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ACTG Operations Center Social & Scientific Systems, Inc. 8757 Georgia Avenue, 12th Floor Silver Spring, MD 20910 DATE: January 30, 2008 TO: A5146 Study Participants FROM: A5146 Protocol Team RE: ACTG A5146 Final Study Results Phone: (301) 628-3000 Fax: (301) 628-3302 We would like to share with you the final results of the A5146 study, “A Phase II Randomized Controlled Trial Evaluating the Impact of Therapeutic Drug Monitoring (TDM) on Virologic Response to a Salvage Regimen in Subjects with a Normalized Inhibitory Quotient (NIQ) 1 to One or More Protease Inhibitors.” This study was done to test whether increasing the dose of protease inhibitors improved treatment responses in people who experienced virologic failure while taking a protease inhibitor-containing regimen. People like you that entered the study had to have an HIV viral load of at least 1,000 copies/mL while taking antiretroviral drugs, and a history of virologic failure (viral load of at least 400 copies/mL) on a protease inhibitor-containing regimen. A new drug regimen that included a protease inhibitor was begun at study entry. Two weeks later, the amount or concentration of protease inhibitor in the blood was measured. This amount was compared to the amount of HIV drug resistance to that protease inhibitor that was found at screening. The ratio of your drug concentration to the 50% inhibitory concentration (IC50, a measure of HIV drug resistance) is called an inhibitory quotient (IQ). A normalized IQ (NIQ) is the ratio of your IQ to the IQ of patients who had good responses to the same protease inhibitor. If your NIQ was greater than one, it means that your IQ is lower than the IQ of people who had good responses to the same protease inhibitor you were taking. This NIQ was used to decide who would get an increased dose of their protease inhibitor. The purpose of the study was to see whether people with NIQs less than or equal to one would have lower viral loads if they got higher than usual doses of their protease inhibitor. Participants that had a low ratio of drug concentration to HIV drug resistance (defined as a normalized inhibitory quotient [NIQ] less than or equal to 1) were then assigned by chance to receive standard of care (SOC arm) or an increase in the dose of their protease inhibitor (TDM arm). Participants that had an NIQ greater than 1 were either assigned to an Observational arm, or went off study at 4 weeks after study entry. These people were followed the same as those in the SOC arm. A5146 Final Study Results (01/30/08) Page 2 of 3 Most participants in the TDM arm were allowed to increase the dose a second time if their NIQ remained less than 1, depending on which protease inhibitor they were taking. The main goal of the study was to find out whether people in the TDM and SOC arms had different viral load responses 20 weeks after being assigned to the TDM and SOC arms. Final Study Results for the Comparison of TDM and SOC Arms A total of 411 HIV-infected people entered the study. Of that total, 233 were assigned to one of the three treatment arms (92 to TDM, 91 to SOC, and 50 to Observational arms). In the TDM and SOC arms, 10% were women and 51% were people of color. The final results showed that there were no significant differences between the TDM and SOC arms in viral load responses to treatment. This means that increasing the dose of protease inhibitors in people with NIQs less than or equal to 1 did not improve their response to treatment. There also were no differences between the TDM and SOC arms in CD4 counts, viral load suppression to either <50 or <400 copies/mL, or side effects. There were no differences between the two treatment arms, even though on average, increasing the protease inhibitor dose increased the levels of protease inhibitor in the blood. Final Study Results for the Observational Arm On average, participants in the Observational arm had been treated with fewer protease inhibitors in the past, and had HIV with less resistance to the protease inhibitor they were taking. This result makes sense, because people in the Observational arm had higher NIQs than people in the TDM and SOC arms; higher NIQs can be due to either higher drug levels or less drug resistance. Overall, participants in the Observational arm had a better viral load response to treatment than participants in the TDM and SOC arms. This difference is likely due to the fact that people in the Observational arm had HIV with less resistance to the drugs they were taking. Results for Different Groups of Participants Some testing was done to look at whether different groups of people did better on the TDM arm compared to the SOC arm. These studies were retrospective (not planned in advance), and so may not be as reliable as the final study results described above. These retrospective studies showed that participants in the TDM and SOC arms who had HIV with less drug resistance to the protease inhibitor they were taking did benefit from dose escalation of their protease inhibitor. It may be that increasing the dose of a protease inhibitor may not help if the drug has no or little activity to begin with. These retrospective studies also showed that black and Hispanic patients may have responded better to increasing the dose of protease inhibitors (the TDM arm) than white patients. The reason for this is not known, but could be due to genetic differences in how drugs are absorbed or broken down by people of different races or ethnic groups. When looking at groups of participants based on both their HIV drug resistance and race or ethnic group, the study team found that black patients with less HIV drug resistance to their protease inhibitor did better on the TDM than the SOC arm. However, white patients with HIV A5146 Final Study Results (01/30/08) Page 3 of 3 that was highly resistant to the protease inhibitor they were taking did worse on the TDM arm compared to the SOC arm. Hispanic patients appeared to have outcomes similar to black patients, but the results were not as statistically significant as for black patients. Conclusions The A5146 study showed that, overall, participants with NIQs less than or equal to 1 did not benefit from increasing their dose of protease inhibitor, and did not have any more side effects, compared to participants that did not increase their protease inhibitor dose. Increased doses of protease inhibitors were well tolerated and there were no safety differences between the TDM and SOC arms. However, some studies analyzing different groups of participants show that patients with less HIV that is less resistant to their protease inhibitor might do better if their dose of protease inhibitor were increased. Black and Hispanic patients also might do better on higher doses of protease inhibitors if their NIQ is less than or equal to 1. The A5146 study team is planning studies to see whether genetic changes could possibly explain the differences between white, black and Hispanic participants, by doing genetic testing on samples from participants who consented to genetic testing as part of the A5128 study. If you have any questions about this study or the results, please feel free to ask the study staff at your site to go over the results with you. If they cannot answer your questions, they will contact the study team for more information. Thank you for your participation in this research. Your efforts have contributed greatly to our understanding of how to best treat patients who are infected with drug-resistant HIV.