Atazanavir

The AIDS Clinical Trials Group Study A5202 is an ongoing phase 3B, randomized, partially blinded study comparing four antiretroviral regimens for the initial treatment of HIV-1 infection. The planned study duration was 96 weeks after enrollment of the last patient. Baseline evaluations included a medical history, physical examination, CD4 cell count, and HIV-1 RNA level. At screening, a genotypic resistance test was required in patients with recent HIV-1 acquisition. Testing for the HLA-B*5701 allele was permitted but not required. Patients were randomly assigned to receive one of four oral once-daily regimens: 600 mg of efavirenz (Sustiva, Bristol-Myers Squibb) or 300 mg of atazanavir (Reyataz, Bristol-Myers Squibb) plus 100 mg of ritonavir (Norvir, Abbott Laboratories) given with either 600 mg of abacavir plus 300 mg of lamivudine (Epzicom, GlaxoSmithKline) or 300 mg of tenofovir DF plus 200 mg of emtricitabine (Truvada, Gilead Sciences). The study was double-blinded with regard to the NRTIs.
Randomization was stratified according to the screening HIV-1 RNA level obtained before study entry (≥100,000 vs. <100,000 copies per milliliter), with the use of a permuted-block design with dynamic balancing according to the main institution. Screening of HIV-1 RNA levels was performed at any laboratory certified under the Clinical Laboratory Improvement Amendments. Study evaluations were completed before entry, at entry, at weeks 4, 8, 16, and 24, and every 12 weeks thereafter for the duration of the study in all patients, regardless of any treatment modification. After screening, the level of HIV-1 RNA was measured (Roche Amplicor Monitor assay, version 1.5) at Johns Hopkins University. At the time of protocol-defined virologic failure, geno-typing for drug resistance was performed at Stanford University; the baseline samples obtained from the patients were genotyped retrospectively.
Abbott Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline provided the study medications and had input into the protocol development and review of the manuscript. All the authors participated in the trial design, data analysis, and preparation of the manuscript, and all the authors vouch for the completeness and accuracy of the reported data.

Every six months the CPQA PT program offered prepared plasma samples containing pre-specified concentrations (unknown to CPLs) of up to 21 ARV analytes: abacavir (ABC), amprenavir (APV), atazanavir (ATV), darunavir (DRV), didanosine (DDI), efavirenz (EFV), emtricitabine (FTC), etravirine (ETR), indinavir (IDV), lamivudine (3TC), lopinavir (LPV), maraviroc (MVC), nelfinavir (NFV), nevirapine (NVP), raltegravir (RGV), ritonavir (RTV), saquinavir (SQV), stavudine (D4T), tenofovir (TFV), tipranavir (TPV), zidovudine (ZDV). In each round and for each ARV, 5 concentrations, spanning an expected therapeutic range of each ARV, as well as occasional concentrations below or above, were provided. Samples are prepared by an outside subcontractor and tested by the CPQA lab prior to distribution. PT samples were stored at −70 ± 15°C and then shipped on dry ice to participating laboratories with detailed instructions. Upon arrival, each laboratory confirmed sample integrity and indicated planned reporting of specific analytes. Results were reported either through an online Laboratory Data Management System (LDMS) or via a template which was then uploaded into the LDMS database. At the end of the submission period, a completeness evaluation was performed to confirm that all planned results were received; discrepancies were queried for resolution. To summarize the proficiency of individual labs, a pre-specified scoring algorithm was applied to the RCs (see next paragraph). The scoring algorithm reflects US Clinical Laboratory Improvement Act (CLIA) PT regulations[13 (link)]. After review and approval by the CPQA advisory board chair, a final report was sent to the participating laboratories (with laboratories de-identified) and key leadership (laboratories identified per network leader).
An individual RC is deemed Acceptable provided a concentration is present where expected, and the concentration is within 20% of the final target (FT)[14 (link)]. (If a concentration is reported as below the lower limit of quantification (BLQ), and the run lower limit was below 80%*FT, the concentration was labeled Unacceptable.) For a given prepared sample, if the number of labs reporting for that sample is large enough, the variability between CPLs is small enough (≤15%) and the percent deviation of the group mean (GM, determined after removal of outliers, if any)from the weighed-in value (WIV) is >5%, the FT is set to the GM. Otherwise, FT is set to the WIV. At the analyte level, a CPL’sperformance is deemed Satisfactory for the round provided at least 80% of RCs are Acceptable. If the CPL score is <80% for an analyte, the CPL submits a corrective action plan to reestablish accuracy; a root cause is requested. Finally, in accordance with CLIA rules, a lab is classified as successful for an analyte provided the round-specific score was Satisfactory in at least 2 of the last 3 rounds (including the current).