Preventing Cytomegalovirus (CMV) Organ Damage With Valganciclovir in People With HIV

A Phase III, Prospective, Randomized, Double-Blind Trial of Valganciclovir Pre-Emptive Therapy for Cytomegalovirus (CMV) Viremia as Detected by Plasma CMV DNA PCR Assay

Cytomegalovirus (CMV) infection is a common opportunistic infection (OI) in HIV patients. The purpose of this study is to find out whether valganciclovir, an antiviral approved by the FDA for the treatment of CMV in the eye, is safe and effective in preventing CMV organ damage in people with HIV.

CMV infection, most commonly of the retina (also known as CMV retinitis), is a common OI observed in HIV patients. Despite treatment, CMV retinitis can result in severe visual impairment and CMV disease is associated with reduced survival time. HIV patients receiving highly active antiretroviral therapy (HAART) for HIV infection who have CD4 counts less than 100 cells/mm3 may be at increased risk of CMV infection and its complications. Valganciclovir was approved by the FDA on March 29, 2001 for treatment of the symptoms of CMV retinitis in patients with weakened immune systems, including people with HIV and AIDS. This study will evaluate the safety and efficacy of valganciclovir in preventing CMV organ damage in HIV patients.

This study will last approximately 6 years. Step 1 is the longitudinal screening phase of the study. Patients at high risk for CMV disease who are enrolled in the study will be screened every 8 weeks for CMV in the blood; medical history assessment, physical examination, and blood work will occur at each visit. Additional blood collection to monitor HIV infection will occur every 16 weeks. Patients will undergo opthalmologic examination every 24 weeks. Patients who develop detectable CMV in their blood during Step 1 then enter Step 2 of the study.

In version 3.0 of this study, participants who test positive for CMV viremia or who are currently in Step 2 will be automatically enrolled into Step 4 and will be randomly assigned to one of two groups: 1) 900 mg valganciclovir twice daily for 3 weeks, followed by 900 mg valganciclovir daily, or 2) placebo. Participants will enter Step 3 if and when they develop CMV end-organ disease, at which point all participants will be offered 900 mg valganciclovir twice daily for 3 weeks, then 900 valganciclovir daily thereafter.

Note: Per a recommendation from NIAID Therapeutic Trials Data Safety Monitoring Board (DSMB), this trial will close on 10/03/05. The DSMB has determined that the study will reach the primary objective. All participants not on valganciclovir must complete all study evaluations by 08/31/05; all participants taking valganciclovir must complete study evaluations by 10/03/05.

Inclusion Criteria for Step 1:

• HIV infected
• Viral load greater than 400 copies/ml
• CD4 count less than 100 cells/mm3
• Have taken HAART for 3 months or longer OR are not taking HAART and do not plan to start HAART for at least 3 months after study entry
• Have serum CMV IgG antibodies
• Have consent of parent or guardian if under 18 years of age
• Willing to use acceptable forms of contraception

Exclusion Criteria for Step 1:

• History of CMV end-organ disease
• Certain antiviral drugs for CMV prophylaxis within 8 weeks of study entry
• Pregnant or breastfeeding
• Currently require ongoing foscarnet or cidofovir. Limited courses of foscarnet or cidofovir for the treatment of diseases other than CMV are permitted if approved by the protocol chairs.