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Objectives: To investigate whether low ganciclovir serum levels in patients on maintenance oral ganciclovir therapy are associated with recurrence of CMV retinitis., Methods: A prospective study of the plasma concentration of ganciclovir after initiation of maintenance oral ganciclovir therapy in 14 AIDS patients who had recovered from acute cytomegalovirus (CMV) retinitis., Results: Five of the 14 patients exhibited a mean time to recurrence of 37 days. The mean trough plasma concentration of ganciclovir in these patients after 1 month of oral ganciclovir therapy, was 0.40 +/- 0.30 mg/L. Nine patients had a mean time of progression of 263 days. The mean trough plasma concentration of ganciclovir in the latter patients was 0.80 +/- 0.60 mg/L., Conclusions: Patients exhibiting trough plasma levels of ganciclovir below 0.6 mg/L may be at higher risk of progression than patients who exhibited levels above 0.6 mg/L.

An 11-year-old boy with severe aplastic anemia underwent unrelated BMT following TBI, antithymocyte globulin and CY. On day +23, CMV antigenemia was detected which resolved with ganciclovir. Eight days after discontinuing ganciclovir, he complained of impaired visual acuity. Ophthalmologic findings and a positive PCR study using anterior chamber fluid from the right eye confirmed the presumptive diagnosis of CMV retinitis, although CMV antigenemia and PCR studies using PBMC were then negative. He was successfully re-treated with ganciclovir. CMV retinitis should be considered even when CMV antigenemia is not present or PCR using PBMC is negative.

Objective: To study the temporal relationships between cytomegalovirus (CMV) viral load and specific UL97 mutations in polymorphonuclear leukocytes (PMNL) and plasma samples from a patient with AIDS who developed ganciclovir-resistant CMV retinitis., Methods: Sequential PMNL and plasma samples were analysed for determination of the CMV viral load using non-molecular methods and a quantitative polymerase chain reaction (PCR) assay. Screening of the same samples for the most common mutations conferring ganciclovir resistance was performed using nested PCR and restriction enzyme analysis., Results: At the time of progression of CMV retinitis (after 6 months of ganciclovir), a rapid increase in the CMV DNA load was found in both PMNL and plasma samples. This increase paralleled the emergence of a specific mutation (V594) in the same samples and recovery of ganciclovir-resistant blood isolates. In this patient, however, the only tests that substantially predicted the progression of CMV disease were the quantitative PCR assay using PMNL and to a lesser extent the pp65 antigenemia assay., Conclusions: Quantitative evaluation of the CMV viral load in PMNL using sensitive assays such as PCR appears to be a promising approach for monitoring antiviral therapy in subjects with AIDS. In addition, common mutations conferring ganciclovir resistance can be detected directly in PMNL and plasma samples.

Introduction: The use of foscarnet and ganciclovir as a combination treatment for cytomegalovirus retinitis is increasing because of limitations associated with single agent therapy., Methods: The pharmacokinetics of foscarnet and ganciclovir were determined in 13 patients receiving either concomitant therapy (regimen A) or daily alternating therapy (regimen B) for maintenance of cytomegalovirus disease. For regimen A, 60 mg/kg intravenous foscarnet and 3.75 mg/kg ganciclovir were sequentially administered daily; for regimen B, 120 mg/kg foscarnet and 6 mg/kg ganciclovir were administered on alternating days. For both regimens, serial blood sampling for pharmacokinetic analysis was performed for each drug alone (day 1 or 2) and after 2 weeks of combination therapy. Plasma samples for foscarnet and ganciclovir analysis were performed by means of high-performance liquid chromatography. Pharmacokinetic analysis was performed with noncompartmental methods., Results: For regimen A, the plasma clearance (CL) of foscarnet did not change in the presence of ganciclovir, averaging 0.12 +/- 0.08 and 0.11 +/- 0.02 L/hr/kg on study days 2 and 14, respectively (p = 0.34). The volume of distribution (VSS) and mean residence time (MRT) also did not change significantly. CL and MRT of foscarnet did not change for regimen B, although a slight increase in VSS was observed before (0.38 +/- 0.05 L/kg) and after (0.46 +/- 0.07 L/kg) alternating therapy (p = 0.03). Ganciclovir CL did not change for either regimen, with mean values of 0.21 +/- 0.10 and 0.25 +/- 0.10 L/hr/kg (regimen A, p = 0.17) and 0.32 +/- 0.10 and 0.34 +/- 0.11 L/hr/kg (regimen B, p = 0.24). MRT and VSS were also not significantly different., Conclusion: These plasma data suggest that further dosage adjustments are unnecessary for or alternating maintenance therapy.

Background: The Foscarnet-Ganciclovir Cytomegalovirus Retinitis Trial compared the use of either ganciclovir or foscarnet for the initial treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. We previously reported that patients treated with foscarnet lived longer but were more likely to have their treatment switched, the latter suggesting foscarnet may not have been as well tolerated as ganciclovir. This study compared the morbidity and toxic reactions reported during the trial., Methods: Two hundred thirty-four patients with the acquired immunodeficiency syndrome and previously untreated cytomegalovirus retinitis at 11 university centers were randomly assigned to receive intravenously either foscarnet (n = 107) or ganciclovir (n = 127). Medical histories, laboratory tests, and drug treatment histories during the first 6 months of treatment were analyzed., Results: Neutropenia was more common in patients assigned to ganciclovir than to foscarnet (34% vs 14%; P = .001). Patients assigned to foscarnet reported more infusion-related symptoms (58% vs 24%; P < .001) and, in male patients, more genitourinary symptoms (36% vs 16%; P > .001); they also experienced a trend toward more nephrotoxic effects (13% vs 6%; P = .082) and electrolyte abnormalities. The incidence of seizures was similar in both groups (foscarnet, 12%; ganciclovir, 9%; P = .511). Patients assigned to foscarnet were more likely to be switched to the alternative treatment (foscarnet to ganciclovir, 46%; ganciclovir to foscarnet, 11%; P < .001), and most of this excess was attributable to toxic reactions. In 88% of cases in which treatment was switched as a result of toxic reactions and in which follow-up data were available, the toxic reaction resolved after the switch. No permanent disability or death resulted from toxic reactions., Conclusions: Compared with ganciclovir, the use of foscarnet was more frequently limited by the occurrence of toxic reactions. However, these toxic reactions rarely had long-term sequelae. In light of the previously reported survival benefit seen in patients treated with foscarnet, these data support the use of foscarnet for the initial treatment of cytomegalovirus retinitis.

Specific mutations in the UL97 region of human cytomegalovirus (HCMV) have been found to confer resistance to laboratory-adapted strains subjected to ganciclovir selection. In this study, mutations in the UL97 region of HCMV isolates obtained from patients receiving ganciclovir therapy were examined to determine whether they would confer ganciclovir resistance, and if these mutations could be detected directly in the plasma of AIDS patients with progressive HCMV disease despite ganciclovir treatment. A single nucleotide change within a conserved region of UL97 was found in five resistant isolates, resulting in an amino acid substitution in residue 595: from leucine to phenylalanine in one, and from leucine to serine in four resistant isolates. A sixth resistant isolate demonstrated a single nucleotide change, leading to a threonine to isoleucine substitution in residue 659. The role of the 595 amino acid substitution in conferring ganciclovir resistance was confirmed by marker transfer experiments. In further studies, direct sequencing of HCMV DNA present in plasma obtained from persons with resistant viruses revealed the identical amino acid substitutions in plasma as those present in the cultured viruses. These findings indicate that clinical resistance to ganciclovir can result from specific point mutations in the UL97 gene, and that the emergence of the resistant genotype can be detected directly in patient plasma.