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Cytomegalovirus disease in AIDS

Ives, David V.1,2

EDITORIAL REVIEW
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Introduction

Cytomegalovirus (CMV) is the most common cause of life-threatening viral infection in HIV-infected patients [1,2]. Retinitis (leading to blindness), gastrointestinal disease (leading to wasting, diarrhea, obstruction or perforation), and central nervous system (CNS) involvement (leading to flaccid paralysis or encephalitis) all may result from CMV infection and reactivation. The potential for rapid loss of sight, chronic crippling diarrhea, and sudden loss of neurologic function makes CMV the most feared of the opportunistic infections in advanced HIV infection. Despite advances in both diagnosis and treatment of CMV and the introduction of protease inhibitors for the treatment of HIV, CMV end-organ disease remains one of the most difficult opportunistic infections to manage for both patient and provider.

I will briefly review the manifestations of CMV reactivation, the history of treatment of CMV in AIDS, discuss the increasingly complex current treatment options, and finally, review future options for treatment and prevention of CMV disease.

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Disease caused by CMV in AIDS patients

The vast majority of CMV-related disease in adults is a function of CMV reactivation in the setting of advanced HIV infection (CD4 counts < 100 × 106 cells/l) [3–9]. Virtually any organ can be affected. Hemorrhagic necrotizing retinitis is the most common presentation of CMV. Gastrointestinal disease, occurring anywhere from mouth to anus, including liver, gallbladder and pancreas, is the second most common site of CMV disease [10–23]. Neurologic disease including chronic meningoencephalitis and polyradiculopathy accounts for an increasing number of CMV cases [24–29]. A wide variety of other clinical syndromes caused by CMV have also been reported [30–35].

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Retinitis

CMV retinitis is the most frequent cause of disease in the eye among HIV-infected persons, affecting approximately 20–40% of patients during the course of HIV infection. The incidence of CMV retinitis rises with a falling CD4 count, reaching 20–40% 2 years after a CD4 count of 50 × 106 cells/l has been documented [8,9]. If CMV retinitis is not treated, it will progress to blindness in the majority of patients.

CMV retinitis can be divided into sight-threatening and non-sight-threatening disease. The latter category describes disease in the periphery of the retina for which therapy can be initiated within several days or even weeks. Sight-threatening retinitis, usually defined as active disease within the central retina (less than three optic disk diameters from either the fovea or optic disk), should be treated as soon as possible, because even very small areas of progression may affect vision. Retinitis that can be visualized using a direct ophthalmoscope through an undilated pupil must be considered immediately sight-threatening and warrants immediate confirmation of the diagnosis by a trained ophthalmologist and initiation of therapy within 24 h.

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Gastrointestinal CMV disease

CMV may cause ulcerative lesions from the mouth to the anus and is one of the most common causes of dilated cholangiopathy in AIDS patients. The incidence of CMV gastrointestinal disease varies widely, depending on the population studied and criteria required for diagnosis [16,17]. Of the gastrointestinal CMV disease syndromes, esophagitis and colitis are the most common [11,12]. Esophagitis presents most frequently with odynophagia (87%), although true dysphagia may also be reported, and spontaneous substernal or midepigastric pain has been reported in up to 50% of patients [12]. Candida esophagitis and CMV esophagitis are clinically indistinguishable and are frequently both on the differential diagnosis list for a patient with advanced HIV infection and odynophagia [19]. CMV should be considered as a causal agent if empiric therapy for candida esophagitis does not result in rapid resolution of symptoms. In patients with severe odynophagia, dysphagia, or symptoms of esophageal obstruction, urgent endoscopy should be performed in an attempt to distinguish between these two syndromes. CMV colitis may present either as chronic diarrhea (persistent in 70% of cases and intermittent in 30%) and wasting, or as fulminant diarrhea with high fever, or even perforation [12,20,21]. Patients presenting for endoscopy who were subsequently found to have CMV colitis had high rates of fever (80%), weight loss (89% with a median loss of 8.9 kg), and crampy abdominal pain (64%). CMV disease of another organ, often the retina, is seen frequently at presentation (45%). CMV has been implicated as a common cause of dilated cholangiopathy of AIDS. Acalculous cholecystitis, pancreatitis, and hepatitis due to CMV have all been reported.

CMV is a common pathogen found in the CNS at autopsy in AIDS patients. Several autopsy studies have revealed an incidence of 20–30% of pathology consistent with active CMV infection in the CNS [27]. Polyradiculopathy and flaccid paralysis due to CMV is an increasingly recognized syndrome that can have a devastating impact on patient's quality of life and independence [25]. Lumbar puncture may reveal findings easily confused with bacterial meningitis with markedly elevated cerebrospinal fluid (CSF) white blood cell count with a polymorphonuclear cell predominance, markedly elevated protein, and low or normal glucose [29]. Culture for CMV is positive less then 50% of the time. In advanced cases, CSF cytology may show CMV nuclear inclusions in lymphocytes. The use of the polymerase chain reaction (PCR) has made it possible to identify CMV DNA in the CSF of patients with suspected CNS infection with CMV [28,36,37]. Two other distinct entities, mononeuritis multiplex and painful peripheral neuropathy, have been attributed to CMV infection [26].

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Diagnosis of CMV disease

The varied manifestations of CMV infection in HIV-infected patients, complicated by the abundance of syndromes that are clinical indistinguishable from CMV-related illness, mandate that tissue be obtained for pathologic examination whenever possible. The major exception to this rule is CMV retinitis, the diagnosis of which remains purely clinical. Even with tissue samples, the diagnosis of CMV may be elusive and multiple procedures are often required to make a diagnosis. Recent advances with PCR or immunoperoxidase techniques have clarified the diagnosis of CMV but have yet to provide a useful role as predictors of CMV disease [38,39]. A combination of CMV culture, viremia (by DNA PCR), and antigenemia may help to identify those patients at very high risk for future development of CMV disease, although no laboratory test has been proven to be significantly superior to clinical diagnosis.

Because of the high rates of prior CMV infection among patients with HIV, the presence of antibody to CMV does not increase the probability that any clinical syndrome is caused by CMV. A negative CMV antibody test result may make CMV-related disease less likely, but loss of antibody to multiple pathogens in advanced HIV infection has been reported, so that a negative serology at the time of a syndrome consistent with CMV reactivation is of little use. Negative serologies earlier in HIV infection are probably better evidence for lack of CMV infection but must be interpreted years later (during which time CMV infection may have been acquired from unprotected sexual contacts, transfusion or needle-sharing) with great care.

Given the expense and time required for a positive culture result (from blood, urine, or biopsy sample) to be reported (up to 1 month) and the high rate of positive cultures in the absence of clinical disease, there is no current indication for routine CMV culturing as part of initial clinical assessment of suspected CMV disease [38].

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Prevention

Oral ganciclovir has been shown to prevent the development of CMV retinitis in subjects with CD4 cell counts of less than 100 × 106/l and a positive serology or culture for CMV [40]. The large number of pills required, currently 12 per day, toxicities, and extremely high cost has prevented the widespread acceptance of oral ganciclovir for prevention at many centers. If newer oral agents are as effective, less of a burden to patients, and cheaper, prevention may become much more feasible.

Frequent screening eye examinations or crude visual field testing (using modified Amsler grids) by patients are both advocated as ways to detect CMV retinitis. A review of the efficacy of screening eye examinations at a single center has demonstrated a trend towards the earlier diagnosis of CMV (less sight-threatening disease and less bilateral disease), but with no impact on ultimate visual loss or survival (S. Weissman, personal communication, 1997).

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Treatment of CMV disease

Early in the AIDS epidemic there was no effective treatment for CMV. Over the past 10 years, three agents have been approved for treatment (Fig. 1). Ganciclovir, foscarnet and cidofovir are all effective, but each has prominent toxicities, and all require special efforts by both provider and patient to administer and monitor these drugs safely. The aim of CMV disease treatment in AIDS patients is to interrupt the ongoing tissue destruction with a course of high-dose induction therapy, and then, in cases of retinitis, to prevent relapse by the use of chronic or maintenance therapy (Table 1). The need for chronic maintenance therapy for CMV-related disease other than retinitis is controversial.

Fig. 1

Fig. 1

Table 1

Table 1

The inconvenience and risk of chronic, daily, intravenous administration of ganciclovir or foscarnet has led to the development of alternative delivery systems for ganciclovir (oral and intravitreous implant) and foscarnet (intravitreous injection) and intermittent intravenous therapy with cidofovir (every 2 weeks). Active research is ongoing to develop other orally bioavailable agents.

Ganciclovir is a guanosine analog and is an inactive prodrug. It requires phosphorylation to ganciclovir triphosphate in order to possess antiviral activity [41,42]. Foscarnet is a pyrophosphate analog that is a close structural analog of phosphonoacetic acid. Foscarnet inhibits CMV DNA chain elongation catalyzed by the CMV DNA polymerase by preventing pyrophosphate exchange [43]. Since foscarnet binds directly to the viral DNA polymerase it is active against thymidine kinase-deficient CMV mutants. Foscarnet is also an inhibitor of HIV reverse transcriptase [44]. Cidofovir is a nucleotide analog with an extremely long intracellular half-life. It is active against ganciclovir-(low level) and foscarnet-resistant strains of CMV in vitro and has been shown to be effective in both initial and salvage treatment (after failure of ganciclovir or foscarnet, or both) of CMV retinitis [45–48].

Ganciclovir, foscarnet, and cidofovir are all effective in delaying the progression of newly diagnosed peripheral CMV retinitis. Depending on the trial design and patient population, ganciclovir (at a maintenance dose of 5 mg/kg daily) and foscarnet (at a maintenance dose of 90 mg/kg daily) have been shown to delay progression by a median of 60–90 days when progression is determined by masked assessment of fundus photographs [41,49–54]. Cidofovir (maintenance dose of 5 mg/kg every 2 weeks) delayed progression by a median of 120 days in one study [45]. A comparative study of ganciclovir and foscarnet in a similar population showed no difference in the control of retinitis, although a survival advantage was accrued to the foscarnet arm [57].

Despite the proven efficacy of all three intravenously administered agents, the median time to progression is under 3 months, and most patients gradually lose sight in the affected eye(s). The intravitreal ganciclovir implant has shown dramatically superior prevention of retinitis progression, with acceptance levels of immediate post-operative complications or transient visual loss [58–61]. Indeed, whereas the provider using intravenous therapy is always waiting for a progression, the ophthalmologist monitoring a patient who has a ganciclovir implant will not see progression until after the effective lifetime of the implant has elapsed. Scheduled replacement of implants may lead to permanent arrest of retinitis. The most efficient and effective treatment to prevent development of systemic CMV infection, or retinitis in the fellow eye, is currently under study.

Treatment of ‘relapsed’ CMV retinitis, that is, retinitis that has failed to be controlled by at least one cycle of induction and maintenance therapy, is a greater challenge then treatment of newly diagnosed disease (Fig. 1). Using either ganciclovir or foscarnet, the length of each successive ‘maintenance’ period becomes shorter until the patient is effectively on continuous induction with one or both drugs [62]. Cidofovir (at 5 mg/kg every 2 weeks) has recently been shown to prevent progression of relapsed disease for a median of greater than 105 days [48].

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Toxicity

Ganciclovir (intravenous or oral) causes bone-marrow suppression in 5–30% of patients, depending upon dose and stage of CMV disease [63]. Use of cytokines is high in recipients of ganciclovir and must be included in the overall cost of treatment [64]. Oral ganciclovir may also cause gastrointestinal upset, but has been relatively well tolerated in placebo-controlled trials [56]. Foscarnet is nephrotoxic and causes electrolyte abnormalities, particularly hypocalcemia, hypokalemia and hypomagnesemia [52,62]. Minimizing the nephrotoxicity of foscarnet is critically dependent upon adequate hydration. Patients must be educated to hold their scheduled doses if vomiting, diarrhea, or high fevers may be causing dehydration. Patients should be monitored weekly for electrolyte imbalances and aggressively repleted as necessary.

Cidofovir's primary toxicity is dose- and schedule-dependent nephrotoxicity [45]. Large doses of probenecid and intravenous fluids given before and after each dose appear to minimize this toxicity. Neutropenia occurred in 15% of patients in one study [43]. As in the case of foscarnet, every effort must be made to avoid giving cidofovir in the presence of prerenal azotemia or other nephrotoxic drugs. The long dosing interval of cidofovir should therefore be used to avoid such occasions.

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Treatment decisions

The availability of three effective agents, two with multiple routes of delivery has made the decision of how to treat active CMV retinitis very complicated (Fig. 1). The first decision that must be made is the urgency with which treatment must begin. Sight-threatening retinitis may progress to blindness rapidly and warrants immediate induction therapy (within 24 h). Some experienced ophthalmologists can provide an intravitreous injection of ganciclovir or foscarnet at the time of diagnosis, allowing the provider and patient more time to make longer term decisions about full induction and maintenance.

Peripheral or non-sight-threatening retinitis will progress towards the posterior pole of the retina, although multiple studies have now shown that the median time to advancement of the lesion edge by 750 µm, the standard definition of ‘progression’ in treatment trials, is about 3 weeks. There is an increased rate of retinal detachment with untreated retinitis that may lead to sudden loss of vision, but, in general, a decision about type and route of treatment can be made over a period of several days [46].

The next decision that needs to be made by patient and provider is the role of daily intravenous therapy (ganciclovir or foscarnet), which will require a permanent indwelling catheter, versus intravitreous, oral or intermittent intravenous therapy, which do not require a catheter (Table 1).

The advantages of daily intravenous ganciclovir or foscarnet are proven efficacy, excellent systemic anti-CMV effect, and extensive provider experience with management of toxicities. The non-catheter options offer more varied efficacies and systemic effect, but do not include the substantial risk of catheter-related complications. There are multiple possible combinations of agents and delivery routes that may offer the best of both the high efficacy of catheter agents and the ease of non-catheter agents (Fig. 1). If and when more effective oral agents become available, the choice of therapies may shift further.

Oral ganciclovir is less effective than intravenous ganciclovir and should not therefore be used for maintenance of sight-threatening retinitis [47]. Ganciclovir implants offer the best local control of retinitis [60] but offer no systemic coverage [58,59,65]. Cidofovir requires dosing only every 2 weeks for maintenance, but the requirement for high doses of probenecid and prehydration to prevent nephrotoxicity require most of 1 day for each infusion, which should probably be administered in a supervised setting for maximum safety.

When using intravenous ganciclovir or foscarnet, the clinician should use all available means to provide the highest dose that can be safely administrated. The use of cytokines to prevent neutropenia and anemia should be encouraged to allow the use of intravenous ganciclovir at a daily dose of 10 mg/kg. Similarly, high-dose maintenance with foscarnet (120 mg/kg daily) is superior to 90 mg/kg daily maintenance in terms of survival. Until more data is available, cidofovir should not be used at higher than recommended doses because its nephrotoxicity is dose- and schedule-dependent. In case of a severe sight-threatening relapse, consideration may be given to administering three weekly doses of cidofovir as induction therapy, although there is no published data comparing the effects or toxicities of this regimen.

Patients receiving stable maintenance therapy for CMV retinitis should be seen by an ophthalmologist at least monthly. Failure to control retinitis is usually due to a combination of lack of adequate host immunity and, ultimately, to drug resistance [66,67]. Treatment of relapsed CMV retinitis or ‘salvage’ therapy is an even more complicated issue than initial therapy. The few trials of salvage regimens have suggested that a combination of ganciclovir and foscarnet is more effective than either agent alone, and that cidofovir is also effective in subjects who have failed to improve on either ganciclovir or foscarnet [48,62,68]. It is often the case that a combination of intravitreous therapy and systemic intravenous therapy is required for adequate control.

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Treatment of other sites of CMV reactivation

CMV esophagitis or colitis should be treated with either intravenous ganciclovir or foscarnet at induction doses for at least 3 weeks [54,69,70]. Symptom response may lag somewhat behind pathological improvement. The only trial to compare ganciclovir with placebo demonstrated a trend towards improvement [54]. The need for maintenance for gastrointestinal CMV is controversial and varies from center to center. Except in cases of extremely severe disease, intravenous maintenance is not generally required. Patients with gastrointestinal CMV are at extremely high risk for development of CMV retinitis and may be the most appropriate population for preventative (prophylactic) therapy. Treatment of the neurologic complications of CMV has been disappointing [71–74]. Successful treatment of CMV polyradiculopathy requires early diagnosis (before paraparesis) and may be a clinical situation in which combination induction with ganciclovir and foscarnet is indicated.

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Future treatment options

Two new oral agents, lobucavir and adefovir, are currently in clinical trials [75] (H. Jaffe, personal communication, 1997). Both are nucleoside analogs with activity against HIV and against CMV and other herpesviruses. Lobucavir has a high enough oral bioavailability for it to be used for induction therapy. If either of these agents proves to be effective, they would offer an ideal combination for suppression of HIV and treatment/prevention of CMV. Ganciclovir is being studied in a new oral prodrug formulation that has similar pharmacokinetics to intravenous ganciclovir (P. Skolnik, personal communication, 1997). If these trials demonstrate its effectiveness, the number of pills required for maintenance or prevention of CMV may fall from 12 daily to one or two daily. Anti-CMV monoclonal antibody preparations have been studied as adjunct therapies to ganciclovir or foscarnet. Unfortunately, the AIDS Clinical Trials Group recently stopped its trial (ACTG 266) of one such drug (MSL-109) because of a lack of efficacy.

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CMV retinitis in the age of highly active antiretroviral therapy

The advent of combination regimens for the treatment of HIV that can result in the rapid decline of HIV load in the blood and substantial increases in CD4 cell count should have a major impact on both the development and treatment of CMV disease. Several cases of new strains of CMV within days of institution of highly active antiretroviral therapy (HAART) and a similar syndrome in disseminated Mycobacterium avium complex disease have been reported [76]. Contrary to historical data, CMV or M. avium complex illness in these patients has been relatively easy to induce and control, suggesting that the persistence of immune reconstitution may have a beneficial effect on control of these late-stage opportunistic infections. Until the frequency and severity of such HAART-related CMV disease is known, it seems reasonable to perform dilated fundoscopic examinations on all patients beginning HAART with very low CD4 counts before and shortly after initiation of therapy. Documentation of active CMV disease prior to initiation of HAART might prompt the counter-intuitive pattern of delaying HAART for a short time until induction therapy for CMV can be successfully concluded.

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Acknowledgement

The author thanks C. Crumpacker for assistance on earlier versions of this manuscript and for mentoring.

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    Keywords:

    Cytomegalovirus; retinitis; ganciclovir; foscarnet; cidofovir

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