The Atlantic Study: Press Release

San Francisco (PROTEXT) - Yesterday researchers unveiled 48-week data from the Atlantic Study, the first trial to directlycompare the effect of the three different available classes ofAIDS drugs within combination regimens. Preliminary results fromthis ongoing 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- infectedpatients. The three treatment combinations being investigated area base of two nucleoside reverse transcriptase inhibitors d4T(stavudine) and once-daily ddI (didanosine) combined with eithertwice-daily 3TC (a nucleoside reverse transcriptase inhibitor),once-daily nevirapine (a non nucleoside reverse transcriptaseinhibitor) or thrice-daily indinavir (a protease inhibitor). Robert Murphy, MD, associate professor of medicine atNorthwestern University Medical School, Chicago, one of theleading investigators, presented the results of the eagerly-awaited 48-week analysis at a latebreaker session at the 39thAnnual Meeting of the Interscience Conference on AntimicrobialAgents and Chemotherapy in San Francisco (13:12 PM, PDT, Room103/103, Moscone Center, San Francisco). It was one of only 11studies presented 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-centerinternational study, and is one of the first large-scale clinicalresearch collaborations between AIDS research centers in NorthAmerica and Central Europe. The countries where the study isconducted are: Belgium, Canada, Germany, France, Hungary, Italy,the Netherlands, Poland, Portugal, Spain, and the USA. 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 (+/- 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 (+/- 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 in patients with abaseline HIV-1 RNA > 51,286 copies/ml, there is trend suggestingthat more patients in the 3TC+d4T+ddI group have HIV-1 RNA > 50c/ml after 48 weeks of therapy compared to the other groups. "Ourpreliminary findings indicate that the indinavir or nevirapine-based combinations also benefited patients with high baselinelevels of HIV RNA," said Dr. Murphy. "However, the results thatwere found in the patients in who had a high viral load at thestart of the study need further investigation before definitiveconclusions can be drawn. Many patients on triple NRTI therapy dorespond well to this treatment, and long-term safety and efficacyneeds to be studied." 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 inantiretroviral 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)/L. 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 inhibitorlamivudine (3TC, Epivir(R)). -- stavudine, didanosine and the non-nucleoside RT inhibitornevirapine (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,that were 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 hasbeen planned. The Atlantic investigators Chairs Joep Lange, NATEC, Amsterdam, the Netherlands Jean-Pierre Sommadossi UAB, Birmingham AL, USA Steering Committee Jose Gatell Hospital Clinic Provincial de Barcelona, Spain Victoria Johnson UAB, Birmingham AL, USA Christine Katlama Hopital Pitie-Salpetriere, Paris, France Joep Lange, NATEC, Amsterdam, the Netherlands Remko van Leeuwen NATEC, Amstardam, the Netherlands Robert Murphy Northwestern University Medical School, Chicago, USA Jean-Pierre Sommaodssi UAB, Birmingham AL, USA Katleen Squires UAB, Birmingham AL, USA Independent Data Safety Monitoring Board (DSMB) Eric Sandstrom Venhalsan Dept. of Dermatovenereology, Stockholm, Sweden John Phair Northwestern University Medical School, Chicago, USA Richard Pollard The University of Texas Medical Branch-Galveston, Texas, USA Andrew Phillips Royal Free Hospital School of Medicine, London, UK Study sites Hopital Pitie-Salpetriere, Paris, France C Katlama, M Valantin, V Calvez, M De Sa, M Pauchard Northwestern University, Chicago IL, USA R Murphy, S Padia, C Achenbach, B Berzins, J Drury AIDS Research Centre, Warsaw, Poland A Horban, A Piasek University of Alabama, Birmingham AL, USA K Squires, V Johnson, J P Sommadossi, K Mcpheeters Hospital Clinic Provincial de Barcelona, Barcelona, Spain J Gatell, E Martinez Germans Trias i Pujol, Badalona, Spain B Clotet, A Jou Goethe-Universitat, Frankfurt am Main, Germany S Steszewski, V Miller, T Leder CHU Saint-Pierre, Brussels, Belgium N Clumeck, P Hermans, E O'Doherty, K Kabeya GG&GD - AMC Amsterdam J Lange, R van Leeuwen, C de Vries, S Gruijs University Hospital, Milan, Italy M Moroni, T Bini University of Utah, Salt Lake City, Utah, USA A Pavia, S Bracken Medizinische Hochschule, Hannover, Germany R Schmidt, M Stoll Institutio de Salut Carlos III, Madrid, Spain J Gonzalez-Lahoz, F Laguna St. Paul's Hospital, Vancouver BC, Canada G Montaner, M Harris Faculdade de Medicina de Lisboa, Lisbon, Portugal F Antunes, M Doroana Cornell University, New York, NY, USA R Gulick, T Sarracco St. Laszlo Hospital, Budapest, Hungary D Banhegyi 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 Interscience Conference on Antimicrobial Agents andChemotherapy (from September 25th - 29th 1999), the leadinginvestigators will be available for more information by cellphone: Joep Lange (co-chair)

Marriott Hotel Robert Murphy

+1-415-896-1600 The fax address for information from September 25th - 29th1999 is: Dr. Remko van Leeuwen, Marriott Hotel, +1-415-775-7555. The slides of the presentation at the Interscience Conferenceon Antimicrobial Agents and Chemotherapy, as well as additionalmaterial on the Atlantic Study is also available on the Internetvia 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:The Atlantic Study Internet: http://www.newsaktuell.de Contact:Remko van Leeuwen, Study coordinator of National AIDS TherapyEvaluation Center, +31-20-566-7158 (office), +31-6-5068-2294(cell phone), +31-20-566-4479 (secretary), fax, +31-20-696-3271,+31-20-691-8821, or r.leeuwen@amc.uva.nl Web site:http://www.geocities.com/ResearchTriangle/Lab/3657/index.html

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