Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I (NCT02616029), a randomized phase 3 study. The primary outcome is Percentage of Participants With Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/mL at Week 12 as Defined by Pure Virologic Response (PVR).

2. Clinical Question

3. Trial Design

This was a Phase 3b, open-label pilot study of switching to E/C/F/TAF in virologically suppressed adults with archived M184V and/or M184I mutations. Enrollment was 66. The study had two parts with different mutation eligibility: Part 1 required the specified mutation without another NRTI resistance mutation, whereas Part 2 included participants with or without 1 or 2 TAMs. Both parts involved switching from a stable regimen of FTC/TDF or ABC/3TC plus a third antiretroviral agent.

The registry reports randomized allocation and no masking, while its model is listed as single-group. The posted outcome groups are Part 1, Part 2 and their total; they do not constitute a concurrent comparison of E/C/F/TAF with another treatment. The way random allocation related to the two parts is not reported in the registry record. Part 2 is described as taking E/C/F/TAF orally once daily for 48 weeks. The Part 1 description gives the E/C/F/TAF dose as 150/150/200/10 mg.

The primary objective was to evaluate efficacy after switching. The study was planned in two parts: continuation to Part 2 depended on an internal data monitoring committee review and an acceptable rate of virologic failure in Part 1. The criteria for acceptability and details of that review are not reported in the registry record. The record lists the study as completed, with primary completion on 2018-10-11.

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: 120 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set included all the randomized participants who received at least one dose of study drug and excluded participants with any major protocol violations.

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.

Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) < 50 Copies/mL at Week 12 as Defined by Pure Virologic Response (PVR), measured over Week 12.

The primary endpoint is the percentage of participants with HIV-1 RNA < 50 copies/mL at Week 12, defined using Pure Virologic Response (PVR). PVR is based on whether a participant had a confirmed virologic rebound during the study, rather than being only a measure of viral load at a single visit. The endpoint definition counts rebound as 2 consecutive HIV-1 RNA values at least 50 copies/mL, or a last available HIV-1 RNA value at least 50 copies/mL followed by premature study discontinuation.

This distinction matters because a one-time viral load result and a confirmed rebound are not the same outcome. PVR uses the pattern of results and the discontinuation rule specified in the registry. It therefore addresses whether participants met the study’s definition of maintaining virologic response through the Week 12 assessment. It does not, on its own, describe every participant’s measurements, explain why any participant discontinued, or establish how missing observations were handled in every other endpoint.

The primary analysis population was the Full Analysis Set: randomized participants who received at least one dose of study drug, excluding participants with major protocol violations. The posted total for this endpoint is 62 participants. Results are also separated by study part, which had different mutation eligibility criteria.

7. Results Posted in the Registry

• Part 2: E/C/F/TAF: 100.0% (26/26) versus 100.0% (36/36) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0), risk ratio 1.00 (1.00–1.00); unadjusted two-proportion z-test p = n/a.

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.

Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Part 2: E/C/F/TAF: 96.2% (25/26) versus 91.7% (33/36) on control; risk difference 4.5 percentage points (95% CI -7.2 to 16.2), risk ratio 1.05 (0.93–1.19); unadjusted two-proportion z-test p = 0.478.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Part 2: E/C/F/TAF and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Part 2: E/C/F/TAF: 100.0% (26/26) versus 91.7% (33/36) on control; risk difference 8.3 percentage points (95% CI -0.7 to 17.4), risk ratio 1.09 (0.99–1.20); unadjusted two-proportion z-test p = 0.131.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Part 2: E/C/F/TAF and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Part 2: E/C/F/TAF: 96.2% (25/26) versus 88.9% (32/36) on control; risk difference 7.3 percentage points (95% CI -5.4 to 19.9), risk ratio 1.08 (0.94–1.24); unadjusted two-proportion z-test p = 0.300.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Part 2: E/C/F/TAF and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes extend the assessment of viral suppression to additional time points and use both PVR and FDA Snapshot definitions. Across the posted FDA Snapshot outcomes, the overall pattern is that a high proportion of participants met the stated HIV-1 RNA thresholds. This is broadly consistent with the primary Week 12 PVR result, while remaining a different description of response because the endpoint definitions and assessment times are not the same.

Some secondary outcomes are reported for the study parts as well as for the total group. These comparisons remain descriptive: the parts have different mutation eligibility, and the registry does not post a concurrent alternative-treatment group. The study-part contrasts therefore do not estimate the effect of switching versus continuing a prior regimen. Differences in the point estimates across secondary outcomes should also be considered with their confidence intervals and the limited numbers in each part, rather than treated as definitive distinctions.

The registry lists 21 posted secondary outcomes, but the outcomes available in the record do not include reported analyses for each listed measure. Detailed results for every secondary endpoint are not reported in the registry record. The secondary findings are best read as supportive context for the primary endpoint, not as independent confirmation of a comparative treatment effect.

As a general statistical explanation, examining many outcomes creates more opportunities for apparently notable results to arise by chance. Unadjusted secondary comparisons do not account for that multiplicity, so their p-values, where posted, carry less weight than a prespecified primary analysis with a clearly reported testing strategy. The registry record does not report a multiplicity adjustment or a complete inferential plan for the secondary outcomes. The pattern across endpoints is informative descriptively, but should not be treated as a collection of independent confirmatory tests.

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

• Percentage of Participants With Emergence of New Mutations in HIV-1 Reverse Transcriptase and Integrase
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using PVR
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using PVR
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 Using the FDA Snapshot Analysis
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 Using the FDA Snapshot Analysis
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 Using the FDA Snapshot Analysis
• Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 12 Using the FDA Snapshot Analysis
• Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Week 24 Using the FDA Snapshot Analysis

9. Statistical Interpretation

10. Statistical Methods Explained

What does the primary percentage represent?

The endpoint is a binary outcome for each participant: meeting or not meeting the PVR definition at Week 12. The reported percentage is the proportion meeting that definition in the analysis group. The registry’s definition focuses on confirmed rebound, including the specified rule for a last available viral load followed by premature discontinuation. This is the endpoint definition, not a general rule for interpreting every HIV-1 RNA measurement.

As a general statistical explanation, a proportion is an estimate of the frequency of an outcome in the analyzed group. It is not a guarantee that the same proportion would be observed in another sample from a broader population. The sample size and the observed pattern of outcomes affect how precisely the proportion can be estimated.

How should the confidence intervals be read?

The registry reports 95% confidence intervals around the primary percentages. As a general statistical explanation, a confidence interval gives a range of values compatible with the data and the method used to calculate the interval. It conveys sampling uncertainty around an estimate; it is not a range containing a known proportion of individual participants, and it does not measure all possible sources of uncertainty, such as limitations in recruitment or endpoint ascertainment.

For outcomes with all participants meeting the endpoint, the point estimate is at the upper boundary of 100.0%, but the lower confidence limit remains below it. That lower limit is important: observing no failures in a group does not establish that the population probability of failure is zero. The lower bounds differ across the study parts and total group, consistent with the different group sizes and the precision of their estimates.

What does a risk difference mean in this record?

A risk difference expresses the difference between two outcome proportions. In this record, comparisons are posted between Part 2 and Part 1, not between E/C/F/TAF and a concurrent untreated or alternative-treatment group. As a general statistical explanation, a difference estimate and its confidence interval describe the contrast between the groups as analyzed. Interpretation as a treatment effect would require a design and analysis supporting that causal comparison. The two study parts have different eligibility criteria, and the registry model is listed as single-group.

The primary risk difference is 0.0, with both confidence limits at 0.0, because the posted primary proportions are identical in the two parts. That arithmetic description does not show that the parts are equivalent on characteristics beyond the endpoint. Nor does it answer what would have happened to these participants had they continued their prior regimens.

Why do endpoint definitions matter?

The primary PVR endpoint and the FDA Snapshot outcomes are distinct analysis definitions. PVR is defined around confirmed rebound. The registry also posts FDA Snapshot percentages at specified time points, but the detailed classification rules for that analysis are not reported in the registry record. The same HIV-1 RNA threshold can therefore appear in more than one outcome without making the outcome definitions identical.

As a general statistical explanation, different analysis rules can classify participants differently when assessments are missing, occur outside a visit window, or are followed by discontinuation. Those general possibilities should not be treated as an account of what occurred for specific participants in this study. Participant-level reasons and detailed handling rules are not reported in the registry record.

What can the planning illustrations say?

The planning illustrations use the observed effects as inputs under stated assumptions: a two-sided significance level of 0.05, equal allocation between two groups and a normal approximation. The requested effect is a stated fraction of the observed effect. These are hypothetical planning calculations, not the study’s original design justification, not observed power, and not evidence that the trial had a particular probability of detecting an effect. The original sample-size justification is not reported in the registry record. Because the observed comparison is between study parts rather than randomized treatment alternatives, the planning figures should not be interpreted as establishing a suitable size for a confirmatory treatment comparison.

As a general statistical explanation, power calculations depend on assumptions about the effect to detect, variability or outcome frequency, allocation and the analysis method. A calculation based on an effect observed in a small study can be especially sensitive to that estimate. These illustrations describe what their assumptions imply for planning; they do not add evidence to the observed endpoint results.

11. Confidence Intervals and Precision

The primary estimate for the total E/C/F/TAF group is 100.0%, with a 95% confidence interval of 94.2 to 100.0. For Part 1, the estimate is 100.0% with an interval of 90.3 to 100.0; for Part 2, it is 100.0% with an interval of 86.8 to 100.0. The common upper limit reflects that the estimate is already at 100.0%. The lower limits show that the data remain compatible with lower underlying proportions, particularly when considering each part separately.

As a general statistical explanation, intervals tend to be less precise when information is limited, and splitting a study population into smaller groups usually leaves fewer observations to inform each group estimate. Confidence intervals describe sampling uncertainty under the method used; they do not account for every source of uncertainty in a study. They cannot correct for the open-label design, differences in eligibility between parts, limitations in the analysis population, or questions about how participants were assigned to parts.

The interval for the combined group is narrower at its lower end than either part-specific interval. The combined estimate draws on both groups, but it also combines people with different eligibility regarding additional NRTI resistance mutations. Its precision should therefore be read alongside the population it represents, not as proof that the subgroup estimates are identical. A narrow or bounded interval does not establish causality, and the endpoint’s 100.0% point estimate does not mean that future participants would necessarily have the same outcome.

12. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary Week 12 PVR endpoint and lists 21 secondary outcomes. It does not report a complete statistical analysis plan, a hierarchy for testing the secondary outcomes, or a multiplicity adjustment. The registry record also lists no reported analyses. This means the posted outcome estimates can be described, but the record does not establish which secondary comparisons, if any, were intended to support formal confirmatory claims.

As a general statistical explanation, testing multiple outcomes can increase the chance of false-positive findings if each is interpreted as a separate confirmatory test without an appropriate strategy. Unadjusted secondary p-values should therefore be treated as exploratory evidence. This does not mean that every secondary result is uninformative; it means that the set of results does not have the same inferential force as a single prespecified test with a reported multiplicity plan.

The primary analysis population is defined as randomized participants who received at least one dose of study drug, excluding participants with major protocol violations. This is the Full Analysis Set described in the registry. The record does not provide participant-level reasons for exclusion or a fuller account of how protocol violations were determined.

The primary PVR definition includes a rule involving a last available HIV-1 RNA value and subsequent premature discontinuation. That rule is part of the endpoint definition. Detailed missing-data methods for the primary analysis and for the FDA Snapshot outcomes are not reported in the registry record. As a general statistical explanation, missing assessments can affect an estimated proportion depending on the endpoint rules and the analysis method; without the detailed rules and participant-level disposition, the extent and direction of any such effect cannot be determined.

The brief study description also states that continuation to Part 2 depended on an internal data monitoring committee review of Part 1 and an acceptable virologic failure rate. The review details, decision criteria and any formal interim-analysis methods are not reported in the registry record. The existence of that planned review should be distinguished from an unreported formal interim statistical analysis.

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 (1.6%), lung adenocarcinoma (1.6%), prostatic adenoma (1.6%), tonsil cancer (1.6%), acute kidney injury (1.6%).

For the total E/C/F/TAF group, the registry reports 5 participants with serious adverse events among 64 at risk, 26 with other adverse events among 64 at risk, and 1 death. The adverse-event population size differs from the primary endpoint analysis total of 62. The registry does not explain this difference in the posted safety summary.

The listed serious adverse event terms each have a reported frequency of 1.6%: Death, Lung adenocarcinoma, Prostatic adenoma, Tonsil cancer, Acute kidney injury and Proteinuria. These are term-level entries; the record does not establish from this summary whether the terms represent distinct participants or whether any event was related to study treatment. The reported death count should not be interpreted as evidence of causation.

As a general statistical explanation, adverse-event counts describe events observed and recorded in the study population over its follow-up. In an open-label study without a concurrent comparison group, such counts cannot by themselves distinguish background events from events caused by treatment. The safety figures are descriptive and do not provide a comparative estimate of risk.

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

The results show that all participants included in the primary analysis met the study’s Week 12 PVR definition, as reported for each part and for the total group. The confidence intervals convey uncertainty around those observed proportions. The result is specific to the enrolled population, the Full Analysis Set definition, the endpoint rules and the study’s follow-up.

It does not establish that E/C/F/TAF is superior to continuing FTC/TDF or ABC/3TC plus a third agent, because the posted results do not include a concurrent group assigned to continue those regimens. It also does not establish equivalence between the study parts, whose eligibility criteria differ. The registry’s randomized-allocation metadata does not resolve these interpretive limits, because the way allocation operated is not reported in the registry record and the model is listed as single-group.

The results do not show that every participant had HIV-1 RNA below the threshold at every measurement, since PVR is defined by confirmed rebound rather than continuous measurement. Nor do the posted aggregate percentages explain individual outcomes, missing assessments, discontinuations, or the reasons behind the adverse events. Those details are not reported in the registry record.

As a general statistical explanation, an observed proportion is evidence about the analyzed sample, while conclusions about other populations or causal effects depend on design, measurement and assumptions. The high observed primary proportion is a descriptive finding from this pilot study. It should be considered together with the confidence intervals, group sizes, eligibility differences and the absence of a concurrent treatment comparator.

15. Why This Trial Matters Statistically

This study is statistically useful because it illustrates how a high observed response proportion can coexist with meaningful uncertainty. Every participant in the primary analysis met the PVR definition, yet the lower limits of the confidence intervals remain below 100.0%, especially for the separately reported study parts. The point estimate alone would conceal that uncertainty.

The distinction between PVR and FDA Snapshot outcomes is also important. Both address virologic response, but their definitions differ. Reading multiple endpoints as if they were interchangeable can blur what was actually measured. The registry’s explicit PVR definition makes clear that the primary result concerns confirmed rebound, including a stated discontinuation rule.

The two-part design brings another interpretive issue into view. Part 1 and Part 2 did not have identical mutation eligibility, and the study did not post a concurrent treatment comparator. Comparisons between parts therefore describe groups within a switch study rather than a randomized contrast between treatment strategies. The registry’s combination of randomized-allocation metadata and a single-group model further underscores why the allocation process must be understood before making causal claims; that process is not reported in the registry record.

Finally, the sample-size illustrations are based on observed effects under explicit assumptions, not on the original study design or observed power. Distinguishing a planning calculation from an observed result is essential. The study supports careful description of its enrolled participants and outcomes, while leaving comparative conclusions and several analysis details unresolved.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The pilot enrolled 66 participants, with 62 in the primary Full Analysis Set. The resulting group sizes limit the precision of part-specific estimates, as reflected in their confidence intervals. The registry record does not report a justification for the original sample size, so it is not possible to assess the planned precision or power from the available record.

The study was open-label and the posted results contain no concurrent alternative-treatment group. The results therefore cannot separate outcomes associated with switching from outcomes that might have occurred while continuing the prior regimen. Although randomized allocation is listed, the model is listed as single-group and the allocation process is not reported in the registry record.

Eligibility differed between the parts: Part 1 excluded other NRTI resistance mutations, while Part 2 allowed participants with or without 1 or 2 TAMs. The part-specific results are consequently not a simple randomized comparison of otherwise equivalent populations. The combined estimate includes both eligibility groups and may not represent either group alone.

The registry does not report detailed missing-data methods for all endpoints, a full analysis plan, or a multiplicity strategy for secondary outcomes. It also does not provide full reported analyses for the listed outcome measures. The primary endpoint has a stated PVR definition, but that does not resolve how missing assessments were handled across the separate FDA Snapshot outcomes.

Safety information is summarized descriptively, and the record does not establish treatment relatedness for the listed events. The internal review that governed continuation to Part 2 is described, but its criteria and analysis details are not reported in the registry record. These limitations constrain interpretation of both efficacy and safety findings.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Study to Evaluate Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF) Fixed Dose Combination (FDC) in Virologically-Suppressed HIV-1 Infected Adults Harboring the Archived Isolated NRTI Resistance Mutation M184V/M184I — NCT02616029.
• Registry record last updated 2020-07-23; status last verified 2020-07.
• Results first posted 2019-11-04.
• 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

NCT02616029 is a completed Phase 3b, open-label pilot study sponsored by Gilead Sciences. It enrolled 66 adults with HIV-1 infection who were virologically suppressed and had archived M184V and/or M184I mutations. Participants switched from FTC/TDF or ABC/3TC plus a third antiretroviral agent to E/C/F/TAF.

The primary endpoint was the Week 12 percentage meeting the PVR definition for HIV-1 RNA < 50 copies/mL. The registry reports 100.0% for Part 1, Part 2 and the total group; the total group’s 95% confidence interval is 94.2 to 100.0. The Full Analysis Set included randomized participants who received at least one dose and excluded those with major protocol violations.

The registry describes two parts with different mutation eligibility, lists randomized allocation and a single-group model, and does not provide a concurrent treatment comparison. It also notes that continuation to Part 2 depended on an internal review. Further details of allocation, analysis planning, missing-data methods and multiplicity are not reported in the registry record.