patterns of visual function abnormalities in hiv positive...
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PATTERNS OF VISUAL FUNCTION ABNORMALITIES
IN HIV POSITIVE CHILDREN ATTENDING HARARE
CENTRAL HOSPITAL’S PAEDIATRIC
OPPORTUNISTIC INFECTIONS
CLINIC
BY
TENDAYI DENFORD MUTUNGAMIRI
R978171T
SUPERVISOR
PROFESSOR R MASANGANISE
SUBMITTED IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS OF THE MASTERS OF MEDICINE
(OPHTHALMOLOGY) DEGREE
UNIVERSITY OF ZIMBABWE
2014
DECLARATION
(Amended)
CERTIFICATE OF COMPLETION OF DESSERTATION
I,……………………………………………………………………..hereby certify that this dissertation is the product of my own work and, in submitting it for my M Med programme, further attest that it has not been submitted in part or in whole to another University or for general publication.
Signature:………………………………… Date……………………………
Student
I/We…………………………………………………………………. having supervised and read this dissertation, am / are satisfied that this is the original work of the author under whose name it is being presented. I/We confirm that the work has been completed satisfactorily and is ready for presentation to the examiners.(Delete sections that are not applicable)
Signatures:
Supervisor 1:…………………………. Date…………………………..
Supervisor 2:…………………………. Date…………………………..
Chairman ………………………….. Date…………………………
Department…………………………
June 2014
DEDICATION
I dedicate this work to my father Denford Mutungamiri, a genuine pure hearted man who believed in me but did not live long enough to see the dream come alive. And to my mother Florence Mutungamiri who sacrificed much for the realization of the dream.
CONTENTS
i ACKNOWLEDGEMENTS …………………..…………………..……………… i
ii LIST OF ABBREVIATIONS ………………………………………….............. ii
iii LIST OF DIAGRAMS ………………………………………………….……….. iii
iv LIST OF TABLES ……………………………………………………….............. iv
ABSTRACT ……………………………………………………………………… 1
1.1 INTRODUCTION ………………………………………………………………. 3
1.2 LITERATURE REVIEW ……………………………………………………… 5
1.2.1 Ocular diseases in HIV ………………………………………………….. 5 1.2.2 Prevention of Mother to Child Transmission (PMTCT) ………………… 7 1.2.3 Antiretroviral Therapy and other drugs ………………………………….. 8 1.2.4 Visual Function ………………………………………………………….. 9 1.2.5 Colour Vision …………………………………………………………….. 10 1.2.6 Contrast Sensitivity ……………………………………………………… 11
1.3 JUSTIFICATION OF STUDY………………………………………………… 12
1.4 PROBLEM STATEMENT ……………………………………………… …… 13
1.5 RESEARCH HYPOTHESIS……………………………………………………. 13
1.6 STUDY OBJECTIVES………………………………………………………….. 14
1.6.1 Primary objective ……………………………………………………….. 14 1.6.2 Secondary objective …………………………………………………….. 14
2.0 RESEARCH METHODOLOGY ……………………………………………… 15
2.1 Study design ……………………………………………………………… 15 2.2 Study setting ……………………………………………………………… 15 2.3 Study population………………………………………………………… 15 2.4 Sampling Frame ………………………………………………………….. 15 2.5 Sampling Methods……………………………………………………….. 16 2.6 Selection Criteria………………………………………………………… 16 2.6.1 Inclusion Criteria ………………………………………………… 16 2.6.2 Exclusion Criteria ………………………………………………… 16 2.7 Sample size ………………………………………………………………. 17 2.8 Study tools ……………………………………………………………….. 18 2.9 Method of Data Collection ………………………………………………. 19 2.10 Statistical section ………………………………………………………… 20 2.11 Ethical Approval…………………………………………………………. 21 2.12 Ethical Considerations ……………………………………………………. 21
3.0 RESULTS ……………………………………………………………………….. 22
3.1 Characteristics of study participants ……………………………………… 22 3.2 Visual Acuity……………………………………………………………….22 3.3 Participants CD4+ T cell count levels ……..………………………...,,….. 23 3.4 Participants WHO HIV clinical stage……………………………………. 24 3.5 Contrast Sensitivity ………………………………………………………. 24 3.6 Contrast Sensitivity and HAART….. …………………………………….. 25 3.7 WHO HIV clinical stage and Contrast Sensitivity …………………….. 26 3.8 Contrast sensitivity and previous anti-TB treatment……………………… 27 3.9 CD4+ T cell count and contrast sensitivity………………………………....28 3.10 Colour vision………………………………………………………………..29 4.0 DISCUSSION ……………………………………………………………………. 31
4.1 Assessment of data ………………………………………………………. 31 4.2 Contrast sensitivity ………………………………………………………. 32 4.2.1 Prevalence of contrast sensitivity abnormality….…...………….….33 4.2.2 Effects of anti-TB treatment on contrast sensitivity………………...35 4.2.3 Contrast sensitivity and CD4+ T Cell count ………………………. 35 4.2.4 HAART and contrast sensitivity……………………………………36 4.3 Colour vision……………………………………………………………….37 4.3.1 Prevalence of colour vision abnormality…………………………...37 4.3.2 Effects of anti-TB treatment on colour vision….………………...38 4.4 Pathogenesis of visual dysfunction in HIV infected individuals ……….. 39 4.5 impact of visual function abnormalities in HIV positive children………….40 4.16 Limitations ………………………………………………………………. 41
5.0 CONCLUSIONS AND RECOMMENDATIONS ……………………………. 42
5.1 Conclusions ……………………………………………………………… 42 5.2 Recommendations ……………………………………….......................... 43
REFERENCES……………………………………………………………………44
APPENDIX I - English Subject Informed Consent …………………………… 52
APPENDIX II – Shona Subject Informed Consent …………………………….. 55
APPENDIX III – English Assent Form …………………………………………. 58
APPENDIX IV – Shona Assent Form …………………………………………… 59
APPENDIX V – Clinical Sheet and Questionnaire………………………………. 60
APPENDIX VI – WHO HIV Clinical staging …………………………………… 62
APPENDIX VII – Harare Central Hospital Ethics Committee Approval letter …. 63
APPENDIX VIII – Joint Research and ethics Committee Approval letter ……….. 64
ACKNOWLEDGEMENTS
I would like to express my gratitude to the following people and organizations for making this
work possible.
• Professor R Masanganise, for accepting my proposal for the study, for his personal
commitment, attention to detail and endless patience in supervising this study.
• Mr Mandozana for assisting me with the analysis.
• Dr M Patel and Dr J Washaya for allowing me to use their ophthalmic equipment for the
duration of the study and for their constant encouragement.
• Dr D Sibanda, Dr Y Jaya and Dr J Dari for their constant support and encouragement.
• The entire staff at Harare Central Hospital Paediatric Opportunistic infections clinic for
allowing me to work with them.
• NECTAR for funding this dissertation, the teaching and guidance they gave me and for
the resources they availed to make this study a success.
• The study participants for their willingness to assist me.
• My children Kristy, Chiara and Ryan for enduring long periods without me as I worked
on this dissertation. Thank you for being the stars in my sky.
• My wife Tsatsawani, whose support is always steadfast. Thank you for all the sacrifice,
love, patience and inspiration. I am forever grateful.
• To all those not mentioned here that contributed to this dissertation, Thank you.
i
LIST OF ABBREVIATIONS.
AIDS Acquired Immune Deficiency syndrome
ART Anti- Retroviral Therapy
BCDVA Best Corrected Distance Visual Acuity
CMV Cytomegalovirus
FM Fansworth Munsell
HAART Highly Active Anti Retroviral Therapy
HIV Human Immune Deficiency Virus
Log CS Logarithm of contrast sensitivity score
OD Right Eye
OI Opportunistic Infection
OS Left Eye
p p value
PMTCT Prevention of Mother To Child Transmission
RNFL Retinal Nerve Fiber Layer
SD Standard Deviation
SKH Sekuru Kaguvi Hospital
TB Tuberculosis
UCDVA Uncorrected Distance Visual Acuity
WHO World Health Organization
ii
LIST OF DIAGRAMS
Diagram I: CD4+ T cell count levels among participants……..…………................23
Diagram II: WHO HIV clinical grading among partic ipants………………………24
Diagram III: Distribution of contrast sensitivity scores among participants………25
Diagram IV: Contrast sensitivity in patients who had taken anti-TB treatment
previously…………………………………………………………………………..…….27
iii
LIST OF TABLES
Table 1: Overview of ocular manifestations of HIV .…………………………………….... 05
Table 2: Association between WHO HIV clinical stage and contrast sensitivity….…. . …26
Table 3: Association between CD4+ T Cell count and contrast sensitivity… ………….. ..28
Table 4: Relationship between color vision and contrast sensitivity……….……………. ..29
iv
1
ABSTRACT
TOPIC
Patterns of visual function abnormalities in HIV positive children attending Harare
Central Hospital’s paediatric Opportunistic Infecti ons clinic:
INTRODUCTION
Vision is composed of five simultaneous functions: visual acuity, colour vision, contrast sensitivity, visual field and stereopsis. These functions of vision are affected by disease processes that affect individual structures of the eye and the visual pathway. Human Immune Deficiency Virus (HIV), Highly Active Antiretroviral Therapy (HAART), Opportunistic Infections (OI) and the drugs used in their treatment have an effect on the eye and the visual pathway. This makes HIV positive children more likely to have poor visual function than the general paediatric population, however there is limited data available on visual function in HIV positive children both in Zimbabwe and sub- Saharan Africa.
OBJECTIVES
1. To characterise the patterns of selected visual function abnormalities (contrast sensitivity and colour vision) in HIV positive children attending an Opportunistic Infections clinic.
2. To quantify the prevalence of contrast sensitivity and colour vision abnormalities in HIV positive children.
3. To establish the existence and type of association between either of these visual functions and CD4+ T cell count, WHO HIV clinical stage and previous anti-Tuberculosis treatment.
DESIGN
This was a cross sectional study of patients attending the Harare Central Hospital’s paediatric Opportunistic Infections Clinic, Harare, Zimbabwe.
METHODOLOGY
Systematic sampling was used to recruit participants. A structured questionnaire was used to gather patient information. A complete ocular examination was done inclusive of Visual acuity (Snellen chart), colour vision (Ishihara plates), Contrast sensitivity (Pelli Robson chart), Slit lamp and dilated fundus examination.
RESULTS
1. A total of 168 participants were enrolled into the study (age range 7-12 years). BCDVA was better or equal to 6/12 in 98.8% of the participants.
2. The mean Log CS was 1.71 (range 1.2-1.95), with a standard deviation of 0.12.
3. The prevalence of poor contrast sensitivity was 12.5%, that of colour vision abnormality was 1.8%.
2
4. An association was established between poor contrast sensitivity and decreasing CD4+ T cell count (p=0.05).
5. Participants on HAART had a lower Log CS than those not on HAART (p=0.002).
6. Participants on second line HAART therapy had a lower Log CS than those on first Line HAART therapy, (p=0.02).
7. There was no associations established between previous anti TB treatment in participants and abnormalities in contrast sensitivity (p=0.63) and colour vision (p=0.50).
CONCLUSION
This study showed that poor contrast sensitivity is common in HIV positive children, with decreasing CD4+ T cell count being associated with poor contrast sensitivity. Contrast sensitivity abnormalities were found to occur even with good visual acuity.
3
CHAPTER 1
1.1 INTRODUCTION
According to the 2012 estimates, Zimbabwe has 180 000 children below the age of 14 years
living with the Human Immunodeficiency Virus (HIV) [1]. Significant progress has been made
towards reducing HIV and Acquired immune deficiency syndrome (AIDS) mortality and
morbidity [2].There however is still much to be done to reduce ophthalmic morbidity in children
with HIV/AIDS. This study aims to contribute towards this by collecting data that will give an
appreciation of the characteristics and magnitude of HIV ophthalmic morbidity in Zimbabwe.
Ocular manifestations of HIV were first described in 1982 [3]. At that time the priority was given
to rapidly progressive manifestations of HIV such as CMV retinitis. The introduction of Highly
Active Anti-Retroviral Therapy (HAART) has led to a dramatic decrease in HIV related
morbidity and mortality in the developed as well as developing world [4]. Whilst HAART has
been effective in reducing rapidly progressive retinopathies, there are other ocular manifestations
of HIV which have yet to be characterised and addressed. These include problems of visual
dysfunctions (reduced contrast sensitivity, altered colour vision and visual field defects) that can
occur in HIV- infected individuals without infectious retinopathies [3], to that end, this study
seeks to characterise selected visual function abnormalities (contrast sensitivity and colour
vision) in an HIV positive paediatric population.
Vision is composed of five simultaneous functions namely: visual acuity, colour vision, contrast
sensitivity, visual field and stereopsis. If vision is normal, seeing is so effortless that we do not
notice the different visual functions [5]
4
These functions of the eye are affected by disease processes that affect the individual structures
of the eye and the visual pathway. Visual dysfunction has also been clearly demonstrated in HIV
positive patients even in the absence of retinitis [6].
Visual Acuity is the minimum angle of separation between two objects that allow them to be
seen as distinct [7]. It is the acuteness or clearness of vision, which is dependent on the sharpness
of the retinal focus within the eye and the sensitivity of the interpretive faculty of the brain [8].
Visual acuity is tested by requiring the person whose vision is being tested to identify
standardized characters, like letters and numbers, on a chart from a known distance. Various
charts can be used to measure visual acuity namely, the Snellen chart, LogMAR chart, Landholt
C, Lea test and Jaeger chart.
Contrast sensitivity describes the ability of the visual system to distinguish an object against its
background [9]. Contrast sensitivity is affected by various factors like age, refractive errors,
amblyopia, optic nerve diseases, glaucoma and changes in the crystalline lens [10]. The Pelli
Robson chart, Hamilton-Veale chart and Sine wave grating tests are used to measure contrast
sensitivity.
Colour vision is the ability of the eye to distinguish objects based on the wavelengths of light
they reflect from their surface [11]. Colour vision testing is done using the Ishihara pseudo-
isochromatic plates, Fansworth Munsell-100 Hue test and the Lanthony desaturated test among
others.
5
1.2 LITERATURE REVIEW
1.2.1 OCULAR DISEASES IN HIV
Ocular diseases in HIV can be divided according to the anatomical segment of the eye involved,
that is to say: adnexal, anterior segment, posterior segment, retro-bulbar and neurological.
Another way of classifying ocular diseases in HIV is with the stage of HIV disease at which they
occur as shown in table 1 below [12].
Table 1: Overview of ocular manifestations of HIV [12].
STAGE CD4/ cells/mm3
EXTERNAL EYE
ANTERIOR SEGMENT
POSTERIOR SEGMENT
NEURO-OPHTHALMOLOGY
Seroconversion Normal
500- 1500
Inflamed conjunctiva
Dry Eye
Headaches
Retro-orbital pain
Early HIV Infection
500-1000
Allergic conjunctivitis
Reiters syndrome
Uveitis
HIV Retinopathy
Uveitis
Retinal Vasculitis
Optic neuropathy
Intermediate HIV Infection
200-500
Dry eye Blepharitis Bacterial and follicular conjunctivis Karposis Sarcoma Molloscum contagiosm
Herpes Zoster Herpes simplex
HIV retinopathy TB Uveitis
Aspergillosis
Late 0-200 Opportunistic infections and tumours affecting all ocular structures.
6
A study carried out in Milan Italy demonstrated a reduction in ocular manifestations of HIV in a
paediatric population in the HAART era [13] So effective was HAART in this regard that the
researchers, Esposito S et al, made a conclusion that the frequency of ophthalmologic follow up
of patients on HAART may need to be reduced. Anecdotal data at Sekuru Kaguvi Eye Unit
Parirenyatwa Hospital, Harare, suggest a reduction in ocular manifestations of HIV. The setting
of the Milan study differ from our Zimbabwean setting in terms of the socioeconomic
circumstances of the study population as well as the fact that the virus sub type that is endemic in
Sub Saharan Africa ( subtype A and C) is different than that in Milan, Europe (Subtype B).
Therefore overarching conclusions cannot be drawn. There is therefore a glaring need for local
research that is relevant to Sub Saharan Africa and Zimbabwe in particular.
In an article reviewing studies published between 2000 and 2002 on ocular manifestations of
HIV/AIDS, Moraes makes the assertion that in this HAART era, many patients with HIV will
still develop ocular manifestations at some point[14] . These ocular manifestations will impact
negatively on the visual function of HIV positive patients. Ocular manifestations of HIV are
common and occur at any stage of the disease, therefore awareness and screening of these
conditions may be necessary [15].
Results from a hospital based cross sectional study in western India by Shah, Kerkar and Pazare
showed that the prevalence of ocular manifestations in HIV/AIDS patients on HAART was 8%.
Visual impairment was found in 6% including one person with blindness[16].
In a pre HAART era study by Padhani, Manji and Mtanda of ocular lesions among 62 HIV
seropositive and 47 HIV sero-negative children admitted to the paediatric ward in Tanzania, the
prevalence of ocular manifestations was 38% among the HIV seropositive children and 25%
among HIV sero-negative children [17]. In addition, HIV seropositive children had a 10%
7
prevalence of abnormal visual acuity compared with HIV sero-negative children who had a 6 %
prevalence. [17]
These findings mirrored those from a similar study by Ikoona et al that sought to describe the
ocular manifestations of HIV/AIDS infection in an African paediatric population in Mulago
Uganda. The population prevalence of HIV was 12% at the time of their study. The overall rate
of ophthalmic involvement was 35%. [18]. There is no published Zimbabwean data on ocular
manifestations of HIV in the paediatric population.
1.2.2 PREVENTION OF MOTHER TO CHILD TRANSMISSION (P MTCT)
Provision of PMTCT services in Zimbabwe started as a pilot in 1999 and was rolled out
nationally in 2002 and it has been rapidly expanding since then [1]. At present 95% of health
facilities in public sector are offering PMTCT services [1]. Zimbabwe is committed to improving
maternal and child health outcomes according to the commitments of the Global Plan to
eliminate new HIV infections among children by 2015 launched in 2011 in New York at a high
level meeting on HIV and AIDS [1]. The country is rolling out the provision of more efficacious
regimen for PMTCT according to the WHO 2010 guidelines. All infants and children below the
age of two years are now receiving HAART regardless of their CD4+ T cell count, because of
this, more children are now on HAART before they get severely immune compromised and this
has increased the life expectancy of these children.
8
1.2.3 ANTIRETROVIRAL THERAPY AND OTHER DRUGS
The pattern of ocular manifestations of HIV has changed with the widespread introduction of
HAART [4, 16]. Whilst HAART treats some HIV related ophthalmic diseases, it has also been
implicated as a cause of others.
Chu DS et al described a keratopathy in HIV positive patients in which all the patients had intra-
corneal precipitates with normal visual acuity (contrast sensitivity and colour vision were not
assessed), in a retrospective case series[19]. These observations warrant further investigation.
Didanosine, a reverse transcriptase inhibitor has been reported to cause retinopathy in children
(20), which may affect visual function.
Anti TB drugs, in particular ethambutol, have been known to cause optic neuropathy.[21].
Ethambutol toxicity most commonly presents between 3 and 5 months after initiation of anti-TB
therapy as bilateral painless visual loss and/or decreased colour vision [22, 23]. With cessation of
treatment visual acuity may recover over several months. This recovery may not be complete
with deficits in visual field, colour vision and contrast sensitivity [22, 23] The reported range in
visual acuity improvement following cessation of therapy is between 20% and 80% [23].
Rifabutin, (another anti-TB drug) has been shown to cause an immune mediated hypersensitivity
type of Uveitis [24].
Sulphonamide containing drugs such as Cotrimoxazole and other drugs like Nevirapine can
cause hypersensitivity reactions such as Stevens Johnson syndrome, which can result in dry eyes,
symblepharon, ankyloblepharon and corneal scarring thus reducing visual function.
9
1.2.4 VISUAL FUNCTION
In American studies by Plummer et al and Mueller et al, they reported visual dysfunctions in a
significant number of HIV positive patients without retinitis [25, 26]. Plummer et al’s patients
were assessed for visual field defects whilst Mueller et al’s participants were assessed for colour
vision, contrast sensitivity and visual fields. A normal visual acuity does not preclude the
possibility of visual function deficits as some sero-positive patients have been found to have
deficits in visual function whilst visual acuity remains normal and CD4 counts relatively high[26].
In another American study by Kaylani et al, they found that retinal vasculopathy was associated
with abnormal visual function in people with AIDS, manifested by visual field loss and possibly
reduced contrast. [27]. Up to 70% of patients with AIDS develop a microangiopathy which is
postulated to be caused by HIV infection of the retinal vascular endothelium, haemorheological
abnormalities and abnormal retinal haemodynamics [28]. This microangiopathy tends to be
associated with a decreasing CD4+ T cell count, and is an indicator of advanced HIV disease [28,
29]. Visual function abnormalities may develop in HIV positive children as a result of the
described retinal microangiopathy and as reported by Kalyani et al.
10
1.2.5 COLOUR VISION
Colour vision is a function of three populations of retinal cone cells each with its specific
sensitivity: blue (tritan) at 414-424nm, green (deutan) at 522-539nm, and red (protan) at 549-
570nm [30]. Colour is therefore determined by the ability of these three populations of cone
receptors to distinguish objects based on the wavelength of light emitted or reflected from their
surface.
Geier et al reported blue colour vision defects in some patients on zidovudine [31]. Zidovudine
also happens to be one of the main drugs used as first line management in our clinics.
In an American adult study by Shah et al on contrast sensitivity and colour vision in human
immunodeficiency virus (HIV)-infected individuals without infectious retinopathy, the
prevalence of abnormal contrast sensitivity and abnormal colour vision were 7.0% and 9.9%,
respectively. They also noted that abnormal contrast sensitivity and abnormal colour vision can
occur independently of each other in HIV-infected individuals and can be present in the absence
of severe immunosuppression [32].
In a study by Geier et al in which they used a highly sensitive computer graphics system to
measure colour contrast, they reported a relationship between impaired tritan colour contrast
sensitivity and progression or severity of HIV disease [33].
11
1.2.6 CONTRAST SENSITIVITY
Contrast sensitivity is a measure of the ability of the visual system to distinguish an object
against its background. The target must be sufficiently seen and be of high enough contrast with
its background. [34].
Tests for visual acuity do not adequately reflect the ability of the eye to see low contrast objects
like faces. In many conditions like optic neuritis, amblyopia, cataracts and higher order
aberrations, the visual acuity may be normal, whilst the contrast sensitivity is considerably
reduced [35].
Defects in contrast sensitivity have been observed in an American study by Mueller A J et al in
which they analyzed visual dysfunction in HIV positive patients without retinitis [26]
In a pilot study done in Scotland by Mutlukan E on low contrast visual acuity changes in HIV
infection, low contrast visual acuities of the HIV positive patients both with and without HIV
retinopathy were found to be significantly lower than the age-matched controls (p < 0.01). This
finding is probably attributable to pathology related to HIV in the visual pathways. Lowest
contrast chart (Landolt Chart C) was found to be a useful diagnostic tool for HIV retinopathy and
presumed neuropathy.[36]
Recent case control studies in an adult South African population done by Pathai et al have shown
that HIV infection is associated with ocular changes in retinal vessel caliber, lens density and
corneal endothelial cell density consistent with accelerated HIV related aging[37,38,39] . In the
same cohort it was reported in a consequent analysis that high viral load >2log copies/ml was an
independent indicator of poor contrast sensitivity in the HIV positive group [40].
12
1.3 JUSTIFICATION OF STUDY
1. To the researcher’s best knowledge, in Zimbabwe there is no baseline information from
research on visual function and ocular diseases in the HIV positive paediatric population.
Makan M studied ocular diseases in HIV sero-positive adults attending an opportunistic
infections clinic in Harare Zimbabwe[41], the results of her study cannot be extrapolated to
the paediatric population. HIV related ophthalmic diseases in children must be studied
because they tend to be more severe than they are in adults and irreversible because of
exaggerated inflammatory reaction and the risk of amblyopia, hence the need for this
study.
2. The introduction of HAART has dramatically increased longevity in HIV positive
children. Most of these children are now living into adulthood. However, the long term
effects of HIV, HAART and associated opportunistic infections on visual function has
not been fully characterized. The type and association between CD4 count and WHO
HIV Clinical stage with Visual function has not been fully characterized.
3. Baseline data on visual impairment of HIV positive children allows for more targeted
allocation of screening activities and funds.
4. Ophthalmologists have a role to play in the multidisciplinary approach to improved
quality of life of HIV/AIDS patients. In order to effectively play our role, we need to
have an idea of the problem and its magnitude so that we can implement evidence based
interventions that will guide our contribution on the care of the HIV infected child.
13
1.4 PROBLEM STATEMENT
In a population of attendees at the paediatric Opportunistic infection clinic at Harare Central
Hospital, Harare, Zimbabwe, a large proportion of the patients would have had or have ocular
manifestations of HIV disease. Some would have been treated for opportunistic infections like
tuberculosis, and a large proportion of them will be on HAART. These factors and the HIV
infection have a predisposition to lower the children’s visual function. The magnitude of visual
abnormalities and the type of associations with HIV WHO clinical stage and CD4 count is not
known to the clinicians attending to these children. There is also no screening in place for visual
function.
1.5 RESEARCH HYPOTHESES
1. HIV sero-positive children are more likely to develop at least one form of abnormal
visual function.
2. The visual function abnormalities in sero-positive children correlate with WHO HIV
clinical stage and CD4+ T cell count.
14
1.6 STUDY OBJECTIVES
1.6.1 PRIMARY OBJECTIVE
1. The primary objective of this study was to characterize patterns of selected visual
function abnormalities (contrast sensitivity and colour vision), in HIV positive children
attending Harare Central Hospital’s paediatric Opportunistic Infections clinic.
1.6.2 SECONDARY OBJECTIVES
1. To quantify the prevalence of contrast sensitivity and colour vision abnormalities in HIV
positive children.
2. To establish the existence and type of association between CD4+ T cell count and visual
function.
3. To establish existence and type of association between WHO HIV clinical stage and
visual function.
4. To analyse the existence and type of any correlation between previous anti-TB treatment
and visual function.
5. To recommend evidence based intervention strategies to lessen the burden of visual
function abnormalities in sero-positive children.
15
CHAPTER 2
RESEARCH METHODOLOGY
2.1 STUDY DESIGN
A hospital based cross sectional study was carried out from November 2013 to May 2014.
2.2 STUDY SETTING
The study was conducted at the paediatric Opportunistic Infections clinic at Harare Central
Hospital, one of the two tertiary referral hospitals in Harare, Zimbabwe. Patients are referred
from Municipal clinics, private clinics and provincial hospitals, or they may present directly to
the hospital. The clinic was started in 2003 and provides service to HIV positive patients below
the age of 16 referred from within its catchment area.
2.3 STUDY POPULATION
HIV sero-positive children aged between 7 and 12 years attending Harare Central Hospital’s
paediatric Opportunistic Infections Clinic. The age group (7 -12 years) was chosen because at
that age full emetropization of the eye is expected to have been complete, and also the required
tests are easier and more accurate to carry out.
2.4 SAMPLING FRAME
Any patient, who met the inclusion criteria and presented to the paediatric Opportunistic
Infections Clinic at Harare Central Hospital, constituted the sampling frame.
16
2.5 SAMPLING METHOD
Each week, participants who presented to the Harare Central Hospital paediatric OI clinic
between Monday to Thursday, and met the inclusion criteria, were recruited into the study.
Systematic sampling was used to recruit participants, taking one in every two patients.
2.6 SELECTION CRITERIA
2.6.1 INCLUSION CRITERIA
• Participants who had tested HIV positive on ELISA test.
• Participants aged 7 years up to 12 years (inclusive).
• Participants with a recent (within 2 months) CD4+ T cell count result.
• Participants who had a guardian above 18 years of age who was able to give consent to
the study.
• Participants who had given assent to the study.
2.6.2 EXCLUSION CRITERIA
• HIV sero-negative.
• Age below 7 years and above 12 years.
• Participants without a recent CD4+ T cell count result.
• Major vision threatening ocular complication that preclude testing for contrast sensitivity
and colour vision
• Accompanying Parent/guardian below 18 years of age.
• Refusal to sign consent or refusal to give assent.
17
2.7 SAMPLE SIZE
Sample size was determined using Dobson’s Formula for cross-sectional studies.
n= Z2 x (P) x (1-P)
C2
n = Sample Size
Z = Reliability coefficient (e.g., 1.96 for a 95 percent confidence level)
p = Prevalence. (0.08%)
C = Effect size.
Data for sample size calculation was taken from a 1999 study carried out in America by Myers
et al, in which the proportion of 8% was the prevalence of poor contrast sensitivity in 10 year old
children in a general paediatric population.
A confidence interval of 95% was used, where Z = 1.96, P = 0.08, (1-p) = 0.92 and C = 0.05
n = 1.962 x (0.08) x (0.92)
0.052
n = 113.1
The minimum sample size required was 113 Patients. However we achieved a sample size of
168.
18
2.8 STUDY TOOLS
The study tools were the following;
• Clinical data collection sheet and questionnaire
• Snellen letter and illiterate E charts.
• Pelli Robson contrast sensitivity chart
• Ishihara pseudoisochromatic plates.
• Slit lamp biomicroscope
• Indirect ophthalmoscope
• 20 Diopter and 90 Diopter lenses
• Retinoscope with trial lens
• Dilating drops, (cyclopentolate 0.5%)
• Patients’ notes and results.
The clinical sheet and interviewer administered questionnaire were used to collect data. To
ascertain and to validate the psychometric reliability of these tools, they were pretested on 10
paediatric OI clinic attendees in June 2013. Subsequently defects in both were amended before
use in the final study. All participant examinations and questionnaire administration was done by
the researcher.
19
2.9 METHOD OF DATA COLLECTION
Patients were recruited by systematic sampling method. Children in the age group 7 -12 years
were included in the study. A questionnaire was used to collect data on medical history, current
treatment and socio-demographic data, during the clinic time. General ocular examination with
emphasis on best corrected distance visual acuity (BCDVA) testing and refraction by cycloplegic
retinoscopic refraction was done.
Color vision was tested using the Ishihara pseudo-isochromatic plates in ambient daylight, in the
same room.
Contrast sensitivity was assessed using the Pelli- Robson contrast sensitivity letter chart (Haag
Steit, Essex, UK), in ambient daylight in the same room. This chart is viewed at 1 meter and
consists of rows of letters of equal size but with decreasing contrast of 0.15 log units for groups
of three letters. The participants read down the rows of letters starting with those of highest
contrast until the last resolvable group of three letters is reached. The score was determined by
the last group in which two or three letters were correctly named [34].
Each participant’s monocular visual acuity was tested using the Snellen’s letter or illiterate E
chart with the participant at 6 meters in ambient daylight. Light from an indirect ophthalmoscope
at maximum light intensity was used to confirm perception of light or no perception of light.
Patients with uncorrected distant visual acuity (UCDVA) worse than 6/12 were assigned as
having defective vision. Distant visual acuity was then assessed for participants with defective
vision with the participants reading through a pinhole. At the end of the examination a
cycloplegic retinoscopic refraction was done. Hirchberg test was used to determine presence of
strabismus. Patients whose best corrected distance visual acuity (BCDVA) did not improve by 2
or more lines on Snellen’s chart in the absence of organic disease were retested using single
20
letters on a subsequent visit to crudely rule out amblyopia. A cover uncover test was carried out
on all patients in order to ascertain the presence or absence of strabismus. Extra-ocular motility
and pupillary reactions were tested before both eyes were dilated with cyclopentolate 0.5% and
slit lamp biomicroscopy examination carried out.
Dilated fundoscopy was performed using a 90D lens on a slit lamp biomicroscope or an indirect
ophthalmoscope using a 20D lens.
Medical records for the participants were reviewed after the clinical examination in order to
mask the examiner and reduce bias. These records were used to collect demographic data and
current CD4 count. WHO HIV Clinical stage was graded by experienced paediatric
opportunistic infections clinicians according to the WHO HIV grading in appendix H. All
patients who were found to have ocular diseases were informed of their condition, treated
accordingly and/or referred to Sekuru Kaguvi Eye Hospital for further management.
2.10 STATISTICAL SECTION
Data were entered into a Microsoft excel spreadsheet database before being exported, cleaned
and analyzed in STATA version 12.0 (STATA Corp, College Station, TX) software. The
patients’ socio-demographic characteristics and measurement results were evaluated using
descriptive statistics, such as tables, frequency tables, pie charts, etc. Proportions were compared
using standard methods, the Chi-square, (χ2) and Fisher’s exact tests as appropriate.
All statistical significance was evaluated with 95% confidence at p≤0.05.
21
2.11 ETHICAL APPROVAL
Permission to carry out the study was obtained from the Harare Central Hospital’s Clinical
Director (See appendix VII)
Ethical clearance was obtained from the Joint Research and Ethics Committee (JREC) (see
appendix VIII)
2.12 ETHICAL CONSIDERATIONS
The participants in this study were minors and consent was given by their respective care givers
who had to be above the age of 18 years (age of majority in Zimbabwe). The participants
themselves also gave assent.
22
3.0 RESULTS
3.1 CHARACTERISTICS OF STUDY PARTICIPANTS.
A total of 168 participants were enrolled. The participants’ ages ranged from 7 years to 12 years
with a mean age of 10.58 years, and SD of 1.3. There were 88 males (52.4%) and 80 females
(47.6%). Most of the participants (140 participants; 83.3%) were on HAART whilst 28
participants (16.7%) were not on HAART. Of those who were on HAART, 117 participants
(83.6%) were on first line HAART treatment and 23 participants (16.4%) were on second line
HAART treatment.
Forty one participants (24.4%) had previously been on anti-TB treatment, and 123 (73.2%) had
never been on anti-TB treatment. Four participants (2.4%) were currently on treatment. Further
analysis regarding previous anti-TB treatment included those participants on current anti-TB
treatment and those who were no longer on treatment, bringing the total number of participants
grouped as ‘previous anti-TB treatment’ to 45 participants (26.8%).
3.2 VISUAL ACUITY
Most of the participants (98.8%) had BCDVA of 6/12 or better. One hundred and fifty one
participants (89.9%) had BCDVA of 6/6.
23
3.3 PARTICIPANTS’ CD4+ T CELL LEVELS
Diagram I: CD4+ T cell count levels among participants.
The participants’ mean CD4+ T cell count was 655 cells/mm3, ranging from 7 - 2219 cells/mm3.
Most of the participants (99 participants; 58.9%) had CD4+ T cell levels above 500cells/mm3
24
3.4 PARTICIPANTS WHO HIV CLINICAL STAGE
22.8%
29.8%
33.9%
13.5%
Stage 1
Stage 2
Stage 3
Stage 4
KEY
Diagram II: WHO HIV clinical grading among particip ants.
Most of the participants were in WHO HIV stage 3 (57 participants; 33.9%), and followed by
WHO HIV clinical stage 2 (50 participants; 29.8%).
3.5 CONTRAST SENSITIVITY
The mean log contrast sensitivity was 1.71 in the right eye, left eye and on binocular vision. The
standard deviation was 0.12 and the minimum and maximum values were 1.2 and 1.95
respectively. There were no inter-ocular differences in mean log contrast sensitivity.
Subsequently, for each participant the Log CS of the right eye was used in the evaluation of any
associations in relation to mean log contrast sensitivity.
25
Diagram III: Distribution of contrast sensitivity scores among participants
Twenty one participants (12.5%) had poor Log contrast sensitivity scores of 1.5 and below.
Most of the participants (147 participants; 87.5%) had normal contrast sensitivity scores of 1.65
and above, with 75 participants (44.6% of all participants) having a log contrast sensitivity score
of 1.65.
3.6 CONTRAST SENSITIVITY AND HAART
The mean (SD) contrast sensitivity of the 140 participants that were on HAART was 1.69 (0.12)
and that of the 28 who were not on HAART was 1.77 (0.12). This difference was statistically
significant, (p=0.002).
The mean CD4+ T cell count of participants on HAART was 642 cells/mm3, and that of
participants not yet on HAART was 719 cells/mm3.
26
Of the participants that were on HAART, most were on first line HAART therapy (119
participants; 85%) and 21 participants (15%) were on second line therapy.
Further subgroup analysis showed the mean Log CS (SD) of the participants that were on first
line HAART therapy was 1.74(0.12), and that of those participants on second line HAART
therapy was 1.68(0.11), (p=0.02). This difference was statistically significant.
The mean CD4+ T cell count or the participants who were on first line therapy was
748cells/mm3, and for the participants who were on second line HAART therapy it was
245cells/mm3.
3.7 HIV CLINICAL STAGE AND CONTRAST SENSITIVITY
Table 2: Association between WHO HIV clinical stage and Contrast sensitivity.
WHO HIV
STAGE
Contrast sensitivity (n=168)
Abnormal Normal Frequency of
Abnormality
N % n % %
1 2 1.2 37 22 5.1
2 7 4.2 44 26.2 13.7
3 8 4.8 47 27.9 14.5
4 4 2.4 19 11.3 17.4
The above table illustrates the frequencies of the WHO HIV clinical stages among the various
participants stratified by contrast sensitivity (whether normal or abnormal).
There was no correlation between WHO HIV clinical stage and contrast sensitivity (p=0.34).
27
3.8 CONTRAST SENSITIVITY AND PREVIOUS ANTI - TB TREATMENT
Diagram IV: Contrast sensitivity in patients who had taken anti-TB treatment previously.
Most of the participants (123 participants; 73.2%) had no previous anti-TB treatment, of which
most, (108 participants) had normal contrast sensitivity.
Most of the participants with previous anti-TB treatment (39 participants; 86.7%), had normal
contrast sensitivity.
There was no correlation between previous anti-TB treatment and contrast sensitivity (p=0.63).
The mean (SD) contrast sensitivity of the 123 participants who had no previous anti- TB
treatment was 1.70 (0.12) whilst that for the 45 participants who had previous anti-TB treatment
was 1.72 (0.11). The difference was not statistically significant, (p=0.3).
28
Four participants were on TB treatment at the time of study. Their mean Log CS (SD) was
1.63(0.23). Forty one participants were no longer on anti TB treatment at the time of study, and
their mean Log CS (SD) was 1.73(0.10). The difference was not statistically significant,
(p=0.10).
3.9 CD4+ T CELL COUNT AND CONTRAST SENSITIVITY
Table 3: Association between CD4+ T Cell count and contrast sensitivity.
CD4+T Cell
Level
Contrast sensitivity (n=168)
Abnormal Normal Frequency of
Abnormality
N % n % %
500+ 8 4.8 92 54.9 8
350 - <500 6 3.6 18 10.7 25
200 - <350 2 1.2 19 11.3 9.5
<200 5 2.9 18 10.7 21.7
The above table illustrates the frequencies of participants CD4+ T cell levels stratified by
contrast sensitivity
There was a marginal correlation between participants CD4+ T cell count levels and contrast
sensitivity (p=0.05). Poor contrast sensitivity was associated with low CD4+ T cell count.
29
3.10 COLOUR VISION
One hundred and sixty five participants (98.2%) had normal colour vision whilst three (1.8%)
had mild dysfunction. Of the 3 participants with mild colour dysfunction, 2 had CD4+ T cell
levels in the range 200 up to less than 350, and 1 had CD4+ T cell levels above 500. There was
no association found between colour vision and CD4+ T cell count (p = 0.75)
Of the three participants with mild colour dysfunction, one was in WHO HIV clinical stage 1, the
other was in stage 2 and the last one was in stage 4. There was no association found between
colour vision and HIV clinical stage (p =0.50)
A history of anti-TB treatment was found in 2 of the participants with mild colour dysfunction
whilst 1 had no prior history of anti-TB treatment. There was no relationship found between
previous anti-TB treatment and colour vision dysfunction (p = 0.50)
Table 4: Relationship between colour vision and contrast sensitivity.
COLOR VISION
Normal Mild dysfunction Abnormal
CONTRAST (n=165) (n=3) (n=0)
Normal (n=147) 144 3 0
Poor contrast
sensitivity (n=21)
21 0 0
The table above illustrates the distribution of colour vision in patients with normal or poor
contrast sensitivity. Most of the participants (144 participants; 85.7%) had both normal colour
vision and contrast sensitivity. Twenty one participants (12.5%) had poor contrast sensitivity but
30
normal colour vision. There was no association between abnormal colour vision and poor
contrast sensitivity (p= 0.91)
31
CHAPTER 4
DISCUSSION
4.1 ASSESSMENT OF DATA
This study reflects the general patterns of visual function (contrast sensitivity and colour vision)
abnormalities in the Zimbabwean paediatric HIV positive population. A key strength of this
study is the large number of the study participants compared to previous studies of visual
function in HIV positive patients. In addition, to the author’s best knowledge, this is the first
study to characterize patterns of visual function abnormalities in a paediatric HIV positive
population not only in Zimbabwe but also in Southern Africa. The results of this study add to the
growing body of literature on visual function in HIV positive paediatric patients in this HAART
era. A case control study would have given more accurate comparisons from which more
conclusions could be drawn; however the results of this study are a reliable indicator of visual
function patterns in this population.
The results of this study prove the two hypotheses put forward by the author. In this study HIV
sero-positive children were 1.6 times more likely to develop at least one form of abnormal visual
function (contrast sensitivity), and that poor contrast sensitivity was associated with low CD4+ T
cell count.
32
4.2 CONTRAST SENSITIVITY
In this study the mean (SD) contrast sensitivity was 1.71(0.12).
Several studies have been conducted which sought to define normative data for contrast
sensitivity in children. Some used measures of contrast sensitivity other than the Pelli Robson
Contrast sensitivity charts, whilst in some; data from children was not separated from adults.
In studies by Myers et al [45], Fitzgerald et al [46], and Dowdesmell et al [47], the Pelli Robson
Chart was used to collate normative data for contrast sensitivity in children. In this way their
studies are more comparable to the researcher’s. Of all normative data studies, the one by Myers
et al [45] compares well with this study. Their cohort was comprised of 10 year olds. This was
similar to the mean age in this study (10.58 years). This study lacked an age matched control
group who are HIV negative. Therefore, Myers et al’s study was used to compare data. In this
study we graded contrast sensitivity using expected distribution from the study by Myers et al
[45]. From their data the mean Log CS was 1.67 (0.12SD). Poor contrast was defined as a Log CS
value of 1.5 and below as calculated and described in a previous paper by Shah et al [42].
Our mean (SD) contrast sensitivity of 1.71(0.12) compared with data from the study by Myers et
al which showed a mean contrast sensitivity of 1.67 (0.12).
In Australia, Fitzgerald et al reported a mean (SD) contrast sensitivity of 1.89(0.97) [45]. Their
cohort consisted of 49 children aged between 8 to 12 years of unknown HIV status. They tested
binocular contrast sensitivity. The mean (SD) for binocular contrast in this study of 1.71(0.12)
was lower than that found by Fitzgerald et al. The small sample size that Fitzgerald et al used
(49 compared to 168 in this study), decreases the accuracy of their results
33
In an American study on a general paediatric population by Hargadon et al, they found a right
eye mean contrast sensitivity (SD) of 1.63(0.12SD) and 1.65(0.06SD) for the left eye. [46], these
values were lower than the value of 1.71 found in this study. Hagardon et al’s study population
of 6 year olds was younger than in this study (7 -12 year olds).
In HIV positive adult populations, the mean contrast sensitivity scores reported by Shah et al [42],
Freeman et al [47] and Kalyani et al [48] were 1.64, 1.65, 1.87 respectively. Shah et al and Freeman
et al’s results were lower than in this study (1.71) whilst that reported by Kalyani et al was
higher.
The setting of these studies differs from the African setting in which this study was done, and
their study participants were mainly Caucasians. A Southern African study with a larger sample
size would allow for more accurate comparisons.
4.2.1 PREVALENCE OF CONTRAST SENSITIVITY ABNORMALITY
The prevalence of poor contrast sensitivity in this study was 12.5%, which was slightly higher
than the 8% prevalence of poor contrast sensitivity in Myers et al’s study [44]. This could be due
to the different study setting and that their participants were mostly Caucasians whilst in this
study they were Black Africans. It may also be because of the effects of the HIV virus, OIs and
HAART therapy in this study’s population. The HIV status of the participants in Myers et al’s
study was unknown
Shah et al[42], Freeman et al[47] and Kalyani et al[48] have conducted studies on visual function in
HIV positive adult American populations. Their reported prevalence of poor contrast sensitivity
were 7.0%, 12.0% and 2.9% respectively. The prevalence of poor contrast sensitivity in this
study was comparable to that by Shah et al and Freeman et al.
34
In a South African study, Pathai et al reported an unadjusted mean contrast sensitivity of 1.77 in
a cohort of 216 HIV positive adults [40]. This value was higher than the one we found in this
study.
These studies were conducted in adult populations. The American studies were done mainly in
Caucasians. The mean age for Shah et al’s study was 46.3 years [42] whilst it was 42 years for
Freeman et al’s study [47]. The participants in Pathai et al’s study were aged 30 years and above.
Contrast sensitivity varies with age. It is lower in the extremities of age [49]; that is in children
and those above 60 years of age, hence we expect the contrast sensitivity values from this study
to be lower than those in the adult study. Comorbidities found in adult populations like diabetes
mellitus [50] and hypertension may result in poor contrast sensitivity and make accurate
comparisons difficult. In addition the mean CD4+ T cell count in this study was higher (655
cells/mm3) than in the American studies (180 cells/mm3 in Freeman et al’s study)
The sample size in this study (168) was larger than that in Shah et al’s (71 participants) and
Kalyani et al’s (57 participants) studies. This reduces the reliability of their studies.
This study was done at one referral hospital by one examiner meaning that all the participants
were examined under the same conditions and using the same tests which increased
comparability of results between individual participants. The study by Freeman et al was done at
19 sites and that by Kalyani et al was done at 2 sites. Different examiners, different study
conditions and in some cases different study tools were used in each study. In Kalyani et al’s
study they used different contrast sensitivity charts between the 2 sites, Different contrast
sensitivity charts can result in different contrast sensitivity scoring [48]. This reduces reliability
and comparability of their results.
35
4.2.2 EFFECTS OF ANTI-TB TREATMENT ON CONTRAST SENSITIVITY
Anti TB drugs, in particular ethambutol and pyrazinamide cause visual function abnormalities
[51]. Goyal et al found that maximum recovery of contrast sensitivity occurred between 6 to 8
weeks post cessation of anti-TB therapy [51]. In this study, participants on anti-TB treatment had
lower mean log CS (1.63) compared to those who were no longer on treatment (1.73). This
difference was however not statistically significant, probably because of the few numbers
(4 participants) of those on anti-TB treatment at the time of study. There was no relationship
established between contrast sensitivity and previous anti TB treatment in this study, (p=0.63.)
A future study with larger numbers may be necessary to determine the extent of the effect of
anti-TB treatment on contrast sensitivity.
The participants in this study had an average of 55 months (range: 2-132 months) post cessation
of anti-TB therapy. This may be the reason why visual dysfunction in relation to anti-
tuberculosis therapy was not significant, as the maximum visual function recovery of patients
with ethambutol optic neuropathy was reported to occur in the first six to eight weeks after
stopping ethambutol .[51]
4.2.3 CONTRAST SENSITIVITY AND CD4+ T CELL COUNT
In this study a marginal association was found between decreasing CD4+ cell count and poor
contrast sensitivity (p =0.05).
Freeman et al reported a relationship between the mean contrast sensitivity and decreasing CD4+
T cell count in eyes that had vision of 20/20. In addition they noted a strong significant
relationship between CD4 + T cell count and the left tail of the distribution curve of contrast
sensitivity [47]. In our study 89.9% of the participants had BCDVA of 20/20 and a marginal
36
relationship between CD4+ T cell count and contrast sensitivity was established. Shah et al could
not identify any relationship between contrast sensitivity and CD4+ T cell count [42].
The mean CD4+ T cell count in Freeman et al’s cohort was 180 cells/mm3 [47] which is lower
than the mean CD4+ T cell count of 655 cells/mm3 in our study. Some of Freeman et al’s
participants were recruited from the Longitudinal Study of Ocular Complications of AIDS
(LSOCA), whose participants had a diagnosis of AIDS and CD4+ T cell counts less than or
equal to 200 cells/mm3. The low CD4+ T cell counts may explain why they found a stronger
association between decreasing CD4+ T cell count and poor contrast (p=0.02) compared to that
found in this study, which was marginal (p=0.05). Low CD4+ T cell count is associated with
poor contrast sensitivity, as has been established in this study.
The average nadir CD4+ T Cell count in Freeman et al study was 42 cells/mm3 (ranging from
13 – 106 cells/mm3) [47] , which is low. However we were unable to accurately compare this with
this study as the nadir CD4+ T Cell count was unavailable for most of the participants. The low
nadir CD4+ T cell count may be another reason why Freeman et al had a stronger association
between CD4+ T cell count and Contrast sensitivity than in this study. Due to the PMTCT
program in Zimbabwe, HIV in children tends to be diagnosed and treated early before significant
decline of CD4+ T cell count ensures.
4.2.4 HAART AND CONTRAST SENSITIVITY
In this study HAART therapy in general, and second line HAART therapy in particular were
found to be associated with poor contrast sensitivity. This could be explained by the low mean
CD4+ T cell counts among participants on second line therapy (245 cells/mm3) compared to
either participants on first line therapy (748 cells/mm3) or participants not on HAART (719
37
cells/mm3). The duration of HAART therapy may be another cause of poor contrast sensitivity.
This forms the basis for future studies.
4.3 COLOUR VISION
4.3.1 PREVALENCE AND ASSOCIATIONS OF COLOR VISION A BNORMALITIES
In this study the prevalence of colour vision dysfunction was 1.8%. We found no association
between colour vision and any of the following: level of CD4+ T cell count, HIV clinical stage
and previous anti TB treatment. No association was found between colour vision and contract
sensitivity (p=0.91).
Shah et al used the FM – 100 test and did not find a relationship between impaired colour vision
and impaired contrast sensitivity [42]. Their study suggested a possible relationship between Low
CD4+T cell count and poor colour vision [42].
In an American study, Kalyani et al reported a 40.2% prevalence of abnormal colour vision in
adults [48]. They tested colour vision using the Lanthony Desaturated 15 –Hue test. Shah et al
found a comparable prevalence of abnormal colour vision of 31% using FM – 100 Hue test [42].
The results from this study using the Ishihara Plates (1.8%) were much lower than in these
studies.
The Ishihara pseudo-isochromatic test plates were used to test colour vision in this study. This is
not the best test to use in this particular study as it is mainly designed to test congenital red-green
colour defects. The more appropriate test to use would have been the Farnsworth – Munsell 100
– Hue test (FM – 100) or the Lanthony Desaturated 15 Hue colour vision tests which are more
sensitive in detecting acquired colour vision abnormalities. The use of a different test makes it
difficult to compare results from this study with previous studies on colour vision.
38
4.3.2 EFFECTS OF ANTI-TB TREATMENT AND COLOUR VISIO N
In this study only 4 participants were on anti TB treatment whilst 46 had a history of having
received anti TB treatment. The average time post cessation of anti TB treatment in the 46
participants was 55 months (Range: 2 months -132 months). Cruz et al in a study in Manila
Phillipines found that colour vision abnormalities returned to normal within an average of 37.85
days after stopping ethambutol and pyrazinamide [52]. At the time of examination the colour
vision of this study’s participants had most probably returned to baseline
Cruz et al found a prevalence of 47.8% of abnormal colour vision in patients on anti-TB
treatment, using the Lanthony Desaturated- 15 Hue test [52]. In the same study no colour vision
abnormalities were detected using the Ishihara plates. Their study participant’s HIV status was
unknown, whilst in this study they were all infected with the HIV virus.
The study by Cruz et al [52] had older participants (age range 13-75years, mean 38.65 years)
compared to our study where the age range was 7 to 12 years with a mean of 10.58 years. Older
age was identified by Cruz et al as a risk factor for colour vision abnormalities in patients on
anti-TB therapy [52]. This finding further reduces the likelihood of colour vision abnormalities in
our young study age group.
A study by Wa Kaimbo D Kaimbo et al in the Democratic Republic of Congo revealed no
colour vision defects using the Ishihara plates, after 5 months of anti – TB treatment but a 36%
prevalence of colour vision defects when they used the FM-100 Hue test [53]. This shows the low
sensitivity of the Ishihara test in detecting acquired colour vision abnormalities.
It is therefore possible that if we had used a different test from the Ishihara plates in our study we
may have been able to report a significant number of participants with colour vision
abnormalities. Drawing conclusions from using the Ishihara plates is highly inaccurate.
39
The most sensitive tests for acquired colour vision testing like the Lanthony test and FM- 100
Hue test are not readily available in Zimbabwe and they are not easy to administer making them
unsuitable for use as screening tools. The Ishihara plates which are commonly used as screening
tools are less sensitive to acquired colour vision abnormalities and would give inaccurate results.
4.4 PATHOGENESIS OF VISUAL DYSFUNCTION IN HIV INFEC TED INDIVIDUALS
Retinal damage due to retinal micro-vasculopathy has been demonstrated in HIV positive
individuals without infectious retinitis [54]. Micro-vasculopathy has also been postulated as a
cause of poor contrast sensitivity in HIV [55]
It has also been postulated that the low contrast sensitivity found in HIV positive people is due to
thinning of the nerve fibre layer. This phenomenon has been reported in several American
studies [56, 57]. However Pathai et al in South Africa did not detect any association between CD4+
T cell count and Retinal Nerve Fibre layer thickness (RNFL) [40]. However, the same study also
found that ART duration was an important factor in determining RNFL thickness [40]. There was
no correlation between HAART duration and poor contrast sensitivity in this study. However,
HIV positive children will be on HAART for a long time, therefore their RNFL thickness may
invariably be affected by the HAART and subsequently visual function may be affected. There is
therefore need for continued surveillance of visual function in HIV positive children on HAART.
Pathai et al showed an association between poor contrast sensitivity and viral load ˃2 log
copies/ml [40]. We were unable to draw comparisons with our study since viral load
measurements were unavailable in the population we studied.
40
4.5 IMPACT OF VISUAL FUNCTION ABNORMALITIES IN HIV POSITIVE
CHILDREN
Poor contrast sensitivity and poor colour vision have negative impact in children, as early child
learning involves working with, identifying and matching colour and contrast. Impairment of
these visual functions during these early formative years leads to learning and reading difficulties
[58]. Functional impact of poor contrast sensitivity and poor colour vision has not been evaluated
in this study. West et al reported that 50% of patients with Log CS less than 1.40 have reading
difficulties [59]. In this study 11 participants (6.5%) had Log CS below 1.40 which means they
may have reading disabilities, which may impact negatively on their learning. Functional effects
of contrast sensitivity abnormalities were not assessed in this study.
It is possible that HIV positive children with low CD4+ T cell counts, who present with poor
vision, may be having poor contrast sensitivity even when their visual acuity is normal. This
necessitates routine contrast sensitivity examination in these children.
41
4.6 LIMITATIONS
1. A major limitation of this study is the lack of comparison with an age matched group who
are HIV sero-negative, tested under the same conditions as this study. Comparisons have
been made with adult populations due to lack of data on paediatric HIV positive
populations. Confounders like smoking and alcohol intake in adults makes accurate
comparison difficult.
2. There are no well established definitions for abnormality for contrast sensitivity. This
made determinations of true prevalence difficult and reliance had to be put on published
data which vary between different studies.
3. The use of Ishihara pseudo isochromatic plates to test colour vision was not the best as
this measures mainly congenital colour vision abnormalities. The more ideal test to use
would have been tests like the Fansworth Munsell 100 Hue test or the Lanthony
Desaturated 15 tests. Not having a baseline colour vision, we could not tell whether the
red-green deficiency was congenital or pathological.
4. The absence of nadir CD4+ T cell count made it difficult to compare visual function
between those severely immune compromised, those immune reconstituted and those who
had never been severely suppressed.
5. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts are the gold
standard for assessment of vision. However due to unavailability, the Snellen letter as well
as the E charts were used in this study.
42
CHAPTER 5
5.1 CONCLUSIONS
• Poor contrast sensitivity is common among HIV positive children attending Harare
Central Hospital’s Paediatric OI clinic.
• Low CD4+ T cell count is associated with poor contrast sensitivity.
• Poor contrast sensitivity can occur even when visual acuity is good in HIV positive
children.
43
5.2 RECOMMENDATIONS
• Functional effects of abnormal visual function were not assessed. Further studies to look
at effects on daily activities like schooling would need to be assessed.
• It is recommended that further research of visual function be done as a case control.
Prospective case control studies would be more informative where baseline data for
visual function is obtained and trends are monitored.
• Further research on the effects of HAART and/or duration of HAART therapy on visual
function is recommended.
• This study has shown no correlation between either of colour vision, contrast sensitivity
and previous anti TB treatment. However we know that anti TB drugs like ethambutol
affects visual function. We recommend further studies on visual function in patients
undergoing TB treatment. Starting with baseline visual function measurements before
anti TB initiation followed by serial visual function assessments so as to accurately plot
the trajectory of visual dysfunction in patients undergoing TB treatment.
• There is need for surveillance of visual function abnormalities in HIV positive children
on HAART. Visual function abnormalities, in particular contrast sensitivity, may need to
be examined for in patients presenting with visual problems, especially when their CD4
count is less than 200 cell/mm3.
44
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52
APPENDICES
APPENDIX I
SUBJECT INFORMED CONSENT
PROTOCOL TITLE:
Patterns of visual function in HIV positive children attending the Harare Hospital’s
Pediatric Opportunistic infections clinic
NAME OF RESEARCHER: Dr Tendayi Denford Mutungamiri
PHONE: 0772279144
PROJECT DESCRIPTION: Analytical cross sectional study.
YOUR RIGHTS Before you decide whether or not to volunteer your child for this study, you must understand its purpose, how it may help your child, the risks to you, and what is expected of you and/or your child. This process is called informed consent.
PURPOSE OF RESEARCH STUDY
1. To find out how the eyes of children who are attending Harare Hospitals’ Opportunistic
Infections Clinic are working.
2. To look for things that may be causing the eyes of the children to work poorly.
3. To find out how big the problem of poorly working eyes is in HIV positive children..
53
4. To find out whether certain levels of CD4 count and Viral load are associated with eyes
that may be working poorly.
5. Recommend ways to help the children attending OI clinic
PROCEDURES INVOLVED IN THE STUDY
Both the child’s eyes will be examined for free. This will include checking how well they can see by reading a chart at a distance and also how well they can see colors and contrast between objects. The examiner will instil drops in your child’s eyes to dilate the pupils so that he can see inside the child’s eyes.
The guardian and/or the child will be required to answer questions that will be asked by the interviewer. These questions will include personal details like child’s name, surname, age, gender, address, level of education, what problems the child has had with their eyes in the past, any past medical or surgical history.
The child’s medical records will be requested if available and data recorded on past ocular, medical and surgical history. This will include blood tests like HIV, Cd4 count and viral load. and any other drugs that the child is taking currently or has taken in the past.
If any diseases are found you and the child will be told and treatment where available will be prescribed. The child will be referred to Sekuru Kaguvi Eye Hospital if follow up treatment is needed.
The interviewer may contact you to confirm any information you will have supplied.
DISCOMFORTS AND RISKS
The drops that the examiner will instill in your eyes will dilate your pupil for easy eye examination. However because of the dilated pupils you will be unable to read small print for the first 2-6 hours . This effect will wear off within 24 hours. This should not be of concern, as it is part of any routine eye examination.
There are no other risks or discomfort to this study.
POTENTIAL BENEFITS
The results of this study will help us understand any visual difficulties that children with HIV/AIDS have and their effect on their quality of life. It will help us put in place programs to be able to be able to detect these problems early and help us improve their quality of life.
54
STUDY WITH DRAWAL
You may choose not to enter your child in the study or withdraw from the study at any time without loss of benefits entitled to your child.
CONFIDENTIALITY OF RECORDS
All the information you will provide will be strictly confidential, only the researcher Dr Tendayi Mutungamiri and the Supervisor Prof R Masanganise will have access to it.
PROBLEMS/QUESTIONS
Please ask questions about this research or consent now. If you have any question in future please ask. Dr Tendayi Mutungamiri (0772 279 144, [email protected] )
AUTHORIZATION
I have read this paper about the study or it was read to me. I understand the possible risks and benefits of this study. I know being in this study is voluntary. I choose for my child to be in this study: I know I can stop my child from being in the study and they will not lose any benefits entitled to them. I will get a copy of this consent form. (Initial all the previous pages of the consent form)
____________________________________________________________________________
Guardian’s Signature Client’s Assent Date
__________________________________________________________________
Guardian’s Name (Printed) Clients Name
______________________________________________________________________________
Researcher Signature Date
______________________________________________________________________________
Witness Signature Date
55
APPENDIX II
UNIVERSITY OF ZIMBABWE
COLLEGE OF HEALTH SCIENCES
CONSENT FORM
ZITA: ONGORORO YEMASHANDIRO EMAZISO MUVANA VANEUTAC HIWANA
HWE HIV VARIKURAPWA PACHIPATARA CHE HIV PA PARIRENY ATWA.
TICHIENZANISA NEAVO VANA VASINA HUTACHIWANA HWE HIV .
MUKURU WETSVAKIRUDZO: DR TENDAYI MUTUNGAMIRI
RUNHARE: 0772279144
MAVAMBO
Ndinokukumbirai kuti mupinde muchidzidzo chekuongorora mashandiro emaziso evana.
Mugwaro rino retenderano, ndinotsanagudza chinaNgwa, njodzi nerubatsiro retsvakiridzo ino.
Makasununguka kubvunza mibvunzo pamunodira. Kana muchinge manzwisisa chinangwa uye
nekubvuma kuvamuchidzidzo, ndichakumbira kuti musaine gwaro rino. Imi muchapihwa gwaro
renyu rekuchengeta rakafanana neirori.
CHINANGWA
Chinangwa chedzidzo ino ndechekuongorora mashandiro emaziso evana vane HIV uye kuti
vanoona zvakanaka sei. Tichaongorora kuti pane musiyano here mumaonero avo uye mashandiro
56
emaziso avo tichienzanisa nevana vasina utachiwana hweHIV. Tichatsvaka zvacho zvinosakisa
kuti maonero avo aveakadzikira kana zvinosakisa kuti maziso avo asashanda zvakanaka.
ZVICHAITWA MUCHIDZIDZO
Kana muchinge matenda kupinda muchidzidzo muchabvunzwa nezveupenyu hwemwana.
Magwaro enyu ehurwere hwemwana achaongororwa. Mwana achatariswa maonero emaziso ake
nemashandiro emaziso ake, nekuzotariswa kuti angaone zvakanaka here nemagirazi. Zvese izvi
zvichaitwa kamwe.
NGOZI NEZVISINA KUNAKA ZVINGANGOITIKA KWAMURI
Zvatichaita hazvinanjodzi kumaziso emwana. Tichangoongorora sezvatinoita maziso ose evana
pavanouya kuchipatara chemaziso. Mwana anogona kumbonetsekana nekuona kwenguvadiki
(isingapfuuri maawa gumi nemairi) kana taisa mushonga wekuti tione kumashure kwemaziso
ake.
RUBATSIRO RWECHIDZIDZO
Chidzidzo chichatibatsira kuziva maonero kana mashindiro emaziso evana vane utachiwana
hweHIV zvichienzaniswa neavovasina utachiwana hweHIV. Zvozotibatsira kuti vanogona
kubatsirwasei pachinenguva kuti vaone zvakanaka, zvigovabatsira muchikoro nemuhupenyu.
Mwana anenge aongororwa muchirongwa chino akaonekwa anedambudziko nemaziso ake
anobvaaendeswa kwaanowana rubatsiro.
CHENGETEDZO ZVAKAVANDIKA
Zvese zvichabvunzwa nekuitwa zvichachengetedzwa zvakavandika. Magwaro enyu
achazivikanwa nenamba kwete nezita renyu. Gwaro richaratidza kuti makapihwa number ipi
57
richachengetwa pane nzvimbo yakasiyana naDr Tendayi Mutungamiri. Pane imwenguva, veJoint
Research and Ethics Committee and Medical Research Council of Zimbabwe vanogona
kudakuona zvinyorwa zvenyu kuti vaone kuti mitemo yekodzero yevapinda mutsvakiridzo iri
kuteverwa here.
KODZERO YAKASUNUNGUKA YOKUPINDA
Makasununguka kuita sarudzo yokupinda mutsvakiridzo musingamanikidzwi. Mukafunga kuti
hamudi hazvikanganisi kurapwa kwenyu kana hukama hwenyu nechipatara. Hamudikubhadhara
kana kubhadharwa kana mapinda muchidzidzo ichi. Kwese kuvhenekwa kwamuchaitwa kunenge
kuchingotevedzera maitirwo anoitwa kuneupi neupi zvake anouya kuzoongororwa maziso.
CHITSIDZIRANO
Ndaverenga kana ndaverengerwa gwaro iri nezvechidzidzo ichi ndikanzwisisa nezvenjodzi kana
rubetsero rwandinogona kuwana muchidzidzo ichi. Ndinoziva kuti ndinogona kurega
kuvemuchidzidzo pandinodira. Izvi hazvikanganisi kurapwa kwangu.
Saini yomurwere_________________________ Zuva ranhasi______________________
Zita remurwere____________________
Saini yechapupu nezita rake.______________________________________
Zuva ranhasi_____________________________
Saini yachiremba vechidzidzo__________________________________________
Zuva ranhasi______________________________
58
APPENDIX III
UNIVERSITY OF ZIMBABWE
COLLEGE OF HEALTH SCIENCES
ASSENT FORM
STUDY NAME: A study to find out problems in eyes of children attending , Harare Central Hospital’s Opportunistic infections Clinic.
STUDY DONE BY: DR TENDAYI MUTUNGAMIRI
PHONE NUMBER 0772279144
We want to tell you about a research study we are doing. A research study is a way to learn information about something. We would like to find out more about problems in how the eyes work in children attending Harare Central Hospital’s Opportunistic infections (OI) clinic. You are being asked to join this study because you are one of the children between 7 and 12 years of age attending this OI clinic.
If you agree to join the study you will be asked some questions about you and your health. Your eyes will be examined by the Doctor to see if there are any problems. If problems are found, they will be treated.
You do not have to join this study. It is up to you. You can say yes now, and you can change your mind later. All you have to do is tell us. No one will be angry at you if you change your mind.
Anything we learn about you from this study will be kept a secret.
Before you say yes to be in this study we will answer any questions you have.
If you want to be in this study please sign your name. You will get a copy of this form to keep for yourself.
( Sign your name here and write date)
59
APPENDIX IV
UNIVERSITY OF ZIMBABWE
COLLEGE OF HEALTH SCIENCES
SHONA ASSENT FORM
ZITA: Chirongwa chekuongorora matambudziko emaziso muvana vanorapwa pa Harare Hospital Opportunistic ( OI ) clinic.
MUONGORORI : DR TENDAYI MUTUNGAMIRI
NHARE : 0772279144
Tinoda kukuudza nezve chirongwa chekuongorora matambudziko kana zvirwere zvemaziso muvana vari kurapwa pachipatara che Harare Central Hospital Opportunistic Infections (OI) Clinic.
Unokumbirwa kuti upinde muchirongwa ichi. Wasarudzwa nemhaka yekuti unemakore ari pakati pe 7years ne 12 years, uye uri kurapwa pa chipatara chino che OI.
Kana ukabvuma kupinda muchirongwa, uchabvunzwa mibvunzomaererano nehupenyu hwako uye utano hwako. Maziso ako achaongororwa nachiremba. Kana paine chirwere chabatwa, chicharapiwa.
Hauna kusungirwa kupinda muchirongwa ichi. Isarudzo yako. Unogona kubvuma kupinda muchirongwa nhasi, uye unotenderwa kushandura pfungwa watove muchirongwa, chete unongofanirwa kutiudza. Hapana anokutsamwira ukashandura pfungwa.
Zvose zvaunotiudza zvichachengetedzwa.
Kana uine mibvunzo unotenderwa kubvunza.
Kana uchida kuve muchirongwa ichi nyora zita rako, uye ne zuva ranhasi pasi apa. Iwe uchawanawo pepa rakadai.
( Nyora zita rako ne zuva ranhasi.)
60
APPENDIX V
Patterns of visual function abnormalities in HIV positive children attending Harare
Central Hospital’s Paediatric OI clinic:
CLINICAL SHEET AND QUESTIONNAIRE
CLINICAL SHEET
Name: Hospital File number: Age/Sex:
Right eye Left eye Unaided distance visual acuity Distance VA with pinhole Distance VA with glasses Best corrected distance VA Refraction Ocular adnexa
Anterior segment
Posterior segment
• Contrast sensitivity score • Colour Vision result Other findings
Main diagnosis
Past drug history: TB treatment Anti Retrovirals Cotrimoxazole Other
61
Is the Participant on HAART? YES NO
Is the Participant on first line HAART Therapy? YES NO
Is the Participant on second line HAART Therapy? YES NO
Date HAART initiated:_______________________________________
CD4+ T cell count at HIV diagnosis______________________________________________
Latest/Current CD4+ T cell Count_______________________________________________
WHO HIVclinical stage_____________________________________________________
COMMENTS
62
63
64
65