Cidofovir in the treatment of cytomegaloviral disease

OBJECTIVE: To review the clinical pharmacology and microbiology of cidofovir in the therapy of cytomegalovirus (CMV) disease. DATA SOURCES: Pertinent literature was identified via a MEDLINE search (October 1986-February 1997), and data from abstracts presented at recent scientific meetings were also included; unpublished information was provided by the manufacturer. STUDY SELECTION: Antiviral activity data were included if widely accepted methodology was used. All clinical data currently available from human studies were also included. DATA SYNTHESIS: Cidofovir is similar to ganciclovir in mechanism of action; however, cidofovir does not require viral enzymes for activation. Although the half-life of cidofovir in plasma is only 2.6 hours, the intracellular half-life may be much longer, allowing efficacy with biweekly maintenance dosing. In vitro, cidofovir appears to be equally or more effective than the other agents currently available for the treatment of CMV. In vivo, cidofovir appears to be effective in delaying the progression of CMV retinitis, although no clinical trials to date have directly compared cidofovir with either ganciclovir or foscarnet. Current intravenous dose recommendations are 5 mg/kg once weekly for two doses (induction), and then 5 mg/kg once every other week (maintenance). Since cidofovir is cleared almost entirely by the kidneys, dosage adjustments must be made in patients with impaired renal function. Disadvantages of cidofovir primarily include its risks of adverse drug reactions, such as nephrotoxicity, which is likely to occur in up to 50% of patients if appropriate preventative measures are not taken. Neutropenia and constitutional reactions to probenecid are also commonly encountered during the course of cidofovir therapy. CONCLUSIONS: Cidofovir is the first acyclic phosphonate nucleoside antiviral agent to be approved for general use in the US. In addition to delaying the progression of CMV retinitis, cidofovir may provide some protective benefits to patients at risk for developing the disease and may be active against certain strains of virus resistant to other currently available therapies. Another advantage of cidofovir is its infrequent dosage schedule, which may prove beneficial in patients who are not compliant with daily intravenous dosing regimens. When determining the appropriate treatment for a patient with CMV retinitis, the benefits of using cidofovir must be weighed carefully against the risk of potentially serious adverse effects.     

AIDS: infections of the retina and choroid

Various viral, bacterial, parasitic and fungal agents have been found to cause infections of retina and choroidea in HIV-infected patients. Usually these infections are opportunistic infections caused by the profound immunodeficiency, which is a result of the decay of lymphocytes by HIV. Before the HIV epidemic only rare cases of cytomegalovirus (CMV) retinitis were known in the literature. Now CMV retinitis has become the most common infection of the eye in AIDS patients. Ocular toxoplasmosis in HIV-infected patients can have a severe clinical appearance without treatment. Spontaneous recovery, as it usually occurs in otherwise healthy patients, does not take place in HIV-infected patients, so that a lifelong maintenance therapy is mandatory. Pneumocystis carinii chorioiditis was unknown before the HIV epidemic. In 1987 Pneumocystis carinii were found in the choroidea and two years later the clinical appearance could be described. Infections of choroidea and retina associated with AIDS may not be seen as isolated diseases. Commonly other organs are infected by the same or another organism. In case of AIDS-associated eye infections other organs should be checked for opportunistic disease. Diagnosis can be difficult. Because most of all intraocular infections associated with AIDS are CMV retinitis, an effective therapy can be initiated in most cases and in the follow-up a diagnosis can finally be made. Serological testing may be inconclusive because of occasional false-negative findings. Treatment often only suppresses the infections and so ongoing maintenance therapy may be necessary, as in the cases of CMV retinitis and Toxoplasma retinochorioiditis. A variety of different diseases, which can be treated by a multitude of different substances with a lot of adverse effects and contraindications, can complicate the therapeutic modalities used for the management of each individual disorder. Additionally HIV-infected patients suffer from at least two or three different diseases and must be treated lifelong with plenty of substances, which often are given with higher doses than usual. Only by cooperation of HIV-experienced doctors of different specialities in hospitals and offices the complex subject of HIV infection can be managed.     

Treatment of cytomegalovirus retinitis with an intraocular sustained-release ganciclovir implant. A randomized controlled clinical trial

BACKGROUND AND METHODS: We performed a randomized controlled clinical trial to assess the safety and efficacy of a 1 microgram/h ganciclovir implant for the treatment of newly diagnosed cytomegalovirus (CMV) retinitis in patients with the acquired immunodeficiency syndrome (AIDS). Patients with previously untreated peripheral CMV retinitis were randomly assigned either to immediate treatment with the ganciclovir implant or to deferred treatment. Standardized fundus photographs were taken at 2-week intervals and analyzed in a masked fashion. The study end point was progression of retinitis based on the photographic assessment. RESULTS: Twenty-six patients (30 eyes) were enrolled. The median time to progression of retinitis was 15 days in the deferred treatment group (n = 16) vs 226 days in the immediate treatment group (n = 14) (P < .00001, log-rank test). During the study, 39 primary implants and 12 exchange implants were placed in immediate-treatment eyes, deferred-treatment eyes that progressed, or contralateral eyes that developed CMV retinitis. Postoperative complications in the total series included seven late retinal detachments and one retinal tear without detachment. Final visual acuity was 20/25 or better in 34 of 39 eyes. The estimated risk of developing CMV retinitis in the fellow eye was 50% at 6 months. Biopsy-proven visceral CMV disease developed in eight (31%) of 26 patients. The median survival was 295 days. CONCLUSION: The ganciclovir implant is effective for the treatment of CMV retinitis. Patients with unilateral CMV retinitis treated with the implant are likely to develop CMV retinitis in the fellow eye, and some patients will develop visceral CMV disease.     

Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome

PURPOSE: To evaluate the impact of foscarnet on the longevity of persons with human immunodeficiency virus, type 1 (HIV-1) infection and cytomegalovirus (CMV) retinitis. PATIENTS AND METHODS: A cohort of 24 patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis received sodium phosphonoformate (foscarnet) as part of a controlled efficacy trial at the National Institutes of Health. Foscarnet was continued for as long as it was tolerated. Antiretroviral therapy was given to the patients as tolerated. Long-term follow-up was available on all patients. RESULTS: Seventeen patients received zidovudine during or after receiving foscarnet, 2 patients received dideoxyinosine, 2 patients zidovudine and dideoxyinosine, and 3 patients received no specific antiretroviral agent. Patients received foscarnet for a mean of 6.2 months (median, 4 months; range, 10 days to 22 months). Ten patients required a change to ganciclovir therapy at some time after receiving foscarnet. The median time from the diagnosis of CMV retinitis until death was 13.5 months (range, 3 to 34 months). Patients lived longer than untreated or ganciclovir-treated historical controls with AIDS and CMV retinitis. There was no difference in the survival of patients treated with foscarnet at the time of diagnosis and those patients treated with foscarnet only after progression of their CMV retinitis. CONCLUSIONS: These data suggest that foscarnet may prolong the survival of persons with AIDS and CMV retinitis and should be the initial treatment of choice in these patients.     

Cytomegalovirus retinitis in patients with AIDS in Europe. AIDS in Europe Study Group

The incidence of cytomegalovirus (CMV) retinitis and risk factors associated with the condition were studied in patients with the acquired immune deficiency syndrome (AIDS) in a multicenter retrospective cohort study of 6458 patients from 52 centers in 17 countries in Europe. Cytomegalovirus retinitis was diagnosed in 154 patients (2.4%) at the time of AIDS diagnosis, the probability of this diagnosis being significantly higher for those with CD4+ cell counts of < 100/mm3 (3.4%) than with counts of 100-200/mm3 (1.3%) or > 200/mm3 (0.8%). The rate of developing CMV retinitis after AIDS diagnosis was 9.4 per 100 patient years of follow-up. Multivariate analysis showed that risk behavior was significantly associated with the risk of developing CMV retinitis: lower for intravenous drug users [relative risk (RR) 0.47] and those engaged in "other risk behavior" (RR 0.58) than for homosexual men. The risk of developing CMV retinitis after AIDS diagnosis was significantly associated with CD4+ cell count at the time of AIDS diagnosis: for counts < 100/mm3 (RR 2.90) and from 100 to 200/mm3 (RR 2.13), there was a higher risk than for counts > 200/mm3. Patients with Pneumocystis carinii pneumonia, toxoplasmosis, or extraocular CMV infection at time of AIDS diagnosis exhibited an increased risk of developing CMV retinitis. Patients treated with zidovudine exhibited an increased rate of CMV retinitis: RR was 1.75 during and 2.87 after the second year of treatment as compared to those who had not received zidovudine. Median survival after CMV retinitis at time of AIDS diagnosis was eight months.     

CMV-specific immune responses and HLA phenotypes of AIDS patients who develop CMV retinitis. HNRC Group. HIV Neurobehavioral Research Center

HLA phenotype and immune responses to CMV were studied to determine whether the subset of AIDS patients who developed CMV retinitis were immunogenetically or immunologically predisposed. CMV retinitis develops in approximately 28-35% of AIDS patients and CMV encephalitis develops in 40% of those with retinitis, often leading to death. T-cell proliferation responses to CMV and HIV were assayed prospectively in individuals enrolled in a longitudinal study at the HIV Neurobehavioral Research Center (HNRC) in San Diego. Seventy-three participants, at various stages of disease, have been HLA typed and followed, clinically and immunologically, for up to 5 years. Six HIV infected individuals who eventually developed CMV retinitis, and were assayed prospectively, had a history of low T-cell proliferation to CMV antigens before they were profoundly immunosuppressed. All 10 individuals with CMV retinitis had at least one of three HLA alleles (or combinations): A2B44 (p = 0.02), B51(p = 0.02), or DR7 (p = 0.01) (collective p value = 0.007). Three of the 10 had two or more of these alleles. Of AIDS patients with CD4 counts below 100 and actively at risk for retinitis, 7/15 with A2B44,51, or DR7 have developed retinitis compared to 0/13 without these HLA alleles (relative risk = 23.8). All 4 patients with these alleles who have died, had retinitis. These results suggest that HIV infected individuals with HLA phenotypes A2B44, B51, and DR7 have low T-cell immune responses to CMV and are predisposed to CMV retinitis and encephalitis as immunodeficiency progresses.     

Quantitative cytomegalovirus DNA level in the blood and its relationship to cytomegalovirus retinitis in patients with acquired immune deficiency syndrome

OBJECTIVE: A pilot study was performed to determine whether relationships exist between changes in a quantitative solution hybridization assay for cytomegalovirus (CMV) DNA in the blood and development of CMV retinitis, development of nonocular CMV disease, or reactivation of pre-existing CMV retinitis lesions. DESIGN: Observational case series. PARTICIPANTS: Two groups of human immunodeficiency virus-infected patients: 10 CMV antibody-positive patients with CD4+ T-lymphocyte counts of less than 50 ml and no CMV disease at baseline and 11 patients with CMV retinitis but no extraocular CMV disease at baseline. INTERVENTION: Quantitative changes in leukocyte-associated CMV DNA levels were observed over time. Anti-CMV therapies were based on clinical findings only. MAIN OUTCOME MEASURES: Development of CMV end-organ disease or change in activity of pre-existing CMV retinitis lesions was measured. RESULTS: Among patients with no CMV disease at baseline, four had CMV disease develop during follow-up (three cases of CMV retinitis, one case of presumed CMV esophagitis); all had CMV DNA levels greater than 5000 genomes/ml before the onset of CMV disease. The remaining six patients had levels less than 5000 genomes/ml throughout follow-up (P = 0.05). Among patients with CMV retinitis at baseline, all whose CMV DNA blood levels rose more than tenfold had extraocular CMV disease or reactivation of CMV retinitis develop. Raised CMV DNA blood levels were not seen in every patient with clinical reactivation of CMV retinitis. CONCLUSION: Elevated or rising CMV DNA blood levels appear to be associated with the development of CMV disease in individuals with low CD4+ T-lymphocyte counts. In patients with CMV retinitis, rising levels appear to be associated with the development of extraocular CMV disease or reactivation of CMV retinitis. Conversely, reactivation of CMV retinitis also may occur in the absence of changes in CMV DNA blood levels. Further studies are warranted to determine whether changes in CMV blood levels can be used as a guide for preemptive therapy to prevent reactivation of CMV retinitis lesions or to help choose between local and systemic therapy for management of reactivations.     

Increasing breast and cervical cancer screening in low-income women

Active cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) was treated with an intraocular sustained-release ganciclovir implant. A total number of 19 implants were performed in 15 eyes of 9 AIDS patients. The intraocular sustained-release ganciclovir was effective in preventing reactivation of CMV retinitis in 15 of the 19 implants, ineffective in 3, and undetermined in 1. All ineffective cases had been resistant to ganciclovir therapy before the implants. Vision after the therapy was maintained at better than 0.5 except for one eye. There were no serious ocular complications caused by the therapy. Among 5 patients with unilateral CMV retinitis, 2 unaffected eyes developed CMV retinitis during this therapy. In addition, another patient developed presumed CMV infection in other systemic organs. Based on these data, the intraocular sustained-release ganciclovir implant was considered to be useful for the treatment of CMV retinitis in AIDS.     

Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy

The suppression of human immunodeficiency virus (HIV) replication and elevation in CD4 cells observed with protease inhibitor combination regimens known as HAART (highly active antiretroviral therapy) may allow AIDS patients to undergo an immune recovery that allows them to suppress the progression of cytomegalovirus (CMV) retinitis. Eleven AIDS patients receiving HAART with healed CMV retinitis in whom CMV-specific maintenance therapy was discontinued were studied. Median CD4 cell counts were 42 before the initiation of HAART and 183 at discontinuation of anti-CMV therapy. While a median 1.1 log10 drop in plasma HIV-1 RNA was obtained between starting HAART and withdrawal of maintenance therapy for CMV, only 3 of 11 patients maintained plasma HIV RNA below the limits of detection. Reactivation of CMV retinitis after withdrawal of anti-CMV therapy did not occur in any of the patients observed for a median of 156 days (range, 92-558).     

Epithelial-mesenchymal transdifferentiation and extracellular matrix gene expression in pleomorphic adenomas of the parotid salivary gland

OBJECTIVES: To determine the incidence of clinical resistance to intraocular cidofovir injection for treatment of acquired immunodeficiency syndrome (AIDS)-related cytomegalovirus (CMV) retinitis, and to identify virologic features associated with cidofovir treatment failure. PATIENTS and METHODS: Clinical resistance to intravitreal cidofovir was examined in 64 patients with CMV retinitis who received at least 1 injection of 20 pg of cidofovir. Histopathologic examination, culture, and polymerase chain reaction were used to detect CMV in ocular specimens. Antiviral resistance was assessed by plaque reduction assay and DNA sequencing. RESULTS: Clinical resistance to intravitreal cidofovir injections was identified in 3 patients (5%) and was associated with prior oral ganciclovir or intravenous cidofovir use. Ganciclovir- and cidofovir-resistant CMV isolates were cultured from 2 patients and harbored resistance-associated mutations in the UL97 and polymerase genes. Resistance mutations were also detected by direct analysis of vitreous. In 1 patient, different resistance mutations were identified in ocular vs extraocular CMV strains. CONCLUSIONS: Clinical failure of intravitreal cidofovir occurs infrequently, but may be associated with cidofovir-resistant CMV selected by prior ganciclovir or cidofovir treatment. Ocular CMV disease can result from a localized infection with a resistant CMV strain, and antiviral resistance may develop at a local site of infection independently from resistance that develops systemically.     

Detection of cytomegalovirus (CMV) antigen for rapid diagnosis and monitoring of CMV diseases in AIDS

Ten to forty percent of the patients with acquired immunodeficiency syndrome (AIDS) develop sight- or life-threatening cytomegalovirus (CMV) infections. In some patients with AIDS, CMV is detected in the bronchoalveolar lavage fluid (BALF), urine, and other specimens, even when there are no symptoms of CMV disease. An indicator of active CMV infection is needed to facilitate the diagnosis of CMV disease in patients with AIDS or HIV infection and the evaluation of the efficacy of subsequent treatment. The present study was conducted during the period from 1993 to 1994. The subjects consisted of three patients with AIDS and a confirmed diagnosis of CMV disease (one case of retinitis, one case of gastrointestinal disease and one case of pneumonia), and five HIV-positive patients in whom CMV associated disease was ruled out. Those patients were monitored occasionally for the following parameters of active CMV infection and disease: expression of CMV antigen in the nucleus of polymorphonuclear leukocyte (CMV antigenemia), as it was determined with a monoclonal antibody against a lower matrix protein (p65); infectious CMV detected by shell vial method; CMV DNA detected by PCR; anti-CMV antibody titer; and histological findings. CMV p65 antigen was detected in the leukocytes of both the peripheral blood and BALF during the early phase of CMV disease in three out of three cases of the CMV disease group, and this antigen became negative in two out of two cases who responded to the therapy. All the five patients in the CMV-related-disease-negative group were negative for CMV antigenemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytomegalovirus retinitis in a pediatric AIDS patient

INTRODUCTION: Cytomegalovirus retinitis (CMV) is the most frequently found opportunistic eye infection in adults with AIDS, with mean incidence of 20%-50%. However, only 5% of children with AIDS have this infection. CLINICAL CASE: We present the case of a six year old girl with stage C3 AIDS diagnosed at the age of 20 months, who developed unilateral diffuse retinitis due to CMV. The infection involved the posterior pole of the right eye, with retinal atrophy along the temporal vascular arcodes, and an active advance front in the temporal macula. The optic nerve was not found to be involved although the peripheral areas of the retina were involved leading to rhegmatogenous detachment of the superotemporal retina. In view of the systemic deterioration of the patient, no specific anti-CMV treatment was given. The patient died of respiratory insufficiency a few weeks later. CONCLUSIONS: CMV retinitis in paediatric AIDS patients is usually associated with more severe illness and a poorer general health than the adult population. In view of the absence of symptoms in these patients, periodic ophthalmoscopic examinations should be done in those who have severe immunological deterioration.     

Endothelial precipitates and laser flare photometry in patients with acquired immunodeficiency syndrome: a screening test for cytomegalovirus retinitis?

Patients with acquired immunodeficiency syndrome (AIDS) who present with cytomegalovirus (CMV) retinitis show pathognomonic endothelial precipitates suggestive of primary anterior uveitis or secondary changes due to a spill-over from the posterior chamber. Laser flare photometry allows quantification of the intensity of anterior affection. We wanted to establish anterior-chamber flare values in AIDS patients with and without CMV retinitis and to find out whether CMV retinitis is preceded by an elevation of the flare value. In all, 25 men with AIDS who presented with CMV retinitis and 27 who did not have CMV retinitis but showed a CD4 count of < or = 200 cells/microliter blood were enrolled in a prospective study. Slit-lamp examination was performed, followed by indirect ophthalmoscopy and laser flare photometry after dilation of the pupil with tropicamide eye drops. Patients with CMV retinitis were followed every 10 days and the others, every 4 weeks. A group of 51 human immunodeficiency virus (HIV)-negative men served as a control group. AIDS patients with CMV retinitis showed a significantly higher flare count in the affected eye (12.4 photons/ms; n = 26) as compared with the unaffected partner eye (4.2 photons/ms; P < or = 0.0001; n = 18) and with eyes of AIDS patients without CMV retinitis (4.1 photons/ms; P < or = 0.0001; n = 50). The count in the latter eyes was also significantly higher than the control value (3.1 photons/ms; P < or = 0.0001; n = 102). Typical reticulate endothelial precipitates were found in 92% of AIDS patients with CMV retinitis. During the study, five eyes of three patients developed a fresh CMV retinitis, but a preceding rise in the flare count was not observed. Laser flare photometry follows the occurrence of pathognomonic reticulate endothelial precipitates. It lags behind the development and the extension of CMV retinitis. Therefore, it cannot be used as a screening test for early detection of CMV retinitis.     

Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients

Seven AIDS patients who were receiving suppressive therapy for previously diagnosed cytomegalovirus (CMV) retinitis were offered treatment with protease inhibitors (PIs). Secondary prophylaxis for CMV was discontinued after 3 months of therapy with PIs if patients had >150 CD4 cells/mm3 and a human immunodeficiency virus (HIV) load of <200 copies/mL and if they were negative for CMV as determined by qualitative CMV polymerase chain reaction (PCR). Ophthalmologic exams were done periodically. After a median follow-up of 9 months (range, 9-12), no new episodes of CMV retinitis were observed. CD4 cell counts were >150 cells/mm3 in all cases, HIV loads were <200 copies/mL, and results for qualitative CMV PCRs remained negative. These observations suggest that for selected patients with healed CMV retinitis who have immunologic and virologic evidence of a clinical response to potent combination antiretroviral therapy, temporary discontinuation of a chronic anti-CMV suppressive therapy may not result in further retinal necrosis. However, the long-term immunologic benefit of PIs and hence the safety of prolonged withdrawal of anti-CMV therapy is unknown.     

T cell subsets and cytomegalovirus retinitis in human immunodeficiency virus-infected patients

A case-control study was done to investigate the relationship between T cell subsets and cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected subjects with or without CMV retinitis and CD4+ cell counts of <0.050 x 10(9)/L. Cell surface markers on peripheral blood lymphocytes were evaluated using flow cytometry. Patients with CMV retinitis had significantly lower levels of CD8+ cells (median: 0.152 x 10(9)/L) compared with levels for controls (median: 0.296 x 10(9)/L, P < .001). Significant down-regulation of costimulatory molecule CD28+ and lymphocyte function-associated antigen-1 (LFA-1) expression was observed in patients versus controls (CD28+: 0.048 x 10(9)/L vs. 0.143 x 10(9)/L, P < .001; LFA-1: 0.238 x 10(9)/L vs. 0.400 x 10(9)/L, P < .001), but no significant differences were noted for NK cells. We propose that progressive loss of the CD3+ CD8+ cell subset and down-regulation of CD28 and LFA-1 accessory molecules are associated with an increased risk of CMV retinitis in HIV-infected patients.     

Isolation and characterization of a mutant of Saccharomyces cerevisiae affected in the FLO1 locus

BACKGROUND: With the progression of acquired immunodeficiency virus (AIDS) and human immunodeficiency virus (HIV) infection to endemic areas of cysticercosis, the simultaneous diagnosis of both diseases is an expected event. METHODS: Among 91 patients with AIDS or HIV infection studied from 1987 to 1993 at a neurologic reference center in Mexico City, 2 patients with AIDS and neurocysticercosis were found. Five previously reported cases were jointly reviewed. RESULTS: The first patient presented with increased intracranial pressure of rapid progression. A single giant cyst was surgically excised and cysticercus was confirmed on histopathologic examination. The second patient had brain toxoplasmosis and concurrent neurocysticercosis as an incidental finding. CONCLUSIONS: Neurocysticercosis in HIV infection/AIDS may appear as a life-threatening condition or as an incidental finding. All reported cases have been found in advanced stages of HIV infection. Management must be individualized depending on the clinical form of cysticercosis, stage of HIV infection, and coexisting opportunistic conditions. Surgery may be lifesaving and some patients apparently responded to cysticidal drugs.     

Clinical utility of cytomegalovirus urine cultures for ophthalmic care in patients with HIV

BACKGROUND: The utility of cytomegalovirus (CMV) urine cultures was checked in patients with HIV (a) to identify those at risk for CMV retinitis and (b) to guide clinical decisions on treatment and prophylaxis of CMV retinitis. METHODS: HIV infected patients were tested for CMVuria by shell vial cell cultures. The prevalence of CMVuria was related to CD4 count, HIV risk group, and time before and after diagnosis of CMV retinitis. RESULTS: A total of 639 shell vial cell cultures were obtained from 266 HIV infected ophthalmic patients. Only 4% of all patients with a CD4 count > 400 x 10(6)/l shed CMV in their urine compared with 42% with a CD4 count < or = 50 x 10(6)/l. Twenty three of 25 patients with CMV retinitis had a CD4 count < or = 50 x 10(6)/l. Among 130 patients with a CD4 count < or = 50 x 10(6)/l (a) those who were CMVuric had a nearly sevenfold risk (p < 0.0001) of developing CMV retinitis (35%) compared with those who did not shed CMV in their urine (5%), and (b) CMVuria and CMV retinitis were more frequent in homosexuals (58%/25%) than in intravenous drug users (23%/15%). More than 1 year before diagnosis of CMV retinitis 18% of patients were CMVuric compared with 83% of patients who were CMV culture positive in the last 3 months. CMVuria under virustatic maintenance therapy is associated with worsening of retinitis in two thirds of cases. CONCLUSION: Ophthalmic screening of patients with HIV should include those with a CD4 count < or = 50 x 10(6)/l and focus on the subgroup with additional CMVuria. Screening of other patients can be dropped without undue risk in order to spare AIDS patients unnecessary hospital visits. CMVuria as a single finding, however, does not justify antiviral prophylaxis of CMV retinitis.     

A case of ganciclovir-resistant cytomegalovirus (CMV) retinitis in a patient with AIDS: longitudinal molecular analysis of the CMV viral load and viral mutations in blood compartments

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.