Herpes Zoster, HIV Infections
Conditions
Keywords
Herpes Zoster Vaccine, Herpes Zoster Virus, HIV
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.
Interventions
BIOLOGICALZOSTAVAX
Subcutaneous injection of 0.65 mL of ZOSTAVAX at Day 0 and Week 6
BIOLOGICALPlacebo
Subcutaneous injection of 0.65 mL of placebo at Day 0 and Week 6
Sponsors
Adult AIDS Clinical Trials Group
Merck Sharp & Dohme LLC
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | During the 6 week study period after receipt of any dose of ZOSTAVAX | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| VZV Antibodies as Measured by gpELISA | Within 6 weeks following one or two doses of ZOSTAVAX | VZV antibody titer measured by gpELISA after one or two doses of ZOSTAVAX/placebo |
| Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses | Entry, Week 6, Week 12 | 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. |
Countries
United States
Participant flow
Recruitment details
The first person was accrued on 04/29/2009. Accrual in the high CD4 stratum was closed in 02/2010 (n=203; 152 on ZOSTAVAX and 51 on placebo). Accrual to the low CD4 stratum proceeded more slowly with the last subject enrolled on 06/30/2011 (n=192; 144 on ZOSTAVAX and 48 on placebo). All 43 participating sites enrolled at least 1 subject.
Pre-assignment details
Enrollment took place in two stages: Stage I were to enroll 48 subjects (24 in the low CD4 stratum and 24 in the high CD4 stratum). Subjects were randomized 3:1 to receive ZOSTAVAX or placebo. Stage II were to enroll approximately 352 subjects who would be randomized and stratified according to the same schedule.
Participants by arm
| Arm | Count |
|---|---|
| ZOSTAVAX Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-349 cells/uL vs. \>=350 cells/uL), will be given one dose of ZOSTAVAX (Zoster Vaccine Live) at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination after which a safety assessment will be conducted. | 296 |
| Placebo Participants with CD4 cell counts of 200 cells/uL or greater in Stage 1 and 2, stratified by CD4 cell counts (200-\<349 cells/uL vs. \>=350 cells/uL), will be given one dose of placebo at Day 0 and Week 6 and will be followed for at least 42 days after each vaccination afer which a safety assessment will be conducted | 99 |
| Total | 395 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Cannot Adhere to Protocol Requirement | 2 | 0 |
| Overall Study | Incarceration | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Site Closure | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | ZOSTAVAX | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 5 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 285 Participants | 94 Participants | 379 Participants |
| Age, Continuous | 49 years | 49 years | 49 years |
| Duration from Historary Retinal Necrosis >5 years | 2 participants | 0 participants | 2 participants |
| Duration from Historary Retinal Necrosis None | 294 participants | 99 participants | 393 participants |
| Entry CD4 | 399 cells/µL | 362 cells/µL | 394 cells/µL |
| History of Chickenpox >5 years | 219 participants | 77 participants | 296 participants |
| History of Chickenpox None | 60 participants | 15 participants | 75 participants |
| History of Chickenpox Zoster/no Chickpox | 17 participants | 7 participants | 24 participants |
| History of most recent Zoster 0-1 year | 2 participants | 1 participants | 3 participants |
| History of most recent Zoster >1-2 years | 13 participants | 1 participants | 14 participants |
| History of most recent Zoster >2-5 years | 23 participants | 7 participants | 30 participants |
| History of most recent Zoster >5 years | 65 participants | 22 participants | 87 participants |
| History of most recent Zoster None | 193 participants | 68 participants | 261 participants |
| HIV-1 RNA | 1.68 log10 copies/mL | 1.68 log10 copies/mL | 1.68 log10 copies/mL |
| IV drug history Never | 244 participants | 86 participants | 330 participants |
| IV drug history Previously | 52 participants | 13 participants | 65 participants |
| Nadir CD4 | 197 cells/µL | 178 cells/µL | 188 cells/µL |
| Prior History of AIDS No | 8 participants | 2 participants | 10 participants |
| Prior History of AIDS Yes | 288 participants | 97 participants | 385 participants |
| Race/Ethnicity, Customized American Indian, Alaskan Native | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized Asian, Pacific islander | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black Non-Hispanic | 90 participants | 26 participants | 116 participants |
| Race/Ethnicity, Customized Hispanic (regardless of race) | 60 participants | 27 participants | 87 participants |
| Race/Ethnicity, Customized More than one race | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Unknown/missing | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White Non-Hispanic | 141 participants | 44 participants | 185 participants |
| Screen CD4 | 373 cells/µL | 353 cells/µL | 372 cells/µL |
| Sex: Female, Male Female | 44 Participants | 18 Participants | 62 Participants |
| Sex: Female, Male Male | 252 Participants | 81 Participants | 333 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 296 | 0 / 99 |
| other Total, other adverse events | 98 / 296 | 15 / 99 |
| serious Total, serious adverse events | 15 / 296 | 7 / 99 |
Outcome results
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.
Time frame: During the 6 week study period after receipt of any dose of ZOSTAVAX
Population: Subjects who received at least one dose of study vaccine/placebo
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ZOSTAVAX | 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 | 15 participants |
| Placebo | 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 | 2 participants |
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.
Time frame: Entry, Week 6, Week 12
Population: Number of participants with ELISpot results available at entry and at the post-entry week (week 6 or week 12, respectively).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| ZOSTAVAX | Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses | Week 6 GMFR | 1.8 fold rise |
| ZOSTAVAX | Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses | Week 12 GMFR | 3.8 fold rise |
| Placebo | Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses | Week 12 GMFR | 1.1 fold rise |
| Placebo | Geometric Mean Fold Rise (GMFR) in VZV ELISpot Responses | Week 6 GMFR | 0.4 fold rise |
Secondary
VZV Antibodies as Measured by gpELISA
VZV antibody titer measured by gpELISA after one or two doses of ZOSTAVAX/placebo
Time frame: Within 6 weeks following one or two doses of ZOSTAVAX
Population: Subjects with both baseline gpELISA result and at least one post vaccination gpELISA result available
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ZOSTAVAX | VZV Antibodies as Measured by gpELISA | Baseline | 5.68 log gpELISA antibody titer | Standard Deviation 1.03 |
| ZOSTAVAX | VZV Antibodies as Measured by gpELISA | 6 weeks after 1st ZOSTAVAX/Placebo | 6.28 log gpELISA antibody titer | Standard Deviation 0.92 |
| ZOSTAVAX | VZV Antibodies as Measured by gpELISA | 6 weeks after 2nd ZOSTAVAX/Placebo | 6.27 log gpELISA antibody titer | Standard Deviation 0.87 |
| Placebo | VZV Antibodies as Measured by gpELISA | Baseline | 5.52 log gpELISA antibody titer | Standard Deviation 1.26 |
| Placebo | VZV Antibodies as Measured by gpELISA | 6 weeks after 1st ZOSTAVAX/Placebo | 5.57 log gpELISA antibody titer | Standard Deviation 1.27 |
| Placebo | VZV Antibodies as Measured by gpELISA | 6 weeks after 2nd ZOSTAVAX/Placebo | 5.52 log gpELISA antibody titer | Standard Deviation 1.27 |
Comparison: Null hypothesis: VZV antibody titer measured by gpELISA, after 1 or 2 doses of ZOSTAVAX/placebo is the same between ZOSTAVAX arm and the placebo armp-value: <0.00195% CI: [0.45, 0.69]Linear mixed effect model