Viral Infections

Cytomegalovirus is a herpesvirus that infects directly through mucous membrane contact or via tissue transplant or blood transfusion. Approximately half the adult population in developed countries, virtually all gay/bisexual men with AIDS, and 75% of other HIV risk groups have been infected with CMV.

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Sites of Infection:

Most frequently the retina, colon and esophagus in AIDS patients; also the lungs, brain, heart, thymus, pancreas, larynx, thyroid, kidneys, gallbladder, liver, and adrenal glands.

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Symptoms:

CMV Retinitis: May include blurred vision, blind spots and moving spots before the eyes and scotoma progressing to blindness. Ophthalmologic signs may include cotton-wool spot appearance, necrotizing retinitis, hemorrhages and minimal vitreal inflammation.

CMV Encephalitis:
While CMV is not considered a neutropenic disease, cases of CMV encephalitis have been reported.Symptoms include headache, confusion, and fever.

CMV Esophagitis:
Most commonly includes painful swallowing or the sense of food sticking in the throat. May also include chest pain or hiccups.

CMV Colitis:
May include intermittent or persistent diarrhea with cramping, abdominal pain, involuntary rectal spasms, weight loss and general status deterioration.

CMV Gastritis:
May be asymptomatic but often results in severe continuous upper abdominal pain fever, hemorrhage or obstruction.

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Diagnosis:

Recovery of CMV by culture is not sufficient to diagnose acute infection. However, periodic assessment of CMV-DNA load in peripheral blood by quantitative PCR may be useful for identification of patients at high risk of developing CMV disease and for monitoring the effects of antiviral therapy (Boivin et al). Histologic findings of viral inclusion bodies in colonic, esophageal, or lung tissue, as well as identification of virus by special stains or culture, are necessary. CMV retinitis, however, is typically diagnosed by ophthalmologic findings alone in high risk patients. A diagnosis of CMV encephalitis can be made by brain biopsy or by detection of CMV-DNA in cerebrospinal fluid (CSF).

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Treatment for CMV Retinitis (Systemic):

Intravenous formulations of ganciclovir (5 mg/kg IV twice daily) and foscarnet (90 mg/kg IV two times daily) are approved for the treatment of CMV retinitis in immune-compromised individuals. Higher doses of ganciclovir (5 mg/kg IV bid) or foscarnet (90 mg/kg IV bid) are used initially for 2-3 weeks as induction therapy followed by maintenance treatment at lower doses. Ganciclovir is preferred treatment by most practitioners. The major side effect associated with ganciclovir is bone-marrow suppression, which may prevent or limit concomitant use of AZT. Ionized hypocalcemia, reversible renal insufficiency, and penile ulcers (mainly in uncircumcised men) are associated with foscarnet treatment.

Foscarnet appears equivalent to ganciclovir in limiting the spread of CMV retinitis; however, it may confer a survival benefit over ganciclovir in patients with advanced HIV, presumably because of its intrinsic anti-HIV activity. The NEI/ACTG study for ocular complications of AIDS (Meinert et al.) randomized 234 patients with CMV retinitis to receive ganciclovir (107 patients) or foscarnet (127 patients). The trial was suspended after 19 months when a significant mortality benefit associated with foscarnet was observed. Although both drugs were equally effective in halting progression of CMV retinitis, the median survival was 12.6 months in the foscarnet group and 8.5 months in the ganciclovir group. This survival benefit could not be attributed to differences in antiretroviral therapy between the two groups. However, foscarnet was associated with substantial toxicity: 22/39 treatment switches from foscarnet to ganciclovir were attributed to foscarnet toxicity, while only 1/14 switches from ganciclovir to foscarnet was attributed to ganciclovir toxicity.

Ganciclovir has been demonstrated to delay progression of peripheral CMV retinitis in AIDS patients (Peripheral CMV retinitis is not immediately sight threatening). Spector et al. randomized 22 patients to deferred treatment and 13 to immediate treatment with ganciclovir (5 mg/kg bid for 14 days followed by 5 mg/kg qd for 14 weeks). Patients in the deferred group were offered ganciclovir if retinitis progressed, 10/13 in the immediate group, and 20/22 in the deferred group had progressive CMV retinitis. The median time to progression was 13.5 days for the deferred group versus 49.5 days for the immediate treatment group (P = 0.001).

The results of a clinical trial in patients who required retreatment of CMV after maintenance therapy has failed were recently reported (Jabs et al.). The study (ACTG 228) compared ganciclovir to foscarnet to a foscarnet/ganciclovir combination in recently treated patients who reported CMV disease progression. A total of 271 patients were randomized to one of three arms; foscarnet (90 mg/kg q 12h x 14 days with 120 mg/kg qd maintenance), ganciclovir (5.0 to 7.5 mg/kg q 12h x 14 days with 10 mg/kg qd maintenance), or a combination of foscarnet (90 mg/kg q 12h x 14 days with 90 mg/kg qd maintenance) and ganciclovir (5 mg/kg qd x 14 days with 5 mg/kg qd maintenance therapy). CMV retinitis progression was reported at 4.8 months in the combination group, 2.1 months in those who received ganciclovir alone, and 1.6 months in those who received foscarnet alone (P = 0.00002). 'Those who reported disease progression in the monotherapy groups were switched to the alternate monotherapy treatment; those who progressed in the combination group received higher doses of both drugs. For patients originally receiving either ganciclovir or foscarnet monotherapy, a median of 1.6 relapses were reported. There was no significant difference between switching to the alternate treatment and remaining on the initial regimen. However rates of visual field loss were significantly lower in the combination group (16- degrees/month compared to 18- and 31- degrees/month) (P = 0.003). Quality of life scores reported were significantly better in the ganciclovir monotherapy group.

MSL-109, a human anti-CMV monoclonal antibody, is being studied in combination with either foscarnet or ganciclovir for the treatment of retinitis (ACTG 266). This phase II double-blind, placebo-controlled trial will randomize patients to one of two doses of MSL-109 or placebo to be administered concomitantly with standard induction therapy. A second study is being conducted by the Studies of the Ocular Complications of AIDS (SOCA) of the National Eye Institute (NEI) with the ACTG (ACTG 294). This trial compares MSL-109 (60 mg IV once every two weeks) to placebo in 167 patients receiving standard therapy for either newly diagnosed or relapsed CMV retinitis.

An intraocular ganciclovir implant has been reported to delay progression of peripheral CMV retinitis. A New Drug Application (NDA) has been submitted to the Food and Drug Administration and has been reviewed by an advisory committee to the FDA, which has recommended approval.

The Chiron Ganciclovir Implant Study Group (Kupperman et al.) has reported the results from a randomized trial examining two release rates of an intraocular ganciclovir implant (1µg/h and 2 µg/h) versus standard dose intravenous ganciclovir. A total of 188 patients with symptomatic CMV retinitis were evenly divided to receive either of the two intraocular ganciclovir doses or IV ganciclovir. While no significant differences in disease progression were reported between the two intraocular dose groups, significant delays in disease progression were reported after 182 days in the 2 µg/h ganciclovir implant group and 72 days in the ganciclovir group (P = 0.000 1). The rate of other eye involvement was 40% in the implant group and 16% in the IV group (NS). Extraocular disease occurred in 15% of the patients in the implant groups combined. There was a slight decrease in visual acuity in the immediate post-operative period for implant patients, although visual acuity returned to preoperative levels within 24 weeks. No statistical differences in survival were reported. Incidences of endophthalmitis, retinal detachment, and vitreous hemorrhage were higher in the implant groups. However, due to the use of G-CSF required by neutropenic patients receiving ganciclovir infusions, the incidences of catheter related sepsis and severe nausea was higher in the IV group.

Martin et al. randomized twenty six patients (30 eyes) to either immediate treatment with a 1 µg/h intraocular ganciclovir implant or deferreded treatment None of the patients enrolled had received prior treatment for CMV retinitis. The median time to progression of retinitis was 15 days in the deferred group (n = 16) versus 226 days in the immediate treatment group (n = 14)(P < .00001). In the entire study population, biopsy- proven visceral CMV disease developed in 8/26 (31%) patients and 67% of the 26 patients developed retinitis in the fellow eye. Seven patients (18%) suffered a treatment-induced retinal detachment, with five occurring between days 30 and 64. There were 2 cases of persistent hypotony reported.

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Resistance/Intolerance to Treatment:

Development of ganciclovir-resistant CMV infection has been reported to occur in approximately 10% of AIDS patients receiving ganciclovir for > 3 months. Most CMV strains resistant to ganciclovir are susceptible to foscarnet, which may be useful for patients who cannot tolerate or are clinically resistant to ganciclovir. Jacobson et al. enrolled 156 patients with CMV retinitis in ACTG 093, a study of foscarnet as salvage therapy. 72 patients were categorized as ganciclovir-intolerant and 84 as ganciclovir-resistant. The median interval between initiating ganciclovir therapy and switching to foscarnet was 180 days. The first 87 patients were randomized to foscarnet either 60 or 90 mg/kg/day and the remaining 69 patients received 120 mg/kg/day. Median time to retinitis progression for all patients was 8, 9 and 9 weeks for the 60, 90 and 120 mg/kg/day groups, respectively. Overall, moderate or severe adverse effects to foscarnet (renal toxicity, seizure, hypocalcemia, nausea, ataxia and altered mental status) were observed in 95% of patients with a trend toward dose-limiting renal toxicity in the 90 and 120/mg/kg/day groups. There was no survival difference among the three treatment groups. Overall median survival was 25 weeks.

The manufacturer of HPMPC (cidofovir), a cytosine-derived nucleotide analogue with a long intracellular half-life, has submitted a New Drug Application (NDA) to the Food and Drug Administration seeking approval of intravenous cidofovir for patients intolerant or failing ganciclovir or foscarnet. HPMPC must be administered with probenecid to protect against renal toxicities.

Lalezari et al. recently presented data from a study comparing two maintenance doses of HPMPC (3 mg/kg vs. 5 mg/kg every other week) in 60 patients who failed induction therapy with either ganciclovir or foscarnet. AR patients received weekly HPMPC (5 mg/kg) for two weeks as induction therapy. No statistically significant difference was seen between the two maintenance doses; a median of 115 days to progression was reported in the 5 mg/kg group and a median of 49 days to progression in the 3 mg/kg group. Adverse reactions due to concomitant of probenecid were reported in 29/60 (48%) patients enrolled.

Lalezari et al. have reported results from a phase II/III immediate versus deferred trial of intravenous HPMPC. In this study, 40 patients were randomized to receive either immediate treatment with HPMPC (5 mg/kg every week for two weeks) or placebo until disease progressed. Time to progression in the immediate treatment group was 120 days, whereas time to progression in the deferred treatment arm was 22 days. Eleven patients (27%) reported renal toxicities. Toxicities attributed to concomitant probenecid use were reported in 38% of patients enrolled.

Phase I/II dose-escalating studies of intravenous HPMPC have been reported in subjects with CMV viruria. Polis et al. administered HPMPC 0.5, 1.5 or 5 mg/kg weekly or twice weekly, with or without probenecid, to 20 patients. CMV urine cultures became negative in 4/6 evaluable patients receiving the highest doses of HPMPC. The maximum tolerated dose was determined to be about 5 mg/kg weekly, with proteinuria, glycosuria, and creatinine elevations being the dose limiting toxicities. Concomitant probenecid administration appeared to protect against renal toxicity.

Two recently reported small case studies (Kirsch et al.) of intravitreal HPMPC (cidofovir) suggest that prolonged control of CMV retinitis may be achieved with a single injection. In the first study, patients who had failed or were non- compliant with standard therapy received one 10, 20, 40 or 100 µg injection with concomitant oral probenecid. Patients were assigned to doses in a non- randomized fashion. The median progression time reported in those patients who received a single 20 µg injection was 64 days; data from other diseases were invaluable. No cases of endophthalmitis were reported. In the second case study, 17 patients (24 eyes) received a single dose of intravitreal HPMPC (20 µg) with oral probenecid. The median time to progression after the initial injection was 55 days. Disease progression was reported in 8/24 eyes treated. These eyes were retreated; median time to progression in retreated eyes was 64 days.

ISIS 2922, an antisense compound for the intravitreal treatment of CMV retinitis in patients who have failed standard therapy, is currently under investigation. In May 1995, the manufacturer suspended patient recruitment because of safety concerns, including the development of decreased peripheral vision with retinal pigment epithelial cell stippling in 20% of patients receiving intravitreal injections at the highest dose. Two phase III trials are currently enrolling. For patients With CMV intolerant or failing standard therapy who do not qualify for the two trials, a compassionate use program is available.

A phase I/II dose-ranging study of ISIS 2922 has been reported. The manufacturer reports that 10 patients with CMV retinitis were treated intravitreally with ISIS 2922 once a week for 4 weeks and every two weeks thereafter. Two patients received 75 µg (low-dose), 3 received 150 µg (middle- dose) and 5 received 300 µg (high-dose). Responses were observed in 0/2, 2/3, and 5/5 in the low, middle, and high dose groups, respectively. Side effects observed were vitreal inflammation, temporary loss of color vision and ocular discomfort.

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Treatment for CMV Gastrointestinal Disease:

Dieterich et al. treated 62 AIDS patients with biopsy-proven CMV colitis with ganciclovir (5 mg/kg IV twice daily) or placebo for 14 days. At entry all patients had diarrhea (>6 stools/day), malabsorption, or unintentional weight loss of >4.5 kg. After 14 days, the groups did not differ for clinical end points (diarrhea, temperature, body weight, abdominal pain, fatigue, serum albumin, cholesterol or magnesium) or for adverse effects. A reduction in colonoscopy scores from baseline to day 14 was seen in 20/32 (62.5%) subjects treated with ganciclovir compared to 11/30 (36.7%) placebo recipients (P = .042) CMV disease at new sites developed in seven placebo recipients (5 retinitis, 1 gastritis, 1 pneumonitis) and three ganciclovir recipients (3 gastritis). The- investigators suggest that the treatment might be more effective if extended to 21 or 28 days.

A randomized controlled study compared ganciclovir with foscarnet for induction therapy in patients with CMV gastrointestinal disease (Blanshard et al.). Nineteen patients were randomized to receive ganciclovir and 25 patients to foscarnet. Mean duration of treatment was 15 days. Endoscopic improvement was observed in 84% and 81% of ganciclovir and foscarnet subjects, respectively. Adverse drug effects occurred with equal frequency in both groups.

Dietrich et al. treated 10 patients, 5 with upper GI CMV disease and 5 with lower GI disease with foscarnet (90 mg/kg IV q12h). Mild edema was noted in 2/10 patients (20%) but resolved. 8/10 patients (80%) required 6 weeks of treatment for complete response. 9/10 (90%) responded histopathologically (P =.0067) and 9/10 responded endoscopically (P =.0004).

A phase III randomized, open-label trial of foscarnet for the treatment of CMV colitis is currently underway.

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Treatment for General CMV Disease in Children:

A phase I, open-label trial (ACTG 226) of oral ganciclovir for the treatment of general CMV in children between the ages of 2 weeks and 20 years is currently underway. Upon completing induction therapy with a single dose of intravenous ganciclovir, patients will be randomized to receive one of four doses of the oral formulation in either syrup or pill form.

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Treatment for CMV Neurologic Disease:

A recently completed study has reported results in using polymerase chain reaction (PCR) to measure CMV's DNA in the cerebrospinal fluid (CSF) of seven patients with presumed neurologic CMV involvement treated with ganciclovir (Cinque et al.). After three weeks of treatment with ganciclovir, all seven patients reported significant decreases or clearance of CMV DNA from CSF. Clinical improvements were reported in 4/7 patients.

A pilot study is being developed by the AIDS Clinical Trials Group (ACTG 305) of cerebrospinal fluid penetration and response to ganciclovir and foscarnet in presumed CMV neurologic disease.

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Maintenance Treatment :

Intravenous formulations of ganciclovir (5 mg/kg IV qd) and foscarnet (90 mg/kg IV qd) are approved as maintenance therapy for CMV. Oral ganciclovir (1,000 mg tid) has been approved by the Food and Drug Administration as maintenance therapy for CMV retinitis, following induction therapy with IV ganciclovir or foscarnet at higher doses.

Drew et al. compared oral and intravenous ganciclovir in 123 patients with newly diagnosed CMV retinitis. 123 patients received induction therapy with IV ganciclovir for three weeks. 117 patients had stable CMV after induction therapy and were entered in the maintenance phase of the study. 57 were randomized to receive induction and maintenance therapy with intravenous ganciclovir (5 mg/kg/day) and 60 were randomized to oral ganciclovir 1,000 mg tid for 20 weeks. When photographic exams were compared on a blinded basis, there was no statistical difference in the mean time to progression (62 days in the IV group vs. 57 days in the oral group. However, median time to progression was 49 days for the IV group and 29 days for the oral group. When progression was monitored by unmasked fundoscopic exam, the mean time to progression was 98 days in the IV group vs. 68 days in the oral group (P = 0.027). No statistically significant difference in visual acuity was observed between groups. Twenty (34%) patients in the IV group compared to 12 (19%) in the oral group developed neutropenia (NS); 13 patients (22%) in the IV group developed sepsis compared to 3 (S%) in the oral group (P < 0.05).

A European study by Volker et al. enrolled 159 patients with newly diagnosed CMV retinitis to compare oral ganciclovir to IV ganciclovir for the maintenance of CMV retinitis. After induction therapy with IV ganciclovir, patients were randomized to receive in a 2:1 ratio oral ganciclovir (500 mg PO 6 x d) or IV ganciclovir (5 mg/kg IV qd) for 20 weeks. When photographic exams were compared on a blinded basis, there was no statistical difference in the mean time to progression (62 days in the IV group vs. 51 days in the oral group). When progression was monitored by unmasked fundoscopic exam, the mean time to progression was 109 days in the IV group vs. 86 days in the oral group (P = 0.02). GI disturbances were more frequent in the oral treatment group, and neutropenia and leukopenia occurred more frequently in the IV group.

In a study by Squires et al., 220 patients with stable CMV retinitis who were receiving intravenous ganciclovir for <4 months were randomized to receive IV ganciclovir 5 mg/kg/d (n = 70), oral ganciclovir 500 mg six times daily (n = 74) oral ganciclovir 1,000 mg three times daily (n = 76) for 20 weeks. When photographic exams were compared on a blinded basis, the mean time to progression was 66, 53, and 54 days in the IV, 500 mg PO, and 1,000 mg PO groups, respectively (difference not significant). When progression was monitored by unmasked fundoscopic exam, the mean time to progression was 99 days in the IV group vs. 75 days in the 500 mg oral group (P = 0.023) vs. 77 days for the 1,000 mg oral groups (P = 0.082). No statistically significant differences in mortality, treatment failure, ophthalmic change, or neutropenia were observed among groups. Sepsis occurred more frequently in the IV group.

Jacobson et al. (1992) treated 30 patients with CMV retinitis who completed a two-week induction course with ganciclovir with either combined or alternating ganciclovir and foscarnet. Patients were randomized to either ganciclovir (3.75 mg/kg/d) plus foscarnet (60 mg/kg/d), or ganciclovir (6 mg/kg/d) alternating daily with foscarnet (120 mg/kg/d). 12/15 subjects in the combination group and 15/15 in the alternating group were evaluable. Median time to retinitis progression was >12 weeks for the combination group and >20 weeks for the alternating groups (difference not significant). Grade 4 neutropenia was seen in 6/12 patients on the combination and 4/15 on the alternating regimen.

In a randomized dose-comparison study of maintenance foscarnet (90 or 120 mg/kg/day), Jacobson et al. (1993) demonstrated that survival was significantly greater at the higher dose without statistically significant evidence of increased serious toxicity. However, there was significantly greater minor toxicity and a trend toward greater serious toxicity at the higher dose. 32 patients who completed a two-week induction treatment with foscarnet (60 mg/kg three times daily) were randomized; 15 patients received foscarnet 90 mg/kg/day and 17 received 120 mg/kg/day. Median survival ft-from the time of study entry was 157 days and 336 days for subjects in the 90 and 120 mg/kg/day groups, respectively (P <0.001). Transient ionized hypocalcemia occurred significantly more often in the 120 mg/kg group.

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Prophylaxis:

Oral ganciclovir has been approved by the Food and Drug Administration (FDA) for the prevention of CMV disease in patients with advanced HIV infection.

Spector et al. randomized 725 patients with CD4+ counts < 50 cells/mm³ or CD4+ counts < 100 cells/mm³ and a history of an AIDS-related opportunistic infection to receive oral ganciclovir 1,000 mg q8h or placebo. After 20 months, the Data Safety Monitoring Board (DSMB) halted the trial due to significant differences between the two arms and all participants were offered open-label ganciclovir. The mean CD4+ count at the time of entry was 26 cells/mm³; median CD4+ count at baseline was 21 cells/mm³. All patients enrolled were followed by an ophthalmologist and had a Careful eye exam every three months regardless of symptoms. At the time of analysis, CMV disease occurred in 76/239 (30%) patients in the placebo group and 76/486 (16%) patients in the ganciclovir group (P =.0001). Death occurred in 66/239(29%) patients in the placebo group and 109/486 (22%) patients in the ganciclovir group (P =.08). Drew et al. have recently reported that the prevalence of ganciclovir resistance was low (< 1%) after a mean of 8.3 months of prophylaxis.

Brosgart et al. recently reported the results of a randomized, placebo-controlled trial of the safety and efficacy of oral ganciclovir for prophylaxis of CMV disease (CPCRA 023). 954 patients with fewer than100 CD4+ cells/mm³ were randomized to either 1,000 mg q8h oral ganciclovir (n = 622) or placebo (n = 332). The mean CD4+ count upon entry was 44 cells/mm³; median CD4+ count at baseline was 34 cells/mm³. All patients were followed by a primary care physician and referred to an ophthalmologist if symptoms were reported by the patient. No statistical difference was reported between the two groups in terms of CMV disease development or survival. 99/622 (15.9%) in the ganciclovir group and 55/332 (16.7%) in the placebo group developed CMV disease. Reported deaths were 221/622 (35.5%) and 132/332 (37.7%), respectively. The development of CMV retinitis was reported in 74/622 (11.9%) patients receiving ganciclovir and 44/332 (13.3%) patients receiving placebo. CMV colitis rates were 21/622 (3.4%) and 12/332 (3.6%), respectively.

Valacyclovir has been found to be moderately effective in preventing CMV disease in HIV-positive people (Feinberg et al). ACTG 204 was a phase III randomized, placebo-controlled study of valacyclovir versus two doses of acyclovir for the prevention of CMV disease. While the trial was prematurely closed due to higher monthly rates in the valacyclovir group, the differences were not statistically significant. This study treated 1227 patients with CD4+ cell counts under 100 cells/mm³ with either valacyclovir (2 g qid or acyclovir (800 mg qid or 400 mg bid). The diagnosis of CMV retinitis was based on clinical examination by an ophthalmologist every 6 months. Confirmed CMV endpoints were reached in 51/523 (11.7%) in the valacyclovir group and 123/174 (17.5%) in the acyclovir groups combined (P = 0.03).

Oral acyclovir is not effective in preventing CMV disease in HIV infected people. Drew et al. randomized 93 HIV-positive symptomatic patients to receive AZT 600 mg daily with acyclovir 4,800 mg PO /d (n = 52) or with placebo (n = 41) to determine if high-dose ACV suppresses CMV viruria. Urine was obtained at 3 month intervals for at least 6 months. The addition of acyclovir did not suppress CMV excretion in the urine in these patients.

Youle et al. enrolled 302 CMV-seropositive subjects with CD4 count <150/mm³ in a double-blind placebo-controlled trial study in oral high-dose acyclovir (800 mg PO four times daily for 48 weeks) in combination with anti-retroviral treatment for the prevention of CMV disease. All patients received AZT, ddl or AZT/ddC; in addition half received acyclovir and half received placebo. After more than one year follow-up 16/153 acyclovir- recipients and 9/149 placebo recipients developed confirmed CMV disease (difference not significant).

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REFERENCES:
Blanshard C et al. Treatment of AIDS-associated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison. JID 172:622-8, 1995.

Boivin G et al. Evaluation of the cytomegalovirus DNA load and polymorphonuclear leukocytes (PMNL) of HIV-infected patients using quantitative PCR (Q-PCR). Abstract #11, 3rd Conf on Human Retro and Opport Infect, Washington DC, 1996.

Cinque P et al. Ganciclovir therapy for cytomegalovirus infection of the central nervous system in AIDS patients: Monitoring by CMV-DNA detection in cerebrospinal fluid. JID 171: 1603-6, 1995.

Cochereau-Massin I et al. Intravitreal ganciclovir: a 3-year experience. Abstract 023, Third European Conference on Clinical Aspects and Treatment of HIV Infection. Paris, 1992.

Cribbin K et al. Intravitreal ganciclovir in patients resistant to ganciclovir and /or foscarnet. Abstract PoB 3159, VIII Intl Conf AIDS, Amsterdam, 1992.

Crumpacker C et al. Oral vs. intravenous ganciclovir (GCV) as maintenance treatment of newly diagnosed cytomegalovirus retinitis (CMVR) in AIDS. 1st Nat Conf Hum Retrov, Abstract 538: 154, 1993.

Dieterich D et al. Ganciclovir treatment of cytomegalovirus colitis in AIDS: A randomized, double-blind, placebo-controlled multicenter study. JID 167: 278- 282, 1993.

Dietrich D et al. Treatment of gastrointestinal cytomegalovirus infection using twice daily administration of foscarnet in AIDS patients. 1st Nat Conf Hum Retrov Abstract 5l3: 146, 1993.

Drew WL et al. Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. NEJM 333: 615-20, 1995.

Drew WL et al. Failure of acyclovir to suppress excretion in symptomatic HIV antibody-positive patients. Abstract 1115, 32nd ICAAC, Anaheim, 1992.

Drew WL et al. Prevalence of ganciclovir resistant cytomegalovirus during oral ganciclovir prophylaxis. Abstract #LB 16, 3rd Conf on Human Retro and Opport lnfect, Washington DC, 1996.

Feinburg J et al. Phase III study of valacyclovir for cytomegalovirus prophylaxis in patients with advanced HIV disease. 35th ICAAC, Abstract #1214, San Francisco, 1995.

Jabs D et al. Combination therapy for retinitis: Results of ACTG 228. 20th ACTG, Washington DC, 1995.

Jacobson MA 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 8: 451-459, 1994.

Jacobson MA et al. A dose-ranging study of daily maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in AIDS. JID 168: 444 448, 1993.

Jacobson MA et al. Randomized phase I study of combined vs. alternating foscarnet (PFA)/ganciclovir (GCV) maintenance therapy (Rx) for CMV retinitis. 32nd ICAAC, Abstract #1223, 1992.

Kirsch LS et al. Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol 119:466-76, 1995.

Kirsch LS et al. Intravitreal cidofovir treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology 102: 533- 42, 1995.

Kupperman B et al. A randomized controlled multicenter trial of sustained- release intraocular ganciclovir implant in AIDS patients with CMV retinitis. 35th ICAAC, Abstract #1215, San Francisco, 1995.

Lalezari J et al. A randomized controlled study of cidofovir for relapsing cytomegalovirus retinitis in patients with AIDS. 35th ICAAC, Abstract #LB-9, San Francisco, 1995.

Martin EF et al. Treatment of cytomegalovirus retinitis with an intraocular sustained -released ganciclovir implant. A randomized controlled clinical trial. Arch Ophthalmol 112: 1521-1539, 1994.

Meinert CL et al. Studies of the Ocular Complications of AIDS Research Group, AIDS Clinical Trials Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovirus retinitis. NEJM 326(4): 213-220, 1992.

Nightingale SD et al. An intraocular slow-releasing ganciclovir drug delivery system for treatment of CMV retinitis. VII Intl Conf AIDS, Florence. Vol 2: 245 (W.B.2255), 1991.

Polis M et al. A phase I/II dose escalation trial of (s)-1-[3-hydroxy- 2- (Phosphonymethoxy)propylcytosine (HPMPC) in HIV-infected persons with CMV viruria. 33rd ICAAC Abstract #98, 1993.

Salzberger B el al. Foscarnet and ganciclovir combination therapy for severe CMV-disease in HIV-infected patients. Abstract PO-BO8-1233, IX Intl Conf AIDS, Berlin, 1993.

Spector S et al. Pharmacokinetics, safety, and antiviral profiles of oral ganciclovir in persons infected with human immunodeficiency virus: a phase I/II study. JID 171:1431-7, 1995.

Spector S et al. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. JID 168: 557-563, 1993.

Squires K et al. Oral ganciclovir (POG) versus intravenous ganciclovir (IVG) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS: preliminary results of a phase III study. 1st Nat Conf Hm Retrov, Abstract 540: 154, 1993.

Verdejo J et al. Intravenous ganciclovir for cytomegalovirus treatment (CMV) retinitis. Abstract PoB 3175, VIII Intl Conf AIDS, Amsterdam 1992.

Volker K et al. Intravenous versus oral ganciclovir. European/Austrailian comparative study of efficacy and safety in the prevention of cytomegalovirus retinitis recurrence in patients with AIDS. AIDS 9: 471-477, 1995.

Youle M et al. Effects of high-dose acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo- controlled study, AIDS 8: 641-649, 1994.

OTHER REPORTS:
Balfour H et al. A Randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. NEJM 320(21): 1381-7, 1990.

Lalezari JP et al. The safety, pharmacokinetics, and anti-CMV activity of weekly HPMPC in HIV-positive patients excreting CMV. 1st Nat Conf Hum Retrov, Abstract 541: 154, 1993.

Leach CT et al. A longitudinal study of cytomegalovirus infection in human immunodeficiency virus type 1-seropositive homosexual men: molecular epidemiology and association with disease progression. J Infect Dis 170: 293- 298, 1994.

Medina DJ et al. Ganciclovir antagonizes the anti-human immunodeficiency virus type-1 activity of zidovudine and didanosine in vitro. Ant Agnt Chemo 36(5): 1127-1130, 1992.

Nelson M et al. Foscarnet in the treatment of cytomegalovirus infection of the esophagus and colon in patients with the acquired immunodeficiency syndrome. Am J Gastroenterology. 86(7): 876-881, 1991.

Plotkin SA et al. Vaccines for varicella-zoster virus and cytomegalovirus: recent progress. Science 265: 1393-1395, 1994.

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