This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Trial to Study the Effect of Dose of Herpes Simplex Virus-2 (HSV-2) Suppressive Therapy on HSV and HIV (NCT00527618), a randomized phase 4 study. The primary outcome is The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00527618 |
| Phase | Phase 4 |
| Condition | Genital Herpes, HIV Infection |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | None (open label) |
| Enrollment | 28 |
| Arms in the primary outcome | 2 |
| Lead sponsor | University of Washington |
| Results posted | Yes |
2. Clinical Question
Population
People with HIV-1 and HSV-2 co-infection. The registry describes a final analysis set of 28 participants; plasma HIV-1 RNA was available for analysis for 27 participants because samples for one participant were persistently inhibited.
Intervention
High-dose valacyclovir: 1000 mg orally twice daily for 12 weeks.
Comparator
Standard-dose acyclovir: 400 mg orally twice daily for 12 weeks.
Primary question
How did plasma HIV-1 RNA levels, measured weekly, compare while participants received valacyclovir versus acyclovir? The registry says the primary analysis compared the average difference in plasma HIV-1 RNA on the two drugs using a linear mixed model. The stated timeframe was 26 weeks, described as 12 weeks per drug intervention.
The clinical question concerns a laboratory measure of HIV-1 in plasma and the comparison of two HSV-2 suppressive regimens. The registry also identifies genital HSV reactivation as an outcome of interest, and lists secondary outcomes concerning days with genital lesions, HSV detected during shedding episodes, and the kinetics of plasma HIV-1 decline after starting high-dose valacyclovir. Those outcomes are distinct from the primary comparison. The posted primary result therefore addresses the plasma HIV-1 RNA comparison, not every aspect of HSV activity or every secondary question. The record does not report a separate primary endpoint result for genital HSV reactivation.
3. Trial Design
This was a randomized, open-label, crossover trial, listed as phase 4 and completed. The University of Washington is named as sponsor. The registry gives a start date of 2007-12 and a primary completion date of 2011-03. Enrollment is listed as 28, while the primary outcome description says that 34 participants were randomized. It further reports that 6 participants did not contribute to both arms and that the final analysis set included 28 participants. These are different enrollment and analysis descriptions in the record and should not be conflated.
In a crossover study, participants receive more than one study condition, so comparisons can use measurements collected from the same participant under each condition. Here, the two regimens were acyclovir 400 mg orally twice daily for 12 weeks and valacyclovir 1000 mg orally twice daily for 12 weeks. The stated primary timeframe was 26 weeks, described as 12 weeks per drug intervention. Weekly plasma HIV-1 RNA measurements on each drug were compared.
Randomization means treatment assignment was allocated by chance, but the registry does not report the allocation sequence, treatment order, or whether the order was balanced. Masking was listed as none, indicating an open-label design. The registry record does not report a washout interval, details of adherence assessment, or how the analysis addressed possible period or carryover effects. It also does not report a detailed statistical analysis plan. The crossover structure is relevant when interpreting the repeated measurements and when considering whether effects of one treatment period might influence measurements in another.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: 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.
Week 1-12 (First Intervention)
| Stage | Acyclovir Followed by Valacyclovir | Valacyclovir Followed by Acyclovir |
|---|---|---|
| STARTED | 16 | 18 |
| COMPLETED | 13 | 16 |
| NOT COMPLETED | 3 | 2 |
Reasons for not completing this period:
| Reason | Acyclovir Followed by Valacyclovir | Valacyclovir Followed by Acyclovir |
|---|---|---|
| Lost to Follow-up | 3 | 1 |
| Adverse Event | 0 | 1 |
Week 13-14 (Washout)
| Stage | Acyclovir Followed by Valacyclovir | Valacyclovir Followed by Acyclovir |
|---|---|---|
| STARTED | 13 | 16 |
| COMPLETED | 12 | 16 |
| NOT COMPLETED | 1 | 0 |
Reasons for not completing this period:
| Reason | Acyclovir Followed by Valacyclovir | Valacyclovir Followed by Acyclovir |
|---|---|---|
| Lost to Follow-up | 1 | 0 |
Week 15-18 (Second Intervention)
| Stage | Acyclovir Followed by Valacyclovir | Valacyclovir Followed by Acyclovir |
|---|---|---|
| STARTED | 12 | 16 |
| COMPLETED | 12 | 13 |
| NOT COMPLETED | 0 | 3 |
Reasons for not completing this period:
| Reason | Acyclovir Followed by Valacyclovir | Valacyclovir Followed by Acyclovir |
|---|---|---|
| Lost to Follow-up | 0 | 1 |
| Censored on initiation of HAART | 0 | 1 |
| Withdrawal by Subject | 0 | 1 |
Analysis population for the primary outcome, as defined in the registry: 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.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Entire Study Population |
|---|---|---|
| Participants analysed | 34 | |
| Age, Continuous | Years | 43 (24 to 66) |
| Sex: Female, Male: Female | Participants | 6 |
| Sex: Female, Male: Male | Participants | 28 |
| Race/Ethnicity, Customized: Caucasian | participants | 23 |
| Race/Ethnicity, Customized: African-American | participants | 9 |
| Race/Ethnicity, Customized: Other | participants | 2 |
| CD4 Count | cells/microliter | 526 (73 to 1094) |
| Plasma HIV-1 RNA | log10 copies/mL | 3.84 (1.17 to 6.93) |
6. Primary Endpoint
The registry lists the primary outcome as The Quantity of HIV-1 RNA in Plasma While on 400 mg Twice Daily of Acyclovir Versus 1000 mg Twice Daily of Valacyclovir., measured over 26 weeks (12 weeks per drug intervention).
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | Full Range |
| Unit | log10 copies/mL |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the quantity of HIV-1 RNA in plasma while participants were receiving acyclovir 400 mg twice daily versus valacyclovir 1000 mg twice daily. The unit was log10 copies/mL. Plasma HIV-1 RNA is a laboratory measure of the amount of viral RNA detected in plasma; the endpoint therefore describes a measured biological quantity, rather than a clinical event or a symptom report.
The registry says measurements were taken weekly on each drug and that the primary analysis compared the average difference in plasma HIV-1 RNA using a linear mixed model. Repeated observations can describe both the participant’s measurements over time and the contrast between treatment periods. The registry also reports per-arm median values and full ranges for the available measurements. These summaries provide a description of the observed values, while the mixed-model estimate is the stated primary inferential comparison.
In general, a laboratory endpoint can be useful when a study seeks to compare biological activity and can collect repeated measurements during treatment. It does not, by itself, establish effects on symptoms, transmission, long-term outcomes, or other endpoints. The record’s primary endpoint is specifically plasma HIV-1 RNA; the listed genital herpes outcomes are secondary questions and should be interpreted separately.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted arm summaries list a median plasma HIV-1 RNA value of 4.08 log10 copies/mL for acyclovir and 3.68 log10 copies/mL for valacyclovir. The reported full ranges were 1.17 to 5.33 for acyclovir and 1.17 to 4.99 for valacyclovir. These are descriptive summaries of the available measurements, not the primary model estimate. The registry reports 27 participants in each arm’s endpoint summary.
The primary inferential result is a mixed-model slope of -0.27, with a 95% confidence interval from -0.41 to -0.14 and p < 0.001. The record labels the parameter as a slope, but does not explain the sign convention or give further operational detail about that parameter. The estimate should therefore be read with that reporting limitation in mind. The registry describes the underlying analysis as a comparison of average plasma HIV-1 RNA on valacyclovir and acyclovir, based on weekly measurements.
A confidence interval expresses the precision of an estimate under the model and analysis used. In general, a narrower interval indicates greater precision than a wider one, while an interval still reflects uncertainty rather than certainty about the underlying effect. The reported interval is entirely below zero. The p-value describes how incompatible the observed result is with a specified null model under the assumptions of the analysis; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. The registry does not report a clinical threshold for interpreting the size of the model estimate.
The arm medians and the model result answer related but not identical descriptive and inferential questions. A median summarizes the middle of observed values, whereas the mixed model uses the repeated measurements and reports a slope parameter. Their numerical forms should not be treated as interchangeable. The registry does not provide enough detail to reconstruct the model specification, verify its assumptions, or translate the slope into a more intuitive scale.
The result pertains to this randomized crossover comparison and the plasma HIV-1 RNA measurements available for analysis. It should not be generalized automatically to other populations, dosing regimens, outcomes, or follow-up periods. The record also lists genital herpes outcomes, but the primary result is not a direct estimate for lesion days, shedding, or HSV reactivation.
9. Statistical Methods Explained
Why use a crossover comparison?
In general, a crossover design gives participants exposure to more than one study condition, with measurements collected during the relevant periods. Because a participant contributes observations under both conditions, some stable differences between participants may be controlled by comparing measurements within the same person. That feature can be useful for outcomes with repeated measurement. It does not remove every source of bias: treatment order, changes over time, or effects that persist from one period into another can matter. The registry identifies a randomized crossover design but does not report the treatment sequence, a washout interval, or details of any assessment of carryover or period effects.
What does the mixed model contribute?
The registry says weekly plasma HIV-1 RNA measurements on each drug were analyzed with a linear mixed model, and describes the primary analysis as the average difference in plasma HIV-1 RNA on valacyclovir and acyclovir. In general, mixed models are used for data with repeated observations, because measurements from the same participant are usually related rather than independent. A model can account for that dependence while estimating a comparison across treatment conditions. The exact model structure matters: for example, which terms were included and how within-participant correlation was represented. Those specifications are not reported in the registry record, so the model cannot be fully assessed or reproduced from the record alone.
How should the reported estimate be read?
The registry reports the model parameter as a slope with an estimate of -0.27 and a 95% confidence interval from -0.41 to -0.14. A slope is a model parameter, but the record does not define precisely how it was coded or explain its sign convention. The estimate and interval can be reported as the sponsor’s posted model result, but the sign should not be assigned a treatment direction beyond what the record explicitly explains. The record does describe the comparison as average plasma HIV-1 RNA on the two drugs.
In general, a confidence interval represents a range of values compatible with the data and model at the stated confidence level. It conveys uncertainty around an estimate, not a guarantee that the true value lies within that particular interval. A p-value addresses how unusual the data or a more extreme result would be under a specified null hypothesis and statistical model. The posted p-value is < 0.001. It does not express the probability that a treatment effect is absent, and it does not determine whether a difference is important to patients or clinically meaningful.
Why also report medians and ranges?
The registry gives median values of 4.08 log10 copies/mL for acyclovir and 3.68 log10 copies/mL for valacyclovir, with full ranges of 1.17 to 5.33 and 1.17 to 4.99, respectively. These summaries describe the distribution of measured values in each arm. A median is less affected by extreme values than a mean, while a full range displays the minimum and maximum. Neither summary, on its own, accounts for the crossover pairing or gives the model-based uncertainty for the treatment comparison. They should be interpreted as descriptive context alongside, not in place of, the stated primary model analysis.
What can be said about model assumptions?
Linear mixed models rely on assumptions about the relationship represented by the model, the distribution of residual variation, and the dependence among repeated measurements. In general, checking those assumptions helps assess whether the model’s estimate and uncertainty are credible. The registry record does not report diagnostic checks, the detailed covariance structure, or sensitivity analyses. It also does not provide a separate analysis by treatment sequence or period. These omissions limit independent evaluation of whether the reported model fully reflects the trial’s repeated-measures structure.
For outcomes with over-dispersion, in general, the observed variability exceeds what a simpler model assumes. A model that allows for extra variability can avoid overstating precision. This endpoint is continuous and reported in log10 copies/mL, and the record does not describe an over-dispersion adjustment. It would not be appropriate to infer one from the mixed-model label.
What is not an observed result?
Sample-size illustrations, when presented, are planning exercises based on assumptions and an effect to detect; they are not measurements from trial participants and are not observed power. The record describes planning assumptions but does not report numerical sample-size illustration results in the registry record for this analysis. Such planning calculations should not be confused with the completed trial’s enrollment or the number included in the endpoint analysis. Likewise, the registry does not report a separate interim analysis plan or a detailed prospective statistical plan.
10. Analyses Reported by the Sponsor
| Method | Estimate | 95% CI | P-value |
|---|---|---|---|
| Mixed Models Analysis | Slope -0.27 | -0.41 to -0.14 | < 0.001 |
The registry’s primary inferential result is the sponsor-reported mixed-model analysis: slope -0.27, 95% confidence interval -0.41 to -0.14, p < 0.001. The posted description says the analysis compared average plasma HIV-1 RNA on valacyclovir and acyclovir using weekly measurements. The arm-level medians and full ranges are descriptive summaries, not an independent recalculation of that mixed-model analysis.
A separate recalculated inferential estimate is not reported in the registry record. The model’s full specification, including details needed to reproduce its treatment contrast and uncertainty, is also not reported. Consequently, the posted model result is the available primary analysis, while the arm summaries provide a separate view of the observed measurements. A median-based comparison would not reproduce the stated mixed-model analysis because it would not use the same model or necessarily the same treatment of repeated observations.
The record does not flag a discrepancy between a recalculation and the sponsor analysis. Without a separately reported recalculated result, there is no second estimate to compare numerically with the sponsor’s result. Interpretation should preserve the registry’s description of the parameter as a slope and its stated uncertainty, while recognizing that the sign convention and detailed model specification are not reported.
11. Multiplicity, Missing Data and Analysis Populations
The registry lists 5 outcome measures and 4 analyses, and identifies 3 posted secondary outcomes. These include the percentage of days with genital herpes lesions, the quantity of genital HSV detected during shedding episodes, and a sub-study of the kinetics of plasma HIV-1 decline over the first three days of high-dose valacyclovir administration. The primary endpoint is the plasma HIV-1 RNA comparison. Having several outcomes and analyses raises a general multiplicity issue: when many hypotheses are assessed, the chance of at least one apparently unusual result can increase. The registry record does not report a multiplicity adjustment, a prespecified hierarchy among secondary outcomes, or a detailed statistical analysis plan. It is therefore not possible to determine from the record whether or how multiple testing was handled.
The primary outcome description states that 34 participants were randomized, 6 did not contribute to both arms, and the final analysis set included 28 participants. It further says plasma HIV-1 RNA was available for 27 participants because one participant’s samples were persistently inhibited. The arm summaries each list 27 participants. The record does not describe how missing measurements within participants were handled, whether the mixed model used all available observations, or whether any imputation or sensitivity analysis was performed. It also does not give reasons for the 6 participants’ not contributing to both arms beyond that statement.
These analysis populations should be distinguished: randomized participants, participants in the final analysis set, and participants with plasma HIV-1 RNA available are described separately. The registry does not provide a full participant flow or clarify the exact contribution of each participant to each repeated-measures analysis. It also does not report an intention-to-treat analysis designation. These details affect how readers assess missingness and the scope of the primary estimate.
12. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Acyclovir | 1 | 32 | 3.1% |
| Valacyclovir | 0 | 30 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Acyclovir | 4 of 32 |
| Valacyclovir | 3 of 30 |
Most frequent serious adverse event terms
| Event term | Organ system | Acyclovir | Valacyclovir |
|---|---|---|---|
| Neutropenia | Blood and lymphatic system disorders | 1 of 32 | 0 of 30 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Acyclovir | Valacyclovir |
|---|---|---|---|
| Upper Resipiratory Tract Infection | Infections and infestations | 4 of 32 | 3 of 30 |
| Nausea | Gastrointestinal disorders | 3 of 32 | 1 of 30 |
| Headache | Nervous system disorders | 2 of 32 | 1 of 30 |
| Yeast vaginitis | Reproductive system and breast disorders | 1 of 32 | 2 of 30 |
| Cough | Respiratory, thoracic and mediastinal disorders | 0 of 32 | 2 of 30 |
| Diarrhea | Gastrointestinal disorders | 0 of 32 | 2 of 30 |
| Depression | Psychiatric disorders | 0 of 32 | 2 of 30 |
Serious events with the highest arm-level rate: neutropenia (3.1%).
The registry reports serious adverse events for 1 of 32 participants at risk in the acyclovir group and 0 of 30 at risk in the valacyclovir group. It lists other adverse events for 4 of 32 at risk in the acyclovir group and 3 of 30 at risk in the valacyclovir group. These are registry counts for the stated groups and should be read with their respective at-risk denominators, not as a direct estimate of comparative risk. The record does not provide a statistical comparison or uncertainty interval for these safety figures.
Neutropenia is listed as the top serious adverse event term, with 3.1%. The record does not specify the arm associated with that term in the registry record presented, so it should not be assigned to either regimen based on the listed group counts. Death counts are not reported in the registry record.
In general, adverse event summaries are descriptive, and interpretation depends on how events were defined, collected, and attributed, as well as on exposure and follow-up. The registry record does not provide detailed event definitions, timing, severity distributions, or an explanation of the relationship between the serious-event term and the group totals. The small group counts and missing details limit what can be inferred from these figures; they are not, by themselves, a complete comparative safety analysis.
13. What the Result Does, and Does Not, Mean
The posted primary result is a mixed-model comparison of weekly plasma HIV-1 RNA measurements during acyclovir and valacyclovir treatment. The model estimate is reported as a slope of -0.27, with a 95% confidence interval from -0.41 to -0.14 and p < 0.001. The record does not define the slope’s sign convention, so the estimate should not be translated into a treatment-direction statement beyond the registry’s description of the comparison.
The per-arm medians were 4.08 log10 copies/mL for acyclovir and 3.68 log10 copies/mL for valacyclovir, with full ranges of 1.17 to 5.33 and 1.17 to 4.99, respectively. These descriptive values show the reported distributions but do not replace the repeated-measures model. Nor do they establish that all participants had values in a particular range throughout treatment.
This result does not answer every question raised by the trial. It is not a direct estimate of the effects on genital lesions, HSV shedding, or HSV reactivation. The record’s listed secondary outcomes address some of those topics, but no numeric results for them are included in the registry record for this analysis. It also does not establish effects on clinical outcomes beyond the measured plasma HIV-1 RNA endpoint.
The trial was open label and used a crossover design. The registry does not report treatment sequence, washout details, or the model’s handling of period and carryover effects. The primary outcome data were not available for one participant because samples were persistently inhibited, and the record does not detail the handling of missing repeated measurements. These features and omissions constrain interpretation and generalization. Statistical evidence against a null model is not the same as evidence of clinical importance, and the record does not provide a threshold for judging the clinical meaning of the estimated slope.
14. Why This Trial Matters Statistically
This trial is statistically notable for combining a randomized crossover design with weekly measurements of a continuous laboratory outcome. Repeated observations can improve the description of how an endpoint behaves across treatment periods, and a within-participant comparison can account for some stable differences between participants. At the same time, these strengths depend on analysis choices that match the design and data structure.
The registry’s use of a linear mixed model is consistent with the general need to account for correlated repeated measurements. But a method label alone is not enough to assess a model. The record does not describe the covariance structure, treatment sequence, period effects, carryover assessment, or sensitivity analyses. Those details matter because crossover results may depend on how time and treatment order are represented.
The endpoint summaries and the model result also illustrate why descriptive and inferential statistics serve different roles. Medians and full ranges convey the observed distribution of plasma HIV-1 RNA measurements, while the mixed model is the stated primary analysis of the repeated measurements. Keeping those summaries distinct avoids treating a difference between arm medians as if it were the trial’s model-based estimate.
Finally, the record distinguishes randomized participants from the final analysis set and from participants with available plasma RNA measurements. Clear accounting of analysis populations and missing data is important in repeated-measures studies. The trial’s posted information makes some of that accounting visible but does not describe all data-handling decisions, limiting independent reproducibility.
15. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
Several trial-specific limitations affect interpretation. The study was open label, and the registry does not report whether treatment order was balanced or how treatment sequence was assigned. It does not describe a washout interval or report analyses addressing possible period or carryover effects, both relevant considerations for a crossover comparison. The primary outcome is a laboratory measure, and the posted primary result does not itself describe genital herpes manifestations or clinical outcomes.
The analysis population information is not fully reconciled in the record. Enrollment is listed as 28, while the primary endpoint description says 34 participants were randomized, 6 did not contribute to both arms, and the final analysis set included 28 participants. Plasma HIV-1 RNA was available for 27 because one participant’s samples were persistently inhibited. The record does not give a full participant flow or explain the handling of every missing measurement. The arm-level endpoint summaries list 27 participants each.
The mixed-model result is reported as a slope, but the registry does not define its sign convention or provide the full model specification. Details of the repeated-measures covariance structure, model diagnostics, sensitivity analyses, and treatment-period terms are not reported. The registry also does not report a detailed statistical analysis plan or explain whether multiplicity was addressed across the listed outcomes and analyses.
Generalizability is limited by the study’s stated population of people with HIV-1 and HSV-2 co-infection, the two specified regimens, and the stated intervention periods. The record does not provide results for the secondary outcomes in the registry record. These limitations do not negate the posted estimate, but they restrict how much can be concluded from it and how independently it can be evaluated.
16. Related Tutorials
17. Related Statistical Calculators
18. Sources
- ClinicalTrials.gov: Trial to Study the Effect of Dose of Herpes Simplex Virus-2 (HSV-2) Suppressive Therapy on HSV and HIV — NCT00527618.
- Registry record last updated 2018-06-07; status last verified 2018-05.
- Results first posted 2012-07-31.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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19. Record Summary
The registry describes a completed, randomized, open-label crossover trial comparing acyclovir 400 mg orally twice daily with valacyclovir 1000 mg orally twice daily, each for 12 weeks. The primary endpoint was weekly plasma HIV-1 RNA in log10 copies/mL, with a stated 26-week timeframe. The primary analysis was described as a linear mixed model comparing average values on the two drugs.
The posted model result was a slope of -0.27, with a 95% confidence interval from -0.41 to -0.14 and p < 0.001. Arm summaries reported medians of 4.08 for acyclovir and 3.68 for valacyclovir, alongside full ranges. The endpoint description reports that 34 participants were randomized, 28 were in the final analysis set, and plasma RNA was available for 27. Treatment-order details, full model specifications, and handling of missing repeated measurements are not reported in the registry record.