of TGF-b and BMPR2 family of receptors in the
development of PAH is an area of active exploration
that will further our mechanistic understanding of
this highly morbid condition and hopefully present
new therapeutic targets in the future.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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