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| |  ICAAC: Interim Data Show Triple Therapies Are Equivalent In AIDS Patients SAN FRANCISCO, CA. -- September 28, 1999 -- Researchers have unveiled 48-week data from the Atlantic Study, the first trial to directly compare the effect of the three different available classes of AIDS drugs within combination regimens. Preliminary results from this ongoing, multi-center, international trial show that triple combination regimens, each having a different mechanism of action, display potent and sustained antiviral activity over 48 weeks of treatment in antiretroviral naïve, HIV-infected patients. The three treatment combinations being investigated are a base of two nucleoside reverse transcriptase inhibitors (d4T (stavudine) and once-daily ddI (didanosine)) combined with either twice-daily 3TC (a nucleoside reverse transcriptase inhibitor), once-daily nevirapine (a non nucleoside reverse transcriptase inhibitor) or thrice-daily indinavir (a protease inhibitor). Robert Murphy, MD, professor of medicine at Northwestern University Medical School, Chicago, one of the leading investigators, presented the results of the eagerly-awaited 48-week analysis at a late-breaker session at the 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco. It was one of only 11 studies presented today as a late-breaker abstract. "These preliminary data show that all three regimens display potent and sustained anti-retroviral activity after 48 weeks of treatment," said Dr. Murphy. "These findings are important because they show that for patients who cannot tolerate protease inhibitors, there are viable options that provide similar anti-viral activity with fewer adherence and toxicity problems." The median increase in CD4 cell counts was approximately 150 * 10(6) cells/mm(3), and appeared similar in the three treatment arms. Additionally, all three combinations were safe and overall were well tolerated. Dr. Murphy indicated that it will be important to test the long-term efficacy and safety of these three regimens. Each patient will be followed for 144 weeks.
Results First-line antiretroviral regimens containing either d4T/ddI/indinavir, d4T/ddI/nevirapine or d4T/ddI/3TC display potent activity at week 48, according to preliminary results from the Atlantic Study. The Atlantic Study is a multi-center, physician-initiated international study, and is one of the first large-scale clinical research collaborations between AIDS research centers in North America and Europe. The countries where the study is conducted are: Belgium, Canada, Germany, France, Hungary, Italy, the Netherlands, Poland, Portugal, Spain, and the USA. At baseline, the three groups were comparable with respect to gender, risk factor for HIV infection, disease stage, CD4 cell count, and HIV-1 RNA load. By July 1999, 235 patients completed 48 weeks of study. The median CD4 cell count for these patients at baseline was 447 (range: 327-523) cells/mm(3) and median HIV-1 RNA at baseline was 4.36 (range: 3.84-4.71) log(10) for all treatment arms. HIV RNA measures are available for 181 of the 235 patients who have completed 48 weeks of the study. An intent-to-treat analysis shows that at week 48 the proportion of patients with a plasma viral load less than 50 copies/ml was (plus or minus 95 confidence interval) 57 (44-70) percent for d4T/ddI/IDV, 51 (38-64) percent for d4T/ddI/NVP, and 49 (37-60) percent for d4T/ddI/3TC. An as-treated analysis shows that at week 48 the proportion of patients with a plasma viral load less than 50 copies/ml was (plus or minus 95 confidence interval) 90 (81-99) percent for d4T/ddI/IDV, 82 (71-93) percent for d4T/ddI/NVP, and 78 (66-89) percent for d4T/ddI/3TC. The Atlantic team presented a sub-analysis of 45 patients with high levels of HIV RNA. Findings show that patients with a baseline HIV-1 RNA > 51,286 copies/ml in the 3TC/d4T/ddI group were more likely to have HIV-1 RNA > 50 c/ml compared to the other groups after 48 weeks of therapy. "Our preliminary findings indicate that the indinavir or nevirapine-based combinations benefited patients with high baseline levels of HIV RNA," said Dr. Murphy.
Background With a combination of three or more antiretroviral agents a durable suppression of viral replication in HIV-1 infection can be achieved. This has resulted in clinical benefit in terms of prolonged (disease free) survival. However, for a sustained clinical benefit, treatment needs to be used for many years, possibly for life. The daily pill burden of current triple or quadruple antiretroviral regimens is large, and a rigid time schedule with complicated dietary restrictions may interfere with the patient’s daily activities. Even with the knowledge of suffering from a life-threatening disease, it is no wonder that strict adherence to therapy is difficult for many. Adherence is a critical issue for a durable suppression of viral replication, which itself is a prerequisite to avoid development of viral drug resistance. Long-term toxicities, such as the recently described lipodystrophy, may further restrict the patient in the long-term use of particular antiretroviral regimens.
Study Design The Atlantic Study is an open-label, randomised, comparative, strategic study to evaluate the efficacy and the safety of three triple drug regimens aimed at different HIV targets in anti-retroviral naive HIV infected patients. The primary study objective is to determine the effect of the three regimens on plasma HIV-1 RNA load. The study has enrolled a total of 298 subjects, who were eligible for the trial if they fulfilled the following criteria: asymptomatic HIV-1 infection (CDC 1993 stage A), antiretroviral drug naive, plasma HIV-1 RNA copies > 500 copies/ml and CD4 cell counts > 200 * 10(6) cells/mm(3). The drug combinations being tested in the study are: - stavudine (d4T, Zerit®), didanosine (ddI, Videx®), and the protease inhibitor indinavir (IDV, Crixivan®). - stavudine, didanosine and the nucleoside RT inhibitor lamivudine (3TC, Epivir®). - stavudine, didanosine and the non-nucleoside RT inhibitor nevirapine (NVP, Viramune®). - Stavudine and didanosine are both nucleoside RT inhibitors. All drugs were administered according to the regular dosing schedule for these drugs; except for didanosine and nevirapine, that were administered as a full dose once-daily. The Atlantic team is currently evaluating the virologic effects of the three regimens on HIV replication in lymphoid tissue. Also, the team is studying the occurrence of lipodystrophy, a long-term toxicity that is frequently seen with the currently used HAART regimens. A follow-up salvage study is in progress.
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