Live Zoster Vaccine in HIV-Infected Adults on Antiretroviral Therapy

HIV Infections Clinical Trial

Official title:

A Phase II, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety, Tolerability, and Immunogenicity of ZOSTAVAX® (Zoster Vaccine Live) in Human Immunodeficiency Virus (HIV)-1-Infected Adults on Potent Combination ART With Conserved Immune Function

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00851786
• Other study ID #: A5247
• Secondary ID: 10519ACTG A5247
• Status: Completed
• Phase: Phase 2
• Start date: April 29, 2009
• Est. completion date: January 3, 2012

Study information

• Verified date: January 2018
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Herpes zoster, or shingles, is the result of a viral infection that causes a painful skin rash, usually in older people or people with suppressed immune systems like those infected with HIV. The ZOSTAVAX vaccine has been shown to reduce the number of infections and symptoms of herpes zoster infection in people over the age of 60. The purpose of this study is to evaluate the safety, tolerability, and immunogenicity of two doses of ZOSTAVAX in HIV-1-infected adults with conserved immune function (Cd4+ T cell counts >=200 cells/uL) virologically suppressed on potent combination antiretroviral therapy (ART).

Description:

The varicella-zoster virus (VZV) which causes herpes zoster (HZ), or shingles, is associated with a painful skin rash and post-herpetic neuralgia (PHN). The incidence and severity of HZ and PHN increase as immune function decreases, as in elderly or HIV-infected people. The live VZV vaccine, ZOSTAVAX, has been shown to reduce the incidence and severity of HZ and PHN in people over the age of 60. The main purpose of this study is to determine whether a two-dose regimen of ZOSTAVAX is safe and well-tolerated in HIV-infected individuals with conserved immune function.

This study has two stages and two arms. It may last up to 24 weeks per subject. In Stage 1, 48 participants with CD4 cell counts of 200 or more cells/uL will be enrolled (24 participants with a CD4 count between 200 and 349 cells/uL and 24 participants with a CD4 count equaling 350 or more cells/uL). These participants will be randomized 3:1 to receive two doses of ZOSTAVAX or placebo at least six weeks apart. If certain safety criteria are met for Stage 1, enrollment will be opened to Stage 2. Stage 2 will enroll approximately 352 subjects with CD4+ T cell counts >= 200 cells/uL. In Stage 2, participants will be stratified using the same parameters as Stage 1 and will then be randomized 3:1 to receive either two doses of vaccine or placebo according to the same schedule. Participants will be followed for at least 42 days after each vaccination. Temperatures will be collected daily for 42 days following each vaccination. Telephone contact will also be made 2 to 3 days after each vaccination and at 24 weeks following the initial vaccination to obtain information regarding vaccination-related symptoms.

All participants will have between 6 and 8 study visits. At the screening visit, documentation of HIV status is required, and blood and urine collection, a physical exam, medical history, and clinical assessment will occur. At each visit, a targeted physical exam will occur. At some visits, blood and urine collection, and a clinical assessment will occur. Antiretroviral medications are not provided by this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 395
• Est. completion date: January 3, 2012
• Est. primary completion date: September 22, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• HIV infected

• Use of potent combination ART regimen within 90 days prior to entry and undetectable plasma HIV RNA level within 90-210 days prior to study entry

• CD4 cell count of at least 200 cells/uL obtained within 30 days prior to study entry

• Laboratory values obtained within 90 days prior to study entry

• Hemoglobin 7.0 g/dL or greater

• Platelet count 50,000/mm3 or greater

• Creatinine 3 x ULN or less

• AST (SGOT), ALT (SGPT), and alkaline phosphatase 5 x ULN or less

• For females of reproductive potential, a negative serum or urine pregnancy test within 24 hours prior to study entry

• Willing to use accepted forms of contraception for the duration of the study

• History of varicella or herpes zoster more than 1 year prior to vaccination or VZV seropositivity at any time prior to entry

• Men and women age >=18 years

• Ability and willingness of subject or legal guardian/representative to provide informed consent

Exclusion Criteria:

• History of nadir CD4+ count <100 cells/uL

• Known or suspected immune dysfunction caused by a medical condition or any cause other than HIV infection, such as congenital immunodeficiency, organ or bone marrow transplantation, leukemia, lymphoma, Hodgkin's disease, multiple myeloma, or generalized malignancy [NOTE: Subjects with prostate or breast cancer who are not on chemotherapeutic drugs (other than hormone blocking drugs), subjects with skin cancer or Kaposi's sarcoma limited to skin who are not receiving radiation therapy or chemotherapy, and subjects with a history of other malignancies who have been disease-free for at least 5 years will be eligible for enrollment.]

• Receipt of any varicella or zoster vaccine prior to study entry

• History of allergy/sensitivity, or hypersensitivity to any vaccine component, including gelatin or neomycin

• Receipt of immunoglobulin or any blood products, other than autologous blood transfusion, given during the 5 months prior to study entry or expected during the 24-week study period

• Receipt of any live virus vaccine within 28 days prior to study entry or during study period

• Receipt of any inactivated vaccine within 7 days prior to study entry or during study period

• Scheduled administration of any live virus vaccine or inactivated vaccine at or between study entry and the Week 12 visit

• Participation in an investigational drug study within the last 30 days prior to study entry

• Use of immunosuppressive therapy. More information can be found in the protocol.

• Any chronic suppressive antiviral therapy with activity against herpes viruses, including but not limited to acyclovir, famciclovir, valacyclovir, ganciclovir, foscarnet, and cidofovir within 7 days prior to study entry or expected use through the 24-week study period except where necessary for acute treatment of intercurrent viral infection.

• Any episode of VZV reactivation in the 12 months prior to study entry

• Active drug or alcohol use, dependence, or any other reason that, in the opinion of the site investigator, would interfere with the study

• Pregnancy (including subjects who are expecting to conceive within 3 months of the second vaccination) or breast feeding

• Any acute intercurrent illness that might interfere with the interpretation of the study

• Significant underlying illness preventing completion of the study

Related Conditions & MeSH terms

• Herpes Zoster
• HIV Infections

Intervention

Biological:
• ZOSTAVAX
Subcutaneous injection of 0.65 mL of ZOSTAVAX at Day 0 and Week 6
• Placebo
Subcutaneous injection of 0.65 mL of placebo at Day 0 and Week 6

Locations

Country	Name	City	State
United States	The Ponce de Leon Center CRS	Atlanta	Georgia
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	IHV Baltimore Treatment CRS	Baltimore	Maryland
United States	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland
United States	Alabama Therapeutics CRS	Birmingham	Alabama
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Bmc Actg Crs	Boston	Massachusetts
United States	Brigham and Women's Hosp. ACTG CRS	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS	Boston	Massachusetts
United States	Bronx-Lebanon Hosp. Ctr. CRS	Bronx	New York
United States	Cooper Univ. Hosp. CRS	Camden	New Jersey
United States	Chapel Hill CRS	Chapel Hill	North Carolina
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois
United States	Univ. of Cincinnati CRS	Cincinnati	Ohio
United States	Case CRS	Cleveland	Ohio
United States	MetroHealth CRS	Cleveland	Ohio
United States	The Ohio State University Medical Center	Columbus	Ohio
United States	Denver Public Health CRS	Denver	Colorado
United States	Henry Ford Hosp. CRS	Detroit	Michigan
United States	Duke Univ. Med. Ctr. Adult CRS	Durham	North Carolina
United States	Greensboro CRS	Greensboro	North Carolina
United States	UCLA CARE Center CRS	Los Angeles	California
United States	University of Southern California CRS	Los Angeles	California
United States	Univ. of Miami AIDS CRS	Miami	Florida
United States	Vanderbilt Therapeutics CRS	Nashville	Tennessee
United States	Cornell CRS	New York	New York
United States	HIV Prevention & Treatment CRS	New York	New York
United States	NY Univ. HIV/AIDS CRS	New York	New York
United States	New Jersey Medical School- Adult Clinical Research Ctr. CRS	Newark	New Jersey
United States	Stanford CRS	Palo Alto	California
United States	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania
United States	Thomas Jefferson Univ. Med. Ctr. CRS	Philadelphia	Pennsylvania
United States	Pitt CRS	Pittsburgh	Pennsylvania
United States	The Research & Education Group-Portland CRS	Portland	Oregon
United States	The Miriam Hosp. ACTG CRS	Providence	Rhode Island
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	Washington U CRS	Saint Louis	Missouri
United States	Ucsd, Avrc Crs	San Diego	California
United States	Ucsf Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	Harbor-UCLA Med. Ctr. CRS	Torrance	California
United States	Georgetown University CRS (GU CRS)	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Adult AIDS Clinical Trials Group, Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United States, 

References & Publications (5)

Gebo KA, Kalyani R, Moore RD, Polydefkis MJ. The incidence of, risk factors for, and sequelae of herpes zoster among HIV patients in the highly active antiretroviral therapy era. J Acquir Immune Defic Syndr. 2005 Oct 1;40(2):169-74. — View Citation

Gilderman LI, Lawless JF, Nolen TM, Sterling T, Rutledge RZ, Fernsler DA, Azrolan N, Sutradhar SC, Wang WW, Chan IS, Schlienger K, Schödel F, Silber JL; Zostavax Protocol 010 Study Group. A double-blind, randomized, controlled, multicenter safety and immunogenicity study of a refrigerator-stable formulation of Zostavax. Clin Vaccine Immunol. 2008 Feb;15(2):314-9. Epub 2007 Dec 12. — View Citation

Holcomb K, Weinberg JM. A novel vaccine (Zostavax) to prevent herpes zoster and postherpetic neuralgia. J Drugs Dermatol. 2006 Oct;5(9):863-6. Review. — View Citation

Oxman MN, Levin MJ, Johnson GR, Schmader KE, Straus SE, Gelb LD, Arbeit RD, Simberkoff MS, Gershon AA, Davis LE, Weinberg A, Boardman KD, Williams HM, Zhang JH, Peduzzi PN, Beisel CE, Morrison VA, Guatelli JC, Brooks PA, Kauffman CA, Pachucki CT, Neuzil KM, Betts RF, Wright PF, Griffin MR, Brunell P, Soto NE, Marques AR, Keay SK, Goodman RP, Cotton DJ, Gnann JW Jr, Loutit J, Holodniy M, Keitel WA, Crawford GE, Yeh SS, Lobo Z, Toney JF, Greenberg RN, Keller PM, Harbecke R, Hayward AR, Irwin MR, Kyriakides TC, Chan CY, Chan IS, Wang WW, Annunziato PW, Silber JL; Shingles Prevention Study Group. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med. 2005 Jun 2;352(22):2271-84. — View Citation

Vafai A, Berger M. Zoster in patients infected with HIV: a review. Am J Med Sci. 2001 Jun;321(6):372-80. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Composite Safety Endpoint of the Occurrence of Serious Adverse Events (SAEs) or Division of AIDS (DAIDS) Grade 3 and 4 Signs and Symptoms, Excluding SAEs Related to Trauma	Although the study was designed as a randomized trial, it was not powered to detect safety related differences between treatment arms. The safety of ZOSTAVAX was determined by comparing the number of subjects from the active arm who experienced safety endpoint to the number from a pre-specified decision rule, which was calculated based on a similar population and calibrated using the number of safety endpoints observed from the placebo arm. The pre-specified decision rule is that ZOSTAVAX would be considered to have acceptable safety if no more than 18 subjects experience a study-defined composite safety endpoint.	During the 6 week study period after receipt of any dose of ZOSTAVAX
Secondary	VZV Antibodies as Measured by gpELISA	VZV antibody titer measured by gpELISA after one or two doses of ZOSTAVAX/placebo	Within 6 weeks following one or two doses of ZOSTAVAX
Secondary	Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses	VZV-specific cellular immune responses in peripheral blood mononuclear cells (PBMC) were tested by ELISpot assay in a subset of participants pooled across CD4 strata. GMFR is the geometric mean of the ratios of Week 6 or Week 12 post-vaccination antibody to the pre-vaccination antibody.	Entry, Week 6, Week 12