YOKOHAMA, Japan _ Citing parallels to tuberculosis treatment 40years ago, AIDS researchers are presenting increased evidence that acombination of drugs is the best approach to fighting a virus thatrapidly mutates and has little trouble outsmarting single-drug therapy."We are at a stage in antiretroviral therapy that is extremely analogousto tuberculosis therapy 40 years ago," said David Berry, an AIDSresearcher for Burroughs Wellcome Foundation Ltd. in London duringthe 10th International Conference on AIDS here.Italian AIDS researcher Vella Stefan, of the Istituto Superiore DiSanita, also pointed to the tuberculosis treatment experience as a modelfor AIDS treatment. "I think we can learn something fromtuberculosis," he said. "It became evident that after promising results ofshort-term clinical studies, the long-term outcome of the patients wasalmost unaffected, and that more aggressive treatment was needed tocounteract clinical resistance."As in the early years of the AIDS epidemic, primary treatment fortuberculosis was limited to one drug _ streptomycin. Against moreadvanced diseases of miliary and pulmonary tuberculosis, however,streptomycin proved ineffective, and indeed, more than one-third ofpatients treated with the drug relapsed after one year, Stefan said. Withthe development of new anti-tuberculosis drugs, combination therapybecame the norm, with as many as five drugs now used for initialtreatment in areas with high incidence of multi-drug resistanttuberculosis.Today, researchers face the same problem with zidovudine (AZT).Although it is the most effective of five approved antiretroviral agents,several studies presented at this conference confirm that thedevelopment of resistance limits survival benefit to an average of twoyears. (See another story on AZT on this page.)Consequently, double and triple combination therapy has beenincreasingly promoted as the future of HIV treatment, even inasymptomatic patients. Although clinical trials are only now underway, laboratory studies have shown that triple-drug combinations cancompletely suppress viral replication under certain conditions."The task before us in the coming years is to deepen the magnitude ofviral suppression," said William Paul, director of the recently formedOffice of AIDS Research at the National Institutes of Health. "We mustpay particular attention to the combination therapy with agents directedagainst distinct molecular targets."Researchers hope that large Phase I trials now assessing potentialadvantages of combination therapy also can delineate how viral loadreduction may translate into clinical benefit. If that linkage is found,future efforts would rely increasingly on virological markers both forclinical trials and individual treatment regimens, said Michael Saag,assistant professor of medicine at University of Alabama inBirmingham."In my view, the most important question we have to answer in thenext year is how well these viral markers correlate with clinicaloutcome," said Saag.Indeed, clinical management of HIV may parallel that used for cancerpatients, using typing, remission and relapse as markers for individualtreatment regimens. New tests to rapidly measure virological markerscould be marketed in several countries, including the U.S., within thenext year, Saag added.With increased evidence that viral replication is on-going, even in earlydisease, Saag and others said developing new markers other than CD4counts are critical in formulating intervention in early therapy.Toward that end, the Inter-Company Collaboration for AIDS DrugDevelopment, a new organization of U.S. and European drugcompanies formed to coordinate AIDS research, has developed amaster protocol that will test triple combinations of eight drugs fromseven companies using drug-naive patients.Results of the first triple combination study using a protease inhibitor_ saquinavir (RO 31-8959) by Hoffmann-La Roche Inc., Nutley, N.J._ showed that three drugs were more effective than AZT and DDI orAZT and saquinavir alone. In patients taking the three drugs, CD4counts were raised after six weeks, and within two weeks viral burdendropped to nearly zero. The three-drug combination also delayed theemergence of resistant virus.The randomized three-arm study followed 302 patients with CD4counts between 51 and 300 for 24 weeks. More than half of the patientsdid not have AIDS defining symptoms. Patients had an average of 26months of previous AZT therapy.Triple combination therapy was associated with the largest and themost sustained decrease in HIV titer compared to the two-drugcombinations. Triple combination also showed the most decrease inRNA copy of the virus, said Ann Collier, an AIDS researcher at theUniversity of Washington in Seattle.Skip Connett is editor of AIDS Alert, another American HealthConsultants Inc. publication.
-- Skip Connett
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