Category Archives: CMV Retinitis

CMV Retinitis

– Christian Hoffmann –

Infections with cytomegalovirus are widespread. In many countries, seroprevalence is around 50-70%, and above 90% in MSM. In severely immunocompromised individuals, (CD4 count below 50 cells/µl), reactivation of CMV infection can lead to retinitis. In the past, CMV retinitis was a common AIDS-associated illness, leading to blindness in up to 30% of patients. It occurs mainly in untreated patients, who are often first diagnosed with HIV infection on presentation (Jacobson 2000). An inflammatory CMV retinitis, usually with severe vitritis, is also possible in the course of an IRIS (see below). If CMV retinitis is not diagnosed and treated promptly, then the patient’s sight is at risk. Impairment of vision is almost always associated with lesions, which are no longer reversible even with adequate treatment. This is why CMV retinitis remains a dangerous illness, although the prognosis has been significantly improved by ART (Goldberg 2003, Salzberger 2005, Thorne 2006).

Other manifestations of disseminated CMV infection are rare (15%), and can affect every organ. The lung (pneumonia), esophagus (ulcers), colon (colitis) and CNS (encephalitis) are most frequently involved. Sinusitis may also occur (Jutte 2000). The clinical signs of these CMV diseases depend on the organ affected. Diagnosis is often difficult and may only be possible on histology (Goodgame 1993). There is insufficient data on the treatment of these manifestations, so that systemic therapies are usually chosen in analogy to treatment for CMV retinitis (Whitley 1998).

Signs and symptoms

Any visual impairment occurring peracutely or acutely, such as blurred vision or floaters – especially unilaterally – should prompt an immediate (same day, if possible) ophthalmological examination of the patient. Symptomatic CMV retinitis is an emergency. Once there is a black spot in the visual field, it will be permanent.  Involvement of the posterior pole (zone 1 retinitis) accounts for approximately one half of incident visual acuity loss. Cataract and retinitis-related retinal detachment are also common causes of vision loss (Thorne 2006).

All CMV treatment regimens can prevent progression of lesions, but not reverse them.  Eye pain, burning, increased production of tears, and conjunctival irritation are not typical. However, many patients suffer from systemic symptoms such as fever and weight loss.

Diagnosis

Diagnosis is made by fundoscopy. Assessment of the usually peripheral, whitish exudates is dependent on the experience of the ophthalmologist. However, this can frequently be a problem, due to the rare occurrence of CMV retinitis nowadays. Unfortunately, incorrect diagnoses that are ill-fated due to the valuable time and, in worst case scenarios, retina lost are no exception. Therefore, if the primary ophthalmologist remains undecided, then it is best to start with oral valgancyclovir and transport the patient to a larger clinical center with ophthalmologists who are experienced in HIV. Furthermore, it is essential that the ophthalmologists receive information about the patient’s immune status. In cases of poor immune status and CD4 count less than 100/µl, chorioretinitis caused by Toxoplasma gondii is the most important differential diagnosis. CMV retinitis can almost be excluded at CD4 T cell counts above 100/µl; other viral infections (HSV, VZV) or even neurosyphilis should then be considered. CMV lesions may also be confused with cotton wool spots, which are not rare in HIV patients with high HIV viral load. Multiple small lesions without hemorrhage or exudates are almost always cotton wool spots, and almost never CMV retinitis. Bilateral involvement is also usually the exception. Vitritis is rare, except with immune reconstitution syndrome.

CMV serology (IgG almost always positive, IgM variable) is only seldomly helpful for diagnosis. CMV PCR or a blood test for pp65 antigen to detect antibodies against a CMV-specific phosphoprotein may be more useful. CMV retinitis or a recurrence is unlikely with a negative PCR or pp65 result. The higher the levels of CMV viremia, the higher the risk of CMV disease. Patients with positive CMV PCR have a 3-5-fold elevated risk (Casado 1999, Nokta 2002). Positive CMV PCR is also independently associated with a poor prognosis for the patient (Deayton 2004, Jabs 2005, Wohl 2005). As with Toxoplasma gondii, there have been efforts to determine the antigen-specific immune response more precisely (Jacobsen 2004), although such testing is not yet routine.

Treatment

CMV treatment should always be initiated promptly and strictly monitored by fundoscopy  at least once a week in the beginning. Photodocumentation is advisable. Initially, an intensive induction therapy is administered for two to three weeks, until there is scar formation of the lesions. HIV clinicians and ophthalmologists should work closely together, particularly during the induction therapy, and when possible, communicate several times a week. Induction therapy is followed by maintenance therapy at a reduced dose.

ART in particular has dramatically improved the prognosis of patients. That said, all diagnosed patients should start ART without delay. This can restore CMV-specific immune responses (Komandouri 1998), so that CMV viremia may disappear even without specific therapy after a few weeks (Deayton 1999, O’Sullivan 1999). However, if retinitis is present, CMV-specific treatment should nevertheless be started, as immune reconstitution may take several months.

Systemic treatment

Valgancyclovir, a prodrug of gancyclovir with good oral absorption, is the first choice in CMV treatment. In a randomized study (Martin 2002) on 160 patients with retinitis, the results were impressive: valgancyclovir tablets were just as effective as gancyclovir infusions. However, the toxicity profile of both agents was comparable. This means, in cases of oral treatment, that the blood count has to be as frequently monitored as for infusions and that the indication has to be equally carefully set. Treating a positive IgM serology (without any further diagnosis) with valgancyclovir is not only expensive, but also usually an unnecessary risk.

Other options for systemic treatment have become less important, and are only used in cases of recurrence. If there is intolerability or more rarely (Martin 2007) resistance to valgancyclovir (Drew 1999), then foscarnet remains an option. This, however, requires daily infusions. Further problems with this drug include nephrotoxicity, and very painful penile ulcers. Very intensive hydration of the patient is therefore necessary under all circumstances. However, there a some experts in the field who prefer intravenous CMV treatment in advanced cases.

There are no direct comparative studies available for cidofovir, which is also used occasionally. The benefit of the long half-life (once weekly dosing possible) is outweighed by the considerable renal toxicity of this drug (Plosker 1999). We observed creatinine elevations in every second patient treated, despite the fact that a strict infusion plan was closely followed (see Drugs section).

New anti CMV drugs are not expected for the next years. Maribavir recently failed to show a benefit in phase III studies (Marty 2011, Snydman 2011). Monoclonal antibodies (MSL-109) or compounds such as cyclopropavir or BAY 38-4766 are still in early phases of development.

Additional treatment with G-CSF (filgrastim) improved survival in one analysis of three large studies enrolling patients with CMV retinitis in the years 1990-1997. In particular, there was a reduction of bacterial infections. However, the reason for this positive effect remains unclear. Thus, administration of filgrastim is presently not generally recommended (Davidson 2002).

Local treatment

Several options for local treatment of CMV retinitis have been tested (review in: Smith 1998). Although such treatments can be safely administered by experienced ophthalmologists and are associated with few complications (infections, hemorrhage), disadvantages remain. Weekly intravitreal injections of gancyclovir or foscarnet, or pellet implantation (Vitrasert®, must be replaced every 6-9 months) do not protect from infection of the contralateral eye or from extraocular manifestations (Martin 1999). The same is true for fomivirsen (Vitravene®), an antisense-oligonucleotide for intravitreal injection, which is astonishingly effective even with multiresistant CMV strains (Perry 1999). These local treatments have become less important since ART and valgancyclovir, and some have been taken off the market.

Treatment/prophylaxis of CMV retinitis (daily doses, if not specified otherwise)

Acute therapy

Duration: always at least three weeks

Treatment of choice

Valgancyclovir

Valgancyclovir (ValcyteÒ) 2 tbl. at 450 mg bid (note: some experts prefer intravenous therapy in advanced cases)

Alternative

Gancyclovir

Gancyclovir 5 mg/kg i.v. bid

Alternative

Foscarnet

Foscarnet 90 mg/kg i.v. bid

Alternative

Gancyclovir +

Foscarnet

Half of the doses above

Maintenance therapy

Discontinue from > 100-150 CD4 cells/µl > 6 months

Treatment of choice

Valgancyclovir

Valgancyclovir (ValcyteÒ) 1 tbl. at 450 mg bid

Alternative

Foscarnet

Foscarnet 120 mg/kg i.v. qd on 5 days/week

Alternative

Cidofovir

Cidofovir 5 mg/kg i.v. qd every 14 days (plus probe-necid, hydration see Drugs section)

Primary prophylaxis

Not recommended

Prophylaxis

Primary prophylaxis: In the prospective studies that have been performed, no primary prophylaxis regimen has been convincing. There is also no effective vaccine. Therefore, the most important method for prevention in patients with CD4 counts less than 200 cells/µl is still fundoscopy every three months. With good immune reconstitution, intervals between examinations can be extended. It is important to perform a fundoscopy in severely immunocompromised patients prior to starting ART. This allows detection of smaller lesions, which may later present with severe inflammation during the course of immune reconstitution.

Secondary prophylaxis: After approximately three weeks of acute therapy, but at the earliest with scar formation of lesions, a reduced dose secondary prophylaxis (maintenance therapy) should begin, preferably with oral valgancyclovir (Lalezari 2002). However, the drug is not only very expensive but also just as myelotoxic as gancyclovir infusions. Discontinuation of secondary prophylaxis as quickly as possible, is therefore also desirable for this OI (MacDonald 1998, Tural 1998, Jouan 2001), but it also requires strict ophthalmologic monitoring. According to US guidelines, discontinuation should occur at the earliest after six months of maintenance therapy and with an immune reconstitution above 100-150 CD4 T cells/µl. However, we have even successfully stopped gancyclovir at lower CD4 T cell counts, if both HIV and CMV PCR in blood were below the level of detection. One study showed that stopping after 18 months of ART/maintenance therapy can be safe above 75 CD4 T cells/µl (Jouan 2001). After stopping maintenance therapy, funduscopy should be performed every four weeks over the first months.

The previously required life-long daily infusions of gancyclovir or foscarnet via port, pumps and nursing service are luckily now a thing of the past. If there are relapses under oral valgancyclovir, it is proposed that re-induction and maintenance therapy with foscarnet or possibly with cidofovir.

References

Casado JL, Arrizabalaga J, Montes M, et al. Incidence and risk factors for developing cytomegalovirus retinitis in HIV-infected patients receiving protease inhibitor therapy. AIDS 1999, 13:1497-1502.

Davidson M, Min YI, Holbrook JT, et al. Use of filgrastim as adjuvant therapy in patients with AIDS-related cytomegalovirus retinitis. AIDS 2002, 16: 757-65.

Deayton J, Mocroft A, Wilson P, et al. Loss of cytomegalovirus viraemia following HAART in the absence of specific anti-CMV therapy. AIDS 1999, 13:1203-6.

Deayton JR, Prof Sabin CA, Johnson MA, et al. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving HAART. Lancet 2004, 363:2116-21.

Goldberg DE, Wang H, Azen SP, Freeman WR. Long term visual outcome of patients with cytomegalovirus retinitis treated with highly active antiretrovi-ral therapy. Br J Ophthalmol 2003, 87:853-5.

Goodgame RW. Gastrointestinal cytomegalovirus disease. Ann Intern Med 1993, 119:924-35.

Jabs DA, Martin BK, Forman MS, et al. Cytomegalovirus (CMV) blood DNA load, CMV retinitis progression, and occurrence of resistant CMV in patients with CMV retinitis. J Infect Dis 2005, 192:640-9.

Jabs DA, Martin BK, Ricks MO, Forman MS. Detection of ganciclovir resistance in patients with AIDS and cytomegalovirus retinitis: correlation of genotypic methods with viral phenotype and clinical outcome. J Infect Dis 2006, 193:1728-37.

Jacobson MA, Maecker HT, Orr PL, et al. Results of a cytomegalovirus (CMV)-specific CD8+/interferon- gamma+ cytokine flow cytometry assay correlate with clinical evidence of protective immunity in patients with AIDS with CMV retinitis. J Infect Dis 2004, 189:1362-73.

Jacobson MA, Stanley H, Holtzer C, et al. Natural history and outcome of new AIDS-related cytomegalovirus retinitis in the era of HAART. Clin Inf Dis 2000, 30:231-3.

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Jutte A, Fätkenheuer G, Hell K, Salzberger B. CMV sinusitis as the initial manifestation of AIDS. HIV Med 2000, 1:123-4.

Komanduri KV, Viswanathan MH, Wieder ED, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and HAART in individuals infected with HIV-1. Nature Med 1998, 8:953-6.

Lalezari J, Lindley J, Walmsley S, et al. A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr 2002, 30:392-400.

Macdonald JC, Torriani FJ, Morse LS, et al. Lack of reactivation of CMV retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4+ T cells in response to HAART. J Infect Dis 1998, 177:1182-7.

Martin DF, Kuppermann BD, Wolitz RA, et al. Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 1999, 340: 1063-70.

Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002, 346:1119-26.

Martin BK, Ricks MO, Forman MS, Jabs DA. Change over time in incidence of ganciclovir resistance in patients with cytomegalovirus retinitis. Clin Infect Dis 2007;44:1001-8.

Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis 2011, 11:284-292.

No authors listed. Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial: 5. Clinical features of cytomegalovirus retinitis at diagnosis. Studies of ocular complications of AIDS Research Group in collaboration with the ACTG. Am J Ophthalmol 1997,124:141-57.

Nokta MA, Holland F, De Gruttola V, et al. Cytomegalovirus polymerase chain reaction profiles in individuals with advanced HIV infection: relationship to CMV disease. J Infect Dis 2002, 185:1717-22.

O’Sullivan CE, Drew WL, McMullen DJ, et al. Decrease of cytomegalovirus replication in HIV infected-patients after treatment with HAART. J Infect Dis 1999, 180:847-9.

Perry CM, Balfour JA. Fomivirsen. Drugs 1999, 57:375-80.

Plosker GL, Noble S. Cidofovir: a review of its use in cytomegalovirus retinitis in patients with AIDS. Drugs 1999, 58:325-45.

Salzberger B, Hartmann P, Hanses F, et al. Incidence and prognosis of CMV disease in HIV-infected patients before and after introduction of combination antiretroviral therapy. Infection 2005, 33:345-9.

Smith CL. Local therapy for cytomegalovirus retinitis. Ann Pharmacother 1998, 32:248-55.

Snydman DR. Why did maribavir fail in stem-cell transplants? Lancet Infect Dis 2011, 11:255-7.

Thorne JE, Jabs DA, Kempen JH, et al. Causes of visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006, 113:1441-5.

Thorne JE, Jabs DA, Kempen JH, et al. Incidence of and risk factors for visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology 2006, 113:1432-40.

Tural C, Romeu J, Sirera G, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in HIV-infected patients. J Infect Dis 1998, 177:1080-3.

Whitley RJ, Jacobson MA, Friedberg DN, et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy: recommendations of an international panel. Arch Intern Med 1998, 158:957-69.

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Filed under 11. Opportunistic Infections, CMV Retinitis, Part 3 - AIDS