27 Cytomegalovirus retinitis in patients with AIDS

Background

Definition

Cytomegalovirus retinitis (CMV-R) is a necrotising retinitis caused by a double-stranded DNA virus that affects immunosuppressed or congenitally infected individuals.

Aetiology

Sight-threatening CMV disease only occurs in immunosuppressed individuals. Following primary infection, CMV is disseminated by the blood stream to various organs. In immunosuppressed hosts, retinal infection can occur at the time of primary infection or after reactivation of latent CMV. Whether latent CMV exists in retinal cells remains to be clarified. It is assumed, however, that in patients with chronic infection the virus reaches the eye to cause CMV-R by haematogenous spread after reactivation elsewhere in the body.1

Infection with CMV is very common among the general population, but in most cases it does not cause clinically apparent disease. Cytomegalovirus is, however, a wellknown cause of serious, even life-threatening, disease in immunosuppressed individuals, and in congenitally infected newborns.

All current specific treatments for CMV-R suppress CMV replication but do not eliminate the virus from the eye. Retinitis therefore eventually reactivates with lesion enlargement. Reactivation may be due to a number of factors, including inadequate drug delivery, resistant CMV strains and increasing immunosuppression.

Epidemiology in patients with AIDS

Cytomegalovirus retinitis is the most common ocular infection in patients with AIDS in the United States.2–5 The reported prevalence of AIDS-related CMV-R, before the use of highly active antiretroviral therapy (HAART), varied from 4% of ambulatory patients (primarily intravenous drug abusers)6 to 34% of eyes in an autopsy series of male

homosexuals.7 Cytomegalovirus retinitis is uncommon among African patients with AIDS, possibly due to death from other opportunistic infections before CMV disease can occur.8

With the introduction of HAART in the 1990s, there has been a fall in the incidence of CMV-R in the United States, and there is also a reducing proportion of Caucasian homosexual males of the total new presentations of CMV-R. In a study by Palella and associates they found that the incidence of cytomegalovirus retinitis declined from about 17 per 100 person-years to less than 4 per 100 person-years by mid 1997.9

Cytomegalovirus retinitis is reported less commonly among HIV-infected children than among HIV-infected adults.10 Cytomegalovirus retinitis in HIV-infected children generally does not develop for several years after birth, which reflects its association with declining immune function. Although CMV-R has been reported in HIVinfected infants,11–14 its occurrence at birth is not diagnostic of AIDS, since it may be a manifestation of congenital cytomegalic inclusion disease.

Prognosis

CMV-R results in relentless progression of disease resulting in expanding areas of retinal necrosis, unless treated by antiCMV drugs or controlled by immune reconstitution. In the pre-HAART era, prognosis for retention of useful vision in patients with CMV-R was reasonable on treatment with anticytomegalovirus therapies. At six months after the start of intravenous (IV) ganciclovir (GCV) or foscarnet therapy, at least 88% of patients retained 6/12 or better vision in the better eye.3 With the advent of HAART, maintenance antiCMV medications may be stopped in individuals who develop immune reconstitution and, providing immune recovery is adequately maintained, the retinitis remains inactive. However, despite stable retinitis, vision may still be affected by immune-recovery uveitis. (Three of 14 patients lost more than three lines of vision in a study by Whitcup et al.15)

Questions

1In HIV-infected people with CMV-R does anti-CMV therapy reduce the risk of loss of vision?

2In HIV-infected people with CMV-R what is the most effective anti-CMV therapy for primary treatment and re-treatment ?

3In HIV-infected people with CMV-R does the use of HAART reduce the risk of loss of vision?

The evidence

The types of studies included here are all randomised clinical controlled trials where anti-CMV-R treatments in AIDS patients were compared with respect to preventing progression of disease and all randomised controlled clinical trials where chronic maintenance therapy for CMV-R was discontinued after initiation of HAART.

There are no randomised controlled trials investigating the efficacy of intravitreal ganciclovir and foscarnet. No randomised controlled clinical trials have been published regarding discontinuation of CMV-R therapy after initiation of HAART. However, prospective non-randomised intervention trials have been published.15 Detailed summaries of the randomised controlled trials are given in table 27.1, with general comments on individual drugs below.

Intravenous ganciclovir

Intravenous GCV has been shown in a small randomised trial16 (n = 25, with 14 excluded) to be statistically significantly better in increasing time to progression of retinitis versus deferred therapy (42 v 16 days, P = 0·07). This study was carried out at a time when no other treatment was available and so suffers from the limitations of the study design and of a non-standard definition of progression. This study also introduced the now established treatment schedule of giving an initial high “induction” dose therapy for two to three weeks followed by a lower dose “maintenance” therapy to control clinically inactive retinitis. The efficacy of ganciclovir has been supported in other trials.3

Problems associated with intravenous therapy include those related to the drug itself, such as neutropenia, and those related to the mode of delivery, i.e. catheter-related sepsis.17

Oral ganciclovir

The studies evaluating the efficacy of oral GCV for therapy were carried out comparing it to IV GCV for maintenance only. Although the studies did not show any statistical difference in time to progression compared to IV

therapy (oral to IV, 50 v 63 days (P = 0·15),17 68 v 98 days (P = 0·63)18 and 53 versus 66 days (P >0·05),19 there was a

trend in all the studies for a longer mean time to progression in the IV group. This difference is more marked if medians and not mean times to progression are evaluated18,19 and reaches statistical significance in one trial when clinical and not photographic end-points are evaluated.19 Higher doses of oral GCV than the conventional 3 g/day may be more comparable in effect to IV GCV for maintenance therapy.20 Oral GCV is therefore used only as a maintenance therapy for controlled disease and has the advantage over IV GCV of avoiding the need of a central line and its associated risk of sepsis (NNH = 11).17

Ganciclovir implant

Ganciclovir may be delivered by means of a sustained release device implanted surgically through the pars plana. This allows high constant levels of drug to be delivered to the treated eye but not to the rest of the body and therefore may not protect against CMV disease elsewhere. The GCV implant is significantly better at delaying median time to retinitis progression compared to both placebo (implant versus placebo, 226 v 15 days)21 and IV GCV (implant versus IV, 221 v 71 days).22 No difference was found in time to progression between two different implant release rates of GCV.22 There is a higher rate of extraocular CMV disease and second eye involvement with CMV-R in patients on implant alone.22 A trial to evaluate the combination of a GCV implant with oral GCV was underpowered and no clear conclusions can be drawn to see if oral GCV helps prevent the extraocular CMV disease associated with the use of implant alone.23

Prodrug valganciclovir

Valganciclovir is an orally administered prodrug that is hydrolysed to GCV. An oral dose of 900 mg achieves similar GCV blood levels as 5 mg/kg of IV GCV. In a study comparing oral valganciclovir to IV ganciclovir for untreated CMV-R no statistically significant difference was found in the median time to progression of the two treatments (oral versus IV 160 v 125 days).24 The frequency of adverse events were similar between the two groups except that diarrhoea was more common in the oral group (NNH = 11) and catheter-related events were more common in the IV group (NNH = 20).24

Foscarnet

Intravenous foscarnet has been shown in a randomised trial25 to be statistically significantly better in increasing time to progression of retinitis versus deferred therapy

induction for 21 progression FOS abnormalities with (2) Not performed

controlled trial of randomised to outside zone 1,

delayedv FOS

3·2v weeks13·3

days then

foscarnet in the deferred treatment age = 18 to 60.

25 AIDSwith

safety in the prevention of cytomegalovirus

retinitis recurrence in patients with

)Continued (

17 AIDS

(1) Median survival

All patients induced The median time to Neutropenia

Oral ganciclovir as 161 patients, of Entry: CMV-R

was months11

anaemia0·17),

=P (

wasprogression

diagnosed within one with IV GCV

maintenance which 123

deferral group and 12%), neutropenia immediate

4 g of oral

retinitis in patients or immediate 13–60.

120 days (95% CI, (6/41 of patients, treatment groups

Exclusion: non-ocular probenecid

= 25)

n( treatment

with AAIDS.

.0·15)

=P (

CDV 5 mg/kg once 40–134 days) 15%), elevated

CMV requiring

randomised,

GI disease”. Low ANC, patient was

maintenance

24 retinitis

For abbreviations see Table 27.1.

Karnofsky score, or progression. The progressed during the CMV-R in fellow eye (2) Not performed

controlled clinical 1:1, if the

separate data for

ganciclovir randomised to 3 vision better than placed through a range 181 to unknown, disease 87 days

)Continued (

3 cells/mm

(2) No significant

implant plus oral into two groups: (1) Karnofsky score, ANC, 1 g tds and GCV GCV group 0·67 per in vitreous

indifference

person-year and 0·71 haemorrhage in GCV

or31) =n

(implant

plateletor Highcount.

diagnosednewly vganciclovir

groups in extraocular for cidofovir

=0·28) P(

powered, interpret

immunodeficiency

induction then and 13 days (95% CI inflammation

peripheral CMV-R One immediate female

in patients with treatment patient did Exclusion: Karnofsky alternate weeks 9–15 days) for 0·48/patient-year,

)Continued (

42 AIDS

(13.3 v 3·2 weeks, P = 0·004). Foscarnet use in this study was associated with renal (NNH = 4·3) and electrolyte abnormalities (NNH = 1·6). No statistically significant difference was found in a study comparing the efficacy of foscarnet to IV GCV (median time to progression foscarnet:GCV 59:56 days, P = 0·69).26 However, mortality was higher in the GCV treated group, with median survival for GCV:foscarnet being 8·5:12·6 months.27

Cidofovir

Intravenous cidofovir has been shown in two randomised trials28,29 to be statistically significantly better at increasing median time to progression of previously untreated retinitis versus deferred therapy (64 days v 21 days, P = 0·0528 and 120 v 22 days, P = 0·00130). In patients who have persistently active CMV-R not responding to foscarnet or GCV cidofovir, high dose (5 mg/kg) was more effective than low dose cidofovir (3 mg/kg)31 but was associated with more side effects such as nephrotoxicity. The major doselimiting effect of cidofovir is nephrotoxicity, but the drug may also cause ocular hypotony and uveitis. Concomitant administration of probenecid reduces nephrotoxicity.

Fomiversen

Fomiversen is an antisense oligonucleotide which has anti-CMV activity and is delivered by intravitreous injection. Fomiversen (at 165 micrograms/injection) has been shown in a randomised trial to be statistically significantly better at increasing median time to progression of previously untreated retinitis versus deferred therapy (71 days v 13 days, P = 0·0001). In patients who have persistently active CMV-R not responding to other therapies, fomiversen 330 micrograms/injection had a similar effect at delaying progression both at intense and less intense treatment frequencies. Ocular side effects included anterior uveitis, raised ocular pressure and a retinal pigment epitheliopathy.

Answering the questions posed

In HIV-infected people with CMV-R does anti-CMV therapy reduce the risk of loss of vision?

The evidence

As the majority of trials involve the proxy measure of “progression of retinitis” rather than change in vision as the study end-point, specific comments regarding a particular therapy with respect to vision loss cannot be made in the majority of trials. There is an assumption that slowing

progression of retinitis will prevent vision loss. However, some trials do address this issue (foscarnet-ganciclovir CMV- R trial).32 This trial showed that retinal detachment was a major cause of visual loss with a risk of 18·9% at 6 months (95% CI 14–23·8%) and 39% at one year,32 not just progression of retinopathy. It should be noted that certain interventions might themselves affect vision, by the complications of the surgical procedure itself (for example, ganciclovir implants or intravitreal injections) or by precipitating uveitis (for example, cidofovir).

In HIV-infected people with CMV-R what is the most effective anti-CMV therapy for primary treatment and re-treatment?

The evidence

Primary treatment

Foscarnet, ganciclovir (given as implant, prodrug or IV form), cidofovir and fomiversen are all significantly better than placebo at controlling progression of retinitis. MSL-109 adjuvant therapy has no effect on progression compared to placebo. Foscarnet and IV ganciclovir are equally effective. Valganciclovir is as effective as IV ganciclovir at delaying progression of retinitis. The ganciclovir implant is significantly better than IV ganciclovir at delaying progression of retinitis. Comparisons between other drugs cannot be made using times to progression alone, as the effect of different background antiretroviral treatment cannot be controlled for. There are no randomised controlled trials investigating the efficacy of intravitreal ganciclovir and foscarnet, and no comment has been made regarding these therapies.

Maintenance therapy

Foscarnet, ganciclovir (given as implant, oral, prodrug or IV form), cidofovir, and fomiversen are all significantly better than placebo at controlling retinitis progression. Comparisons between other drugs cannot be made using times to progression alone, as the effect of different background antiretroviral treatment cannot be controlled for, except when a specific trial addressed this issue. Trials designed to compare maintenance therapies showed that oral versus IV ganciclovir comparison in three trials showed no significant difference in time to progression. There was a trend, however, in all the trials of a longer time to progression in the IV group, and in one study there was a significant difference in the clinical but not the photographic mean time to progression.19 In the oral versus IV studies, the mean and not the more usual median time to progression was used for analysis and this may mask real difference in efficacy between the groups. In the setting of

patients receiving HAART, the ganciclovir implant plus oral drug and IV cidofovir have similar efficacy at controlling CMV-R progression (although this study was underpowered).

In HIV-infected people with CMV-R does the use of highly active anti-retroviral combination therapy reduce the risk of loss of vision?

The evidence

No randomised controlled trails are available. However non-randomised interventional studies suggest that antiCMV medications may be stopped in patients with stable CMV-R and elevated CD4+ T-lymphocyte counts.15

Summary

Currently there is no antiviral regimen that can completely prevent progression of disease unless a certain level of immune reconstitution has been achieved. Available treatments that are significantly better than placebo at controlling retinitis at induction are ganciclovir (IV, oral, prodrug and implant forms), IV foscarnet, IV cidofovir and intravitreal fomiversen. Maintenance therapies shown to be efficacious compared to placebo include ganciclovir (oral, IV and implant), IV foscarnet, IV cidofovir and intravitreal fomiversen. Comparative studies between drugs are limited; comparisons between times to progression from different studies should be viewed with great caution due to variation in both the study populations and the antiretroviral therapy in different studies. Comparative studies have shown similar efficacy in delaying progression of retinitis for IV ganciclovir and foscarnet, IV ganciclovir and oral valganciclovir for induction of treatment, and oral and IV ganciclovir for maintenance of stable retinitis. The ganciclovir implant is more effective at delaying progression than IV ganciclovir, and a combination of foscarnet and ganciclovir is more effective than each drug alone in treating relapsed retinitis.

Implications for research

Currently, information is lacking on comparative studies between different combinations of systemic treatments and local treatments. Future studies should utilise measures of quality of life outcomes, as well as time to loss of vision and progression in their analyses. Studies are required to better understand when anti-CMV therapy may be stopped after commencement of HAART and why, after a good response to HAART, some patients develop immune reconstitution uveitis or develop reactivation of CMV-R.

Implications for practice

Given the relative lack of comparative studies choice of treatment currently needs to take into account the side effect profile, the therapeutic regimen, quality of life, the presence or absence of extraocular CMV disease (as local therapy to the eye is not effective at treating systemic disease) and previous treatment (resistance may develop). Relatively few studies have made use of quality of life data (as treatment regimens themselves may affect this) or visual acuity outcome. Most studies use the proxy measurement of effect, “progression”.

In the available studies there are no randomised trials looking at the effect of HAART on control of CMV-R although non-randomised interventional studies and “expert-opinion” groups have suggested that anti-CMV therapy may be stopped once CD4+ T-cell count is above 150 cells × 106/l for six months.33 Occasional cases of new CMV-R have been reported in case series on patients that fulfil these parameters (one in 60 patients in a series by Song et al.43).

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