Evaluation of Safety and Immunogenicity of a Human Papillomavirus (HPV) Vaccine in Human Immunodeficiency Virus (HIV) Infected Females: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Safety and Immunogenicity of a Human Papillomavirus (HPV) Vaccine in Human Immunodeficiency Virus (HIV) Infected Females (NCT01031069), a randomized phase 4 study. The primary outcome is Number of Human Immunodeficiency Virus Positive Subjects (HIV+) With Any and Grade 3 Solicited Local Symptoms.

2. Clinical Question

The registry describes a randomized, triple-masked, parallel Phase IV study with enrollment of 873. Its brief summary says the safety and immunogenicity of Cervarix in HIV-infected females would be evaluated in comparison with Gardasil, while HIV-negative females would also be evaluated for comparative purposes. Thus, the study includes both a vaccine comparison within HIV-status groups and a comparison of HIV-positive and HIV-negative groups. Those are distinct contrasts: HIV status was not described as a randomized intervention.

The primary outcome is a count of HIV-positive participants reporting solicited local symptoms, with any intensity and Grade 3 intensity considered separately. The registry lists other safety outcomes, including symptoms, adverse events, serious adverse events, medically significant conditions, potential immune-mediated disease, pregnancy outcomes, and laboratory abnormalities. It also lists immunogenicity in the study purpose, but the outcome details available in the registry record do not give a specific immunogenicity endpoint. The primary question is therefore about short-term local symptoms, not whether either vaccine prevents HPV infection or cervical cancer.

3. Trial Design

This is a Phase IV, randomized, parallel-group study. The registry classifies masking as triple; the brief summary describes the study as observer-blind. Which specific groups were masked is not reported in the registry record. Enrollment is recorded as 873. The study status is completed, with a start date of 2010-10-26 and primary completion date of 2016-01-13.

The four arm descriptions combine HIV status and vaccine: HIV-positive participants receiving Cervarix, HIV-positive participants receiving Gardasil, HIV-negative participants receiving Cervarix, and HIV-negative participants receiving Gardasil. Each description specifies three intramuscular doses in the deltoid muscle of the non-dominant arm at Day 0, Week 6, and Month 6. The listed age range is 15 to 25 years, inclusive. The record does not report the allocation ratio or the method used to generate or conceal the randomization sequence.

The trial’s stated focus is safety and immunogenicity. The primary outcome is limited to solicited local symptoms among HIV-positive participants. The secondary outcomes listed in the record cover adverse events and other safety measures, including several outcomes specifically described for HIV-negative subjects. The registry lists 34 outcome measures and 6 analyses. A protocol, detailed statistical analysis plan, and the rationale for the enrollment target are not reported in the registry record.

The brief summary says all subjects would receive one of the two vaccines according to the three-dose schedule. The arm descriptions likewise state that participants received three doses. However, how many participants completed all doses, and how departures from the planned schedule were handled in the analyses, are not reported in the registry record. The reported analysis population for the primary symptom assessment is the Total Vaccinated cohort, defined as vaccinated subjects with available data and completed symptom sheets.

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: Screening involved: checking of inclusion/exclusion criteria, demographic data, history and physical examination, AF B sputum test and/or chest X-ray, blood sampling for HIV testing and safety, urine pregnancy testing, birth control and HIV, STI, STD counselling, checking records for concomitant medication/vaccination, subject card distribution.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the Total Vaccinated cohort, which included all vaccinated subjects for whom data were available and who had available symptom sheets completed.

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 Human Immunodeficiency Virus Positive Subjects (HIV+) With Any and Grade 3 Solicited Local Symptoms, measured over During the 7-day follow-up period (from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses.

The primary endpoint counts HIV-positive participants with solicited local symptoms: pain, redness, and swelling. The registry defines “any” as occurrence regardless of intensity. It defines Grade 3 pain as significant pain at rest or pain that prevented normal activity. Grade 3 redness or swelling is defined by a maximum diameter greater than 50 millimeters. The assessment covers the 7-day follow-up period, from the day of vaccination through the next 6 days, after each dose and across doses.

Counting participants with an event provides a direct summary of how many people reported a symptom, rather than how many separate episodes occurred. Considering any symptom and Grade 3 symptoms separately distinguishes reports of any intensity from reports meeting the specified severe-intensity criteria. In general, solicited symptoms are actively queried using predefined categories and a defined observation window, which can make the assessment more structured than relying only on spontaneous reports. This endpoint concerns local symptoms in the short period following vaccination; it does not measure long-term safety, HPV infection, or immunogenicity.

The registry identifies the analysis population as the Total Vaccinated cohort: vaccinated participants for whom data were available and symptom sheets were completed. The primary endpoint title indicates that counts were assessed for HIV-positive participants. The actual outcome counts and any comparative estimates for this endpoint are not reported in the registry record, so the size and precision of a vaccine-group difference cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the study as randomized, triple-masked, and parallel-group. Randomization is generally used to balance measured and unmeasured participant characteristics across assigned interventions, on average. Masking is generally intended to reduce the influence of expectations on care, reporting, or assessment. These are general statistical and design principles; the registry does not describe its randomization procedure or identify exactly who was masked. The brief summary’s observer-blind wording and the triple-masking classification are both recorded, but their relationship is not explained.

What does the primary outcome count?

The primary outcome is a binary participant-level event summarized as a count: whether each HIV-positive participant reported a solicited local symptom under the stated definition. For “any” symptoms, an occurrence at any intensity qualifies. The Grade 3 categories use the severity criteria in the registry. The timeframe includes the 7-day period after each vaccine dose and an across-doses assessment. In general, participant counts can be easier to interpret than a model-based score, but a count alone does not quantify a comparative effect or its uncertainty. For that, group-specific results and an estimate with an appropriate uncertainty interval would be needed; those primary results are not reported in the registry record.

Why does the analysis population matter?

The registry says the primary symptom analysis used the Total Vaccinated cohort, including vaccinated subjects for whom data were available and who had completed symptom sheets. This is a description of who contributed to that analysis, rather than a statement that every randomized participant was included. In general, analyses based on participants with available outcome data may differ from analyses of all randomized participants if missingness is related to treatment assignment or symptom reporting. The registry does not report how many participants were excluded from this cohort, why data or symptom sheets were unavailable, or how missing symptom assessments were handled.

How should the safety counts be read?

The adverse-event summary gives the number at risk and the number affected by serious adverse events in each of four groups. Such counts describe the observed participants in those groups. In general, a comparative safety analysis may also consider exposure time, event timing, severity, and whether events are repeated or related; those details and a formal comparative model are not reported in the registry record. The listed deaths are counts, not evidence of a causal relationship. The registry does not state whether any event was judged related to a vaccine.

What do planning sample sizes mean?

The record describes sample-size illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. In general, such calculations illustrate the sample size that would be needed under chosen assumptions; they are not the study’s observed power and do not show the probability that the trial’s findings are true. The record expressly distinguishes the illustrations from the trial’s own design. The protocol’s sample-size justification and the assumptions used by the investigators are not reported in the registry record. No sample-size values for those illustrations are included in the registry record for this analysis.

What inference can be made from the posted information?

To interpret a comparative estimate, readers generally need the group-specific outcome data, the estimated contrast, an uncertainty measure such as a confidence interval, and the analysis method. A confidence interval is a range of values compatible with the data and the model at a stated confidence level; its width communicates precision. A p-value, when reported, measures how incompatible the observed data are with a specified null model, subject to the assumptions of the test. Neither measure establishes clinical importance on its own. The registry record does not report primary symptom estimates, confidence intervals, or p-values in the registry entries.

For event counts, methods also depend on whether the endpoint is a participant experiencing at least one event, the number of repeated events, or an event rate over time. The primary endpoint is defined as the number of participants with symptoms, so it is not described as a rate or time-to-event endpoint. No adjustment method, covariates, subgroup analysis plan, or model specification for the primary comparison is reported. Those omissions prevent reconstruction of the inferential analysis from the endpoint definition alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 34 outcome measures and 6 analyses, alongside a primary symptom outcome and several secondary safety outcomes. Assessing many outcomes can create multiplicity: when multiple hypotheses are tested, the chance of at least one apparently unusual result can increase. In general, investigators may prespecify a primary outcome, use a testing hierarchy, adjust significance thresholds, or emphasize estimation rather than a series of tests. The multiplicity strategy, if any, is not reported in the registry record. The number of outcome measures and analyses does not by itself show how many statistical tests were performed or whether any adjustment was used.

The primary analysis population is described as vaccinated participants with available data and completed symptom sheets. The record does not report the number of participants with missing symptom data, the reasons for missingness, or whether participants with incomplete follow-up were included in any particular way. It also does not report an imputation method, sensitivity analysis for missing outcomes, or a comparison of included and excluded participants. The number analyzed for the primary symptom outcome therefore cannot be established from the registry entries.

Randomization is reported, but the primary population description is not an all-randomized analysis. The registry does not report an intention-to-treat analysis population or a detailed analysis plan. It also does not explain how protocol deviations, incomplete vaccine schedules, or missing data were addressed. These details matter because the analysis population and missing-data approach can affect the interpretation of a comparison. No adjustment for multiplicity or missingness should be assumed in the absence of a reported method.

11. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: appendicitis (1.6%), gastritis (0.8%), pneumonia bacterial (0.8%), pulmonary tuberculosis (0.8%), tonsillitis (0.8%).

The registry’s serious-adverse-event summary lists 9 affected participants among 129 at risk in the HIV+/Cervarix Group and 9 among 128 in the HIV+/Gardasil Group. In the HIV-negative groups, it lists 4 affected among 144 at risk for Cervarix and 1 among 145 at risk for Gardasil. Death counts are 0, 1, 0, and 0 in the same group order. These figures describe the recorded groups; they do not establish that a vaccine caused an event or death.

The registry also lists serious-event terms with percentages: appendicitis, 1.6%; gastritis, 0.8%; bacterial pneumonia, 0.8%; pulmonary tuberculosis, 0.8%; tonsillitis, 0.8%; and urinary tract infection, 0.8%. The available record does not give a causal assessment or enough detail to interpret these terms as vaccine-related. It also does not report a comparative statistical analysis for serious events. The HIV-positive and HIV-negative groups are separate population groups, not randomized levels of HIV status. These counts should therefore be read as descriptive safety information, not as definitive comparisons of risk or evidence of causation.

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

The study record supports a description of a randomized Phase IV design with four groups defined by HIV status and vaccine, a three-dose schedule, and a primary endpoint concerning solicited local symptoms in HIV-positive participants. It also provides serious-adverse-event counts and death counts for each group. These details clarify what was planned and which safety information is recorded, but the primary symptom counts and comparative estimates are not reported in the registry record.

Without the primary results, it is not possible to describe the observed frequency of local symptoms, estimate a difference between Cervarix and Gardasil for that endpoint, or assess the precision of such a difference. No equivalence or non-inferiority conclusion can be inferred from the absence of reported estimates. Likewise, serious-event counts are not evidence on their own that an event was caused by a vaccine, and they do not establish a difference in safety between groups.

The study’s purpose includes safety and immunogenicity, but the registry entries do not include specific immunogenicity results. The endpoint and adverse-event data also do not establish vaccine efficacy against HPV infection or cervical cancer. In general, a study result answers only the questions measured by its reported outcomes, in the analyzed populations and over the specified follow-up. The primary symptom window is limited to the 7 days after each dose and across doses; it cannot by itself characterize long-term safety.

The planning illustrations described in the record are based on the observed effect and specified assumptions. They should be understood as planning exercises rather than observed power or evidence about the certainty of a treatment effect. The registry’s reported design and safety counts are useful for understanding the trial’s scope, but the missing primary estimates and statistical analysis details constrain stronger interpretation.

13. Why This Trial Matters Statistically

This trial raises a statistical question about comparing two vaccines while also including participants with different HIV status. The four-group structure makes it important to distinguish the within-status vaccine comparisons from comparisons between HIV-positive and HIV-negative participants. Only vaccine assignment is described as randomized; HIV status is a characteristic defining the groups. Treating those contrasts as interchangeable would obscure the design and could lead to unsupported conclusions.

The primary outcome also illustrates the importance of precise endpoint definitions. The registry specifies the symptoms, severity criteria, follow-up window, and analysis population. These details determine what counts as an event and which participants contribute information. A participant count for solicited symptoms is not the same measure as a count of all adverse events, a rate of repeated events, or an immunogenicity measure.

Reporting completeness is central to statistical interpretation. The registry gives detailed endpoint definitions and serious-event counts but does not report the primary symptom results, comparative estimates, uncertainty intervals, or analysis plan in the registry record for this account. As a result, the design can be described, but the precision and direction of the primary comparison cannot. This distinction—between a clearly defined endpoint and a reported result—is important in clinical research reading.

Finally, the serious-event figures show why descriptive safety counts require context. The groups have recorded numbers at risk and affected, but the registry information does not supply causal assessments, event timing, or a formal comparison. Statistical interpretation must reflect what is actually measured and reported, rather than treating raw counts as proof of a vaccine effect.

14. 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 primary limitation for interpreting the main clinical question is that the registry record does not report the primary endpoint counts or comparative statistical estimates in the registry record for this analysis. Without those results, the frequency and precision of solicited symptoms cannot be assessed. Although the record gives serious-adverse-event counts, these do not substitute for the primary symptom results.

The analysis population is described as vaccinated subjects with available data and completed symptom sheets, but the numbers excluded from the primary analysis and reasons for missingness are not reported in the registry record. The missing-data approach, handling of incomplete vaccination schedules, and sensitivity analyses are also not reported. The record does not describe the randomization method, allocation ratio, masking details beyond the triple classification and observer-blind summary, or the statistical model used for the primary comparison.

The record lists 34 outcome measures and 6 analyses, but the multiplicity strategy is not reported. The investigators’ sample-size rationale is not reported; the listed planning assumptions are expressly described as illustrations rather than the trial’s own design. The registry does not report a detailed immunogenicity outcome in the registry record, despite immunogenicity being part of the study purpose.

For serious adverse events, the available information gives counts and selected terms but not event timing, duration, relatedness assessments, participant-level context, or a formal comparison. The record’s completion status and dates do not fill these reporting gaps. These limitations restrict conclusions to describing the stated design and recorded safety counts; they do not support conclusions about causation, comparative immunogenicity, or efficacy.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of Safety and Immunogenicity of a Human Papillomavirus (HPV) Vaccine in Human Immunodeficiency Virus (HIV) Infected Females — NCT01031069.
• Registry record last updated 2020-07-21; status last verified 2020-07.
• Results first posted 2019-07-24.
• 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.

18. Record Summary

NCT01031069 is a completed Phase IV randomized parallel-group study of Cervarix and Gardasil in females aged 15 to 25 years, with HIV-positive and HIV-negative groups. Enrollment is recorded as 873. The arm descriptions specify three vaccine doses at Day 0, Week 6, and Month 6. The primary endpoint counts HIV-positive participants with any and Grade 3 solicited local symptoms during the 7-day follow-up after each dose and across doses.

The primary analysis population is described as vaccinated participants with available data and completed symptom sheets. The primary outcome results and comparative estimates are not reported in the registry record. Serious-adverse-event counts are listed for all four groups, along with deaths and selected serious-event terms. The record does not report the primary statistical analysis plan, missing-data method, or multiplicity strategy. Its planning sample-size calculations are described as illustrations, not as the trial’s design justification or observed power.