Faculty Bibliography

OBJECTIVE: To provide recommendations for the treatment of acquired immunodeficiency syndrome-related cytomegalovirus (CMV) end-organ diseases, including retinitis, colitis, pneumonitis, and neurologic diseases. PARTICIPANTS: A 17-member panel of physicians with expertise in clinical and virological research and inpatient care in the field of CMV diseases. EVIDENCE: Available clinical and virological study results. Recommendations are rated according to the quality and strength of available evidence. Recommendations were limited to the treatment of CMV diseases; prophylaxis recommendations are not included. PROCESS: The panel was convened in February 1997 and met regularly through November 1997. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although the epidemiological features of CMV diseases are changing in the setting of potent, combination antiretroviral therapy, continued attention must be paid to CMV diseases in patients infected with the human immunodeficiency virus to prevent irreversible endorgan dysfunction. The initial and maintenance treatment of CMV retinitis must be individualized based on the characteristics of the lesions, including location and extent, specific patient factors, and characteristics of available therapies among others. Management of relapse or refractory retinitis must be likewise individualized. Ophthalmologic screening for patients at high risk for retinitis or who have a prior diagnosis of extraretinal disease is recommended. Recommendations for gastrointestinal, pulmonary, and neurologic manifestations are included

A decision-analytical simulation model was constructed to perform a pharmacoeconomic analysis of the following 3 treatment strategies for previously untreated cytomegalovirus (CMV) retinitis in patients with AIDS: (i) intravenous foscarnet (IVF) for induction and maintenance therapy; (ii) intravenous ganciclovir (IVG) for induction and maintenance therapy; and (iii) intravenous ganciclovir for induction therapy, followed by oral ganciclovir for maintenance therapy (IVG-ORG). Patients who experienced significant adverse effects during, or who failed, initial therapy were switched once to one of the other 2 treatments. The model was used to estimate the direct medical cost (from the perspective of a public payer), survival, and survival adjusted for disutility because of lost vision, for each strategy in the first year following treatment initiation. The expected first-year costs of treatment initiated with IVF, IVG and IVG-ORG were $US47,918, $US38,817 and $US32,036 (1994 values), respectively, while expected first-year survival was 41 weeks, 35 weeks and 35 weeks, respectively. The incremental cost per incremental year of survival using IVF was $US78,000 versus IVG and $US138,000 versus IVG-ORG before adjustment for lost vision, and $US93,000 versus IVG and $US166,000 versus IVG-ORG after adjustment for lost vision. About 23% of the cost of the IVG treatment strategy was attributable to treatment-related adverse events, compared with 14% of the cost of IVF and 16% of the cost of IVG-ORG. Because of the high failure rate with IVG-ORG, initial treatment with IVG-ORG frequently led to switching to another treatment. Only 27% of the costs associated with the IVG-ORG treatment strategy were in fact attributable to the cost of induction and maintenance therapy prior to a switch to alternative treatment. In this analysis, initial treatment with IVG-ORG was the least costly approach for treating CMV retinitis in patients with AIDS. Initial treatment with IVF resulted in slightly longer survival adjusted for vision-related quality of life. New treatments for AIDS may reduce the survival benefit of initial treatment with IVF

Objective: To evaluate the the efficacy and safety of an intravenous human monoclonal antibody to cytomegalovirus (CMV), MSL-109, as adjuvant treatment for CMV retinitis. Methods: Two hundred nine patients with acquired immunodeficiency syndrome and active CMV retinitis were enrolled in a multicenter, phase 2/3, randomized, placebo-controlled clinical trial. Patients received adjuvant treatment with MSL-109, 60 mg intravenously every 2 weeks, or placebo. Randomization was stratified on the basis of whether patients had untreated or relapsed retinitis. Primary drug therapy for CMV retinitis was determined by the treating physician. Results: The rates of retinitis progression, as evaluated in a masked fashion, were 3.04/person-year in the MSL-109-treated group and 3.05/person-year in the placebo-treated group (P=.98; Wald test); the median times to progression were 67 days in the MSL-109-treated group and 65 days in the placebo-treated group. No differences between the 2 groups were noted in the rates of increase in retinal area involved by CMV, visual field loss, or visual acuity outcomes. The mortality rate in the MSL-109-treated group was 0.68/person-year, and in the placebo-treated group, 0.31/person-year (P=.01). The mortality difference was not explained by differences in baseline variables or in concurrent antiretroviral therapy. Among patients with newly diagnosed retinitis, mortality rates were similar (MSL-109, 0.41/person-year; placebo, 0.42/person-year; P=.95), whereas among patients with relapsed retinitis the MSL-109-treated group had a greater mortality rate (MSL-109, 0.83/person-year, placebo, 0.24/person-year; P=.003). However, the mortality rate in the placebo-treated patients with relapsed CMV retinitis was lower than that in the placebo-treated patients with newly diagnosed CMV retinitis and lower than that in other trials of patients with relapsed CMV retinitis. Conclusions: Intravenous MSL-109, 60 mg every 2 weeks, appeared to be ineffective adjuvant therapy for CMV retinitis. The mortality rate was higher in the MSL-109-treated group, but the reasons for this difference remain uncertain

Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients

Liver involvement with opportunistic infections and neoplasms is a well-recognized component of AIDS, affecting most patients. The cause of hepatic disease in these patients may be divided into hepatitis, granulomatous disease, mass lesions, vascular lesions, hepatotoxic drugs, and nonspecific findings. With a rational approach, most patients with AIDS and liver disease can be diagnosed and treated in a cost-effective manner with low morbidity

Diarrhea is a major complication of HIV infection and adversely impacts health care costs, quality of life, and even survival of patients. There is a wide variety of potential causes of diarrhea in HIV-infected patients, and the number of pathogens found continues to increase with time. In addition, there is some controversy concerning the role of some organisms in the pathogenesis of diarrhea and the appropriate diagnostic evaluation of affected patients. This article reviews our current understanding of these pathogens and some of the diagnostic and therapeutic approaches for diarrhea associated with HIV infection

Background: Cytomegalovirus (CMV) retinitis is a common infection and a major cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). Objective: To evaluate intravenous cidofovir as a treatment for CMV retinitis. Design: Two-stage, multicenter, phase II/III, randomized, controlled clinical trial. Setting: Ophthalmology and AIDS services at tertiary care medical centers. Patients: 64 patients with AIDS and previously untreated, small, peripheral CMV retinitis lesions (that is, patients at low risk for loss of visual acuity). Intervention: Patients were randomly assigned to one of three groups: the deferral group, in which treatment was deferred until retinitis progressed; the low-dose cidofovir group, which received cidofovir, 5 mg/kg of body weight once weekly for 2 weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks; or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with hydration and probenecid. Measurements: Progression of retinitis, evaluated in a masked manner by a fundus photograph reading center; the amount of retinal area involved by CMV; the loss of visual acuity; and morbidity. Results: Median time to progression was 64 days in the low-dose cidofovir group and 21 days in the deferral group (P = 0.052, log-rank test). The median time to progression was not reached in the high-dose cidofovir group but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis of the rates of increase in the retinal area affected by CMV confirmed the data on time to progression. The three groups had similar rates of visual loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in the deferral group, 2.8 per person-year in the low-dose cidofovir group (P > 0.2), and 6.8 per person-year in the high-dose cidofovir group (P = 0.135). No patient developed 4+ proteinuria, but two cidofovir recipients developed persistent elevations of serum creatinine levels at more than 177 mu mol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per person-year. Conclusions: Intravenous cidofovir, high- or low-dose, effectively slowed the progression of CMV retinitis. Concomitant probenecid and hydration therapy, intermittent dosing, and monitoring for proteinuria seemed to minimize but not eliminate the risk for nephrotoxicity

Wasting decreases immune function, and is associated with decreased quality of life and increased mortality in patients with AIDS. Many modalities have been used in the treatment of this problem, but few promote positive nitrogen balance and increase body cell mass. We studied 21 patients with AIDS-related weight loss, defined as loss of greater than 5% usual body weight, or a baseline of less than 100% ideal body weight (IBW). Patients were treated with oxandrolone, 10 mg orally, twice daily. All subjects were men who acquired HIV through unprotected homosexual sex, with the exception of one woman who acquired the disease through unprotected heterosexual contact. The mean age of patients was 38 years, and mean CD4 count was 55. All patients were evaluated with bioelectrical impedance analysis (BIA). BIA mean values for weight, body cell mass (BCM), fat, intracellular water (ICW) and extracellular water (ECW) were calculated for patients at baseline, and then for those patients who took the medication for 30 days, 60 days, 90 days, and 120 days, respectively. Mean changes from baseline in weight, BCM, fat and ICW were significant (p is less than 0.05) at all points in time (except at 120 days, due to the small sample size at this time). At 30 days, weight increased by a mean of 6.5 pounds, BCM increased by a mean of 3.4 pounds, fat increased by a mean of 1.6 pounds, and ICW increased by a mean of 1.4 liters. At 60 days, weight increased by a mean of 12.9 pounds, BCM increased by a mean of 6.9 pounds, fat increased by a mean of 3.0 pounds, and ICW increased by a mean of 2.9 liters. At 90 days, weight increased by a mean of 11.3 pounds, BCM increased by a mean of 4.2 pounds, fat increased by a mean of 5.2 pounds, and ICW increased by a mean of 1.8 liters. At 120 days, weight increased by a mean of 16.0 pounds, BCM increased by a mean of 6.6 pounds, fat increased by a mean of 6.8 pounds, and ICW increased by a mean of 2.7 liters. Change in ECW was significant (p is less than 0.05) only at 90 days. At that time, ECW was decreased by a mean of 1.1 liters from baseline. Of note, values for mean body composition, including % ideal body weight, % BCM, and % fat were also recorded at baseline, and at 30-day intervals thereafter, and were noted to rise steadily throughout the study period. Percent IBW increased from 92.2% at baseline to 101.3% at 90 days and to 106.7% at 120 days. Treatment with oxandrolone resulted in a significant (p is less than 0.05) increase in weight gain, and importantly, in BCM at 90 days. A significant (p is less than 0.05) increase in ICW and a significant (p is less than 0.05) decrease in ECW were also found to occur at 90 days. Final analysis for the 120-day follow-up has not been completed at this time. Thus, the common nutritional abnormalities that occur in AIDS-related weight loss and wasting were reversed