Tenofovir Alone Versus Tenofovir With Emtricitabine to Treat Chronic Hepatitis B: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Tenofovir Alone Versus Tenofovir With Emtricitabine to Treat Chronic Hepatitis B (NCT00524173), a randomized phase 2 study. The primary outcome is Number of Subjects With Hepatitis b Virus (HBV) DNA <1000 IU/ml at Week 48.

2. Clinical Question

The clinical question is whether adding emtricitabine to tenofovir changes the likelihood of reaching the specified HBV DNA threshold at Week 48. The posted primary outcome is a count of participants who met that threshold, rather than a comparison of average viral-load values or a time-to-event measure. It therefore describes the proportion meeting a defined criterion among those analyzed.

The registry’s brief description frames the study as testing whether the combination is safer and more effective than tenofovir alone. The primary endpoint concerns HBV DNA; safety is described separately through adverse-event counts. These are distinct questions and should not be treated as interchangeable evidence. The record also lists alanine aminotransferase normalization and loss of HBsAg as secondary outcomes.

The result addresses the posted comparison in this trial, with its recorded treatment groups and endpoint. It does not by itself answer broader questions about other patient populations, treatment approaches, or outcomes not reported in the registry record.

3. Trial Design

This was a Phase 2, randomized, parallel-group trial with no masking. Participants were assigned to tenofovir alone or tenofovir with emtricitabine. The registry lists enrollment of 35 and gives the study status as terminated. The study start date is 2007-08-29, and the primary completion date is 2017-02-16.

The treatment descriptions specify daily oral dosing for 192 weeks: tenofovir 300mg in the single-drug group, and tenofovir 300mg with emtricitabine 200mg in the combination group. The posted primary endpoint, however, is assessed at Week 48. These are different time references: the endpoint is a Week 48 measure, while the treatment descriptions specify the planned treatment duration. The registry record does not report further detail about adherence or treatment received through the full stated duration.

The primary outcome description notes that 32 participants started and 25 were analyzed for the Week 48 endpoint. It states that one participant was lost to follow-up before the endpoint, one died before the endpoint, and five had not reached the endpoint at study closure. The posted endpoint counts are 12 analyzed participants in the tenofovir-only group and 13 in the combination group.

Randomization can help balance measured and unmeasured characteristics on average, but the registry record does not report how the allocation sequence was generated or concealed. No masking was used, so participants and study personnel were not blinded according to the record. The registry record does not report the reason for termination, a detailed protocol, the sample-size justification, or an interim-analysis plan. Those omissions limit what can be said about the original design decisions and conduct.

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: The enrollment number in the Protocol Section (35) conflicts with the number of participants Started in the Participant Flow module (32). Two participants failed screening and one participant declined participation after enrollment and prior to beginning treatment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The number of participants analyzed (25) is smaller than the number of participants started (32). One participant was lost to follow-up prior to the endpoint, one died prior to the endpoint, and 5 had not reached the endpoint at study closure. Patients were transferred to another protocol to continue treatment as appropriate.

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Hepatitis b Virus (HBV) DNA <1000 IU/ml at Week 48, measured over At Week 48.

The primary endpoint counts participants whose serum HBV DNA was below 1000 IU/ml at Week 48. It is a binary outcome at the participant level: each analyzed participant either met the stated threshold or did not. The reported results are counts in each treatment group, with the group denominators indicating how many participants were analyzed for this endpoint.

HBV DNA is the measured quantity in the endpoint, and the threshold defines what qualifies as meeting it. Such a threshold-based endpoint can make the result easier to interpret than a continuous viral-load measurement when the study question is framed around attaining a specified level. It also discards information about how far an individual’s value lies above or below the threshold, so it does not describe the full distribution of HBV DNA values.

The endpoint is measured at one specified time, Week 48. It does not describe how quickly participants reached the threshold, whether they remained below it at other times, or what happened after that assessment. Those outcomes are not reported in the registry record.

The registry’s primary outcome is a laboratory-defined measure, not a direct report of symptoms, liver outcomes, or quality of life. The record lists other outcomes separately, including normalized alanine aminotransferase and loss of HBsAg. The endpoint therefore answers a focused question about HBV DNA at Week 48; it should not be interpreted as a complete measure of every aspect of disease status or treatment experience.

7. Results Posted in the Registry

• Tenofovir & Emtricitabine: 100.0% (13/13) versus 91.7% (11/12) on control; risk difference 8.3 percentage points (95% CI -7.3 to 24.0), risk ratio 1.09 (0.92–1.29); unadjusted two-proportion z-test p = 0.288.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Participants With Normalized Alanine Aminotransferase (ALT)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Tenofovir & Emtricitabine: 100.0% (13/13) versus 66.7% (8/12) on control; risk difference 33.3 percentage points (95% CI 6.7 to 60.0), risk ratio 1.50 (1.01–2.24); unadjusted two-proportion z-test p = 0.023.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Tenofovir & Emtricitabine than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Number of Participants With Loss of HBsAg

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Tenofovir & Emtricitabine: 0.0% (0/13) versus 8.3% (1/12) on control; risk difference -8.3 percentage points (95% CI -24.0 to 7.3); unadjusted two-proportion z-test p = 0.288.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Tenofovir & Emtricitabine and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists two secondary outcomes: normalized alanine aminotransferase (ALT) and loss of HBsAg, both assessed at 192 weeks. Together, they broaden the outcome picture beyond the Week 48 HBV DNA threshold. They concern different biological measures and time points, so they should be interpreted as complementary observations rather than as alternate versions of the primary endpoint.

The posted secondary comparisons do not form a single consistent pattern that can replace the primary result. Secondary results are best treated as exploratory in the absence of a reported analysis plan, and the registry record does not state whether these outcomes were prespecified as confirmatory hypotheses. Their relationship to the primary finding is therefore descriptive: they provide additional outcome information but do not resolve the uncertainty in the Week 48 comparison.

The reported secondary comparisons are unadjusted. When multiple outcomes are examined, the chance of observing an apparently notable result by chance can increase. In general, multiplicity procedures can control that concern, but the registry record does not report a multiplicity adjustment or a hierarchy of outcomes. It would therefore be inappropriate to read an unadjusted secondary p-value as if it came from a single isolated test with no other comparisons.

Secondary findings can also be less precise than their point estimates suggest, particularly with small groups. Their counts, denominators, and confidence intervals should be read alongside the endpoint definitions and follow-up time. The registry record does not report detailed methods for these analyses. Consequently, the secondary outcomes add context, but they should carry less inferential weight than a clearly prespecified, adequately powered primary analysis with a documented statistical plan.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Participants With Normalized Alanine Aminotransferase (ALT)
• Number of Participants With Loss of HBsAg

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: a participant either had HBV DNA below 1000 IU/ml at Week 48 or did not. For a binary outcome, a natural group summary is the count meeting the endpoint divided by the number analyzed in that group. The registry’s posted counts are 11 of 12 for tenofovir alone and 13 of 13 for the combination. These summaries describe the observed analysis groups, not necessarily every participant who started the study.

What does the risk difference represent?

The risk difference is the proportion meeting the endpoint in one group minus the proportion in the comparison group. Here, the comparison is combination treatment relative to tenofovir alone, and the posted estimate is 0.083. A positive value means the observed proportion was higher in the combination group; a negative value would mean it was lower. A value of zero corresponds to equal observed proportions. This is a general explanation of the measure, not a separate calculation.

The risk difference expresses an absolute contrast, rather than a relative change. It is often useful because it directly describes the separation between group proportions on the outcome scale. Its interpretation depends on the endpoint definition and the population analyzed. The estimate does not account for factors beyond the posted group summaries unless an adjusted analysis is reported. No adjusted analysis is reported in the registry record.

How should the p-value be read?

The posted primary comparison has an unadjusted p-value of 0.288. In general, a p-value measures how unusual results at least as incompatible with a specified null model would be if that model and the test assumptions were correct. It is not the probability that the null hypothesis is true, nor is it a measure of the size or clinical importance of an effect. The word “unadjusted” indicates that the value is not presented as adjusted for multiple comparisons. The registry record does not report the test method or a statistical analysis plan, so the exact analysis assumptions cannot be confirmed from the record.

A p-value above a commonly used significance threshold is not proof that groups are the same. It can reflect a small effect, limited information, or both. In this trial, the estimate and its confidence interval are more informative when read together: the point estimate is positive, but the interval includes zero and spans values on both sides of it.

What does a confidence interval add?

In general, a confidence interval represents uncertainty around an estimated quantity under the statistical method used. It gives a range of values compatible with the observed data and method, rather than a single best estimate alone. The primary interval is -0.073 to 0.240. Because this range includes zero, the posted data do not rule out no risk difference at the conventional interpretation of that interval. Because the range also includes both negative and positive values, it allows for differences in either direction.

Confidence intervals do not correct for biases, missing outcome data, or limitations in trial conduct. They also do not guarantee that the true value lies within the interval. They quantify sampling uncertainty under the analysis framework; uncertainty about design, measurement, and missingness remains relevant.

Why do the analysis counts matter?

The primary endpoint description says 32 participants started, while the posted primary analysis includes 25. One participant was lost to follow-up before the endpoint, one died before the endpoint, and five had not reached the endpoint by study closure. The registry also notes transfer to another protocol. The record does not provide a full account of how every missing outcome was treated in the statistical analysis. An analysis restricted to participants with an endpoint measurement can differ from an analysis that includes all randomized participants, especially if outcome availability is related to prognosis or treatment group.

Randomization is intended to support a fair comparison between assigned groups, but its benefits are best preserved when outcome data and analysis follow an appropriate plan. The record does not report whether an intention-to-treat analysis was used, how allocation was generated, or how missing outcomes were handled. No particular method should be assumed.

What analyses are documented?

The record posts the primary comparison and two secondary outcome comparisons, but it does not report analysis methods in detail. No reported analyses are listed for the posted secondary outcomes, and the registry record does not report an interim-analysis plan. The primary p-value is described as unadjusted. Without a stated analysis plan, readers cannot determine which statistical choices were prespecified, whether other analyses were conducted but not posted, or whether any adjustment was planned.

The sample-size assumptions describe planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are hypothetical planning calculations, not observed power and not evidence that the trial was originally planned around those assumptions. The registry record does not report the trial’s own sample-size justification. These distinctions matter: the observed result, an analysis plan, and a planning illustration answer different questions.

11. Confidence Intervals and Precision

The primary risk-difference estimate is 0.083, with a 95% confidence interval from -0.073 to 0.240. The point estimate is only one summary of the comparison; the interval describes its uncertainty under the method used. The interval includes zero, so the result is compatible with no difference. It also extends into both negative and positive values, leaving room for effects in either direction.

The interval is broad relative to the point estimate. This reflects limited precision in the comparison, which is unsurprising given the small analyzed groups: 12 participants in one group and 13 in the other. Small groups provide limited information for estimating proportions, especially when nearly all analyzed participants meet the endpoint. The fact that all 13 analyzed participants in the combination group met the endpoint does not make the underlying group response rate known with certainty.

A confidence interval is not a range containing a fixed proportion of individual participant outcomes, and it does not show the probability that the true risk difference lies within its endpoints. In general, it is a range generated by a statistical method that would have a stated long-run coverage property under its assumptions. The registry record does not name the method used for this interval, so the method-specific assumptions cannot be assessed from the posted information.

Precision is also affected by the endpoint analysis population. The primary outcome description says that 25 participants were analyzed, fewer than the 32 who started. Missing or not-yet-observed endpoint data can affect the interpretation of the estimate, beyond the sampling uncertainty represented by the interval. The confidence interval does not address possible bias arising from those missing outcomes.

The p-value of 0.288 and the interval tell related but distinct parts of the statistical story. The p-value summarizes compatibility with a null model under a particular test, while the interval displays a range of plausible effect values under its method. Neither supplies certainty about the treatment comparison or resolves the limitations of the available data.

12. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study assesses more than one outcome, time point, subgroup, or statistical comparison. Testing multiple hypotheses without accounting for that process can increase the chance of at least one apparently unusual result under null assumptions. The registry lists a primary endpoint and two secondary outcomes. The record does not report a multiplicity adjustment, a testing hierarchy, or a plan specifying how secondary findings would be interpreted. The secondary comparisons are unadjusted, so they warrant cautious, exploratory interpretation.

The registry record does not report the statistical analysis plan, a sample-size justification, or interim analyses. It also does not report whether the primary endpoint and analysis population were finalized before outcome data were examined. These details matter because prespecification helps distinguish confirmatory analyses from analyses selected after results are known. The absence of documentation in the registry record does not establish what occurred outside the record; it means that the relevant procedures cannot be evaluated from the posted information.

Missing endpoint information is directly noted. The primary outcome description states that 32 participants started and 25 were analyzed. One was lost to follow-up before the endpoint, one died before it, and five had not reached the endpoint by study closure. The record notes that patients were transferred to another protocol, but does not provide a complete account of how all missing outcomes were handled in the primary comparison.

Missingness matters because an analysis of participants with observed endpoints can be biased if having an observed endpoint is related to the outcome or differs meaningfully across groups. Randomization alone does not remove that concern once outcome data are missing. The registry record does not report an imputation method, sensitivity analysis, or a clear intention-to-treat analysis. No particular approach should be inferred. The posted counts and comparison should therefore be understood as applying to the analyzed participants, with uncertainty about how missing endpoint data might affect the full randomized comparison.

13. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death (5.9%).

The registry reports serious adverse events among 17 participants at risk in the tenofovir-only group and 15 in the combination group. One serious adverse event is reported in the tenofovir-only group and none in the combination group. The record also reports one death in the tenofovir-only group and none in the combination group. Death is listed as a top serious-event term at 5.9%.

These are counts, not a complete comparison of treatment safety. With small groups and few events, the observed counts provide limited precision. A zero count in one group does not establish that the underlying risk is zero. The record does not report a statistical comparison or confidence interval for serious adverse events, nor does it provide enough detail to assess event timing, relatedness, or severity beyond the serious-event classification.

Serious adverse events and other adverse events are distinct summaries. The record reports other adverse events among the same at-risk group counts, but those totals should not be combined with serious events. Differences in counts should be read descriptively and not as proof that one regimen is safer. These safety figures also do not answer the primary HBV DNA endpoint question.

14. What the Result Does, and Does Not, Mean

The primary result describes a numerical difference in the proportion of analyzed participants meeting the Week 48 HBV DNA threshold. The estimate favors the combination group, but its confidence interval includes zero and the unadjusted p-value is 0.288. This means the posted primary comparison does not provide clear statistical evidence of a difference, while also failing to establish that the regimens are equivalent.

The result does not show that either treatment works or does not work. The analysis is a comparison between two groups on a particular laboratory endpoint at a particular time. It does not include a no-treatment group, and it cannot by itself establish how either group compares with no treatment or other therapies. The registry record also does not report outcomes beyond the measures and time points listed.

The endpoint does not capture every aspect of chronic hepatitis B or treatment experience. It records whether serum HBV DNA fell below a specified threshold at Week 48. It does not directly measure symptoms, liver-related events, quality of life, long-term durability, or viral resistance in this trial’s posted primary result. Those questions are not answered by this endpoint unless separately measured and reported.

The analyzed sample is smaller than the number of participants who started. Incomplete endpoint coverage, the terminated status, and the absence of a reported detailed analysis plan limit how confidently the posted estimate can be generalized. The confidence interval reflects statistical uncertainty under the analysis method, but does not correct for possible bias due to missing data or other design and conduct limitations.

The most defensible interpretation is narrow: among the participants analyzed for the Week 48 endpoint, the combination group had a higher observed count meeting the threshold, but the comparison remains imprecise. The available record does not establish a definitive treatment difference, equivalence, or an overall benefit-risk conclusion.

15. Why This Trial Matters Statistically

This trial illustrates why an observed difference and evidence of a clear difference are not the same thing. The primary point estimate is positive, but the confidence interval covers zero and values in either direction. Reporting the estimate together with its uncertainty avoids treating a single number as a conclusive answer.

It also shows why denominators matter. The primary result is based on 25 analyzed participants, while the endpoint description says 32 started. A count that appears simple can conceal important questions about who was included, why outcomes were missing, and whether the analysis preserves the advantages of randomization. Those questions are especially consequential in small studies, where each participant contributes substantially to the group summary.

The trial has multiple outcome measures, and the secondary comparisons are unadjusted. This is a useful reminder that a notable secondary result should not be interpreted in isolation when the record does not document a multiplicity plan or analysis hierarchy. Statistical interpretation depends on the whole analysis context, not just a p-value or point estimate.

Finally, the registry record distinguishes a planning illustration from the trial’s original design. Sample-size calculations based on the observed effect are not observed power and do not demonstrate that the trial was adequately planned for its primary question. The original sample-size justification is not reported in the registry record. Together, these features highlight the importance of prespecified methods, complete outcome reporting, and appropriately cautious interpretation.

16. 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.

The study is listed as terminated, and the registry record does not report the reason. The primary endpoint description indicates that five participants had not reached the endpoint at study closure, while one was lost to follow-up and one died before the endpoint. This incomplete follow-up limits the directness of the comparison for all participants who started.

The analyzed groups are small, with 12 participants in the tenofovir-only group and 13 in the combination group. As a result, the primary estimate is imprecise. The registry record does not report a detailed missing-data strategy or sensitivity analyses to examine how unavailable endpoint results could affect the comparison.

No masking was used. The record does not describe how randomization was generated or concealed, nor does it report baseline characteristics in the registry record listed. It is therefore not possible to assess allocation procedures or group balance from this record alone. The trial is Phase 2, and its findings should be understood within that study context rather than assumed to answer broader treatment questions.

The registry record does not report the original sample-size justification, a detailed statistical analysis plan, an interim-analysis plan, or a multiplicity strategy. The primary p-value is unadjusted, and the secondary comparisons are also presented without reported multiplicity adjustment. These omissions constrain assessment of prespecification and the inferential status of the secondary findings.

The primary endpoint is a threshold-based laboratory measure at Week 48, whereas treatment descriptions specify 192 weeks. The record does not report whether the threshold was sustained or how outcomes evolved between or after the listed assessment times. The primary result also cannot substitute for detailed assessment of clinical outcomes, long-term effects, or safety. These limitations are specific to the posted design and reporting and should accompany interpretation of its estimates.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Tenofovir Alone Versus Tenofovir With Emtricitabine to Treat Chronic Hepatitis B — NCT00524173.
• Registry record last updated 2019-06-05; status last verified 2018-03-16.
• Results first posted 2018-04-18.
• 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.

20. Record Summary

The registry record describes a randomized, unmasked, parallel Phase 2 trial comparing tenofovir alone with tenofovir plus emtricitabine for chronic hepatitis B. Enrollment is listed as 35, and the study status is terminated. The primary endpoint is the number of participants with HBV DNA below 1000 IU/ml at Week 48.

For that endpoint, 11 of 12 analyzed participants in the tenofovir-only group and 13 of 13 in the combination group met the threshold. The posted risk difference is 0.083, with a 95% confidence interval from -0.073 to 0.240 and an unadjusted p-value of 0.288. The endpoint description says 32 participants started and 25 were analyzed, with some participants not contributing a Week 48 result for stated reasons.

The registry also lists normalized ALT and loss of HBsAg as secondary outcomes and reports serious adverse-event counts. The statistical analysis plan, original sample-size justification, missing-data methods, and multiplicity strategy are not reported in the registry record. The primary result is therefore best interpreted as an imprecise comparison among the analyzed participants, rather than a definitive conclusion about treatment differences.