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

Condition(s) targeted: Cytomegalovirus Infections; HIV Infections

Intervention: Valacyclovir hydrochloride (Drug); Acyclovir (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)

Official(s) and/or principal investigator(s):
Feinberg J, Study Chair

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.

Official title: 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)

Study design: Treatment

Detailed description: 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.

Minimum age: 13 Years. Maximum age: N/A. Gender(s): 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.

Saint Vincent's Hosp Med Centre, Sydney, Australia

Hvidovre Univ Hosp, Hvidore, Denmark

Services des Maladies Infectieuses, Paris Cedex 12, France

Universitatsklinikum Rudolf Virchow, Berlin, Germany

Universita Cattolica del Sacro Cuore, Rome, Italy

South Hosp, Stockholm, Sweden

Medizinische Universibatspoliklinik Infekbiologie, Bern, Switzerland

Westminster Hosp, London, United Kingdom

Royal Free Hosp, London, United Kingdom

Birmingham Veterans Administration Med Ctr, Birmingham, Alabama 35233, United States

Southern Alberta HIV Clinic / Foothills Hosp, Calgary, Alberta, Canada

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

Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States

Yale Univ, New Haven, Connecticut 06519, United States

Northwestern Univ Med School, Chicago, Illinois 60611, United States

Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States

Johns Hopkins Hosp, Baltimore, Maryland 212052196, United States

Harvard (Massachusetts Gen Hosp), Boston, Massachusetts 02114, United States

Boston Med Ctr, Boston, Massachusetts 02118, United States

Washington Univ, St. Louis, Missouri 63110, United States

Mount Sinai Med Ctr, New York, New York 10029, United States

North Central Bronx Hosp / Bronx Municipal Hosp, Bronx, New York 10467, United States

Univ of North Carolina School of Medicine, Chapel Hill, North Carolina 275997215, United States

Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States

Toronto Hosp, Toronto, Ontario, Canada

Sunnybrook Health Science Ctr, Toronto, Ontario, Canada

Girard Med Ctr, Philadelphia, Pennsylvania 191046073, United States

Montreal Gen Hosp, Montreal, Quebec, Canada

Montreal Chest Institute, Montreal, Quebec, Canada

Univ TX Galveston Med Branch, Galveston, Texas 775550882, United States

Univ of Washington / Madison Clinic, Seattle, Washington 98122, United States

Click here for more information about Acyclovir

Related publications:

Feinberg JE, Hurwitz S, Cooper D, Sattler FR, MacGregor RR, Powderly W, Holland GN, Griffiths PD, Pollard RB, Youle M, Gill MJ, Holland FJ, Power ME, Owens S, Coakley D, Fry J, Jacobson MA. A randomized, double-blind trial of valaciclovir prophylaxis for cytomegalovirus disease in patients with advanced human immunodeficiency virus infection. AIDS Clinical Trials Group Protocol 204/Glaxo Wellcome 123-014 International CMV Prophylaxis Study Group. J Infect Dis. 1998 Jan;177(1):48-56.

Fry J, Coakley D, Power M, Feinberg J. International collaborative clinical trials: the ACTG 204 experience. Int Conf AIDS. 1996 Jul 7-12;11(2):276 (abstract no ThB4146)

Griffiths PD, Feinberg J. Detection of cytomegalovirus in samples from patients enrolled in ACTG 204 / Glaxo Wellcome 123-014. Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:54

Brosgart C, Fisher E, Pulling C, Chaloner K, Cohn D, Elsadr W, Verheggen R, Schmetter B, Alston B. Prevalence of asymptomatic CMV retinitis (CMVR) in AIDS patients. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:152 (abstract no 453)

Fisher E, Brosgart C, Cohn D, Chaloner K, Pulling C, Alston B, Schmetter B, El-Sadr W. Placebo (PLC)-controlled, multicenter trial of adefovir dipivoxil (ADV) in patients (pt) with HIV disease. . Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:160 (abstract no 491)

Feinberg JE, Bell WR, Chulay JD. A thrombotic microangiopathy (TMA)-like syndrome in patients with advanced HIV disease in a cytomegalovirus (CMV) prophylaxis trial (ACTG 204). Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:196 (abstract no 715)

Sprenger HG, Law G, Pastoor G, Postma S, Schirm J, Weits J, The TH. Cytomegalovirus antigenemia (CMVAg) compared with other CMV tests during phase III study of valaciclovir (VACV) for CMV prophylaxis in advanced HIV disease (ACTG 204 study). Int Conf AIDS. 1996 Jul 7-12;11(2):285 (abstract no ThB4200)

Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytomegalovirus prophylaxis trial (ACTG 204). Medicine (Baltimore). 1997 Sep;76(5):369-80. No abstract available.

Emery V, Sabin C, Feinberg J, Grywacz M, Knight S, Griffiths P. Quantitative effects of valaciclovir on the replication of cytomegalovirus in patients with advanced HIV disease. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:153 (abstract no 459)

Weinberg A, Schneider SA, Clark JC. Acyclovir (ACV) and valacyclovir (VAL) prophylaxis of AIDS patients does not alter cytomegalovirus (CMV) susceptibility to ganciclovir (GCV) or foscarnet (FOS). Program Abstr Intersci Conf Antimicrob Agents Chemother. 1996 Sep 15-18:202 (abstract no I87)

Nokta MA, Holland F, De Gruttola V, Emery VC, Jacobson MA, Griffiths P, Pollard RB, Feinberg JE. Cytomegalovirus (CMV) polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to CMV disease. J Infect Dis. 2002 Jun 15;185(12):1717-22.

Last updated: June 23, 2005