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Trial record 29 of 35 for:    " August 29, 2007":" September 28, 2007"[FIRST-RECEIVED-DATE]AND HIV[CONDITION]

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

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ClinicalTrials.gov Identifier: NCT00527618
Recruitment Status : Completed
First Posted : September 11, 2007
Results First Posted : July 31, 2012
Last Update Posted : June 7, 2018
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Jared Baeten, University of Washington

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Genital Herpes
HIV Infection
Interventions Drug: valacyclovir
Drug: acyclovir
Enrollment 28

Recruitment Details We recruited HIV-1/HSV-2 coinfected patients in Seattle, WA, between January 2008 and June 2010.
Pre-assignment Details 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
Hide 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 [1] 18 [2]
Completed 13 [1] 16 [3]
Not Completed 3 2
Reason Not Completed
Lost to Follow-up             3             1
Adverse Event             0             1
[1]
Acyclovir
[2]
Valacyclovir; one participant was removed from the study due to urticaria after 2.5 weeks
[3]
Valacyclovir
Period Title: Week 13-14 (Washout)
Started 13 16
Completed 12 16
Not Completed 1 0
Reason Not Completed
Lost to Follow-up             1             0
Period Title: Week 15-18 (Second Intervention)
Started 12 [1] 16 [2]
Completed 12 [1] 13 [2]
Not Completed 0 3
Reason Not Completed
Lost to Follow-up             0             1
Censored on initiation of HAART             0             1
Withdrawal by Subject             0             1
[1]
Valacyclovir
[2]
Acyclovir
Arm/Group Title Entire Study Population
Hide 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 Number of Baseline Participants 34
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 34 participants
43
(24 to 66)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants
Female
6
  17.6%
Male
28
  82.4%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 34 participants
Caucasian 23
African-American 9
Other 2
CD4 Count  
Mean (Full Range)
Unit of measure:  Cells/microliter
Number Analyzed 34 participants
526
(73 to 1094)
Plasma HIV-1 RNA  
Mean (Full Range)
Unit of measure:  Log10 copies/mL
Number Analyzed 34 participants
3.84
(1.17 to 6.93)
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.
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 27 27
Median (Full Range)
Unit of Measure: log10 copies/mL
4.08
(1.17 to 5.33)
3.68
(1.17 to 4.99)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
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
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.
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 28 28
Measure Type: Number
Unit of Measure: percentage of swabs collected with HSV
8.2 7.8
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value 0.78
Comments [Not Specified]
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
Estimation Comments [Not Specified]
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.
Hide 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)
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 28 28
Measure Type: Number
Unit of Measure: percentage of days with genital lesions
4.0 1.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Acyclovir, Valacyclovir
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.16
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
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.
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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)
Overall Number of Participants Analyzed 28 28
Median (Full Range)
Unit of Measure: log10 copies/mL
3.0
(2.2 to 6.4)
3.0
(2.2 to 6.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Acyclovir, Valacyclovir
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.67
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
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.
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide Arm/Group Description:
Valacyclovir, 1000 mg orally twice daily
Overall Number of Participants Analyzed 10
Mean (95% Confidence Interval)
Unit of Measure: log10 copies/mL/day
-0.20
(-0.38 to -0.19)
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
Hide 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 (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Acyclovir Valacyclovir
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/32 (3.13%)      0/30 (0.00%)    
Blood and lymphatic system disorders     
Neutropenia  [1]  1/32 (3.13%)  1 0/30 (0.00%)  0
Indicates events were collected by systematic assessment
[1]
One participant developed neutropenia on acyclovir: nadir ANC 570 cells/µL. This was thought to be related to concomitant interferon use. With cessation of interferon, the ANC normalized remaining normal with 12 weeks of high-dose valacyclovir.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Acyclovir Valacyclovir
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/32 (12.50%)      3/30 (10.00%)    
Gastrointestinal disorders     
Nausea   3/32 (9.38%)  3 1/30 (3.33%)  2
Diarrhea   0/32 (0.00%)  0 2/30 (6.67%)  2
Infections and infestations     
Upper Resipiratory Tract Infection   4/32 (12.50%)  4 3/30 (10.00%)  3
Nervous system disorders     
Headache   2/32 (6.25%)  2 1/30 (3.33%)  1
Psychiatric disorders     
Depression   0/32 (0.00%)  0 2/30 (6.67%)  2
Reproductive system and breast disorders     
Yeast vaginitis   1/32 (3.13%)  3 2/30 (6.67%)  3
Respiratory, thoracic and mediastinal disorders     
Cough   0/32 (0.00%)  0 2/30 (6.67%)  2
Indicates events were collected by systematic assessment
Our findings are limited by the high loss to follow up, which is especially problematic in cross-over studies.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Tara Perti, MD
Organization: University of Washington, Virology Research Clinic
Phone: (206) 520-4340
Responsible Party: Jared Baeten, University of Washington
ClinicalTrials.gov Identifier: NCT00527618     History of Changes
Other Study ID Numbers: 31203
GSK VAL111009 - VAL140 ( Other Grant/Funding Number: GlaxoSmithKline )
First Submitted: September 7, 2007
First Posted: September 11, 2007
Results First Submitted: June 26, 2012
Results First Posted: July 31, 2012
Last Update Posted: June 7, 2018