Genital Herpes, HIV Infection
Conditions
Keywords
Herpes Simplex Virus Type 2, Human Immunodeficiency Virus, Treatment Naive
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.
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.
Interventions
DRUGvalacyclovir
valacyclovir 1000 mg orally twice daily for 12 weeks.
DRUGacyclovir
acyclovir 400 mg orally twice daily for 12 weeks.
Sponsors
GlaxoSmithKline
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population 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. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Week 1-12 (First Intervention) | Adverse Event | 0 | 1 |
| Week 1-12 (First Intervention) | Lost to Follow-up | 3 | 1 |
| Week 13-14 (Washout) | Lost to Follow-up | 1 | 0 |
| Week 15-18 (Second Intervention) | Censored on initiation of HAART | 0 | 1 |
| Week 15-18 (Second Intervention) | Lost to Follow-up | 0 | 1 |
| Week 15-18 (Second Intervention) | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 43 Years |
| CD4 Count | 526 cells/microliter |
| Plasma HIV-1 RNA | 3.84 log10 copies/mL |
| Race/Ethnicity, Customized African-American | 9 participants |
| Race/Ethnicity, Customized Caucasian | 23 participants |
| Race/Ethnicity, Customized Other | 2 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 32 | 3 / 30 |
| serious Total, serious adverse events | 1 / 32 | 0 / 30 |
Outcome results
Primary
The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir.
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Acyclovir | The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. | 8.2 percentage of swabs collected with HSV |
| Valacyclovir | The Genital HSV Shedding Rate While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. | 7.8 percentage of swabs collected with HSV |
Comparison: 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%.p-value: 0.7895% CI: [0.66, 1.37]Random effects poission regression
Primary
The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir.
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)
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir | The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. | 4.08 log10 copies/mL |
| Valacyclovir | The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir. | 3.68 log10 copies/mL |
Comparison: 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%.p-value: <0.00195% CI: [-0.41, -0.14]Mixed Models Analysis
Secondary
Sub-Study: To Evaluate the Kinetics of Plasma HIV-1 Decline Over the First Three Days of High-dose Valacyclovir Administration.
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Acyclovir | Sub-Study: To Evaluate the Kinetics of Plasma HIV-1 Decline Over the First Three Days of High-dose Valacyclovir Administration. | -0.20 log10 copies/mL/day |
Secondary
The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions.
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Acyclovir | The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions. | 4.0 percentage of days with genital lesions |
| Valacyclovir | The Effect of Valacyclovir 1 Gram Twice Daily Compared to Acyclovir 400 mg Twice Daily on the Percentage of Days With Genital Herpes Lesions. | 1.0 percentage of days with genital lesions |
p-value: 0.16Wilcoxon (Mann-Whitney)
Secondary
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.
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Acyclovir | 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. | 3.0 log10 copies/mL |
| Valacyclovir | 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. | 3.0 log10 copies/mL |
p-value: 0.67Mixed Models Analysis