Early in the AIDS epidemic, cytomegalovirus (CMV) was a major cause of morbidity and mortality in patients with AIDS in the United States.(1) Epidemiologic studies indicated that through 1992 nearly half of HIV-infected patients eventually developed CMV end-organ disease including chorioretinitis, esophagitis, colitis, pneumonia, and central nervous system disease.(2) With the advent of effective antiretroviral treatment (ART) there has been a dramatic decline in the occurrence of CMV disease in AIDS patients to approximately 5-10% of previous estimates. A diagnosis of CMV disease can be based on clinical evaluation (eg, CMV retinitis) but often requires tissue biopsy with histologic evidence of viral inclusions and inflammation (eg, CMV colitis).(3) Culture of CMV from blood, urine, or even biopsied tissue may only reflect infection rather than true end-organ disease. Detection of CMV inclusions, antigens, or nucleic acids in situ are preferred methods for making a diagnosis of CMV end-organ disease.
Ganciclovir (and its oral prodrug, valganciclovir), foscarnet, and cidofovir are available for management of CMV infection. This chapter is a review of the most common clinical syndromes caused by CMV and the risks and benefits of available treatment options.
CMV, a beta-herpesvirus, is the major cause of non-Epstein-Barr virus infectious mononucleosis in the general population and an important pathogen in immunocompromised hosts, including patients with AIDS, neonates, and transplant recipients. The risk of exposure to CMV increases with age, and serologic evidence of prior infection can be detected in approximately 60% of the general adult population in the United States.(4) Asymptomatic excretion of CMV in saliva, respiratory secretions, urine, and semen is common and explains the increasing risk of exposure over time. As with other herpesviruses, CMV remains latent in the infected host throughout life and rarely reactivates to cause clinical illness except in immunocompromised individuals.
CMV infection is more prevalent in populations at risk for HIV infection; approximately 75% of injection drug users and >90% of homosexual men who are infected with HIV have detectable IgG antibodies to CMV.(5) Higher prevalence rates among homosexual men correlates with the increased risk of exposure associated with receptive anal intercourse.(6) In addition, high prevalence rates of CMV IgM antibody in longstanding CMV-seropositive homosexual men suggest that this group is frequently re-exposed to (and at least sometimes reinfected with) differing exogenous strains of CMV.(7)
In patients with AIDS, progressive loss of immune function, and, in particular, loss of cell-mediated immunity, permits CMV reactivation and replication to begin; asymptomatic excretion of CMV in urine can be detected in approximately 50% of HIV-infected individuals with a CD4 lymphocyte count <100 cells/µL.(8) Cell-to-cell transmission of CMV results in tissue necrosis in association with nonspecific inflammation. Transient episodes of CMV viremia can also occur.(9) Although the clinical significance of viremia is uncertain, such episodes probably result in dissemination of CMV to other organs (eg, the retina), thereby setting the stage for subsequent end-organ disease. Prior to the availability of effective ART, >90% of patients with AIDS in the United States had evidence of disseminated CMV infection at autopsy.(10) ART leads to at least a partial return of CMV immune responses in most patients and to substantial decreases in CMV titers in blood.(11) Thus, in settings where ART is in widespread use, CMV retinitis is usually seen in those who have not begun or cannot tolerate ART. Surprisingly, CMV retinitis is relatively rare in patients with HIV viral loads that increase despite ART. There appears to be a prolonged lag time between failure of ART and impairment of CMV immune responses to an extent that allows CMV retinitis to develop. Apparently, a critical level of immune impairment and, in turn, CMV replication is required for CMV disease to develop, and as long as the CMV load can be kept below this critical level, there is protection against retinitis and other end-organ manifestations.(11)
CMV infection results in large atypical cells with intranuclear and intracytoplasmic inclusion bodies. These cells are 2 to 4 times larger than normal cells and have an eccentrically displaced nucleus resulting in an owl-like appearance.
| Clinical Manifestations|
Chorioretinitis most commonly occurs in patients with CD4 lymphocyte counts <50 cells/µL and accounts for 80% to 90% of CMV disease in patients with AIDS.(12) Common presenting symptoms include decreased visual acuity, the perception of floaters, or visual field loss. Ophthalmologic screening of patients with a CD4 lymphocyte count <50 cells/µL can detect asymptomatic retinitis. It is unclear, however, whether routine screening results in a different clinical outcome, and screening practices for retinitis vary within different health care settings.
Ophthalmologic examination of patients with CMV retinitis typically reveals large creamy to yellowish-white granular areas with perivascular exudates and hemorrhages. These lesions may occur at either the periphery or center of the fundus. If left untreated, lesions generally progress within 2 to 3 weeks and can result in blindness. Retinitis often begins unilaterally, but progression to bilateral disease is common. Systemic CMV disease involving other viscera may also be present.
CMV retinitis accounts for at least 90% of HIV-related infectious retinopathies.(13) Differentiating suspected CMV retinitis from cotton wool spots is essential. Cotton wool spots appear as small, fluffy white lesions with indistinct margins and are not associated with exudates or hemorrhages. These lesions do not progress and often undergo spontaneous regression. Toxoplasmosis is the second most common opportunistic infection of the eye, but it is not associated with hemorrhage and typically occurs in patients with cerebral toxoplasmosis. Syphilis, herpes simplex virus, varicella-zoster virus, and tuberculosis are other infections that may rarely involve the retina.
Patients with confirmed CMV chorioretinitis should begin treatment promptly. A variety of systemically administered agents as well as local, intravitreal therapies have demonstrated efficacy in delaying time to progression of retinitis. The choice of initial treatment should be based on several factors, including the patient's antiretroviral history (treatment naive vs failing therapy) and clinical status (especially underlying myelosuppression or renal impairment), location of lesion (sight threatening or not), concomitant medication (with potentially overlapping toxicity), and patient preference (especially regarding placement of an indwelling intravenous catheter). Before the availability of ART, CMV retinitis regularly progressed once therapy was discontinued, so maintenance treatment was considered necessary; and even with maintenance therapy, reactivation of retinitis and/or development of new lesions would commonly occur. However, if ART is successful in restoring CD4 counts to at least 100 cells/µL (although to 150-200 cells/µL is better), it is possible to stop maintenance therapy. This should not be attempted until a patient's CD4 count has remained above the levels mentioned for at least 3 months because the lymphocyte response requires time to reach full effectiveness. If maintenance therapy is discontinued, patients should be followed carefully for clinical or laboratory evidence of drug failure. Other factors to consider when deciding to discontinue maintenance therapy include patient adherence to ART medications, location of the retinal lesion, and the patient's vision in the unaffected eye.
(See also HIV InSite Knowledge Base chapter "Ophthalmic Manifestations of HIV.")
| Gastrointestinal Disease|
Prior to the availability of effective ART in the U.S., CMV enterocolitis occurred in 5% to 10% of patients with AIDS who had CD4 lymphocyte counts below 50 cells/µL.(14) In patients with CMV enterocolitis, diarrhea, weight loss, abdominal pain, anorexia, and fever are frequently present. The differential diagnosis includes diseases due to other gastrointestinal pathogens, including Cryptosporidium, Giardia, Mycobacterium, Shigella, Campylobacter, and Strongyloides stercoralis and Entamoeba histolytica as well as involvement by lymphoma or Kaposi sarcoma. Endoscopy usually reveals diffuse submucosal hemorrhages and mucosal ulcerations, although a grossly normal-appearing mucosa may be encountered in up to 10% of those individuals with histologic evidence of CMV colitis. Biopsy reveals vasculitis, neutrophilic infiltration, and nonspecific inflammation; the diagnosis is confirmed by the presence of characteristic CMV inclusions and the absence of other pathogens.
Esophagitis in patients with AIDS is most commonly due to either Candida albicans or herpes simplex virus, but may also be caused by CMV.(15) Patients with CMV esophagitis often have pain on swallowing in association with a large distal ulceration. As in colitis, diagnosis should be established through endoscopic examination and tissue biopsy.
Patients with symptomatic esophagitis or enterocolitis who do not have other pathogens detected by endoscopy, histology, or culture and who have confirmed tissue invasion by CMV should receive treatment until clinical improvement occurs. Ganciclovir and foscarnet have demonstrated equivalent efficacy in treating CMV colitis and esophagitis, but the benefits are not dramatic.(16)
Patients with pulmonary disease due to Pneumocystis jiroveci (formerly carinii) often have CMV isolated from lung biopsy specimens or lavage fluid.(17) Many of these patients respond to therapy directed at P jiroveci pneumonia alone, indicating that CMV is not a pathogen in such cases. When CMV causes pulmonary disease in patients with AIDS, the syndrome is that of an interstitial pneumonia. Patients often complain of shortness of breath, dyspnea on exertion, and a dry, nonproductive cough. The heart and respiratory rates are elevated, but auscultation of the lungs often reveals minimal findings with no evidence of consolidation. Chest radiography shows diffuse interstitial infiltrates, and hypoxemia is usually present.
Patients with interstitial pneumonia and positive CMV histology from lung tissue may have invasive CMV pneumonia. Anti-CMV therapy should be instituted in patients with a progressive, deteriorating clinical course after the exclusion of other pathogens.(18) In transplant patients with CMV pneumonia, the addition of CMV immune globulin to antiviral therapy improves outcome, but no such benefit has been observed in patients with AIDS.
| Central Nervous System Disease|
A distinct neurologic syndrome caused by CMV in patients with AIDS is radiculopathy, a spinal cord syndrome characterized by lower extremity pain and weakness, spasticity, areflexia, urinary retention, and hypoesthesia.(19) The cerebrospinal fluid (CSF) findings are atypical for viral infection and include polymorphonuclear pleocytosis and a moderately low glucose concentration. Culture of CSF may be negative, but antigen or DNA assays are usually positive.
Subacute encephalitis in conjunction with isolation of CMV from brain tissue or CSF has been reported.(20) Clinical manifestations of CMV encephalitis in patients with AIDS are comparable to subacute encephalitis from other pathogens. Personality changes, difficulty concentrating, headaches, and somnolence are frequently present. The diagnosis can be confirmed by brain biopsy, with evidence of periventricular necrosis, giant cells, intranuclear and intracytoplasmic inclusions, and positive CMV culture or by identification of CMV by antigen staining or DNA assay in brain tissue or CSF.
Patients with suspected CMV polyradiculopathy or encephalitis should be promptly treated.. Anecdotal reports of successful administration of ganciclovir and foscarnet, alone or in combination, have appeared,(21) but controlled data on efficacy are not available.
| Treatment of CMV Disease|
| Ganciclovir and Valganciclovir|
Ganciclovir (Cytovene, DHPG) is an acyclic nucleoside analogue of guanine that is a potent inhibitor of CMV replication in vitro.(22) Ganciclovir is rapidly phosphorylated inside virus-infected cells. Ganciclovir triphosphate competitively inhibits binding of deoxyguanosine triphosphate to DNA polymerase, resulting in inhibition of DNA synthesis and termination of DNA elongation. A controlled trial comparing ganciclovir with no treatment in patients with peripheral retinitis demonstrated efficacy in delaying progression of CMV retinitis.(23)
| Ganciclovir/Valganciclovir Administration|
For induction therapy, ganciclovir is given at an intravenous dose of 5 mg/kg twice daily for 2 to 3 weeks or until stabilization of retinitis. Maintenance therapy with ganciclovir (5 mg/kg) is administered once daily. Ganciclovir undergoes renal elimination, so dose reduction in patients with renal insufficiency is required. However, intravenous ganciclovir has been supplemented by valganciclovir (Valcyte), the more convenient oral prodrug of ganciclovir. Valganciclovir at a dose of 900 mg (two 450-mg tablets) orally results in ganciclovir blood levels similar to those obtained with a dose of 5 mg/kg intravenous ganciclovir, and has been shown to be similar in efficacy to intravenous ganciclovir as induction therapy in treating HIV-associated CMV retinitis.(24)
| Ganciclovir/Valganciclovir Toxicity|
The toxicity of valganciclovir is identical to that of intravenous ganciclovir (except for phlebitis associated with intravenous administration).(25) Because valganciclovir achieves blood levels comparable with intravenous ganciclovir, its bone marrow suppression is equivalent. Ganciclovir or valganciclovir causes neutropenia in approximately 20% to 40% of patients and thrombocytopenia in 5% of patients.(26) Gastrointestinal symptoms, rash, and nephrotoxicity have also been reported. Complete blood counts should be monitored twice a week during induction dosing with either drug and weekly during maintenance treatment. Patients who develop severe neutropenia (absolute neutrophil count <=500 cells/µL) can be maintained on ganciclovir or valganciclovir by addition of a colony-stimulating factor and/or discontinuing concomitant myelosuppressive therapy (eg, zidovudine [ZDV]).(27) Patients with persistent neutropenia below 500 cells/µL should be considered for alternative anti-CMV therapy.
| Oral Ganciclovir|
Prior to the availability of valganciclovir, oral ganciclovir was used to reduce the need for and risks associated with indwelling catheters, and it causes less neutropenia and anemia than intravenous (IV) ganciclovir. Randomized studies comparing oral ganciclovir (3 g/day) to intravenous ganciclovir (5 mg/kg per day) concluded that oral ganciclovir caused less neutropenia and anemia, but was also somewhat less effective than intravenous ganciclovir as maintenance therapy in delaying progression of CMV retinitis.(28,29) A study of higher doses of oral ganciclovir, comparing 3, 4.5, and 6 g/day with intravenous therapy (5 mg/kg) showed that, although oral ganciclovir at 3 g/day was inferior to intravenous ganciclovir in time to progression of retinitis as well as functional vision, outcomes on the 4.5- and 6-g arms were similar to intravenous therapy. As with the intravenous formulation, oral ganciclovir can cause neutropenia, thrombocytopenia, rash, nephrotoxicity, and gastrointestinal symptoms, although the incidence of these adverse effects is reduced with oral treatment. Even at 6 g/day, oral ganciclovir does not appear to cause more gastrointestinal toxicity than intravenous ganciclovir. As with intravenous ganciclovir, monitoring of blood counts during maintenance therapy is recommended.
Taken together, these results suggest that oral ganciclovir can be used most effectively in patients with early, stable, and peripheral CMV retinitis following intravenous therapy. However, the availability of valganciclovir for both induction and maintenance therapy has rendered oral ganciclovir obsolete.
Foscarnet (Foscavir, trisodium phosphonoformate) is a pyrophosphate analogue with in vitro activity against all human herpes viruses as well as HIV.(30) Unlike ganciclovir, foscarnet does not require intracellular phosphorylation to inhibit viral DNA polymerase and, therefore, retains activity against most ganciclovir-resistant strains of CMV.(31) In patients with peripheral retinitis, a controlled trial comparing foscarnet with no treatment demonstrated efficacy in delaying progression of CMV retinitis.(32) A randomized trial that compared foscarnet with ganciclovir demonstrated no difference between these agents in time to progression of retinitis.(33)
| Foscarnet Administration|
Intravenous administration of foscarnet usually requires placement of an indwelling catheter. For induction therapy, 90 mg/kg is given intravenously with an infusion pump over 1 hour with 1 L normal saline twice daily for 2 to 3 weeks or until stabilization of retinitis. Maintenance therapy with foscarnet (90-120 mg/kg) is administered over 2 hours with 1 L intravenous normal saline once a day.(34) Foscarnet is eliminated renally, and frequent (eg, twice weekly) monitoring of renal function with dose reduction based on estimates of creatinine clearance is required.
| Foscarnet Toxicity|
Nephrotoxicity is the most common serious toxicity associated with foscarnet.(35) Nephrotoxicity can be reduced by concomitant intravenous hydration and careful monitoring of renal function with appropriate dose modification. Abnormalities in serum phosphorus and calcium concentrations, ionized calcium in particular, also occur. Consequently, patients receiving foscarnet should also be monitored using weekly chemistry profiles. Because the risk of hypocalcemia may correlate with the rate of infusion, foscarnet must be administered with an infusion pump. Other less common adverse effects associated with foscarnet therapy include nausea, genital ulcers, anemia, nephrogenic diabetes insipidus, hypokalemia, hypomagnesemia, and central nervous system abnormalities, including seizure.
| Combination Intravenous Ganciclovir and Foscarnet|
Results of laboratory studies suggest that combination ganciclovir and foscarnet may have a synergistic effect on CMV replication.(36) In a trial of combination ganciclovir and foscarnet versus either drug alone in patients failing monotherapy,(37) combination therapy (5 mg/kg per day ganciclovir and 90 mg/kg per day foscarnet) was superior in delaying progression of retinitis to either ganciclovir alone (10 mg/kg per day) or foscarnet alone (120 mg/kg per day). This study also showed no advantage to switching from one monotherapy to another. Although combination therapy was associated with a negative impact on quality of life, due mostly to the increased infusion time, it remains an important option for patients with progressive and sight-threatening CMV retinitis. Laboratory monitoring of patients receiving combination ganciclovir/foscarnet should follow the guidelines described previously for each individual agent.
Cidofovir (Vistide, HPMPC) is a nucleotide analogue with a prolonged intracellular half-life and potent activity against a broad spectrum of herpesviruses, including CMV.(38) As a nucleotide, cidofovir does not require virus-mediated activation by phosphorylation and therefore retains activity against many ganciclovir-resistant CMV clinical isolates that are resistant because of mutations in the kinase that phosphorylates ganciclovir. Studies in patients with newly diagnosed and relapsing CMV retinitis have demonstrated significant benefits in delaying progression of retinitis.(39,40) Cidofovir's infrequent dosing schedule is more convenient for patients and can eliminate the need for indwelling catheters.
| Cidofovir Administration|
Cidofovir is administered intravenously as induction therapy at 5 mg/kg once a week for 2 weeks followed by maintenance treatment with 5 mg/kg every 2 weeks. On the day of each infusion, patients must take 4 g of oral probenecid to reduce renal uptake of cidofovir. (Probenecid is administered as a 2-g dose 3 hours preinfusion and a 1-g dose 2 hours and again 8 hours postinfusion). Patients who can tolerate the fluid load should also receive 2 L of intravenous hydration with normal saline (1 L minimum) with each cidofovir infusion.
| Cidofovir Toxicity|
Approximately 25% of patients in cidofovir studies of retinitis developed treatment-limiting nephrotoxicity or probenecid reactions. The severity of nephrotoxicity has substantially limited the use of cidofovir in clinical practice. To reduce toxicity, patients must be instructed on the critical role of probenecid administration and hydration.(41,42) Probenecid contains a sulfa moiety, and adverse reactions, similar to those seen with trimethoprim-sulfamethoxazole, can occur in up to 50% of patients. Administration of probenecid with food and adjunctive therapy with antihistamines, antipyretics, and/or antiemetics can reduce probenecid adverse effects.
Cidofovir should be administered in a controlled infusion setting with a carefully maintained treatment log that ensures strict adherence to the treatment regimen. To avoid nephrotoxicity, urine protein and serum creatinine levels must be checked within the 48 hours preceding each infusion and the dosage modified for proteinuria (2+). In addition, cidofovir is contraindicated in patients receiving other nephrotoxic agents and patients with baseline renal insufficiency (serum creatinine >1.5 mg/d, calculated clearance <=55 mL/min, or urine protein >2+). Indeed, if a patient is taking a potentially nephrotoxic agent, it should be discontinued 1 to 2 weeks before initiating cidofovir therapy.
| Drug-Resistant CMV|
After 3 months of treatment with intravenous ganciclovir, approximately 8% of patients excrete ganciclovir-resistant strains of CMV in their urine.(45) Development of resistance is associated with a more rapid progression of retinitis, and such individuals can often be identified clinically by a failure to respond to reinduction ganciclovir therapy. Patients with suspected ganciclovir resistance should not receive an ocular implant until resistance is ruled out by in vitro susceptibility testing of CMV isolates or there is a successful therapeutic trial of intravitreal injections or high-dose (10 mg/kg per day) intravenous ganciclovir.
Ganciclovir resistance is most often mediated by a mutation in the UL97 gene, which encodes the viral kinase that activates ganciclovir to the monophosphate form.(46) As a result, most ganciclovir-resistant strains of CMV remain susceptible to both foscarnet and cidofovir, the activities of which do not depend on viral activation. Most patients with ganciclovir resistance can therefore be effectively managed with either foscarnet or cidofovir. Ganciclovir resistance, however, can also (although less frequently) evolve through mutations in the viral DNA polymerase. Unfortunately, such polymerase mutants can demonstrate cross resistance to cidofovir and, rarely, foscarnet.(47) The management of patients with these highly resistant CMV strains can be challenging and may require higher doses of systemic agents, often in combination. In patients treated initially with either foscarnet or cidofovir, the time course of developing resistance is very similar to that of ganciclovir (ie, approximately 25% by 12 months of treatment).
| CMV Prophylaxis|
Oral ganciclovir has been licensed for the prevention of CMV disease in patients with advanced AIDS. In one study in patients with serologic or tissue culture evidence of CMV infection, oral ganciclovir administered as 3 g/day reduced the incidence of CMV disease by approximately 50% compared with placebo.(48) This result correlated with virologic outcome; about 40% of placebo recipients remained culture positive for CMV compared with <10% of ganciclovir recipients.
Routine prophylaxis, however, has not become standard in most HIV care settings. Some explanations include: the high cost of prophylaxis; the inconvenience of taking 12 capsules per day; potential toxicity (including neutropenia and anemia); results from a second study of oral ganciclovir prophylaxis that did not demonstrate a benefit (probably as a result of enrolling patients with higher baseline CD4 counts and the failure to perform regular and complete ophthalmologic examinations at entry and during follow-up)(49); and concerns about the emergence of ganciclovir-resistant disease. Concerning this last point, preliminary results indicate that approximately 1-3% of patients who receive oral ganciclovir prophylaxis develop phenotypic evidence of reduced susceptibility to ganciclovir after 1 year.(50)
CMV prophylaxis with oral ganciclovir should be considered for patients with CD4 lymphocyte counts below 50 cells/µL who may be at increased risk for retinitis on clinical grounds (eg, patients with confirmed extraocular CMV disease). Given its efficacy in treating CMV infection, it seems likely that valganciclovir could also be used as prophylaxis.
|| || Spector SA, Weingeist T, Pollard RB, Dieterich DT, Samo T, Benson CA, Busch DF, Freeman WR, Montague P, Kaplan HJ, et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. AIDS Clinical Trials Group and Cytomegalovirus Cooperative Study Group. J Infect Dis 1993; 168:557-63.|
|| || Lalezari J, Lindley J, Walmsley S, Kuppermann B, Fisher M, Friedberg D, Lalonde R, Matheron S, Nieto L, Torriani FJ, Van Syoc R, Sutton MA, Buhles W, Stempien MJ. A safety study of oral valganciclovir maintenance treatment of cytomegalovirus retinitis. J Acquir Immune Defic Syndr 2002; 30:392-400.|
|| || Drew WL, Ives D, Lalezari JP, Crumpacker C, Follansbee SE, Spector SA, Benson CA, Friedberg DN, Hubbard L, Stempien MJ, et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. Syntex Cooperative Oral Ganciclovir Study Group. N Engl J Med 1995; 333:615-20.|
|| || Palestine AG, Polis MA, De Smet MD, Baird BF, Falloon J, Kovacs JA, Davey RT, Zurlo JJ, Zunich KM, Davis M, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991; 115:665-73.|
|| || Jacobson MA, Wulfsohn M, Feinberg JE, Davis R, Power M, Owens S, Causey D, Heath-Chiozzi ME, Murphy RL, Cheung TW, et al. Phase II dose-ranging trial of foscarnet salvage therapy for cytomegalovirus retinitis in AIDS patients intolerant of or resistant to ganciclovir (ACTG protocol 093). AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases. Aids 1994; 8:451-9.|
|| ||Lalezari JP, Stagg R, Kupperman B, et al. A phase II/III randomized study of immediate versus deferred intravenous cidofovir (HPMPC) for the treatment of peripheral CMV retinitis in patients with AIDS. In: Program and Abstracts of The II National Conference on Human Retroviruses and Related Infections 1995; Washington:LB18.|
|| ||Lalezari JP, Holland G, Stagg R, et al. A randomized, controlled study of cidofovir for relapsing CMV retinitis in patients with AIDS. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, 1995.|
|| || Lalezari JP, Drew WL, Glutzer E, James C, Miner D, Flaherty J, Fisher PE, Cundy K, Hannigan J, Martin JC, et al. (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis 1995; 171:788-96.|
|| || Polis MA, Spooner KM, Baird BF, Manischewitz JF, Jaffe HS, Fisher PE, Falloon J, Davey RT, Jr., Kovacs JA, Walker RE, et al. Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrob Agents Chemother 1995; 39:882-6.|
|| ||The Chiron Ganciclovir Study Group. A randomized controlled multicenter clinical trial of a sustained-release intraocular ganciclovir implant in AIDS patients with CMV retinitis. Program of The 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco 1995:1215.|
|| || Drew WL, Miner RC, Busch DF, Follansbee SE, Gullett J, Mehalko SG, Gordon SM, Owen WF, Jr., Matthews TR, Buhles WC, et al. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis 1991; 163:716-9.|
|| ||Cherrington JM, Smith IL, Jiles RE, et al. Ganciclovir resistant CMV: Implications of UL97 and polymerase mutations in cross resistance to cidofovir. Antiviral Res 1996;30:A44.|
|| || Spector SA, McKinley GF, Lalezari JP, Samo T, Andruczk R, Follansbee S, Sparti PD, Havlir DV, Simpson G, Buhles W, Wong R, Stempien M. Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group. N Engl J Med 1996; 334:1491-7.|
|| ||Brosgart C, Craig C, Hillman D, et al. Final results from a randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of CMV retinal and gastrointestinal disease. Program and Abstracts of The XI International Conference on AIDS, July 7-12, 1996, Vancouver, B.C. Abstract Th.b.301.|
|| ||Drew WL, Miner RC, Crager M, et al. Does resistance to ganciclovir develop in patients receiving prophylactic drug? 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1995.|