A Study of Valacyclovir Hydrochloride in the Prevention of Life-Threatening Cytomegalovirus Disease in HIV-Infected Patients

A Randomized, Double-Blind Trial of Valacyclovir Hydrochloride (BW 256U87) Prophylaxis for Opportunistic Cytomegalovirus End-Organ Disease in Patients With Advanced HIV Infection (< 100 CD4+ Lymphocytes)

PRIMARY: To evaluate the efficacy of valacyclovir hydrochloride (BW 256U87) in the prevention of cytomegalovirus (CMV) end-organ disease in HIV/CMV co-infected patients with CD4+ lymphocytes < 100 cells/mm3. To assess the impact of BW 256U87, high-dose oral acyclovir and low-dose oral acyclovir on survival.

SECONDARY: To evaluate the effect of BW 256U87 on quality of life, the safety of the drug administered concurrently with standard antiretroviral agents and other essential therapies for the treatment and prevention of opportunistic diseases, and the efficacy of BW 256U87 in suppressing activation of other herpesviruses. To evaluate serologic and virologic risk factors for the development of CMV disease, including assessment of HIV activation, and the risk of developing drug-resistant CMV, HSV, and VZV.

Gastrointestinal absorption of acyclovir is not high enough to prevent CMV disease in patients with advanced HIV disease, although there is evidence that high doses of the drug may extend survival. Valacyclovir, a prodrug that is rapidly converted to acyclovir after oral administration, has a higher absorption rate and may therefore provide inhibitory activity against CMV.

Gastrointestinal absorption of acyclovir is not high enough to prevent CMV disease in patients with advanced HIV disease, although there is evidence that high doses of the drug may extend survival. Valacyclovir, a prodrug that is rapidly converted to acyclovir after oral administration, has a higher absorption rate and may therefore provide inhibitory activity against CMV.

Patients are randomized to receive BW 256U87 alone or acyclovir alone as control at either high-dose or low-dose. The acyclovir controls will provide suppressive therapy for herpes simplex infections and may affect survival.

Inclusion Criteria

Concurrent Medication:

Recommended:

• PCP prophylaxis.

Allowed:

• Any antiretroviral therapies available by prescription or through expanded access or Treatment IND programs, including combination or sequential use.
• Chemotherapy for Kaposi's sarcoma, lymphoma, or other malignancies IF patient is hematologically stable for at least 30 days prior to study entry.
• Discrete courses of oral or parenteral acyclovir for VZV or HSV infection, not to exceed 21 days per episode (may co-enroll on ACTG 169). For recurrent episodes, open-label acyclovir for a total of 60 days over a 12-month period is allowed. Study drug is interrupted.
• Supportive therapies available by prescription, expanded access, or Treatment IND programs, such as G-CSF, GM-CSF, and erythropoietin.
• Other medications necessary for the patient's welfare, at the discretion of the investigator.

Patients must have:

• HIV infection or AIDS-defining conditions.
• CD4+ count < 100 cells/mm3.
• IgG antibodies to CMV.
• No active CMV disease or history of CMV end-organ disease.
• Consent of parent or guardian if less than 18 years of age.
• Ability to comply with protocol.

NOTE:

• Patients may be co-enrolled in ACTG primary infection Phase II/III studies, ACTG opportunistic infection protocols, or treatment protocols or similar studies sponsored by other research networks as long as those studies do not violate the restrictions placed on concomitant therapies and toxicity management.

Prior Medication:

Allowed:

• PCP prophylaxis.
• Any antiretroviral therapies available by prescription or through expanded access or Treatment IND programs, including combination or sequential use.
• Chemotherapy for Kaposi's sarcoma, lymphoma, or other malignancies.
• Acyclovir.
• Supportive therapies available by prescription, expanded access, or Treatment IND programs, such as G-CSF, GM-CSF, and erythropoietin.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

• Nausea or vomiting that precludes oral dosing.
• Ocular media opacities that preclude adequate visualization of fundi.
• Pregnancy.
• Known hypersensitivity to acyclovir.
• Known lactose intolerance.

Concurrent Medication:

Excluded:

• Systemic interferons and immunomodulators (including CMV hyperimmune serum/globulin and chronic corticosteroids at doses in excess of physiologic replacement).
• Probenecid.
• Investigational or marketed agents with potential activity against CMV, herpes simplex, and/or Varicella zoster, EXCEPT as specifically allowed.

Patients with the following prior condition are excluded:

• Pre-existing necrotizing retinopathy that may interfere with a subsequent diagnosis of CMV retinitis.

Prior Medication:

Excluded:

• Prior ganciclovir, foscarnet, or any investigational anti-CMV agent including use of foscarnet for acyclovir-resistant herpes.
• Interferons, immunomodulators (other than colony stimulating factors), or CMV hyperimmune globulin within 30 days prior to study entry.