D20 Cytomegalovirus diseases
Cytomegalovirus (CMV) is a double-stranded DNA virus in the herpes virus family. CMV is the commonest viral opportunistic pathogen in patients with AIDS. CMV disease in AIDS patients is mainly due to reactivation of latent infection rather than primary infection. Risk factors for development of CMV diseases include advanced immunosuppression with a CD4 count <50/μL, high level CMV viraemia and prior corticosteroid use.
In the pre-HAART era, CMV disease causes significant morbidity and mortality, with around 21-44% of AIDS patients developing CMV diseases during the course of their illness. In early case series, patients with CMV retinitis who survived beyond 6 months became severely visually impaired and the mean survival after the diagnosis was only 6-10 months. Patients with CMV gastrointestinal disease generally died within several months without CMV-specific treatment. Even with ganciclovir therapy, the median survival was only 4 months in CMV colitis and 8 months in CMV oesophagitis. After the introduction of highly active antiretroviral therapy (HAART), CMV disease occurs mainly in patients who are not receiving antiretroviral therapy or who fail to respond to such therapy. The overall incidence of CMV disease has decreased significantly with improvement in survival. In a European multicenter cohort study conducted from 1994 to 2001, patients with a baseline CD4 count of <200/μL carried a significantly lower risk of developing CMV disease when receiving HAART (1.8% on HAART vs 14% without any antiretroviral treatment). HAART initiation has also resulted in 37% reduction in mortality. However, a recent systematic analysis did not show similar reduction in the prevalence of CMV retinitis in low- and middle-income countries partly due to late presentation and diagnosis of HIV.
Disease entities and clinical presentations
The commonest presentation is CMV retinitis, which accounts for 75-85% of CMV diseases in AIDS patients. CMV retinitis is a full-thickness infection through the retinal cells. Histologically, it is characterised by full-thickness retinal necrosis which is later replaced by thin, atrophic scar tissue that is susceptible to tearing. Retinal detachment is the most fearful complication of CMV retinitis. Blindness can occur within 4-6 months in untreated cases. Clinical approach for the diagnosis and management of CMV retinitis is given at [Algorithm 20].
Patients with CMV retinitis present with blurring of vision, loss of central vision, scotomata, floaters, flashing lights or sudden loss of vision if retinal detachment occurs. HIV infected patients with low CD4 counts (e.g. <50 cells/μL) who presents with these symptoms warrant urgent ophthalmological referral for assessment.
Gastrointestinal tract disease
Gastrointestinal tract is the commonest extraocular site of involvement, which accounts for 66% of extraocular CMV diseases. Colon and oesophagus are the most commonly affected areas when there is gastrointestinal CMV infection. It is characterised by mucosal erosions and ulcers on endoscopic examination. Potential complications include gastrointestinal bleeding and gut perforation which can be life-threatening.
Clinical presentation depends on the site of involvement. CMV oesophagitis manifests with fever, odynophagia, nausea and substernal burning pain. Patients with CMV gastritis also present with substernal or epigastric burning pain. Generalised abdominal pain and diarrhoea are the most common presenting symptoms of CMV enteritis. Patients with CMV colitis usually present with fever, weight loss, anorexia, malaise, abdominal pain, explosive watery diarrhoea or bloody diarrhoea. It rarely presents as a mass lesion causing partial obstruction.
Neurological involvement of CMV infection is an uncommon but serious complication of AIDS. In the pre-HAART era, it occurred in up to 2% of AIDS patients. The brain, spinal cord, dorsal column nerve roots or peripheral nerves can get involved. It can cause paralysis or rapidly fatal encephalitis.
Patients with meningoencephalitis present with severe headache, photophobia, lethargy, confusion and rapidly progressive cognitive impairment. Focal neurological abnormalities with cranial nerve palsy, brainstem involvement or pyramidal tract signs can be present. CMV myelitis presents with lower limb weakness with hyperactive reflexes on neurologic examination. Those with polyradiculopathy also present with lower limb weakness but will have loss of deep tendon reflexes on neurological examination. Some patients may have progression of symptoms with eventual loss of bowel & bladder control. Patients with peripheral nerve disease usually present with the syndrome of mononeuritis multiplex, consisting of multifocal or asymmetric sensory and motor deficits in the distribution of major peripheral or cranial nerves.
CMV as a sole cause of pneumonia is not common in HIV/AIDS patients. Some autopsy studies showed that >50% had histological evidence of CMV infection in the lungs, but other causative agents were also found in most of these patients. The most common coexisting pathogen was Pneumocystis jirovecii. Most studies did not show improvement in survival when anti-CMV treatment was given. Patients with CMV pneumonia usually complain of shortness of breath and a dry, nonproductive cough. Auscultation of the lungs often reveals minimal findings. Radiographic pattern is varied and overlaps with other HIV-associated pulmonary diseases, in particular PCP.[Chapter D25] Usual features include ground-glass opacification, nodules, perihilar and lower zone interstitial infiltrates, and effusions.
A diagnosis of CMV disease in HIV-infected patients is often made in the presence of clinical symptoms, characteristic findings in fundoscopic/endoscopic examination and/or histological findings in biopsy specimens. Clinically CMV retinitis is diagnosed based on characteristic fundoscopic appearance by an experienced ophthalmologist. The characteristic lesions are yellow-white, fluffy, or granular retinal infiltrates, often located close to retinal vessels, in association with areas of haemorrhage. For difficult cases, detection of CMV DNA in vitreous specimens can be useful for establishing the diagnosis. Patients with extraocular CMV disease are also at high risk of concurrent CMV retinitis. They should be referred for formal ophthalmologic assessment even if they have no visual symptom.
There are different laboratory diagnostic methods for CMV infection, the diagnostic value of which for active CMV disease varies. Serology is not clinically useful since most CMV diseases in HIV-infected patients are due to reactivation of latent infection instead of primary infection. CMV gastrointestinal and respiratory tract diseases are diagnosed by the presence of CMV inclusion bodies and tissue destruction in biopsy specimens. Detection of CMV DNA in the cerebrospinal fluid is the definitive diagnostic tool for CNS involvement by CMV. Detection of CMV in urine or bronchoalveolar lavage (BAL) by standard cell culture or shell viral culture does not confirm active CMV disease since asymptomatic shedding and asymptomatic viraemia is common in immunocompromised patients. CMV viraemia is usually present in active CMV disease and can be detected by antigen assays or Polymerase chain reaction (PCR). Presence of CMV pp65 antigenaemia correlates well with viraemia. Quantitative detection of CMV DNA in plasma by real-time PCR is highly sensitive. However, both methods cannot differentiate between asymptomatic viraemia and active CMV disease.
Observational studies showed that subclinical CMV viraemia is an independent risk factor for future CMV disease and mortality in patients with advanced AIDS. Pre-emptive anti-CMV therapy could be a therapeutic strategy for preventing CMV end-organ disease in those patients.
Effective treatment for CMV infections includes ganciclovir, valganciclovir, foscarnet and cidofovir. A summary of these anti-CMV regimens with their common dosage and potential side effects are listed in Box 20.1.
Ganciclovir & valganciclovir are the initial drug of choice in most cases of CMV disease in AIDS patients. Ganciclovir can be given orally, intravenously or via intraocular injections. The oral bioavailability of ganciclovir is 6-8% only. Its oral form is seldom used now when oral valganciclovir, a valine ester of ganciclovir, has become available. Valganciclovir has a much higher oral bioavailability (68%) and is rapidly absorbed and hydrolysed to ganciclovir after oral administration. It has been proven to be effective for CMV retinitis with similar toxicity profile as intravenous ganciclovir.
Foscarnet can only be administered via the intravenous route. It can cause acute tubular necrosis and transient electrolyte disturbance, namely hypocalcaemia and hypomagnesaemia during infusion due to chelation of the drug with these cations.
Cidofovir is also administered via the intravenous route. The activity of cidofovir against CMV in vitro is 10-100 folds greater than that of other currently available anti-CMV drugs. It also has a very prolonged half-life that makes intermittent dosing feasible. However, it can cause irreversible nephrotoxicity via proximal tubular cell injury and a life-threatening Fanconi-like syndrome. Caution must be exercised when using cidofovir for treatment of CMV diseases. Concomitant administration of cidofovir with saline and high dose oral probenecid has been shown to be protective against the nephrotoxicity.
Duration and drug of choice for CMV diseases in HIV/AIDS patients vary slightly when different organ systems are involved. For CMV retinitis, an induction therapy of 2-3 weeks followed by lower dose maintenance therapy is recommended. For patients who have gastrointestinal disease, it has been recommended to give anti-CMV therapy for 3-6 weeks or until signs and symptoms have resolved. There is no evidence to support routine use of maintenance therapy for gastrointestinal disease but this should be considered if relapses occur. Due to poor disease prognosis, some experts recommend a combination of IV ganciclovir and IV foscarnet for the treatment of CMV neurological diseases even though clinical evidence is limited. The role of maintenance therapy for CMV neurological and pulmonary diseases has not been established.
Apart from the use of maintenance therapy, initiation of HAART is an important adjunct to prevent future relapses.
Intravitreal therapy delivers higher intraocular concentrations than systemic anti-CMV agents and is useful in selected patients. Intraocular ganciclovir implant achieves 4-fold higher intraocular ganciclovir levels than intravenous ganciclovir. Studies of the ganciclovir implant have demonstrated effective control of retinitis for up to 6 to 8 months from a single implant. However, ganciclovir implant is no longer manufactured.
Intravitreal injections of ganciclovir or foscarnet have been shown to slow the progression of retinitis in patients with treatment failure or intolerance to systemic therapy. Intravitreal injections provide immediate high intraocular drug levels and presumably faster control of the retinitis. Intravitreal ganciclovir or foscarnet injections plus oral valganciclovir is often recommended as the preferred initial therapy for patients with immediate sight-threatening lesions (adjacent to the optic nerve or fovea). Concomitant systemic anti-CMV therapy is advised because of its proven benefits in reduction in mortality, contralateral eye involvement and visceral disease.
Early relapses that occur within 3 months are usually due to progression of disease in the absence of effective HAART or lack of anti-CMV drug adherence. Reinduction with the same drug or an alternative drug, followed by reinstitution of maintenance therapy is usually effective. For patients who develop relapses after receiving prolonged maintenance therapy, anti-CMV drug resistance may have been developed. A randomised controlled trial showed that reinduction with combination regimen (ganciclovir + foscarnet) was twice as effective as reinduction with either drug alone in this situation. However, this drug combination is associated with substantial toxicity. In the HAART era, the rate of anti-CMV drug resistance has decreased, which is probably attributed to better control of CMV replication.
For CMV disease, there’s the need to monitor for: (a) treatment efficacy and early detection of relapse or refractory diseases, (b) treatment related side effects, and (c) immune recovery uveitis (IRU).
Regular indirect ophthalmoscopy through a dilated pupil should be performed by an experienced ophthalmologist at the time of diagnosis of CMV retinitis, after completion of induction therapy, one month after initiation of therapy, and monthly thereafter while patient is on anti-CMV treatment. Tests to monitor for potential side effects from anti-CMV treatment should be performed according to the anti-CMV regimens used.[Box 20.1]
Box 20.1. Commonly used anti-CMV agents
|Drug||Induction regimen||Maintenance regimen||Side effects||Monitoring||Remarks|
|Ganciclovir||5mg/kg q12h iv||5mg/kg/day iv||Marrow suppression leading to neutropaenia & thrombocytopaenia||CBP, LRFT||Consider the use of G-CSF (granulocyte-colony stimulating factor) if neutrophil count <500 cells/μL.
Caution with co-administration of other marrow suppressive drugs.
Adjust dose in renal impairment.
|Valganciclovir||900mg bd po||900mg daily po||Same as ganciclovir||Same as ganciclovir||To be given with meals|
|Foscarnet||90mg/kg q12h iv||90-120mg/kg/day iv||Nephrotoxicity due to ATN, electrolyte disturbance e.g. hypocalcaemia & hypomagnesaemia, penile ulcer, anaemia||CBP, LRFT||Give 0.5-1L NS (normal saline) with foscarnet infusion.
Avoid nephrotoxic drugs.
Adjust dose in renal impairment.
|Cidofovir||5mg/kg once weekly iv||5mg/kg every 2 weeks iv||Nephrotoxicity due to proximal tubular cell injury, Fanconi-like syndrome, neutropaenia, peripheral neuropathy, hypotony (up to 25% in those receiving concomitant protease inhibitor), anterior uveitis, alopecia.
Side effects of high dose probenecid includes fever, rash, nausea, vomiting, headache
|CBP, RFT, urine dipstick for protein, spot urine for TP/Cr ratio||Give 1L NS and 2g probenecid 3 hours before cidofovir, 1g probenecid 2 and 8 hours after cidofovir to reduce nephrotoxicity.
Contraindicated if urine dipstick for protein is 2+ or more or if serum creatinine rises by 44μmol/L or more above baseline.
Avoid nephrotoxic drugs.
Adjust dose in renal impairment.
Need monthly ophthalmologic examinations for hypotony in patients receiving concomitant protease inhibitors.
A potential complication of note is IRU in patients with CMV retinitis who have been initiated on HAART. The rate of clinically significant IRU following initiation of HAART appears to be low (1.7/100 person-year). IRU can cause substantial visual loss. IRU is an ocular form of Immune Reconstitution Inflammaotory Syndrome (IRIS), [Chapter C17] which is characterised by inflammation in the anterior chamber or vitreous cavity, with or without cystoid macular oedema, epiretinal membrane or retinal neovascularisation. It typically occurs in patients with a substantial rise in CD4 counts in the first 4-12 weeks after initiation of HAART, but it can also occur years after the initial diagnosis of CMV retinitis. Patients with IRU may present with similar symptoms as the initial episode of CMV retinitis. These 2 entities can be distinguished by full ophthalmologic examination. Risk factors for IRU include prior CMV involvement of >25% of the retina, involvement of the posterior pole of the eye and treatment with intravitreal cidofovir. Although there is a potential risk of IRU after immune recovery with HAART, the risk of this complication is not related to the time interval between starting anti-CMV therapy and HAART. Therefore, the initiation of HAART should not be delayed in patients with CMV retinitis.
Primary prophylaxis against CMV is currently not recommended due to cost implication, the potential to induce CMV resistance, and lack of survival advantage. All HIV infected patients should be made aware of the symptoms of CMV disease, especially that of CMV retinitis when their CD4 count falls below 100/μL. Prompt referral for ophthalmological evaluation is required when symptoms occur.
Patient with a prior episode of CMV retinitis should be put on maintenance therapy/secondary prophylaxis until they have immune recovery after HAART. Secondary prophylaxis can be discontinued in patients on HAART with quiescent retinitis and who have a sustained rise in CD4 counts to >100/μL for 3-6 months or longer. By the same token, patients with prior CMV retinitis whose CD4 count has dropped below 100/μL should have their secondary prophylaxis reinitiated to prevent reactivation of disease.
Algorithm 20. Diagnosis and Management of CMV retinitis
- Gallant JE, Moore RD, Richman DD, Keruly J, Chaisson RE. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis 1992;166(6):1223-7. link
- Yust I, Fox Z, Burke M, Johnson A, Turner D, Mocroft A, Katlama C, Ledergerber B, Reiss P, Kirk O; EuroSIDA. Retinal and extraocular cytomegalovirus end-organ disease in HIV-infected patients in Europe: a EuroSIDA study, 1994-2001. Eur J ClinMicrobiol Infect Dis 2004;23(7):550-9. link
- Ford N, Shubber Z, Saranchuk P, Pathai S, Durier N, O’Brien DP, Mills EJ, Pascual F, Hoen E, Holland GN, Heiden D. Burden of HIV-related cytomegalovirus retinitis in resource-limited settings: a systematic review. Clin Infect Dis 2013;57(9):1351-61. link
- Boeckh M, Huang M, Ferrenberg J, Stevens-Ayers T, Stensland L, Nichols WG, Corey L. Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR. J Clin Microbiol 2004;42(3):1142-8. link
- Martin DF, Sierra-Madero J, Walmsley S, Wolitz RA, Macey K, Georgiou P, Robinson CA, Stempien MJ; Valganciclovir Study Group. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002;346(15):1119-26. link
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at link
- See RF, Rao NA. Cytomegalovirus retinitis in the era of combined highly active antiretroviral therapy. Ophthalmol Clin North Am 2002;15(4):529-36. link
- Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Arch Ophthalmol 1996;114(1):23-33. link
- Martin BK, Ricks MO, Forman MS, Jabs DA; Cytomegalovirus Retinitis and Viral Resistance Study Group. Change over time in incidence of ganciclovir resistance in patients with cytomegalovirus retinitis. Clin Infect Dis 2007;44(7):1001-8. link
- Jabs DA, Ahuja A, Van Natta M, Lyon A, Srivastava S, Gangaputra S, & Studies of the Ocular Complications of AIDS Research Group. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: five-year outcomes. Ophthalmology 2010;117(11):2152-61. link
- Nguyen QD, Kempen JH, Bolton SG, Dunn JP, Jabs DA. Immune recovery uveitis in patients with AIDS and cytomegalovirus retinitis after highly active antiretroviral therapy. Am J Ophthalmol 2000;129(5):634-9. link
- Robinson MR, Reed G, Csaky KG, Polis MA, Whitcup SM. Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy. Am J Ophthalmol 2000;130(1):49-56. link