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Keywords:

  • cytomegalovirus (CMV) retinitis;
  • varicella-zoster virus retinitis

5.1 CMV retinitis (CMVR)

  1. Top of page
  2. 5.1 CMV retinitis (CMVR)
  3. 5.2 Other ocular infections of particular importance in the setting of HIV
  4. 5.3 References

5.1.1 Background and epidemiology

For potential CMV and antiretroviral drug–drug interactions please refer to Table 5.1.

Table 5.1.   Potential CMV and antiretroviral drug interactions
Drug nameInteraction with antiretroviralAction required
  1. This table lists some examples of drug–drug interactions with antiretrovirals and drugs used for the treatment of cytomegalovirus. As data and advice change frequently, this information should always be interpreted in conjunction with the manufacturer's information (http://www.medicines.org.uk). Other useful web-based reference sources include the Liverpool HIV drug information website (http://www.hiv-druginteractions.org) and the Toronto Clinic (http://www.hivclinic.ca/main/drugs_interact.html).

Antiviral  
Valganciclovir/ganciclovirZidovudine levels increased and valganciclovir/ganciclovir levels reduced (slightly)Monitor for signs of haematological toxicity
Didanosine levels increased with both oral valganciclovir, ganciclovir and IV ganciclovirMonitor
LamivudineNot recommended to be used together. Seek HIV specialist pharmacist advice
TenofovirCaution – monitor for signs of increased renal toxicity with concurrent or recent use of valganciclovir/ganciclovir
FoscarnetLamivudineNot recommended to be used together. Seek HIV specialist pharmacist advice
TenofovirCaution – monitor for signs of increased renal toxicity with concurrent or recent use of foscarnet
CidofovirZidovudine levels increasedMonitor for signs of zidovudine toxicity Consider potential interaction with probenecid which is coadministered with cidofovir
TenofovirCaution – monitor for signs of increased renal toxicity with concurrent or recent use of cidofovir

Since the advent of potent antiretroviral therapy in 1996 the incidence, clinical features and long-term prognosis of CMV retinitis have changed dramatically. Highly active antiretroviral treatment (HAART) has significantly decreased the number of patients with CD4 counts of <50 cells/μL and therefore the proportion of patients at risk of developing CMVR, as well as significantly prolonging disease-free intervals in patients with pre-existing CMVR [1–3].

In spite of improvements in the era of potent antiretroviral treatments, CMVR remains a significant clinical problem as well as the leading cause of ocular morbidity for patients with AIDS [4]. Despite improvements in immune function (immune reconstitution) due to HAART, new cases of CMVR continue to occur because of late diagnosis of HIV, poor adherence or poor tolerance of treatment and failure of antiretroviral treatment.

5.1.2 Presentation

CMVR usually presents in persons who are severely immunosuppressed with CD4 counts of <50 cells/μL. It may affect one eye at first, but without systemic treatment or improvement of the immune system the other eye usually becomes affected [5]. Symptoms depend on the site and severity of retinal involvement of CMV. Common clinical presentations include floaters, blind spots, blurred vision or a sudden decrease in vision. However, approximately 15% of patients with active CMVR are asymptomatic.

  • Routine screening with dilated indirect ophthalmoscopy is recommended at 3-monthly intervals in patients with CD4 counts less than 50 cells/μL [6].

5.1.3 Diagnosis

CMVR is a clinical diagnosis. Virological confirmation is not ordinarily required. Visualization of the retina should be performed through a dilated pupil to enable peripheral lesions to be seen. Once the diagnosis of CMVR is suspected urgent assessment is required by an ophthalmologist to confirm the diagnosis and advise on appropriate treatment.

5.1.4 Treatment

Treatment is indicated for incident cases of CMVR and progression (extension of CMVR by 750 μm along a 750 μm-wide front) or reactivation (development of a new CMVR lesion either at the edge of an old lesion or at a new focus) of pre-existing CMVR [7].

Treatment limits progression of retinitis and reduces the risk of blinding complications such as retinal detachment and macular involvement of CMVR [8]. Systemic anti-CMV treatment also provides prophylaxis to an unaffected contralateral eye. Intravitreal injections or implants containing anti-CMV treatment provide more expedient loading dosages if required and are localized treatments for those patients unable to tolerate systemic therapy.

Treatment of CMVR consists of an induction period of between 2 and 4 weeks of therapy followed by a maintenance period in which the drug dosage is lower. The duration of maintenance therapy depends on immune recovery with HAART and lack of evidence of CMVR progression or reactivation.

In a randomized study published by the Valganciclovir Study Group, the median time to progression of CMVR was 125 days for patients originally assigned to intravenous ganciclovir and 160 days for patients originally assigned to oral valganciclovir. The proportions of patients in each group having a satisfactory response to induction therapy were similar between the two drugs, as were the rates of adverse events [7].

  • Systemic anti-CMV therapy should be considered as the first-line treatment strategy for CMVR (category 1 recommendation).
  • Oral valganciclovir is the preferred induction and maintenance therapy but iv ganciclovir, iv foscarnet, and iv cidofovir can be considered if there are potential issues with adherence, absorption or specific contraindications to oral therapy (category Ib recommendation).

The standard treatment regimens used in induction include oral valganciclovir 900 mg bd, iv ganciclovir 5 mg/kg bd, iv foscarnet 90 mg/kg bd. Intravenous cidofovir (5 mg/kg) is given weekly for 2 weeks.

All intravenous dosages need adjustment in cases of renal impairment. Close monitoring for adverse events is required as anti-CMV medications may cause significant toxicities such as renal and electrolyte abnormalities, and bone marrow suppression.

The additional use of a ganciclovir implant or intravitreal injections of ganciclovir/foscarnet is recommended for CMVR affecting zone 1 (see Fig. 5.1) [9].

image

Figure 51.  Diagram of an entire retina and the zones of CMVR involvement: based on the standardized system published by the UCLA CMV Retinopathy Study Group [51] and the Studies of the Ocular Complications of AIDS (SOCA) [52].

Description of areas of involvement of CMV retinitis: Zone 1, within 3000 μm of the centre of the fovea or 1500 μm from the disc; zone 2, from zone 1 to the ampulla of the vortex veins (equator of the globe); zone 3, from zone 2 to the ora serrata.

Download figure to PowerPoint

Induction and maintenance with a ganciclovir implant should be considered in patients for whom systemic therapy is contraindicated. The median time to progression of CMVR with a ganciclovir implant was approximately 220 days in the pre-HAART era [9].

5.1.5 Maintenance and duration of anti-CMV treatment for CMVR

The standard treatment regimens used in maintenance include oral valganciclovir 900 mg od, iv ganciclovir 5 mg/kg daily or 6 mg/kg/day for 5 days of the week, iv foscarnet 90 mg/kg od daily or 120 mg/kg for 5 days of the week. Intravenous cidofovir (5 mg/kg) is given fortnightly.

CMVR can be expected to relapse in spite of ongoing anti-CMV treatment if immune reconstitution does not occur [7].

Maintenance treatment can be stopped if there is good immune reconstitution (CD4>100 cells/μL and undetectable viral loads) [10–13]. This decision should be made following careful discussion between the HIV physician and the ophthalmologist involved in the patient's care.

5.1.6 Reactivation or progression of CMVR

When disease occurs in zones 1 and 2 (see Fig. 5.1), induction is achieved with oral valganciclovir as above. Adjunctive intraocular ganciclovir/foscarnet may also be used. Oral valganciclovir alone is used for induction of treatment with reactivation or progression in zone 3 (see Fig. 5.1) disease.

Failure with systemic ganciclovir in end organ eye disease can be dose or resistance related. Options for treatment are dose increase, if toxicity allows, and implant or intravitreal ganciclovir. Intravitreal foscarnet is an alternative option, as is a switch to foscarnet or cidofovir.

If the individual has failed foscarnet, options are ganciclovir implant or a switch to ganciclovir.

Importantly, if an implant alone has been utilized, the fact that implants do not release ganciclovir steadily may mean that ‘failures’ have just ceased to have release of active drug.

Cidofovir failure is rare in end organ eye disease. It cannot be given intravitreally. Failure is rarely due to true viral resistance in the eye.

Combined foscarnet/ganciclovir remains an option in all scenarios.

5.1.7 Resistance to anti-CMV treatment

Ganciclovir-resistant cultures were demonstrated in 25–28% of patients after 9–24 months of treatment in the pre-HAART era. The incidence of viral resistance to ganciclovir has decreased significantly in the HAART era to 9% in a 2-year period [14,15].

5.1.8 Pregnancy and breastfeeding

The management of CMVR in pregnancy is covered in the pregnancy section (see 11 Special considerations in pregnancy). Female patients should be advised to avoid getting pregnant during, and for 1 month after, treatment with cidofovir. Men should not father a child during or within 3 months of cidofovir treatment.

5.1.9 Impact of HAART

As with other opportunistic infections, effective antiretroviral therapy prevents relapses of CMVR and prompt initiation of therapy, where possible, is recommended. CMV-associated IRIS is reported to occur in individuals commencing HAART, and may occur many months after commencement of HAART [16,17]. Specific manifestations include uveitis, retinitis, vitritis, cystic macular oedema and papillitis [18]. The commonest clinical presentation is with a vitritis, which has been reported to occur in 16–63% of individuals commencing HAART with a previous diagnosis of CMVR and is most likely in those with large retinal lesions at baseline [2,19,20]. Immune recovery uveitis (IRU) is an intraocular inflammatory reaction that occurs in patients with CMVR who experience immune reconstitution following antiretroviral treatment [21]. Patients with CMVR involvement of greater than 25% of the retina are at higher risk of IRU [19,22]. It tends to be seen as the CD4 count hovers between 50–150 cells/μL and resolves as it rises further. Long-term ophthalmological follow up is recommended in cases of CMV IRIS involving the eye due to the possibility of retinal neovascularization occurring in some patients years after diagnosis [23]. Treatment of CMV IRIS requires close coordination between an experienced HIV physician and ophthalmologist and often requires corticosteroids either systemically or periocularly [24,25]. Uncontrolled studies suggest a possible additional role of ganciclovir [26].

5.2 Other ocular infections of particular importance in the setting of HIV

  1. Top of page
  2. 5.1 CMV retinitis (CMVR)
  3. 5.2 Other ocular infections of particular importance in the setting of HIV
  4. 5.3 References

5.2.1 Syphilis

Syphilis may manifest in the eye as iritis, vitritis, optic neuritis, papillitis, neuroretinitis, retinal vasculitis or a necrotizing retinitis [4,27].

In the setting of HIV, all cases of ocular syphilis should be investigated for neurosyphilis as CNS involvement occurs at a higher rate in HIV-seropositive patients compared with non-HIV-seropositive patients [28,29]. Syphilis may also have a more aggressive course in HIV-seropositive individuals [27,30,31].

For the specific treatment of syphilis refer to the British Association for Sexual Health and HIV guidelines (2008) [32]. The treatment of ocular syphilis is identical to the treatment for neurosyphilis.

5.2.2 Toxoplasmosis

Pre-HAART data suggests that ocular toxoplasmosis accounts for 0.3–3% of eye infections in HIV-seropositive patients [33–35]. It is much less common than cerebral toxoplasmosis in these patients. Ocular toxoplasmosis is the most common cause of posterior uveitis in immunocompetent individuals [36].

Ocular toxoplasmosis can occur as a reactivation of a pre-natal infestation; however, it has been shown to be frequently acquired postnatally [37]. In HIV-seropositive patients ocular toxoplasmosis occurs at an earlier stage than CMV retinitis. As a result a vitreous inflammatory response can usually be seen on examination. The clinical appearance may be similar to the classic appearance found in immunocompetent patients with a focus of retinochoroiditis adjacent to a chorioretinal scar from previous infestation. There is overlying vitreous haze and cellular response. However, in AIDS atypical presentations have been reported and can include the presence of multiple, large or bilateral lesions. Other atypical manifestations include punctate lesions in deep retina, retinal vasculitis, a pigmentary retinopathy, neuroretinitis and scleritis [38].

The diagnosis is usually made on the basis of clinical suspicion. Corroborating tests include detection of plasma and intraocular fluid anti-toxoplasma antibody titres or detection of toxoplasma DNA in ocular fluids by polymerase chain reaction-based techniques [39]. However, intravitreal assays in this setting are not well validated. Central nervous system involvement should be excluded with magnetic resonance imaging.

Treatment is started in all cases of ocular toxoplasmosis and long-term maintenance therapy is required. Treatment should be systemic in all cases and maintenance therapy may be stopped if there is good immune recovery with HAART. The standard multi-drug regimens used in the immunocompetent, such as sulphadiazine and pyrimethamine, have good efficacy; however, problems with toxicity and drug interactions may limit their long-term use. Atovaquone has also been used with success as it has potent activity against the tachyzoite and cyst forms of Toxoplasma gondii and has relatively fewer problems with toxicity [40,41].

5.2.3 Varicella zoster virus retinitis

The progressive outer retinal necrosis syndrome (PORN) and acute retinal necrosis syndrome (ARN) are descriptions of an aggressive necrotising retinitis. The most common cause of both is varicella zoster virus (VZV). ARN typically affects healthy individuals and can be caused by herpes simplex virus in younger patients and VZV in older patients [42,43].

The clinical picture is of a rapidly progressive visual loss occurring unilaterally initially. The hallmark is a progressive full-thickness retinal necrosis with confluent lesions spreading inwards from the retinal periphery. There may be associated uveitis but this is less evident in significantly immunocompromised patients, who may experience early macular involvement with no vitritis. Papillitis may occur early and result in visual loss. Retinal haemorrhages may also be present [43–46].

Visual prognosis is poor due to the associated complications of retinal detachment, ischaemic optic neuropathy from vascular occlusion or optic nerve inflammation and macular involvement [43,44,46].

Although vitreous sampling and analysis has a role in the diagnosis of VZV retinitis it is not used routinely for the monitoring of the success of therapy. However, it has been used in the research setting [47,48].

Treatment outcomes are often disappointing, with patients becoming blind within weeks from macular involvement and complications such as retinal detachment. A combination of intravenous ganciclovir alone or in combination with foscarnet, and intravitreal ganciclovir/foscarnet have been used to halt the progression of retinitis; however, intravenous cidofovir is probably the drug of choice, with or without the addition of intravitreal ganciclovir or foscarnet [49,50].

5.3 References

  1. Top of page
  2. 5.1 CMV retinitis (CMVR)
  3. 5.2 Other ocular infections of particular importance in the setting of HIV
  4. 5.3 References
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