Pilot Study of Adding Raltegravir (MK-0518) to Antiretroviral Therapy in Patients With Low Level Viremia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pilot Study of Adding Raltegravir (MK-0518) to Antiretroviral Therapy in Patients With Low Level Viremia (NCT00618371), a na na study. The primary outcome is Number of Participants With HIV-1 RNA Response: ≥ 1 Log Decrease in Viral Load.

2. Clinical Question

3. Trial Design

This was a completed, single-group pilot study sponsored by the University of Pittsburgh. The registry lists 10 participants enrolled, with HIV infection as the condition studied. The start date is 2007-10 and the primary completion date is 2009-03. The intervention was raltegravir, also called MK-0518, added to antiretroviral therapy. The arm description states that participants received 400 mg orally twice daily in addition to their existing therapy.

The registry identifies masking as none and allocation as NA. It does not describe a randomized treatment assignment or a concurrent control arm; its record explicitly characterizes the design as single-group. This means the study was set up to observe participants receiving the added drug, not to estimate a contrast between separately assigned treatment groups. The absence of a control group limits what can be concluded about whether changes over time were attributable to intensification rather than other influences.

The stated primary outcome was the number of participants with an HIV-1 RNA response, defined as at least a 1 log decrease in viral load. The timeframe was 4 weeks. The registry describes a non-commercial, sensitive single copy assay for measuring HIV RNA. It also lists a secondary outcome concerning proviral DNA response, sequence variation, and genetic variation during raltegravir addition among individuals who have declines in HIV. The detailed analysis plan, eligibility criteria, and sample-size justification are not reported in the registry record. The study is marked completed, but completion alone does not provide the missing outcome estimate.

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: Participants had Cluster of Differentiation 4(CD4) counts of greater than 200 cells/microliter, HIVRNA\< 50 copies/mL plasma for ≥12 months; and not receiving prophylaxis for opportunistic infections (OI)s; no history of exposure to raltegravir, HIV-1 drug resistance,febrile illness within 3 weeks or vaccination within 6 weeks before enrollment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Number of participants based on estimates of how many will have decreased viral RNA levels. If 10 participants do not have decreased RNA, the number of patients with potential for decrease is \<15% of all suppressed patients.

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 Participants With HIV-1 RNA Response: ≥ 1 Log Decrease in Viral Load, measured over 4 weeks.

The primary endpoint counts participants who meet a defined viral-load response threshold: a decrease of at least a 1 log in HIV-1 RNA. The registry describes this as a decrease of at least 10fold and specifies measurement at 4 weeks. HIV RNA was assessed with a non-commercial, sensitive single copy assay. The endpoint is therefore a binary response for each participant: the measured decrease either reaches the stated threshold or it does not. The primary summary is the number of participants meeting the criterion, rather than an average change in viral load.

A threshold-based endpoint can make a response criterion explicit and can focus attention on changes large enough to meet a prespecified definition. It also discards information about the size of changes that fall short of the threshold and does not, by itself, explain the biological source of residual virus. The registry's scientific rationale concerns latent infection versus ongoing infection, but the listed primary endpoint measures viral RNA response, not those mechanisms directly.

The actual number of participants meeting the response definition is not reported in the registry record. Therefore, the response proportion and its precision cannot be described from this record. The endpoint definition and assay are reported, but no participant-level values or primary response estimate are available.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a count of participants meeting a binary response definition. For each participant, the assay result is classified according to whether HIV-1 RNA decreased by at least a 1 log. The study-level result would be the number meeting that criterion, accompanied, where available, by an estimate of uncertainty. This type of endpoint differs from a continuous outcome such as the average RNA change: it answers how many crossed the chosen threshold, not how large each participant's change was. The registry record does not report the response count or a confidence interval.

What does a confidence interval add?

In general, a confidence interval communicates statistical uncertainty around an estimate. For a binary response, it can show how much the estimated response frequency might vary because the study observes only a sample of the population of interest. A narrow interval indicates greater precision than a wide interval, while neither width nor position alone determines clinical importance. No confidence interval for this primary response is reported in the registry record, so precision cannot be evaluated from the posted outcome information.

Why does the study design matter?

This study has one treatment group and no concurrent control group. A within-group response count describes participants who received raltegravir in addition to antiretroviral therapy. It does not directly estimate the difference between that strategy and continuing antiretroviral therapy without the addition. General statistical interpretation of a treatment effect relies on an appropriate comparison; without one, time trends, measurement variation, and other influences cannot be separated from the intervention's possible contribution. The registry record lists allocation as NA and masking as none, and does not describe randomization.

How should a binary outcome be analyzed?

For a binary endpoint, methods often estimate the response frequency and its uncertainty, with the precise approach depending on the design and the amount of data. When counts are small, some approximations can perform poorly, and exact or otherwise appropriate methods may be considered. This is general statistical context, not a description of the analysis used in this study. The registry record lists no analyses and does not report the statistical procedure, a response estimate, or its uncertainty. It would therefore be inappropriate to infer which method was used.

What do the planning assumptions mean?

The registry information describes planning illustrations based on a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of an observed effect. These are assumptions for an illustrative two-arm planning exercise, not a description of this single-group pilot's design. The posted planning values are not available in the registry record. Such calculations concern a hypothetical future design and must not be interpreted as observed power for the completed study. Sample-size illustrations are planning aids, not evidence that an effect was detected or that a particular number of participants was sufficient.

In general, a two-sided significance level defines how a statistical test treats departures in either direction under its null model. Equal allocation is an assumption that divides planned enrollment evenly between two groups, while a normal approximation uses a mathematical distribution to approximate a sampling distribution. These concepts do not establish that the assumptions fit this single-group study. No trial-specific sample-size justification or detailed statistical plan is reported in the registry record.

What can the assay and endpoint tell us?

The registry says HIV RNA was measured using a non-commercial, sensitive single copy assay. Sensitivity matters because the scientific question concerns low-level plasma virus; a more sensitive measurement can detect levels that less sensitive methods may not resolve. Measurement sensitivity does not remove uncertainty, establish the source of detected virus, or replace reporting the observed results. The threshold endpoint also reduces a potentially graded change to a response classification. Its interpretation depends on the stated definition and the actual number meeting it, which is not reported in the registry record.

The registry lists a secondary outcome involving proviral DNA response and sequence variation during raltegravir addition in individuals who have declines in HIV. Such measures may address aspects of the study's biological question that a viral-load threshold alone cannot. However, the record does not report their numerical results or the methods used to analyze them. No additional model assumptions, adjustments, interim analyses, or handling of repeated measurements are reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Raltegravir Intensification")
n      <- c(10)
events <- c(0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Raltegravir Intensification  10  0  0.0  0.0  30.8  0.0  27.8  0.2  28.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary viral RNA response outcome and a secondary outcome concerning proviral DNA response and sequence variation. It also records two outcome measures and no analyses. It does not explain how multiple outcomes or multiple possible comparisons were handled. In general, examining several outcomes can increase the chance of finding an apparently notable result by chance if no suitable strategy is used. That general concern cannot be translated into a trial-specific adjustment because a multiplicity procedure is not reported in the registry record.

The registry record does not describe how missing outcome measurements were handled, whether participants were analyzed according to a defined analysis population, or how exclusions from an analysis would be determined. It also does not report whether all enrolled participants had an endpoint measurement. Absence of these details is not evidence that there were missing observations or that there were none; the missing-data status and analysis populations are not reported in the registry record.

Because the primary response count itself is not reported, readers cannot reconstruct the endpoint summary or assess whether the analysis included all 10 enrolled participants. Details such as imputation, sensitivity analyses, and rules for classifying participants without a measurement are not reported in the registry record. These gaps limit reproducibility and make it harder to judge whether the reported outcome, if available elsewhere, would represent all enrolled participants or a subset.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry safety figures list Group 1 with 10 participants at risk for serious adverse events and 0 affected. The same group has 10 at risk for other adverse events and 0 affected. These are the counts recorded for this group; they should not be read as proof that no adverse event of any kind occurred outside the categories or reporting scope captured in the registry.

The death count is not reported in the registry record. It is distinct from the recorded zero counts for serious and other adverse events, so it should not be interpreted as zero deaths. The record also lists no top serious adverse-event terms. A lack of listed terms does not provide detail about event definitions, collection procedures, or the duration of safety follow-up, which are not reported in the registry record.

These figures describe the recorded safety counts in a small, single-group study. They do not compare safety with a control group, and the registry does not provide further detail about exposure or event ascertainment. The count of zero affected participants should therefore be read narrowly as the posted count, not as a general estimate of safety.

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

The record establishes that investigators enrolled 10 participants in a completed, single-group pilot study of raltegravir added to antiretroviral therapy. It specifies a primary outcome based on an HIV-1 RNA decrease of at least a 1 log at 4 weeks and identifies the assay used. These details show what the study set out to measure and provide context for the scientific question about residual low-level virus.

The record does not report the primary response count, an estimate of uncertainty, or the results of the listed secondary outcome. It therefore does not show how many participants met the viral-load threshold or how consistent the response was. Nor does the primary endpoint alone identify whether residual virus arose from latent infection or ongoing new infection. The absence of those results should not be mistaken for a finding of no response.

The single-group design also means that the study does not offer a randomized, concurrent comparison with antiretroviral therapy alone. Even if a response count were available, the design would not by itself determine whether observed changes were caused by raltegravir. A control comparison and appropriate analysis would be needed to estimate a treatment contrast more directly.

Thus, the registry record is informative about the pilot's question, intervention, endpoint, and design, but incomplete for judging the observed efficacy outcome or its precision. The safety counts show zero affected participants in the posted serious and other adverse-event categories, while the death count is not reported. These limited figures do not support broader conclusions about treatment effects or safety. They describe what the registry records, not what should be done in clinical care.

14. Why This Trial Matters Statistically

Statistically, this trial illustrates the difference between defining an outcome and reporting its result. The registry gives a threshold for response, a measurement timeframe, and an assay, but does not report how many participants crossed the threshold. Without that count, readers cannot estimate the response frequency, assess its precision, or evaluate whether the observed data align with the study's stated question.

The design also matters to the kind of inference that is possible. A single group can describe outcomes among people receiving an added treatment, but cannot supply the same direct contrast as a concurrent randomized control group. That distinction is important when interpreting changes in a biological measurement over time. It is not enough to know that an endpoint was measured; readers also need a design and analysis that support the intended comparison.

The study's biological motivation concerns the source of residual HIV-1 viremia, while its primary endpoint is a threshold-based change in plasma RNA. These are related but not identical questions. The difference highlights why endpoints should be matched carefully to the scientific claim: a change in a measured marker does not necessarily resolve the mechanism behind that marker.

Finally, the record separates safety counts from the missing efficacy result. Zero recorded serious adverse events is a descriptive count, not a comparative safety estimate. The absent death count and the lack of detailed analysis and missing-data methods further demonstrate why transparent reporting matters. Together, these features make the trial a useful example of how design, endpoint definition, result availability, and uncertainty shape what a small pilot can establish.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most important limitation in interpreting this specific trial is that the primary response count is not reported in the registry record. Without it, the main outcome cannot be quantified. The record also lacks a confidence interval or other precision estimate, so uncertainty around the primary result cannot be assessed. The listed secondary outcome has no reported results.

The study enrolled 10 participants and used a single-group design. It has no concurrent comparison arm, and the registry does not describe randomized allocation. As a result, even a reported before-and-after change would not isolate the contribution of raltegravir from other possible influences. The registry does not provide participant characteristics or detailed eligibility criteria, limiting assessment of how well the enrolled group represents the intended population.

The primary endpoint is measured at 4 weeks and applies a threshold to RNA change. It does not capture the full range of changes below or above that threshold, and the record does not report follow-up beyond that timeframe for the primary measure. Although the assay is described as sensitive, the assay description cannot substitute for outcome values or an analysis of their uncertainty.

Other trial-specific details are also absent: the statistical analysis plan, sample-size justification, handling of missing measurements, analysis populations, and procedures for multiple outcomes are not reported in the registry record. The safety record lists zero serious and zero other adverse events among the recorded group counts, but the death count is not reported and further safety follow-up details are unavailable. These limitations restrict interpretation to the study's design and posted counts rather than a firm estimate of treatment effect.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pilot Study of Adding Raltegravir (MK-0518) to Antiretroviral Therapy in Patients With Low Level Viremia — NCT00618371.
• Registry record last updated 2017-02-01; status last verified 2016-12.
• Results first posted 2016-12-06.
• 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.

19. Record Summary

This completed pilot study examined raltegravir added to antiretroviral therapy in participants with HIV infection and low-level viremia. The registry records 10 participants enrolled and describes a single-group design with no masking. The intervention was raltegravir 400 mg orally twice daily in addition to antiretroviral therapy.

The primary endpoint was the number of participants with at least a 1 log decrease in HIV-1 RNA at 4 weeks, measured with a sensitive single copy assay. The primary response count and its uncertainty are not reported in the registry record. A secondary outcome concerning proviral DNA and sequence variation is listed, but its results are not reported.

The safety record lists 0 serious and 0 other adverse events among 10 participants at risk in the group. The death count is not reported. The record does not provide a randomized comparison, detailed analysis methods, or a sample-size justification.