Clinical trial NCT00851786: Live Zoster Vaccine in HIV-Infected Adults on Antiretroviral Therapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Herpes Zoster
HIV Infections
Keywords: Herpes Zoster Vaccine
Herpes Zoster Virus
HIV
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Adult AIDS Clinical Trials Group
name: Merck Sharp & Dohme LLC
First posted: 2009-02-26
Enrollment: 395
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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).

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: During the 6 week study period after receipt of any dose of ZOSTAVAX
Secondary outcomes:
measure: VZV Antibodies as Measured by gpELISA
timeFrame: Within 6 weeks following one or two doses of ZOSTAVAX
measure: Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses
timeFrame: Entry, Week 6, Week 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: University of Southern California CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Denver
country: United States
facility: Denver Public Health CRS
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS)
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hosp. CRS
state: Michigan
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Camden
country: United States
facility: Cooper Univ. Hosp. CRS
state: New Jersey
city: Newark
country: United States
facility: New Jersey Medical School- Adult Clinical Research Ctr. CRS
state: New Jersey
city: Bronx
country: United States
facility: Bronx-Lebanon Hosp. Ctr. CRS
state: New York
city: New York
country: United States
facility: Cornell CRS
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: HIV Prevention & Treatment CRS
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: The Research & Education Group-Portland CRS
state: Oregon
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ. Med. Ctr. CRS
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
affiliation: University of California, San Diego
name: Constance A. Benson, MD
role: STUDY_CHAIR
affiliation: Emory University
name: Jeffrey L. Lennox, MD
role: STUDY_CHAIR
References:
citation: 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. doi: 10.1097/01.qai.0000178408.62675.b0.
citation: Gilderman LI, Lawless JF, Nolen TM, Sterling T, Rutledge RZ, Fernsler DA, Azrolan N, Sutradhar SC, Wang WW, Chan IS, Schlienger K, Schodel 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. doi: 10.1128/CVI.00310-07. Epub 2007 Dec 12.
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.
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. doi: 10.1056/NEJMoa051016.
citation: Vafai A, Berger M. Zoster in patients infected with HIV: a review. Am J Med Sci. 2001 Jun;321(6):372-80. doi: 10.1097/00000441-200106000-00003.
citation: Benson CA, Andersen JW, Macatangay BJC, Mailliard RB, Rinaldo CR Jr, Read S, Bozzolo DR, Purdue L, Jennings C, Keefer MC, Glesby M, Tebas P, Russell AF, Martin J, Annunziato P, Popmihajlov Z, Lennox JL. Safety and Immunogenicity of Zoster Vaccine Live in Human Immunodeficiency Virus-Infected Adults With CD4+ Cell Counts >200 Cells/mL Virologically Suppressed on Antiretroviral Therapy. Clin Infect Dis. 2018 Nov 13;67(11):1712-1719. doi: 10.1093/cid/ciy242.