Atlantic Study Positions Zerit(R) (D4T, Stavudine) and Once-Daily Videx(R)

San Francisco (PROTEXT) - Today researchers unveiled 48-weekdata from the Atlantic Study, the first trial to directly comparethe effect of the three different available classes of AIDS drugswithin combination regimens. Preliminary results from thisongoing multi-center international trial show that triplecombination regimens, each having a different mechanism ofaction, display potent and sustained antiviral activity over 48weeks of treatment in antiretroviral naive HIV-infected patients.The three treatment combinations being investigated are a base oftwo nucleoside reverse transcriptase inhibitors (d4T (stavudine)and once-daily ddI (didanosine)) combined with either twice-daily3TC (a nucleoside reverse transcriptase inhibitor), once-dailynevirapine (a non nucleoside reverse transcriptase inhibitor) orthrice-daily indinavir (a protease inhibitor). Robert Murphy, MD, professor of medicine at NorthwesternUniversity Medical School, Chicago, one of the leadinginvestigators, presented the results of the eagerly-awaited 48-week analysis at a latebreaker session at the 39th Annual Meetingof the Interscience Conference on Antimicrobial Agents andChemotherapy in San Francisco (1:00 PM, PDT, Room 103/104,Moscone Center, San Francisco). It was one of only 11 studiespresented today as a latebreaker abstract. "These preliminary data show that all three regimens displaypotent and sustained antiretroviral activity after 48 weeks oftreatment," said Dr. Murphy. "These findings are importantbecause they show that for patients who cannot tolerate proteaseinhibitors, 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 treatmentarms. Additionally, all three combinations were safe and overallwere well tolerated. Dr. Murphy indicated that it will beimportant to test the long-term efficacy and safety of thesethree regimens. Each patient will be followed for 144 weeks. Results First-line antiretroviral regimens containing eitherd4T/ddI/indinavir, d4T/ddI/nevirapine or d4T/ddI/3TC displaypotent activity at week 48, according to preliminary results fromthe Atlantic Study. The Atlantic Study is a multi-center,physician-initiated international study, and is one of the firstlarge-scale clinical research collaborations between AIDSresearch centers in North America and Europe. The countries wherethe study is conducted are: Belgium, Canada, Germany, France,Hungary, Italy, the Netherlands, Poland, Portugal, Spain, and theUSA. At baseline, the three groups were comparable with respect togender, risk factor for HIV infection, disease stage, CD4 cellcount, and HIV-1 RNA load. By July 1999, 235 patients completed48 weeks of study. The median CD4 cell count for these patientsat baseline was 447 (range: 327-523) cells/mm(3) and median HIV-1RNA at baseline was 4.36 (range: 3.84-4.71) log(10) for alltreatment arms. HIV RNA measures are available for 181 of the 235 patients whohave completed 48 weeks of the study. An intent-to-treat analysisshows that at week 48: -- the proportion of patients with a plasma viral load lessthan 50 copies/ml was (plus or minus 95 confidence interval) 57(44-70) % for d4T/ddI/IDV, 51 (38-64) % for d4T/ddI/NVP, and 49(37-60) % for d4T/ddI/3TC. An as-treated analysis shows that at week 48: -- the proportion of patients with a plasma viral load lessthan 50 copies/ml was (plus or minus 95 confidence interval) 90(81-99) % for d4T/ddI/IDV, 82 (71-93) % for d4T/ddI/NVP, and 78(66-89) % for d4T/ddI/3TC. The Atlantic team presented a sub-analysis of 45 patients withhigh levels of HIV RNA. Findings show that patients with abaseline HIV-1 RNA > 51,286 copies/ml in the 3TC/d4T/ddI groupwere more likely to have HIV-1 RNA > 50 c/ml compared to theother groups after 48 weeks of therapy. "Our preliminary findingsindicate that the indinavir or nevirapine-based combinationsbenefited patients with high baseline levels of HIV RNA," saidDr. Murphy. Background With a combination of three or more antiretroviral agents adurable suppression of viral replication in HIV-1 infection canbe achieved. This has resulted in clinical benefit in terms ofprolonged (disease free) survival. However, for a sustainedclinical benefit, treatment needs to be used for many years,possibly for life. The daily pill burden of current triple orquadruple antiretroviral regimens is large, and a rigid timeschedule with complicated dietary restrictions may interfere withthe patient's daily activities. Even with the knowledge ofsuffering from a life-threatening disease, it is no wonder thatstrict adherence to therapy is difficult for many. Adherence is acritical issue for a durable suppression of viral replication,which itself is a prerequisite to avoid development of viral drugresistance. Long-term toxicities, such as the recently describedlipodystrophy, may further restrict the patient in the long-termuse 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 threetriple drug regimens aimed at different HIV targets in anti-retroviral naive HIV infected patients. The primary studyobjective is to determine the effect of the three regimens onplasma HIV-1 RNA load. The study has enrolled a total of 298subjects, who were eligible for the trial if they fulfilled thefollowing criteria: asymptomatic HIV-1 infection (CDC 1993 stageA), antiretroviral drug naive, plasma HIV-1 RNA copies > 500copies/ml and CD4 cell counts > 200 * 10(6) cells/mm(3). The drug combinations being tested in the study are: -- stavudine (d4T, Zerit(R)), didanosine (ddI, Videx(R)), andthe protease inhibitor indinavir (IDV, Crixivan(R)). -- stavudine, didanosine and the nucleoside RT inhibitor lamivudine (3TC, Epivir(R)). -- stavudine, didanosine and the non-nucleoside RT inhibitor nevirapine (NVP, Viramune(R)). Stavudine and didanosine are both nucleoside RT inhibitors.All drugs were administered according to the regular dosingschedule for these drugs; except for didanosine and nevirapine, thatwere administered as a full dose once-daily. The Atlantic team is currently evaluating the virologiceffects of the three regimens on HIV replication in lymphoidtissue. Also, the team is studying the occurrence oflipodystrophy, a long-term toxicity that is frequently seen withthe currently used HAART regimens. A follow-up salvage study isin progress. Coordination NATEC (National AIDS Therapy Evaluation Center), is part ofthe University of Amsterdam, and is responsible for the overallcoordination, data collection, management, and analysis of theAtlantic Study. NATEC conducts and supports research aimed attreating HIV infection and HIV related diseases in various partsof the World. Currently, NATEC has active collaborations invarious countries in West and East Europe, North America, Africaand Asia. NATEC is supported by the Dutch Department of Health. More information on this press release and the study can beobtained from: Dr. Remko van Leeuwen, Study coordinator National AIDS Therapy Evaluation Center (NATEC) University of Amsterdam, Academical Medical Centre Room F5-108, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Phone: +31-20-566-7158 (office)

+31-6-5068-2294 (cell phone)

+31-20-566-4479 (secretary) Fax: +31-20-696-3271 or +31-20-691-8821 E-mail: r.leeuwen@amc.uva.nl During the ICAAC meeting (from September 25th - 29th 1999),the leading investigators will be available for more information.For interviews, please call: 917-864-7283 or the following: Joep Lange (co-chair)

Renaissance Parc +1-415-403-6602 Robert Murphy

+1-312-656-5029 The fax address for information from September 25th - 29th1999 is: Dr. Remko van Leeuwen, Marriott Hotel, +415-775-7555 The slides of the presentation at the ICAAC, as well asadditional material on the Atlantic study is also available onthe Internet via the Atlantic Study home page:http://www.geocities.com/ResearchTriangle/Lab/3657/index.html, orhttp://www.NATEC.nl (Oct. 1st 1999). ots Original Text Service:National AIDS Therapy Evaluation Center (NATEC) Internet:http://www.newsaktuell.de Contact: Remko van Leeuwen, Studycoordinator of National AIDS Therapy Evaluation Center, +31-20-566-7158 (office), +31-6-5068-2294 (cell phone), +31-20-566-4479(secretary), or fax, +31-20-696-3271, or +31-20-691-8821, orr.leeuwen@amc.uva.nl Web site:http://www.geocities.com/ResearchTriangle/Lab/3657/index.html

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