PREVALENCE AND CORRELATES OF PULMONARY HYPERTENSION IN

HIV INFECTED NIGERIAN PATIENTS ATTENDING A TERTIARY

HOSPITAL: AN ECHOCARDIOGRAPHY-BASED STUDY.

DISSERTATION SUBMITTED TO NATIONAL POSTGRADUATE

MEDICAL COLLEGE OF NIGERIA IN PARTIAL FULFILMENT OF THE

AWARD OF FELLOWSHIP IN THE FACULTY OF INTERNAL MEDICINE

(CARDIOLOGY).

By

ELUOGU Chinedum Obiora

MBBS (NAU) 2004

DEPARTMENT OF MEDICINE, LAGOS UNIVERSITY TEACHING

HOSPITAL, IDI-ARABA, LAGOS.
NOVEMBER 2017

i
 CERTIFICATION

a) Head of Department’s name:

Year of Fellowship:

Signature and date:

b) First supervisor’s name:

Year of fellowship:

Signature and date:

c) Second supervisor’s name:

Year of fellowship:

Signature and date:

d) Candidates name:

Signature and date:

ii
 DEDICATION
This work is dedicated to Almighty God who has continued to guide, protect and bless my

efforts in life.

iii
 ACKNOWLEDGEMENT

My gratitude goes to my wife and children for their support during my Residency programme.

My gratitude also goes to Dr J. N. Ajuluchukwu. My Supervisor, Professor of Medicine and

Head of Department who supervised & guided me through this work and training as a

Cardiology Resident.

My gratitude also goes to Dr A. Mbakwem, Professor of medicine, who supervised this work

and trained me as a Cardiology Resident.

I appreciate Dr C. Amadi, my Supervisor and Dr Olusegun-Joseph who also supervised this

work and trained me as a Cardiology Resident.

I also appreciate Dr Ale, Dr Adegoke and other Consultants in medicine department for their

contribution in my training as a Cardiology Resident.

I deeply appreciate my Cardiology and other Residents whose discussions helped in the

knowledge acquired.

Special thanks to the UNILAG Medical students for allowing me teach them and remember

what was learnt.

Special thanks also to the Matrons at the cardiovascular laboratory for their assistance at the

echocardiography room during this study.

May God reward, bless and protect you all in Jesus name. Amen.

iv
 TABLE OF CONTENTS

Title Page.......................................................................................................... i

Certification...................................................................................................... ii

Dedication......................................................................................................... iii

Acknowledgment............................................................................................... iv

Table of Content................................................................................................ v

Abstract.............................................................................................................. vii

Glossary of Abbreviation.................................................................................... ix

List of Tables....................................................................................................... xi

List of Figure……………………………………………………………………. xiii

CHAPTER ONE: INTRODUCTION

1.1: Introduction …………………………………………………………………. 1

1.2: Justification …………………………………………………………………. 4

1.3: Objectives …………………………………………………………………… 6

CHAPTER TWO: LITERATURE REVIEW

2.1: Introduction. 7

2.2: Epidemiology of HIV associated Pulmonary Hypertension. 12

2.3: Pathogenesis of HIV associated Pulmonary Hypertension. 17

2.4: Clinical presentation of HIV associated Pulmonary Hypertension. 20

2.5: Diagnosis of HIV associated Pulmonary Hypertension. 22

2.6: Treatment of HIV associated Pulmonary Hypertension. 26

v
CHAPTER THREE: MATERIALS AND METHODS

3.1: Place of study. 33

3.2: Ethical consideration. 33

3.3: Study design. 33

3.4: Inclusion criteria. 34

3.5: Exclusion criteria. 34

3.6: Sample size. 35

3.7: Equipment, procedures and measurements. 35

3.8: Data analysis. 42

CHAPTER FOUR

4.0: Results. 43

5.0: Discussion. 61

6.0: Conclusion. 74

7.0: Limitations. 75

8.0: Recommendations. 75

Reference 76

Appendix

vi
 SUMMARY

BACKGROUND

Pulmonary Arterial Hypertension (PAH) is a life threatening condition whose prevalence is

much higher in persons living with HIV. Life expectancy from diagnosis varies from 6 months

to one year. Transthoracic echocardiography is a well validated tool for PAH screening. The

aim of this study was to establish the prevalence and correlates of PAH in HIV positive patients.

METHODS

Consecutive HIV-infected individuals attending the APIN clinic, LUTH, Lagos, during year

2015 to 2016 who met the inclusion and exclusion criteria were selected. Demographic and

clinical data were recorded and a Transthoracic echocardiography was performed in the study

participants and control. PAH was considered when pulmonary artery systolic pressure was

more than 36 mmHg. Two hundred and forty subjects in 3 groups of 80 each were studied. The

groups were: HIV positive HAART experienced (HE) group, HIV positive HAART naïve

(HN) group and HIV negative CONTROL group. They were age (p=0.98) and sex (p=0.89)

matched.

RESULT

Mean age was 47.51±9.06, 45.11±9.22 and 44.66±9.03 for the HE, HN and CONTROL groups

respectively (p=0.98). Of the 160 HIV positive participants (HE plus HN groups), 48% was

male while 47% was male in the CONTROL group of 80 HIV negative subjects. Post-diagnosis

period ranged from 1-17 years (median 6.0, IQR 3.0-10.0) for the HE group and 1- 8 years

(median 4, IQR 3.0-10.0) for the HN group (p=<0.00). The duration of therapy for HE group

ranged from 1-16 years (median 5, IQR 3.0-10.0) Compared to the HN group, the HE group

had a higher mean BMI (26.54±6.24 vs 24.32±4.89) and SBP (143.66±29.92 vs 124.43±13.82).

vii
In the HIV positive group, SBP was the clinical variable that had correlation with PAH and

this was in the HN group. There was no correlation between age and sex with PAH though

78% of the HIV positive population with PAH was female.

In univariate analysis, PAH had correlation with some echocardiographic variables in both the

HE and HN groups though the relationship was weak. In the HE group, these included RVOT

(r=0.23; p= 0.04) and MPI (r=0.28; p=0.01) while in the HN group the variables included ERV

(r=0.46; p=0.001), RAA (r=0.24; p=0.04) and RVOT-AT (r=0.26; p=0.02). No clinical or

echocardiographic variable had independent relationship with PAH on multiple linear logistic

regression analysis.

PAH was diagnosed in 9 (5.6%) of HIV positive subjects, 7 (78%) were females giving a

female to male ratio of 3.5: 1. The 9 subjects were all middle aged. In the HE group, 5 (6.2%)

subjects had PAH while 4 (5%) subjects had PAH in the HN group. Subjects in the CONTROL

group had normal clinical and echocardiographic variables.

CONCLUSION

The prevalence of HIV-aPAH is 5.6% (HE plus HN groups). The prevalence in HE (6.2%) and

HN (5%) subgroups are comparable. PAH has significant correlation with SBP, RVOT, ERV

and RVOT-AT and MPI in the HIV positive groups. This information will prove useful in the

follow up and management of HIV patients and also provide data for further longitudinal

studies.

viii
 GLOSSARY OF ABREVIATIONS

APIN: AIDS Prevention Initiative Nigeria.

ART: Antiretroviral Therapy

ARV: Antiretroviral drugs.

BMI: Body Mass Index.

CTEPH: Chronic thromboembolic pulmonary hypertension

DBP: Diastolic Blood Pressure.

ERV: Estimated Right Ventricular diameter.

FAC: Fractional Area Change.

HAART: Highly Active Anti-Retroviral Therapy.

HE: HAART experienced.

HN: HAART naïve.

HREC: Health Research and Ethical Committee

HIV: Human Immunodeficiency Virus.

HIV-aPAH: Human Immunodeficiency Virus associated Pulmonary Arterial Hypertension.

IVC: Inferior vena cava.

IDU: Intravenous drug use.

mPAP: Mean Pulmonary Artery Pressure

MPI: Myocardial Performance Index

PSAX: Parasternal short axis

PAH: Pulmonary Arterial Hypertension.

PASP: Pulmonary Artery Systolic Pressure.

PH: Pulmonary Hypertension.

PI: Protease Inhibitor

PR: Pulse Rate.

ix
r: Spearman’s rho coefficient

RAA: Right Atrial Area.

RAP: Right Atrial Pressure.

RVOT: Right Ventricular Outflow Tract.

RVOT AT: Right Ventricular Outflow Tract Acceleration Time.

SCOPE: Study of the Consequences of the Protease Inhibitor Era.

SBP: Systolic Blood Pressure.

Sm: Systolic motion

TAPSE: Tricuspid Annular Plane Systolic Excursion

TR Vmax: Peak Tricuspid Regurgitant flow velocity.

x
 LIST OF TABLES

PAGE

Table 1: Comparison of clinical and Anthropometric variables among the study groups 44

Table 2: Comparison of selected Right Ventricular echocardiographic variables of the

study groups 47

Table 3a: Comparison of PASP across the 3 groups. 49

Table 3b: Comparison of PASP between HIV positive and HIV negative groups. 50

Table 4: Relationship between presence of clinical symptoms and Pulmonary Arterial

Systolic Pressure among HIV patients. 52

Table 5: Relationship between Socio-Demography/Physical measurements and PASP

among HAART experienced and HAART naive HIV subjects. 53

Table 6: Spearman’s correlation showing relationship between PASP, Clinical and 58

Echocardiographic variables among HIV patients on HAART and HAART Naïve.

Table 7a: Comparison of echocardiographic correlates between HAART experienced

and HAART naïve patients. 60

xi
 LIST OF FIGURES

Figure 1: Duration of diagnosis of HAART experienced and HAART naïve subjects 45

Figure 2: Scatter diagram of relationship between systolic blood pressure and

PASP in the HAART experienced group. 55

Figure 3: Scatter diagram of relationship between systolic blood pressure and

PASP in the HAART naïve group. 56

Figure 4: Scatter diagram of relationship between systolic blood pressure and

PASP in the control group. 57

xii
 CHAPTER ONE

1.1 INTRODUCTION

Human immunodeficiency virus (HIV) infection is a pandemic affecting approximately 34

million people worldwide, with an estimated 2 million deaths annually.1 The prevalence of HIV

infection in sub-Saharan Africa is 5% affecting about 22.9 million adults with mortality of 1.2

million annually.2 Mortality has risen in Sub-Saharan Africa where modern healthcare is less

accessible to many.3 In Nigeria, the prevalence of HIV infection is 4.1% affecting about 3.1

million adults.4

HIV affects many systems in the body including the cardiovascular system.5 The mechanisms

of HIV-induced cardiovascular diseases could be direct6,7 or indirect.5,8 Direct mechanism

includes direct toxicity of the virus to the myocardium as evidenced by isolation of the virus

from the myocardium at autopsy.6,7 Indirect mechanisms are via opportunistic viral, fungal and

protozoal infections; induction of chronic inflammation with release of cytokines; malignant

neoplasms and their treatment, all of which affect the heart adversely.5,8

Cardiovascular manifestations of HIV infection have been altered by the introduction of highly

active anti-retroviral therapy (HAART). The number of patients in need of HAART is about

1.5 million and the number on it is 359,181.9 On one hand, HAART has significantly modified

the course of HIV disease, lengthened survival and improved the quality of life of HIV-infected

patients.7 Also, Zuber et al10 in their study on ‘Pulmonary arterial hypertension related to HIV

infection’ documented improved haemodynamics and survival on treatment with HAART. On

the other hand, approximately 50% of HIV-infected people treated with HAART develop a

cluster of peripheral metabolic complications that include cardiovascular disease risk factors

such as dyslipidemia11,12, peripheral insulin resistance13 and elevated blood pressure14 which

are associated with an increase in both peripheral and coronary arterial diseases.7 HAART

components, especially nucleoside reverse transcriptase inhibitors, are associated with a

1
myocardial mitochondrial toxicity15 that may impair myocardial fatty acid metabolism in HIV

infected patients. Both HIV infection and HAART are associated with a pro-inflammatory state

which further increases cardiovascular disease risk.16 Pugliese et al17 in their study on ‘Impact

of HAART in HIV-positive patients with cardiac involvement’ reported an increased incidence

of pulmonary arterial hypertension (PAH) in patients who received HAART. Another study by

Nunes et al.18 in Prognostic factors for survival in human immunodeficiency virus-associated

pulmonary arterial hypertension showed that survival was worse in patients who were started

on HAART in the absence of therapy with epoprostenol. Hence, while HAART could be

beneficial to the cardiovascular system, it can also be toxic to it.

Although not fully appreciated in the early days of HIV epidemic, cardiac involvement has

been reported with increased frequency in recent years.19,20,21,22,23 The documented cardiac

diseases include pericardial effusion, myocarditis, endocarditis, dilated cardiomyopathy, left

ventricular dysfunction, pulmonary hypertension, coronary artery disease, malignant

neoplasm, and drug related cardiotoxicity.24,25

Pulmonary hypertension in HIV infected population is classified under group 1 of the Updated

Clinical Classification of Pulmonary Hypertension (Nice, France 2013) as one of the diseases

associated with Pulmonary Arterial Hypertension (PAH).26 The association between PAH and

HIV infection is well established.27 Pulmonary hypertension (PH) is a disease characterized by

vasoconstriction, proliferation and remodelling of the pulmonary vascular wall that result in

progressive increase in vascular resistance, right heart failure and eventually, death.28,29 HIV-

associated PAH (HIV-aPAH) exists when PAH develops in a patient who has the human

immunodeficiency virus (HIV) infection and an alternative cause cannot be identified.30

The documented prevalence of HIV-aPAH varied from place to place for example 10% in

Spain31 to 38.5% in Ghana.32 HIV-aPAH occurs at all stages of HIV infection and does not

2
seem to be related to the degree of immune deficiency5 as no relationship has been established

between either CD4 count or the stage of HIV infection and the prevalence or severity of

pulmonary hypertension. PAH is an independent risk factor for mortality in HIV infected

population with a mean survival time of 6 months from diagnosis.34,35

Clinical features of HIV-aPAH are related to the degree of pulmonary hypertension and vary

from a mild asymptomatic condition to severe cardiac impairment with cor-pulmonale and

death.34,35 They include progressive shortness of breath, cough, fatigue, syncope, chest pain

and features of right heart failure like pedal oedema with cardiac impairment.34,37 Laboratory

features frequently seen in HIV-aPAH include cardiomegaly and prominent pulmonary artery

on chest X-ray; right ventricular hypertrophy and right axis deviation on electrocardiogram;

right ventricular myocardial hypertrophy and abnormal septal motion on echocardiography.34,38

Some factors and co-morbidities associated with HIV-aPAH include prolonged intake of anti-

retroviral drugs (ARV),39 older age39, sex,31 intravenous drug use,31 treatment with factor

VIII,40 uncontrolled HIV replication,31 chronic hepatitis C infection31 and chronic liver

disease.41

The use of echocardiography in investigating and diagnosing cardiovascular diseases,42

including PAH,43,44,45,46 has been well validated. Echocardiography is very helpful in detecting

cardiac dysfunction at an early stage, even if clinically silent/asymptomatic.47,48,50 When HIV-

infected patients are examined by echocardiography, cardiac abnormalities are detected more

often than would be expected from clinical symptoms and physical examination.5 This

emphasizes the fact that cardiovascular involvement may occur early in HIV infection while

remaining subclinical over an appreciable length of time.

There is paucity of data on the prevalence of HIV-aPAH and its correlates among HIV infected

population on HAART or in treatment-naïve patients in Nigeria. Hence, this study aims to

3
assess the prevalence and correlates of pulmonary hypertension, using echocardiography, in

HIV infected Nigerian patients on HAART regimen, and in treatment naïve patients. In order

to delineate HAART effects from HIV effects, HAART treated patients will be compared to

treatment-naïve patients.

JUSTIFICATION FOR THE STUDY

HIV/AIDS is one of the leading Public Health problems in the world, especially in sub-Saharan

Africa, where it is one of the greatest health challenges facing the continent.51In 2011, an

estimated 23.5 million people living with HIV resided in sub-Saharan Africa, representing 68%

of the global HIV burden.2 Mortality has risen in Sub-Saharan Africa as modern healthcare is

less accessible to many.5 There is, also, varying and high incidence of HIV associated

pulmonary hypertension in developing countries from 8% in Heart of Soweto study52 to 38.5%

in Ghana.32 HIV-aPAH is an independent risk factor for mortality in HIV infected population

with a mean survival time of six (6) months34,35 from diagnosis. Zuber et al10 in their study on

‘Pulmonary arterial hypertension related to HIV infection’ documented improved

haemodynamics and survival on treatment with HAART while Pugliese et al17 in their study

on ‘Impact of HAART in HIV-positive patients with cardiac involvement’ reported an

increased incidence of pulmonary arterial hypertension (PAH) in patients who received

HAART. Also, another study by Nunes et al18 in ‘Prognostic factors for survival in human

immunodeficiency virus-associated pulmonary arterial hypertension’ showed that survival was

worse in patients who were started on HAART.

Information on the prevalence of pulmonary hypertension in HIV patients on HAART and in

treatment naïve patients in Nigeria is scarce. Data is, also, scarce on the possible effects of

HAART on HIV-aPAH in Nigeria. Available studies did not give information on the

4
prevalence and risk factors of HIV-aPAH in HIV infected patients on HAART and in

treatment-naïve patients in Nigeria.51,53,54

This study will contribute information on the prevalence of HIV-aPAH and associated risk

factors in HIV infected Nigerian patients irrespective of their treatment status. It will compare

and provide information on well matched groups of HAART and treatment naïve patients. It

will also give information and provide data for further studies regarding the possible effect(s)

of HAART on HIV-aPAH as in other studies.10

AIM

5
To assess the prevalence of pulmonary arterial hypertension and its correlates in HIV infected

patients using echocardiography.

SPECIFIC OBJECTIVES

 To assess the prevalence of pulmonary arterial hypertension (PAH) in HIV infected

patients on HAART and HAART naïve patients in Nigeria.

 To determine the clinical and echocardiographic variables associated with pulmonary

arterial hypertension in HIV positive patients on HAART and HAART naïve patients.

 To compare the differences in the prevalence and correlates of PAH among HIV

patients on HAART regimen and HAART naïve patients.

6
 CHAPTER TWO

LITERATURE REVIEW

2.1 INTRODUCTION.

Human immunodeficiency virus (HIV) infection is a global public health problem and a major

problem in sub-Saharan Africa.1 HIV infection is now the principal cause of death in young

adults in many parts of the world, and morbidity and mortality have increased several folds in

sub-Saharan Africa with modern health care less accessible to many.5,55

HIV disease is characterized by an acquired, irreversible, profound immune-suppression that

predisposes patients to multiple opportunistic infections, malignancies, and progressive

dysfunction of multiple organ systems.5,37 The exact pathogenesis of the cardiac manifestations

remains unclear, but is most likely multifactorial.5,56

HIV infection is frequently associated with cardiac involvement and commonly affects all

layers of the heart: endocardium, myocardium or pericardium.57 Cardiac involvement in HIV

infection was first reported in 1983 in a postmortem description of a 24 year old woman of

Haitian origin with multiple complications of AIDS, including Kaposi’s sarcoma which

involved the entire anterior cardiac wall without pericardial effusion.5 Cardiac involvement

may be due to direct toxicity, as HIV nucleic acid sequences have been detected in cardiac

myocytes,7 or indirectly, due to opportunistic infections or therapy (antiretroviral drugs) side

effects or release of inflammatory mediators as a consequence of HIV infection.8

Almost any agent that can cause disseminated infection in patients with HIV infection may

involve the myocardium, but clinical evidence of cardiac disease is usually overshadowed by

manifestations in other organs, primarily the brain and lungs. Thus, the number of patients with

HIV infection and cardiac involvement at necropsy greatly exceeds the number with significant

cardiac disease during life.8 Estimates of prevalence of cardiac abnormalities in HIV infection

vary widely from 28-73%.37,56

7
In 1987, Kim and Factor59 reported the first documented case of pulmonary hypertension

associated with HIV infection in a hemophiliac with membranoproliferative

glomerulonephritis. The causal link between HIV infection and pulmonary hypertension has

been established.27 Given that survival in HIV infection has improved with anti-retroviral

therapy, previously unmanisfested cardiovascular diseases like severe pulmonary hypertension

are becoming life-limiting factors.27

CLASSIFICATION OF PULMONARY HYPERTENSION

In the last four decades, the classification of PH has undergone various changes and

modifications at successive international meetings. The first clinical classification of PH was

drafted in 1973 at the first international conference on primary pulmonary hypertension

endorsed by the World Health Organization.60 The Evian-Venice classification proposed at the

second and third world meetings on PAH in 1998 and 2003, respectively classified PH into

five clinical groups according to pathological, pathophysiological, and therapeutic

characteristics.61 The later classifications was developed in 2008 (Dana Point, California) and

most recently in 2013 (Nice, France) still maintained the general philosophy and organization

of the Evian-Venice classifications while amending some specific points to improve clarity and

to take into account new information.62

8
Updated clinical classification of PH (NICE 2013) 62

Group1: Pulmonary arterial hypertension (PAH)

A Idiopathic

B Heritable

- BMPR2 mutation

- Other mutations

C Drugs and toxins induced

D Associated with:

- Connective tissue diseases

- HIV infection

- Portal hypertension

- Congenital heart disease

- Schistosomiasis

Group1’: Pulmonary veno-occlusive disease and/or pulmonary

capillary haemangiomatosis

A Idiopathic

B Heritable

- EIF2AK4 mutation

- Other mutations

C Drugs and toxins and radiation induced

9
 D Associated with:

- Connective tissue diseases

- HIV infection

Group 1’’: Persistent pulmonary hypertension of the new born

Group 2: Pulmonary hypertension due to left heart disease

A Left ventricular systolic dysfunction

B Left ventricular diastolic dysfunction

C Valvular disease

D Congenital/acquired left heart inflow/outflow tract obstruction and

congenital cardiomyopathies

E Congenital/acquired pulmonary vein stenosis

Group 3: Pulmonary hypertension due to lung diseases and/or hypoxia

A Chronic obstructive pulmonary disease

B Interstitial lung disease

C Other pulmonary diseases with mixed restrictive and

obstructive pattern

D Sleep-disordered breathing

E Alveolar hypoventilation disorders

F Chronic exposure to high altitude

G Developmental lung diseases

10
Group 4: Chronic thromboembolic pulmonary hypertension and other pulmonary

artery obstructions

A Chronic thromboembolic pulmonary hypertension

B Other pulmonary artery obstructions

- Angiosarcoma

- Other intravascular tumours

- Arteritis

- Congenital pulmonary artery stenoses

- Parasites (Hydatidosis)

Group 5: PH with unclear and/or multifactorial mechanisms

A Haematological disorders: Chronic haemolytic anaemia

myeloproliferative disorders, splenectomy.

B Systemic disorders: sarcoidosis, pulmonary Langerhans cell

histiocytosis, lymphangioleiomyomatosis

C Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid

disorders

D Others: pulmonary tumoral thrombotic microangiopathy, fibrosing

mediastinitis, chronic renal failure (with/without dialysis), segmental

pulmonary hypertension.

__________________________________________________________________________

Legend: BMPR2 – bone morphogenetic protein receptor type2, EIF2AK42 – eukaryotic

translation initiation factor 2 alpha kinase 4.

11
2.2 EPIDEMIOLOGY OF HIV-ASSOCIATED PULMONARY HYPERTENSION

The prevalence rate of HIV-a PAH ranges from 0.5% to 38.5% based on the research

methodology, clinical status (symptomatic/asymptomatic), treatment status (HAART

experienced/HAART naïve) and country (developed/undeveloped).

DEVELOPED COUNTRIES

In the 80s, Speich et al63 and Himelman et al 64 estimated the prevalence of HIV-aPAH to be

0.5%. However, these studies were conducted on hospitalized symptomatic HIV patients. A

similar prevalence was documented by Sitbon et al65 who studied 7648 HIV-positive patients

in 14 HIV clinics in France from 2004 to 2005 and calculated the prevalence of PAH to be

0.46% (95% confidence interval 0.32 -0.64).

In 2006, the prevalence of HIV-related PAH was found to be 6.2% (n=42) by Humbert et al66

who analysed 674 patients with PAH from a registry of 17 university hospitals in France. In

2008, Hsue et al67 studied 196 patients with HIV infection recruited from the SCOPE cohort

(Study of the Consequences of the Protease Inhibitor Era) and compared their systolic

pulmonary arterial pressure (PASP) to those of 52 non-HIV-infected patients. Among the 196

HIV-infected participants, the median PASP was 27.5 mm Hg, and 35.2% had PASP > 30 mm

Hg. This was compared to a median of 22 mm Hg among 52 HIV-uninfected participants (p <

0.001) in whom 7.7% had a value > 30 (p < 0.001). After adjustment for stimulant use,

smoking, age, and gender, HIV-infected participants had 5.1 mm Hg higher mean PASP (p <

0.001) and had 7.0-fold greater odds of having a PASP > 30 mm Hg (p < 0.001). This study

concluded that HIV-infected persons have a high prevalence of elevated PASP, which is

independent of other risk factors for PAH and this suggested a causal role of HIV in PAH. Also

in 2008, Byers et al68 in their study on ‘Prevalence of pulmonary hypertension in asymptomatic

HIV-infected patients receiving antiretroviral therapy’ in Washington DC reported a

12
prevalence of 5.5%. However, 91 subjects were studied and PAH diagnosis was based on PASP

>35mmHg.

In 2011, Quezeda et al31 examined consecutive HIV infected individuals attended to at one

HIV reference clinic, in Madrid, to establish the prevalence and factors associated with PAH

in HIV-infected patients using doppler echocardiography. PAH was considered when right

ventricular pressure was more than 35mmHg (mild if <40mmHg, moderate if 40-65mmHg,

and severe if >65mmHg). Three hundred and ninety-two individuals were examined (83.4%

were men). 84% were on HAART, 76% had undetectable HIV viral load and median CD4 cell

counts were 577cells/μl. PAH was diagnosed in 9.9% of patients (6.4% mild, 2.8% moderate

and 0.8% severe).

In 2013, Isasti et al39 in Spain, carried out an observational study, using transthoracic

echocardiogram, to determine the prevalence of PAH in a cohort of HIV-infected patients and

the related factors. The study included 194 patients (85.2% men) with a mean age of 47.0 years,

94% of whom were on antiretroviral therapy (ART). Diagnosis of PAH was based on

pulmonary arterial systolic pressure (PASP) >40mmHg. A prevalence of 2.6% for HIV-aPAH

was documented. However, this study was conducted on asymptomatic HIV patients of whom

some were on ARV. Also, interestingly, 7.2% of the study patients were in the intermediate or

‘gray zone’ with a PASP between 36 and 40mmHg.

AFRICA

In Burkina Faso, Niakara et al69 2002, conducted a retrospective study of consecutive cases of

HIV positive African patients admitted to the cardiology unit of the Yalgado Ouedraogo

National Hospital of Ouagadougou between 1st January 1993 and 31st March 1999. Seventy

nine patients were studied, 5% of patients were found to have evidence of PH.

13
In 2012, Chillo et al70 in a cross-sectional study of Echocardiographic diagnoses in HIV-

infected patients presenting with cardiac symptoms at Muhimbili National Hospital in Dar es

Salaam, Tanzania documented HIV-aPAH prevalence of 12.7%. They had 102 subjects with a

mean age of 42 years (18-72) and 69% females. Their diagnosis of PAH was based on PASP

>35mmHg. No factor was associated with PAH in their study. Sliwa et al71 also reported a

prevalence of 8% in South Africa in 2012.

Ferrand et al72 in a cross-sectional study on ‘Chronic lung disease in adolescents with delayed

diagnosis of vertically acquired HIV infection in Zimbabwe’ reported HIV-aPAH of 7%.

However, 116 subjects with a mean age of 14 years (10-19) comprised the study population.

69% were females and they did not probe for factors associated with PAH.

Also in 2012, Olusegun-Joseph et al53 performed a study on echocardiographic patterns in

treatment-naïve HIV positive patients in Lagos, South-West Nigeria. One hundred cases and

50 healthy controls comprised the study population. Echocardiographic abnormalities were

significantly more common in the cases than the controls (78% vs 16%; p = 0.001), including

systolic dysfunction (30% vs 8%; p = 0.024) and diastolic dysfunction (32% vs 8%; p = 0.002).

Other abnormalities noted in the cases were pericardial effusion in 47% (χ2 = 32.10; p = 0.000)

and dilated cardiomyopathy in 5% (five); none of the controls had either complication. The

prevalence of HIV-aPAH was, however, not highlighted in that study.

In 2013, Syed et al,52 in the Heart of Soweto Study reported that 10% of patients with newly

diagnosed cardiovascular disease were HIV positive, and the most common HIV-related

presentations were cardiomyopathy (38%), pericardial disease (13%) and pulmonary arterial

hypertension (8%). Part of their conclusion was that HIV-associated pulmonary hypertension

was significantly more common in sub-Saharan Africa than in developed countries, possibly

14
as a result of interactions between HIV and other infectious agents, with very limited treatment

options.

In Jos, 2013, Isiguzo et al,54 in a hospital-based cross-sectional study, evaluated the ‘Prevalence

of pulmonary hypertension among patients living with HIV/AIDS and its contribution to

cardiac dysfunction’. The mean age of the patients was 38 ± 9 years, and there were 142

females (71%). Eight of the subjects had pulmonary hypertension, with a case prevalence of

4%. The treatment status of HIV patients used in the study (e.g. percentage on

HAART/treatment naïve) was, however, not stated.

In 2014, Owusu et al32 documented a prevalence of 38.5% for pulmonary hypertension in an

echocardiography-based study in Ghana of 200 asymptomatic HIV infected individuals of

which 74.5% were females. The study showed that pulmonary hypertension occurs with

increased frequency among patients with HIV infection.

PROGNOSTIC FACTORS ASSOCIATED WITH HIV-aPAH

Prognostic factors have received attention by several researches. Opravil et al73 in their study

on HIV-associated primary pulmonary hypertension enrolled 19 patients with HIV-related

PAH and 19 control subjects with HIV infection alone. They also showed that the diagnosis of

HIV-related PAH and lower CD4 cell count were associated with decreased survival.

Nunes et al74 studied 82 patients with HIV-related PAH to investigate associated prognostic

factors. They documented that greater New York Heart Association (NYHA) functional class

at the time of diagnosis was associated with a poorer survival. After multivariate analysis, CD4

cell count >212 cells mm−3 was associated with a better prognosis. Epoprostenol infusion and

antiretroviral therapy were not independently associated with improved survival.

15
Degano et al75 investigated the prognostic factors for HIV-related PAH in 77 patients. All

patients received antiretroviral therapy, and 50 subjects were started on PAH-specific therapies.

Antiretroviral therapy led to an improvement in physical endurance, but not in hemodynamic

parameters. PAH-specific therapies were found to improve both hemodynamic parameters and

physical endurance. It was demonstrated that lower CD4 cell count and cardiac index

<2.8L/min/m2 were associated with a worse prognosis.

OTHER CLINICAL AND LABORATORY FACTORS ASSOCIATED WITH HIV-

aPAH.

Isasti et al39 carried out a study to determine the prevalence of PAH in a consecutive cohort of

asymptomatic HIV-infected patients and the associated factors. The only associations found

were with older age and longer ART time.

Mondy et al76 studied 643 patients from the SUN study- Study to Understand the Natural

history of HIV and AIDS in the era of effective therapy: a cohort of 692 HIV-infected patients

using echocardiography and determined clinical, behavioural and laboratory predictors of

prevalent echocardiographic abnormalities. Predictors of PAH included total cholesterol >154

mg/dL, age >35 years, and boosted protease inhibitor treatment.

In studying ‘Prevalence and risk factors associated with pulmonary hypertension in HIV

infected patients’ Quezeda et al31 examined 392 individuals. The demographic profile included

83.4% men, median age 47 years, 53% homosexuals and 53% former intravenous drug addicts.

Overall, 84% were on HAART, 76% had undetectable HIV viral load and median CD4 cell

counts were 577cell/μl. Traditional cardiovascular risk factors were smoking 50%, arterial

hypertension 16% and diabetes mellitus 9%. A total of 28.5% had chronic hepatitis C (CHC)

and 4.8% chronic hepatitis B. Multivariate logistic regression analysis showed that detectable

16
plasma HIV-RNA and female sex were independently associated with PAH. Patients with

chronic hepatitis C and/or uncontrolled HIV replication exhibit a higher risk of PAH.

Other known risk factors for HIV-aPAH include: intravenous drug abuse or chronic liver

disease. Tomashefski et al77 documented that illicit intravenous drugs derived from tablets

or pills contain insoluble microcrystals that can cause angiocentric foreign body granulomatous

inflammation, thrombosis, and pulmonary hypertension when injected long-term.

Portal hypertension and cirrhosis have also been associated with pulmonary

hypertension78 Hadengue et al79 in a prospective study of 507 patients with portal hypertension,

documented that the prevalence of pulmonary hypertension was 2%, with the majority of

patients having plexogenic pulmonary arteriopathy on biopsy or autopsy. Liver disease

accounted for a minority of cases of HIV-aPAH, as only 15% of patients who had HIV-aPAH

had been reported have a history of hepatitis, evidence of cirrhosis, or portal hypertension.41

2.3 PATHOGENESIS OF HIV-ASSOCCIATED PULMONARY HYPERTENSION.

The exact mechanism of the development of pulmonary hypertension in HIV disease is not

clear, though a number of postulated explanations exist.56,80 In the majority of the cases of HIV-

associated pulmonary hypertension (HIV-aPAH), the development of pulmonary hypertension

was solely related to HIV infection.81 This observation demonstrates that HIV infection itself

plays a major role in the development of pulmonary hypertension. However, Mette et al80

posited that this role is not by a direct viral action because attempts to locate evidence of HIV

in human lung tissue by either electron microscopy or by a variety of immunohistochemical

techniques including in situ hybridization and polymerase chain reaction have been

unsuccessful. Also, Beilke et al82 in their study stated there is no published data demonstrating

that the cultured endothelial cells support the growth of HIV. The most dominant

histopathologic finding in cases of HIV-aPAH is plexiform arteriopathy. Perivascular

17
inflammation has been detected in cases of plexiform pulmonary hypertension, which suggests

that different inflammatory mediators and growth factors derived from the inflammatory cells

may play a role in the development of pulmonary hypertension.83

HIV contains several proteins which are implicated in the pathogenesis of HIV-aPAH.

According to Kestler et al84, one such HIV-related factor is the negative factor or Nef, which

is essential for HIV replication and pathogenesis. Mareckiet al85 went further to show in a

macaque model that Nef-positive simian immunodeficiency virus (SIV) induces plexiform

pathology in the pulmonary vasculature compared to Nef negative SIV. James et al86 observed

that Nef can enter into the pulmonary endothelial cells via the CXCR 4 receptor and can induce

proliferation and apoptosis of pulmonary endothelial cells.

Trans-Activator of Transcription (Tat) is another HIV-related protein that has been shown to

enhance the activity of vascular endothelial cells via interleukin-6 by Hofman et al87 More

recently, Caldwell et al88 documented that the Tat protein represses the transcription of bone

morphogenic protein receptor 2 (BMPR-2) and led to abnormal pulmonary vascular function

with exuberant cellular proliferation.

Rucker et al89 documented that Glycoprotein 120 (Gp-120) is a crucial protein responsible for

HIV entry into the target cells, such as macrophages and CD4 T lymphocytes. Kanmogne et

al90 went further to show that Gp-120 induces vascular smooth cell proliferation and

endothelial cell apoptosis as well as increases the production of endothelin-1, which is a well-

established culprit molecule in the pathogenesis of PAH.90, 91 Mermis et al.92 also showed in a

rat model that HIV-related proteins (Gp-120 and Tat) led to oxidative stress with the resultant

activation of hypoxia-inducible factor-1 and platelet-derived growth factor. They speculated

that this might be a pathological pathway implicated in the occurrence of HIV-aPAH.

18
Another factor involved in the pathogenesis of HIV-aPAH is enhanced systemic inflammation

which is associated with HIV infection as reported by Fauci et al.93 This was supported by

Boccara et al who reported that HIV-associated inflammation is among the key factors

responsible for a greater burden of cardiovascular disease among HIV-infected patients.94 HIV-

associated systemic inflammation may activate platelet derived growth factor and vascular

endothelial growth factor pathway (Ascheri et al95), with resultant aberrant pulmonary vascular

activity.

Certain viral infections have been implicated in the pathogenesis of PAH. Cool et al.96

demonstrated that Human herpes virus 8 (HHV-8) related latency nuclear antigen 1 was present

in 62% of lung tissue samples from patients with sporadic PAH, but not in lung tissues of

secondary PH. It is worthy to note that Martin et al97 reported that HHV-8 is common among

HIV-infected homosexual men. Cool et al,98 in a different study, reported that other viral

infections like hepatitis B virus, hepatitis C virus, and cytomegalovirus play a role in the

pathophysiology of PAH. It is important to note that previous Pneumocystis infection was

shown to lead to PH via deranged immune response to the pathogen (Swain et al99).

Patients with HIV infection may have a greater burden of venous thromboembolic events

compared to the general population.100 Hence, it is has been postulated that chronic pulmonary

embolization may lead to CTEPH-like (chronic thromboembolic pulmonary hypertension)

pathology similar to other conditions (like anti-phospholipid antibody syndrome).

Intravenous drug use (IDU) is a common route for the acquisition of HIV and other infectious

diseases. For example, most of the patients in the study by Nunes et al74 were intravenous drug

users.74 Dhillon et al101 showed that cocaine use had additive effects to HIV infection on the

pulmonary vascular endothelial dysfunction and smooth muscle cell proliferation. Activation

of platelet-derived growth factor was implicated in the pathobiology of the above findings.

Spikes et al102 showed that morphine injection had additive effects to the simian

19
immunodeficiency virus on the occurrence of PAH in a macaque model of HIV-aPAH.

Inflammation involving the pulmonary vasculature with resultant aberrant cellular apoptosis

and proliferation were hypothesized to underlie the pathogenesis between Intravenous Drug

Use (IDU) and HIV infection (Spikes et al102; George et al 103) in the development of PAH.

Genetic susceptibility likely plays a role in the pathogenesis of HIV-a PAH. Humbert et al104

reported that platelet-derived growth factor is overexpressed in patients with HIV-aPAH.

However, a recent study by Nunes et al74 did not identify any mutations in the protein BMRP-

2 among HIV-infected patients with PAH.

In addition, certain human leukocyte antigen (HLA) may be implicated in the pathogenesis of

HIV-aPAH. Morse et al105 showed that HLA-DR6 and HLA-DR52 were common in patients

with HIV-related PAH compared to HIV positive patients without PAH. They speculated that

the HIV-aPAH in these individuals may have an autoimmune basis. It is also essential to

mention that left-sided heart disease, which is common in patients with HIV,7 can also

contribute to the elevated pulmonary arterial pressure.

In summary, the pathogenesis of HIV-aPAH is complex with multiple contributing factors.

Viral proteins and factors, HIV-related inflammation, IDU, coinfections with certain

organisms, genetic susceptibility, and other yet unidentified factors contribute to the occurrence

of HIV-aPAH.

2.4 CLINICAL PRESENTATION OF HIV-ASSOCIATED PULMONARY

HYPERTENSION.

Clinical features are related to the degree of pulmonary hypertension (PH), varying from a mild

asymptomatic condition to severe cardiac impairment with cor-pulmonale and

death.36,37According to Peacock106 and Runo and Loyd,107 the initial symptoms of PH result

from inadequate increase in cardiac output during exertion. Such symptoms include exertional

20
dyspnea, lethargy, and fatigue. Additional symptoms emerge as the PH progresses and right

ventricular hypertrophy and failure develop. In contributing to the Updated Clinical

Classification of Pulmonary Hypertension, Simonneau et al108 stated that clinical presentation

of PH is nonspecific, and that patients typically present with exertional symptoms such as

progressive dyspnea, chest pain/discomfort, and in advanced cases dizziness and syncope.

Symptoms, generally, include: dyspnea on exertion,106,107,108 fatigue,34,106,107 lethargy,106,107

syncope with exertion,34,108 chest pain,34,38,108 anorexia,106,107 right upper quadrant pain.106,107

Less common symptoms include: cough,34,38 hemoptysis,106,107 hoarseness (due to compression

of the recurrent laryngeal nerve by the distended pulmonary artery).109,110,111

Mehta et al34 reviewed 131 HIV patients. Presenting symptoms were progressive shortness of

breath (85%), pedal edema (30%), non-productive cough (19%), fatigue (13%), syncope or

near-syncope (12%), and chest pain (7%).

Limsukon et al38 in their study on HIV-related pulmonary hypertension documented that

patients present with symptoms as diverse as progressive shortness of breath, pedal edema, dry

cough, fatigue, syncope, as well as chest pain.

Physical examination findings may include the following:

A prominent A wave may be observed in the jugular venous pulse. A right ventricular heave

may be palpated. On auscultation, the intensity of the pulmonic component of the second heart

sound (P2) may be increased and the P2 may demonstrate fixed splitting. A systolic ejection

murmur may be heard over the left sternal border. This murmur may be augmented by

inspiration. A right-sided fourth heart sound (S4) may be auscultated and may be associated

with a left parasternal heave. When right ventricular failure develops, the signs include

hepatomegaly, ascites, and peripheral edema. In this scenario, a right ventricular third heart

(S3) sound may be heard.111,37,109,110

21
2.5 DIAGNOSIS OF HIV-ASSOCIATED PULMONARY HYPERTENSION

INVASIVE METHOD

Several instrumental tests could be used in evaluating a patient with suspected HIV-aPAH for

the purpose of diagnosis. However, the confirmatory diagnostic test is right heart

catheterization (RHC). RHC is the gold standard for the diagnosis of pulmonary hypertension

because it allows the essential parameters of pulmonary hemodynamics to be evaluated. These

parameters include Pulmonary Artery Pressure, PAP [systolic, diastolic, mean], right atrial

pressure [RAP] and Pulmonary Wedge Pressure [PWP], RV pressure. Another pertinent aspect

of RHC is testing for reversibility of pulmonary hypertension which is to identify patients who

will respond to vasodilative therapy.62 However, it is invasive and its use as a routine clinical

tool is constrained by cost, availability and expertise.121 Measurement of mPAP (mean

pulmonary artery pressure) at rest [and mean pulmonary capillary wedge pressure (mPCWP)]

is performed during right heart catheterization. PH is diagnosed when mPAP at rest is

≥25mmHg and mPCWP < 15mmHg. The measurement of mPCWP is important since PH due

to left heart disease is essentially ruled out with value less than 15mmHg.108

NON-INVASIVE METHODS

Echocardiography is the main non-invasive tool for the assessment of PH.62 The use of

echocardiography in investigating and diagnosing PAH43,44,45,46 has been well validated.

Echocardiography has also been documented as one of the most commonly performed cardiac

investigations and gives comprehensive information about cardiac structure and function.113

Echocardiography is useful for identifying and exclusion of the commonest cause of pulmonary

hypertension which is left heart disorders/diseases. The European Society of Cardiology (ESC)

guidelines62 on diagnosis of PH stated that transthoracic echocardiography (TTE) provides

several parameters which correlate with right heart haemodynamic information including

22
Pulmonary Arterial Pressure (PAP). They recommend performing TTE in cases of suspected

pulmonary hypertension (PH).

Doppler Echocardiographic techniques

i) Tricuspid Regurgitant Jet velocity method

This is the most commonly used echocardiographic method in routine clinical practice and

large studies.81 It involves the use of continuous wave Doppler to determine the peak tricuspid

regurgitant jet velocity (VTR). The pressure gradient between the right ventricle (RV) and right

atrium (RA) is then derived from the VTR using the simplified Bernouilli equation. The RV-RA

pressure gradient added to the estimated right atrial pressure (RAP) gives the right ventricular

systolic pressure gradient (RVSP). In the absence of pulmonary stenosis (which is rare in

adults)42 the RVSP is equal to the pulmonary artery systolic pressure (PASP).42,62

• RV-RA Pressure gradient = 4(VTR)2 (simplified Bernoulli equation)

• RVSP = RV-RA PG + RAP

• RVSP = PASP (in the absence of Pulmonary Stenosis)

• PASP = RV-RA PG+ RAP

= 4(VTR) 2 + RAP

PG = Pressure gradient; VTR= peak TR jet velocity;

The TR jet velocity method has been well validated by several studies with RHC.114-116 The

largest of these was done by Currie et al114 with 127 patients with a standard error estimate of

7mmHg. RAP is commonly estimated from the diameter and respiratory variability of the

inferior vena cava (IVC).62,117 This method of using TTE derived PASP was used by Chillo et

al,70 ferrand et al,72 Owusu et al32 and Byer et al68 in their studies on PAH in HIV subjects. It

23
is also worthy to note that the use of echocardiography in diagnosing PAH has been well

validated by different studies.43,44,45,46

i) Acceleration Time method

Kitabatake et al118 were the first to discover an inverse correlation between the time to peak

velocity (acceleration time [AcT]) of the pulsed wave Doppler profile obtained in the right

ventricular outflow tract (RVOT) and the mPAP derived at RHC. The equation relating both

is:

mPAP = 79 – 0.45 [ RVOT AcT]81

This method is relatively easy to perform, more reproducible, and unlike the TR jet method,

RVOT Doppler tracings can be obtained in virtually all patients. However, it is not always

easy to measure the acceleration time because the orientation of the beam may not be parallel

to flow and it may be difficult to define the peak of the curve. Also, tachycardia and severe

pulmonary regurgitation affect its measurement.

Potential systolic gradient between the right ventricle (RV) and pulmonary artery (PA) is

important. Fisher et al117 reported that calculation of mean PAP from PA systolic pressure is

possible (mean PAP = 0.61 x PASP + 2 mmHg) theoretically. This allows the use of Doppler

measurements, using an accepted definition of PH as mean PAP ≥ 25 mmHg.

12-lead electrocardiogram (ECG) is a relatively inexpensive diagnostic tool, which can also

assist in detecting other potential explanations for the patient’s presentation. ECG features

associated with PH include “p” pulmonale consisting of tall P waves (≥3mm) in the inferior

leads, right axis deviation, or right bundle branch block and R to S ratio > 1 in lead V1,

indicative of right ventricular hypertrophy [Aibek et al119]. Widimsky120 reported similar

findings of tall right precordial R waves, right axis deviation and right ventricular strain and

noted that the higher the pulmonary artery pressure, the more sensitive the ECG. RV

24
hypertrophy on ECG is present in 87% and right axis deviation in 79% of patients with

idiopathic PAH (Rich et al121). ST depressions in leads V1 to V3 suggest right ventricular strain

in combination with other findings. However, these findings have limited sensitivity (55%) and

specificity (70%)62 and are of limited prognostic value122 for diagnosing PH, especially in

patients with mild PH.

Chest X-ray (CXR) is another non-invasive investigation modality used in assessing PH.

Widimsky120 however, noted that it is inferior to ECG in assessing PH. Aibek et al119 also

reported that in PH, the CXR may be completely normal but is apt to show evidence of RV or

PA enlargement in advanced cases. However, the utility of CXR in diagnosing PH is limited

due to its lack of sensitivity.119

Pulmonary function tests (PFT) are important mostly to exclude other potential causes of PH

(such as chronic obstructive pulmonary disease and interstitial lung diseases).123, 124 However,

Sun et al123 and Meyer et al124 documented that patients with PAH may have mild to moderate

decreases in forced vital capacity, forced expiratory volume in one second, and diffusion

capacity for carbon monoxide compared to healthy control subjects.

Another investigative modality that could be done on patients with PH is Nuclear ventilation

perfusion (V/Q) scans. Mirrakhimov et al125 stated that V/Q scans could be performed in order

to exclude chronic thromboembolic pulmonary hypertension (CTEPH). V/Q scans can show

large ventilation perfusion mismatch126 but may underestimate the severity of CTEPH 127
,

especially central clot load. Other limitations of V/Q scans are decreased sensitivity and

specificity in patients with underlying pulmonary disease and low specificity, since other

pathologies may give similar findings. Due to the limited specificity of V/Q scans, patients

with positive findings typically undergo further imaging studies to better quantify disease

severity and exclude alternative diagnoses. As long as renal function is acceptable, computed

25
tomography-pulmonary angiography (CT-PA) is usually performed next in cases of suggestive

V/Q scans, since it has greater specificity than V/Q scans, useful in inoperable patients and can

help exclude other diseases.

Several laboratory tests may be needed to better understand the etiology of PH in a particular

patient. For example, antinuclear antibody and rheumatoid factor to screen for possible

underlying systemic connective tissue disorder.119 Liver function tests, albumin level, and

international normalized ratio may be useful in screening for portopulmonary hypertension in

appropriate clinical scenario.119 Haemoglobin electrophoresis is important because sickle cell

disease is another differential to consider which may lead to PH.128

2.6 TREATMENT OF HIV ASSOCIATED PULMONARY HYPERTENSION.

ADJUNCTIVE THERAPIES

Treatment of HIV-aPAH is similar to the treatment of other forms of PAH.

ANTICOAGULATION

Patients with PAH are known to be at increased risk of intrapulmonary vascular thrombosis

due to prothrombotic state, sedentary lifestyle, and cardiac dilation (Nauser et al129). In such

populations, McLaughlinet al130 documented that even a small intrapulmonary thrombus can

lead to acute right-sided heart failure and death. Therefore, chronic therapy with

anticoagulation should be instituted in patients with PAH, including HIV-aPAH. Among

anticoagulants, McLaughlinet al130 and Nauser et al129 recommended the use of warfarin given

the availability of scientific data in patients with PAH. They also advocated periodic

International normalized ratio (INR) check in patients using warfarin with an INR goal of 1.5–

2.5, which has been found to be associated with a better survival in patients with PAH.129-130

OXYGEN THERAPY

26
Patients with PAH have been found to develop hypoxemia, which can further exacerbate

pulmonary arterial vasoconstriction.130 Because hypoxia is a potent pulmonary vasoconstrictor,

the Nocturnal Oxygen Therapy Group131 recommends its immediate identification and

reversal/treatment with supplemental oxygen.

DIURETICS

Another common complication of HIV-aPAH is the development of right-sided heart

dysfunction. This causes volume overload, and therapy with diuretic agents helps reduce liver

congestion (McLaughlinet al138). Nauser et al129 and Aibek et al127 also documented that

diuretic therapy should be carefully monitored in patients with PAH, since these agents can

decrease cardiac venous return and preload and lead to hypokalemia, which may lead to fatal

heart arrhythmia in the settings of dilated heart and the development of metabolic alkalosis.

The development of diuretic-associated metabolic alkalosis can lead to respiratory acidosis (via

physiologic acid base compensatory mechanism), which can be dangerous to patients with

PAH.

CALCIUM CHANEL BLOCKERS (CCB)

Rich et al132 reported that CCBs, which are vasodilators, may alleviate pulmonary

vasoconstriction and prolong life in about 20% of patients with pulmonary hypertension.

Unfortunately, there is no way to predict which patient will respond to the orally administered

vasodilators and these drugs frequently have significant side effects. Hence, prior to prescribing

CCB, the vasoreactivity test should be performed (Fuso et al133). The vasoreactivity test is

performed with the administration of vasodilator agent (typically adenosine or epoprostenol or

inhaled nitric oxide). CCB trial should be considered only in patients who develop decrease in

mPAP of at least 10mmHg and to a value less than 40mmHg. This reduction in mPAP must be

accompanied by improved or at least unchanged cardiac output and unchanged or minimally

27
reduced systemic blood pressure.130 In patients who do not meet the above criteria, CCB

therapy is not recommended. Amlodipine, diltiazem, and nifedipine are the most commonly

used medications in the treatment of PAH (Fuso et al133).

PAH-Specific Therapies

Studies134-139 have been done on some therapeutic agents specifically designed for treatment of

PAH. These agents include endothelin receptor antagonists, prostaglandin analogs, and

phosphodiesterase 5 inhibitors (PDE-5).140 Endothelin receptor antagonists are orally

administered medications, with bosentan, sitaxsentan, and ambrisentan being available on the

market. Prostaglandin analog class contains parenterally administered medications such as

epoprostenol and treprostinil as well as inhaled iloprost. Class of PDE-5 includes orally

administered sildenafil, tadalafil, and vardenafil.

Classification of PAH severity by the World Health Organization (WHO) is paramount in

deciding which therapy to use.141

The WHO functional assessment classification of PAH (adapted from135).

28
 Patients with PH but without resulting limitation of physical activity. Ordinary
Class
physical activity does not cause undue dyspnea or fatigue, chest pain, or near
I:
syncope.

Patients with PH resulting in slight limitation of physical activity. They are

Class
comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue,
II:
chest pain, or near syncope.

Patients with PH resulting in marked limitation of physical activity. They are

Class
comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue,
III:
chest pain, or near syncope.

Patients with PH with inability to carry out any physical activity without symptoms.
Class
These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may
IV:
even be present at rest. Discomfort is increased by any physical activity.

McLaughlin et al130 recommended that patients with WHO functional classes II and III can be

initially managed with any oral agents unless contraindicated while patients with WHO

functional class IV should be started with prostaglandin analogs plus the addition of other

medications if needed.

29
PDE-5 inhibitors block the cellular degradation of cyclic guanosine monophosphate, thereby

leading to vasodilation. Several case reports134–

136
http://www.hindawi.com/journals/isrn/2013/903454/ - B73 have been published regarding the

use of sildenafil in patients with HIV-aPAH. These case reports showed beneficial effects of

sildenafil on patients’ symptomatology and hemodynamic parameters.

Endothelin receptor blockers are an important part of PAH treatment. Sitbon et al.134

investigated the utility of bosentan in 16 patients with HIV-related PAH. This study showed

that bosentan therapy for 16 weeks led to an improvement in exercise capacity, quality of life,

and hemodynamics as well as echocardiography variables. Degano et al.137 studied the utility

of bosentan therapy in 59 patients with HIV-related PAH. Bosentan therapy was shown to be

beneficial in terms of symptomatology, exercise capacity, and hemodynamics.

Several reports highlighted the beneficial effects of prostaglandin-based therapy of HIV-aPAH.

Aguilar and Farber138 studied 6 patients with HIV-related PAH to assess the impact of

epoprostenol therapy. Follow-up cardiac catheterization showed improved hemodynamic

parameters, and patients experienced a better quality of life with improvement in NYHA

functional class. Cea-Calvo et al.139 showed improvements in 6-minute walk test and NYHA

functional class in 3 patients with HIV-aPAH treated with treprostinil. Ghofrani et al. enrolled

6 patients with severe HIV-related PAH to investigate the utility of inhaled iloprost.140 These

researchers showed that iloprost was associated with an improvement in the 6-minute walk test

and pulmonary vascular function.

The Role of Highly Active Antiretroviral Therapy in the Management of HIV-aPAH

Different studies have documented different therapeutic effects of HAART on a patient with

HIV-aPAH. Some documented beneficial effects.10,75,143 while others noted adverse or negative

effects.17,74 Sterne et al143 reported that antiretroviral therapy is beneficial and its availability

30
greatly reduced HIV-associated morbidity and mortality. Adding to Sterne’s report, Degano et

al75 showed that low CD4 cell count was predictive of poor outcome in patients with HIV-

aPAH. Degano et al.75 in their study on HIV-aPAH also demonstrated that antiretroviral

therapy was associated with improved 6-minute walk test; however, no improvement in

hemodynamics was noted. Zuber et al.10 in a retrospective study including 35 patients noted

that HAART was related to improvement in right atrial pressure gradient assessed by

echocardiogram as well as reduced mortality from HIV-aPAH and other causes. Gary-Bobo et

al144 also reported that HAART mitigates hypoxia-related pulmonary vasoconstriction.

However, another retrospective study by Pugliese et al.17 documented a negative effect of

HAART on HIV-PAH. They reported an increased incidence of PAH in patients who received

HAART vs. NRTI [2.0% (n=10) vs. 0.7% (n=30); P=0.048].

Also, a prospective study performed by Nunes et al.74 showed that survival was worse in

patients who were started on HAART in the absence of therapy with epoprostenol. Hence, they

recommended that HAART should not be used as a sole therapy for HIV-aPAH, and that the

initiation of PAH-specific therapy is of paramount importance.74 HAART can decrease the rate

of infections in patients with HIV and thus, improve mortality in patients with HIV-associated

PAH. Pulmonary infections, including Pneumocystis infection, can exacerbate PAH and even

lead to death in patients with pre-existent pulmonary vascular disease.

Surgical Options in the Management of PAH

There are different documented surgical options in the management of PAH. Lammers et al145

studied the use of atrial septostomy in the management of PAH. This involves creation of a

right to left shunt in patients with advanced PAH in whom pharmacologic therapy is unable to

control the disease. An opening between the right and left atria is surgically created to bypass

some of the blood from right atrium to the left atrium. Atrial septostomy is considered in

31
patients with advanced PAH and evidence of right-sided heart failure and frequent syncope in

whom pharmacological therapy including diuretics is not effective. However, patients with

elevated mPAP, older patients, and patients with renal dysfunction and low cardiac output have

worse outcomes after atrial septostomy.

Another surgical option described by Esch et al146 is the creation of a shunt between left

pulmonary artery and descending aorta which is known as a Potts shunt. However, the

perioperative mortality is high in adults and currently cannot be recommended for adult patients

with PAH.

Lung and heart transplantation are reserved for patients with advanced PAH who do not

respond to the above measures (Keogh et al147). However, the presence of HIV was a

contraindication to transplantation because of concerns regarding the immunosuppressive

therapies in patients with HIV though recent studies like from Grossi et al148 suggest that

patients with HIV infection can successfully undergo lung and heart transplantation with no

adverse control of HIV infection.

32
 CHAPTER THREE

MATERIALS AND METHODS

3.1 PLACE OF STUDY

This study was done at the Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos

State. LUTH is a tertiary hospital which serves as a referral centre for other hospitals in Lagos,

neighbouring states (e.g Ogun, Ekiti, Osun) and countries (eg Lome). Lagos state had a

population of 9,113,605 million people as at 2006 census.149

3.2 ETHICAL CONSIDERATIONS

Ethical clearance was duly obtained from the Health Research and Ethical Committee (HREC)

of LUTH. Participants in this study were counselled adequately and informed consent obtained

from them (see Appendix I for informed consent).

3.3 STUDY DESIGN

This is a cross sectional study. The study population comprised HIV infected (positive) adults,

attending the AIDS PREVENTION INITIATIVE NIGERIA (APIN) CLINIC in LUTH, who

satisfied the inclusion criteria and were willing to participate.

Consecutive consenting HIV positive patients attending the clinic were recruited. The control,

another group of participants, who are healthy HIV negative adults comprising blood donors

at the blood bank, interns, students and other members of the hospital community, were also

recruited. The control group were age, height, weight and sex matched with the HIV positive

patients.

33
STUDY GROUPS

There were 3 groups in this study:

(1) HIV positive HAART experienced. (2) HIV positive HAART naive group. (3) HIV

negative, healthy, control group.

3.4 INCLUSION CRITERIA

 HIV positive aged between 18 and 65 years, not on HAART for the HAART naïve

group.

 HIV positive aged between 18 and 65 years on HAART for at least 3 months (for the

HAART group).

 HIV negative, healthy control aged between 18 and 60 years.

 Informed consent.

3.5 EXCLUSION CRITERIA

 Less than 18 years or older than 65 years.

 HIV positive with known cardiovascular disease prior to HIV diagnosis.

 History of chronic respiratory disorder prior to HIV diagnosis.

 History of connective tissue disease.

 Pregnancy or within 3 months of puerperium.

 Significant alcohol or smoking history or use of drugs known to affect the

cardiovascular system (apart from HAART).

 Known sickle cell disease or diabetes mellitus patient.

 Refusal to give consent.

34
3.6 SAMPLE SIZE

This was calculated based on the estimated prevalence of pulmonary hypertension in HIV

using the formula: n = Z2pq/d2[150]:

Where

n = minimum sample size;

Z= standard normal deviation which comes to 95%

confidence level i.e. 1.96;

P= prevalence of Pulmonary Hypertension reported in a study of similar population which is

10% 31;

q= 1.0 – p;

d = degree of accuracy desired at 0.05;

n = (1.96)2X 0.10 X 0.90 = ~ 138.

(0.05)2

For the purpose of this study, sample size of 80 was used in each of the HIV positive groups

(HAART compliant and HAART naïve) and 80, for the HIV negative, healthy, Control group.

This made it a total of 160 HIV positive patients and 80 HIV negative controls.

3.7 EQUIPMENT, PROCEDURES AND MEASUREMENTS

3.7.1 Equipment used for the Study

 Sonoscape SI-8000 Echocardiography machine.

 Accoson’s Mercury sphygmomanometer.

 Littmann’s cardiology stethoscope.

 Weighing scale

 Stadiometer

 Stationeries.

35
Procedures and Measurements

3.7.2 Clinical assessment

The bio-data of the subjects were obtained. A history and physical examination were done by

the researcher (See appendix II).

3.7.3 Anthropometric Indices

The weight measurement was done with a Seca weighing scale, with subjects wearing light

clothes and no foot wears.151 Measurements were taken to the nearest 0.1kg. A Seca

stadiometer was employed for height measurement with the subject standing erect, back against

the height meter rule such that the occiput, back and heels made contact with the height meter

rule.152

The body mass index was calculated using the formula below:

BMI = Weight (Kg)/Height (m2)153

3.7.4 Blood Pressure (BP)

The BP was taken after a 5 minute rest to eliminate anxiety.154 Subjects sat comfortably on a

chair, free of any constrictive clothing. Appropriate cuff sizes connected to an Accoson branded

mercury sphygmomanometer was used to measure their BP. The sphygmomanometer was

placed on a table at the level the subject’s heart. BP was taken on both arms and the arm with

the higher BP was used. The systolic blood pressure was determined by the onset of Korotkoff

phase 1 sound while the diastolic blood pressure was determined by the complete

disappearance of Korotkoff sounds (phase V).154

3.7.5 Echocardiography

Echocardiographic study was done using the Sonoscape SI-8000 Machine in the LUTH

cardiovascular laboratory using 3.5 MHz transducer probe. The subjects laid in the left

36
decubitus position and the researcher performed a 2 Dimensional (2D), 2D directed M-mode

and Doppler transthoracic echocardiography in parasternal, apical and subcostal views on all

240 participants in the study.

2D-directed M-mode measurements were done in accordance with the recommendations of the

American Society of Echocardiography.113 M-mode measurements at aortic valve level from

the parasternal long axis view (PLAX) were: left atrial diameter (LAD), aortic root diameter

(AO), right ventricular outflow tract (RVOT) diameter. M-mode measurements at mitral valve

tip level were: left ventricular end systolic and diastolic diameters (LVESD, LVEDD), right

ventricular end diastolic diameter (RVDD), right ventricular free wall thickness, left ventricular

wall thickness consisting of interventricular septal thickness (IVS) and posterior wall thickness

(PWTd) at end diastole and E point septal separation (EPSS).

LV ejection fraction (LVEF) and fractional shortening were also derived by the menu already

preset.

ECHOCARDIOGRAPHY DIAGNOSTIC VIEWS AND MEASUREMENTS

PAH affects right heart function/parameters/variables and its diagnosis requires exclusion of

left heart dysfunction as a cause of Pulmonary Hypertension. This study was essentially a study

of selected right heart variables with measurement of left heart variables to exclude left heart

dysfunction. Selected right heart variables include ERV, RVOT, TAPSE, RAA, FAC, TR

Vmax, RVOT-AT, RAP and MPI. These variables assess right heart function. TR Vmax is a

diagnostic marker of PAH while TAPSE and RVOT-AT are surrogate markers of PAH. RAP

is utilised in calculation of Pulmonary Hypertension. FAC has been shown to correlate with

right ventricular ejection fraction. MPI is an assessment of ventricular function which utilises

systolic and diastolic parameters in its measurement.

37
(1) Peak tricuspid regurgitant velocity (TR Vmax): This is a reflection of the pressure

difference between the right ventricle (RV) and right atrium (RA). It was obtained by

performing a colour doppler guided continuous wave (CW) doppler on the regurgitant

jet of the tricuspid valve in the apical 4 chamber (A4CH) view, right ventricular inflow

tract view and parasternal short axis view of the tricuspid valve. The highest velocity

obtained from any of these views was selected. TR Vmax cut off for this study was ≥

2.9 m/s.62

(2) Tricuspid regurgitant pressure gradient (TR PG): Also a reflection of pressure difference

between the RV and RA was derived from the formula: 4 x (TR Vmax)2 = TR PG.62 This

calculation was pre-set in the machine.

(3) Right atrial pressure (RAP): This was derived from the inferior vena cava (IVC)

diameter and its variation with respiration. The long axis of the IVC was visualized in

the subcostal view. IVC diameter was measured by 2D-guided M-mode measurement

just distal to the junction of the hepatic veins which lie approximately 0.5-3.0cm to the

ostium of the right atrium.155 Two IVC measurements were obtained. IVC max at end

expiration and IVC min after the patient was asked to sniff. See Appendix IV for the

guide that was used in calculating the RAP.32,113

NB: PASP ≈ RVSP = 4(TR Vmax)2 + RAP (in the absence of pulmonary stenosis). [PASP:

pulmonary artery systolic pressure; RVSP: right ventricular systolic pressure; TR Vmax:

tricuspid regurgitant maximal velocity]

A cut off value of PASP > 36mmHg suggesting PH was employed in this study based on ESC

2009158 and ASE 2010159 recommendations. These were the prevailing guidelines during the

planning and execution of this study. However, the recently published 2015 ESC guideline has

de-emphasized the use of PASP and suggests simply quoting the maximum TR-jet velocity.62

38
This method of using TTE derived PASP was used by Chillo et al,70 ferrand et al,72 Owusu et

al32 and Byer et al68 in their studies on PAH in HIV positive subjects.

Median values of PASP and TR Vmax of the controls were also obtained and can be used as

our local values.

(4) Right ventricular outflow tract acceleration time (RVOT AT): This is a surrogate

measure of pulmonary artery pressure (PAP) measured from onset of flow to peak

velocity. This measurement was done in the parasternal short axis (PSAX) view with the

pulse wave (PW) Doppler sample volume placed in the (RVOT). Normal RVOT AT for

this study was >110ms. Values lower than 105ms are highly suggestive of PH.113,118,156

(5) Left ventricular mitral E and A157 (LV M E/A): Transmitral pulse wave Doppler velocity

measurements were obtained with a 2mm sample volume placed at the tips of the mitral

valve leaflets to assess peak E (early diastolic), A (late diastolic) velocities and E wave

deceleration time (DT).

(6) LV Isovolumetric relaxation time157 (LV IVRT): Time between closure of the aortic

valve and opening of the mitral valve. IVRT was also measured from an apical 5

chamber view with the sample volume placed midway between the aortic and mitral

valves.

See Appendix V for the diastolic pattern used in this study.

(7) Myocardial performance index (MPI): Myocardial Performance Index, also known as

Tei Index,160 is a combination of systolic and diastolic measurements of IVCT + IVRT

/RVOT ET. Two different views were obtained for the determination of MPI - the apical

four-chamber view for the tricuspid inflow pattern and the parasternal short axis right

ventricular outflow tract view for the determination of ejection time.

39
 The normal range for RV MPI is 0.28-0.33.113, 160-161 It is relatively unaffected by heart

rate, loading conditions or the presence and the severity of tricuspid regurgitation. In

patients with idiopathic pulmonary arterial hypertension, the index correlates with

symptoms.

(8) RV tissue Doppler investigation (RV TDI): This is a measure of RV longitudinal

diastolic function. Measured in the A4CH view using PW tissue Doppler investigation

(TDI). The sample volume was placed at the basal lateral RV myocardium and

measurement taken at diastole. Values <10 cm·s−1 was diagnostic of right ventricular

diastolic dysfunction.42

(9) Left Ventricular tissue Doppler investigation (LV TDI): This is a measure of LV

diastolic function. Measured in the A4CH view using PW tissue Doppler investigation

(TDI). The sample volume was placed at the basal lateral wall of LV myocardium and

measurements taken. Values <10 cm·s−1 were diagnostic of left ventricular diastolic

dysfunction.42

(10) Right atrial area (RAA): RAA was obtained by tracing the right atrial endocardium in

systole from the annulus, along the free wall to the apex, and then back to the annulus,

along the interventricular septum in the A4CH view. Normal is < 20cm2.42

(11) Left atrial area (LAA): LAA was also obtained by tracing the left atrial endocardium

in systole from the annulus, along the free wall to the apex, and then back to the

annulus, along the interventricular septum in the A4CH view. Normal is < 20cm2.42

(12) Right ventricular fractional area change (RV FAC): Right ventricular fractional area

change (FAC) was calculated as follows:

RV FAC (%) = (AED – AES) / AED X 100

40
 Where AED is end-diastolic area and AES is end-systolic area, measured from the apical

four chamber view. FAC was obtained by tracing the RV endocardium both in systole

and diastole from the annulus, along the free wall to the apex, and then back to the

annulus, along the interventricular septum. Normal: 32 – 60. Values < 32 indicate

reduced RV systolic function.113,164,165

(13) Left ventricular end-diastolic dimension (LVeDD) (cm): vertical distance from the left

side of the interventricular septum to the endocardium of the left ventricular posterior

wall at end of diastole measured in the PLAX.113

(14) Septal wall thickness (IVS): vertical distance between right and left septal surfaces at

end diastole and was measured in the PLAX.113

(15) Left ventricular end-systolic dimension (LVeSD) (cm): vertical distance measured

from the left side of the interventricular septum to the endocardium of the left

ventricular posterior wall at end of systole (peak downwards motion).113

(16) Tricuspid annular plane systolic excursion (TAPSE): This is a measure of RV

longitudinal systolic function. The measurement was taken in the A4CH view with the

M mode cursor placed across the lateral tricuspid annulus and the total excursion

measured. Normal TAPSE was taken as >1.5mm.113

(17) RV free wall thickness: Vertical distance between right and left surfaces of the anterior

free wall was measured at end diastole in the PLAX. Values > 0.5 cm was diagnostic

of RV hypertrophy.160

41
3.8 DATA ANALYSIS

Data was analysed with the statistical package for social sciences (SPSS) version 16.0.

Normally distributed numerical data were presented as means and standard deviations, while

the skewed data were expressed as medians and ranges. Categorical variables were presented

as proportions. Means were compared using Students T test or the analysis of variance

(ANOVA) or Kruskal Wallis test when not normally distributed. Categorical variables were

compared using the chi-square test or the Fisher’s exact test when cell counts were less than 5.

Correlation analyses were done to demonstrate relationship between PASP and specific clinical

and echocardiograhic variables. Pearson’s correlation was performed for normally distributed

variables. Spearman’s rank correlation was employed for variables not normally distributed.

Multiple linear regression analyses were performed in order to determine the clinical and

echocardiographic parameters that were independently associated with PASP amongst the

study population. A P value ≤ 0.05 was taken as statistically significant.

42
 CHAPTER FOUR

RESULTS

4.1 CHARACTERISTICS OF THE STUDY GROUPS

A total of 240 subjects were recruited for this study comprising of 115 males (47.9%) and 125

females (52.1%) with a male to female ratio of 1: 1. Other clinical parameters of the general

population are summarized in Table 1.

The subjects were divided into 3 groups comprising 80 HIV positive HAART-Experienced

(HE) group, 80 HIV positive HAART Naïve (HN) group and 80 HIV negative CONTROL

group. The subjects were age and sex matched. The means of the clinical and anthropometric

variables of each group are summarized in Tables 1. There was statistically significant

difference in the mean of BMI, Systolic BP and Diastolic BP across the 3 groups.

Post-diagnosis duration ranged from 1-17 years and 1-8 years for the HE and HN groups

respectively. The difference in post-diagnosis duration between the HE and HN groups was

statistically significant with a p value of < 0.001 (Table 1). Most, 36 (45%) HE and 64 (80%)

HN subjects belong to the group of <5 years duration of HIV diagnosis. The 5-10 years duration

category had 26 (32.5%) HE and 15 (18.8%) HN subjects. The least number of subjects were

in the >10 years category, 18 (22.5%) for HE and 1 (1.2%) for HN.

In the HE group, the duration of HAART ranged from 1-16 years with a median of 5. The

antiretroviral drug classes used in APIN clinic LUTH were divided into 3 groups: (a)

Nucleoside Reverse Transcriptase Inhibitors (NRTI) (b) Protease Inhibitors (PI) and (c) Others.

The combination therapy was also divided into (1) NRTI plus PI and (2) NRTI plus others.

Ninety percent was taking NRTI plus others. NRTI include zidovudine, abacavir, emtricitabine,

tenofovir, didanosine, stavudine and lamivudine. Protease Inhibitors include atazanavir,

ritonavir, indinavir. Others include nevirapine, efavirenz. All 5 HE subjects who had PAH were

taking NRTI plus others combination therapy.

43
Table 1: Comparison of Clinical and Anthropometric Variables among the study

groups

Variables HAART-E HAART-N CONTROL p-Value

n=80 n=80 n=80
Mean±SD Mean±SD Mean±SD
Age (years) 47.51±9.06 45.11±9.22 44.66±9.03
< 30 1(1.25%) 3(3.75%) 1(1.25%) 0.98
30 – 59 72 (90.0%) 72 (90.0%) 74 (92.5%)
≥ 60 7 (8.75%) 5 (6.25%) 5 (6.25%)

Sex
Male (n/%) 37(46.20%) 40(50%) 38(47.50%) 0.89
Female (n/%) 43(53.80%) 40(50%) 42(52.50%)

0.71
Height (m) 1.61±0.11 1.65±0.07 1.65±0.11

0.08
Weight (kg) 68.89±14.93 66.05±14.63 70.95±11.91

0.02
BMI(kg/m2) 26.54±6.24 24.32±4.89 26.35±5.05

Duration of < 0.001

diagnosis (years), 6 (3-10) 4 (3-10) NA

median (IQR)
Duration of NA
HAART(years), 5 (3-10) NA NA

median (IQR)
Pulse Rate (b/min) 84.70±11.31 82.96±10.45 80.20±8.85 0.06

SBP (mmHg) 143.66±29.92 124.43±13.82 119.61±15.65 < 0.001

DBP (mmHg) < 0.001

89.66±19.21 100.61±142.22 75.45±8.63

Legend: HAART- Highly Active Anti-Retroviral Therapy; HAART E- HAART Experienced;

HAART N- HAART Naïve; NA- Not applicable; BMI - Body Mass Index; SBP- Systolic

Blood Pressure; DBP- Diastolic Blood Pressure.

44
Figure 1: Duration of diagnosis of HAART experienced and HAART naïve subjects
Frequency

DURATION OF DISEASE
Legend: HAART: Highly Active Anti-Retroviral Therapy.

45
4.2 Important echocardiographic variables of the study groups.

The means of selected echocardiographic variables of the study groups are shown in Table 2.

There were statistically significant differences in the means of ERV, RVOT and RAA. (Table

2) The median of TR Vmax and PASP are also shown in Table 2. ANOVA comparison of

echocardiographic variables among the study groups showed the significant differences were

between the groups. (Appendix VI). The median TR Vmax and PASP for the HIV negative

population are 1.29 and 14.34 respectively.

46
Table 2: Comparison of Selected Right Ventricular echocardiographic variables of the

study groups.

Variable HAART-E HAART-N CONTROL P-Value

(n=80) (n=80) (n=80)
ERV(cm;mean±sd) 2.05±0.51 2.35±0.417 2.05±0.53 <0.001

RVOT(cm;mean±sd) 2.92±0.42 2.93±0.34 2.72±0.42 <0.001

0.07
TAPSE(cm;mean±sd) 1.98±0.32 1.98±0.27 2.07±0.27

RAA(cm2;mean±sd) 13.57±2.57 12.16±1.95 13.19±2.16 <0.001

FAC(%;mean±sd) 0.33±0.12 0.34±0.11 0.37±0.15 0.73

RVOT 0.79
0.17±0.02 0.16±0.07 0.15±0.03
AT(sec;mean±sd)

RAP(mmHg;mean±sd) 7.25±2.63 6.94±2.45 6.75±2.40 0.44

MPI(sec;mean±sd) 0.59±0.33 0.50±0.29 0.40±0.32 0.16

TR Vmax(m/s;median) 1.51 1.63 1.29 0.001

PASP(mmHg;median) 15.96 18.92 14.34 0.02

Legend: HAART- Highly Active Anti-Retroviral Therapy; HAART E- HAART Experienced;

HAART N- HAART Naïve; ERV- Estimated Right Ventricular diameter; RVOT- Right

Ventricular Outflow Tract diameter; TAPSE- Tricuspid Annular Plane Systolic Excursion;

RAA- Right Atrial Area; FAC- Fractional Area Change; RVOT-AT- Right Ventricular

Outflow Tract Acceleration Time; MPI- Myocardial Performance Index; TR Vmax- Tricuspid

regurgitant maximal velocity; PASP- Pulmonary arterial systolic pressure;

47
4.3 Comparison of PASP across the groups

PASP was compared across the groups: between the HIV positive (HE plus HN) and HIV

negative (CONTROL) groups and between the 2 HIV positive groups (HE and HN). The

prevalence of PAH (PASP >36 mmHg) was 5.6% in the HIV positive population (all HIV

positive subjects in the study which includes both the HE and HN groups). The prevalence of

PAH was 6.2% and 5% in the HAART experienced and HAART naïve subgroups respectively.

There was no PAH among subjects in the CONTROL group. The difference in the prevalence

of PAH between the HIV positive and HIV negative was statistically significant p=0.031.

Details are summarized in tables 3a and 3b.

48
Table 3a: Comparison of PASP across the 3 groups

PASP(mmHg) HAART-E HAART-N CONTROL Total

Normal 75(93.8) 76(95.0) 80(100.0) 231(96.2)

Elevated 5(6.2) 4(5.0) 0(0.0) 9(3.8)

Total 80(100.0) 80(100.0) 80(100.0) 240(100.0)

Legend: HAART- Highly Active Anti-Retroviral Therapy; HAART E- HAART

experienced; HAART N- HAART naïve; PASP- Pulmonary Artery Systolic Pressure.

Fishers exact = 5.508, p= 0.082. NB: A PASP >36 mmHg was considered elevated in this

study.

49
Table 3b: Comparison of PASP between HIV positive and HIV negative groups

HIV Positive HIV Negative Total p-value

PASP n(%) n(%) n(%)

Normal 151(94.4) 80(100.0) 231(96.2)

Elevated 9(5.6) 0(0.0) 9(3.8) 0.03

Total 160(100.0) 80(100.0) 240(100.0)

Legend: PASP- Pulmonary Artery Systolic Pressure; HIV- Human Immunodeficiency Virus.

Fishers exact = 4.675

50
4.4 Relationship between clinical/echocardiographic variables and PASP

Clinical and echocardiographic variables were tested for association with PASP. Cough was

the only clinical variable associated with PASP in the HE group. (Table 4) SBP was the only

clinical variable that demonstrated significant association with PASP in the HN group. (Table

5) In the HE group, RVOT and MPI were the echocardiographic variables that demonstrated

relationship with PASP. In the HN group, ERV, RAA and RVOT-AT were the

echocardiographic variables that demonstrated significant relationship with PASP. (Table 6).

51
Table 4: Relationship between presence of clinical symptoms and Pulmonary Arterial

Systolic Pressure among HIV patients

HAART-E PASP (mmHg) HAART-N PASP (mmHg)

Clinical Not Elevated p – value Not Elevated p – value

symptoms elevated, elevated, n=4,
n=5,
n=75, n=76, n(%)
n(%)
n(%) n(%)
Cough
No 71(95.9) 3(4.1) 0.05 70(95.9) 3(4.1) 0.79
Yes 4(66.7) 2(33.3) 6(85.7) 1(14.3)
Weight
loss
No 63(94.0) 4(6.0) 1.00 70(97.2) 2(2.8) 0.06
Yes 12(92.3) 1(7.7) 6(75.0) 2(25.0)
Diarrhea
No 73(94.8) 4(5.2) 0.45 76(95.0) 4(5.0) ___
Yes 2(66.7) 1(33.3) 0(0.0) 0(0.0)

Legend: HAART- Highly Active Anti-Retroviral Therapy; HAART E- HAART experienced;

HAART N- HAART naïve; PASP- Pulmonary Artery Systolic Pressure.

52
Table 5: Relationship between Socio-Demography/Physical measurements and PASP

among HAART experienced and HAART naive HIV subjects.

Variables HAART-E PASP (mmHg) HAART-N PASP (mmHg)

Not Elevated p- value Not Elevated p-value
elevated, elevated
n=75 n=5 n=76 n=4
n(%) n(%) n(%) n(%)
Age range
< 30 years 1(100) 0 (0.0) 3 (100) 0 (0.0)
30 – 59 years 67(93.10) 5 (6.90) 1.00 68 (94.40) 4 (5.60) 1.00
≥ 60 7 (100) 0 (0.0) 5 (100) 0 (0.0)
SEX
Male 36(97.3) 1(2.7) 0.45 39(97.5) 1(2.5) 0.61
Female 39(90.7) 4(9.3) 37(92.5) 3(7.5)
Duration of
diagnosis (yrs)
1-5 34 (94.40) 2 (5.60) 0.92 60 (94.80) 4 (6.20) 1.00
6-10 24 (92.30) 2 (7.70) 15 (100) 0 (0.0)
>10 17 (94.40) 1 (5.60) 1 (100) 0 (0.0)
BMI
Underweight 2(100.0) 0(0.0) 2(100.0) 0(0.0)

Normal 31(94.4) 2(6.1) 0.98 50(94.3) 3(5.7) 0.83

Overweight 25(92.6) 2(7.4) 18(94.7) 1(5.3)

Obese 17(94.4) 1(5.6) 6(100.0) 0(0.0)

Pulse rate

High (≥ 100) 10(100.0) 0(0.0) 0.86 8(100.0) 0(0.0) 1.00

SBP (mmHg)

≥ 140 47(62.67) 2(40.0) 0.26 12(15.79) 3(75.0) 0.04

DBP (mmHg)

≥ 90 39(52.0) 3(60.0) 0.86 58(76.32) 4(100.0) 0.61

Legend: HAART- Highly Active Anti-Retroviral Therapy; HAART E- HAART experienced; HAART
N- HAART naïve; PASP- Pulmonary Artery Systolic Pressure; BMI- Body Mass Index; PR-Pulse rate;
SBP- Systolic Blood Pressure; DBP- Diastolic Blood Pressure; HTN- Hypertension.

53
4.5 Relationship between Systolic Blood Pressure and PASP.

The Systolic Blood Pressure (SBP) of the 3 groups was tested for relationship with PASP.

There were different relationships between SBP and PASP in the 3 groups. All the relationship

were weak and only that of HN group is statistically significant. The SBP of the HE group has

a weak, negative linear relationship with PASP and it is not statistically significant. The SBP

of the HN group has a weak, positive linear relationship with PASP and this is statistically

significant. The SBP of the CONTROL group also has a weak, positive linear relationship with

PASP but this is not significant. The correlation coefficients and p-values are highlighted in

figures 2, 3 and 4.

54
Figure 2: Relationship between Systolic Blood Pressure and Pulmonary Arterial Systolic

Pressure among HAART experienced patients.

r = -0.167; p = 0.138

55
Figure 3: Relationship between Systolic Blood Pressure and Pulmonary Arterial Systolic

Pressure among HAART naïve patients.

r = 0.255 P=0.036

56
Figure 4: Relationship between Systolic Blood Pressure and Pulmonary Arterial

Systolic Pressure among HIV negative patients.

r = 0.034; p = 0.764

57
Table 6: Spearman’s correlation showing relationship between PASP, Clinical and

Echocardiographic variables among HIV patients on HAART and HAART Naive

HAART E HAART Naïve

Variable being r P r P
correlated with PASP

Age (years) -0.08 0.51 -0.00 0.98

BMI (kg/m2) 0.08 0.49 -0.12 0.29

PR (bpm) 0.30 0.13 0.14 0.23

SBP (mmHg) -0.17 0.13 0.26 0.02

DBP (mmHg) -0.13 0.29 0.10 0.38

RVOT (cm) 0.23 0.04 0.08 0.55

ERV (cm) 0.129 0.25 0.46 <0.001

TAPSE (cm) 0.10 0.37 -0.09 0.45

RAA (cm2) 0.16 0.17 0.24 0.04

FAC (%) -0.10 0.38 0.16 0.17

RVOT-AT (sec) 0.19 0.10 -0.26 0.02

MPI (sec) 0.28 0.01 0.03 0.79

Legend: r- Spearman’s rho coefficient; p- p value; BMI - Body Mass Index; PR- Pulse Rate;

SBP- Systolic Blood Pressure; DBP- Diastolic Blood Pressure; ; RVOT- Right Ventricular

Outflow Tract; ERV- Estimated Right Ventricular diameter; TAPSE- Tricuspid Annular Plane

Systolic Excursion; RAA- Right Atrial Area; ; FAC- Fractional Area Change; RVOT-AT-

Right Ventricular Outflow Tract Acceleration Time; TR Vmax- Tricuspid Regurgitant

maximal Velocity; RAP- Right Atrial Pressure; MPI- Myocardial Performance Index; bpm-

beats per minute Sec- seconds; cm- centimeter; mmHg- millimeters of mercury.

58
4.6 Independent predictors of PAH and comparison of significant echocardiographic

correlates between HAART experienced and HAART naïve patients.

Clinical and echocardiographic variables with statistically significant correlations on univariate

analysis were tested to identify independent determinants of PAH. In the HE group, the clinical

variable which demonstrated significant association with PASP on univariate analysis was

cough. In the HN group, SBP was the only clinical variable significantly associated with PASP.

In the HE group, MPI and RVOT were the echocardiographic variables with significant

correlation with PASP. In the HN group, ERV, RVOT-AT and RAA were the

echocardiographic variables demonstrating significant correlation with PASP with a p-value

range of <0.02 to 0.04.

On multivariate analysis, no clinical or echocardiographic variable was independently

associated with PASP.

The echocardiographic variables which correlated significantly with PASP were compared

between HE and HN groups. Only RAA and ERV had statistically significant differences.

(Tables 7a and b). The TR Vmax of the HE and HN groups were also compared. There were

37 and 43 HE and HN subjects, respectively, who had TR Vmax above the median (1.60). The

difference between the 2 groups was not significant with a p-value of o.43.

59
Table 7a: Comparison of echocardiographic correlates of PAH between HAART

experienced and HAART naïve subjects.

Variables HAART E HAART t P

Mean±SD NAIVE
(n= 80) Mean±SD
(n=80)

ERV 2.05±0.51 2.35±0.42 -4.05 <0.001

RAA 13.57±2.56 12.16±1.95 3.91 <0.001

RVOT-AT 0.17±0.32 0.16±0.07 0.35 0.73

Legend: HAART – Highly Active Anti-Retroviral Therapy; HAART E- HAART experienced;

RAP- Right Atrial Pressure, RAA- Right Atrial Area; RVOT AT- Right Ventricular Outflow Tract

Acceleration Time, ERV- Estimated Right Ventricular diameter.

60
 CHAPTER FIVE

DISCUSSION

5.1 PREVALENCE OF PULMONARY ARTERIAL HYPERTENSION

(PAH) AMONG HIV POSITIVE SUBJECTS IN THIS STUDY.

Varying prevalence of PAH has been reported in African countries. In this study, a total of 160

HIV positive subjects were assessed for PAH. The prevalence of PAH was assessed by
158
echocardiography using a PASP cut-off value of >36mmHg according to ESC 2009 and

American Society of Echocardiography 2010159 guidelines which were in place during the

planning and execution of this study. (NB: the recently published 2015 ESC guideline has de-

emphasized the use of PASP and suggests simply quoting the maximum TR-jet velocity.)62

Among the 160 (HE plus HN groups) HIV positive subjects, 9 had elevated PASP giving a

PAH prevalence of 5.6%. This study prevalence of 5.6% is comparable to 4% (8 participants)

reported by Isiguzo et al54 in a similar hospital-based cross-sectional study in Jos University

Teaching Hospital in North Central Nigeria. Despite using a different definition of PAH which

was a mean Pulmonary Arterial Pressure (mPAP) >25mmHg, a similar prevalence was

reported. It is worthy to note that mPAP and PASP are connected with the formula: mPAP =

0.61 x PASP + 2 mmHg.117 Being in the same environment (Nigeria) with similar AIDS

Preventive Initiative could account for the similarity in the prevalence. In Burkina Faso,

Niakara et al 69 reported an HIV-aPAH prevalence of 5% among HIV positive patients in the

National Hospital of Ouagadougou. Though their 5% prevalence was comparable to this study,

it was not an expected outcome considering that their Inclusion criteria included progressive

heart affectation with a clinical presentation of heart failure in 79% of the study population.

Ferrand et al72 also reported a comparable 7% prevalence of HIV-aPAH in a cross-sectional

study with 116 subjects in Zimbabwe. However, the mean age for their study was 14 years with

a female preponderance of 69% and a PAH definition of >25mmHg mPASP. The Heart of

61
Soweto study reported a prevalence of 8%.52 Chillo et al70 in another cross-sectional study with

102 subjects in Tanzania got a higher prevalence of 12.7% for HIV-aPAH. This was probably

because HIV patients with cardiac complaints were part of their inclusion criteria. This study

prevalence is however very different from 38.5% in Ghana reported by Owusu et al,32 This

high prevalence in Ghana was unexpected as it was a marked deviation from reports in other

African countries. It was a descriptive cross-sectional study with 200 treatment-naïve subjects

(74.5% females). Possible reasons for the high prevalence in the Ghana study include poor

implementation of the Global Strategies for the Eradication of HIV, high pulmonary disease

burden (eg pulmonary TB), poor socio-economic factors with poor nutrition. Nevertheless, the

prevalence in this study (in LUTH) and most Africa studies correspond to a documented

prevalence range of 5 – 13% in Africa by Ntsetke et al.55 Outside Africa, Humbert et al66 and

Byers et al68 reported a prevalence of 6.2% and 5.5% in France and Washington DC, USA,

respectively. In France also, Quezeda et al31 and Isasti et al39 reported varying prevalence rates

of 10% and 2.6% respectively. The low prevalence of 2.6% was likely because Isasti et al used

a high PASP cut-off of >40 mmHg for PAH. The present comparable prevalence rates between

African countries and developed countries suggest that the African strategies in combating

HIV/AIDS may be helping in reducing associated co-morbidities.

Generally, reason for the varying prevalence rates is methodological with different cut-off

points for diagnosis of PAH and selection criteria with presence or absence of underlying

cardiac pathology. For instance, while this study used > 36 mmHg as diagnostic cut-off for

PASP, some others used a different diagnostic cut-off. Isasti et al39 used a PASP cut-off of

>40mmHg, Chillo et al70 used >35mmHg and Ferrand et al72 used mPAP of > 25mmHg with

Doppler echocardiography. Another reason could be that some studies were carried out on

asymptomatic patients (Quezeda et al31, Owusu et al32) and others on symptomatic patients

(Chillo et al70).169 The prevalence of HIV-aPAH is noted to be higher in symptomatic HIV

62
positive patients than in asymptomatic.55 Owusu et al32 reported the possibility of some of these

subjects having cardiovascular diseases before HIV infection. Another reason might be genetic.

Genetic influence on the variability of the prevalence of HIV-aPAH may be contributory.

Morse et al105 reported a genetic predisposition to PAH in the pathophysiology of PAH in HIV

patients. This was one of the limitations of this study as genetic studies like typing for HLA-

DR6 and HLA-DR52 was not done. Also, the different health care policies and its application

might also play a role in the differences in the prevalence rates.56 For instance, difficulty with

accessing and utilizing adequate health care services as a result of poor socio-economic factors

and poor health care policies is common in Sub-Saharan Africa.56

5.2 PREVALENCE OF PAH AMONG SPECIFIC HIV SUB-GROUPS.

5.2.1 HAART EXPERIENCED (HE) GROUP

In the HE group (HIV patients taking HAART), 5 subjects out of 80 had elevated PASP giving

a prevalence of 6.2% for PAH. There is dearth of studies on the prevalence of PAH among

HAART experienced HIV patients in Africa. However, Byers et al68 in their study on

Prevalence of pulmonary hypertension in asymptomatic HIV-infected patients receiving

antiretroviral therapy in Washington DC, USA, reported a prevalence of 5.5% which is

comparable to the value in this study. Isasti et al39 with 94% of their study participants taking

antiretroviral reported a HIV-aPAH prevalence of 10%. In their study, all the subjects who had

HIV-aPAH were taking HAART. The role of antiretroviral therapy (ART) in PAH is still

controversial. Varying reports have been documented on the effect(s) of ART on PAH.

Pellicelli et al170 reported that HIV-aPAH develops regardless of ART. Degano et al137

reported that hemodynamic parameters by Right Heart Catheterization remain unchanged with

ART while Reinsch et al169 reported that ART may accelerate the onset of HIV-aPAH.
17
Pugliese et al in their study on Impact of HAART in HIV-positive patients with cardiac

63
involvement reported an increased incidence of pulmonary arterial hypertension (PAH) in

patients who received HAART. Also, another study by Nunes et al18 in Prognostic factors for

survival in human immunodeficiency virus-associated pulmonary arterial hypertension

documented increased mortality in patients who were started on HAART. On the other hand,

Zuber et al10 in their study on Pulmonary arterial hypertension related to HIV infection reported

improved haemodynamic function and survival on treatment with HAART. Antiretroviral

drugs like P Is and NRTIs have been shown to have adverse effects on the cardiovascular

system.171

More subjects 5(6.2%) taking HAART had elevated PASP as against 4(5%) HAART naïve

participants with elevated PASP but this difference is not statistically significant. The

difference in the post-diagnosis duration for the HE group (1-17 years, median 6) and the HN

group (1-8years, median 4) was statistically significant. However, in this (LUTH) study, there

was no correlation between duration of HAART and PAH. Some studies have demonstrated a

relationship between HAART and PAH. Olalla et al172 in a cross-sectional study involving 400

HIV infected patients, reported that a current use of Tenofovir (NRTI) was associated with

lower PAH prevalence. Cicallini et al33 and Reinsch et al169 also demonstrated a beneficial

effect of the use of HAART in HIV patients with PAH. However, Isiguzo et al 54 (with 200

subjects) and Chillo et al70 (with 102 subjects) also did not find any association between

HAART and PAH in their study.

5.2.2 HAART NAÏVE (HN) GROUP

64
Four of the 80 HN subjects had elevated PASP giving a PAH prevalence of 5%. In the absence

of HAART and with a shorter post-diagnosis duration compared to the HE group, this

comparable prevalence with the HE group suggests that HIV is an independent risk factor for

developing PAH. There is evidence from available literature that HIV has a causal relationship

with PAH.27 This study (in LUTH) suggests that PAH is more likely to develop in treatment-

naïve HIV patients than in their HE counterparts. PAH prevalence in the HN group is, however,

still in the African range of 5 – 13%.55 Data on prevalence of PAH among HN HIV patients is

also scarce. Owusu et al32 had 200 treatment naïve subjects in their study. Their report of 38.5%

prevalence for HIV-aPAH also lends credence to the fact that HIV increases the risk of

developing PAH. Despite having fewer number of individuals with elevated PASP (4 as against

5 on HAART), the difference was not statistically significant. A longitudinal study with larger

participants will be essential in determining the possible effect(s) of HIV on the cardiovascular

system and, more specifically, PAH in HIV positive patients in our environment.

5.2.3 PAH IN THE CONTROL GROUP

Nine subjects out of the 240 study population had PAH. All nine subjects with PAH were HIV

positive. No member of the CONTROL group had PAH. This was possibly because the

Inclusion criteria for the CONTROL group included healthy, negative HIV status. Also, the

documented prevalence of idiopathic PAH in HIV negative subjects is 1-2 per million,56 hence,

this study outcome as regards the PAH in HIV negative subjects was an expected finding.

Though there was no elevated PASP above 36 mmHg in the CONTROL group of this study,

Hsue et al,67 documented elevations in PASP among 7.7% of the CONTROL in their study.

However, they used a lower PASP cut-off of >30 mmHg without specifying the exact PASP

of those with elevated PASP. This could have accounted for the elevation in PASP among the

control in their study.

65
From this study, the prevalence of PAH among the HIV positive group was 5.6% comprising

5(3.1%) HE and 4(2.5%) HN subjects. When the prevalence of PAH in the HIV positive group

(5.6%) was compared to 0(0.0%) in the HIV negative CONTROL group, the difference was

statistically significant. This finding is also in-line with reports in the literature. Crothers et

al166 in their study on HIV infection and risk for incident pulmonary diseases in the

combination antiretroviral therapy era reported that HIV infected patients have a greater

incidence of Pulmonary Hypertension compared to general population. Correale et al167 in their

study on HIV-aPAH also reported that in comparison with the incidence of idiopathic PAH in

the general population (1–2 per million), HIV-infected patients have a 2500-fold increased risk

of developing PAH. Hsue et al67 also concluded that HIV-infected persons have a high

prevalence of elevated PASP, which is independent of other risk factors for PAH suggesting a

causal role of HIV in PAH. Data from this study comparing the TR Vmax and PASP across

the 3 groups was also in agreement with the reports above. Fewer number of subjects in the

CONTROL group (27, 31) had TR Vmax and PASP values above the median for the study

population respectively. More subjects in the HE group (42, 40) and HN group (51, 49) had

their TR Vmax and PASP values above the median for the study population. Hsue et al67 also

reported similar findings in their study. The reason for the difference in the TR Vmax and

PASP between the HIV positive and HIV negative groups is most-likely the effect of the HIV

virus which studies 56,67,166,167 have reported. HIV contains some proteins like Negative factor

(Nef) and Trans-Activator of Transcription (Tat) which have been shown to induce

proliferation and apoptosis of pulmonary endothelial cells.86 They also lead to abnormal

pulmonary vascular function.88

5.3 CLINICAL AND DEMOGRAPHIC VARIABLES ASSOCIATED WITH

PULMONARY ARTERIAL HYPERTENSION IN HIV PATIENTS

66
The clinical and demographic characteristics of the HE and HN subjects with and without PAH

were assessed for relationship with PAH. Statistically significant association was found only

with systolic blood pressure in the HN group. Age, sex, BMI, duration of diagnosis, duration

of HAART, DBP and SBP for HE group was not associated significantly with PAH in this

study.

5.3.1 CLINICAL SYMPTOMS

Different studies have found varying clinical symptoms among HIV positive subjects with

PAH.34,38,106,107,108 In this study, the clinical symptoms recorded were cough, weight loss and

diarrhoea. An explanation for this reduced incidence of clinical symptoms in this study groups

could be that there is improved nutritional status among HIV positive participants in this study

who were ambulant and not on hospital admission. Also, better access to Healthcare could be

another reason. These symptoms were seen more with the HAART experienced group than

HAART naïve group. This is expected considering that guidelines for commencing HAART

(as at the time of this study) included development of these clinical symptoms among other

criteria.178

Six HAART experienced participants had cough. Two of them had elevated PASP. The

presence of cough in HAART experienced HIV positive subjects was significantly associated

with PASP. Cough has been reported to be a common clinical presentation in HIV infection

and HIV-aPAH.34,37 Mehta et al34 reported that 19% of the 131 cases reviewed had cough.

Other symptoms in the HE group were not statistically significant. None of the symptoms in

the HAART naïve group was statistically significant.

5.3.2 AGE

67
Different studies have reported different relationship between age and PAH. Some studies39,76

found a relationship between age and PAH while others31,70 did not find any relationship

between age and PAH. In this study, all 9 (5.6%) HIV positive subjects who had elevated PASP

were within the age range of 30 - 59 years. The mean age for this study was 47.51 and 45.11

for the HE and HN groups respectively. There was however no relationship between age and

PASP in this study. This is different from the report of Isasti et al39 which reported that HIV

positive participants who had PAH were 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). Carolyn et al168

reported a population-based evidence of age-related increase in pulmonary artery pressure. The

mean age of their study population was 63±11 years. This difference in age between their study

population and this study in LUTH (47.51±9.06 for HE group and 45.11±9.22 for HN group)

may account for the difference in relationship between age and PAH in the above studies.

However, Mondy et al76 reported that one of the predictors of HIV-aPAH was age >35 years.

No association was found with any other parameter from their study. An average age of 33

years for HIV-aPAH was reported by Mehta et al34 The Swiss HIV study75 and French study10

also reported an average age 38 and 41 years, respectively, for patients with HIV-Related PAH,

though the range can span from infancy to old age. This LUTH study data with a mean age of

39.2 and 42.3 years respectively for HE and HN subjects with PAH agrees with studies10,34,75,76

above on the mean age for PAH.

In this study, age was not significantly associated with PAH though all subjects with PAH were

within the age range of 30 – 59 years. Reason for this is not clear presently. Quezeda et al31

and Chillo et al70 also did not find any relationship between age and HIV-aPAH in their study.

5.3.3 GENDER/SEX

68
Varying reports have been documented on the relationship between sex and PAH. This study

had a preponderance of females (78%) who had elevated PASP but this (female sex) had no

relationship with PAH. This study report is different from most studies which have reported a

male preponderance of HIV-aPAH with a male/female ratio of 1.5: 1.66,34,18,158 This ratio is

different from that of HIV negative patients with idiopathic PAH, in whom the female/male

ratio is 1.7: 1.33 More recently, however, a slightly marked female predominance in HIV-aPAH

patients was suggested by Reinch et al.169 Quezada et al31 after performing multivariate logistic

regression analysis, reported that female gender was associated with the presence of PAH but

Degano et al75, Zuber et al10 and Nunes et al18 reported that men are slightly more affected by

HRPAH (HIV Related PAH) than women (ratio of 1.2:1).

Bigna et al56 and Chillo et al70 however reported no association of HIV-aPAH with sex. On

the contrary, Shapiro et al177 in their study on Sex differences in the diagnosis, treatment, and

outcome of patients with pulmonary arterial hypertension reported that there are similarities

and differences between men and women with PAH. They recommended future exploration

regarding the role of hormones and sex in causation and survival in PAH.

5.3.4 BODY MASS INDEX (BMI)

Though BMI in this study showed no association with PASP, the result has highlighted that

HAART experienced patients with PAH were more likely to have a higher BMI than HAART

naïve patients with PAH. This might be due to the fact that HAART components like Protease

Inhibitors cause abnormal lipid metabolism and fat deposition which can cause weight gain.11,12

The mean of the BMI of the HE group is slightly higher than that of the HN group but

comparable to the CONTROL group. Reason for this could be that HAART prevents HIV-

induced weight loss in HE subjects giving them a comparable BMI with CONTROL. Dimalla

et al173 also documented a slightly higher mean BMI in the HE group than in the HN group.

69
The BMI of HE subjects was not associated with PASP in this study. No association was also

found between the BMI of the HN group and PASP on a statistical scale. Shapiro et al177 also

found no association between BMI and PAH in their study.

5.3.5 BLOOD PRESSURE [BP] PATTERN OF THE STUDY POPULATION.

SYSTOLIC

Different studies have highlighted varying reports on blood pressure among HIV positive

subjects. In this study, the HAART experienced group had the highest systolic blood pressure

readings. They were followed by the HAART naïve and CONTROL groups respectively. The

difference in the means of the systolic BP across the 3 groups was statistically significant.

Dimalla et al173 in their study on Prevalence of Hypertension in HIV/AIDS Patients on HAART

Compared with HAART-Naïve Patients at the Limbe Regional Hospital, Cameroon reported

that mean SBP values of their participants on HAART were higher than that of HAART-naïve

participants though not significantly. This study agrees with studies by Ekali et al174 and

Bergersen et al175 who reported similar findings of significant difference between mean SBP

of HE and HN subjects. This result was an expected finding considering the reported adverse

cardiovascular effects of some of the HAART constituents like P Is and NRTI. 11,12,15

Hypercholesterolaemia, hyperglycaemia, hyperinsulinaemia, and lipodystrophy are

cardiovascular risk factors11,12,171 and frequent adverse effects of potent antiretroviral

combination therapy, particularly involving protease inhibitors.11 Hyperlipidaemia affects

approximately 50% of patients using protease inhibitors, with average increases in total

cholesterol and triglyceride concentrations of 28% and 96%, respectively. The degree of

increase seems to be proportional to the duration of treatment and type of drug. This is

supported by the findings of the Multicenter AIDS Cohort Study176 which suggested a link

between the duration of HAART and BP, demonstrating that prolonged HAART (defined as

2–5 years in duration) was independently associated with development of HTN, whereas

70
HAART of less than 2 years in duration was not. Chillo et al70 had a lower mean SBP of

118mmHg in their study but most of their subjects had heart failure symptoms and this disease

state could account for the lower SBP. When systolic BP within the HAART experienced group

was tested for relationship with elevated PASP, a weak, negative, linear relationship was found.

This negative correlation is different from that of HN and CONTROL groups who also had a

weak, linear but positive relationship with PASP.

The mean for HAART naïve SBP was higher than the mean for the CONTROL group. One

can infer that this increase above that for HIV negative CONTROL group is as a result of the

cardiovascular effect of Human immunodeficiency virus. The positive linear relationship

between the SBP of the HN group and PASP is statistically significant. The mean SBP of the

CONTROL group was the least of the 3 groups. The SBP of the CONTROL group also has a

positive but very weak linear relationship with PASP with a correlation coefficient that is very

close to zero. The HN group has a more positive and significant correlation with PASP. The

reason for this variation in the relationship between the 3 groups and PASP is not immediately

clear. However, Atkins et al182 in their study on Increased Vascular Resistance with Systemic

Hypertension reported that the positive correlation between pulmonary and systemic vascular

resistance (in their study) suggests the possibility of a causal hypertensive relation/factor in the

2 vascular beds. Also, Alpert et al183 in their study on Pulmonary Hemodynamics in Systemic

Hypertension documented that neurohumoral or other factors may produce a hypertensive

response in both the systemic and pulmonary arterial circulation. Perhaps, HIV-induced blood

pressure increase which occurs through direct and indirect mechanisms like premature

atherosclerosis5,8 affects both the pulmonary and systemic circulation simultaneously resulting

in the more positive and significant correlation of SBP with PASP in the HN group. It is also

possible that the effect(s) of HAART (which also mitigates HIV effects/actions) may be

responsible for the weak, negative correlation between SBP and PASP in the HE group.

71
5.3.6 DIASTOLIC BLOOD PRESSURE (DBP)

The HAART naïve group had the highest mean DBP. This was followed by the mean of the

HAART experienced and HIV negative CONTROL groups respectively. Also, the mean of the

DBP of both HIV positive groups was higher than the mean of HIV negative CONTROL group

suggesting possible effects of HIV and or HAART on the DBP. Chillo et al70 reported a lower

mean DBP in their study but this could be because their subjects were recruited with heart

failure symptoms. The reason for the higher DBP in the HAART naïve group could be a result

of the adverse effects of HIV on the myocardium which is not checked by HAART. When

tested statistically, no association was found between DBP and PASP in the 2 HIV groups.

Chillo et al70 also found no association between DBP and PAH in their study.

5.3.7 ECHOCARDIOGRAPHIC CORRELATES OF HIV-aPAH

Selected echocardiographic variables were compared across the 3 groups and between HE and

HN groups. Variables with statistically significant correlation with PAH include RVOT and

MPI (for HE group), ERV, RVOT-AT and RAA (for the HN group).

Right MPI had a weak but positive correlation with PASP in the 2 groups but this was only

significant in the HE group. This suggests that worsening MPI is associated with increasing

PASP. MPI is an assessment of right ventricular function which utilizes a combination of

systolic and diastolic parameters. The reason for the disparity in the significance between the

2 groups is not clear but MPI has been documented to be a surrogate marker of PAH.158,159,181

This association was not significant on multivariate analysis.

RVOT diameter is not one of the known surrogate markers for PAH but in this study it

correlated weakly with PASP in both groups. It was however, only significant in the HE group.

72
This suggests that increasing RVOT diameter is associated with increasing PASP in the HE

group.

In this study, RAA correlated positively (though weakly) with PASP in the 2 groups. This was,

however, only significant with the HN group. This suggests that increasing RAA is associated

with increasing PASP in the HN group. This association has also been reported in the

literature.180 The reason it was not significant in the HE group is not immediately clear. RVOT-

AT is another surrogate marker for PAH which also correlated weakly with PASP in both

groups. This was however only significant in the HN group. This suggests that worsening

RVOT-AT is associated with increasing PASP. This association has also been reported in the

literature.158 Also in this study, there was a weak and positive correlation between ERV and

PASP in both groups. This suggests that increasing ERV is associated with increasing PASP.

It was however, only significant in the HN group. The reason this was not significant in the HE

group is not immediately clear. FAC is one of the indices that are used in assessing individuals

with PAH. In this study, FAC had a weak correlation with PASP which not significant in either

group. Possible reason(s) for this is not clear presently.

TAPSE, which is a marker of right ventricular dysfunction, can also be a surrogate marker for

PAH. In this study, it had no significant correlation with PASP in both HIV subgroups. Reason

for this is not immediately clear. However, Forfia et al,181 in their study on Tricuspid Annular

Displacement Predicts Survival in Pulmonary Hypertension noted that the measured TAPSE

may not change significantly over time (even in those who continue to develop progressive RV

failure) and thus may not be a sufficiently reliable marker of RV function to measure serially.181

5.3.8 Independent determinants of Pulmonary artery pressure

In univariate analysis, PAH had varying degrees of relationship with echocardiographic

variables in the HE group and these include RVOT and MPI. Similarly, in the HN group, PAH

73
had relationship with ERV, RAA and RVOT-AT. However, on multiple linear logistic

regression no variable had independent relationship with PASP. Chillo et al70 in their study

also did not find any independent predictor of pulmonary hypertension.

5.3.9 Comparison of the differences in the correlates of PAH among HIV patients on

HAART regimen and HAART naïve patients.

The mean of significant clinical and echocardiographic variables were compared between the

HE and HN HIV groups. Significant differences were observed only in RAA and ERV. The

reason for this difference is not clear. Studies are scarce on differences in the correlates of PAH

among HIV patients on HAART and HAART naïve patients. Larger longitudinal studies are

needed to better understand these differences.

6.0 CONCLUSION

(1) The results of this study show that PAH is present among HIV positive patients

attending APIN clinic LUTH at a much higher prevalence (5.6%) than in HIV negative

individuals (0.0%). The prevalence is slightly higher (6.2%) in HAART experienced

HIV positive patients when compared to control (0.0%).

(2) The prevalence of PAH in HE HIV positive subjects (6.2%) is comparable to that in

HAART naïve patients (5%).

(3) The higher mean systolic BP in the HIV groups when compared to HIV negative

individuals suggests adverse effects of HIV and HAART on the blood pressure.

(4) PAH has significant correlation with SBP, RVOT, ERV, RVOT-AT and MPI in the

HIV positive groups.

(5) There is no independent clinical or echocardiographic determinant of PAH in the 2 HIV

groups. Age and sex are not predictors of HIV-aPAH in LUTH APIN clinic.

74
(6) This information will prove useful in the follow up and management of persons living

with HIV.

7.0 LIMITATIONS

(1) The true duration of HIV infection is difficult to determine as patients present to clinic

at variable times post infection.

(2) HIV negative CONTROL group was made up of LUTH doctors, nurses and students

(among others) whose HIV status was not confirmed.

(3) Genetic and autoimmune studies were not done to exclude other possible causes of

HIV-aPAH than left heart dysfunction.

8.0 RECOMMENDATIONS

(1) All HIV positive patients should have echocardiographic evaluation as part of their

initial laboratory workup and subsequently, at least once every year as part of their

follow up.

(2) Echocardiography should be performed as part of investigation in HIV patients

presenting with unexplained cough.

(3) Longitudinal studies on the effect(s) of HIV and HAART on the cardiovascular system

among HIV positive individuals should be encouraged.

(4) A multicentre study with same methodology is needed to further assess the relationship

between age and PAH in HIV positive individuals.

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167. Correale M, Palmiotti GA, Lo Storto MM, Montrone D, Foschino Barbaro MP, Di

Biase M, et al. HIV-associated pulmonary arterial hypertension: from bedside to the

future. Eur J Clin Invest. 2015;45(5):515–28.

168. Carolyn S, Barry A, Garvan C, Felicity T, Richard J, Margaret M. Age-Associated

Increases in Pulmonary Artery Systolic Pressure in the General Population. Circulation,

2009. http://dx.doi.org/10.1161/CIRCULATIONAHA. 108.838698.

169. Reinsch N, Buhr C, Krings P, et al. Competence Network of Heart Failure Effect of

gender and highly active antiretroviral therapy on HIV-related pulmonary arterial

hypertension: results of the HIV-HEART Study. HIV Med. 2008;9(7):550–556.

170. Pellicelli AM, Barbaro G, Palmieri F,et al. Primary pulmonary hypertension in HIV

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171. Barbaro G, Fisher SD, Lipshultz SE. Pathogenesis of HIV-associated cardiovascular

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172. Olalla J, Urdiales D, Pombo M, del Arco A, de la Torre J, Prada JL. Pulmonary

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L et al. Fasting blood glucose and insulin sensitivity are unaffected by HAART duration

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175. Bergersen BM, Sandvik L, Dunlop O, Birkeland K, Bruun JN. Prevalence of

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 APPENDIX I

LAGOS UNIVERSITY TEACHING HOSPITAL

HEALTH RESEARCH & ETHICS COMMITTEE

CONSENT FORM

HREC approval number………………..……

HREC Expiration date……………………….

Please tick one of the following:

A] You are an adult participant in this study

Are you participating in any other research studies?

Participant ID ……………………………………………..

A research study is designed to answer specific questions, sometimes about a drug’s or device’s

safety and effectiveness. When you are a research participant, the researcher will follow the

rules of the research study (protocol) as closely as possible, without compromising your health.

Title of the research: PREVALENCE AND CORRELATES OF PULMONARY

HYPERTENSION IN HIV INFECTED NIGERIAN PATIENTS ATTENDING A

TERTIARY HOSPITAL: AN ECHOCARDIOGRAPHY-BASED STUDY.

Name and affiliation of researcher:

Name: Dr ELUOGU Chinedum Obiora

Department of Medicine, Lagos University Teaching Hospital, Idi-Araba, Lagos state.

Sponsors:

99
This research is self-sponsored (i.e. the researcher bears the cost of the research alone).

Purpose of Research:

You have been invited to participate in a research study on ‘PREVALENCEAND

CORRELATES OF PULMONARY HYPERTENSION IN HIV INFECTED NIGERIAN

PATIENTS ATTENDING A TERTIARY HOSPITAL: AN ECHOCARDIOGRAPHY-

BASED STUDY’.

We want to check for the presence of a heart disorder called Pulmonary Hypertension among

HIV positive individuals and the factors associated with it.

You were selected as a possible participant in this study either because you have HIV infection

and are taking or not taking HIV drugs or because you do not have HIV infection and will serve

as control in the study.

Procedure of Research:

If you choose to participate,

- Your height, weight and blood pressure will be measured. An ECG will also be done.

- You will then do an echocardiography (ultrasound of the heart). This will be done by a

doctor. When doing echocardiography, you will lie down on a hospital couch and

expose your chest wall (a chaperon will be around). A plastic probe will be put on top

of your chest and moved round it. A colourless gel will be applied on your chest to

make this probe work better. Measurements will be taken from a TV monitor that will

be by your side after which the gel will be cleaned off your body and that will be the

end of the echocardiography.

Possible risks, discomforts and inconveniences:

100
There is no risk with the echocardiography or blood pressure check or weight and height

measurements.

Potential benefits:

These include:

(a) Free echocardiography and ECG

(b) Which will give you a comprehensive information on present medical condition of your

heart.

Cost to participant for joining the research:

You shall not pay any money in the course of this research.

Voluntariness:

Your participation in this study is entirely voluntary.

Your decision to participate or not in this study will not prejudice you or your medical care.

Confidentiality:

All information collected in this study will be coded and no name will be recorded. This cannot

be linked to you in any way. Your name or identifier will not be used in any publication or

reports from this study.

The result of this research study may be presented at scientific or medical meetings or published

in scientific journals. However, your identity will not be disclosed.

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Participant Responsibilities:

As a participant, your responsibility will be to:

 Come to the cardiovascular laboratory in Lagos University Teaching Hospital (LUTH),

Idi-Araba, for the echocardiography, ECG, weight and height measurements.

 Keep your study/research appointment. If it is necessary to miss an appointment, please

contact the research study staff to reschedule as soon as you know you will miss the

appointment.

 Tell the research staff if you believe you might be pregnant.

 Ask questions as you think of them.

 Tell the research staff if you change your mind about staying in the study.

Consequences of participant’s decision to withdraw from research and procedure for

orderly termination of participants:

If you first agree to participate and then you change your mind, you are free to withdraw your

consent and discontinue your participation at any time. Your decision will not affect the routine

medical care for your illness and you will not lose any benefits to which you would be

otherwise entitled to.

Please note that some of the information that has been obtained about you before you chose to

withdraw may have been modified or used in reports and publications. These cannot be

removed anymore. However, the researchers promise to make good faith effort to comply with

your wishes as much as possible.

What happens to research participants when the research is over?

When the research is over, the research participants will continue their APIN clinic visits as

scheduled by their doctors. Those on drugs will continue their drugs.

Statement about sharing of benefits:

102
This study will not bring about any financial benefit.

The study outcome shall be communicated to the participants via text/sms messages.

Any apparent or potential conflict of interest:

There is no apparent or potential conflict of interest in this study.

Statement of person obtaining informed consent:

I have fully explained this research to ___________________________ and have given

sufficient information, including about risks and benefits, to make an informed decision.

DATE: ____________________ SIGNATURE_______________________

NAME: ________________________________________

Statement of person giving consent:

I have read the description of the research or have had it translated into the language

I understand. I have also talked it over with the doctor to my satisfaction. I understand that my

participation is voluntary. I know enough about the purpose, method, risks and benefits of the

research study to judge that I want to take part in it. I understand that I may freely stop being

part of this study at any time. I have received a copy of this consent form and additional

information sheet to keep for myself.

DATE: _____________________ SIGNATURE: ____________________________

NAME: _____________________________________________________________

WITNESS/TRANSLATOR’S SIGNATURE (if applicable)____________________

WITNESS NAME (if applicable): ________________________________________

RESEARCHER’S CONTACT:

103
NAME: Dr ELUOGU Chinedum Obiora.

DEPARTMENT: of Medicine, Lagos University Teaching Hospital, Idi-Araba, Lagos.

PHONE: 08034720584

Email: educieco@yahoo.com

LUTH HREC CONTACT:

LUTH HREC RESEARCH ETHIC COMMITTEE ROOM 107, Administrative Building,

LUTH.

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 APPENDIX II

STUDY PROFORMA (fill or tick as appropriate)

Date:___________________________________________

Hospital No._____________________________________

Study No._______________________________________

Age_______________________________________ years

Sex M F

Marital status: Single Married Divorced Widowed

Occupation _____________________Known Hbss

Pregnant or within 3 months of delivery Yes No
Identifiable risk factors to HIV

Multiple sexual partners

Heterosexual Homosexual Bisexual

Transfusion Intravenous drug use

Occupational exposure

Past medical history (including history of hypertension, diabetes mellitus, tobacco use, alcohol
abuse, hepatitis, use of antiretroviral drugs, use of cardiotoxic drugs such as vasopressors)
______________________
Anti-Retroviral Therapy (ART) Yes No

If yes

Name Date started Any break in therapy?

1. _______________________________________________________________
2. _______________________________________________________________
3. _______________________________________________________________
4. _______________________________________________________________
Change made/comments_________________________________________________

Other comments________________________________________________________
_____________________________________________________________________

105
SYMPTOMS/SIGNS

Chronic cough Weakness

Progressive weight loss Breathlessness

Chronic diarrhea Palpitations

Pruitus/skin rashes

Duration of diagnosis ____________________years

Prolonged fever Leg swelling

Oral thrush Abdominal swelling

Gen. lymphadenopathy Mouth

Herpes zoster

Height __________m _______ Weight_______kg

BMI___________kg/m-2

CARDIOVASCULAR SYSTEM

Pulse rate _________beats/min

Regular irregular

Small volume normal volume large volume

Blood pressure systolic_____mmHg diastolic _____mmHg

JVP normal elevated

Apex beat displaced not displaced

Heart sounds normal abnormal

S3 Others

106
CHEST

Respiratory rate _______min

Adventious sounds

Basal Crepitations Other

ABDOMEN

Hepatomegaly Others

Ascites

HIV 1 …………………

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 ECHOCARDIOGRAPHY STUDY FORM (Appendix III)
Name:…………………………………………………………………………………….
Age:…………….. Sex………………. Date………………. Hosp. No…………………
LAD -----------------cm
AO -------------------cm RVOT AT--------------ms
RVOT---------------cm TR Vmax -----------------m/s
…
ERVD----------------cm TR PG -------------------mmHg
LVEDD--------------cm RAP ---------------------mmHg
LVESD--------------cm PASP--------------mmHg
IVSd-----------------cm
Mitral E------------ E’---------
LVPW---------------cm
Mitral A----------- A’---------
EPSS----------------cm
Mitral E/A …………
EF -------------------%
DT …………………..
FS ------------------%
LV IVRT……………..
LV Mass………….g
MPI: IVCT……
TAPSE ……………cm IVRT…….
RV wall thickness……..cm ET…….
IVC Max …………..cm IVCT-IVRT/ET…………….
IVC Min(sniff)……..cm LV TDI
S'------------
LAA ………………cm2 E------- A-----
RAA……………….cm2 RV TDI
S’----------------cm/s
RV FAC AED…….
E-----------------cm/s
AES……..
A-----------------cm/s
AED-AES/AED………

Comments:
_____________________________________________________________________________________

_____________________________________________________________________________________

_____________________________________________________________________________________

108
 APPENDIX IV

Estimation of right atrial pressure from the inferior vena cava.32,113

IVC and diameter Change with respiration Estimated RAP (mmHg)

Normal (1.5 – 2.5 cm) Decrease by > 50% 5

Normal Decrease < 50% 10

Dilated ( > 2.5 cm) Decrease by < 50% 15

Dilated with dilated No change 20

hepatic veins

Legend: IVC:- Inferior vena cava; RAP:- Right Atrial Pressure.

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 APPENDIX V

Guide to diastolic pattern 42 in this study.

Normal Mild (Grade I) Moderate (Grade II) Severe

(Grade III)
Pathophysiology Impaired Pseudonormalisation Restrictive
relaxation
E/A ratio 1–2 < 0.8 0.8 – 2.0 ≥2.0
Deceleration 150-200ms >200ms 150- 200ms <150ms
time (DT)
IVRT 50-100ms ≥100ms 60-100ms ≤60ms
E’ velocity ≥ 10 <8 <8 <5
(cm/s)
E/E’ ≤8 ≤8 9 – 14 ≥ 15

Legend: E:- Early diastolic velocity; A:- Late diastolic velocity; IVRT:- Isovolumetric Relaxation Time;
E’:- Early diastolic velocity on Tissue Doppler Imaging.

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 APPENDIX VI

ANOVA TABLE for the comparison of echocardiographic variables among the study

groups.

Variable Sum of Df Mean Sig.

Squares Square
ERV Between Groups 4.751 2 2.376 0.000
Within Groups 57.114 237 0.241
Total 61.866 239
RVOT Between Groups 2.275 2 1.137 0.001
Within Groups 36.956 237 0.156
Total 39.230 239
RAP Between Groups 10.20 2 5.10 0.442
Within Groups 1474.68 237 6.22
Total 1484.90 239
TAPSE Between Groups 0.45 2 0.23 0.068
Within Groups 19.81 237 0.08
Total 20.26 239
MPI Between Groups 29.70 2 14.85 0.158
Within Groups 1891.42 237 7.98
Total 1921.12 239
FAC Between Groups 0.06 2 0.03 0.729
Within Groups 23.75 237 0.10
Total 23.81 239
RAA Between Groups 84.978 2 42.489 <0.001
Within Groups 1191.858 237 5.029
Total 1276.837 239
RVOT AT Between Groups 0.017 2 0.009 0.789
Within Groups 8.641 237 0.036
Total 8.659 239
ERV- Estimated Right Ventricular diameter; RVOT- Right Ventricular Outflow Tract diameter; RAP- Right

Atrial Pressure; TAPSE- Tricuspid Annular Plane Systolic Excursion; RAA- Right Atrial Area; FAC- Fractional

Area Change; MPI- Myocardial Performance Index; RVOT AT- Right Ventricular Outflow Tract Acceleration

Time.

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 APPENDIX VII

Doppler study of TR Vmax in the apical 4 chamber view of a HAART experienced subject
showing TR Vmax of 2.89m/s with PG of 33mmHg. These values are suggestive of PAH

RA

IVC sniff IVC max

Measurement of IVC diameter of the above subject in subcostal view. An IVC max and
sniff of 1.89cm and 0.78cm respectively give a normal RAP pressure of  5mmHg.

112
 APPENDIX VIII

LV
RV
LA

Doppler study of TR Vmax in apical 4 chamber view of a HAART naive subject showing
TR Vmax of 3.12m/s with PG of 39mmHg. These values are suggestive of PAH.

IVC
RA

IVC sniff IVC max

Measurement of IVC diameter of the above subject in subcostal view. An IVC max and sniff
of 2.45cm and 1.51cm respectively give a high RA pressure gradient of 10mmHg.

113
 APPENDIX IX

TDI of the left ventricular free wall of a HAART naïve subject in apical 4 chamber view
showing a normal E’, A’, and Sm values of 11.53 cm/s, 7.00cm/s and 7.49cm/s respectively.

114