This CMV research section contain details of the following topics:

• Intravenous treatments for CMV retinitis

• Oral ganciclovir and valganciclovir

• Ganciclovir eye implants

• Intravitreal injections

• Experimental treatments for CMV

• Treating other forms of CMV disease

See Cytomegalovirus (CMV) - key research on prophylaxis in Symptoms and illnesses: A to Z of illnesses for details of prophylaxis research, and Cytomegalovirus (CMV) - references in Symptoms and illnesses: A to Z of illnesses for references to these studies.

Intravenous treatments for CMV retinitis

Spector (1993) randomized 35 people with peripheral CMV retinitis to receive either immediate treatment with intravenous ganciclovir (5 mg/kg twice daily for 14 days followed by 5 mg/kg once daily for 14 weeks), or deferred treatment (ACTG 071). People randomized to deferred treatment whose retinitis progressed were offered ganciclovir. 20/22 people randomized to deferred treatment were found to have progressive CMV retinitis compared with 10/13 randomized to immediate treatment. (The median time to progression in the deferred treatment group, as determined by masked fundoscopy, was 13.5 days compared with 49.5 days in the immediate treatment group). These data indicate that ganciclovir delays the progression of CMV peripheral retinitis in people with AIDS.

Palestine randomized 24 people with previously untreated CMV retinitis who were at low risk for loss of their visual acuity to receive either no therapy, delayed treatment or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. The mean time to progression of retinitis was 3.2 weeks in the control group of 11 people compared with 13.3 weeks in the treatment group of 13 people. Nine of 13 people in the treatment group had positive blood cultures for CMV at entry and all nine cleared their blood of CMV by the end of the induction period compared with one of six people in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet were seizures (2/13 participants, hypomagnesemia (9/13), hypocalcemia (11/13) and elevations in serum creatinine (3 of 13).

Meinert compared ganciclovir versus foscarnet in the treatment of CMV retinitis in 234 patients with AIDS (ACTG 129). 127 patients received ganciclovir (induction therapy of 5 mg/kg every 12 hours for 14 days, followed by maintenance therapy of 5 mg/kg/day) and 107 patients received foscarnet (induction therapy of 60 mg/kg every 8 hours for 14 days, followed by maintenance therapy of 90 mg/kg/day). At 19 months, 65 (51%) of the patients assigned to ganciclovir had died compared with 36 (34%) patients assigned to foscarnet. The median survival was 8.5 months in the ganciclovir group and 12.6 months in the foscarnet group. This survival benefit could not be attributed to differences in anti-retroviral therapy between the two groups. In the foscarnet group, the only subgroup of patients identified as having excess mortality were those whose renal function was compromised on entry. There was no difference between the two treatment groups in the rate of progression of retinitis.

Jabs enrolled 279 people with either persistently active or relapsed CMV retinitis in a study comparing three regimens: foscarnet (induction at 90 mg/kg every 12 hours for 2 weeks, followed by maintenance at 120 mg/kg/day); ganciclovir (induction at 5 mg/kg every 12 hours for 2 weeks followed by maintenance at 10 mg/kg/day); or continuation of previous maintenance therapy plus induction with the other drug (either ganciclovir or foscarnet), followed by maintenance with the combination of ganciclovir (5 mg/kg/day) and foscarnet (90 mg/kg/day). Median survival was similar among the three groups, ranging from 8.4 to 9 months. Median time to progression of retinitis was 4.3 months for the combination, compared with 1.3 months on foscarnet and 2.0 months on ganciclovir. Switching from one monotherapy to another was no more effective than remaining on the same monotherapy. Side-effects were similar, but the combination had the greatest negative impact on quality of life measures.

Stoehr randomised 44 people with first or second episode CMV retinitis to receive either ganciclovir (5 mg/kg IV) or the combination of half doses of ganciclovir (2.5 mg/kg) plus foscarnet (45 mg/kg) twice daily. 17/22 ganciclovir recipients (74%) were treated successfully, with 20 days median duration of treatment. In the combination arm, 18/22 episodes (82%) were treated successfully, requiring a median of 21 days therapy. There was no significant difference in haematological toxicity, although greater use of GCSF in the ganciclovir group was noted (25 vs 11 days). No severe renal toxicity was observed.

Hardy (1992) enrolled 51 patients with CMV-retinitis in a phase II safety, tolerance and efficacy study (ACTG 073) of ganciclovir (GCV) and GM-CSF versus ganciclovir alone. Twenty-two subjects received the GCV/GM-CSF combination and 29 received GCV alone. 15/22 GCV/GM-CSF recipients and 12/29 GCV recipients also had AZT (600 mg/day) after 16 weeks of study. GCV/AZT subjects who developed neutropenia received GM-CSF for the remainder of the study. Overall, 4/22 (18%) GCV/GM-CSF subjects developed neutropenia compared with 13/29 (45%) GCV subjects. Within one year, 19% of GCV/GM-CSF subjects and 60% of GCV subjects had multiple neutropenic episodes. Progression of CMV-retinitis during first 16 weeks (prior to addition of AZT or GM-CSF for neutropenia) was detected in 4/21 (19%) combination recipients (19%) and 9/28 (32%) GCV recipients.

Bowen (1996) reported that among 45 people with CMV retinitis, 85% of those who were CMV PCR-positive at diagnosis became PCR-negative after 21 days ganciclovir induction therapy. Six individuals who remained PCR-positive after 21 days of treatment had significantly higher CMV load on presentation and a shorter time to first progression of retinitis (40 days). High CMV loads in blood on presentation were associated with shorter time to progression and shorter time to death.

Lalezari (1997) randomised 48 people with peripheral CMV retinitis to receive either immediate or deferred therapy with intravenous cidofovir 5 mg/kg once a week for two weeks followed by 5 mg/kg every two weeks (Gilead study 106). People whose therapy was deferred progressed significantly faster (median delay of 21.5 days) than those receiving immediate therapy (median delay of 120 days), based on masked readings of retinal photographs. 10 out of 41 patients stopped therapy because of a rise in serum creatinine. A reanalysis of these data by the US Food and Drug Administration estimated the median delay in the treated group was shorter, at 78 days.

The SOCA Research Group (1997a) randomised 64 people with peripheral CMV retinitis to receive either immediate or deferred therapy with intravenous cidofovir (5 mg/kg once a week for two weeks followed by either 5 mg/kg or 3 mg/kg every two weeks). The median time to progression in the deferred therapy group was 20 days, versus 64 days in the low-dose maintenance group. The median time to progression in the high-dose maintenance group was not assessable because 50% of the group had not progressed after six months of follow-up. The sample size was too small to allow a comparison between the high and low dose groups.

Lalezari (1998) conducted a study in which 150 people who had progressive CMV retinitis despite treatment with ganciclovir and/or foscarnet received intravenous cidofovir (5 mg/kg once weekly for 2 weeks) and were then randomised to receive maintenance therapy at either 5 mg/kg (Group A) or 3 mg/kg (Group B) once every other week (study 107). Oral probenecid was administered to minimize potential kidney toxicity. An interim intent-to-treat analysis on the first 100 participants found that median time to retinitis progression was not reached in Group A and was 49 days in Group B. Cidofovir-related kidney toxicity was common: 39% of participants developed protein in the urine and 24% had elevated serum creatinine. 43% of participants experienced mild/moderate probenecid reactions. Survival was similar in the two groups.

Jabs (1998) studied the emergence of drug-resistant CMV strains in patients receiving prolonged therapy. For ganciclovir, the incidence of drug-resistant CMV was 3% at baseline, rising to 7% at month 3, 12% at month 6, 27% at month 9 and 27% at month 12. For foscarnet, the incidence was 3%, 9%, 26%, 37% and 37% respectively. For cidofovir, the incidence was 7%, 29%, 29%, 29% and 100% respectively.

Also see research summaries under the heading CMV in the age of HAART in Cytomegalovirus (CMV) - key research on prophylaxis in Symptoms and illnesses: A to Z of illnesses.

Oral ganciclovir and valganciclovir

Martin (1999) randomised 377 individuals with CMV retinitis in one eye alone, diagnosed less than 6 months prior to recruitment, to receive either: 1500mg oral ganciclovir and intraocular ganciclovir implant; or twice daily 5mg/kg intravenous (IV) ganciclovir; or oral placebo and ganciclovir implant. After 6 months, oral ganciclovir/implant was more effective than implant/placebo at preventing the progression of retinitis in the affected eye, and the progression of retinitis was less frequent in both implant arms compared to the IV ganciclovir group. The incidence of new CMV disease (either in the other eye or in another part of the body) at six months was 44.3% in implant/placebo group, versus 24.3% in the implant/oral ganciclovir group (p=0.002) and 19.6% in the IV ganciclovir group (p<0.001). After one year the risk of new CMV complications was reduced by 37% in the oral ganciclovir group and 51.6% in the IV ganciclovir group compared to placebo. Concurrent protease inhibitor treatment significantly reduced the risk of new CMV disease across all arms to the extent that there was no significant difference in the risk of CMV disease after 6 months on ganciclovir across the treatment arms (11%, 9% and 7% respectively).

Lalezari (2002) conducted a study of high dose oral ganciclovir as maintenance therapy for CMV retinitis in 281 AIDS patients with previously treated, stable retinitis. Participants were randomised to 3.0, 4.5 or 6.0 g/day oral ganciclovir or 5 mg/kg/day intravenous ganciclovir. Median days to progression were 41, 50, 57 and 70, respectively (p=0.052; 3.0 g vs. IV). The risk of progression relative to intravenous ganciclovir were 1.66, 1.28 and 1.19.

Martin (2002) randomised 160 people with newly diagnosed CMV retinitis to IV ganciclovir (5 mg/kg bid for 3 weeks and then daily for one week) or valganciclovir (900mg daily for 3 weeks then daily for one week). Groups were well matched with average CD4 counts of 54 in the IV group and 58 in the valganciclovir group. At 4 weeks, progression rates were 10% in both groups. Average time to progression was 125 days in the IV group and 160 days in the valganciclovir group. 64% of both groups had a satisfactory clinical response. 13-14% of participants developed neutropenia. 19% of the valganciclovir group developed diarrhoea compared to 10% of the IV group.

Brown reported that a 900mg/day dose of valganciclovir, an oral pro-drug of ganciclovir, resulted in exposure to ganciclovir comparable to the standard daily intravenous maintenance therapy dose of 5 mg/kg.

Pescovitz reported that oral valganciclovir delivers systemic ganciclovir exposure equivalent to that of standard oral ganciclovir or intravenous ganciclovir.

Ganciclovir eye implants

Martin (1994) enrolled 26 people (30 eyes) with previously untreated peripheral CMV retinitis in a controlled trial comparing immediate treatment with a 1 ug/hr ganciclovir implant with deferred treatment. The median time to progression was 15 days in the deferred group versus 226 days in the implant group. This latter time is approximately four times longer than the median time to progression seen in other randomized trials using intravenous ganciclovir, intravenous foscarnet or oral ganciclovir using similar endpoints. Post-operative complications included mild vitreous haemorrhage, seven late retinal detachments and one retinal tear without detachment. The risk of developing retinitis in the untreated eye was approximately 50% at 6 months, and biopsy-proven visceral CMV disease developed in 31% of participants.

The Chiron Ganciclovir Implant Study Group conducted a randomised, controlled multicentre clinical trial (study 601) to evaluate the safety and efficacy of a sustained release ganciclovir implant as compared with standard intravenous ganciclovir therapy. 188 participants with CMV retinitis who were assigned to receive either a 1 µg/hr implant, a 2 µg/hr implant or intravenous ganciclovir. The median time to progression (defined as movement of retinitis borders by at least 750 µm or development of a new lesion in either eye) was 221 days in the 1 µg/hr groups, 191 days in the 2 µg/hr group, and 71 days in the IV group. However, the risk of disease in the initially uninvolved eye was lower with intravenous ganciclovir than with an implant (risk ratio 0.5), as was the risk of extraocular disease (0% versus 10.3% in the two implant groups). No significant differences between the groups were noted with regards to survival.

Martin (1999) compared ganciclovir implant plus placebo, with implant and oral ganciclovir and standard intravenous ganciclovir. Progression of retinitis in the implanted eye was significantly delayed in the combination group compared with those receiving an implant alone. Both implant groups were superior to the IV group in delaying disease progression in the affected eye. See above for details.

Kupperman reported on the use of ganciclovir implants among people who experienced progression of CMV retinitis following initial treatment with either intravenous ganciclovir or an implant in a clinical trial. Among participants originally assigned to receive IV ganciclovir in the study (23 eyes), the median time to first progression was 55 days; they then received a ganciclovir implant and median time to second progression was 115 days. Among those who received an implant as initial therapy (23 eyes), median time to first progression was 181 days; following insertion of a second implant, the median time to second progression was 259 days. Adverse effects seen in a series of 72 people (107 eyes) treated with implants were endophthalmitis in 1.9% and retinal detachment in 15.9%. Extraocular disease developed in 12 participants (16.7%).

Intravitreal injections

Cochereau-Massin treated 110 patients (162 affected eyes) on an open-label basis with intravitreal ganciclovir (400 µg twice weekly for induction and once weekly for maintenance). All patients were intolerant of, or had refused, systemic ganciclovir therapy. 141/151 induction courses were successful, with a ten-week relapse rate of 48%. Bi-lateralization of disease occurred in 11%, and extraocular disease developed in 15%. Retinal detachments were observed in 5% and intravitreal haemorrhage in 1%. The investigators suggested that while intravitreal ganciclovir is effective, it should remain a salvage treatment since it is non-systemic.

Kirsch (1995a) conducted a Phase I/II pilot trial of intravitreal injections of cidofovir for the treatment of CMV retinitis. In Group 1, a total of 10 eyes (9 people) received 14 injections. The highest safe dose was 20 µg. Group 2 consisted of eight people, six of whom were intolerant to ganciclovir or foscarnet or both, and two of whom had refused intravenous therapy. The median time to progression of CMV retinitis after the first injection of 20 µg of cidofovir was 64 days. No complications of retinal detachment, bleeding or infections were seen.

Kirsch (1995b) enrolled 17 people with CMV retinitis in a separate study. There were 37 cidofovir injections into 24 eyes. Median time to progression was 55 days. For those eyes which received more than one injection, median time to progression after the repeated injections was 63 days. Five participants (21%) developed inflammation of the iris (iritis), and 3 retinal detachments occurred. There was also a significant decrease in median eye pressure, which may have been linked with retinal detachment.

Rahhal treated 22 people with CMV retinitis with intravitreal cidofovir (20 µg at 5 to 6 week intervals). 15 eyes received cidofovir as initial therapy, and 17 had previously been treated with intravenous therapy. Mean duration of follow-up was 15.3 weeks. Of eyes with active retinitis, 100% were healed with first injection. Two eyes experienced retinitis progression. There was one case of detached retina. Mild iritis developed after 14% of the injections that had been preceded with prophylaxis with oral probenecid. Irreversible, visually significant hypotonia developed in one eye.

Taskintuna analysed case records of 63 patients who received 246 intravitreal cidofovir injections. Three percent of eyes (1% of injections) experienced permanent vision loss due to hypotony, and a further 14% of eyes experienced transient mild-to-moderate vision loss.

Orellana treated 19 eyes of 16 patients presenting with recurrent CMV retinitis with high-dose intravitreal foscarnet (one 2400 mg every 48 hours for four injections) in addition to systemic therapy. At the end of this induction phase intravitreal foscarnet was discontinued for patients with no CMV activity, but continued on a weekly basis for those whose disease was stabilised but not eradicated. Over ten weeks, 17/19 eyes (89.5%) improved their visual acuity, with resolution or stabilisation of CMV activity.

Palestine (1995) treated 22 people with CMV retinitis that was not responding to conventional therapies (28 eyes) in an open-label, dose-escalating study of an antisense oligonucleotide, fomivirsen (ISIS 2922). Participants received either intravitreal doses of 83, 165, 330 or 495 µg given once weekly for three weeks (induction) followed by biweekly dosing (maintenance), or biweekly dosing of 330 µg from initial therapy. A dose response was noted with decreased CMV activity in 0/2 eyes at 83 µg, 2/4 eyes at 165 µg and 6/10 eyes at 330 µg, and in 7/11 eyes treated with 330 µg through the study. Marked retinal toxicity was noted in the only person to receive 495 µg. The most frequent ocular side-effect was anterior and posterior chamber inflammation that responded well to topical steroid treatment.

Lieberman (1997) treated 71 eyes that were highly refractory to conventional CMV therapies with fomivirsen (330 µg once weekly for three weeks, with at least one follow-up injection at day 28. The median progression-free survival was 70 days, with a range of 26 to 601 days.

Muccioli (1998) conducted a phase III study of intravitreal fomivirsen comparing 34 people who received 330ug fomivirsen weekly for three weeks and fortnightly thereafter, and 20 people who received 330ug on days 1 and 15, and monthly thereafter. All had recurrent retinitis and had previously been treated with other agents. In both groups, median time to progression was 90 days.

Experimental treatments for CMV

Borucki (2004) randomised 82 HIV-positive patients newly diagnosed with CMV to receive standard therapy plus placebo or the monoclonal antibody directed against CMV gH (MSL-109) at 15mg or 60mg every two weeks. Median time to disease progression was 8.0, 8.3 and 12.1 weeks in the standard therapy group, the MSL-109 15mg and 60mg groups, respectively (p = 0.087 for placebo vs. 60mg). There were 9, 9 and 4 deaths in the 3 groups (p = 0.006). There were no significant adverse events.

Drew reported on 28 HIV-positive men with CMV shedding who were administered 1263W94 (100mg, 200mg, 400mg three times daily, or 600mg twice daily) for 28 days. Semen and urine cultures found viral load reductions of between 2 and 3.5 logs with better results at the higher doses. Five men discontinued due to rash. Other side-effects were headache, fatigue, taste disturbance and nausea. Common resistance mutations of 1263W94 and ganciclovir were detected.

Petersen enrolled 15 HIV-positive people with CMV-positive cultures in a study of TI-23 (40-80 mg/m²/day intravenously for 90 days). 13/15 participants completed treatment. 8 participants had CMV-retinitis; 4/8 had progression of disease. Severe fatigue was the most frequently reported side-effect. No-one developed antibodies to TI-23. A study of single-dose induction treatment of TI-23 followed by either foscarnet or ganciclovir is under development.

Huang reported that etoposide (VP-16 or VePesid) can irreversibly inhibit CMV replication, through the inhibition of viral DNA and late viral-proteins synthesis, at a concentration (2.5 µg/ml) greatly below the toxic levels to stationary phase cells. In vitro etoposide inhibits topoisomerase II, an enzyme essential for CMV to replicate in vitro.

The SOCA Research Group (1997b) randomized 209 people with CMV retinitis to receive an anti-CMV monoclonal antibody, MSL-109 (5 mg/kg IV every two weeks), or placebo in addition to their approved anti-CMV therapy. The study was stopped early due to increased mortality in the MSL-109 group. There was no difference in the median time to progression of CMV retinitis between the MSL-109 group and the placebo group.

Treating other forms of CMV disease

Dieterich (1993a) treated 62 people with biopsy-proven CMV colitis with ganciclovir (5mg/kg intravenously twice daily) or placebo for 14 days. At entry all participants had diarrhoea (more than 6 stools/day), malabsorption or unintentional weight loss of more than 4.5kg. After 14 days, the groups did not differ for clinical endpoints (diarrhoea, 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%) people treated with ganciclovir compared to 11/30 (36.7%) placebo recipients. CMV disease at new sites developed in seven placebo recipients (5 retinitis, 1 gastritis, 1 pneumonitis) and three ganciclovir recipients (3 gastritis). The investigators suggested that the treatment might be more effective if extended to 21 or 28 days.

Dieterich (1993b) treated ten people, five with upper gastrointestinal CMV disease and 5 with lower gastrointestinal disease with foscarnet (90mg/kg intravenously every 12 hours). Mild oedema was noted in 2/10 but resolved. 8/10 required six weeks of treatment for complete response. 9/10 responded histopathologically and 9/10 responded endoscopically.

Nelson reported on the treatment of CMV infection of the oesophagus and colon in patients with AIDS with foscarnet. In 15/18 episodes of oesophageal ulceration, there was complete loss of symptoms within two weeks, with only 3/15 relapses, two of whom were successfully retreated with foscarnet. Of 22 patients experiencing 27 episodes of CMV colitis, 4 died during foscarnet therapy. Of 18 completing the course for first episode CMV colitis, 11 remitted completely and six had a partial remission. Only one patient receiving a course of foscarnet failed to respond endoscopically to treatment. Three patients experienced relapse of their colitis, two of whom responded to further courses of foscarnet.

Blanshard (1993) randomized 19 people with CMV gastrointestinal disease to receive either ganciclovir or 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.

Kim summarized 22 previously reported cases of CMV radiculopathy and presented two new case reports of patients with this disease. The most common initial symptom was leg weakness that often progressed in the absence of therapy. Over two-thirds of patients experienced urinary retention. Characteristic cerebrospinal fluid findings included very low glucose levels, an increased number of neutrophils, and elevated levels of protein. In almost half the cases, CMV was isolated from cerebro-spinal fluid. In one-third, concurrent CMV retinitis was reported. MRI and CT scans were helpful only to exclude other diagnoses. The average survival for untreated patients was three weeks. In contrast, over 50% of ganciclovir-treated patients survived the acute illness with a median survival of 11 weeks. Response to ganciclovir therapy can take more than two months. The authors recommend lifelong therapy with either ganciclovir or foscarnet for documented or suspected CMV polyradiculopathy.

Couderc successfully treated four people with CMV encephalopathy or myeloradiculitis using a combination of foscarnet (60mg/kg every eight hours) plus ganciclovir (5mg/kg every 12 hours) as induction therapy, followed by foscarnet (90mg/kg daily) plus ganciclovir (5mg/kg daily) maintenance therapy. Combination intravenous therapy is now being studied in ACTG 305.

Hardy (1995) reported that hearing loss may be an early predictor of relapse of CMV polyradiculopathy.

Anduze-Faris treated 31 people with CMV related encephalitis or CMV myelitis with intravenous induction therapy with foscarnet 90mg/kg plus ganciclovir 5mg/kg twice daily, followed by maintenance therapy. Clinical improvement or stabilisation occurred in 74%. Ten withdrew due to side-effects. Of the 23 who progressed to maintenance therapy, CMV disease progressed in ten. The trial was conducted prior to combination antiretroviral therapy.