Evaluating the generalizability of clinical trials of direct-acting antivirals for HIV–hepatitis C virus coinfection
Bibliographic record
Abstract
HIV coinfection accelerates hepatitis C virus (HCV) progression and interferon-based therapies have shown relatively poor efficacy and tolerability in the HIV–HCV-coinfected population. The introduction of direct-acting antivirals (DAAs) for the treatment of HCV represented a paradigm shift leading to cure of chronic HCV infection, and was held to be a promising alternative for patients with HIV–HCV coinfection. Clinical trials have demonstrated the efficacy and tolerability of various DAAs in patients with HIV–HCV coinfection, bringing the added benefits of simplified dosing and shorter treatment times. However, there continues to be significant concern about the generalizability of DAA clinical trial results to the highly heterogeneous population of patients with HIV–HCV coinfection. To illustrate this point, Saeed et al.[1] compared the eligibility criteria from clinical trials of various DAAs to the characteristics of a representative HIV–HCV-coinfected population, the Canadian Coinfection Cohort. Cohort participants with active HCV infection (N = 874) were subdivided by HCV genotype to match those of the five trial populations. A large proportion of the Cohort participants had a history of drug use and poverty. The majority were receiving antiretroviral therapy (ART; 86%) and had undetectable HIV loads (78%). The median duration of HCV infection was approximately 22 years; 13% had cirrhosis and 15% had advanced liver disease. With the goal of examining how many of the Canadian Coinfection Cohort participants would have been included in the DAA clinical trials, the authors compared the characteristics of the Cohort against the eligibility criteria of five trials: NCT01479868 (simeprivir), PHOTON-1 (sofosbuvir), TURQUOISE-I (ombitasvir, paritaprevir/ritonavir/dasabuvir), ION-4 (sofosbuvir/ledipasvir), and ALLY-2 (daclatasvir/sofosbuvir). For four of the five trials, only 6–10% of the Canadian Coinfection Cohort would have been eligible for inclusion, primarily because of restrictions on the use of specific ART agents (would have excluded 63–79% of the cohort) and active drug use (would have excluded 53–55% of the cohort). The authors commented that even if individuals had switched ART to meet trial eligibility, 74–77% of the cohort would continue to have been excluded because of active drug use. Approximately, 15% of the cohort would have been ineligible for the DAA trials because of HIV loads or CD4+ cell counts that did not meet prespecified thresholds. Few of the cohort participants would have been excluded based on safety-related criteria, such as anemia or renal or liver function. The authors concluded that the eligibility criteria used in DAA clinical trials exclude important subpopulations of HIV–HCV-coinfected patients – specifically, active drug users – and call into question whether the results of the trials are applicable to the broader population of coinfected patients. The concerns of Saeed et al. regarding the applicability of the DAA clinical trial results to the larger HIV–HCV-coinfected population are widely recognized; in the past year alone, several prospective cohort studies in the United States and Europe have reported on the real-world safety and efficacy of DAAs in coinfected individuals, many with advanced liver disease [2–5]. More observational studies are needed to accurately evaluate the efficacy and safety of DAAs in representative HIV–HCV-coinfected populations. Acknowledgements Conflicts of interest There are no conflicts of interest.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.570 | 0.719 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.007 | 0.016 |
| Bibliometrics | 0.005 | 0.006 |
| Science and technology studies | 0.002 | 0.006 |
| Scholarly communication | 0.008 | 0.008 |
| Open science | 0.005 | 0.005 |
| Research integrity | 0.009 | 0.007 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".