THE ATLANTIC STUDY: PRESS RELEASE

San Francisco, September 28 (PROTEXT) - Yesterday researchersunveiled 48- week datafrom the Atlantic Study, the first trial to directly compare theeffect ofthe three different available classes of AIDS drugs withincombinationregimens. Preliminary results from this ongoing multi-centerinternationaltrial showthat triple combination regimens, each having a differentmechanism ofaction, display potent and sustained antiviral activity over 48weeks oftreatment in antiretroviral naive HIV-infected patients.The three treatment combinations being investigated are a base oftwonucleoside reverse transcriptaseinhibitors d4T (stavudine) and once-daily ddI (didanosine)combined witheither twice-daily 3TC (a nucleoside reverse transcriptaseinhibitor),once-daily nevirapine (a non nucleoside reverse transcriptaseinhibitor) orthrice-daily indinavir (a protease inhibitor).Robert Murphy, MD, associate professor of medicine atNorthwesternUniversity Medical School, Chicago, one of the leadinginvestigators,presented the results of the eagerly-awaited 48-week analysis atalatebreaker session at the 39th Annual Meeting of theInterscienceConference on Antimicrobial Agents and Chemotherapy in SanFrancisco (13:12PM, PDT, Room 103/103, MosconeCenter, San Francisco). It was one of only 11 studies presentedtoday as alatebreaker abstract.''These preliminary data show that all three regimens displaypotent andsustained antiretroviral activity after 48 weeks of treatment,''said Dr.Murphy. ''These findings are important because they show that forpatientswho cannot tolerate protease inhibitors, there are viable optionsthatprovidesimilar anti-viral activity with fewer adherence and toxicityproblems.''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. Murphyindicated that it will be important to test the long-termefficacy andsafetyof these three regimens. Each patient will be followed for 144weeks.:: ResultsFirst-line antiretroviral regimens containing eitherd4T/ddI/indinavir,d4T/ddI/nevirapine or d4T/ddI/3TC display potent activity at week48,according to preliminary results from the Atlantic Study. TheAtlantic Studyis a multi-center international study, and is one of the firstlarge-scaleclinical research collaborations between AIDS research centers inNorthAmerica and Central Europe. The countries where the study isconducted are:Belgium, Canada, Germany, France, Hungary, Italy, theNetherlands, Poland,Portugal, Spain, and the USA.At baseline, the three groups were comparable with respect togender, riskfactor for HIV infection, disease stage, CD4 cell count, and HIV-1 RNA load.By July 1999, 235 patients completed 48 weeks of study. Themedian CD4 cellcount 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 alltreatment arms.HIV RNA measures are available for 181 of the 235 patients whohavecompleted 48 weeks of the study. An intent-to-treat analysisshows that atweek 48::: The proportion of patients with a plasma viral load less than50copies/ml was (+/- 95 confidence interval) 57 (44-70) % ford4T/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 less than50copies/ml was (+/- 95 confidence interval) 90 (81-99) % ford4T/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 levelsof HIV RNA. Findings show that in patients with a baseline HIV-1RNA >51,286 copies/ml, there is trend suggesting that more patients inthe3TC+d4T+ddI group have HIV-1 RNA > 50 c/ml after 48 weeks oftherapycompared to the other groups. ''Our preliminary findings indicatethat theindinavir or nevirapine-based combinations also benefitedpatients with highbaseline levels of HIV RNA,'' said Dr. Murphy. ''However, theresults thatwere found in the patients in who had a high viral load at thestart of thestudy need further investigation before definitive conclusionscan be drawn.Many patients on triple NRTI therapy do respond well to thistreatment, andlong-term safety and efficacy needs to be studied.'':: BackgroundWith a combination of three or more antiretroviral agents adurablesuppression of viral replication in HIV-1 infection can beachieved. Thishas resulted in clinical benefit in terms of prolonged (diseasefree)survival. However, for a sustained clinical benefit, treatmentneeds to beused for many years, possibly for life. The daily pill burden ofcurrenttriple or quadruple antiretroviral regimens is large, and a rigidtimeschedule with complicated dietary restrictions may interfere withthepatient's daily activities. Even with the knowledge of sufferingfrom alife-threatening disease, it is no wonder that strict adherenceto therapyis difficult for many. Adherence is a critical issue for adurablesuppression of viral replication, which itself is a prerequisiteto avoiddevelopment of viral drug resistance. Long-term toxicities, suchas therecently described lipodystrophy, may further restrict thepatient in thelong-term use of particular antiretroviral regimens.:: Study DesignThe Atlantic Study is an open-label, randomised, comparative,strategicstudy to evaluate the efficacy and the safety of three tripledrug regimensaimed at different HIV targets in antiretroviral naive HIVinfectedpatients. The primary study objective is to determine the effectof thethree regimens on plasma HIV-1 RNA load. The study has enrolled atotal of298 subjects, who were eligible for the trial if they fulfilledthefollowing 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)), and theproteaseinhibitor 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 nucleosideRTinhibitors. All drugs were administered according to the regulardosingschedule for these drugs; except for didanosine and nevirapine,that wereadministered as a full dose once-daily.The Atlantic team is currently evaluating the virologic effectsof the threeregimens on HIV replication in lymphoid tissue. Also, the team isstudyingthe occurrence of lipodystrophy, a long-term toxicity that isfrequentlyseen with the currently used HAART regimens. A follow-up salvagestudy hasbeen planned.The Atlantic investigatorsChairsJoep Lange,NATEC, Amsterdam, the NetherlandsJean-Pierre SommadossiUAB, Birmingham AL, USASteering CommitteeJose GatellHospital Clinic Provincial de Barcelona, SpainVictoria JohnsonUAB, Birmingham AL, USAChristine KatlamaHopital Pitie-Salpetriere, Paris, FranceJoep Lange,NATEC, Amsterdam, the NetherlandsRemko van LeeuwenNATEC, Amstardam, the NetherlandsRobert MurphyNorthwestern University Medical School, Chicago, USAJean-Pierre SommaodssiUAB, Birmingham AL, USAKatleen SquiresUAB, Birmingham AL, USAIndependent Data SafetyMonitoring Board (DSMB)Eric SandstromVenhalsan Dept. of Dermatovenereology,Stockholm, SwedenJohn PhairNorthwestern University Medical School, Chicago, USARichard PollardThe University of Texas Medical Branch-Galveston, Texas, USAAndrew PhillipsRoyal Free Hospital School of Medicine, London, UKStudy sitesHopital Pitie-Salpetriere, Paris, FranceC Katlama, M Valantin, V Calvez, M De Sa, M PauchardNorthwestern University, Chicago IL, USAR Murphy, S Padia, C Achenbach, B Berzins, J DruryAIDS Research Centre, Warsaw, PolandA Horban, A PiasekUniversity of Alabama, Birmingham AL, USAK Squires, V Johnson, J P Sommadossi, K McpheetersHospital Clinic Provincial de Barcelona, Barcelona, SpainJ Gatell, E MartinezGermans Trias i Pujol, Badalona, SpainB Clotet, A JouGoethe-Universitat, Frankfurt am Main, GermanyS Steszewski, V Miller, T LederCHU Saint-Pierre, Brussels, BelgiumN Clumeck, P Hermans, E O'Doherty, K KabeyaGG&GD - AMC AmsterdamJ Lange, R van Leeuwen, C de Vries, S GruijsUniversity Hospital, Milan, ItalyM Moroni, T BiniUniversity of Utah, Salt Lake City, Utah, USAA Pavia, S BrackenMedizinische Hochschule, Hannover, GermanyR Schmidt, M StollInstitutio de Salut Carlos III, Madrid, SpainJ Gonzalez-Lahoz, F LagunaSt. Paul's Hospital, Vancouver BC, CanadaG Montaner, M HarrisFaculdade de Medicina de Lisboa, Lisbon, PortugalF Antunes, M DoroanaCornell University, New York, NY, USAR Gulick, T SarraccoSt. Laszlo Hospital, Budapest, HungaryD Banhegyi:: CoordinationNATEC (National AIDS Therapy Evaluation Center), is part of theUniversityof Amsterdam, and is responsible for the overall coordination,datacollection, management, and analysis of the Atlantic Study. NATECconductsand supports research aimed at treating HIV infection and HIVrelateddiseases in various parts of the World. Currently, NATEC hasactivecollaborations in variouscountries in West and East Europe, North America, Africa andAsia. NATEC issupported by the Dutch Department of Health.:: More information on this press release and the study can beobtained fromDr. Remko van Leeuwen,Study coordinatorNational AIDS Therapy Evaluation Center (NATEC)University of Amsterdam,Academical Medical CentreRoom F5-108,Meibergdreef 9,1105 AZ Amsterdam,The NetherlandsPhone: +31-20-566-7158 (office)+31-6-5068-2294 (cell phone)+31-20-566-4479 (secretary)Fax: +31-20-696-3271 or +31-20-691-8821E-mail: r.leeuwen@amc.uva.nlDuring the Interscience Conference on Antimicrobial Agents andChemotherapy(from September 25th - 29th 1999), the leading investigators willbeavailable for more information by cell phone:Joep Lange (co-chair)

Marriott HotelRobert Murphy

+1-415-896-1600The fax address for information from September 25th - 29th 1999is:Dr. Remko van Leeuwen, Marriott Hotel, +1-415-775-7555.The slides of the presentation at the Interscience Conference onAntimicrobial 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).Contact: Remko Van Leeuwen, Study Coordinator of National AidsTherapy Evaluation 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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