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

HIV Infections Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00001038
• Other study ID #: ACTG 204
• Secondary ID: FDA 104C
• Status: Completed
• Phase: Phase 3
• First received: November 2, 1999
• Last updated: February 28, 2011

Study information

• Verified date: February 2011
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1200
• Est. primary completion date: May 1996
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 13 Years and older

Eligibility

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.

Study Design

Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Communicable Diseases
• Cytomegalovirus Infections
• HIV Infections
• Infection

Intervention

Drug:
• Valacyclovir hydrochloride

• Acyclovir

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Glaxo Wellcome

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  France,  Germany,  Italy,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (11)

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. — View Citation

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)

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)

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)

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. — View Citation

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)

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

Nokta MA, Holland F, De Gruttola V, Emery VC, Jacobson MA, Griffiths P, Pollard RB, Feinberg JE; AIDS Clinical Trials Group, Protocol 204/GlaxoWellcome 123-014, International CMV Prophylaxis Study Group. 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. Epub 2002 May 31. — View Citation

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)

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)

* Note: There are 11 references in all — Click here to view all references

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