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Randomized, Placebo Controlled Trial of Valganciclovir to Prevent CMV End-organ Disease among HIV-infected Subjects with Detectable Plasma CMV DNA PCR: ACTG 5030
David Wohl*1, M Kendall2, J Andersen2, C Crumpacker3, S Spector4, J Feinberg5, B Alston-Smith6, S Owens7, S Chafey8, and M Jacobson9
1Univ of North Carolina at Chapel Hill, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Beth Israel Deaconess Hosp, Boston, MA, US; 4Univ of California, San Diego, US; 5Univ of Cincinnati Med Ctr, OH, US; 6DAIDS, NIH, Bethesda, MD, US; 7Frontier Sci & Tech Res Fndn, Amherst, MA, US; 8UCLA ISAP/ Project Flow, San Francisco, CA, USA; and 9Univ of California, San Francisco, US
Background: Detection of
cytomegalovirus (CMV) DNA in the blood has been associated with increased risk
of CMV end-organ disease and death among patients receiving HAART. Whether
pre-emptive anti-CMV therapy in CMV viremic patients
reduces this risk is unknown.
Methods: In this randomized,
placebo-controlled trial, HIV+ subjects with CD4 <100 cells/mm3,
HIV RNA >400 copies/mL on stable HAART or no ART
were enrolled. Plasma CMV DNA polymerase chain reaction (PCR; lower limit of
detection = 400 copies/mL) was measured every 8 weeks
(step 1). Those with detectable CMV viremia were randomized to induction and
maintenance doses of valganciclovir (VGCV) or placebo
(step 2) and underwent dilated indirect ophthalmoscopy
every 8 weeks.
Results: We enrolled 338 subjects
of whom 80% were receiving ART. Median step 1 entry CD4 and HIV RNA were 30
cells/mm3 and 4.98 log10 copies/mL,
respectively. CMV DNA was detected by PCR in 68 (20%), 47 of whom entered the
randomized phase (24 in VGCV and 23 in placebo arms). At step 2 entry, the
median CD4 was 12 cells/mm3; all but 10 subjects were receiving ART.
Median CD4 counts remained well below 100/mm3 for the first 128 weeks
after step 2 randomization. With 65 weeks’ median follow-up, 9 (19%) step 2 subjects
were diagnosed with probable or confirmed CMV end-organ disease (4 in the VGCV
arm and 5 in placebo arm) and 15 (32%) died (7 on VGCV and 8 on placebo). An additional
10 subjects developed CMV end-organ disease, and 52 died prior to randomization
(i.e. during step 1). Of 9 subjects with CMV end-organ disease on step 2, 7
were on ART. There was no significant difference in rates of CMV end-organ
disease or death or in the combined endpoint of CMV end-organ disease or death between
treatment arms. The rates of adverse events grade 2 or higher were not
significantly different between the treatment arms.
Conclusions: Although studies in the pre-HAART
era reported that >50% of patients with CD4 <50 cells/mm3 and CMV viremia developed CMV end-organ
disease, we observed a much lower
CMV end-organ disease
rate among such patients in the HAART era, but did observe a high rate of
mortality in this cohort. Our findings indicate that pre-emptive anti-CMV does
not significantly reduce the risk of CMV end-organ disease or of death in subjects receiving
HAART.
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