Perturbing of HIV Reservoir With Immune Stimulation

• Sponsor: University of California, San Diego (Other)
• Overall Status: Completed
• CT.gov ID: NCT02707692
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 54
• Location: 1
• Arms: 6
• Actual Duration (Months): 65
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the impact of Pneumococcus and Influenza vaccines on the HIV transcriptional activity in individuals who are virologically suppressed for at least 48 weeks on similar ART. The proposed study is a randomized double-blinded control trial conducted over 28 weeks. Randomized interventions will be injections of Influenza vaccine, Pneumococcal vaccine, and Placebo. Each participant will receive each injection but in a randomized order.

Condition or Disease	Intervention/Treatment	Phase
AIDS; HIV	Biological: Fluarix; Biological: Pneumovax; Other: Placebo	N/A

Detailed Description

Title: Perturbing the HIV Reservoir

Sample Size: 56

Study Population: HIV-infected individuals between 18 and 65 years old who started similar antiretroviral therapy (ART) during chronic infection and remained virally suppressed for at least 48 weeks before enrollment. Participants will have CD4 >250 cells/μl at enrollment and a CD4 nadir >100 cells/μl.

Participating Sites: UCSD's Antiviral Research Center (AVRC)

Study Design: The proposed study is a randomized double-blinded control trial conducted over 28 weeks. Randomized interventions will be injections of Influenza vaccine, Pneumococcal vaccine, and Placebo. Each participant will receive each injection but in a randomized order.

Schedule of Evaluations: Study evaluations will be based on three 30 day cycles (Influenza vaccine, Pneumococcus vaccine, Placebo in random order) over 28 weeks of the RCT. Pre injection: one paired blood and genital secretion sample will be collected before each injection. Post-injection: paired blood and genital secretion samples will be collected on days 2, 4, 7, 14 and 30 after each injection.

Study Duration: 240 weeks

Study Regimen/Intervention: This is a double blind RCT of two vaccines (Pneumovax®23 and Fluarix®) plus placebo (sterile saline injection). Study participants will be followed for 28 weeks after enrollment. During this 28-week period, blood and genital secretion samples will be collected on day 0 and five subsequent time points after each injection (days 2, 4, 7, 14 and 30). Injections (vaccine or placebo) will be administered 12 weeks apart and in a random order, to minimize a possible bias due to the order of the vaccines.

Primary Objective: To determine the impact of Pneumococcus and Influenza vaccines on the HIV transcriptional activity in individuals who are virologically suppressed for at least 48 weeks on similar ART.

Primary Outcome: Average level of CD4+ T cell-associated HIV RNA transcription measured at days 2, 4, 7, 14 and 30 after each injection.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: Perturbing the HIV Reservoir With Immune Stimulation
• Actual Study Start Date: Aug 1, 2016
• Actual Primary Completion Date: Apr 1, 2020
• Actual Study Completion Date: Jan 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: Pneumococcal, then Influenza, then Placebo vaccination Participants first received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of saline (placebo).	Biological: Fluarix; Intramuscular injection with Fluarix® .; Biological: Pneumovax; Intramuscular injection with Pneumovax.; Other: Placebo; Intramuscular injection with sterile saline (placebo).
Other: Pneumococcal, then Placebo, then Influenza vaccination Participants first received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of saline (placebo). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).	Biological: Fluarix; Intramuscular injection with Fluarix® .; Biological: Pneumovax; Intramuscular injection with Pneumovax.; Other: Placebo; Intramuscular injection with sterile saline (placebo).
Other: Influenza, then Pneumococcal, then Placebo vaccination Participants first received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of saline (placebo).	Biological: Fluarix; Intramuscular injection with Fluarix® .; Biological: Pneumovax; Intramuscular injection with Pneumovax.; Other: Placebo; Intramuscular injection with sterile saline (placebo).
Other: Influenza, then Placebo, then Pneumococcal vaccination Participants first received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of saline (placebo). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).	Biological: Fluarix; Intramuscular injection with Fluarix® .; Biological: Pneumovax; Intramuscular injection with Pneumovax.; Other: Placebo; Intramuscular injection with sterile saline (placebo).
Other: Placebo, then Pneumococcal, then Influenza vaccination Participants first received a 0.5 mL injection of saline (placebo). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).	Biological: Fluarix; Intramuscular injection with Fluarix® .; Biological: Pneumovax; Intramuscular injection with Pneumovax.; Other: Placebo; Intramuscular injection with sterile saline (placebo).
Other: Placebo, then Influenza, then Pneumococcal vaccination Participants first received a 0.5 mL injection of saline (placebo). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).	Biological: Fluarix; Intramuscular injection with Fluarix® .; Biological: Pneumovax; Intramuscular injection with Pneumovax.; Other: Placebo; Intramuscular injection with sterile saline (placebo).

Outcome Measures

Primary Outcome Measures

1. Change From Vaccination (Day 0) in Mean CD4+ T Cell-associated HIV RNA Transcription at Day 7 [Day 0 and Day 7]

   CD4+ T cell-associated HIV RNA was measured before vaccination on Day 0 and again on Day 7. The Day-0 measure of CD4+ T cell-associated HIV RNA transcription was subtracted from the Day-7 measure.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Documented HIV-1 infection more than 365 days ago (HIV antibody or viral load positive).

2. Capable of signing written informed consent.

3. Documented viral s suppression for at least 48 weeks (≤50 copies/mL)

4. Men and women between 18 and 65 years of age.

5. Read and comprehend English.

6. Documented CD4 count at enrollment (>250 cells/µl)

7. Reported CD4 nadir >100 cells/µl.

8. Received seasonal flu vaccination at least 6 weeks prior to first trial injection (and not more recently)

9. Received vaccination for pneumococcal disease at least 12 months prior to first trial injection (and not more recently)

10. Started ART during chronic infection (> 6 months from estimated date of injection)

Exclusion Criteria

1. Uncontrolled psychiatric condition.

2. Under the influence of drug(s) or alcohol at time of screening.

3. Any condition that, in the opinion of the investigator, would limit follow-up and adequate consent.

4. History of allergic reactions to any of the proposed vaccines or egg allergy.

5. History of Gullian Barre syndrome

6. Receiving immunosuppressive medications.

7. Pregnancy or lactation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD Antiviral Research Center (AVRC)	San Diego	California	United States	92103-8208

Sponsors and Collaborators

• University of California, San Diego
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 15, 2018

More Information

Publications

None provided.

• Responsible Party: David Smith, Professor of Medicine, University of California, San Diego
• ClinicalTrials.gov Identifier: NCT02707692
• Other Study ID Numbers: 160089; 1R01AI118422-01A1
• First Posted: Mar 14, 2016
• Last Update Posted: Aug 24, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by David Smith, Professor of Medicine, University of California, San Diego: HIV; AIDS; Immune Stimulation; HIV Reservoir
• Additional relevant MeSH terms: Heptavalent Pneumococcal Conjugate Vaccine

Study Results

Participant Flow

Recruitment Details	Recruitment dates: 2016 to 2020 Recruitment location: Conducted in HIV clinics and at clinical trial site, UC San Diego AntiViral Research Center in San Diego, CA
Pre-assignment Detail	Participants had a wash out period of no less than 4 weeks between vaccination series. Participants were excluded from the study before randomization and study assignments if their HIV viral loads were detectable from blood samples collected at screening.

Arm/Group Title	Pneumococcal, Then Influenza, Then Placebo Vaccination	Pneumococcal, Then Placebo, Then Influenza Vaccination	Influenza, Then Pneumococcal, Then Placebo Vaccination	Influenza, Then Placebo, Then Pneumococcal Vaccination	Placebo, Then Pneumococcal, Then Influenza Vaccination	Placebo, Then Influenza, Then Pneumococcal Vaccination
Arm/Group Description	Participants first received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of saline (placebo).	Participants first received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of saline (placebo). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).	Participants first received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of saline (placebo).	Participants first received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of saline (placebo). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).	Participants first received a 0.5 mL injection of saline (placebo). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).	Participants first received a 0.5 mL injection of saline (placebo). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).
Period Title: Cycle 1 (30 Days)
STARTED	9	9	9	9	9	9
COMPLETED	8	6	8	9	8	8
NOT COMPLETED	1	3	1	0	1	1
Period Title: Cycle 1 (30 Days)
STARTED	8	6	9	9	8	8
COMPLETED	7	6	9	8	7	8
NOT COMPLETED	1	0	0	1	1	0
Period Title: Cycle 1 (30 Days)
STARTED	7	6	9	8	7	8
COMPLETED	6	6	9	7	4	7
NOT COMPLETED	1	0	0	1	3	1
Period Title: Cycle 1 (30 Days)
STARTED	7	6	9	7	6	7
COMPLETED	7	6	9	5	6	6
NOT COMPLETED	0	0	0	2	0	1
Period Title: Cycle 1 (30 Days)
STARTED	7	6	9	5	6	6
COMPLETED	5	5	9	5	5	5
NOT COMPLETED	2	1	0	0	1	1

Baseline Characteristics

Arm/Group Title	Pneumococcal, Then Influenza, Then Placebo Vaccination	Pneumococcal, Then Placebo, Then Influenza Vaccination	Influenza, Then Pneumococcal, Then Placebo Vaccination	Influenza, Then Placebo, Then Pneumococcal Vaccination	Placebo, Then Pneumococcal, Then Influenza Vaccination	Placebo, Then Influenza, Then Pneumococcal Vaccination	Total
Arm/Group Description	Participants first received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of saline (placebo).	Participants first received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of saline (placebo). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).	Participants first received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of saline (placebo).	Participants first received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of saline (placebo). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).	Participants first received a 0.5 mL injection of saline (placebo). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).	Participants first received a 0.5 mL injection of saline (placebo). After a washout period of at least 6 weeks, they then received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK). After another washout period of at least 6 weeks, the participant received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).	Total of all reporting groups
Overall Participants	9	9	9	9	9	9	54
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.8 (13.4)	42.9 (9.5)	42.2 (13.4)	44.3 (10.2)	46.9 (10.1)	48.0 (10.9)	45.0 (11.0)
Sex/Gender, Customized (Count of Participants)
Male	6 66.7%	8 88.9%	8 88.9%	8 88.9%	7 77.8%	8 88.9%	45 83.3%
Female	3 33.3%	1 11.1%	0 0%	0 0%	1 11.1%	1 11.1%	6 11.1%
Trans or non-binary	0 0%	0 0%	1 11.1%	1 11.1%	1 11.1%	0 0%	3 5.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 66.7%	5 55.6%	3 33.3%	4 44.4%	5 55.6%	4 44.4%	27 50%
Not Hispanic or Latino	3 33.3%	4 44.4%	6 66.7%	5 55.6%	4 44.4%	5 55.6%	27 50%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 11.1%	0 0%	0 0%	0 0%	1 1.9%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 11.1%	2 22.2%	1 11.1%	2 22.2%	0 0%	2 22.2%	8 14.8%
White	8 88.9%	7 77.8%	7 77.8%	6 66.7%	9 100%	5 55.6%	42 77.8%
More than one race	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 11.1%	2 3.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	1 11.1%	1 1.9%
Region of Enrollment (participants) [Number]
United States	9 100%	9 100%	9 100%	9 100%	9 100%	9 100%	54 100%
Virologically suppressed (Count of Participants)
Suppressed (< 50 copies/ml)	9 100%	9 100%	9 100%	9 100%	8 88.9%	8 88.9%	52 96.3%
Viremic (>= 50 copies/ml)	0 0%	0 0%	0 0%	0 0%	0 0%	1 11.1%	1 1.9%
Unknown	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 1.9%
CD4 Counts (cells/microliters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cells/microliters]	785.4 (248.5)	814.9 (267.9)	798.4 (280.0)	724.4 (256.7)	753.8 (242.4)	639.9 (222.1)	752.8 (248.6)

Outcome Measures

1. Primary Outcome

Title	Change From Vaccination (Day 0) in Mean CD4+ T Cell-associated HIV RNA Transcription at Day 7
Description	CD4+ T cell-associated HIV RNA was measured before vaccination on Day 0 and again on Day 7. The Day-0 measure of CD4+ T cell-associated HIV RNA transcription was subtracted from the Day-7 measure.
Time Frame	Day 0 and Day 7

Outcome Measure Data

Analysis Population Description

Within each cycle, all participants who received the vaccination and completed the Day-7 visit were included in the analysis.

Arm/Group Title	Pneumococcal Vaccine	Influenza Vaccine	Placebo
Arm/Group Description	Participants received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®) and a 0.5 mL of saline (placebo) with at least 6 weeks of washout between injections, in random order.	Participants received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK) and a 0.5 mL of saline (placebo) with at least 6 weeks of washout between injections, in random order.	Participants received a 0.5 mL injection of saline (placebo).
Measure Participants	42	44	45
Mean (Standard Deviation) [HIV RNA copies per million cell]	-471.8 (2998.0)	-45.9 (243.2)	332.3 (2266.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pneumococcal Vaccine, Placebo
	Comments	Primary hypothesis: Participants will have a higher absolute difference in levels of CD4+ T cell-associated HIV RNA transcription seven days after receiving either Pneumococcal or Influenza vaccinations, when compared to seven days after receiving placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Paired t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-988.0
	Confidence Interval	(2-Sided) 95%; -2996.3 to 1020.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Influenza Vaccine, Placebo
	Comments	Primary hypothesis: Participants will have a higher absolute difference in levels of CD4+ T cell-associated HIV RNA transcription seven days after receiving either Pneumococcal or Influenza vaccinations, when compared to seven days after receiving placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Paired t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-405.0
	Confidence Interval	(2-Sided) 95%; -1199.7 to 389.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From baseline until the end of Cycle 3 (up to 417 days on study)
Arm/Group Title	Pneumococal Vaccine		Influenza Vaccine		Placebo
Arm/Group Description	Participants received a 0.5 mL injection of Pneumococcal vaccine (Pneumovax-23®).		Participants received a 0.5 mL injection of Influenza vaccine (Fluarix®, GSK).		Participants received a 0.5 mL injection of saline (placebo).
All Cause Mortality
	Pneumococal Vaccine		Influenza Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/45 (0%)		0/48 (0%)
Serious Adverse Events
	Pneumococal Vaccine		Influenza Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/45 (2.2%)		0/45 (0%)		0/48 (0%)
Gastrointestinal disorders
Elevated ALT/AST	1/45 (2.2%)	1	0/45 (0%)	0	0/48 (0%)	0
Other (Not Including Serious) Adverse Events
	Pneumococal Vaccine		Influenza Vaccine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/45 (0%)		0/48 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.