Trial to Study the Effect of Dose of Herpes Simplex Virus-2 (HSV-2) Suppressive Therapy on HSV and HIV

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00527618
• Collaborator: GlaxoSmithKline (Industry)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 39
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

To compare the effect of high-dose valacyclovir (1 gram orally twice daily) versus standard-dose acyclovir (400 mg orally twice daily) on the frequency of genital HSV reactivation and on plasma HIV-1 levels among HSV-2/HIV-1 co-infected individuals. The investigators hypothesize that high-dose valacyclovir will result in greater reduction in plasma HIV-1 and genital HSV reactivation.

Condition or Disease	Intervention/Treatment	Phase
Genital Herpes; HIV Infection	Drug: valacyclovir; Drug: acyclovir	Phase 4

Detailed Description

We propose to conduct a randomized, open-label, cross-over study of 38 individuals who are HIV-1 seropositive and HSV-2 seropositive. Both men and women will be recruited for the study. Participants must not be on antiretroviral therapy and must not be planning to initiate antiretroviral therapy during the anticipated study period. Participants will be randomized 1:1 to receive acyclovir 400 mg twice daily or valacyclovir 1000 mg twice daily. After 12 weeks on the initial treatment, each participant will be crossed over to the alternative treatment arm for 12 weeks. The treatment periods will be separated by a 2-week washout period. During the first four weeks of each treatment period (i.e. weeks 1-4 and weeks 15-18), participants will provide self-collected genital swabs daily for HSV DNA quantification. Each week during the entire study period plasma samples will be collected from participants for HIV-1 RNA quantification.

Open-label acyclovir and valacyclovir will be used for this trial, as the primary outcome measures (genital HSV and plasma HIV-1) are unlikely to be influenced by knowledge of treatment assignment. However, laboratory staff performing plasma HIV-1 and genital HSV measurements will not be aware of treatment assignment.

Optional Sub-Study A: Sub-study A will be offered to study participants. The purpose of sub-study A is to measure the effect of valacyclovir twice daily on plasma HIV-1 replication.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Crossover Trial of the Effect of Dosing of Daily HSV-2 Suppressive Therapy on HSV Reactivation and Plasma HIV-1 Levels Among HIV-1/ HSV-2 Co-infected Persons
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard-dose acyclovir acyclovir 400 mg orally twice daily for 12 weeks.	Drug: acyclovir; acyclovir 400 mg orally twice daily for 12 weeks.; Other Names: Zovirax
Experimental: High-dose valacyclovir valacyclovir 1000 mg orally twice daily for 12 weeks.	Drug: valacyclovir; valacyclovir 1000 mg orally twice daily for 12 weeks.; Other Names: Valtrex

Outcome Measures

Primary Outcome Measures

1. The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. [26 weeks (12 weeks per drug intervention)]

   Weekly measurements of plasma HIV-1 RNA on each drug were compared. The primary analysis was of the average difference in plasma HIV-1 RNA on valacyclovir and acyclovir as determined by a linear mixed model. The median of the average per-participant plasma HIV-1 RNA levels on valacyclovir and valacyclovir is also listed.

2. The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. [The first four weeks of each intervention]

   HSV DNA quantitated from daily self-collected genital swabs for the first four weeks of each drug intervention. The shedding rate was determined by the combined number of swabs with HSV detected divided by the combined number of swabs collected from participants, multiplied by 100.

Secondary Outcome Measures

1. The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions. [26 weeks (12 weeks per drug intervention)]

   The percentage of days with genital herpes lesions was determined by the combined diary days in which genital lesions were recorded divided by the combined number of diary days for participants in the first four weeks of each drug intervention, multiplied by 100.

2. The Effect of Valacyclovir 1 g Twice Daily Compared With Acyclovir 400 mg Twice Daily on the Quantity of Genital HSV Detected During Shedding Episodes. [The first four weeks of each intervention]

   HSV DNA was quantitated from daily self-collected genital swabs for the four weeks of each drug intervention. The quantity of genital HSV DNA present, when HSV DNA was detected, was compared.

3. Sub-Study: To Evaluate the Kinetics of Plasma HIV-1 Decline Over the First Three Days of High-dose Valacyclovir Administration. [72 hours]

   Plasma HIV-1 RNA was measured one day prior to, at initiation, and at 6, 24, 48, and 72 hours after initiating valacyclovir. Measurements at 24, 48, and 72 hours were used to determine the rate of HIV-1 RNA decline.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age 18 years or older

• Documented HIV-1 seropositive

• Not on HIV-1 antiretroviral therapy nor planning to initiate antiretroviral therapy during the study period

• Detectable HIV-1 plasma viral load

• HSV-2 seropositive as determined by western blot

• Not intending to move out of the area for the duration of study participation

• Willing and able to provide independent written informed consent

• Willing and able to undergo clinical evaluations

• Willing and able to take study drug as directed

• Willing and able to adhere to follow-up schedule

Exclusion Criteria:

• Known history of adverse reaction to acyclovir, valacyclovir, or famciclovir

• Planned open label use of acyclovir, valacyclovir, or famciclovir

• History of evidence of CMV disease

• Known medical history of seizures

• Known renal insufficiency, defined as serum creatinine greater than 1.5 mg/dl

• AST or ALT greater than 3 times upper limit of normal

• Hematocrit less than 30 %

• Neutropenia, defined as absolute neutrophil count less than 1000

• Thrombocytopenia, defined as platelet count less than 75,000

• History of thrombotic microangiopathy

• For women, pregnancy as confirmed by a urine pregnancy test

• Any other condition which, in the opinion of the principal investigator, may compromise the ability to follow study procedures and complete the study

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
• GlaxoSmithKline

Investigators

• Principal Investigator: Jared Baeten, MD, PhD, University of Washington
• Study Director: Anna Wald, MD, MPH, University of Washington

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jared Baeten, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT00527618
• Other Study ID Numbers: 31203; GSK VAL111009 - VAL140
• First Posted: Sep 11, 2007
• Last Update Posted: Jun 7, 2018
• Last Verified: May 1, 2018

• Keywords provided by Jared Baeten, Principal Investigator, University of Washington: Herpes Simplex Virus Type 2; Human Immunodeficiency Virus; Treatment Naive
• Additional relevant MeSH terms: Herpes Simplex; Herpes Genitalis; Valacyclovir; Acyclovir

Study Results

Participant Flow

Recruitment Details	We recruited HIV-1/HSV-2 coinfected patients in Seattle, WA, between January 2008 and June 2010.
Pre-assignment Detail	Of 49 persons screened, 15 were found to be ineligible for reasons including lack of HSV-2 infection (n=5), plans to initiate ART (n=3), undetectable plasma HIV-1 RNA (n=3), neutropenia (n=2), elevated hepatic transaminases (n=1), and incarceration (n=1). The remaining 34 participants were randomized.

Arm/Group Title	Acyclovir Followed by Valacyclovir	Valacyclovir Followed by Acyclovir
Arm/Group Description	Acyclovir 400 mg twice daily, followed by a two-week washout period, then valacyclovir 1000 mg twice daily	Valacyclovir 1000 mg twice daily, followed by a two-week washout period, then acyclovir 400 mg twice daily
Period Title: Week 1-12 (First Intervention)
STARTED	16	18
COMPLETED	13	16
NOT COMPLETED	3	2
Period Title: Week 1-12 (First Intervention)
STARTED	13	16
COMPLETED	12	16
NOT COMPLETED	1	0
Period Title: Week 1-12 (First Intervention)
STARTED	12	16
COMPLETED	12	13
NOT COMPLETED	0	3

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	This includes all 34 participants who were randomized. A subset of 28 participants were included in the analysis since only 28 participants contributed samples on both arms of the crossover study.
Overall Participants	34
Age (Years) [Mean (Full Range) ]
Mean (Full Range) [Years]	43
Sex: Female, Male (Count of Participants)
Female	6 17.6%
Male	28 82.4%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	23 67.6%
African-American	9 26.5%
Other	2 5.9%
CD4 Count (cells/microliter) [Mean (Full Range) ]
Mean (Full Range) [cells/microliter]	526
Plasma HIV-1 RNA (log10 copies/mL) [Mean (Full Range) ]
Mean (Full Range) [log10 copies/mL]	3.84

Outcome Measures

1. Primary Outcome

Title	The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir.
Description	Weekly measurements of plasma HIV-1 RNA on each drug were compared. The primary analysis was of the average difference in plasma HIV-1 RNA on valacyclovir and acyclovir as determined by a linear mixed model. The median of the average per-participant plasma HIV-1 RNA levels on valacyclovir and valacyclovir is also listed.
Time Frame	26 weeks (12 weeks per drug intervention)

Outcome Measure Data

Analysis Population Description

Of the 34 participants who were randomized, 6 participants did not contribute to both arms of the study. The final analysis set therefore included 28 participants. 27 participants had plasma HIV-1 RNA levels available for analysis, since samples for one participant were persistently inhibited.

Arm/Group Title	Acyclovir	Valacyclovir
Arm/Group Description	Acyclovir, 400 mg orally twice daily (assigned to the acyclovir arm in either the first or second intervention periods)	Valacyclovir, 1000 mg orally twice daily (assigned to the valacyclovir arm in either the first or second intervention periods)
Measure Participants	27	27
Median (Full Range) [log10 copies/mL]	4.08	3.68

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir, Valacyclovir
	Comments	We estimated that a sample size of 29 participants, with 4 weeks of weekly plasma HIV-1 RNA levels per treatment arm, would be required to detect a 0.25 log10 copies/ml difference in plasma HIV-1 RNA between the study arms with 80% power, at a two-sided type I error rate of 5%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Mixed Models Analysis
	Comments	Adjusted for baseline plasma HIV-1 RNA.
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Acyclovir was coded as 0 and valacyclovir as 1. The beta-coefficient (slope) indicates the average difference in HIV-1 RNA on valacyclovir and acyclovir; a negative number indicates that plasma HIV-1 RNA was lower on valacyclovir than acyclovir.

2. Primary Outcome

Title	The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir.
Description	HSV DNA quantitated from daily self-collected genital swabs for the first four weeks of each drug intervention. The shedding rate was determined by the combined number of swabs with HSV detected divided by the combined number of swabs collected from participants, multiplied by 100.
Time Frame	The first four weeks of each intervention

Outcome Measure Data

Analysis Population Description

Of the 34 participants who were randomized, 6 participants did not contribute to both arms of the study. The final analysis set therefore included 28 participants.

Arm/Group Title	Acyclovir	Valacyclovir
Arm/Group Description	Acyclovir, 400 mg orally twice daily (assigned to the acyclovir arm in either the first or second intervention periods)	Valacyclovir, 1000 mg orally twice daily (assigned to the valacyclovir arm in either the first or second intervention periods)
Measure Participants	28	28
Number [percentage of swabs collected with HSV]	8.2	7.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir, Valacyclovir
	Comments	We estimated that 26 participants would be required to detect a 50% reduction in genital HSV shedding with 80% power, at a two-sided type I error rate of 5%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments
	Method	Random effects poission regression
	Comments	Adjusted for age.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions.
Description	The percentage of days with genital herpes lesions was determined by the combined diary days in which genital lesions were recorded divided by the combined number of diary days for participants in the first four weeks of each drug intervention, multiplied by 100.
Time Frame	26 weeks (12 weeks per drug intervention)

Outcome Measure Data

Analysis Population Description

Of the 34 participants who were randomized, 6 participants did not contribute to both arms of the study. The final analysis set therefore included 28 participants.

Arm/Group Title	Acyclovir	Valacyclovir
Arm/Group Description	Acyclovir, 400 mg orally twice daily (assigned to the acyclovir arm in either the first or second intervention periods)	Valacyclovir, 1000 mg orally twice daily (assigned to the valacyclovir arm in either the first or second intervention periods)
Measure Participants	28	28
Number [percentage of days with genital lesions]	4.0	1.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir, Valacyclovir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	The Effect of Valacyclovir 1 g Twice Daily Compared With Acyclovir 400 mg Twice Daily on the Quantity of Genital HSV Detected During Shedding Episodes.
Description	HSV DNA was quantitated from daily self-collected genital swabs for the four weeks of each drug intervention. The quantity of genital HSV DNA present, when HSV DNA was detected, was compared.
Time Frame	The first four weeks of each intervention

Outcome Measure Data

Analysis Population Description

Of the 34 participants who were randomized, 6 participants did not contribute to both arms of the study. The final analysis set therefore included 28 participants.

Arm/Group Title	Acyclovir	Valacyclovir
Arm/Group Description	Acyclovir, 400 mg orally twice daily (assigned to the acyclovir arm in either the first or second intervention periods)	Valacyclovir, 1000 mg orally twice daily (assigned to the valacyclovir arm in either the first or second intervention periods)
Measure Participants	28	28
Median (Full Range) [log10 copies/mL]	3.0	3.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir, Valacyclovir
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.67
	Comments
	Method	Mixed Models Analysis
	Comments

5. Secondary Outcome

Title	Sub-Study: To Evaluate the Kinetics of Plasma HIV-1 Decline Over the First Three Days of High-dose Valacyclovir Administration.
Description	Plasma HIV-1 RNA was measured one day prior to, at initiation, and at 6, 24, 48, and 72 hours after initiating valacyclovir. Measurements at 24, 48, and 72 hours were used to determine the rate of HIV-1 RNA decline.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

In April 2010, we invited participants, including those who already completed the study, to participate in the substudy. Two participants had plasma HIV-1 RNA <40 copies/mL at the time of valacyclovir initiation and were excluded from analysis.

Arm/Group Title	Valacyclovir
Arm/Group Description	Valacyclovir, 1000 mg orally twice daily
Measure Participants	10
Mean (95% Confidence Interval) [log10 copies/mL/day]	-0.20

Adverse Events

Time Frame	26 weeks
Adverse Event Reporting Description	Assessment of any adverse events was performed at each weekly clinic visit during the trial by a study investigator, including 12 weeks during acyclovir administration, 12 weeks during valacyclovir administration and 2 weeks during the washout period.
Arm/Group Title	Acyclovir		Valacyclovir
Arm/Group Description	Acyclovir, 400 mg orally twice daily (assigned to the acyclovir arm in either the first or second intervention periods)		Valacyclovir, 1000 mg orally twice daily (assigned to the valacyclovir arm in either the first or second intervention periods)
All Cause Mortality
	Acyclovir		Valacyclovir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Acyclovir		Valacyclovir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/32 (3.1%)		0/30 (0%)
Blood and lymphatic system disorders
Neutropenia	1/32 (3.1%)	1	0/30 (0%)	0
Other (Not Including Serious) Adverse Events
	Acyclovir		Valacyclovir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/32 (12.5%)		3/30 (10%)
Gastrointestinal disorders
Nausea	3/32 (9.4%)	3	1/30 (3.3%)	2
Diarrhea	0/32 (0%)	0	2/30 (6.7%)	2
Infections and infestations
Upper Resipiratory Tract Infection	4/32 (12.5%)	4	3/30 (10%)	3
Nervous system disorders
Headache	2/32 (6.3%)	2	1/30 (3.3%)	1
Psychiatric disorders
Depression	0/32 (0%)	0	2/30 (6.7%)	2
Reproductive system and breast disorders
Yeast vaginitis	1/32 (3.1%)	3	2/30 (6.7%)	3
Respiratory, thoracic and mediastinal disorders
Cough	0/32 (0%)	0	2/30 (6.7%)	2

Limitations/Caveats

Our findings are limited by the high loss to follow up, which is especially problematic in cross-over studies.

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.