Genital Herpes
Conditions
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.
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.
Interventions
DRUGacyclovir
Acyclovir 400 mg PO BID for 28 days
Sponsors
National Institutes of Health (NIH)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Quantity of HSV Detected, Median | 9 weeks | Median quantity of HSV detected, among swabs with any HSV detected |
| 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 |
| Duration of Genital HSV Shedding Episodes | 9 weeks | Median duration of HSV shedding episodes, in hours |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| No Medication | 25 |
| Acyclovir 400 mg Twice Daily | 23 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention | Lost to Follow-up | 7 | 3 |
Baseline characteristics
| Characteristic | No Medication | Acyclovir 400 mg Twice Daily | Total |
|---|---|---|---|
| Age, Continuous | 46.6 years STANDARD_DEVIATION 12.3 | 42.1 years STANDARD_DEVIATION 13.1 | 44.4 years STANDARD_DEVIATION 12.7 |
| HIV serostatus HIV seronegative | 16 Participants | 16 Participants | 32 Participants |
| HIV serostatus HIV seropositive | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 5 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 16 Participants | 33 Participants |
| Sex: Female, Male Female | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 38 | 0 / 38 |
| serious Total, serious adverse events | 0 / 38 | 0 / 38 |
Outcome results
Primary
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
Population: Participants collected at least one swab on each study arm
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| No Medication | 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. | HIV seronegative | 24 percentage of swabs with HSV detected |
| No Medication | 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. | HIV seropositive | 15 percentage of swabs with HSV detected |
| Acyclovir 400 mg Twice Daily | 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. | HIV seronegative | 3 percentage of swabs with HSV detected |
| Acyclovir 400 mg Twice Daily | 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. | HIV seropositive | 7 percentage of swabs with HSV detected |
Comparison: The trial had 80% power to detect a 35% reduction in genital shedding rates for acyclovir 400 mg twice daily.p-value: <0.00195% CI: [0.17, 0.25]Regression, poisson
Comparison: Among HIV seronegative individuals.p-value: <0.00195% CI: [0.03, 0.08]Regression, Poisson
Comparison: Among HIV seropositive individuals.p-value: <0.00195% CI: [0.4, 0.6]Regression, Poisson
Secondary
Duration of Genital HSV Shedding Episodes
Median duration of HSV shedding episodes, in hours
Time frame: 9 weeks
Population: Only episodes of known duration were included
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| No Medication | Duration of Genital HSV Shedding Episodes | HIV seronegative | 13 Hours |
| No Medication | Duration of Genital HSV Shedding Episodes | HIV seropositive | 6 Hours |
| Acyclovir 400 mg Twice Daily | Duration of Genital HSV Shedding Episodes | HIV seronegative | 7 Hours |
| Acyclovir 400 mg Twice Daily | Duration of Genital HSV Shedding Episodes | HIV seropositive | 8 Hours |
Secondary
Number of Genital HSV Shedding Episodes
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
Population: The number of participants analyzed is the same as the overall number. No participants were excluded from this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| No Medication | Number of Genital HSV Shedding Episodes | HIV seronegative | 49 Episodes |
| No Medication | Number of Genital HSV Shedding Episodes | HIV seropositive | 20 Episodes |
| Acyclovir 400 mg Twice Daily | Number of Genital HSV Shedding Episodes | HIV seronegative | 17 Episodes |
| Acyclovir 400 mg Twice Daily | Number of Genital HSV Shedding Episodes | HIV seropositive | 17 Episodes |
Secondary
Quantity of HSV Detected, Median
Median quantity of HSV detected, among swabs with any HSV detected
Time frame: 9 weeks
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| No Medication | Quantity of HSV Detected, Median | HIV seronegative | 3.3 log 10 copies/ml |
| No Medication | Quantity of HSV Detected, Median | HIV seropositive | 5.4 log 10 copies/ml |
| Acyclovir 400 mg Twice Daily | Quantity of HSV Detected, Median | HIV seronegative | 2.9 log 10 copies/ml |
| Acyclovir 400 mg Twice Daily | Quantity of HSV Detected, Median | HIV seropositive | 3.3 log 10 copies/ml |