Dolutegravir/Lamivudine as a First-Line Regimen in a Test-and-Treat Setting for Newly Diagnosed People Living With HIV

Charlotte-Paige Rolle; Mezgebe Berhe; Tulika Singh; Roberto Ortiz; Anson Wurapa; Moti Ramgopal; Peter A. Leone; Jessica E. Matthews; Marybeth Dalessandro; Mark R. Underwood; Konstantinos Angelis; Brian R. Wynne; Deanna Merrill; Christopher Nguyen; Jean van Wyk; Andrew R. Zolopa

Disclosures

AIDS. 2021;35(12):1957-1965. 

In This Article

Methods

Study Design and Population

STAT (ClinicalTrials.gov, NCT03945981) is a phase 3b, multi-center, open-label, single-arm, 52-week pilot study evaluating the feasibility, efficacy, and safety of using DTG/3TC FDC as a first-line regimen in a US test-and-treat setting. Eligible participants were ART-naive adults (aged ≥18 years) with a newly confirmed HIV-1 diagnosis (within 14 days of screening), no prior history of hepatic or renal impairment, and no known or suspected HBV co-infection. For a confirmed diagnosis, participants must have had positive results from two different HIV rapid tests or have had positive results using a US Food and Drug Administration (FDA)-approved fourth-generation assay antigen/antibody combination immunoassay or third-generation immunoassay that detects and differentiates HIV-1 and HIV-2 antibodies, confirmed by HIV western blot or an HIV-1 RNA. Participants who received previous post-exposure prophylaxis or pre-exposure prophylaxis were eligible to participate if the last dose was taken more than 6 months from HIV diagnosis or if HIV seronegativity was documented 2 months after the last prophylactic dose and before the date of HIV diagnosis.

The current study was conducted in accordance with International Conference on Harmonization Good Clinical Practice guidelines, following the principles of the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, with approval of the protocol and all study-related documents and written informed consent obtained before study initiation.

Procedures

Participants were screened and enrolled on the same day (i.e. baseline) and started DTG 50 mg/3TC 300 mg FDC before availability of baseline laboratory results. Baseline laboratory results and baseline genotype for HIV-1 drug resistance mutations [assessed using standard PhenoSense and GenoSure testing methods (Monogram Biosciences, South San Francisco, California, USA)] were available at Week 1 or by Week 4. Participants with creatinine clearance less than 30 ml/min per 1.73 m2, evidence of chronic HBV infection, or grade 3 or 4 laboratory abnormalities were evaluated for potential modification of their current DTG/3TC treatment. For participants with chronic HBV infection, testing for HBV 3TC resistance was performed using samples from Week 1 and Week 4 (depending on when ART modification occurred) as well as baseline samples. If baseline mutations associated with resistance to DTG or 3TC were detected, the ART regimen would be adjusted. Participants could also have their treatment modified for other intervention criteria such as pregnancy or safety considerations and remain on study.

Virologic non-response was defined as a confirmed decrease in baseline plasma HIV-1 RNA less than 2.0 log10 copies/ml at Week 8 (unless plasma HIV-1 RNA is <200 copies/ml), confirmed plasma HIV-1 RNA at least 1000 copies/ml at Week 12, or confirmed plasma HIV-1 RNA at least 200 copies/ml on or after Week 24. Virologic rebound was defined as confirmed rebound in plasma HIV-1 RNA to at least 200 copies/ml after prior suppression to less than 200 copies/ml. For participants who met virologic failure criteria, plasma samples were analyzed for genotypic and phenotypic HIV-1 resistance testing using GenoSure and PhenoSense testing. Participants who met confirmed virologic failure criteria could remain on study; however, their ART regimen may have been modified based on resistance testing results. Lymphocyte subsets were assessed at baseline and Weeks 4, 12, and 24. Disease progression and HIV-associated conditions were assessed according to the 2014 CDC Revised Classification System for HIV Infection in Adults.[16]

Safety was assessed throughout the study, including adverse events, serious adverse events (SAEs), adverse events leading to discontinuation of DTG/3TC, drug-related adverse events, and laboratory abnormalities. Clinical chemistry and weight were assessed at baseline and Weeks 4, 8, 12, and 24. Laboratory and vital signs data were summarized by visit for participants on treatment with DTG/3TC only. Adverse events were graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 2.1, March 2017.

Outcomes and Statistical Analyses

This is a single-arm study with no formal hypothesis testing. Therefore, the sample size was not statistically powered and was determined to require approximately 120 participants to allow estimation of the primary endpoint with sufficient precision [95% confidence interval (CI) width ≤15% assuming proportion of participants with HIV-1 RNA < 50 copies/ml ≥80%]. All enrolled participants who received at least one dose of DTG/3TC formed the intention-to-treat exposed (ITT-E) and safety populations. The primary endpoint was the proportion of participants in the ITT-E population with plasma HIV-1 RNA less than 50 copies/ml at Week 24; treatment modifications were not penalized (ITT-E missing = failure analysis). Missing HIV-1 RNA data for any reason (e.g. study withdrawal or missing data while on study) at Week 24 was considered HIV-1 RNA at least 50 copies/ml. Other key efficacy endpoints included the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml among those with available HIV-1 RNA at Week 24 (treatment modifications were not penalized; observed analysis) and the proportion of participants in the ITT-E population with HIV-1 RNA less than 50 copies/ml at Week 24 still on DTG/3TC (treatment modifications were penalized; FDA Snapshot algorithm). Other secondary endpoints included the proportion of participants with modification from the first-line regimen, time to suppression from enrollment, and change from baseline in CD4+ cell count and CD4+/CD8+ cell count ratio at Week 24. Exploratory endpoints included the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml summarized by participant subgroups and change from baseline in overall symptom bother score.[17] Non-parametric Kaplan–Meier method was used to estimate median time to virologic suppression (i.e. HIV-1 RNA < 50 copies/ml) regardless of treatment modification.

The Symptom Distress Module,[17] a 20-item questionnaire that evaluates patient-reported distress linked to symptoms associated with HIV or treatment, was administered at baseline and Weeks 4, 8, 12, and 24. Symptom bother score was calculated as the sum of the bothering level of each symptom (0 = does not have symptom, 1 = it doesn't bother me, up to 4 = it bothers me a lot) and ranged from 0 to 80. Missing values or values after participants switched from DTG/3TC were imputed using last observation carried forward (LOCF).

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