LOCALISED.html
ORIGINAL ARTICLE
Localised treatment and 6-month outcomes in
patients with cytomegalo-virus retinitis at a tertiary ophthalmology
service in Ga-Rankuwa
Fatima Laher, MB BCh, Dip HIV Man (SA)
Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg
Claire Cullen, FCOphth, MMed
J Baile Matlala, FCOphth, MMed
Department of Ophthalmology, Dr George Mukhari Hospital, Ga-Rankuwa, Gauteng
Corresponding author:
F Laher (laherf@phru.co.za).
Objective.
There are few data from before the antiretroviral therapy (ART) era for
cytomegalovirus retinitis (CMV-R) from settings where cost limits use
of systemic treatment. This study examines CMV-R treatment and survival
outcomes in a public hospital ophthalmology service in Ga-Rankuwa,
South Africa.
Methods.
From October 2009 to October 2010, voluntarily consenting participants
over the age of 15 years with incident clinically diagnosed CMV-R seen
at the Dr George Mukhari Hospital ophthalmology clinic were
prospectively enrolled in an observational study. Treatment was per
clinic protocols and patients were followed up with structured data
collection for up to 6 months.
Results.
Eight individuals, all HIV infected and 50% female, were identified and
enrolled. At enrolment, median age was 38 years (interquartile range
(IQR) 32 - 39 years), median CD4 count 20 cells/μl (IQR 13 - 46.5
cells/µl), and 50% were currently receiving ART (mean duration of ART
use 18 days, standard deviation (SD) 2.99 days). No participant
received systemic ganciclovir, but 6 reported symptom combinations
suggesting systemic CMV: shortness of breath (n=3), diarrhoea (n=3) and/or central nervous system complaints (n=3).
Ten eyes had visual impairment less than counting fingers at enrolment.
Treatment combinations were: ART plus intravitreal ganciclovir (n=5), intravitreal ganciclovir alone (n=2), and ART alone (n=1). Six-month outcomes were: death (n=1), survival (n=6), loss to follow-up (n=3), untraceable (n=1), systemic symptom resolution (4/4), visual acuity deterioration (0/5), and persisting uveitis (2/3).
Conclusion.
In the ART era, incident CMV-R appears to be uncommon in this setting.
CMV-R may occur within the first 3 weeks after ART initiation. Even in
CMV-R patients with suggestive systemic symptoms, 6-month survival is
good despite no systemic CMV therapy.
S Afr J HIV Med 2012;13(2):68-71.
South Africa has both a high burden of HIV disease1 and a large, expanding antiretroviral therapy (ART) programme.2 It is noteworthy that many South African HIV patients present for treatment when the CD4 count is less than 50 cells/μl.3
Particularly in these individuals with advanced immune compromise,
opportunistic infections such as cytomegalovirus (CMV) may present. The
most commonly recognised manifestation of CMV is CMV retinitis (CMV-R),
but pneumonitis, colitis, oesophagitis, adrenalitis, and neurological
involvement are also described.4
In Africa, data describing the disease burden of CMV-R in the ART
era are limited. In the pre-ART era, a 20-month longitudinal study in
AIDS patients in Togo confirmed a 21.4% incidence.5
Also in the pre-ART roll-out era in South Africa, 90 AIDS patients were
treated for CMV-R at the University of Natal, and the incidence was
noted to increase with time.6 A cross-sectional study screening all HIV patients with CD4 counts of <50 cells/μl in Khayelitsha, South Africa, found 2% of these patients to have CMV-R.5
CMV-R treatment strategies include localised and systemic
therapies optimally used in combination and in initiation and
maintenance phases, and the use of ART in the context of HIV diagnosis.
CMV has been called the ‘neglected disease of the AIDS
pandemic’, in part because of limited access to treatment,
especially in the developing world, where localised intra-ocular
ganciclovir implants and systemic oral valganciclovir are unavailable
or too costly.5
Intravitreal ganciclovir injections, although more cost-effective,
require highly skilled administration and may be inconvenient and/or
unacceptable to patients.7
ART combined with CMV treatment strategies is associated with an
improvement in median survival after CMV-R diagnosis from 6 months to
over 1 year.8
,
9 There are few ART-era data for CMV-R from African countries where cost limits the use of systemic CMV therapy.
This study describes the incidence of CMV-R in a public
hospital outpatient ophthalmology clinic in Ga-Rankuwa, South Africa,
over a 1-year period and examines treatment and survival outcomes of
CMV-R cases over a 6-month follow-up period, so as to inform future
CMV-R care.
Methods
Setting
A prospective longitudinal observational study was
conducted at the ophthalmology outpatient clinic of the Dr George
Mukhari Hospital, a state tertiary academic service situated in
Ga-Rankuwa, Gauteng province, South Africa. The hospital has a
catchment population of 1 800 000 people from the surrounding Tshwane
and Metsweding areas. In 2007, the antenatal HIV seroprevalence in
Tshwane was 27% and in Metsweding it was 33%.10
At the time of the study, the hospital also offered an on-site HIV
clinic with free ART access for HIV-infected adults with CD4 counts
less than 200 cells/µl or World Health Organization (WHO) stage 4
disease. ARV roll-out began in August 2004. In this setting,
ophthalmology referrals are made by healthcare workers in the hospital
and HIV clinic or in secondary and primary level facilities. Referral
is based on presentation with any visual symptoms. In 2011, the HIV
clinic saw 7 853 patients of whom 193 initiated ART during that year.
Eligibility
Patients were eligible for entry into the study if
they were aged 15 years or older; able to provide voluntary written
informed consent (for those 18 years or older) or assent with
parent/guardian consent (for those between 15 and 17 years old); and
presented at Dr George Mukhari Hospital ophthalmology clinic with new
clinically diagnosed CMV-R during the 1-year enrolment period of the
study.
Case definition
The CMV-R case definition was visualisation of at
least one of the following on dilated pupil indirect ophthalmoscopy:
indolent retinitis characterised by mild granular retinal opacification
which may be associated with a few punctuate haemorrhages but absent
vasculitis, or fulminating retinitis characterised by mild vitritis,
vasculitis with perivascular sheathing and retinal opacification,
dense, white, well-demarcated, geographical area of confluent
opacification often associated with retinal haemorrhages, and slow
relentless brushfire-like extension along retinal vascular arcades that
may involve the optic nerve.11
Data collection
From 6 October 2009 to 6 October 2010,
participants identified by clinic staff as having a possible CMV-R
diagnosis from routine retinal screening (indirect ophthalmoscopy with
fully dilated pupils) were referred to study representatives at the
same clinic for assessment of eligibility, voluntary informed consent
procedures and enrolment into the study.
Structured data collection by ophthalmologists was done at
enrolment on the day of referral, and at months 3 and 6. This involved
two components: (i)
a clinical interview to record demographics, HIV status, CD4 count
results, use of ART and CMV treatments, ocular symptoms, and a brief
systemic symptom screen probing shortness of breath, diarrhoea, fever,
headache, change in personality and decreased concentration; and (ii)
visual acuity measurements using a Snellen chart or gross visual tests
for vision worse than 6/120, and an ophthalmological examination
including indirect ophthalmoscopy with fully dilated pupils to
categorise CMV-R zonal location and to assess the presence of CMV-R
complications, namely vitreous haemorrhage, cataract, endophthalmitis
and uveitis.
Treatment was neither influenced nor provided by the study,
but was managed by the clinic according to local standard of care.
Patients were referred to the HIV clinic for ART per South African
guidelines. Management of CMV-R in this setting was predetermined by
availability of ganciclovir only. Current accepted practice in the
developing world is intravitreal ganciclovir injection twice a week for the first 2 weeks, and then weekly until the CD4 count recovers to over 150 cells/µl
or retinitis becomes quiescent. However, intravitreal ganciclovir is
not recommended for patients who will not have recoverable vision, who
have less than 3 clock hours of disease in retinal zone 3 and no fundal
view, and who cannot come for regular injections.6
Telephonic tracing was undertaken for participants who did not attend follow-up appointments.
Statistical analysis
Descriptive statistics are reported. There were insufficient cases reported to analyse risk factors for outcomes.
Ethical considerations
Ethical approval was received from the Medunsa Research and Ethics Committee before initiating the study.
Results
Baseline characteristics
Over the 1-year enrolment period, 8
individuals were eligible and all agreed to participate in the study
(Table 1). All were HIV infected and 50% were female. The median age at
first appearance of CMV symptoms was 38 years (intraquartile rage (IQR)
32 - 39 years). At enrolment, the median CD4 count was 20 cells/μl
(IQR 13 - 46.5 cells/μl) and 50% were currently receiving ART (mean
duration of ART use prior to CMV presentation 18 days, standard
deviation (SD) 3 days).
Presenting ocular symptoms were either one or a combination of: blind spots (n=3), decreased vision (n=2), dry eyes (n=2), photophobia (n=2), eye redness (n=1), visual distortions (n=1) and ‘floaters’ (n=1).
Six participants (75%) reported systemic symptoms: shortness of breath (n=3), diarrhoea (n=3) and/or central nervous system complaints of headaches, personality changes and/or decreased concentration (n=3).
A summary of visual acuity is presented in Table 2. Ten eyes were
classified as having visual impairment less than counting fingers at
enrolment.
Indirect ophthalmoscopy at enrolment revealed bilateral retinal
involvement in 7 participants (88%). The most common retinal zone
affected was zone 3 (10 eyes), then zone 2 (8 eyes) and zone 1 (6 eyes).
Uveitis was found in 7 cases, and vitreous haemorrhage was present in 1 case (Figs 1 and 2).
Treatment
None of the participants received systemic therapy,
although 6 complained of systemic symptoms. The combination of ART and
intravitreal ganciclovir injections was given to 5 participants.
Intravitreal ganciclovir alone was given to 2 male participants who
both refused ART and defaulted from study follow-up. One patient, who
had no light perception bilaterally, received only ART because visual
benefit with intravitreal ganciclovir was not deemed likely.
Six-month outcomes
By month 6, 1 participant had died, 6 were alive and 1 was untraceable. Three participants had defaulted from follow-up.
Resolution of symptoms and complications at 6 months is described
for the 4 participants who remained in follow-up. Ocular symptoms
resolved for all 3 participants who received both intravitreal
ganciclovir and ART, but did not resolve in the participant who
received ART only. All 4 participants reported resolution of their
systemic symptoms.
Visual acuity outcomes are presented in Table 2. Among the 5
participants who were followed up to month 6, there was no recorded
deterioration in visual acuity from enrolment; 6 eyes demonstrated no
change and 4 eyes showed slight improvement.
Uveitis resolved in 2 of 3 cases, and in the third case where it
persisted, a cataract developed. There were no cases of endophthalmitis.
Discussion
This study found a low incidence of CMV-R at
a resource-constrained public hospital outpatient ophthalmology clinic
in Ga-Rankuwa, South Africa: only 8 cases were identified in a 1-year
period. The low incidence may be explained by the availability of ART
in this population.
In this setting, CMV-R remains an AIDS manifestation, and the late
presentation to care is highlighted not only by the low median CD4
count of 20 cells/μl but also by the advanced stage of visual loss
at enrolment.
Several studies from the pre-ART era describe improved or stable
visual outcomes with intravitreal ganciclovir injections for CMV-R
lesions.12
,
13 Importantly,
even though none of the 75% of participants who reported systemic
symptoms received systemic ganciclovir, the combination of ART and
intravitreal ganciclovir did ameliorate visual symptoms in our study.
However, possibly owing to severe visual loss, no patient had complete
recovery of vision.
Currently the authors are unable to predict whether the 6-month
outcomes reported here would have been better if state-of-the-art
treatments such as ganciclovir implants and systemic valganciclovir had
been available in our setting. A pressing question in the field of
cytomegalovirus medicine is the relative efficacy of localised versus
systemic treatment when CMV-R has been diagnosed, and until this is
answered, management remains individualised. When comparing localised
with systemic treatments, the latter carry an increased risk of
systemic side-effects but also a reduced risk of systemic CMV
dissemination.
There are several limitations to our study. First, the small sample
size prevents statistical comparison of outcomes by treatment
combination. Second, incidence may be underestimated because of missed
diagnoses and lack of presentation to hospital. Third, when screening
for systemic symptoms of CMV infection, no attempt was made to
discriminate from co-morbidities. It has been noted, however, that
systemic CMV symptoms have been misdiagnosed as Pneumocystis jirovecii pneumonia and tuberculosis, among others.14
Last, though we attempted in our mortality assessment to control for
treatment defaulting by telephonic tracing, loss to follow-up may
signify an underestimation of mortality, a phenomenon well described in
studies of ART programmes.15
In conclusion, CMV-R is an uncommon disease in the ART era in
Ga-Rankuwa, South Africa. Intravitreal ganciclovir, complemented with
ART, was an effective option to treat CMV-R.
Acknowledgements. The authors wish to
thank the hospital and the participants for their co-operation. This
study was not funded. The authors declare that they have no conflicts
of interest.
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Table 1. Summary of participant characteristics, treatment and symptoms at baseline and 6 months
Participant
Baseline characteristics
Six-month follow-up of symptomatic outcomes
Gender
Age (years)
Presenting ocular symptoms
Presenting systemic symptoms
CMV-R treatment
ART use
1
F
27
Decreased vision
Shortness of breath, diarrhoea, fever, headache, personality changes, decreased concentration
No
Yes
Ocular symptoms unresolved but systemic symptoms resolved
2
F
31
Ocular dryness
Diarrhoea
Intravitreal ganciclovir
Yes
Ocular and systemic symptoms resolved
3
M
44
Ocular redness and photophobia
Shortness of breath
Intravitreal ganciclovir
Yes
Defaulted follow-up but confirmed alive
4
F
39
Decreased vision
Nil
Intravitreal ganciclovir
Yes
Death
5
F
31
Ocular dryness
Diarrhoea
Intravitreal ganciclovir
Yes
Ocular and systemic symptoms resolved
6
M
39
Blind spots, visual distortions
Headaches, generalised pain
Intravitreal ganciclovir
Yes
Ocular and systemic symptoms resolved
7
M
44
Blind spots, ‘floaters’
Nil
Intravitreal ganciclovir
No
Defaulted follow-up and survival not ascertained
8
M
37
Blind sports, photophobia
Shortness of breath, decreased concentration
Intravitreal ganciclovir
No
Defaulted follow-up but confirmed alive
Table 2. Visual acuity at enrolment and month 6
Right eye (N=8)
Left eye (N=8)
Visual acuity category
Enrolment
Month 6
Enrolment
Month 6
6/6 - 6/12 vision
0
0
4
2
6/18 - 6/60 vision
2
2
0
0
Counting fingers to hand motions vision
3
1
2
2
Light perception to no light perception
3
2
2
1
Defaulted/died
Not applicable
3
Not applicable
3
Fig. 1. Fundus photograph of the
right eye of a 40-year-old woman with CMV-R. Vitreous haemorrhage,
retinal detachment and retinitis are shown by the retinal opacification
with associated retinal haemorrhages indicative of active CMV-R. The
picture appears out of focus because the vitreous haemorrhage is
anterior to the retina.
Fig. 2. Fundus photograph
of the left eye of the same patient as in Fig. 1. Retinal detachment
and retinitis are demonstrated by the retinal opacification and frosted
branch angiitis, indicating active CMV-R disease.