Evaluating the Safety and Effectiveness of Interferon-Free Treatment of Hepatitis C Virus Infection in HIV-Coinfected Adults on Antiretroviral Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluating the Safety and Effectiveness of Interferon-Free Treatment of Hepatitis C Virus Infection in HIV-Coinfected Adults on Antiretroviral Therapy (NCT02194998), a non-randomized phase 2 study. The primary outcome is Percentage of Participants With Sustained Virologic Response at 12 Weeks After HCV Treatment Discontinuation (SVR12).

2. Clinical Question

This was a study of interferon-free HCV treatment in adults managing both HIV and HCV. Its primary outcome focused on whether HCV RNA remained below the specified assay threshold at a defined follow-up point after treatment ended. The question is clinically focused on virologic response, while the design also allowed the investigators to examine safety and HIV-related outcomes during concurrent antiretroviral therapy.

The study does not estimate a randomized treatment contrast. The cohorts were defined by antiretroviral regimen and treatment duration, and allocation was non-randomized. Differences across cohorts could therefore reflect differences in the participants or their treatment contexts as well as differences in the regimens. The registry record does not report a primary response percentage or confidence interval, so the magnitude and precision of the observed SVR12 result cannot be described from the registered information.

3. Trial Design

This was a phase 2, non-randomized, unmasked, parallel-cohort study with planned enrollment of 46 participants. The registry record lists the study as terminated. Its start date was 2015-09-16, and its primary completion date was 2018-05-17. The reason for termination is not reported in the registry record.

Four cohorts combined two antiretroviral therapy backbones with two HCV treatment durations. Cohorts A and B used integrase inhibitor-based antiretroviral therapy, with raltegravir or dolutegravir. Cohorts C and D used protease inhibitor-based antiretroviral therapy, with darunavir or atazanavir. Cohorts A and C received 24 weeks of HCV treatment; cohorts B and D received 12 weeks.

The HCV regimen included paritaprevir/ritonavir/ombitasvir and dasabuvir, with ribavirin use varying by treatment version. In version 1, ribavirin was used for all participants; in version 2, it was used only for participants with HCV genotype 1a. Cohort descriptions specify concurrent HIV antiretroviral therapy during the HCV treatment period.

Because assignment was not randomized and there was no like-for-like control comparison, these cohorts should not be treated as interchangeable arms in a controlled efficacy trial. The cohort structure describes different treatment contexts; it does not by itself isolate the effect of treatment duration or antiretroviral backbone. The registry record does not report the allocation process, cohort-specific enrollment targets, or the rationale for the design choices.

The National Institute of Allergy and Infectious Diseases (NIAID) is listed as sponsor. In addition to the primary HCV response outcome, registered outcomes included HIV-1 virologic failure and resistance, soluble CD14 and IP-10 measures, HCV resistance mutations, and sustained virologic response 24 weeks after treatment discontinuation. Numerical results for these outcomes are not reported in the registry record.

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: There was no randomization in this study. Participants were stratified according to evidence of cirrhosis (yes versus no). The enrollment to the strata level for cirrhosis=yes was limited to no more than 30% within any particular study cohort.

On-HCV Treatment

Reasons for not completing this period:

Post-HCV Treatment Follow-Up

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants who initiated study treatment.

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: Participants who initiated study treatment.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Sustained Virologic Response at 12 Weeks After HCV Treatment Discontinuation (SVR12), measured over At 12 weeks after last dose of HCV study treatment. The duration for study treatment for Cohorts A and C and Cohorts B and D was 24 and 12 weeks, respectively..

The primary endpoint was the percentage of participants with sustained virologic response 12 weeks after HCV treatment discontinuation, called SVR12. The registry defines response as HCV RNA below the assay’s lower limit of quantification, stated as <15 IU/mL, at the specified follow-up point. The primary population was participants who initiated study treatment.

SVR12 is a virologic endpoint: it classifies participants according to an HCV RNA measurement after treatment has stopped. A threshold-based definition makes the outcome interpretable as a proportion meeting a prespecified laboratory criterion, rather than as a change in RNA level. In general, a post-treatment measurement is used to assess whether the response persists beyond the treatment period; that is the purpose of the 12-week follow-up timing in this endpoint.

The registry describes rules for assigning outcomes when follow-up is incomplete or when earlier HCV measurements met criteria for virologic failure. Participants meeting those failure criteria before SVR12 assessment were counted as non-responders. Participants missing the week 12 result and all subsequent evaluations were also counted as non-responders. If a later HCV RNA result was available, the first such result was used instead to define the primary outcome.

The registry specifies a two-sided 90% confidence interval using the Clopper-Pearson method. The numerical SVR12 percentage, its confidence interval, and the number of participants contributing to that result are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry states that SVR12 was expressed as a percentage of participants and that a two-sided 90% confidence interval was calculated using the Clopper-Pearson method. These details describe how the primary outcome was intended to be summarized. The registry record does not report the resulting percentage, interval limits, or analysis denominator.

What does a percentage estimate describe?

General statistical explanation: for a binary outcome, each participant is classified into one of two categories, such as meeting or not meeting the SVR12 definition. The estimated percentage describes the share of the analysis population classified as meeting that definition. It is a summary of the observed participants, not by itself a comparison with another treatment or a statement about what would have happened under a different regimen.

Here, the outcome rules define who counts as a responder and who counts as a non-responder. Early HCV virologic failure before SVR12 evaluation leads to a non-response classification. Missing the week 12 HCV RNA result and all later evaluations also leads to a non-response classification. If a subsequent HCV RNA evaluation is available, the first such evaluation is used for the primary outcome. These rules affect the binary outcome assigned to participants and should be considered when interpreting any reported percentage.

What does the confidence interval add?

General statistical explanation: a confidence interval gives a range of values compatible with the observed data under a specified statistical procedure. It communicates sampling uncertainty in the estimated proportion. The interval is not a guarantee that the true value lies in the range, and it does not measure all sources of uncertainty. In particular, it cannot correct for non-random allocation, outcome misclassification, or systematic differences between cohorts.

The Clopper-Pearson method is an exact method for constructing a confidence interval for a binomial proportion. Its use is specified for the primary endpoint, with a two-sided 90% confidence level. The registry record does not report the estimate or interval, so no statement can be made about whether the interval is narrow or wide. In general, precision depends in part on the amount of outcome information available; the total enrollment alone does not reveal the primary analysis denominator.

Why does the cohort design matter?

The study is non-randomized and uses parallel cohorts. Cohorts A and B used an integrase inhibitor-based antiretroviral regimen; cohorts C and D used a protease inhibitor-based regimen. The HCV treatment duration was 24 weeks in cohorts A and C and 12 weeks in cohorts B and D. Since treatment assignment was not randomized, cohort comparisons can be affected by differences in the people who entered each cohort or in other features of care. General statistical explanation: random allocation is one method for reducing systematic differences between comparison groups. Without it, observed group differences are descriptive unless additional design and analysis information supports stronger conclusions. That information is not reported in the registry record.

The study was unmasked. That describes the masking status but does not, on its own, establish whether assessment of the laboratory-based endpoint was influenced by knowledge of treatment. The registry does not report additional information about endpoint assessment procedures.

What can planning calculations tell readers?

General statistical explanation: a sample-size calculation can describe the number of participants that a planned design would require under stated assumptions. It is a planning quantity, not an observed outcome and not evidence that a study achieved a particular probability of detecting an effect. The registry’s stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such illustrations are not the trial’s own design justification. The registry record does not report the numerical planning results or the trial’s sample-size justification.

The primary analysis specifies a 90% interval, while the planning illustration specifies a two-sided significance level of 0.05. These are descriptions of different statistical contexts: one concerns uncertainty around the endpoint proportion, and the other is an assumption for a planning illustration. They should not be treated as interchangeable. The registry record does not report a hypothesis test for the primary endpoint, an interim analysis plan, or a complete statistical analysis plan.

General statistical explanation: over-dispersion matters when observed variability is greater than a model assumes, because standard errors and resulting intervals or tests may then be too optimistic. The primary endpoint is defined as a binary proportion and the specified interval method is Clopper-Pearson; the registry record does not describe an over-dispersion adjustment. It also does not report a model-based comparison among cohorts. No additional model or adjustment should be inferred from the endpoint description alone.

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("Cohort A [INI-based ART + PTV/r/OBT + DSV +/- RBV ", "Cohort B [INI-based ART + PTV/r/OBT + DSV +/- RBV ", "Cohort C [PI-based ART + PTV/r/OBT + DSV +/- RBV 2", "Cohort D [PI-based ART + PTV/r/OBT + DSV +/- RBV 1")
n      <- c(21, 5, 15, 4)
events <- c(20, 3, 15, 4)
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  Cohort A [INI-based ART + PTV/r/OBT + DSV +/- RBV   21  20  95.2  76.2  99.9  77.3  99.2  77.2  98.9
ARM  Cohort B [INI-based ART + PTV/r/OBT + DSV +/- RBV   5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2
ARM  Cohort C [PI-based ART + PTV/r/OBT + DSV +/- RBV 2  15  15  100.0  78.2  100.0  79.6  100.0  79.4  99.8
ARM  Cohort D [PI-based ART + PTV/r/OBT + DSV +/- RBV 1  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures and 8 analyses. The primary endpoint is SVR12; the listed secondary outcomes include HIV-1 virologic failure, HIV resistance mutations among participants with virologic failure, levels and changes in soluble CD14 and IP-10, HCV resistance mutations, and SVR24. Numerical results for these outcomes are not reported in the registry record.

When several outcomes or analyses are considered, the chance of at least one apparently notable result can increase if each is assessed separately. General statistical explanation: multiplicity procedures can address that issue by adjusting testing or by defining a hierarchy of outcomes. The registry record does not report whether multiplicity was controlled, whether analyses were prioritized beyond the designation of SVR12 as primary, or how any multiple comparisons were handled. No adjustment strategy should be assumed.

The primary endpoint description specifies how missing HCV RNA information was handled. Participants with qualifying early HCV virologic failure were counted as non-responders. Participants missing the week 12 post-treatment HCV RNA result and all later evaluations were also counted as non-responders. If a later HCV RNA result was available, the first subsequent result replaced the missing week 12 assessment for defining the primary outcome. These rules are part of the endpoint definition and are not evidence that missing results were absent or present in any particular number.

The primary analysis population is participants who initiated study treatment. The registry does not report the number who initiated treatment, the number with an evaluable endpoint, or the missing-data count. It also does not report how missing data were handled for the secondary outcomes, whether other analysis populations were used, or whether sensitivity analyses were conducted. Further information about the statistical analysis plan, interim analyses, and multiplicity methods is not reported in the registry record.

12. 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: neuropathy peripheral (20.0%), respiratory distress (20.0%), myocardial infarction (6.7%), hemiparesis (6.7%), bronchitis (4.8%).

The safety record separates serious adverse events from other adverse events and gives the number at risk and the number affected for each cohort. For serious adverse events, the listed at-risk and affected counts are 21 and 2 in cohort A, 5 and 2 in cohort B, 15 and 2 in cohort C, and 4 and 0 in cohort D. The record lists zero deaths in each cohort.

These counts are descriptive. Because the study was non-randomized and cohort sizes differ, they do not establish a comparative safety effect across regimens or durations. In particular, a count from a small cohort should not be read as a stable estimate of comparative risk. The registry record does not provide a causal comparison or additional details needed to interpret differences among cohorts.

The registry also lists serious adverse event terms with percentages: peripheral neuropathy, 20.0%; respiratory distress, 20.0%; myocardial infarction, 6.7%; hemiparesis, 6.7%; bronchitis, 4.8%; and pulmonary embolism, 4.8%. These are reported term percentages; the registry information does not establish from this listing alone whether they represent participant-level incidence across a specified analysis population or another presentation basis. They should not be converted into cohort-specific risks.

The counts for other adverse events were 21 of 21 at risk in cohort A, 5 of 5 in cohort B, 15 of 15 in cohort C, and 4 of 4 in cohort D. Those figures describe the registry’s affected counts, not the severity or clinical importance of every event. The registry record does not report further detail on event timing, duration, or attribution.

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

The record documents a phase 2 study of interferon-free HCV treatment in adults with HIV/HCV coinfection who were receiving antiretroviral therapy. It identifies the treatment combinations, the four cohort structures, the primary SVR12 definition, and the intended analysis method. It also records serious and other adverse event counts by cohort.

The numerical primary response result is not reported in the registry record. Therefore, the record does not establish the observed SVR12 percentage, the precision of that estimate, or how many treated participants contributed to the primary outcome analysis. The endpoint definition alone does not show what the response rate was.

The study’s non-randomized design also limits what can be inferred from comparisons among cohorts. The cohorts differ in antiretroviral backbone and treatment duration, and the registry cautions that the arms are not like-for-like controls. Even if cohort results are available from another source, differences should be interpreted as descriptive unless the design and analysis justify a causal comparison.

The safety counts show that serious adverse events were recorded in some cohorts and that no deaths were listed. They do not establish whether treatment caused an event, and the registry’s term percentages should not be treated as arm-specific risks without a clearly stated denominator and analysis basis. The listed secondary outcomes likewise cannot support conclusions about HIV virologic control, resistance, biomarkers, or SVR24 because their numerical results are not reported in the registry record.

In general, a registered trial record is useful for understanding the planned question and outcome definitions, but the strength of conclusions depends on reported estimates, denominators, uncertainty, and design limitations. For this record, the available information supports a description of the study and its methods, not a numerical judgment about HCV response or a claim that one cohort performed better than another.

14. Why This Trial Matters Statistically

This study addresses an important statistical setting: evaluating an HCV outcome in participants who also receive ongoing HIV antiretroviral therapy. The regimen was not a single uniform exposure across all participants. It combined several HCV drugs with different antiretroviral backbones and treatment durations, making clear outcome definitions and cohort descriptions especially important.

SVR12 is a binary endpoint defined by a laboratory threshold at a specified time after treatment discontinuation. The registry also makes explicit how early virologic failure and incomplete follow-up affect the assigned outcome. Such rules matter because a percentage is only interpretable when readers understand which observations count as responses and how missing measurements are treated.

The record also illustrates why study design and statistical summaries answer different questions. A confidence interval can describe uncertainty around a proportion, but it cannot make non-randomized cohorts comparable. Conversely, the cohort structure may be useful for describing treatment contexts without supporting a causal estimate of the effect of duration or antiretroviral backbone.

Finally, the record’s limited numerical outcome reporting constrains interpretation. Registration of multiple secondary outcomes shows the range of questions the study set out to examine, but it does not provide evidence about their results. A careful statistical reading distinguishes the registered questions and methods from observed estimates, and distinguishes descriptive safety counts from comparative evidence.

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 central limitation for interpreting efficacy from this record is that the numerical SVR12 result and confidence interval are not reported in the registry record. The number of participants who initiated treatment and the denominator for the primary outcome are also not reported. Planned enrollment of 46 does not establish the number contributing to the primary analysis.

The design was non-randomized, unmasked, and organized into four cohorts that differed by antiretroviral regimen and HCV treatment duration. The record cautions that the arms are not like-for-like control comparisons. These features limit causal comparisons between cohorts; the registry record does not report adjustment methods or other information that would address potential differences among them.

The study status is listed as terminated, but the reason for termination and its effect on enrollment, follow-up, or analysis are not reported in the registry record. The record does not report the sample-size justification, numerical planning illustrations, interim analyses, or a complete statistical analysis plan. It also does not report whether or how multiplicity was addressed across the listed outcomes and analyses.

For safety, counts and selected event-term percentages are available, but the record does not give enough context to infer causation or make a reliable comparative assessment between cohorts. Numerical results for the listed secondary outcomes are not reported. These gaps mean that the registry information supports study description and endpoint interpretation more strongly than conclusions about efficacy, comparative safety, or secondary outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluating the Safety and Effectiveness of Interferon-Free Treatment of Hepatitis C Virus Infection in HIV-Coinfected Adults on Antiretroviral Therapy — NCT02194998.
• Registry record last updated 2021-11-04; status last verified 2019-05.
• Results first posted 2019-06-04.
• 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.

19. Record Summary

NCT02194998 is a phase 2, non-randomized, unmasked, parallel-cohort study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID). It planned enrollment of 46 adults with HIV/HCV coinfection receiving antiretroviral therapy and is listed as terminated. The record gives a start date of 2015-09-16 and a primary completion date of 2018-05-17.

Four cohorts combined integrase inhibitor-based or protease inhibitor-based antiretroviral therapy with 12- or 24-week HCV treatment using paritaprevir/ritonavir/ombitasvir and dasabuvir, with ribavirin use depending on treatment version and genotype. The primary endpoint was SVR12 among participants who initiated study treatment, using a two-sided 90% Clopper-Pearson confidence interval.

The numerical SVR12 result, its analysis denominator, and numerical secondary outcome results are not reported in the registry record. Serious adverse event counts and selected event terms are listed, but the non-randomized cohort design does not support treating the arms as like-for-like controls.