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The per-protocol effect of immediate versus deferred antiretroviral therapy initiation
Open accessAbstract
OBJECTIVE: The Strategic Timing of AntiRetroviral Treatment (START) trial found a lower risk of a composite clinical outcome in HIV-positive individuals assigned to immediate initiation of antiretroviral therapy (ART) compared with those assigned to deferred initiation. However, 30% of those assigned to deferred initiation started ART earlier than the protocol specified. To supplement the published intention-to-treat (ITT) effect estimates, here we estimate the per-protocol effect of immediate versus deferred ART initiation in START. DESIGN: The START trial randomized 4685 HIV-positive participants with CD4 cell counts more than 500 cells/μl to start ART immediately after randomization (immediate initiation group) or to wait until the CD4 cell count dropped below 350 cells/μl or an AIDS diagnosis (deferred initiation group). METHODS: We used the parametric g-formula to estimate and compare the cumulative 5-year risk of the composite clinical outcome in the immediate initiation group, and deferred initiation groups had all the trial participants adhered to the protocol. RESULTS: We estimated that the 5-year risk of the composite outcome would have been 3.2% under immediate ART initiation and 7.0% under deferred initiation. The difference of 3.8% (95% confidence interval 1.5, 6.5) was larger than the ITT effect estimate of 3.1%, corresponding to a difference in effect estimates of 0.72% (-0.35, 2.35). CONCLUSION: The ITT effect estimate may underestimate the benefit of immediate ART initiation by 23%. This estimate can be used by patients and policy-makers who need to understand the full extent of the benefit of changes in ART initiation policies.
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Data from a randomised trial can be used to derive an unbiased estimate of the effect of adhering to intervention.
“Data from a randomised trial can be used to derive an unbiased estimate of the effect of adhering to intervention. 19 20”
From RoB 2: a revised tool for assessing risk of bias in randomised trials (2019) · cites this paper as [20]
The Methods describe using randomized START trial data to estimate the effect had all participants adhered to their assigned strategy. But the Discussion says the adjusted estimate depends on accurately measuring prognostic factors and correctly specifying the models—conditions the authors say cannot be guaranteed. The claim’s unqualified assertion of an unbiased estimate overstates the source. (LLM, conf=0.87)
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Additional file 1 of Per-protocol analysis of the ZINC trial for HIV disease among alcohol users
Lodi, S., Freiberg, M. S., Gnatienko, N., Blokhina, E. A., Yaroslavtseva, T., Krupitsky, E., Murray, E. J., Samet, J. H., & Cheng, D. M. (2021) · Figshare · doi:10.6084/m9.figshare.14274762
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Metadata
- Authors
- Lodi, S., Sharma, S., Lundgren, J. D., Phillips, A. N., Cole, S. R., Logan, R., Agan, B. K., Babiker, A., Klinker, H., Chu, H., Law, M., Neaton, J. D., & Hernán, M. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Lodi, Sara
- ORCID
- Venue
- AIDS
- Published
- 2016-11-13
- Volume
- 30
- Issue
- 17
- Pages
- 2659-2663
- ISSN
- 0269-9370 (ISSN-L)
- PMC
- PMC5339063
- OpenAlex
- W2541050038
- Cited by
- 27
- References
- 7
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 5
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- AIDS (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- U.S. Department of Defense (Y1-AI-5072)
- Patient-Centered Outcomes Research Institute (ME-1503-28119)
- National Institutes of Health (Y1-AI-5072, NIH-R01, AI102634, NIH R01 AI102634)
- Uniformed Services University of the Health Sciences (Y1-AI-5072)
- National Institute of Allergy and Infectious Diseases (R01AI100654, UM1AI120197, UM1AI068641, R01AI102634, Y01 AI005072, P30AI050410)
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- HIV, antiretroviral therapy, START trial, intention-to-treat effect, CD4 count, parametric g-formula, medication adherence
- MeSH terms
- Adult, Female, Follow-Up Studies, Humans, Male, Time Factors, HIV Infections, Treatment Outcome, Antiretroviral Therapy, Highly Active, Anti-Retroviral Agents
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