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.

Condition	Treatment or Intervention	Phase
Cytomegalovirus Infections HIV Infections	Drug: Valacyclovir hydrochloride  Drug: Acyclovir	Phase III

Further Study Details: 

Expected Total Enrollment:  1200

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.

Ages Eligible for Study:  13 Years and above,  Genders Eligible for Study:  Both

Criteria

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.

Alabama
      Birmingham Veterans Administration Med Ctr, Birmingham,  Alabama,  35233,  United States
California
      Univ of California / San Diego Treatment Ctr, San Diego,  California,  921036325,  United States
      Highland Gen Hosp / San Francisco Gen Hosp, Oakland,  California,  946021018,  United States
      Los Angeles County - USC Med Ctr, Los Angeles,  California,  90033,  United States
      CARE Ctr / UCLA Med Ctr, Los Angeles,  California,  900951793,  United States
      Kaiser Permanente Med Ctr, San Francisco,  California,  94115,  United States
Colorado
      Univ of Colorado Health Sciences Ctr, Denver,  Colorado,  80262,  United States
Connecticut
      Yale Univ, New Haven,  Connecticut,  06519,  United States
Illinois
      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States
Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States
Maryland
      Johns Hopkins Hosp, Baltimore,  Maryland,  212052196,  United States
Massachusetts
      Harvard (Massachusetts Gen Hosp), Boston,  Massachusetts,  02114,  United States
      Boston Med Ctr, Boston,  Massachusetts,  02118,  United States
Missouri
      Washington Univ, St. Louis,  Missouri,  63110,  United States
New York
      Mount Sinai Med Ctr, New York,  New York,  10029,  United States
      North Central Bronx Hosp / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States
North Carolina
      Univ of North Carolina School of Medicine, Chapel Hill,  North Carolina,  275997215,  United States
Ohio
      Ohio State Univ Hosp Clinic, Columbus,  Ohio,  432101228,  United States
Pennsylvania
      Girard Med Ctr, Philadelphia,  Pennsylvania,  191046073,  United States
Texas
      Univ TX Galveston Med Branch, Galveston,  Texas,  775550882,  United States
Washington
      Univ of Washington / Madison Clinic, Seattle,  Washington,  98122,  United States
Australia
      Saint Vincent's Hosp Med Centre, Sydney,  Australia
Canada, Alberta
      Southern Alberta HIV Clinic / Foothills Hosp, Calgary,  Alberta,  Canada
Canada, Ontario
      Toronto Hosp, Toronto,  Ontario,  Canada
      Sunnybrook Health Science Ctr, Toronto,  Ontario,  Canada
Canada, Quebec
      Montreal Gen Hosp, Montreal,  Quebec,  Canada
      Montreal Chest Institute, Montreal,  Quebec,  Canada
Denmark
      Hvidovre Univ Hosp, Hvidore,  Denmark
France
      Services des Maladies Infectieuses, Paris Cedex 12,  France
Germany
      Universitatsklinikum Rudolf Virchow, Berlin,  Germany
Italy
      Universita Cattolica del Sacro Cuore, Rome,  Italy
Sweden
      South Hosp, Stockholm,  Sweden
Switzerland
      Medizinische Universibatspoliklinik Infekbiologie, Bern,  Switzerland
United Kingdom
      Westminster Hosp, London,  United Kingdom
      Royal Free Hosp, London,  United Kingdom

Study chairs or principal investigators

Feinberg J,  Study Chair

Study ID Numbers:  ACTG 204; FDA 104C
Record last reviewed:  June 1996
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00001038
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08