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 limited to the ClinicalTrials.gov record for HVTN 702.
1. Trial at a Glance
HVTN 702 was a randomized, parallel, quadruple-masked phase 2/3 prevention study evaluating ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 against placebo in participants at risk for HIV infection. The registry reports 5404 participants enrolled and two study arms.
| Feature | HVTN 702 |
|---|---|
| Trial name | HVTN 702 |
| Brief title | Pivotal Phase 2b/3 ALVAC/Bivalent gp120/MF59 HIV Vaccine Prevention Safety and Efficacy Study in South Africa |
| Phase | 2/3 |
| Status | Completed |
| Condition | HIV Infections |
| Primary purpose | Prevention |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 5404 |
| Lead sponsor | National Institute of Allergy and Infectious Diseases (NIAID) |
| Sponsor type | NIH |
| Start | 2016-10-26 |
| Primary completion | 2021-11-16 |
| ClinicalTrials.gov | NCT02968849 |
2. Clinical Question
The central statistical question was whether participants assigned to the ALVAC-HIV (vCP2438) and bivalent subtype C gp120/MF59 vaccine regimen experienced a different incidence of diagnosed HIV-1 infection than participants assigned to placebo during the prespecified follow-up periods.
Population
Participants enrolled in the HVTN 702 HIV vaccine prevention study in South Africa, with efficacy analyses reported in the MITT cohort.
Intervention
ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59, both identified in the registry as biological interventions.
Comparator
Placebo, identified in the registry as a biological intervention.
Primary question
How does the hazard of diagnosed HIV-1 infection in the vaccine group compare with that in the placebo group over the specified follow-up periods?
3. Trial Design
ALVAC / Bivalent gp120/MF59
- ALVAC-HIV (vCP2438)
- Bivalent Subtype C gp120/MF59
- Both classified as biological interventions in the registry
Placebo
- Placebo
- Classified as a biological intervention in the registry
4. Trial Timeline
Study start
The registry records the study start date as 2016-10-26.
Primary-outcome supersession
The registry definition for the later HIV-1 infection endpoint states that a 23 January 2020 DSMB finding that monitoring boundaries for non-efficacy had been met resulted in the earlier primary outcome being superseded by the later primary outcome.
Primary completion
The registry records primary completion on 2021-11-16.
5. Primary Endpoints
The registry lists 12 primary endpoints. Two are HIV-1 infection incidence endpoints with formal statistical analyses reported in the ClinicalTrials.gov record. The remaining primary endpoints concern reactogenicity, adverse events, serious adverse events, adverse events of special interest, chronic medical conditions, early study termination, and study product discontinuation.
| Primary endpoint | Time frame | Endpoint type | Formal analysis in the ClinicalTrials.gov record |
|---|---|---|---|
| Incidence Rate of HIV-1 Infection Diagnosed After Enrollment (Concurrent With First Vaccination) Through 24 Months After Enrollment | Measured through 24 months after first vaccination | Count / rate | Yes |
| Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Pain and/or Tenderness | Measured through 3 full days following each vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting Local Reactogenicity Signs and Symptoms: Erythema and/or Induration | Measured through 3 full days following each vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms | Measured through 3 full days following each vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting Adverse Events (AEs), by Relationship to Study Product | Measured through 30 days after each vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting Adverse Events (AEs), by Severity Grade | Measured through 30 days after each vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting Serious Adverse Events (SAEs) | Measured through 12 months after last vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting Adverse Events of Special Interest (AESIs) | Measured through 12 months after last vaccination | Binary | No statistical analysis reported |
| Number of Participants Reporting New Chronic Medical Conditions | Measured through 12 months after last vaccination | Binary | No statistical analysis reported |
| Number of Participants With Early Study Termination Associated With an AE or Reactogenicity | Measured through study completion (through 6 months after confirmation of HIV-1 diagnosis for participants who acquired HIV and through 12 months after last vaccination for the rest) | Binary | No statistical analysis reported |
| Number of Participants With Study Product Discontinuation Associated With an AE or Reactogenicity | Measured through study completion (through 6 months after confirmation of HIV-1 diagnosis for participants who acquired HIV and through 12 months after last vaccination for the rest) | Binary | No statistical analysis reported |
| Incidence Rate of HIV-1 Infections Diagnosed Following Enrollment and Throughout All Participant Follow-Up | Measured through 36 months after first vaccination | Count / rate | Yes |
6. Endpoint Definitions and Measurement
HIV-1 infection incidence
The first infection endpoint concerns the incidence rate of HIV-1 infection diagnosed after enrollment, concurrent with first vaccination, through 24 months. The registry definition states that vaccine efficacy was calculated as 1 minus the hazard ratio for HIV-1 infection, with the hazard ratio estimated using a sex-stratified Cox proportional-hazards model and tested using a sex-stratified log-rank test. The definition also states that vaccine efficacy was measured using a ratio of cumulative incidences.
The later primary infection endpoint covers HIV-1 infections diagnosed following enrollment throughout all participant follow-up and has a time frame of 36 months after first vaccination. Its registry definition states that vaccine efficacy was calculated as 1 minus the hazard ratio, with the hazard ratio estimated using a sex-stratified Cox proportional-hazards model and tested using a sex-stratified log-rank test.
Reactogenicity
Local pain and/or tenderness, local erythema and/or induration, and systemic reactogenicity were measured through 3 full days following each vaccination. The registry states that these outcomes were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1, July 2017, with the maximum grade observed for each symptom over the time frame presented.
Adverse events
Adverse events were measured through 30 days after each vaccination. For participants reporting multiple adverse events over the time frame, the maximum relationship was counted for the relationship-to-study-product endpoint, while the maximum severity grade was counted for the severity endpoint.
Serious adverse events and other longer-term safety endpoints
Serious adverse events and adverse events of special interest were measured through 12 months after last vaccination. The registry definition identifies potential immune-mediated diseases among the adverse events of special interest. New chronic medical conditions were defined as a new onset or exacerbation of a medical condition requiring 2 or more visits to a medical provider during a period of at least 30 days.
7. Statistical Methodology
Time-to-event analysis
The principal efficacy endpoint is a time-to-event outcome: the time from enrollment and first vaccination to diagnosis of HIV-1 infection. This structure matters because participants can have different lengths of follow-up and because some participants may remain infection-free at the end of their observed follow-up.
For HVTN 702, the reported hazard ratio uses the vaccine group as the numerator and placebo as the denominator. An HR of 1 represents equal estimated hazards; an HR above 1 indicates a higher estimated hazard in the vaccine group; an HR below 1 indicates a lower estimated hazard.
Sex-stratified Cox proportional-hazards model
The registry states that the hazard ratio was estimated using a sex-stratified Cox proportional-hazards model. Stratification allows the baseline hazard to differ across sex strata while estimating the treatment comparison within the specified survival-analysis framework.
The important distinction is between stratification and adjustment with an ordinary regression coefficient. In a stratified Cox model, the strata can have separate baseline hazards while the treatment effect is estimated across the strata. The registry-reported analysis notes specifically identify sex as the stratification factor.
Sex-stratified log-rank test
The reported log-rank analyses tested the hazard ratio using a sex-stratified log-rank test. The log-rank framework compares the observed and expected numbers of events between treatment groups over follow-up, taking the time ordering of events into account.
Unlike a simple comparison of cumulative infection proportions at one fixed date, a survival-analysis test uses the information accumulated across the follow-up period and can accommodate censoring.
Wald / z-test analyses
The ClinicalTrials.gov record also reports Wald analyses for the primary infection endpoints. In the 24-month analysis, the hazard ratio was estimated using Nelson-Aalen cumulative hazard estimates. The same approach was reported for the 36-month analysis.
The Wald framework provides a model-based inferential route for testing and constructing uncertainty around an estimated effect. The ClinicalTrials.gov record reports these analyses separately from the log-rank analyses, so the two sets of estimates should not be silently substituted for one another.
Nelson-Aalen cumulative hazard estimates
The Wald analyses used Nelson-Aalen cumulative hazard estimates. Cumulative hazard describes the accumulated event hazard over time and is distinct from the survival probability itself. This provides a nonparametric foundation for describing event accumulation before forming the reported hazard-ratio estimate in the registry-reported analysis.
8. Primary Efficacy Results Through 24 Months
The first primary efficacy endpoint was the incidence rate of HIV-1 infection diagnosed after enrollment, concurrent with first vaccination, through 24 months after enrollment. The analysis population was the MITT cohort, and the comparison was vaccine versus placebo.
Sex-stratified log-rank analysis
Hazard ratio for HIV-1 infection
95% CI: 0.81–1.30 · P = 0.84
Analysis: sex-stratified log-rank test with a sex-stratified Cox proportional-hazards model for the hazard ratio.
The estimated hazard ratio of 1.02 means that the estimated instantaneous hazard of diagnosed HIV-1 infection in the vaccine group was 1.02 times that in the placebo group under the reported Cox model. Because the vaccine group is the numerator and placebo is the denominator, the estimate is close to 1.
The estimate does not mean that exactly 2% more participants became infected, nor does it represent a 2% absolute increase in infection risk. A hazard ratio is a relative time-to-event measure rather than a difference in cumulative incidence.
The 95% confidence interval of 0.81–1.30 describes uncertainty around the estimated hazard ratio. Its width shows that the estimate is not known with arbitrary precision. The interval also spans 1, the value corresponding to equal hazards.
The P = 0.84 value is evidence about compatibility with the null comparison under the specified testing framework; it is not a measure of the size of the observed effect. A p-value should not be interpreted as the probability that the vaccine is effective or ineffective.
Because this is a Cox-model hazard ratio, interpretation also depends on the proportional-hazards framework. The ClinicalTrials.gov record does not provide a formal assessment of that assumption, so the single HR should not be treated as a complete description of how infection hazards behaved at every point in follow-up.
Wald analysis
Hazard ratio from Nelson-Aalen cumulative hazard estimates
95% CI: 0.81–1.31 · P = 0.83
Analysis: Wald; hazard ratio estimated using Nelson-Aalen cumulative hazard estimates.
The Wald analysis produces an HR of 1.03, again with vaccine as the numerator and placebo as the denominator. This is a closely related estimate to the log-rank/Cox analysis, but it comes from the separately reported Nelson-Aalen-based approach.
The 95% CI of 0.81–1.31 indicates uncertainty around the estimate and includes 1. The P = 0.83 value addresses the corresponding statistical test; it does not quantify the clinical importance of the difference.
The close correspondence between the two reported 24-month estimates—1.02 and 1.03—does not justify combining them into a new estimate. They are separate registry-reported analyses and should be retained as such.
9. Primary Efficacy Results Through 36 Months
The later primary endpoint was the incidence rate of HIV-1 infections diagnosed following enrollment and throughout all participant follow-up, measured through 36 months after first vaccination. The analysis population was the MITT cohort.
Sex-stratified log-rank analysis
Hazard ratio for HIV-1 infection
95% CI: 0.85–1.28 · P = 0.66
Analysis: sex-stratified log-rank test with a sex-stratified Cox proportional-hazards model for the hazard ratio.
The estimated HR of 1.05 means that the estimated instantaneous hazard of diagnosed HIV-1 infection in the vaccine group was 1.05 times that in the placebo group under the reported Cox model.
This is a relative hazard estimate, not a statement that 5% more participants became infected and not an absolute risk difference. It also does not mean that every participant had the same individual-level change in risk.
The 95% CI of 0.85–1.28 expresses uncertainty around the estimated hazard ratio. It includes 1, so the interval is compatible with equal hazards as well as with hazard ratios on either side of 1 within the interval.
The P = 0.66 value is not an effect-size measure. It describes the statistical evidence generated by the specified test; it should not be translated into a probability that the treatment works or does not work.
As with the 24-month analysis, the interpretation of the single HR depends on the Cox proportional-hazards framework and on how censoring and follow-up contribute information to the analysis.
Wald analysis
Hazard ratio from Nelson-Aalen cumulative hazard estimates
95% CI: 0.81–1.23 · P = 0.98
Analysis: Wald; hazard ratio estimated using Nelson-Aalen cumulative hazard estimates.
The Wald analysis gives an HR of exactly 1.00 in the ClinicalTrials.gov record. With vaccine as numerator and placebo as denominator, an HR of 1.00 corresponds to equal estimated hazards under this analysis.
The 95% CI of 0.81–1.23 provides the uncertainty range around that estimate and includes values below and above 1. The P = 0.98 value indicates very little statistical evidence against the equal-hazard reference under this specific Wald analysis, but the p-value itself is not a measure of the magnitude or clinical importance of an effect.
The fact that the 36-month log-rank/Cox estimate is 1.05 while the separately reported Wald estimate is 1.00 is not a contradiction. They are results from different statistical procedures applied to the same endpoint and should be reported using their stated methods.
10. Primary Efficacy Results at a Glance
| Endpoint / analysis | Population | HR | 95% CI | P-value |
|---|---|---|---|---|
| 24 months · sex-stratified log-rank / Cox | MITT cohort | 1.02 | 0.81–1.30 | 0.84 |
| 24 months · Wald / Nelson-Aalen | MITT cohort | 1.03 | 0.81–1.31 | 0.83 |
| 36 months · sex-stratified log-rank / Cox | MITT cohort | 1.05 | 0.85–1.28 | 0.66 |
| 36 months · Wald / Nelson-Aalen | MITT cohort | 1.00 | 0.81–1.23 | 0.98 |
11. Secondary Time-to-Event Results
The registry also reports several secondary HIV-1 infection analyses. These analyses use the same broad time-to-event framework but focus on a different at-risk cohort or prespecified participant subgroup.
Week 26 at-risk cohort: after Month 6.5 through 24 months
| Analysis | Population | HR | 95% CI | P-value |
|---|---|---|---|---|
| Sex-stratified log-rank / Cox | Week 26 at-risk cohort | 1.15 | 0.84–1.58 | 0.39 |
| Wald / Nelson-Aalen | Week 26 at-risk cohort | 1.12 | 0.81–1.54 | 0.50 |
The time frame for both analyses was measured after Month 6.5 through 24 months after first vaccination. The registry-reported analysis notes state that the vaccine group is the numerator and the placebo group is the denominator.
Female participants through 24 months
| Population | Method | HR | 95% CI | P-value |
|---|---|---|---|---|
| Females in MITT cohort | Sex-stratified log-rank / Cox | 1.03 | 0.80–1.33 | 0.82 |
| Males in MITT cohort | Sex-stratified log-rank / Cox | 0.99 | 0.50–1.98 | 0.98 |
Both analyses were measured through 24 months after first vaccination. The ClinicalTrials.gov record identifies these as secondary analyses rather than the primary treatment comparison.
Female participants by age
| Population | Method | HR | 95% CI | P-value |
|---|---|---|---|---|
| Females in MITT cohort aged 25 or younger | Sex-stratified log-rank / Cox | 1.08 | 0.80–1.47 | 0.60 |
| Females in MITT cohort older than 25 | Sex-stratified log-rank / Cox | 0.92 | 0.58–1.46 | 0.71 |
These analyses were also measured through 24 months after first vaccination. They are subgroup-specific estimates, and their confidence intervals reflect the precision of those particular subgroup comparisons.
12. How to Read the Secondary Hazard Ratios
The secondary results illustrate why the point estimate alone is not enough. For example, the female analysis has an HR of 1.03 with a 95% CI of 0.80–1.33, while the male analysis has an HR of 0.99 with a much wider 95% CI of 0.50–1.98.
The wider interval in the male analysis indicates greater uncertainty in that subgroup estimate. The point estimate being close to 1 does not by itself establish equivalence, and a confidence interval that includes 1 does not prove that there is no treatment effect. It indicates that the registry-reported analysis does not precisely distinguish among a range of possible hazard ratios represented by that interval.
The same principle applies to the female age analyses. An HR of 1.08 among females aged 25 or younger and an HR of 0.92 among females older than 25 are descriptive subgroup estimates. Without a formal interaction analysis reported in the ClinicalTrials.gov record, they should not be treated as evidence that age modifies the treatment effect.
13. Safety Results
The ClinicalTrials.gov record identifies serious adverse events by randomized arm. It reports 103/2704 affected/at risk in the vaccine group and 95/2700 affected/at risk in the placebo group.
| Safety measure | Vaccine | Placebo |
|---|---|---|
| Serious adverse events | 103/2704 | 95/2700 |
The reported safety figures are participant counts expressed as affected/at risk for each arm. They should be distinguished from the HIV-1 infection hazard ratios because they address a different clinical outcome and use a different data structure.
The ClinicalTrials.gov record does not provide a formal statistical comparison, confidence interval, or p-value for the serious-adverse-event counts. Accordingly, this page does not manufacture a comparative test from the reported counts.
The registry also lists primary safety endpoints covering local reactogenicity, systemic reactogenicity, adverse events by relationship and severity, serious adverse events, adverse events of special interest, new chronic medical conditions, early study termination associated with an AE or reactogenicity, and study product discontinuation associated with an AE or reactogenicity. The registry-reported statistical-analyses dataset does not provide formal comparative estimates for those endpoints.
14. Statistical Methods Explained
Why was a sex-stratified analysis used?
The registry analysis notes explicitly identify a sex-stratified log-rank test and a sex-stratified Cox proportional-hazards model. Stratification allows the analysis to account for different baseline hazards across the specified strata while estimating the vaccine-versus-placebo comparison within the survival-analysis framework.
What does an HR of 1.02 mean?
Because the vaccine group is the numerator and placebo is the denominator, an HR of 1.02 means the estimated instantaneous hazard in the vaccine group was 1.02 times that in the placebo group under the reported model. It is not an absolute risk difference and is not the percentage of participants who experienced infection.
Why is the confidence interval important?
A point estimate such as 1.02 is only one estimate from the available data. The 95% CI of 0.81–1.30 communicates uncertainty around that estimate. The interval should be read as a range generated by the statistical estimation procedure, not as the range of effects experienced by individual participants.
Why does the p-value not measure effect size?
The p-value describes the statistical evidence under the specified null-testing framework. It depends on the observed data and the statistical procedure, but it is not a scale of clinical magnitude. The HR and its confidence interval provide the effect estimate and its precision; the p-value addresses the hypothesis test.
Why use a log-rank test for HIV-1 infection?
HIV-1 infection is recorded as a time-to-event outcome. A log-rank test is designed to compare event-time distributions between groups while incorporating the timing of events and the information contributed by participants who are censored before experiencing the event.
What is the role of the Nelson-Aalen estimate?
The registry-reported Wald analyses use Nelson-Aalen cumulative hazard estimates. The Nelson-Aalen estimator accumulates observed event information over time to estimate cumulative hazard. It therefore provides a different statistical route from the sex-stratified log-rank/Cox analysis, even though both are being used to characterize the vaccine-versus-placebo comparison.
Why should subgroup HRs not be compared by eye?
Separate estimates can differ simply because of sampling variability. An HR of 1.08 in one subgroup and 0.92 in another does not, by itself, establish effect modification. A formal interaction test is generally required to test whether treatment effects differ across subgroups, and no such interaction result is reported in the ClinicalTrials.gov record.
15. Understanding the Hazard Ratio
Values above 1 correspond to a higher estimated instantaneous hazard in the vaccine group; values below 1 correspond to a lower estimated instantaneous hazard in the vaccine group.
| Reported HR | Statistical reading |
|---|---|
| 1.02 | Estimated vaccine-group hazard is 1.02 times the placebo-group hazard. |
| 1.03 | Estimated vaccine-group hazard is 1.03 times the placebo-group hazard. |
| 1.05 | Estimated vaccine-group hazard is 1.05 times the placebo-group hazard. |
| 1.00 | Estimated hazards are equal under the reported analysis. |
| 1.15 | Estimated vaccine-group hazard is 1.15 times the placebo-group hazard. |
| 1.12 | Estimated vaccine-group hazard is 1.12 times the placebo-group hazard. |
| 0.99 | Estimated vaccine-group hazard is 0.99 times the placebo-group hazard. |
| 1.08 | Estimated vaccine-group hazard is 1.08 times the placebo-group hazard. |
| 0.92 | Estimated vaccine-group hazard is 0.92 times the placebo-group hazard. |
This table is a translation of the reported effect measures into their statistical meaning. It does not convert the hazard ratios into absolute infection probabilities because the ClinicalTrials.gov record does not provide the necessary event and person-time quantities for that calculation.
16. Confidence Intervals and Precision
The confidence intervals provide an important second dimension of interpretation beyond the point estimates. The primary 24-month Cox estimate is 1.02 with a 95% CI of 0.81–1.30. The corresponding Wald estimate is 1.03 with a 95% CI of 0.81–1.31.
At 36 months, the Cox estimate is 1.05 with a 95% CI of 0.85–1.28, while the Wald estimate is 1.00 with a 95% CI of 0.81–1.23.
Point estimate
The hazard ratio is the single numerical estimate produced by the specified analysis.
Confidence interval
The interval communicates uncertainty around that estimate under the statistical framework used.
Reference value
For a hazard ratio, 1 represents equal estimated hazards between the two groups.
P-value
The p-value addresses the corresponding hypothesis test; it is not a measure of effect size or clinical importance.
17. Randomization, Masking, and Causal Interpretation
Randomization is a central design feature because treatment assignment is randomized rather than chosen according to participant characteristics. This creates the foundation for comparing the subsequent infection experience between the vaccine and placebo groups while reducing systematic confounding from measured and unmeasured baseline factors, subject to the usual assumptions of randomized-trial inference.
The trial is described as quadruple-masked. Masking can reduce the influence of knowledge of treatment assignment on participant behavior, clinical assessment, reporting, and other aspects of trial conduct. Its relevance is particularly clear in a prevention study where infection ascertainment and adverse-event reporting occur over time.
18. Analysis Populations
The statistical analyses posted on ClinicalTrials.gov identify the MITT cohort for the primary infection analyses. Secondary analyses use the Week 26 at-risk cohort, females in the MITT cohort, males in the MITT cohort, and specified female age subgroups.
| Analysis population | Use in the ClinicalTrials.gov record |
|---|---|
| MITT cohort | Primary HIV-1 infection analyses through 24 and 36 months; female and male subgroup analyses. |
| Week 26 at-risk cohort | Secondary HIV-1 infection analysis after Month 6.5 through 24 months. |
| Females in MITT cohort | Secondary HIV-1 infection analysis through 24 months. |
| Males in MITT cohort | Secondary HIV-1 infection analysis through 24 months. |
| Females in MITT cohort aged 25 or younger | Secondary HIV-1 infection analysis through 24 months. |
| Females in MITT cohort older than 25 | Secondary HIV-1 infection analysis through 24 months. |
The distinction between these populations matters. An estimate from the Week 26 at-risk cohort is not directly interchangeable with the estimate from the full MITT cohort, because the populations entering the analyses are defined differently.
19. Multiplicity and Multiple Analyses
The ClinicalTrials.gov record identifies 12 registered primary endpoints and reports 10 statistical analyses in total, including four primary-endpoint analyses and six secondary analyses.
The four primary statistical analyses comprise two methods for the 24-month HIV-1 infection endpoint and two methods for the 36-month HIV-1 infection endpoint. The ClinicalTrials.gov record does not provide a formal multiplicity-adjustment scheme or an alpha-allocation procedure for these reported analyses.
20. What the Results Do and Do Not Establish
What the HR describes
A relative comparison of the instantaneous event hazard between vaccine and placebo under the specified time-to-event model.
What the HR does not describe
It is not an absolute infection probability, an absolute risk difference, or the proportion of participants who benefit.
What the CI describes
Uncertainty around the estimated hazard ratio under the stated statistical framework.
What the p-value describes
Evidence under the specified hypothesis-testing procedure, not the magnitude or clinical importance of the treatment effect.
The primary hazard-ratio estimates are close to 1: 1.02 and 1.03 through 24 months, and 1.05 and 1.00 through 36 months. The corresponding confidence intervals all include 1. The registry-reported p-values are 0.84, 0.83, 0.66, and 0.98.
Those statements describe the reported statistical results. They should not be expanded into claims about absolute vaccine effectiveness beyond the quantities reported in the ClinicalTrials.gov record. In particular, the ClinicalTrials.gov record does not provide the cumulative infection rates needed to construct an independent absolute-risk comparison here.
21. Missing Data, Censoring, and Proportional Hazards
Time-to-event analyses generally distinguish participants who experience the event from participants who are censored before an event is observed. The ClinicalTrials.gov record identifies the infection outcomes as time-to-event endpoints and identifies Cox proportional-hazards and log-rank methods, but it does not provide a detailed missing-data or censoring specification.
Accordingly, this page does not infer a particular imputation method or censoring rule beyond what is explicitly present in the ClinicalTrials.gov record.
A survival analysis can use the information contributed by participants up to their censoring time. This is one reason a time-to-event analysis is preferable to simply ignoring participants who do not experience HIV-1 infection during the observed period.
The Cox proportional-hazards model also makes a structural assumption about the relative hazard over time. The ClinicalTrials.gov record does not report a formal proportional-hazards diagnostic, so the HR should be understood as the model-based summary reported by the registry rather than as proof that the proportional-hazards assumption was perfectly satisfied.
22. Limitations
- Registry-level information: this analysis is restricted to the ClinicalTrials.gov record and does not add results from external publications.
- Summary-level results: the ClinicalTrials.gov record contains hazard ratios, confidence intervals, and p-values but not participant-level event and censoring times.
- No reconstructed Kaplan-Meier curves: valid curves cannot be reconstructed from the registry-reported summary statistics alone.
- Safety analysis detail: serious adverse events are reported as affected/at-risk counts by arm, but the ClinicalTrials.gov record does not provide formal comparative estimates for the safety endpoints.
- Subgroup uncertainty: subgroup analyses use narrower populations and can therefore have less precise estimates, as illustrated by the 95% CI of 0.50–1.98 for the male analysis.
- No registry-reported interaction tests: the data does not provide formal tests establishing whether treatment effects differ by sex or female age subgroup.
- Multiplicity information: the ClinicalTrials.gov record identifies multiple registered endpoints and analyses but does not provide a complete multiplicity-control procedure.
- Censoring and missing-data details: detailed censoring and imputation rules are not included in the ClinicalTrials.gov record.
- Proportional-hazards assumption: the ClinicalTrials.gov record identifies Cox proportional-hazards modeling but does not report a formal diagnostic for the assumption.
23. Why This Trial Matters Statistically
HVTN 702 is a useful teaching case because it combines randomized prevention-trial design with a time-to-event efficacy endpoint, sex-stratified survival analysis, multiple effect-estimation approaches, subgroup analyses, and a separate safety framework.
| Concept | How it appears in HVTN 702 |
|---|---|
| Randomization | The trial uses randomized allocation in a parallel two-arm design. |
| Blinding | The registry describes the study as quadruple-masked. |
| Time-to-event endpoint | HIV-1 infection is analyzed according to time from enrollment/first vaccination to diagnosis. |
| Hazard ratio | The primary efficacy effect measure is the hazard ratio, with vaccine as numerator and placebo as denominator. |
| Log-rank test | Primary and secondary infection analyses include sex-stratified log-rank tests. |
| Cox model | The primary HR estimates are obtained using sex-stratified Cox proportional-hazards models. |
| Nelson-Aalen | The Wald analyses use Nelson-Aalen cumulative hazard estimates. |
| Wald / z-test | Wald analyses provide a second reported inferential approach for the primary infection endpoints. |
| Confidence intervals | Each reported primary HR has a two-sided 95% confidence interval. |
| Subgroup analysis | Secondary analyses examine female and male participants and female age groups. |
| Safety analysis | Serious adverse events are reported separately by randomized arm. |
| Endpoint evolution | The registry definition states that the later 36-month HIV-1 infection endpoint superseded the earlier primary outcome after the 23 January 2020 DSMB finding. |
24. Statistical Concepts in This Trial
Learn more about the methods used in this trial:
25. Related Statistical Calculators
26. Sources
- ClinicalTrials.gov: HVTN 702 (NCT02968849).
- PubMed: PMID 41121745.
- PubMed: PMID 40190112.
- PubMed: PMID 38772835.
- PubMed: PMID 37355583.
- PubMed: PMID 34895272.
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27. Record Summary
HVTN 702 provides a detailed example of statistical analysis for a randomized HIV vaccine prevention study. The ClinicalTrials.gov record combines a randomized, parallel, quadruple-masked design with time-to-event analysis of HIV-1 infection. The primary efficacy analyses use sex-stratified log-rank testing and sex-stratified Cox proportional-hazards models, alongside separately reported Wald analyses using Nelson-Aalen cumulative hazard estimates.
The four reported primary analyses produce hazard ratios of 1.02, 1.03, 1.05, and 1.00, with corresponding two-sided 95% confidence intervals of 0.81–1.30, 0.81–1.31, 0.85–1.28, and 0.81–1.23. The associated p-values are 0.84, 0.83, 0.66, and 0.98.
The most important statistical lesson is that these numbers should be interpreted together rather than individually. A hazard ratio supplies a relative time-to-event estimate; its confidence interval communicates precision; the p-value describes evidence under the specified test; and the analysis population and modeling assumptions determine what the estimate represents. Secondary subgroup estimates require additional caution because a difference between subgroup estimates is not itself an interaction test.