This section contains details of the following subjects:

• Stopping CMV prophylaxis

• CMV immune recovery vitritis/uveitis

• CMV in the age of HAART

• CMV colitis & polyradiculopathy

• Maintenance therapy

• Prophylaxis

• CMV viraemia and antigenaemia

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

Stopping CMV prophylaxis

Song reported a prospective observational study of 102 patients at the AIDS Ocular Research Unit in California. 47/102 responded well to HAART and 35 stopped CMV prophylaxis. After a median of 74.7 weeks (range 4.86-144 weeks) after discontinuation, four people had a reactivation of CMV retinitis. Median CD4 count at reactivation was 31.5 CD4 cells. Reactivation was significantly associated with a CD4 count falling below 50.

Perez reported an observational study of 19 people with a previous diagnosis of CMV eye disease, and who stopped CMV prophylaxis after a median of 40 months on antiretroviral therapy. At the time of stopping prophylaxis, the average CD4 count was 289 and all had viral loads below 50. After median follow-up of 17 months, no reactivation of CMV occurred.

Macdonald (2000) conducted an observational study of 22 individuals with a history of CMV retinitis who ceased prophylaxis. After a median of 72 weeks follow-up, 3 had experienced a CD4 decline to below 50 and reactivation of CMV. CD4 counts in the 3 people with CMV progression were 35, 37 and 47.

Torriani (2000) reported that 5/17 people who stopped CMV therapy when their CD4 counts were above 70 experienced CMV reactivation an average of 14.5 months after stopping prophylaxis and between 8 days and 10 months after their CD4 count fell below 50. Four out five reactivations occurred in the same site as prior retinitis. CMV-specific lymphocyte proliferative responses were undetectable or weak in those who experienced reactivation, compared with an index of 20 in a control group of 12 individuals who experienced no reactivation. HIV RNA was greater in those who experienced reactivation.

MacDonald (1998) reported that 11 AIDS patients receiving HAART with healed CMV retinitis stopped CMV prophylaxis. Median CD4 nadir was 42, and median CD4 when prophylaxis was stopped was 183. Only 3 had viral loads below detection. After 156 days of follow up, no CMV reactivation occurred.

Tural discontinued CMV prophylaxis in seven individuals with CD4 counts above 150 and viral loads below 200 who were CMV PCR negative. After nine months follow-up, no new CMV developed.

Vrabec reported no CMV reactivation or progression in eight individuals who stopped CMV prophylaxis after an average of 11.4 months follow-up. CD4 range was 70-725 (average 255) and viral load ranged from undetectable to 139,000.

Jouan reported one reactivation of CMV retinitis in a group of 48 patients who discontinued CMV maintenance after a median 18 months of HAART. Median CD4 count was 239 and 75% had HIV RNA less than 500 copies. Two recurrences of CMV disease occurred during the 48 week follow-up period. One reactivation of CMV retinitis occurred at a CD4 count of 300 and a viral load of about 20,000 copies 11 weeks after stopping intravenous ganciclovir. A case of CMV-related peripheral neuropathy occurred at 106 cells/mm³ five weeks after CMV maintenance therapy was discontinued. CMV viremia was detectable in neither case.

Johnson reported one person with a CD4 count over 300 on anti-CMV treatment who had four CMV relapses. Ganciclovir-resistant CMV was detected in the blood but not in the eye. Tests showed no CMV-specific immune response in this individual.

CMV immune recovery vitritis/uveitis

Schrier reported that immune reconstitution in over half of patients for CMV retinitis was accompanied by a debilitating ocular inflammation and macular edema termed immune recovery uveitis (IRU, n=15). Certain factors were associated with IRU: a shorter course of anti-CMV maintenance therapy (18.7 IRU versus 36.2 months non-IRU); receiving HAART more rapidly after the initial CMV retinitis diagnosis (5.0 versus 12.3 months); treatment with intraocular cidofovir injections (40% versus 25%). Some immune responses to CMV were higher in patients with IRU (p = 0.02). Eyes with IRU had higher levels of IL-12 (p = 0.05) compared to control eyes or eyes with active CMV retinitis. These results suggest that remaining CMV antigen or protein expression may trigger the IRU.

Whitcup reported that 14 individuals with CD4 counts greater than 150 receiving maintenance treatment with either ganciclovir, foscarnet or cidofovir were followed for an average of 16 months after stopping CMV treatment. All were receiving HAART with at least three drugs. 12/14 had documented immune recovery uveitis at baseline; this condition worsened in three individuals during the study. During the follow-up period, no progression of CMV disease was reported, and the median CD4 count of all participants rose above 300. Nine individuals were intermittently positive for CMV but experienced no flare-up of CMV disease.

Nguyen reviewed the records of 82 people with CMV retinitis who commenced HAART and experienced a CD4 increase. 33 (40.2%) achieved a CD4 count over 100 or an increase of 50 cells/micro/L. Six responders developed uveitis producing an incidence rate of 13.6% or 0.109 cases per person-year of follow-up. Other associated ocular complications associated with uveitis included cystoid macular edema (n=4), epiretinal membranes (n=2) and optic disk neovascularisation (n=1).

Karavellas followed 30 people who responded to HAART with CD4 increases over 60. Symptomatic immune recovery vitritis (IRV) developed in 19 (63%) of participants, and in 26 of 44 eyes over a median of 13.5 months. Previous treatment with cidofovir did not affect likelihood of IRV.

O'Moore reported on four cases of successful treatment with anti-CMV therapy, followed by loss of visual acuity due to cystoid macular oedema(CMO) and inflammation of the eye. The participants were all on combination therapy and experienced sustained reductions in viral load over 1 log. At the time of diagnosis with CMO, the average viral load was 1,240 and the average CD count was 114. CMO was treated with acetazolamide and steroid preparations with varying success. CMO and eye inflammation was attributed to a strengthened immune response to CMV due to HAART.

CMV in the age of HAART

Deayton (2004) conducted a prospective study of 374 HIV-positive individuals with CD4 cell counts <100 cells/mm³. At entry, median VL was 80,000 copies/ml and CD4 cell count was 80 cells/mm³. 95% were on HAART. Baseline CMV tests were positive in 16%: these patients were 11 times more likely to experience a new CMV event, even after controlling for CD4 cell count (p = 0.007) and HIV VL (p = 0.008). The incidence of AIDS-defining events was 8.0 per 100 patient years in CMV-negative patients and 16.4 per 100 patient years in CMV positive patients (p = 0.04, adjusted for CD4 cell count and HIV VL). This was also the case when CMV was excluded as an AIDS-defining event (p < 0.001). 7% of CMV-negative and 19% of CMV-positive patients died in the 36 months of follow-up.

Deayton (2000c) conducted a retrospective analysis of 103 HIV-infected people with CMV attending the Ian Charleson Day Centre at the Royal Free Hospital in London between 1990 and 1998 to investigate the impact of highly active antiretroviral therapy (HAART) on the CMV retinitis, survival and HAART-related side-effects. 87 patients died during the study period. 97% of the group received ganciclovir, 32% received foscarnet, 10% received cidofovir, and 20.4% received HAART (first commenced in 1995). Prior to HAART, the median survival time following CMV diagnosis was 0.65 years. From 1995-1998, median survival time was 1.07 years (p=0.004). No patients receiving HAART experienced CMV progression during the 6 months after CMV diagnosis. HAART was associated with a 61% reduction in risk of death. 39 people experienced complications of retinitis, such as retinal detachment. 8 people, all taking HAART, experienced inflammatory complications of retinitis such as vitritis and cystoid macular oedema. Median time to vitritis was 105 days. Maximum CD4 count during the first 12 months after HAART was not significantly difference between those who did and did not develop inflammatory responses.

Deayton (2000a) compared CMV viraemia and symptoms in 11 patients on HAART with 11 patients not on HAART in the absence of anti-CMV treatment. At baseline, CMV viral load was 4.90 log in the HAART group and 2.94 log in the untreated controls. CMV viral load fell by 1.8 log at one month and 2.6 log at six months in the treated group. Half-life of CMV was highly variable (from 1.52 days to 25 days). The authors found that following the anti-HIV effect of HAART, the immune system had an anti CMV effect of 63%, equivalent to some other CMV treatments such as oral ganciclovir.

Deayton (2000b) studied CMV viraemia and disease progression in 11 HIV-infected patients diagnosed with CMV retinitis and treated with HAART. No CMV disease progression or viraemia occurred among patients who received at least six months of HAART but three individuals did have intermittent viraemia associated with neutropenia due to hydroxycarbamide (previously known as hydroxyurea) or HAART failure. In one case, CMV viraemia was ganciclovir resistant. Deayton recommended reinduction with anti-CMV treatment when recurrent viraemia occurs.

Yust examined the incidence of CMV retinitis among 8495 HIV-infected individuals enrolled in the EuroSIDA cohort between 1994-2000. The overall incidence of CMV retinitis was 1.2 per 100 person years. Incidence of CMV retinitis and extraocular CMV fell by 46% and 51% respectively each year. Mortality due to CMV disease fell as CD4 levels rose and viral load declined. Only 1.9% of people on HAART developed CMV compared to 11%-16% of those on no treatment, monotherapy or dual therapy. Rates of maintenance therapy fell from 64% to 23% during the six years of the study.

Jalali reported that the Davis Medical Center in Sacramento, USA treated 974 HIV-infected patients during 1992-1993 of whom 2.6% had CMV retinitis. During 1997-1998, 1,274 HIV-infected people were treated of whom 0.07% had CMV. In most cases, retinitis occurred prior to or shortly after initiation of antiretroviral therapy. Rates of retinal detachment among those with retinitis did not change over time.

Jacobson (2000) conducted a review of patients from a San Francisco HIV clinic with a caseload of about 3,500 people with HIV. New cases of CMV were 47 per year 1994-95, four cases in 1997 and ten new cases in 1998. Five of 10 cases in 1998 were among people previously on HAART with CD4 counts below 50 and viral loads above 35,000. The 1997 cases were among people who had not taken HAART. Good response to anti-CMV treatment was associated with a good response to HAART.

Deayton (1999) reported that 16 people treated with first-line HAART became CMV PCR negative after an average of 13.5 weeks treatment. This was sustained in 14 participants for up to 21 months. No cases of CMV occurred.

Van den Horn studied 15 people receiving maintenance therapy for CMV retinitis. Participants were reviewed for CMV retinitis and intraocular inflammation and then started on HAART. Seven recurrences of CMV retinitis occurred, all among people who did not have sustained increases in CD4 levels. CMV remained inactive among five surviving participants who sustained CD4 levels above 100 after one year of follow-up. Poor initial response to HAART was associated with relapse.

Walsh analysed changes in the survival of individuals diagnosed with CMV retinitis following the introduction of protease inhibitors. By May 1996, the mean survival after diagnosis was 224 days for individuals who took no further antiretroviral therapy, 353 days for those who took NRTI drugs but no protease inhibitors, and 914 days for those who received a protease inhibitor. In multivariate analysis, the strongest independent predictor of improved survival was having ever received a protease inhibitor after diagnosis of CMV retinitis.

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 oral placebo and ganciclovir implant; or twice daily 5mg/kg intravenous (IV) ganciclovir. See Cytomegalovirus (CMV) - key research on treatment in Symptoms and illnesses: A to Z of illnesses under the sub-heading 'Oral ganciclovir and valganciclovir' for full details. 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).

Arrizabalaga followed 172 patients with CMV antibody after initiation of HAART; 11% were CMV PCR positive at baseline. Of the remainder, 7% were CMV PCR positive at least once during the first three months of therapy. Amongst those CMV PCR positive at baseline, the proportion with detectable CMV viraemia declined to 7% at one month, 2% at 3 months and 0% at 6 months. After two years of follow up 6% of the cohort had been diagnosed with CMV-related disease, with most cases (67%) occurring during the first three months of therapy. 75% of those with CMV viraemia greater than 1,000 copies developed CMV disease, but no association was reported with HIV viral load.

Casado studied 172 individuals with baseline CD4 counts below 100 who were followed for at least 12 months after starting HAART. The cumulative incidence of CMV retinitis was 5% at 1 year and 6% at 2 years. A positive PCR test for CMV was associated with CMV retinitis, and people who developed CMV retinitis had an higher average CMV viral load than those who did not develop retinitis. 7% of participants had a transient increase in CMV viral load during the first month of HAART which was associated with a greater risk of disease.

French measured CMV-specific CD4 T-cell responses in patients with HIV RNA <50 copies/mL who had received HAART for a median time of 5.7 years (range 4.3 to 6.2; n = 13) and in CMV+ controls (n = 8). In addition, CD8 T-cell responses to CMV peptides were measured after four to five years to determine if patients had CD8 T-cell responses to CMV. CMV-specific CD4 T-cell responses remained low in year but increased, peaking at 40 weeks, when they were higher than baseline (p <0.005) and not significantly different to CMV+ healthy controls. However, by year five there was a marked decline to baseline levels that was not associated with a decrease in CD4 T-cell counts or an increase in viral load. CD8 T-cell responses were higher in patients than controls (p = 0.038). Severely immunodeficient HIV patients on HAART for 5 years appear not to maintain CMV-specific CD4 T-cell responses. Additionally, increased CD8 T-cell responses may be an early indicator of recurrent CMV replication.

CMV colitis & polyradiculopathy

Dieterich (1993a) treated 62 people with biopsy-proven CMV colitis with ganciclovir (5 mg/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 4.5 kg. 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 (five cases of retinitis, one of gastritis, one of pneumonitis) and three ganciclovir recipients (three cases of 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 gastro-intestinal CMV disease and five with lower gastro-intestinal disease with foscarnet (90 mg/kg intravenously every 12 hours). Mild oedema was noted in 2/10 but resolved. 8/10 required 6 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 three relapses, two of whom were successfully retreated with foscarnet. Of 22 patients experiencing 27 episodes of CMV colitis, four died during foscarnet therapy. Of 18 completing the course for first episode CMV colitis, eleven 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 gastro-intestinal 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 2 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 cerebro-spinal 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 (60 mg/kg every 8 hours) plus ganciclovir (5 mg/kg every 12 hours) as induction therapy, followed by foscarnet (90 mg/kg daily) plus ganciclovir (5 mg/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.

Maintenance therapy

Weinberg reported on foscarnet resistance in 176 people enrolled in the Cytomegalovirus Retinitis and Viral Resistance Study. drug resistance was associated with estimated relative CMV progression of 14 (p = 0.016) in 44 people with foscarnet resistance. The incidence of CMV resistance to foscarnet at 6, 9, and 12 months was estimated to be 13%, 24%, and 37%, respectively.

Drew (1995) compared oral (500 mg six times daily) versus intravenous ganciclovir as maintenance therapy in 117 people whose CMV retinitis had been stabilised through use of intravenous ganciclovir (trial 1653). After 20 weeks follow-up, the mean time to progression was 96 days in the IV group and 68 days in the oral group. However, the two treatments seemed to be equally effective when assessment was made by masked fundus photographs (mean 62 days for IV and 57 for oral). There was no difference between the groups in the proportion of participants with worsened visual acuity in either eye. Oral ganciclovir was well-tolerated, with no difference in gastro-intestinal events between the treatment. Neutropenia, fever and sepsis were more common in the IV recipients.

Crumpacker treated 117 people who had a new diagnosis of CMV retinitis with intravenous ganciclovir for 3 weeks, then if their retinitis was stable randomized them to receive either continued intravenous ganciclovir (5 mg/kg/day) or oral ganciclovir (500 mg six times a day) for 20 weeks. When assessed by fundoscopy, the mean time to progression was 111 days in the intravenous group and 48 days in the oral group. However, the time to progression was comparable between the two groups when assessed by masked retinal photographs. Oral ganciclovir was well-tolerated with no increase in gastro-intestinal side-effects. Neutropenia, fever and sepsis occurred more frequently in the intravenous ganciclovir recipients.

Squires enrolled 216 people whose CMV retinitis had been stabilised by at least 4 weeks' intravenous therapy in trial 1774, in which they received maintenance therapy with either continued intravenous ganciclovir (5 mg/kg/day) or oral ganciclovir (3 g/day or 6 g/day). Median time to progression as assessed by fundoscopy was 105 days, 68 days and 56 days respectively. However, again the time to progression was comparable between the treatment groups when assessed by masked retinal photographs. People who experienced a relapse of retinitis while on study were treated intravenously, then re-randomized to one of the two doses of oral ganciclovir. Preliminary analysis of these patients suggested that 6 g/day delayed progression for longer than 3 g/day.

Danner on behalf of the Oral Ganciclovir European and Australian Co-operative Study Group randomized 159 people whose CMV retinitis had been stabilised after intravenous treatment to receive maintenance therapy with either oral ganciclovir (3 g/day) or intravenous ganciclovir (5 mg/kg every 12 hours) for 20 weeks (trial 034). By examination of retinal photographs, there was no statistically significant difference between the groups in the mean time to progression (51 days on oral ganciclovir vs 62 days on intravenous ganciclovir). Using fundoscopic evaluation the mean time to progression was 86 days for the oral group and 109 days for the intravenous group. Diarrhoea and neutropenia were the most common side-effects in both groups. 14% of the oral ganciclovir recipients developed haematological toxicities, compared with 23.3% of the intravenous group.

Lalezari (1996) compared the efficacy of 3 g, 4.5 g and 6 g of oral ganciclovir daily versus IV ganciclovir (5 mg/kg) for maintenance treatment among 281 people whose CMV retinitis had been stabilised by at least one course of IV ganciclovir. Mean time to progression was 81.1 days for the IV ganciclovir group. The mean times to progression in the oral ganciclovir group were shorter; 6.2 days shorter (74.9 days) for the 6 g arm, 15.8 days shorter for the 4.5 g arm and 23.5 shorter in the 3 g arm.

Mathieson compared the efficacy of 3 g and 6 g of oral ganciclovir daily for maintenance treatment among 270 people whose CMV retinitis had been stabilised by at least one course of IV ganciclovir. No statistically significant differences in the risk of progression were seen. Mean times to progression by fundoscopic assessment were 107 vs 122 days, and median times were 84 vs 112 days. By assessment of fundus photographs, mean times to progression were 74 vs 79 days, and median times were 43 vs 56 days. Neutropenia occurred in 10% vs 15%, and required colony stimulating factors in 24% vs 35%.

Bowen (1998) reported that in a cohort of 45 people receiving maintenance therapy for CMV retinitis, the presence of CMV PCR viraemia correlated significantly with recurrent episodes of retinitis. 10 of 14 PCR-positive individuals had genotypic markers of ganciclovir resistance.

Prophylaxis

Lowance studied valacyclovir in organ transplant recipients. 208 CMV negative and 408 CMV positive recipients were randomly assigned to valacyclovir or placebo. After 90 days prophylaxis, 45% of the CMV negative group treated with placebo had developed CMV compared with 3% of CMV negative people given the drug. Among the CMV positive group, 6% of the placebo group developed CMV compared with none of the valacyclovir group.

Youle enrolled 302 CMV seropositive patients with advanced symptomatic HIV disease and CD4 counts below 150 (mean baseline CD4 count was 51 in the treated and 56 in the placebo group) in an international study of the efficacy of aciclovir in preventing CMV and other herpes virus diseases (study H14-325). Participants received oral aciclovir (800 mg four times daily) or placebo. At week 48 the study was stopped on the basis that statistically there was no evidence of a significant decrease in CMV disease occurring in the aciclovir group. At this time CMV disease had occurred in 16/123 patients in the aciclovir group and 9/123 in the placebo group. However, there was a statistically significant reduction in mortality in the high-dose aciclovir arm: 43/149 (29%) placebo recipients died, versus 27/153 (18%) in the aciclovir group. On an intention-to-treat analysis the overall probability of dying was 39% in the placebo group versus 23% in the aciclovir group; for those with CD4 counts below 50 the probability of dying was 56% vs 32%.

Spector (1996a) conducted a randomized double-blind placebo-controlled trial (Syntex 1654) of oral ganciclovir as primary prophylaxis against CMV disease in 725 people with CD4 counts below 50, or a previous AIDS-defining illness and CD4 count below 100. Participants were randomized 2:1 to receive either oral ganciclovir (1000 mg every 8 hours) or placebo. CMV disease occurred in 26% of placebo recipients compared with 14% of ganciclovir recipients, representing an overall reduction in risk of 49%. The incidence of CMV retinitis after 12 months was 24% in the placebo group and 12% in the oral ganciclovir group. 24% of ganciclovir recipients developed neutropenia that required treatment with G-CSF, compared with 9% of the placebo group. There was no difference in gastro-intestinal adverse events.

Drew (1996) reported that 40% to 50% of placebo-recipients in the above study were CMV culture-positive throughout the study. Among those treated with oral ganciclovir, culture positivity fell to around 10% and remained at that level throughout the study. CMV isolates from ganciclovir recipients were tested for resistance to ganciclovir. After at least 90 days of treatment, 2 of 18 isolates were resistant. This represents a prevalence of less than 1% among the entire ganciclovir-treated group after an average of 10 months of treatment. Previous studies of intravenous ganciclovir have reported a resistance prevalence of around 8% after an average of 7.4 months of treatment.

Spector (1996b) reported that in the above study, PCR of plasma for CMV DNA identified the individuals most likely to benefit from oral ganciclovir prophylaxis. Among the 95% of patients who had positive PCR levels of 50,000 or below, the one year risk of developing CMV disease was 40% among those receiving placebo, but this was reduced to 20% among those receiving ganciclovir. Among participants with PCR levels above 50,000 (5%), there was no significant difference in the risk of CMV disease between ganciclovir and placebo recipients.

Brosgart enrolled 994 participants in CPCRA 023, a placebo-controlled trial of oral ganciclovir (1000 mg three times daily) in people with CD4 counts below 100 and positive CMV serology but no CMV disease. Median baseline CD4 count was 34. After the Syntex 1654 study was terminated, participants in this trial were allowed to switch to open label oral ganciclovir; nevertheless, exposure to oral ganciclovir was 9.3 months in the treated arm and 2.1 months in the control arm. There was no difference between the arms in terms of development of any CMV disease, but there was a suggestion of a reduction in death rate among the treated group. 25% of treated people developed grade III or higher neutropenia versus 16% of the control arm. In a post hoc, non-randomised sub-analysis, the risk of developing CMV disease appeared to be significantly higher among participants who were receiving ddI at baseline. No such effect of ddI treatment was observed in the Syntex 1654 study (above).

Feinberg enrolled 1227 people who were CMV IgG+ and had CD4 counts below 100 in ACTG 204, a trial comparing high-dose valacyclovir (2 g four times daily) versus acyclovir (700 or 400 mg four times daily). Median CD4 count was 32; 67% of participants had baseline CD4 counts below 50. In February 1995, the trial was stopped due to an observed higher mortality in the valacyclovir arm. However, when all endpoints until July 1995 were included, there was no significant difference in mortality between the groups and there were no differences in primary causes of death between the arms. Estimated 12-month death rates were 24.3%, 19.5% and 18.8% for the valacyclovir, high-dose acyclovir and low-dose acyclovir arms respectively. Confirmed CMV disease was reduced from 17.5% in the two acyclovir arms to 11.7% in the valacyclovir arm. This reduction was seen for all forms of CMV end-organ disease. Reduction in CMV disease was most marked among participants with CD4 counts above 50, and among those who developed CMV disease while on study drug. 4% of valacyclovir recipients discontinued treatment due to adverse events, compared with 1.4% of high-dose acyclovir and 0.3% of low-dose acyclovir recipients.

Bell reported the occurrence of haemolytic uremic syndrome among valacyclovir recipients in ACTG 204.

CMV viraemia and antigenaemia

Nieto demonstrated a link between CMV antibody titre and narrowing of the arteries (as measured by carotid intimal thickness) but Thiebaut found no link between CMV serology or disease and narrowing of the arteries. This disproves the earlier claim by Nieto that atherosclerosis is related to CMV viraemia.

Pan reported that the CD69 expression marker on T cells is a cheaper test for identifying people at risk of CMV disease.

Wohl (2000) tested 141 individuals with CMV and HIV for CMV viraemia comparing 4 assays (Roches CMV DNA PCR assay, Digenes hybrid capture CMV DNA assay, Biotests CMV antigen pp65 assay and Organon-Technikas pp67 mRNA NucliSens assay). Tests were conducted four times over a median of 12 months. 24% developed CMV viraemia during follow-up. Two assays (DNA PCR and Hybrid) were able to predict disease. Detection of DNA PCR was predictive of death. Wohl (2003) further reported an increased risk of death among 200 HIV-positive people with advanced disease enrolled in this prospective study since mid 1997, irrespective of the cause of death.

Bush monitored 121 HIV/CMV+ women using three CMV assays - Hybrid Capture, pp65 antigen and Chirons plasma bDNA CMV assay. 64% of participants were on PI-containing treatment. Despite this, 64% of the women had at least one CMV positive test during the two year study period. 21% were CMV+ for a three month period. At two years, only two women had developed CMV disease.

Baldanti reported four cases of detectable CMV despite undetectable viral load and CD4 levels about 100.

Dodt observed that plasma PCR for CMV DNA became positive a median of 46 days before onset of clinically diagnosed disease.

Chevret studied 214 people with HIV for risk of CMV disease. A positive antigenaemia assay at baseline was associated with risk of CMV disease and death. Increasing levels of CMV antigen were associated with greater risk.

Grzywacz conducted an open-label study of 3g or 6g per day in 14 HIV-infected people with CMV viraemia for 28 days. All participants experienced a decline in CMV viral load during treatment, but people on the lower dose all had CMV PCR rebound after ceasing treatment. None of the people on the 3g dose achieved undetectable CMV PCR after 21 days compared to 6/8 on the 6g dose. Results were confounded by HAART usage: 5/8 on the 6g dose were on HAART compared with 2/9 on the 3g dose.

Shinkai followed 94 people with median CD4 of 56 for 12 months; 28% developed CMV disease during follow-up. Plasma PCR for CMV DNA was the most accurate predictor of future disease; the median interval between detection of CMV DNA and clinically diagnosed disease was 6 months, and a peak in plasma CMV DNA occurred 4.1 months prior to diagnosis.

Spector evaluated plasma CMV DNA in 619 participants in a randomised study of oral ganciclovir as prophylaxis for CMV disease. In participants without detectable CMV DNA at baseline, 14% of the placebo group and 1% of the treatment group developed CMV disease over 12 months of follow-up. In those CMV DNA positive at baseline, 43% of the placebo group and 26% of the treatment group developed CMV disease over 12 months. Each 1 log increase in CMV DNA was associated with 3.1 fold increase in CMV disease risk and 2.2 fold increase in mortality over 12 months.

Griffiths reported that participants in ACTG 204 who had detectable CMV DNA (using non-nested PCR) in their blood on entry to the trial had the best response to valacyclovir.

Bowen (1997) enrolled HIV-positive people with CD4 counts below 50 in a prospective study of the use of PCR measurement of CMV viraemia in identifying patients at high risk of CMV disease. Participants who were PCR-viraemic were allocated to monthly virological and ophthalmological follow-up, and their CMV viral load was determined using a quantitative assay. PCR-negative participants received 3-monthly virological and ophthalmological follow-up. 16/27 (59%) PCR-positive participants developed CMV disease compared with 3/70 (4%) of those who were CMV-negative. A positive CMV PCR result was associated with a 20.15 relative hazard of CMV disease. In PCR-positive patients, each 0.25 log increase in viral load was associated with an increased risk of disease.