Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS.

To assess the effect of intravenous cidofovir on delaying progression of previously treated, relapsing cytomegalovirus (CMV) retinitis, we conducted a randomized, controlled comparison of two maintenance dose levels of cidofovir. One hundred and fifty patients with AIDS and CMV retinitis that had progressed or was persistently active despite treatment with ganciclovir, foscarnet, or both were randomized to receive induction cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with either 5 mg/kg or 3 mg/kg once every other week. Concomitant probenecid and intravenous hydration were administered with each cidofovir dose. Retinitis progression was assessed in the first 100 patients by bilateral, full-field retinal photographs read at a central reading center by an ophthalmologist masked to treatment assignment. Incidence of side effects, changes in visual acuity, and mortality were also assessed. Median time to retinitis progression as assessed by retinal photography was not reached (95% confidence interval [CI], 115 days-upper limit not reached) in the 5-mg/kg group, and was 49 days (95% CI, 35-52 days) in the 3-mg/kg group (p = .0006). Dose-dependent asymptomatic proteinuria (39%) and serum creatinine elevation (24%) were the most common adverse events thought to be related to cidofovir. Reversible probenecid reactions including constitutional symptoms and nausea occurred in 65 of 150 (43%) patients. Cidofovir therapy is effective in delaying progression of CMV retinitis that had previously progressed using other anti-CMV therapies.

Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial.

BACKGROUND: Cytomegalovirus (CMV) retinitis is the most common intraocular infection in patients with the acquired immunodeficiency syndrome (AIDS). If left untreated, it may lead to progressive destruction of retinal tissue and blindness. Cidofovir is a nucleotide analogue of cytosine that has potent, prolonged in vitro and in vivo activity against herpesviruses, including many CMV isolates that are resistant to ganciclovir and foscarnet. OBJECTIVE: To determine whether intravenous cidofovir delays progression of previously untreated CMV retinitis. DESIGN: Randomized, controlled trial comparing immediate with deferred cidofovir treatment. Patients in the deferred treatment group were eligible to receive cidofovir after progression of CMV retinitis was documented by retinal photography. SETTING: Eight academic medical centers and an independent center that read retinal photographs. PATIENTS: 48 patients with AIDS and previously untreated peripheral CMV retinitis who were randomly assigned to immediate (n = 25) or deferred treatment (n = 23). INTERVENTION: Intravenous cidofovir, 5 mg/kg of body weight, once weekly for 2 weeks and then once every other week. To minimize nephrotoxicity, oral probenecid and intravenous hydration with normal saline were administered with each cidofovir infusion. MEASUREMENTS: Progression of CMV retinitis was assessed by bilateral, full-field retinal photographs that were read by an ophthalmologist who was masked to treatment assignment. Incidence of side effects, changes in visual acuity, effect on CMV shedding in urine and blood, and mortality were also assessed. RESULTS: The median time to progression of CMV retinitis was 22 days (95% CI, 10 to 27 days) in the deferred treatment group and 120 days (CI, 40 to 134 days) in the immediate treatment group (P < 0.001). Neutropenia (15%) and proteinuria (12%), both asymptomatic, were the most common serious adverse events considered to be possibly related to cidofovir. Cidofovir treatment was discontinued in 10 of 41 patients (24%) because of protocol-defined treatment-limiting nephrotoxicity. Transient reactions to probenecid, including mild to moderate constitutional symptoms or nausea, occurred in 23 of 41 patients (56%) and were dose limiting in 3 (7%). CONCLUSIONS: Cidofovir was efficacious in delaying progression of previously untreated CMV retinitis. Treatment was associated with manageable side effects; strict adherence to monitoring of renal function before cidofovir was administered and concomitant administration of probenecid and saline hydration appeared to minimize drug-related nephrotoxicity.

Impact of clarithromycin and azithromycin on patterns of treatment and survival among AIDS patients with disseminated Mycobacterium avium complex.

OBJECTIVE: To determine the impact of the introduction of clarithromycin and azithromycin on the treatment and survival of patients with AIDS and disseminated Mycobacterium avium complex (DMAC). DESIGN: Retrospective review over a 3.5-year interval. SETTING: Tertiary-care, university teaching hospital. PATIENTS: Charts of all patients with cultures of blood or bone-marrow positive for acid-fast bacilli (n = 103) were reviewed. Data on laboratory results at the time of DMAC diagnosis, antimycobacterial therapy, antiretroviral therapy, and survival was collected. RESULTS: Prior to the availability of clarithromycin and azithromycin 61.5% of patients received antimycobacterial treatment compared with 92% afterwards (P = 0.0014). Median survival of treated patients was 255 versus 145 days for untreated patients (P < 0.001). Median survival of macrolide-treated patients was 284 versus 168 days for patients receiving treatment without a macrolide (P = 0.09). Univariate predictors of survival were antimycobacterial treatment, use of antiretrovirals, and year of diagnosis. In a multivariate model, no antimycobacterial treatment (hazard ratio, 3.83; P = 0.003) was associated with shorter survival, and treatment without a macrolide (hazard ratio, 2.29; P = 0.075) showed a trend towards shorter survival versus treatment with macrolide-containing regimens. CONCLUSIONS: The introduction of clarithromycin and azithromycin has been associated with an increase in the proportion of patients with DMAC receiving treatment and with increased survival of these patients.

Acute uveitis associated with rifabutin use in patients with human immunodeficiency virus infection.

PURPOSE: We studied patients with a new anterior uveitis syndrome associated with rifabutin use. METHODS: Nine patients with the acquired immunodeficiency syndrome (AIDS) who developed acute anterior uveitis were identified retrospectively from institutional ophthalmology, infectious disease, and AIDS primary care practices. Five patients initially had hypopyon; in three patients hypopyon was bilateral and recurrent. The medical history, initial signs and symptoms, diagnostic examination, clinical course, and response to therapy were ascertained by a review of the medical records. RESULTS: All nine patients were being treated with rifabutin for treatment of, or prophylaxis against, Mycobacterium avium complex. In no patient was another untreated cause of uveitis found. In each patient the uveitis resolved rapidly without sequelae with treatment with topical corticosteroids alone. In eight patients uveitis resolved completely while treatment or prophylaxis for M. avium complex was maintained. CONCLUSIONS: We studied a new hypopyon uveitis syndrome in patients with AIDS who are being treated with rifabutin. The interaction of multiple drugs may contribute to this uveitis syndrome. This uveitis is remarkable because it is fulminant yet responds rapidly to topical corticosteroids. Characterization of this syndrome is important because hypopyon in the immunocompromised patient generally mandates intensive, and sometimes invasive, ophthalmic and systemic examination and therapy. Additional study is required to determine whether immune status, underlying infection, or drug-related factors contribute to the development of this uveitis syndrome. Although this syndrome remains a diagnosis of exclusion, ophthalmologists must be aware of it, so that intervention is guided appropriately.