A Randomized Trial to Evaluated the Suppressive Effect of Acyclovir on Rapidly Cleared HSV-2 Reactivation

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00723229
• Collaborator: National Institutes of Health (NIH) (NIH)
• Enrollment: 48
• Location: 1
• Arms: 2
• Duration (Months): 37
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

We propose to study the episode rate, duration, and quantity of HSV-2 genital shedding in patients taking standard, FDA approved, CDC recommended doses of acyclovir (400 mg PO BID) for HSV-2 suppression compared to taking no medication to better define the effect of acyclovir on short bursts of rapidly cleared HSV-2 shedding. This study will be a randomized, open label, cross-over trial. We hypothesize that short bursts of HSV-2 reactivation will not be suppressed by acyclovir.

Condition or Disease	Intervention/Treatment	Phase
Genital Herpes	Drug: acyclovir	Phase 4

Detailed Description

We propose to study the episode rate, duration, and quantity of HSV-2 genital shedding in patients taking standard, FDA approved, CDC recommended doses of acyclovir (400 mg PO BID) for HSV-2 suppression compared to taking no medication to better define the effect of acyclovir on short bursts of rapidly cleared HSV-2 shedding. This study will be a randomized, open label, cross-over trial.

We propose to perform this study in two study populations. Cohort 1 will be comprised of 25 HSV-2 seropositive, HIV seronegative adults, and Cohort 2 will be comprised of 25 HSV-2 seropositive, HIV seropositive adults with a CD4 count>250 cells/mm3. As suppression of HSV-2 using acyclovir is currently being studied in large, multi-center, international clinical trials as an HIV prevention strategy, these results will have broad implications for public health around the world.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Cross-Over Study to Evaluate the Suppressive Effect of Acyclovir on Rapidly Cleared Herpes Simplex Virus Type 2 Genital Reactivation Episodes in Herpes Simplex Virus-2 Seropositive Adults
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1	Drug: acyclovir; Acyclovir 400 mg PO BID for 28 days
No Intervention: 2

Outcome Measures

Primary Outcome Measures

1. Frequency of HSV-2 Total Shedding From the Genital Tract as Measured by PCR, Calculated Using a Per-day Shedding Rate in Participants Treated With Suppressive Acyclovir as Compared to no Medication in HIV Seronegative and HIV Seropositive Individuals. [9 weeks]

Secondary Outcome Measures

1. Quantity of HSV Detected, Median [9 weeks]

   Median quantity of HSV detected, among swabs with any HSV detected

2. Number of Genital HSV Shedding Episodes [9 weeks]

   The number of HSV shedding episodes. A shedding episode is defined as any number of positive swabs preceded and followed by 2 negative swabs

3. Duration of Genital HSV Shedding Episodes [9 weeks]

   Median duration of HSV shedding episodes, in hours

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

COHORT 1: HIV seronegative

1. Older than 18 years;

2. HSV-2 seropositive by Western Blot;

3. not receiving any drugs with known anti-HSV-2 activity for study duration;

4. women of child bearing potential who are sexually active with men must be using a medically accepted method of contraception as judged by the investigator;

5. women of child-bearing potential must have a negative pregnancy test (urine) at screening visit;

6. in general good health, without other serious medical conditions and specifically with normal renal and hepatic function, as determined by the patient's medical history;

7. planning to remain resident in the area of the study center for the duration of the study participation;

8. HIV seronegative

COHORT 2: HIV seropositive

1. Older than18 years;

2. HSV-2 seropositive by Western Blot;

3. not receiving any drugs with known anti-HSV-2 activity for study duration;

4. women of child bearing potential who are sexually active with men must be using a medically accepted method of contraception as judged by the investigator;

5. women of child-bearing potential must have a negative pregnancy test (urine) at screening visit;

6. in general good health, without other serious medical conditions and specifically with normal renal and hepatic function, as determined by the patient's medical history;

7. planning to remain resident in the area of the study center for the duration of the study participation;

8. HIV seropositive

9. CD4 count over 250 cell/mm3

10. Not taking antiretroviral therapy

Exclusion Criteria:

For both cohorts:

1. hypersensitivity to acyclovir or valacyclovir;

2. pregnant women;

3. Taking immunosuppressive therapies, such as chronic oral steroids or immune modulatory drugs.

For cohort 2:

1. CD4 count<250 cell/mm3

2. Taking antiretroviral therapy at the time of study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Washington Virology Research Clinic	Seattle	Washington	United States	98122

Sponsors and Collaborators

• University of Washington
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Christine Johnston, MD, MPH, University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Christine Johnston, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT00723229
• Other Study ID Numbers: 34187-B; U19AI031448
• First Posted: Jul 28, 2008
• Last Update Posted: Mar 9, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Herpes Genitalis; Acyclovir

Study Results

Participant Flow

Recruitment Details	Participants were recruited between July 2008 and March 2010. Participants were enrolled at the University of Washington Virology Research Clinic, Seattle, WA.

Arm/Group Title	No Medication First, Then Standard-dose Acyclovir	Acyclovir 400 mg Twice Daily First, Followed by no Medication
Arm/Group Description	No medication for 4 weeks, then 1 week washout, followed by acyclovir 400 mg twice daily for 4 weeks	Acyclovir 400 mg twice daily for 4 weeks, then 1 week washout, followed by no medication for 4 weeks
Period Title: First Intervention
STARTED	25	23
COMPLETED	18	20
NOT COMPLETED	7	3
Period Title: First Intervention
STARTED	18	20
COMPLETED	18	20
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	No Medication	Acyclovir 400 mg Twice Daily	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	25	23	48
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (12.3)	42.1 (13.1)	44.4 (12.7)
Sex: Female, Male (Count of Participants)
Female	10 40%	10 43.5%	20 41.7%
Male	15 60%	13 56.5%	28 58.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 24%	5 21.7%	11 22.9%
White	17 68%	16 69.6%	33 68.8%
More than one race	2 8%	2 8.7%	4 8.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
HIV serostatus (Number) [Number]
HIV seropositive	9 36%	7 30.4%	16 33.3%
HIV seronegative	16 64%	16 69.6%	32 66.7%

Outcome Measures

1. Primary Outcome

Title	Frequency of HSV-2 Total Shedding From the Genital Tract as Measured by PCR, Calculated Using a Per-day Shedding Rate in Participants Treated With Suppressive Acyclovir as Compared to no Medication in HIV Seronegative and HIV Seropositive Individuals.
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

Participants collected at least one swab on each study arm

Arm/Group Title	No Medication	Acyclovir 400 mg Twice Daily
Arm/Group Description
Measure Participants	38	38
Measure Swabs	3525	3496
HIV seronegative	24	3
HIV seropositive	15	7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	No Medication, Acyclovir 400 mg Twice Daily
	Comments	The trial had 80% power to detect a 35% reduction in genital shedding rates for acyclovir 400 mg twice daily.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, poisson
	Comments	Adjusted for period effects.
Method of Estimation	Estimation Parameter	Incidence Risk Ratio
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	No Medication, Acyclovir 400 mg Twice Daily
	Comments	Among HIV seronegative individuals.
	Type of Statistical Test	Superiority
	Comments	Adjusted for period effects.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Poisson
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	No Medication, Acyclovir 400 mg Twice Daily
	Comments	Among HIV seropositive individuals.
	Type of Statistical Test	Superiority
	Comments	Adjusted for period effects.
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Poisson
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; 0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Quantity of HSV Detected, Median
Description	Median quantity of HSV detected, among swabs with any HSV detected
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

The number of swabs with HSV detected was analyzed. This is a subset of overall numbers of swabs collected, since not all swabs had HSV detected.

Arm/Group Title	No Medication	Acyclovir 400 mg Twice Daily
Arm/Group Description
Measure Participants	38	38
Measure Swabs	587	120
HIV seronegative	3.3	2.9
HIV seropositive	5.4	3.3

3. Secondary Outcome

Title	Number of Genital HSV Shedding Episodes
Description	The number of HSV shedding episodes. A shedding episode is defined as any number of positive swabs preceded and followed by 2 negative swabs
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

The number of participants analyzed is the same as the overall number. No participants were excluded from this analysis.

Arm/Group Title	No Medication	Acyclovir 400 mg Twice Daily
Arm/Group Description
Measure Participants	38	38
HIV seronegative	49	17
HIV seropositive	20	17

4. Secondary Outcome

Title	Duration of Genital HSV Shedding Episodes
Description	Median duration of HSV shedding episodes, in hours
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

Only episodes of known duration were included

Arm/Group Title	No Medication	Acyclovir 400 mg Twice Daily
Arm/Group Description
Measure Participants	38	38
Measure Episodes	56	33
HIV seronegative	13	7
HIV seropositive	6	8

Adverse Events

Time Frame	Adverse event data was collected during the 9 week study period.
Adverse Event Reporting Description	Adverse event data is reported only for 38 participants who completed both arms the trial.
Arm/Group Title	No Medication		Acyclovir 400 mg Twice Daily
Arm/Group Description
All Cause Mortality
	No Medication		Acyclovir 400 mg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	No Medication		Acyclovir 400 mg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	No Medication		Acyclovir 400 mg Twice Daily
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/38 (0%)

Limitations/Caveats

The study was performed at a single site and enrolled a mostly white population. Whether these results are generalizable to other populations is not known.

More Information

Certain Agreements

Principal Investigators are NOT 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.