Approach

In immunocompetent patients, cytomegalovirus (CMV) infection is typically self-limiting, and antiviral treatment is not indicated.

The clinical manifestation of CMV infection in transplant patients depends on the overall immune status of the host. Therefore, in cases of severe clinical disease, reducing the intensity of immunosuppression should be considered, if feasible. For patients with AIDS, initiation of antiretroviral therapy (ART) should be considered for the treatment of underlying HIV infection. However, there is a risk of immune reconstitution CMV uveitis among patients initiated on ART.

Immunocompetent individuals

CMV infection and disease resolve without antiviral treatment in patients with a competent immune system. The generation of CMV-specific immunity during the course of illness is sufficient to resolve the clinical illness.

Transplant recipients with CMV disease

The goal of therapy for CMV infection is rapid control of viral replication and clinical disease with the use of oral valganciclovir or intravenous ganciclovir.[1]​​[51] Oral valganciclovir is preferred due to a reduced risk of complications related to intravenous administration and hospital stay.[51]​ It has been shown to be non-inferior to intravenous ganciclovir for the treatment of CMV disease in kidney, liver, and heart transplant recipients.[52] However, intravenous ganciclovir may be preferred in severe and life-threatening CMV disease (i.e., pneumonitis, disease necessitating intensive care unit admission, severe gastrointestinal disease with profuse diarrhoea, or when optimal drug exposure is essential or may be an issue).[51] In this context, valganciclovir should be used as a step-down approach following initial therapy with intravenous ganciclovir, once clinical improvement is seen. Owing to its significant associated nephrotoxicity, foscarnet is a second-line option for the treatment of CMV disease and should be reserved for patients intolerant to valganciclovir or ganciclovir during the induction phase.[1][51]​​​

Routine use of immunoglobulins (unselected or CMV-hyper-immune globulins) is not currently recommended as adjunctive treatment.[51] In the case of severe CMV disease, especially in lung transplant and haematopoietic stem cell transplant patients with CMV pneumonitis, the adjunctive use of immunoglobulins may be considered, although evidence for a clear benefit is lacking.[1]​ There are no guidelines to define severity of disease; a judgement is made by the managing clinician.

Patients with AIDS and CMV disease, such as retinitis

In addition to anti-CMV therapy, patients should also be promptly initiated on ART to control their HIV infection and promote immune reconstitution. In some patients with a recovering immune system, an immune reconstitution syndrome may occur, characterised by worsening of the inflammation due to CMV retinitis.[53]

Retinitis

In patients with AIDS, blindness caused by CMV chorioretinitis is often irreversible, and treatment is aimed at arresting disease progression. Forms of ganciclovir are the usual first choice for CMV infection or disease. Treatment should be individualised and ideally involve an ophthalmologist experienced in the management of CMV retinitis.[2]

For patients with immediate sight-threatening CMV retinitis, intravenous ganciclovir or oral valganciclovir, with or without intravitreal ganciclovir or foscarnet, is the preferred initial therapy.[2] Alternative therapies include intravitreal ganciclovir or foscarnet in combination with intravenous foscarnet or cidofovir (with probenecid and saline hydration therapy before and after cidofovir therapy).[2] It is important that systemic therapy be administered when intravitreal ganciclovir is given, to prevent progression to contralateral retinitis and other extraocular CMV disease. Although effective, cidofovir and foscarnet are less-preferred choices because of associated toxicities.[2]​ For small peripheral lesions that are not sight-threatening, oral valganciclovir alone may be adequate.[2]​

Initial therapy (lasting a minimum of 14-21 days, with duration determined by clinical response based on retinal examination) should be followed by chronic maintenance therapy.[2] Regimens for chronic suppression include oral valganciclovir, IV ganciclovir, IV foscarnet, and IV cidofovir with probenecid.[2][32]

Maintenance therapy can be safely discontinued in patients with inactive disease and sustained CD4+ count (>100 cells/microlitre for ≥three to six months); consultation with an ophthalmologist is recommended. Regular eye examinations should be performed every three months in patients who have discontinued maintenance therapy, to ensure early detection of relapse or immune recovery uveitis.[2]

Early relapse is most often caused by the limited intraocular penetration of systemically administered drugs.[54]​ If patients relapse while receiving maintenance therapy, reinduction with the same drug followed by reinstitution of maintenance therapy is recommended. Changing to an alternative drug at the time of first relapse should be considered if drug resistance is suspected or if side effects or toxicities interfere with optimal courses of the initial agent.

Gastrointestinal disease

For gastrointestinal disease, intravenous ganciclovir for 3-6 weeks (or until signs and symptoms have resolved) is recommended; intravenous foscarnet is an alternative. Oral valganciclovir is the first line option when symptoms are not severe enough to interfere with oral absorption. Maintenance therapy is usually not needed for CMV oesophagitis or colitis, but should be considered following relapses.[2][32]

Pneumonitis

Intravenous ganciclovir or foscarnet is used, although limited data is available regarding therapy impact outcomes and the optimal duration of therapy has not been established.[2]

Neurological disease

Intravenous ganciclovir and foscarnet are used in combination to stabilise neurological disease and maximise response. The optimal duration of therapy has not been established.[2] Maintenance therapy should be continued for life unless there is evidence of immune recovery.[32]

Refractory/resistant CMV

Refractory or resistant CMV should be suspected in the presence of persistent or recurrent CMV viraemia and prolonged exposure to antivirals, and it should be tested for with genotypic resistance analysis.[51] 

Maribavir is the first-line option for post-transplant CMV infection that does not respond to available antiviral treatment (with or without genotypic resistance). Maribavir is a benzimidazole riboside antiviral which inhibits CMV pUL97 kinase. In the US, maribavir is approved for treating adults and children (aged 12 years and older and weighing at least 35 kg). However, in Europe, it is currently approved for adults only.

In the phase 3 SOLSTICE trial, maribavir demonstrated superior viral clearance compared with investigator-assigned therapy (valganciclovir/ganciclovir, foscarnet, cidofovir, or foscarnet plus valganciclovir/ganciclovir) in transplant recipients with refractory/resistant CMV infection (55.7% achieving CMV clearance at 8 weeks compared with 23.9%).[55]

In the AURORA trial, maribavir and valganciclovir were evaluated for managing initial asymptomatic CMV infections in patients following haematopoietic cell transplantation. Although maribavir did not achieve the targeted noninferiority for clearing CMV viraemia by the 8th week, it effectively maintained CMV suppression without disease progression up to the 16th week, similar to valganciclovir. Maribavir demonstrated a better safety profile with reduced cases of neutropenia and fewer treatment discontinuations due to adverse events, highlighting its utility as a preferred option for managing CMV in the early post-transplant period.[56]

There is a concern of the acquisition of resistance against maribavir in cases of refractory/resistant CMV infection manifesting with high viral loads or in cases of severe disease. In these cases, expert opinion suggests starting therapy with foscarnet, with a step down to maribavir after clinical improvement and once viral load has decreased. A clear viral load threshold for preferring the use of foscarnet has not been established.[57]

UL97-mutant CMV confers resistance to ganciclovir, and antiviral treatment for these patients typically involves the use of maribavir, foscarnet, and less commonly, cidofovir. Occasionally, higher than normal doses of ganciclovir may also be an option. Although maribavir targets UL97, cross-resistance with ganciclovir is uncommon. UL54-mutant CMV, which has a mutation in CMV DNA polymerase, may confer cross-resistance among ganciclovir, foscarnet, and cidofovir, (depending on the exact site of the mutation), leading to more limited treatment options for these patients.

Letermovir, an oral antiviral agent that targets the CMV DNA terminase complex, is currently approved for prevention of CMV infection in hematopoietic stem cell transplant recipients and kidney transplant recipients, but not for therapy of established CMV disease due to its low genetic barrier.

Reduction in immunosuppression should accompany antiviral therapy, to allow immune reconstitution and subsequent control of the virus by the immune system.

Congenital CMV

Neonates with moderate-to-severe, symptomatic congenital CMV disease are commonly treated with oral valganciclovir, initiated in the first month of life and continued for six months.[32][58][59]​​​​​ Intravenous ganciclovir is an alternative option for severe, symptomatic congenital infection, although it is seldom used.[32][60][61]​​​​​ Valganciclovir and ganciclovir have been shown to prevent progression of hearing loss in patients with symptomatic congenital CMV infection.[30][59][60][61]​​​ One trial demonstrated no improvement in the short term, but significant, although modest, improvement in neurodevelopment and hearing in the long term, with a six-month valganciclovir regimen compared with placebo.[59] Neutropenia is a frequent adverse event associated with ganciclovir.[60][61]

To date, there is insufficient evidence to recommend treatment of neonates with asymptomatic or mild congenital CMV. Evidence from randomised trials to inform the initiation of antiviral therapy beyond the first month of life is also lacking.[58]​ Several ongoing studies aim to establish whether there is a benefit in treating neonates with isolated sensorineural loss or in treating newborns beyond the first month of life.[58]

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